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|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
PMC11277410_p21
|
PMC11277410
|
sec[1]/sec[1]/sec[7]/p[0]
|
Hemocompatibility assay
| 4.109375 |
biomedical
|
Study
|
[
0.99951171875,
0.00030422210693359375,
0.0001709461212158203
] |
[
0.9990234375,
0.0005059242248535156,
0.00034236907958984375,
0.00007194280624389648
] |
Healthy human blood was obtained and 200 μg/mL EDTA was added in tubes, which were then centrifuged at 3500 rpm for 5 min at 4 °C. The plasma was separated. The RBCs were washed three times with cold PBS. The purified RBCs were then resuspended in an isotonic solution of PBS diluted to 1:10. To perform the assay, different concentrations of nanocarriers (6.25, 12, 25, 50, 100, 200 μg/mL), 2 % Triton X-100 (as a positive control showing 100 % hemolysis), and 500 μL of PBS as the negative control (0 % hemolysis) were used. 200 μL of test samples were added to tubes containing 200 μL of RBC pellets and placed in a shaker incubator at 37 °C for 4 h. After incubation, the samples were centrifuged at 4000 rpm for 10 min. The absorbance was measured at 540 nm using a spectrophotometer . H e m o l y s i s ( % ) = A t r e a t e d s a m p l e − A n e g a t i v e c o n t r o l A p o s i t i v e c o n t r o l − A n e g a t i v e c o n t r o l × 100 In this equation, A treated sample , A negative-control , and A positive control are representative of the mean absorbance of the sample, negative control, and positive control, respectively.
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277410_p22
|
PMC11277410
|
sec[1]/sec[1]/sec[8]/p[0]
|
Cellular uptake of nanocarrier
| 4.085938 |
biomedical
|
Study
|
[
0.99951171875,
0.000263214111328125,
0.0001863241195678711
] |
[
0.99951171875,
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0.0002486705780029297,
0.00006115436553955078
] |
To determine the uptake efficiency of the nanocarrier system in NTERA-2 cells, decoy ODNs labeled with Cy3 were used. The cells were cultured in 24-well plates and incubated until reached approximately 70 % confluence. The medium was then discarded. The cells were washed twice with PBS to remove any cell debris. The NTERA-2 cells were treated with DMEM medium containing various concentrations (0.25, 0.5, 0.75, 1 μg/mL) of NISM@BSA-ODN-Zn and NISM@BSA-Zn (1 μg/mL) and incubated under standard culture conditions for 6 h. Then, the media was discarded from the wells and replaced with 500 μL of fresh complete DMEM. Finally, the cells were harvested and analyzed using flow cytometry (BD Biosciences, San Jose, CA) to determine the cellular uptake of the nanocarrier system .
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277410_p23
|
PMC11277410
|
sec[1]/sec[1]/sec[9]/p[0]
|
Cellular toxicity assay
| 4.097656 |
biomedical
|
Study
|
[
0.99951171875,
0.00033593177795410156,
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] |
[
0.99951171875,
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0.00006902217864990234
] |
To determine the cytotoxicity effects of the nanocarrier systems, an MTT assay was performed. The NTERA-2 cells were cultured in 96-well plates at a density of 10 4 cells per well and incubated with a complete growth medium for 24 h. The cells were then treated with the test samples (NISM@BSA, NISM@BSA-SCR, NISM@BSA-DEC, ZnNPs, NISM@BSA-Zn, NISM@BSA-SCR-Zn, NISM@BSA-DEC-Zn) at different concentrations (0.5, 1, 3 μg/mL). In a parallel procedure to investigate the effect of radiation exposure, 5 h after treatment with the test samples, the treatment medium was removed, and 100 μL of fresh media was added to each well. Then, the plate was irradiated with a fractionated X-ray with a dose of 2 Gy. After 24 h, 20 μL of MTT solution (5 mg/mL) was added to each well, and after 4-h incubation, DMSO (100 μL) was added to each well. The absorbance at 570 nm wavelength was measured. All assays were performed in triplicate .
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277410_p24
|
PMC11277410
|
sec[1]/sec[1]/sec[10]/p[0]
|
Cell cycle assay
| 4.136719 |
biomedical
|
Study
|
[
0.99951171875,
0.00031876564025878906,
0.00017952919006347656
] |
[
0.9990234375,
0.0005335807800292969,
0.0003533363342285156,
0.00007623434066772461
] |
To assess the cell cycle, flow cytometry was performed 24 h after treatment. NTERA-2 cells were seeded in 12-well plates at a density of 3 × 10 4 cells per well and incubated at 37 °C in a 5 % CO 2 incubator for one day before treatment. The cells were then treated with 1 μg/mL of nanocarriers (NISM@BSA-Zn, NISM@BSA-SCR-Zn, and NISM@BSA-DEC-Zn). In a parallel procedure, 5 h after treatment, the medium in each well was removed, and 500 μL of fresh medium was added to each well. Then, the cells were immediately irradiated with fractionated X-ray with a dose of 2 Gy. After 24 h, the cells were detached using 0.05 % trypsin/EDTA and pelleted by centrifugation at 1200 rpm for 3 min. The obtained cells were washed with 50 μL of PBS and fixed with 70 % cold ethanol, followed by centrifugation to remove excess ethanol. Next, the cells were processed with 1 mL of PI Master Mix solution (40 μL PI Sigma-Aldrich, 10 μL RNase, 950 μL PBS) and incubated for 30 min at room temperature. The data gathered from flow cytometry was analyzed using FlowJo v.7 software (Tree Star, Ashland, OR) to calculate the percentage of cells in each phase of the cell cycle .
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277410_p25
|
PMC11277410
|
sec[1]/sec[1]/sec[11]/p[0]
|
Apoptosis assay
| 4.117188 |
biomedical
|
Study
|
[
0.99951171875,
0.0002715587615966797,
0.00020778179168701172
] |
[
0.99951171875,
0.0003345012664794922,
0.0002772808074951172,
0.00006031990051269531
] |
To assess the apoptosis rate, NTERA-2 cells were seeded in 12-well plates at a density of 3 × 10 4 cells per well and incubated for 24 h at 37 °C in a 5 % CO 2 incubator. The cell groups were treated with different nanocarriers (NISM@BSA-Zn, NISM@BSA-SCR-Zn, and NISM@BSA-DEC-Zn) at a concentration of 1 μg/mL for 24 h. In a parallel procedure to investigate the effect of radiation, 5 h' post-treatment, the medium in each well was removed, and a fresh medium was added to each well. Then, the cells were immediately irradiated with fractionated X-ray with a dose of 2 Gy. After 24 h, the cells were washed with PBS and suspended in 100 μL of Annexin V binding buffer, and then stained with Annexin V-FITC and PI (Sigma-Aldrich). Data analysis was performed using a flow cytometry apparatus (BD Biosciences, San Jose, CA, USA) and FlowJo software (Tree Star, Ashland, OR) .
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277410_p26
|
PMC11277410
|
sec[1]/sec[1]/sec[12]/p[0]
|
Wound-healing (scratch) assay
| 4.105469 |
biomedical
|
Study
|
[
0.99951171875,
0.0003070831298828125,
0.00019443035125732422
] |
[
0.99951171875,
0.00022995471954345703,
0.0003006458282470703,
0.0000622868537902832
] |
To determine the migration inhibition rate, a wound-healing or scratch assay was performed. NTERA-2 cells were cultured in 24-well plates at a density of 2 × 10 4 cells per well and incubated under standard conditions for 24 h until reached a confluence of more than 70 % of cells. Artificial wounds were created using the end of a 10 μL pipette tip (time 0 h), and detached cells and media were removed. The cells were then treated with a concentration of 0.5 μg/mL of nanocarriers (NISM@BSA-Zn, NISM@BSA-SCR-Zn, and NISM@BSA-DEC-Zn). In a parallel procedure, cells were subjected to radiation exposure by fractionated X-ray with a total dose of 2 Gy. For all plates, cell migration was monitored, and photos were taken at times 0 and 72 h. The assays were performed in triplicate. The cell migration inhibition rate was quantified using the ImageJ program .
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277410_p27
|
PMC11277410
|
sec[1]/sec[2]/p[0]
|
Statistical analysis
| 3.148438 |
biomedical
|
Study
|
[
0.9990234375,
0.00021588802337646484,
0.0008325576782226562
] |
[
0.95166015625,
0.046478271484375,
0.0014200210571289062,
0.00035262107849121094
] |
The analysis of acquired statistical data for this research project was performed using GraphPad Prism 8 software. The results are presented as mean ± standard deviation (SD). One-way analysis of variance (ANOVA) was used for statistical analysis. Values with * representing p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001 were considered statistically significant. All tests were performed a minimum of three times.
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277410_p28
|
PMC11277410
|
sec[2]/sec[0]/sec[0]/p[0]
|
FT-IR spectroscopy
| 4.207031 |
biomedical
|
Study
|
[
0.99951171875,
0.0003230571746826172,
0.0003733634948730469
] |
[
0.99951171875,
0.00018262863159179688,
0.0004639625549316406,
0.0000616312026977539
] |
The FT-IR spectra of BSA, NISM, and various nanocarrier formulations (NISM@BSA, NISM@BSA-SCR, NISM@BSA-DEC, NISM@BSA-Zn, NISM@BSA-SCR-Zn, NISM@BSA-DEC-Zn) were compared, confirming the successful synthesis of the nanocarrier system . The FT-IR spectrum of BSA displayed characteristic peaks related to (amide I) bonds between 1600 and 1700 cm −1 and (amide II) bonds between 1500 and 1550 cm −1 , which corresponded to the stretching vibrations of the C–O bond and bending of the N–H bond, respectively . In the spectrum of NISM@BSA, the intensity of C–O and N–H bonds was decreased, while the N–H bending vibration in its spectrum indicated the successful synthesis of the NISM@BSA nanocarrier. The FT-IR spectra of DEC and SCR showed characteristic bands at 3440 cm −1 and 1650 cm −1 , respectively, which corresponded to the stretching of N–H and C–O bonds. The spectra of NISM@BSA-DEC and NISM@BSA-SCR displayed peaks from NISM@BSA as well as overlapping peaks from DEC and SCR. The intensities in the area between 1600 and 1700 cm −1 were decreased in the spectra of NISM@BSA-DEC and NISM@BSA-SCR due to the incorporation of ODNs into NISM@BSA. Fig. 1 Fourier-transform infrared (FT-IR) absorption spectra for all formulations and components. (A) Comparison of FT-IR absorption peaks for NISM@BSA, BSA, and NISM. (B) Comparison of FT-IR absorption peaks for NISM@BSA, NISM@BSA-SCR, and free SCR. (C) Comparison of FT-IR absorption peaks for NISM@BSA, NISM@BSA-DEC, and free DEC. Fig. 1 Fig. 2 Fourier-transform infrared (FT-IR) absorption spectra for all formulations and components. (A) Comparison of FT-IR absorption peaks for NISM@BSA, NISM@BSA-Zn, and ZnNPs. (B) Comparison of FT-IR absorption peaks for NISM@BSA-Zn, NISM@BSA-SCR-Zn, and free SCR. (C) Comparison of FT-IR absorption peaks for NISM@BSA-Zn, NISM@BSA-DEC-Zn, and free DEC. Fig. 2
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277410_p29
|
PMC11277410
|
sec[2]/sec[0]/sec[1]/p[0]
|
Morphology, average hydrodynamic diameter & zeta potential
| 4.085938 |
biomedical
|
Study
|
[
0.99951171875,
0.00025463104248046875,
0.000400543212890625
] |
[
0.99951171875,
0.00021266937255859375,
0.0003287792205810547,
0.000048100948333740234
] |
The morphologies of NISM@BSA, ZnNPs, NISM@BSA-Zn, and NISM@BSA-ODN-Zn were investigated using field-emission scanning electron microscopy (FESEM). As shown in Fig. 3 A–D, all the nanocarriers exhibited spherical and uniform shapes. Additionally, FESEM analysis revealed that the size of NISM@BSA-ODN-Zn was larger than that of NISM@BSA. This observation indicates that the incorporation of ODN and Zn into NISM@BSA increased the size of the nanocarrier. This finding provides valuable insights into the structural characteristics of the nanocarriers, which are crucial for their optimal performance in drug delivery applications. Fig. 3 FESEM image of the (A) NISM@BSA (B) ZnNPs (C) NISM@BSA-Zn (D) NISM@BSA-ODN-Zn nanocarriers. Fig. 3
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277410_p30
|
PMC11277410
|
sec[2]/sec[0]/sec[1]/p[1]
|
Morphology, average hydrodynamic diameter & zeta potential
| 4.207031 |
biomedical
|
Study
|
[
0.9990234375,
0.0002970695495605469,
0.00044417381286621094
] |
[
0.9990234375,
0.0002377033233642578,
0.00048828125,
0.00005263090133666992
] |
The average hydrodynamic size of nanocarriers was NISM:107.20 ± 1.21 nm, NISM@BSA:117.67±; 1.21 nm, NISM@BSA-Zn:130.43±; 1.97, NISM@BSA-SCR:143.06±; 2.62, NISM@BSA- SCR-Zn:175.47 ± 2.91 nm, NISM@BSA-DEC:158.63±; 1.52 nm, NISM@BSA- DEC-Zn: 176.67 ± 4.68 nm. Zeta potential results from DLS were NISM: 29.03 ± 0.51 mV, NISM@BSA: 30.73 ± 0.35 mV, NISM@BSA-Zn: 32.07 ± 1.39 mV, NISM@BSA-SCR: 34.50 ± 0.62 mV, NISM@BSA-SCR-Zn: 37.37 ± 0.45 mV, NISM@BSA-DEC: 34.97 ± 1.81 mV, NISM@BSA-DEC-Zn: 36.60 ± 0.95 mV. The differences in the size and zeta potential among nanocarriers were statistically significant. At last, the polydispersity index (PDI) for nanocarriers were: NISM:0.210 ± 0.012, NISM@BSA:0.261±; 0.009, NISM@BSA-Zn:0.348±; 0.010, NISM@BSA SCR:0.359 ± 0.025, NISM@BSA-SCR-Zn: 0.418 ± 0.041, NISM@BSA-DEC: 0.537 ± 0.007, NISM@BSA-DEC-Zn: 0.424 ± 0.021. The average hydrodynamic size, zeta -potential, and PDI of nanocarrier systems are shown in Fig. 4 , Fig. 5 C. Fig. 4 Hydrodynamic average size of NISM, NISM@BSA, NISM@BSA-SCR, NISM@BSA-DEC, NISM@BSA-Zn, NISM@BSA-SCR-Zn and NISM@BSA-DEC-Zn nanocarriers. Fig. 4 Fig. 5 Zeta potential of NISM, NISM@BSA, NISM@BSA-SCR, NISM@BSA-DEC, NISM@BSA-Zn, NISM@BSA-SCR-Zn and NISM@BSA-DEC-Zn nanocarriers. Fig. 5
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277410_p31
|
PMC11277410
|
sec[2]/sec[0]/sec[2]/p[0]
|
Entrapment efficiency, behavior ODNs release, and kinetics
| 4.214844 |
biomedical
|
Study
|
[
0.99951171875,
0.0003597736358642578,
0.00022685527801513672
] |
[
0.9990234375,
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] |
The EE% values of NISM@BSA-DEC-Zn and NISM@BSA-SCR-Zn formulations were 78.40 % + 1.22 % and 76.33 % + 1.43 %, respectively. To assess the release profiles of decoy ODN, experiments were conducted at 37 °C (human body temperature) using PBS in different pH media (7.4 and 5.8), as illustrated in Fig. 6 A and B. At both pH values, the release of ODN was slow, with only 3.43%–6.89 % released within 6 h. However, sustained and controlled release behavior was observed between 8 and 120 h, with a plateau phase reached after 144 h ( Table 1 ). The release of ODN was pH-dependent, with a faster release rate observed at pH 5.8 (0.576–0.462 %/h) than at pH 7.4 (0.420–0.436 %/h). The empirical release data was fitted to different mathematical kinetic models, and the Weibull model showed the best fit with the experimental data for NISM@BSA-SCR at both pH values (7.4 and 5.8), as well as for NISM@BSA-DEC-Zn and NISM@BSA-SCR-Zn at pH 7.4 media ( Table 2 ). Similarly, the Gompertz model was the best fit for NISM@BSA-DEC at both pH values (7.4 and 5.8), as well as for NISM@BSA-SCR-Zn and NISM@BSA-DEC-Zn at pH 5.8 media ( Table 2 ). Fig. 6 In vitro accumulative ODN release profile of the nanocarriers at (A) pH = 7.4 and (B) pH = 5.8. (C) Hemocompatibility assay of synthesized nanocarriers (* represents a significant difference with a difference of p ˂0.05). Fig. 6 Table 1 Release profile parameters of the formulations. Table 1 Formulations NISM@BSA-SCR NISM@BSA-SCR-Zn NISM@BSA-DEC NISM@BSA-DEC-Zn pH 5.8 7.4 5.8 7.4 5.8 7.4 5.8 7.4 ODNs release after 2h (%) 2.41 ± 0.33 1.65 ± 0.75 1.97 ± 0.27 1.39 ± 0.63 3.52 ± 1.36 2.16 ± 0.93 2.86 ± 1.17 1.76 ± 0.76 Cumulative ODNs release after 24h (%) 37.77 ± 0.51 31.97 ± 2.73 30.91 ± 0.42 20.42 ± 0.65 41.64 ± 0.34 35.33 ± 2.60 33.83 ± 0.28 28.90 ± 2.12 Maximum ODNs depletion (%) 77.77 ± 2.26 57.63 ± 2.47 63.63 ± 1.85 48.64 ± 2.08 76.64 ± 2.49 68.68 ± 2.76 62.27 ± 2.02 56.19 ± 2.26 Release rate (%/h) 0.576 0.420 0.471 0.355 0.568 0.360 0.462 0.410 Table 2 R 2 , Akaike's information criterion (AIC), and mean squared error (MSE) parameters from fitting release data of formulations on various models. Values in bold indicate best fits. Table 2 Models Zero Order First Order Higuchi Hixson-Crowell Weibull Gompertz pH 7.4 5.8 7.4 5.8 7.4 5.8 7.4 5.8 7.4 5.8 7.4 5.8 Formulations Parameters NISM@BSA-SCR R 2 0.7304 0.7622 0.8689 0.9344 0.9384 0.9430 0.8296 0.8975 0.9872 0.9822 0.9834 0.9786 AIC 107.39 113.37 97.30 95.33 86.73 93.37 100.69 101.58 66.34 78.77 69.24 80.56 MSE 143.05 219.21 69.57 60.43 32.70 52.53 90.39 94.44 6.77 16.45 8.81 19.77 NISM@BSA-SCR-Zn R 2 0.7304 0.7622 0.8421 0.8966 0.9384 0.9430 0.8088 0.8609 0.9861 0.9719 0.9794 0.9770 AIC 102.65 107.75 95.16 96.09 81.98 87.75 97.83 100.25 62.76 79.49 67.49 75.91 MSE 101.91 146.74 59.69 63.82 23.29 35.16 72.26 85.87 5.24 17.31 7.77 14.18 NISM@BSA-DEC R 2 0.7226 0.7106 0.8604 0.9093 0.9237 0.9382 0.8228 0.8633 0.9528 0.9573 0.9547 0.9752 AIC 110.90 115.33 101.29 99.09 92.83 93.71 104.62 104.84 87.76 90.21 86.39 81.79 MSE 183.79 252.18 92.49 79.03 50.54 53.83 117.36 119.16 31.26 37.24 29.98 21.57 NISM@BSA-DEC-Zn R 2 0.7226 0.7106 0.8294 0.8612 0.9237 0.9382 0.7980 0.8194 0.9680 0.9514 0.9518 0.9725 AIC 105.28 109.52 98.48 99.23 87.21 87.89 100.84 102.92 76.73 86.20 81.67 77.43 MSE 123.03 166.48 75.67 79.87 33.83 35.53 89.57 103.92 14.21 27.97 21.39 15.80
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277410_p32
|
PMC11277410
|
sec[2]/sec[0]/sec[3]/p[0]
|
Hemocompatibility assessment of nanocarrier systems
| 4.101563 |
biomedical
|
Study
|
[
0.99951171875,
0.0003466606140136719,
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[
0.99951171875,
0.0001990795135498047,
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] |
The obtained hemocompatibility results, as depicted in Fig. 6 C, indicated that the nanocarrier systems exhibited minimal hemolytic activity. Hemolysis percentages ranging from 1 % to 12 % were observed for concentrations ranging from 6.25 to 200 μg/mL of the nanocarriers. The low hemolytic activity indicates that the nanocarrier formulations are unlikely to cause significant damage to the red blood cells or induce adverse effects on the blood components.
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277410_p33
|
PMC11277410
|
sec[2]/sec[1]/p[0]
|
High cellular uptake of Cy3-labeled NISM@BSA-ODN-Zn in NTERA-2 cells
| 4.121094 |
biomedical
|
Study
|
[
0.99951171875,
0.0002880096435546875,
0.00022912025451660156
] |
[
0.99951171875,
0.0001804828643798828,
0.00024056434631347656,
0.0000584721565246582
] |
The flow cytometry analysis revealed a remarkable increase in cellular uptake for Cy3-labeled NISM@BSA-ODN-Zn (85.68 %) compared to the control group (1.33 %). NTERA-2 cells efficiently took up Cy3-labeled NISM@BSA-ODN-Zn at concentrations above 0.25 μg/mL , with the optimal uptake observed at 0.5 μg/mL (71.56 %). The cellular uptake of Cy3-labeled NISM@BSA-ODN-Zn exhibited a dose-dependent behavior, displaying significant differences in uptake efficiency across concentrations ranging from 0.25 μg/mL to 1 μg/mL. Fig. 7 The cellular uptake rate of NISM@BSA-ODN-Zn (Cy3-labeled ODNs) into NTERA-2 cells at concentrations of 0.25, 0.5, and 1 μg/mL. NISM@BSA-Zn (1 μg/mL) as a negative control. The obtained results were analyzed by one-way ANOVA. ns (No significant), values with * p < 0.05 and **** p < 0.0001 were regarded as statistically meaningful. Fig. 7
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277410_p34
|
PMC11277410
|
sec[2]/sec[2]/p[0]
|
Cytotoxicity effect of nanocarriers without and under X-irradiation exposure
| 4.234375 |
biomedical
|
Study
|
[
0.99951171875,
0.00029349327087402344,
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] |
[
0.9990234375,
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] |
In the absence of X-irradiation exposure, at a concentration of 0.5 μg/mL, the NISM@BSA-Zn nanocarrier showed no significant cytotoxicity effect, while at 1 μg/mL, it caused a slight increase in cytotoxicity . Similarly, 0.25 μg/mL concentrations of NISM@BSA-DEC-Zn did not significant cytotoxicity effect, but concentrations of 0.5 and 1 μg/mL led to an increase in cytotoxicity. The most significant increase in cytotoxicity was observed at concentrations of 0.5 and 1 μg/mL for NISM@BSA-DEC-Zn nanocarriers. Moreover, NISM@BSA-DEC-Zn at 3 μg/mL showed a significant difference in increasing cytotoxicity compared to concentrations of 0.25, 0.5, and 1 μg/Ml . Under X-irradiation conditions, NISM@BSA nanocarrier at concentrations of 0.5 and 1 μg/mL showed no significant difference in cytotoxicity compared to the cell control group, but there was a significant difference at the 3 μg/mL concentration. Similarly, NISM@BSA-SCR at a concentration of 0.5 μg/mL had no significant cytotoxicity effect, but the concentration of 3 μg/mL significantly increased cytotoxicity. For NISM@BSA-DEC, a concentration of 0.5 μg/mL did not show an increase in cytotoxicity, while concentrations of 1 and 3 μg/mL significantly increased cytotoxicity. In contrast, cytotoxicity was significantly increased by ZnNPs, NISM@BSA-Zn, NISM@BSA-SCR-Zn, and NISM@BSA-DEC-Zn nanocarriers at all concentrations (0.5, 1, and 3 μg/mL). Even NISM@BSA-DEC-Zn at a concentration of 0.25 μg/mL showed a significant increase in cytotoxicity . Furthermore, NISM@BSA-DEC-Zn at a concentration of 3 μg/mL revealed a significant increase in cytotoxicity compared to concentrations of 0.25, 0.5, and 1 μg/mL. Concentrations of 0.5, 1, and 3 μg/mL of NISM@BSA-DEC-Zn showed a significant increase in cytotoxicity even more than the corresponding concentrations of NISM@BSA-SCR-Zn and NISM@BSA-Zn nanocarriers . The IC50 value for the NISM@BSA-DEC-Zn, NISM@BSA-SCR-Zn, and NISM@BSA-Zn were 1.20 ± 2.33, 1.22 ± 0.25, and 2.34 ± 0.45 μg/mL, respectively. Altogether, the IC50 values for the NISM@BSA-DEC-Zn were less than other groups . Fig. 8 Evaluation of nanocarriers effect (NISM@ BSA, NISM@BSA-SCR, NISM@BSA-DEC, ZnNPs, NISM@BSA-Zn, NISM@BSA-SCR-Zn, NISM@BSA-DEC-Zn) on cytotoxicity. (A) without X-irradiation and (B) under X-irradiation conditions. The obtained results were analyzed by one-way ANOVA. values with * p < 0.05, ** p ˂0.01, *** p ˂0.001, and **** p < 0.0001 were regarded as statistically meaningful. Fig. 8
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277410_p35
|
PMC11277410
|
sec[2]/sec[3]/p[0]
|
Cell cycle arrest without and under X-irradiation exposure
| 4.113281 |
biomedical
|
Study
|
[
0.99951171875,
0.0003218650817871094,
0.00028133392333984375
] |
[
0.99951171875,
0.00016820430755615234,
0.0004115104675292969,
0.000054955482482910156
] |
In the absence of X-irradiation exposure, the NISM@BSA-DEC-Zn nanocarriers induced a significantly higher percentage of cells arrested in the G1 phase compared to the other groups. Additionally, the NISM@BSA-Zn and NISM@BSA-DEC-Zn groups exhibited a lower percentage of cells in the S phase compared to the cell control group (Ctrl). Notably, the number of cells in the G2/M phase in the NISM@BSA-Zn group was slightly higher than in the Ctrl group . Under X-irradiation conditions (2Gy fractionation), the percentage of cells arrested in the G1 phase significantly decreased in all treatment groups compared to the Ctrl group. Among these groups, the NISM@BSA-DEC-Zn group showed the lowest percentage of cells in the G1 phase, demonstrating a more significant effect in reducing cell cycle progression at this stage compared to the groups treated with NISM@BSA-Zn and NISM@BSA-SCR-Zn nanocarriers. In contrast, the NISM@BSA-DEC-Zn group exhibited a higher percentage of cells in the S phase compared to the Ctrl group. The other treatment groups did not show significant differences in the percentage of cells in the S phase compared to the Ctrl group. Furthermore, in the G2/M phase, the percentage of cells arrested was higher in all treatment groups compared to the Ctrl group. However, the NISM@BSA-DEC-Zn group showed the most profound effect in halting cell cycle progression at this stage, as evidenced by the significantly higher number of cells arrested in G2/M compared to the groups treated with NISM@BSA-Zn and NISM@BSA-SCR-Zn nanocarriers . Fig. 9 Evaluation of nanocarriers (NISM@BSA-Zn, NISM@BSA-SCR-Zn, NISM@BSA-DEC-Zn) effect on cell cycle arrest. (A) without X-irradiation and (B) under X-irradiation conditions. The obtained results were analyzed by two-way ANOVA. values with * p < 0.05, ** p ˂0.01, *** p ˂0.001, and **** p < 0.0001 were regarded as statistically meaningful. Fig. 9
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277410_p36
|
PMC11277410
|
sec[2]/sec[4]/p[0]
|
Apoptosis induction without and under X-irradiation exposure
| 4.097656 |
biomedical
|
Study
|
[
0.99951171875,
0.0002884864807128906,
0.0003070831298828125
] |
[
0.99951171875,
0.00016891956329345703,
0.0003285408020019531,
0.000051021575927734375
] |
In the absence of X-irradiation exposure, the cell group treated with NISM@BSA-Zn did not exhibit a significant difference in apoptosis compared to the Ctrl group. However, the group treated with NISM@BSA-SCR-Zn showed a significant increase in apoptosis compared to the Ctrl group ( p < 0.05). Remarkably, the rate of apoptosis induced by the NISM@BSA-DEC-Zn nanocarriers revealed a highly significant difference compared to the Ctrl group . The apoptosis rate in the NISM@BSA-DEC-Zn-treated group was also significantly different from the NISM@BSA-SCR-Zn group ( p < 0.01) and the NISM@BSA-Zn group ( p < 0.001). Under X-irradiation conditions, the cell group treated with NISM@BSA-Zn showed a significant increase in apoptosis compared to the Ctrl group ( p < 0.01). Moreover, the NISM@BSA-SCR-Zn group exhibited a substantial increase in apoptosis compared to the Ctrl group ( p < 0.001), and the NISM@BSA-DEC-Zn group demonstrated the highest apoptotic rate, significantly different from the Ctrl group . Furthermore, the comparison of the NISM@BSA-DEC-Zn group with the NISM@BSA-SCR-Zn group revealed a highly significant difference , emphasizing the potent apoptotic effect of the NISM@BSA-DEC-Zn nanocarrier. Similarly, the NISM@BSA-DEC-Zn group displayed a significant difference compared to the NISM@BSA-Zn group . Fig. 10 Evaluation of nanocarriers (NISM@BSA-Zn, NISM@BSA-SCR-Zn, NISM@BSA-DEC-Zn) effect on apoptosis. (A) without X-irradiation and (B) under X-irradiation conditions. The obtained results were analyzed by one-way ANOVA. values with * p < 0.05, ** p ˂0.01, *** p ˂0.001, and **** p < 0.0001 were regarded as statistically meaningful. Fig. 10
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277410_p37
|
PMC11277410
|
sec[2]/sec[5]/p[0]
|
Cell migration inhibition without and under X-irradiation exposure
| 4.09375 |
biomedical
|
Study
|
[
0.99951171875,
0.0002694129943847656,
0.0003218650817871094
] |
[
0.99951171875,
0.00016570091247558594,
0.00031304359436035156,
0.00004589557647705078
] |
In the absence of X-irradiation exposure, the cell group treated with the NISM@BSA-DEC-Zn nanocarrier revealed significant cell migration inhibition (scratch repair) compared to other groups (Ctrl, NISM@BSA-Zn, and NISM@BSA-SCR-Zn). Under X-irradiation conditions, the cell group treated with the NISM@BSA-DEC-Zn nanocarrier exhibited even higher efficiency in inhibiting cell migration in comparison with the absence of X-ray conditions. The cell groups treated with both NISM@BSA-Zn and NISM@BSA-SCR-Zn nanocarriers revealed cell migration inhibition that could be due to the presence of zinc metal in the prepared nanostructure as a radiosensitizer . Fig. 11 Evaluation of nanocarriers (NISM@BSA-Zn, NISM@BSA-SCR-Zn, NISM@BSA-DEC-Zn) effect on cell migration. (A) without X-irradiation and (B) under X-irradiation conditions. The obtained results were analyzed by two-way ANOVA. values with * p < 0.05, ** p ˂0.01, *** p ˂0.001, and **** p < 0.0001 were regarded as statistically meaningful. Fig. 11
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277410_p38
|
PMC11277410
|
sec[3]/p[0]
|
Discussion
| 4.097656 |
biomedical
|
Study
|
[
0.99951171875,
0.0002942085266113281,
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] |
[
0.9990234375,
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0.00007522106170654297
] |
Cancer stem cells have been recognized as a key contributor to the metastatic spread of cancer, which has a profound impact on patient prognosis and treatment outcomes. To enhance the delivery of Sox2-Oct4 decoy ODNs, a combination of niosomes nanocarriers, BSA-coated niosomes, and zinc nanoparticles (ZnNPs) were employed to construct the hybrid nanocarriers. A thorough evaluation of the physical and chemical properties of these nanocarriers, including their dimensions, zeta potential, structure, and ODN release kinetics, was conducted. In order to ensure their suitability for potential clinical applications, the hemocompatibility of the nanocarriers was carefully assessed. Additionally, a comprehensive series of in vitro experiments were carried out to examine the effects of Sox2-Oct4 decoy ODNs enclosed within the nanocarriers on cytotoxicity, cell cycle arrest, induction of apoptosis, and cell migration inhibition in NTERA-2 cancer cells, which were utilized as a representative model of cancer stem-like cells.
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277410_p39
|
PMC11277410
|
sec[3]/p[1]
|
Discussion
| 4.136719 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.99169921875,
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0.00012242794036865234
] |
The hybridization of niosomes with ZnNPs introduces distinct properties to the nanocarriers. ZnNPs within the nanocarrier have the potential to contribute to improved stability, antitumor activity, and cellular uptake, while the coating of BSA enhances biocompatibility . The inclusion of ZnNPs into the niosomes also enhances the structural integrity of the nanocarriers, providing an appropriate environment for encapsulating and safeguarding the therapeutic payload, such as the Sox2-Oct4 decoy ODNs .
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277410_p40
|
PMC11277410
|
sec[3]/p[2]
|
Discussion
| 4.15625 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.99951171875,
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0.0004379749298095703,
0.0000762939453125
] |
The FT-IR results confirm the successful synthesis of the nanocarrier system and the incorporation of BSA, DEC, and SCR into the NISM@BSA nanocarriers. The observed alterations in peak intensities and characteristic bands validate the formation of the desired nanocarrier structure and the successful incorporation of the components. These findings lend support to the feasibility and effectiveness of the prepared nanocarrier system for targeted delivery of the Sox2-Oct4 decoy ODNs to NTERA-2 cancer stem-like cells. The agreement of the FT-IR spectra of BSA and NISM with prior research further corroborates the dependability and replicability of the synthesis techniques employed in this study . These findings establish a strong basis for further examinations and evaluations of the physicochemical properties, biocompatibility, and therapeutic effectiveness of the nanocarrier system against NTERA-2 cancer stem-like cells.
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277410_p41
|
PMC11277410
|
sec[3]/p[3]
|
Discussion
| 4.40625 |
biomedical
|
Study
|
[
0.9990234375,
0.0005550384521484375,
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] |
[
0.99462890625,
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0.00017654895782470703
] |
The results of the nanocarriers' structure, average hydrodynamic diameter, zeta potential, and polydispersity index (PDI) play a critical role in determining their suitability for drug delivery applications. These parameters offer valuable insights into the structural attributes and stability of the nanocarrier system. The spherical structure is acknowledged to enhance cellular uptake due to the augmented surface area in contact with target cells, thus potentially improving the therapeutic effectiveness of the nanocarrier system . Additionally, the hydrodynamic diameter proves to be a vital parameter as it determines the stability and pharmacokinetics of the nanocarrier system. Smaller nanocarriers generally demonstrate enhanced tumor tissue penetration and extended circulation times in the bloodstream, thereby augmenting their capacity to reach the intended site and enhance therapeutic outcomes . Additionally, lower PDI values indicate a narrower size distribution, which is highly desirable for drug delivery applications as it guarantees a homogeneous population of nanocarriers with consistent therapeutic efficacy. As evidenced by the findings, NISM exhibited the lowest PDI value, denoting a relatively uniform size distribution, whereas the inclusion of supplementary components resulted in marginally higher PDI values in other formulations . The zeta potential values of the nanocarriers were also assessed via DLS and exhibited negative values across all formulations. The negative zeta potential could potentially be attributed to the presence of BSA and hydroxyl groups in cholesterol, indicating that the nanocarriers possess surface charges capable of averting aggregation and ensuring stability during storage and in physiological environments. Moreover, the integration of ZnNPs and ODNs into NISM@BSA resulted in more negative zeta potential values, indicating an augmentation in the stability and dispersion of the nanocarrier system . These findings establish the foundation for further in vitro and in vivo investigations to evaluate the stability, biocompatibility, cellular uptake, and therapeutic efficacy of the nanocarrier system for potential clinical applications.
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277410_p42
|
PMC11277410
|
sec[3]/p[4]
|
Discussion
| 4.375 |
biomedical
|
Study
|
[
0.99951171875,
0.0004229545593261719,
0.00015234947204589844
] |
[
0.99755859375,
0.0003514289855957031,
0.0018301010131835938,
0.00016188621520996094
] |
The outcomes of entrapment efficiency (EE%) of the ODNs reveal that a substantial portion of the decoy ODNs was successfully encapsulated within the nanocarriers, validating the effectiveness of the preparation technique in preserving the therapeutic payload. The release of the decoy ODNs was determined to be reliant on pH, with a swifter release rate observed at pH 5.8 (0.576%–0.462 % per hour) in contrast to pH 7.4 (0.420 %-0.436 % per hour). The pH sensitivity exhibited by the nanocarriers is of great value, as it allows them to effectively respond to the slightly acidic microenvironment present in tumors. This capability has the potential to enhance the efficiency and precision of drug release specifically within cancer cells . In order to gain a deeper understanding of the release kinetics of the decoy ODNs from the nanocarriers, the experimental release data was subjected to fitting with various mathematical kinetic models. The successful fitting of the release data to these models yields valuable insights that can be utilized to optimize the design and performance of the nanocarrier system, thereby enhancing its therapeutic efficacy and potential application in cancer treatment . The substantial entrapment efficiency and pH-dependent release of ODNs observed in the system demonstrate its capacity to safeguard and deliver therapeutic payloads.
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277410_p43
|
PMC11277410
|
sec[3]/p[5]
|
Discussion
| 4.027344 |
biomedical
|
Study
|
[
0.99951171875,
0.00023686885833740234,
0.00019216537475585938
] |
[
0.98828125,
0.0009465217590332031,
0.0104522705078125,
0.00011640787124633789
] |
When considering the potential biomedical applications of the nanocarrier systems, particularly for intravenous administration, it is imperative to thoroughly evaluate their hemocompatibility. The nanocarriers can be safely administered in the bloodstream without causing hemolysis or other detrimental effects on the blood cells due to their high level of hemocompatibility. The results of the hemocompatibility assay overall indicate that the nanocarrier systems are biocompatible with the blood components, thereby suggesting their potential as secure and promising candidates for further examination in drug delivery applications . Nevertheless, to verify the safety and appropriateness of these nanocarrier systems for clinical applications, additional in vivo studies and comprehensive toxicity assessments are indispensable.
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277410_p44
|
PMC11277410
|
sec[3]/p[6]
|
Discussion
| 4.328125 |
biomedical
|
Study
|
[
0.99951171875,
0.00033402442932128906,
0.0001531839370727539
] |
[
0.99853515625,
0.0004048347473144531,
0.0007081031799316406,
0.00011944770812988281
] |
The high cellular uptake of Cy3-labeled NISM@BSA-ODN-Zn is of great significance for therapeutic applications as it allows for enhanced delivery of the encapsulated decoy ODNs to the targeted cancer stem-like cells. The selection of 0.5 μg/mL as the optimal concentration for cellular uptake (71.56 %) elucidates the dose-dependent behavior of Cy3-labeled NISM@BSA-ODN-Zn, where increasing the nanocarrier concentration resulted in a proportional increase in cellular uptake. This dose-dependent behavior is crucial in therapeutic applications as it allows for precise control over the amount of therapeutic payload delivered to the target cells, maximizing the therapeutic effect while minimizing potential toxicity to healthy cells. The notable uptake of Cy3-labeled NISM@BSA-ODN-Zn in NTERA-2 cells can be attributed to multiple factors. Primarily, the presence of a BSA-coated surface on the nanocarrier system enhances its compatibility with living organisms, thereby preventing undesired interactions with cell membranes and aiding in efficient cellular internalization. Additionally, the inclusion of ZnNPs in the nanocarriers may contribute to increased uptake by cells, owing to the role played by zinc in promoting cellular endocytosis .
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277410_p45
|
PMC11277410
|
sec[3]/p[7]
|
Discussion
| 4.339844 |
biomedical
|
Study
|
[
0.99951171875,
0.00040435791015625,
0.00021648406982421875
] |
[
0.99853515625,
0.000240325927734375,
0.0009207725524902344,
0.00011485815048217773
] |
The evaluation of cytotoxicity effects of NISM@BSA-DEC-Zn on the NTERA-2 cells revealed important insights about its potential as an anticancer agent. The obtained results demonstrated that NISM@BSA-DEC-Zn induced a concentration-dependent increase in cytotoxicity, signifying its effectiveness in inhibiting the growth and survival of NTERA-2 cells . The most substantial increase in cytotoxicity was observed at concentrations of 0.5 and 1 μg/mL for NISM@BSA-DEC-Zn nanocarriers. As can be shown in the MTT results (without applying radiation), the cell viability at concentrations of 0.5, 1, and 3 μg/mL was decreased, though it did not reach IC50 in used concentrations . This enhanced cytotoxic effect may be attributed to the presence of the decoy ODNs encapsulated within the nanocarrier system, specifically designed to target and interfere with cancer stem-like cells' self-renewal and metastatic properties. Interestingly, the MTT test conducted under X-irradiation conditions showed varying responses to different nanocarriers. NISM@BSA and NISM@BSA-SCR at concentrations of 0.5 and 1 μg/mL did not exhibit a significant difference in cytotoxicity compared to the Ctrl group. Conversely, NISM@BSA-DEC at 0.5 μg/mL did not show a significant increase in cytotoxicity, whereas concentrations of 1 and 3 μg/mL significantly increased cytotoxicity. This highlights the potential of the decoy ODNs to exert a cytotoxic effect on NTERA-2 cells, leading to decreased cell survival. The data obtained from the study strongly suggest that NISM@BSA-DEC-Zn possesses a potent cytotoxic effect against NTERA-2 cells, potentially disrupting their growth and survival . Nosrati et al. have suggested that photoabsorption and secondary electrons caused by X-irradiation can generate reactive oxygen species (ROS) that are necessary to control the fate of cancer cells during radiotherapy and chemotherapy . The targeted delivery of decoy ODNs via the nanocarrier system offers a promising approach to combat cancer stem-like cells, which are known to contribute to tumor progression and resistance to conventional therapies .
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277410_p46
|
PMC11277410
|
sec[3]/p[8]
|
Discussion
| 4.375 |
biomedical
|
Study
|
[
0.99951171875,
0.0003619194030761719,
0.00018227100372314453
] |
[
0.99853515625,
0.00033354759216308594,
0.0011701583862304688,
0.00012421607971191406
] |
The results obtained from cell cycle arrest indicate that the NISM@BSA-DEC-Zn nanocarriers have a potent influence on cell cycle regulation, particularly in arresting cells in the G1 and G2/M phases . The enhanced G1 arrest without X-irradiation and reduced G1 arrest under X-irradiation exposure suggest that the decoy ODNs delivered by the NISM@BSA-DEC-Zn nanocarriers may interfere with key cell cycle checkpoints, leading to cell cycle arrest and potential suppression of cell growth. Additionally, the increased percentage of cells in the S phase without X-irradiation exposure suggests the activation of DNA replication, possibly indicating DNA damage repair mechanisms. The ability of NISM@BSA-DEC-Zn to modulate cell cycle progression may offer valuable insights into its potential as a targeted therapeutic strategy for cancer treatment. Previous studies revealed that cells in the late S-phase and the G2/M phase have the most potent resistance and the most sensitivity against radiation, respectively . The cell cycle arrest observed in NTERA-2 cells treated with NISM@BSA-DEC-Zn supports its potential to disrupt cancer stem-like cells' proliferation and metastatic properties, which are essential factors in cancer progression.
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277410_p47
|
PMC11277410
|
sec[3]/p[9]
|
Discussion
| 4.21875 |
biomedical
|
Study
|
[
0.99951171875,
0.00029587745666503906,
0.00012922286987304688
] |
[
0.99755859375,
0.0003981590270996094,
0.00205230712890625,
0.00011861324310302734
] |
The apoptosis results highlight the remarkable pro-apoptotic potential of the NISM@BSA-DEC-Zn nanocarrier in both non-irradiated and X-irradiated conditions. The higher rate of apoptosis induced by NISM@BSA-DEC-Zn can be attributed to the specific delivery of decoy ODNs targeting essential pathways involved in apoptosis regulation. This targeted approach to trigger apoptosis in cancer stem-like cells holds great promise for improving cancer therapy outcomes . The findings underscore the significance of the NISM@BSA-DEC-Zn nanocarrier as a potent inducer of apoptosis in NTERA-2 cells, irrespective of X-irradiation exposure. The ability to enhance apoptosis, a crucial mechanism for eliminating cancer cells, makes NISM@BSA-DEC-Zn a promising candidate for further investigation as a targeted therapeutic agent for cancer treatment. This outcome aligns with the concept of combining therapeutic agents to enhance their overall efficacy in cancer treatment .
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277410_p48
|
PMC11277410
|
sec[3]/p[10]
|
Discussion
| 4.144531 |
biomedical
|
Study
|
[
0.99951171875,
0.00025916099548339844,
0.00011724233627319336
] |
[
0.994140625,
0.0007696151733398438,
0.004749298095703125,
0.0001417398452758789
] |
Scratch results emphasize the potent inhibitory effect of the NISM@BSA-DEC-Zn nanocarrier on cell migration, both in the absence and presence of X-irradiation exposure. The enhanced inhibition of cell migration in the NISM@BSA-DEC-Zn group can be attributed to the specific delivery of decoy oligodeoxynucleotides, which may effectively disrupt the migration and metastatic properties of cancer stem-like cells . The ability of NISM@BSA-DEC-Zn to efficiently inhibit cell migration is of utmost importance in cancer therapy, as cell migration and metastasis are crucial factors contributing to cancer progression and treatment resistance. The targeted inhibition of cell migration offered by NISM@BSA-DEC-Zn holds great promise for developing novel and effective therapeutic strategies against cancer.
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277410_p49
|
PMC11277410
|
sec[3]/p[11]
|
Discussion
| 4.199219 |
biomedical
|
Study
|
[
0.99951171875,
0.0003249645233154297,
0.00015115737915039062
] |
[
0.99755859375,
0.0002753734588623047,
0.0020732879638671875,
0.00010907649993896484
] |
Altogether, the high rate of uptake of NISM@BSA-DEC-Zn by NTERA-2 cells suggests the effective efficacy of synthesized nanocarrier in drug delivery to cancer stem-like cells. This efficient delivery allows the decoy ODNs to interfere with key agents in signaling pathways within these cells, leading to antitumor effects, including cytotoxicity, cell cycle arrest, apoptosis induction, and migration inhibition. Our findings resonate with previously established research highlighting the potential of ODNs in targeting cancer stem-like cells . Additionally, the integration of ZnNPs within nanocarriers for enhanced antitumor activity and stability finds support in existing literature . The present study serves as a valuable stepping stone by demonstrating the promise of BSA-coated niosomes for drug delivery. While this study establishes a strong foundation in vitro, further in vivo investigations are crucial to confirm the safety and efficacy of NISM@BSA-DEC-Zn in complex biological systems. Furthermore, optimizing the nanocarrier design for specific tumor targeting and maximizing therapeutic efficacy will necessitate further research efforts.
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277410_p50
|
PMC11277410
|
sec[4]/p[0]
|
Conclusion
| 4.097656 |
biomedical
|
Study
|
[
0.99951171875,
0.00024628639221191406,
0.00016963481903076172
] |
[
0.9990234375,
0.0002167224884033203,
0.0008134841918945312,
0.00006663799285888672
] |
In this study, niosomes coated with BSA and hybridized with zinc nanoparticles (ZnNPs) were successfully prepared and characterized. These niosomes were further loaded with Sox2-Oct4 decoy oligodeoxynucleotides (ODNs) to create the NISM@BSA-DEC-Zn nanocarrier system. In conclusion, the findings from this study open new avenues for developing advanced nanocarrier systems with potential anticancer properties against NTERA-2 cancer stem-like cells. The innovative combination of decoy ODNs, ZnNPs, and BSA-coated niosomes within the NISM@BSA-DEC-Zn nanocarrier system showcases its promising potential in the fight against cancer. However, further research, including in vivo studies and mechanistic investigations, is required to validate the safety and efficacy of this nanocarrier system in complex biological systems before its translational application in cancer treatment.
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277410_p51
|
PMC11277410
|
sec[5]/p[0]
|
Funding statement
| 0.899902 |
other
|
Other
|
[
0.108154296875,
0.001861572265625,
0.89013671875
] |
[
0.005634307861328125,
0.9931640625,
0.0006461143493652344,
0.00039649009704589844
] |
The present study was supported by 10.13039/501100008323 Zanjan University of Medical Sciences , Zanjan, Iran .
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277410_p52
|
PMC11277410
|
sec[6]/p[0]
|
Ethics approval and consent to participate
| 1.274414 |
biomedical
|
Other
|
[
0.953125,
0.0013799667358398438,
0.04571533203125
] |
[
0.076416015625,
0.92138671875,
0.0012607574462890625,
0.0010747909545898438
] |
Not applicable. The NTERA-2 cell line was purchased from the Iranian Biological Resource Center.
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277410_p53
|
PMC11277410
|
sec[7]/p[0]
|
Data availability statement
| 0.855957 |
biomedical
|
Other
|
[
0.6884765625,
0.0034313201904296875,
0.307861328125
] |
[
0.0163116455078125,
0.98193359375,
0.0009098052978515625,
0.0007615089416503906
] |
All supporting data included in article/supplementary material. Raw data will be made available on request.
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277410_p54
|
PMC11277410
|
sec[8]/p[0]
|
CRediT authorship contribution statement
| 0.979004 |
other
|
Other
|
[
0.1707763671875,
0.0035152435302734375,
0.82568359375
] |
[
0.0041351318359375,
0.9951171875,
0.000431060791015625,
0.0004112720489501953
] |
Behrooz Johari: Writing – review & editing, Writing – original draft, Validation, Supervision, Software, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Shabnam Tavangar-Roosta: Methodology, Investigation, Data curation. Mahmoud Gharbavi: Writing – review & editing, Software, Methodology, Investigation, Formal analysis, Conceptualization. Ali Sharafi: Writing – review & editing, Methodology. Saeed Kaboli: Methodology. Hamed Rezaeejam: Methodology, Investigation.
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277410_p55
|
PMC11277410
|
sec[9]/p[0]
|
Declaration of competing interest
| 0.981934 |
other
|
Other
|
[
0.004878997802734375,
0.0006570816040039062,
0.99462890625
] |
[
0.0019664764404296875,
0.99658203125,
0.0006356239318847656,
0.0005822181701660156
] |
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
|
[
"Behrooz Johari",
"Shabnam Tavangar-Roosta",
"Mahmoud Gharbavi",
"Ali Sharafi",
"Saeed Kaboli",
"Hamed Rezaeejam"
] |
https://doi.org/10.1016/j.heliyon.2024.e34096
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277422_p0
|
PMC11277422
|
sec[0]/p[0]
|
1. Introduction
| 4.027344 |
biomedical
|
Study
|
[
0.99951171875,
0.0004050731658935547,
0.000278472900390625
] |
[
0.50927734375,
0.132568359375,
0.3564453125,
0.0018701553344726562
] |
In the field of nuclear medicine, many diseases are diagnosed using positron emission tomography (PET) or single photon emission computed tomography (SPECT) or treated using radiopharmaceuticals . PET with 2-deoxy-2-[fluorine-18]fluoro-D-glucose ([ 18 F]FDG) is the most widely used technique radiotracer in nuclear medicine for cancer imaging . [ 18 F]FDG, a glucose analog, is taken up by cells and undergoes phosphorylation through the same mechanism as glucose. However, unlike glucose, [ 18 F]FDG does not enter the glycolytic pathway and accumulates inside the cells . Consequently, [ 18 F]FDG reflects glucose metabolism and enables imaging of tumors that do not exhibit morphological changes .
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277422_p1
|
PMC11277422
|
sec[0]/p[1]
|
1. Introduction
| 4.207031 |
biomedical
|
Study
|
[
0.99951171875,
0.0001819133758544922,
0.0001653432846069336
] |
[
0.99072265625,
0.00589752197265625,
0.0032939910888671875,
0.0001703500747680664
] |
Cancer cells consume more glucose and fatty acids as energy sources than normal cells . Fatty acids are composed of hydrocarbon chains and carboxyl groups and are categorized into short-chain fatty acids (SCFAs), medium-chain fatty acids, and long-chain fatty acids (LCFAs) based on their carbon content . PET imaging with 11 C-acetate, a type of SCFA, reflects fatty acid synthesis . 11 C-acetate is taken into the cancer cell through monocarboxylate transporters and converted to acetyl CoA by acetyl CoA synthase, which is then converted to LCFAs by fatty acid synthase . Because the accumulation of 11 C-acetate is correlated with the function of fatty acid synthesis enzymes, 11 C-acetate PET imaging is used to evaluate fatty acid synthase .
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277422_p2
|
PMC11277422
|
sec[0]/p[2]
|
1. Introduction
| 4.230469 |
biomedical
|
Study
|
[
0.99951171875,
0.0002636909484863281,
0.00019109249114990234
] |
[
0.9990234375,
0.00028061866760253906,
0.0007200241088867188,
0.00008082389831542969
] |
In addition to fatty acid synthesis, fatty acid oxidation (FAO), which produces energy through β-oxidation of LCFA, is also an important source of energy for cancer cells . FAO has attracted attention as a target for cancer therapy, as it has recently been shown that loading with FAO inhibitors suppresses cancer cell growth . To confirm the effect of FAO inhibitors, etc., several fluorescent probes have been developed . Fluorescence imaging has the advantage of no radiation exposure, but the sensitivity is poor, and clinical imaging in humans is difficult . Therefore, nuclear medicine probes, which enable clinical imaging, would be useful. However, there are no nuclear medicine imaging agents for cancer that reflect FAO. [ 123 I]β-methyl-p-iodophenyl-pentadecanoic acid ([ 123 I]BMIPP), whose parent compound is palmitic acid, is currently used for nuclear medicine imaging of ischemic heart diseases as myocardial fatty acid metabolism scintigraphy . In the fatty acid metabolism of [ 123 I]BMIPP myocardial scintigraphy, FAO is involved in [ 123 I]BMIPP accumulation. Although [ 123 I]BMIPP accumulates in cancer cells in patients with cancer as well , the accumulation mechanism of [ 123 I]BMIPP in cancer cells remains unclear. Thus, this study aimed to elucidate the accumulation mechanism of [ 123 I]BMIPP in cancer cells.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277422_p3
|
PMC11277422
|
sec[1]/p[0]
|
2. Results
| 4.011719 |
biomedical
|
Study
|
[
0.99951171875,
0.00023043155670166016,
0.0002796649932861328
] |
[
0.9990234375,
0.0006151199340820312,
0.0002237558364868164,
0.00006943941116333008
] |
Figure 1 shows the accumulation of [ 123 I]BMIPP and [ 18 F]FDG in (a) H441, (b) PC-14, (c) LS180, and (d) DLD-1cells. In all cancer cells, the accumulation of [ 123 I]BMIPP was much higher than that of [ 18 F]FDG early after its administration. It was also shown that the accumulation of [ 123 I]BMIPP increased over time.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277422_p4
|
PMC11277422
|
sec[1]/p[1]
|
2. Results
| 4.101563 |
biomedical
|
Study
|
[
0.99951171875,
0.00023365020751953125,
0.0003268718719482422
] |
[
0.99951171875,
0.0002925395965576172,
0.0002181529998779297,
0.00004780292510986328
] |
Figure 2 shows the accumulation of [ 123 I]BMIPP in (a) H441, (b) PC-14, (c) LS180, and (d) DLD-1 cells in the presence of SSO and lipofermata. The accumulation of [ 123 I]BMIPP decreased in H441, LS180, and DLD-1 cells when loaded with SSO and lipofermata. In addition, the decrease in the accumulation of [ 123 I]BMIPP was more pronounced in SSO-loaded cells than in lipofermata-loaded cells. Conversely, the accumulation of [ 123 I]BMIPP in PC-14 was not significantly changed by the two inhibitor loadings.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277422_p5
|
PMC11277422
|
sec[1]/p[2]
|
2. Results
| 4.082031 |
biomedical
|
Study
|
[
0.99951171875,
0.0002359151840209961,
0.00029349327087402344
] |
[
0.9990234375,
0.0004878044128417969,
0.00023221969604492188,
0.000059485435485839844
] |
Figure 3 shows the accumulation of [ 123 I]BMIPP in (a) H441, (b) PC-14, (c) LS180, and (d) DLD-1 under low-temperature conditions (4 °C). In all cancer cells, the accumulation of [ 123 I]BMIPP was considerably reduced at low temperatures compared to that of the control at 37 °C.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277422_p6
|
PMC11277422
|
sec[1]/p[3]
|
2. Results
| 4.101563 |
biomedical
|
Study
|
[
0.99951171875,
0.0002313852310180664,
0.0002448558807373047
] |
[
0.99951171875,
0.00030875205993652344,
0.00024437904357910156,
0.00005537271499633789
] |
Figure 4 shows the accumulation of [ 123 I]BMIPP in (a) H441, (b) PC-14, (c) LS180, and (d) DLD-1 cells with etomoxir, an FAO inhibitor, and loading. The accumulation of [ 123 I]BMIPP was significantly increased in all cancer cells when loaded with etomoxir. The increase in the accumulation of [ 123 I]BMIPP was more prominent in the lung adenocarcinoma cell lines H441 and PC-14 than in the colon cancer cell lines LS180 and DLD-1.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277422_p7
|
PMC11277422
|
sec[1]/p[4]
|
2. Results
| 4.214844 |
biomedical
|
Study
|
[
0.99951171875,
0.0004189014434814453,
0.00021314620971679688
] |
[
0.9990234375,
0.00026726722717285156,
0.0004954338073730469,
0.00008541345596313477
] |
The biological distribution of [ 123 I]BMIPP in LS180 tumor-bearing mice is shown in Table 1 , and the tumor-to-blood, tumor-to-large-intestine, tumor-to-small intestine, and tumor-to-muscle ratios of [ 123 I]BMIPP are shown in Table 2 . The biological distribution of [ 18 F]FDG in LS180 tumor-bearing mice is shown in Table 3 , and the tumor-to-blood, tumor-to-large-intestine, tumor-to-small intestine, and tumor-to-muscle ratios of [ 18 F]FDG are shown in Table 4 . The accumulation of [ 123 I]BMIPP in the blood increased up to 30 min after its administration. Conversely, the accumulation of [ 18 F]FDG in the blood peaked 5 min after its administration and decreased over time. There was little accumulation of [ 123 I]BMIPP in the brain and thyroid gland. At 5 min after its administration, the accumulation of [ 123 I]BMIPP in the heart and liver was observed, followed by a decrease in its accumulation over time. The accumulation of [ 123 I]BMIPP in the large intestine tended to increase over time. At 30 min after its administration, the accumulation of [ 123 I]BMIPP in LS180 cells was at its highest (2.50% ± 0.25%ID/g). The accumulation of [ 18 F]FDG in the LS180 cells similarly peaked at 30 min after its administration (3.02 ± 0.44%ID/g) but decreased considerably at 60 min after its administration (0.99 ± 0.08%ID/g). The tumor-to-blood ratio was 0.45, the tumor-to-large-intestine ratio was 1.63, and the tumor-to-muscle ratio was 1.16 at 30 min after the administration of [ 123 I]BMIPP. The maximum tumor-to-large-intestine ratio was 1.96 at 5 min after [ 123 I]BMIPP administration. Furthermore, the tumor-to-blood ratio was 3.02, the tumor-to-large-intestine ratio was 1.70, and the tumor-to-muscle ratio was 1.46 at 30 min after the administration of [ 18 F]FDG. These results indicated [ 123 I]BMIPP might be useful for colon cancer imaging.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277422_p8
|
PMC11277422
|
sec[2]/p[0]
|
3. Discussion
| 4.140625 |
biomedical
|
Study
|
[
0.99951171875,
0.0002429485321044922,
0.00017571449279785156
] |
[
0.99951171875,
0.0002276897430419922,
0.00035190582275390625,
0.00006496906280517578
] |
[ 123 I]BMIPP accumulates in the cancer cells of patients with cancer . However, cancer imaging with [ 123 I]BMIPP has not been used as a routine clinical examination. Our in vitro studies demonstrated significantly higher [ 123 I]BMIPP accumulation in all cancer cells than [ 18 F]FDG , which was similar to [ 18 F]FDG accumulation in cancer cells in Iwamoto’s study . This suggests that cancer cells may take up more LCFA than glucose as a nutrient source. LS180 cells showed the highest accumulation of [ 123 I]BMIPP at 5 min after its administration among all cell lines, suggesting that [ 123 I]BMIPP is taken up into cancer cells via transporters. Furthermore, the two lung cancer cells showed a more pronounced increase in accumulation from 30 to 60 min compared to the two colon cancer cells, suggesting that [ 123 I]BMIPP could be retained in the cells by its metabolism.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277422_p9
|
PMC11277422
|
sec[2]/p[1]
|
3. Discussion
| 4.261719 |
biomedical
|
Study
|
[
0.99951171875,
0.000278472900390625,
0.00019443035125732422
] |
[
0.99951171875,
0.00026106834411621094,
0.00039124488830566406,
0.0000768899917602539
] |
Regarding the mechanism by which [ 123 I]BMIPP accumulates in cancer cells, we focused on the fatty acid transporters CD36 and FATPs because LCFAs enter cells through fatty acid transporters of CD36 and FATPs on the cell membrane , although there are other fatty acid transporters such as fatty acid binding proteins (FABPs) . Notably, CD36 mediates the uptake of [ 123 I]BMIPP into the myocardium . Since no specific inhibitor for all subtypes of FABPs has been reported, [ 123 I]BMIPP accumulation was assessed in the presence of SSO, a CD36 inhibitor, and lipofermata, a FATP inhibitor. The accumulation of [ 123 I]BMIPP was reduced in the presence of SSO and lipofermata in H441, LS180, and DLD-1 cells but not in PC-14 . The expression of CD36 and FATPs in PC-14 cells may be lower than those in H441, LS180, and DLD-1 cells. However, FABPs may be more involved with respect to [ 123 I]BMIPP uptake into PC-14 because [ 123 I]BMIPP in PC-14 showed similar high accumulation compared to other cell lines. In H441, LS180, and DLD-1, the reduction was more pronounced with SSO than with lipofermata. Although it has been reported that [ 123 I]BMIPP uptake in the myocardium is mediated by CD36 , [ 123 I]BMIPP is primarily transported into cancer cells by CD36 and FATP, which is newly evident in cancer.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277422_p10
|
PMC11277422
|
sec[2]/p[2]
|
3. Discussion
| 4.144531 |
biomedical
|
Study
|
[
0.99951171875,
0.00021779537200927734,
0.00022423267364501953
] |
[
0.99951171875,
0.00025653839111328125,
0.00027751922607421875,
0.00005513429641723633
] |
The accumulation and retention of [ 123 I]BMIPP in the heart is dependent on fatty acid metabolism in the cytoplasm and mitochondria after myocardial uptake via CD36 and FATP1, 4, and 6 . In addition, we have shown that [ 123 I]BMIPP accumulates in bacteria through metabolic activity . In the symbiotic theory of biology, mitochondria are thought to have originally been aerobic bacteria . Thus, we investigated the metabolism of [ 123 I]BMIPP in cancer cells and compared it with [ 123 I]BMIPP accumulation under low-temperature conditions and 37 °C. Because the accumulation of [ 123 I]BMIPP was significantly reduced at 4 °C compared to 37 °C in all cancer cell lines , [ 123 I]BMIPP in cancer cells also accumulates depending on its metabolic activity.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277422_p11
|
PMC11277422
|
sec[2]/p[3]
|
3. Discussion
| 4.492188 |
biomedical
|
Study
|
[
0.99951171875,
0.0004432201385498047,
0.0002486705780029297
] |
[
0.9990234375,
0.00042366981506347656,
0.0005159378051757812,
0.00016486644744873047
] |
LCFAs are transported into cells and subsequently incorporated into mitochondria, where they undergo β-oxidation to generate energy . However, native fatty acids cannot directly penetrate mitochondrial membranes. Therefore, fatty acids are converted to acyl CoA, and the enzyme known as carnitine palmitoyl transferase I (CPT1) converts acyl CoA and carnitine to acylcarnitine, which can be transported into the mitochondria, where it is involved in energy production through β-oxidation . Etomoxir, an inhibitor of FAO, inhibits the metabolic pathway by blocking CPT1 . It has been shown that when loaded with etomoxir, the contribution of β-oxidation of [ 123 I]BMIPP in the myocardium decreased from 10% to 0% . In the myocardium, a small portion of [ 123 I]BMIPP is incorporated into the mitochondria, and most of the other molecules remain in the cytoplasm (mainly triglycerides). Conversely, when cancer cells were exposed to etomoxir at a high concentration for 60 min, there was a notable increase in the accumulation of [ 123 I]BMIPP compared with the control in all cancer cells . Herein, the increase in [ 123 I]BMIPP accumulation at 60 min after etomoxir loading, which may mainly include metabolites of [ 123 I]BMIPP, was higher in lung adenocarcinoma cell lines than in colon cancer cell lines . Reportedly, etomoxir does not alter cardiac long-chain fatty acid uptake via CD36 and FABPs . Therefore, etomoxir loading did not affect the intracellular accumulation of fatty acids. Thus, etomoxir loading inhibited CPT1 function and might increase [ 123 I]BMIPP accumulation into cytoplasmic triglycerides by altering cellular function, excluding transporter function in lung adenocarcinoma rather than colon cancer. Furthermore, the uptake of palmitic and oleic acids is markedly increased in CPT1 knockdown cells, which is close to the inhibition state of CPT by etomoxir loading, but the mechanism is unclear . Further investigation is needed to identify how CPT1 knockdown and CPT1 inhibition by etomoxir loading in cancer cells increase fatty acid uptake using metabolic pathway analysis of fatty acids, including [ 123 I]BMIPP. Based on the results of the present and Yao’s studies , [ 123 I]BMIPP would be taken up by mitochondria via CPT1.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277422_p12
|
PMC11277422
|
sec[2]/p[4]
|
3. Discussion
| 4.160156 |
biomedical
|
Study
|
[
0.99951171875,
0.00036454200744628906,
0.00020253658294677734
] |
[
0.99951171875,
0.00019097328186035156,
0.0003268718719482422,
0.00007480382919311523
] |
We also investigated whether [ 123 I]BMIPP highly accumulated in tumors in vivo using tumor-bearing mice implanted with LS180 cells, which exhibited the highest accumulation of [ 123 I]BMIPP in vitro in the thigh. The mice were allowed to fast for 6 h pre-experiment and injected venously with [ 123 I]BMIPP and [ 18 F]FDG. Ikeda et al. reported a significant reduction in triglycerides and fatty acid synthase in mice after 9 or 13 h of fasting compared with mice after 6 h of fasting . Herein, we primarily investigated fatty acid metabolism in cancer. Furthermore, we focused on fatty acid metabolism in cancer, speculating that fasting for >9 h could affect lipid metabolism in mice. Therefore, in this experiment, a 6 h fasting period was chosen, which did not significantly differ from that of nonfasting mice. The accumulation of [ 18 F]FDG in the blood achieved peak values at 5 min after its administration and then decreased over time ( Table 3 ), whereas the accumulation of [ 123 I]BMIPP increased up to 30 min after its administration and then decreased at 60 min ( Table 1 ). Furthermore, the accumulation of [ 123 I]BMIPP in the tumor reached a maximum of 2.50%ID/mg at 30 min after its administration, with a tumor-to-blood ratio of 0.45 ( Table 2 ).
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277422_p13
|
PMC11277422
|
sec[2]/p[5]
|
3. Discussion
| 4.261719 |
biomedical
|
Study
|
[
0.99951171875,
0.00023221969604492188,
0.0001863241195678711
] |
[
0.9990234375,
0.0002894401550292969,
0.0003972053527832031,
0.00007611513137817383
] |
Fatty acids bind to serum albumin in the blood . The albumin binding rate of [ 123 I]BMIPP was >99%, as evaluated by the ultrafiltration method of Nishi et al. . Therefore, [ 123 I]BMIPP accumulation in the blood was high, resulting in a low tumor-to-blood ratio. Little accumulation of [ 123 I]BMIPP in the mouse brain was observed ( Table 1 ), although the accumulation of [ 123 I]BMIPP in the human brain has not been fully confirmed . Since the expression of FATP1/4 on the blood–brain barrier has been confirmed in humans , [ 123 I]BMIPP may not have an affinity for FATP1/4. Oleic acid has an affinity for FATP1 , and palmitic acid, the parent compound of [ 123 I]BMIPP, has an affinity for FATP4 . However, the chemical structure of these fatty acids is different from that of [ 123 I]BMIPP, which has a benzene and methyl group, potentially explaining why [ 123 I]BMIPP does not have an affinity for FATP1/4. Additionally, FATP3 and FATP5 are primarily expressed in lung adenocarcinoma and colon cancer, respectively . These transporters showed some expression levels in all cancer cell lines ( Table 1 ). FATP2, 6, and FABPs are also expressed in cancer cells . Therefore, [ 123 I]BMIPP may have an affinity for CD36, FATPs (excluding FATP1/4), and FABPs as fatty acid transporters.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277422_p14
|
PMC11277422
|
sec[2]/p[6]
|
3. Discussion
| 4.15625 |
biomedical
|
Study
|
[
0.99951171875,
0.0002033710479736328,
0.0002002716064453125
] |
[
0.99951171875,
0.0002682209014892578,
0.00031685829162597656,
0.00005793571472167969
] |
The accumulation of [ 123 I]BMIPP in whole normal tissues (such as the heart and liver) was high early after its administration and tended to decrease over time compared to its accumulation in LS180 cells. Coburn et al. reported that systemic CD36 knockout in mice did not reduce fatty acid uptake into the liver , suggesting that FATPs or FABPs are involved in the uptake of [ 123 I]BMIPP into the liver. CD36 in the heart and FATPs or FABPs in the liver suggest higher expression levels than CD36 and FATP expressed on the cell membrane of the tumor due to the substantial impact of transporters in the early post-administration period. Additionally, [ 123 I]BMIPP, a fatty acid derivative, potentially has not much affinity for efflux drug transporters and would be gradually transferred from the liver to the intestine.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277422_p15
|
PMC11277422
|
sec[2]/p[7]
|
3. Discussion
| 4.316406 |
biomedical
|
Study
|
[
0.99951171875,
0.00032806396484375,
0.00019371509552001953
] |
[
0.9990234375,
0.0003044605255126953,
0.0005621910095214844,
0.00010526180267333984
] |
[ 123 I]BMIPP accumulation increased over time, up to 60 min after in vivo administration, but decreased 60 min after in vivo administration. No correlation was observed between the in vitro and in vivo results because [ 123 I]BMIPP is metabolized in cancer cells and some organs, including the liver, in vivo, whereas [ 123 I]BMIPP is metabolized only in cancer cells in vitro. The tumor-to-large-intestine ratios in the colon cancer cell line LS180 exceeded 1.0 during the 30 min that followed [ 123 I]BMIPP administration, reaching a maximum of 1.96 at 5 min of administration. Because it has been reported that the blood flow in the colon is lower than that in other organs , [ 123 I]BMIPP may have resulted in the tumor-to-large-intestine ratios exceeding 1.0 even though the tumor-to-blood ratios did not exceed 1.0. The maximum tumor-to-large-intestine ratio was 1.63 at 30 min after [ 18 F]FDG administration. [ 123 I]BMIPP can be applied to imaging bacterial infections . Herein, the ratio of infected to uninfected areas was approximately 1.3. Thus, a tumor-to-large-intestine ratio of 1.6 at 30 min after [ 123 I]BMIPP administration could be used to visualize the tumor. Therefore, [ 123 I]BMIPP could be used for imaging cancers with activated fatty acid metabolism, such as colon cancer. In addition, the accumulation of [ 123 I]BMIPP in muscle was at the same level as that in cancer. Increased FAO has been shown to be activated in skeletal muscle tissues after exercise , and the mice used in this experiment were active before and after [ 123 I]BMIPP administration, which may have increased [ 123 I]BMIPP accumulation in the skeletal muscle. Because patients can also rest until the starting time of examination after [ 123 I]BMIPP administration, [ 123 I]BMIPP could visualize cancer cells in humans, unlike the biological distribution of mice.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277422_p16
|
PMC11277422
|
sec[2]/p[8]
|
3. Discussion
| 4.136719 |
biomedical
|
Study
|
[
0.99951171875,
0.00026535987854003906,
0.00013625621795654297
] |
[
0.9990234375,
0.0002340078353881836,
0.0006079673767089844,
0.00007748603820800781
] |
Currently, the primary clinical examination methods for colorectal cancer are the fecal occult blood test (FOBT) and colonoscopy . While FOBT is relatively easy to perform, it can give false-positive or false-negative results . In addition, colonoscopy allows for direct observation of the inside of the intestine but imposes a significant burden on the patient because of the insertion of the endoscope into the body, along with the associated risks of bleeding and perforation of the digestive tract . Therefore, nuclear medicine imaging, which is less burdensome and may enable the early detection of tumors with subtle morphological changes, can prove valuable in the diagnosis of colorectal cancer. The results of this study suggest that [ 123 I]BMIPP can visualize fatty acid metabolism accumulated in mitochondria via CPT1 and is useful for early colon cancer imaging. Furthermore, loading palmitic acid (the precursor compound of [ 123 I]BMIPP) onto colorectal cancer induces ferroptosis, leading to cell death . Therefore, [ 123 I]BMIPP imaging for the measurement of fatty acid metabolism is a valuable tool for colon cancer. However, SPECT imaging could not be performed in colon cancer-bearing mice with implants in the thigh because the tumor-to-muscle ratio was less than 1.0 ( Table 3 ). Thus, new techniques for implanting colon cancer cells into the large intestine for SPECT imaging are needed.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277422_p17
|
PMC11277422
|
sec[2]/p[9]
|
3. Discussion
| 3.916016 |
biomedical
|
Study
|
[
0.99951171875,
0.00021147727966308594,
0.0002582073211669922
] |
[
0.7705078125,
0.201171875,
0.0275115966796875,
0.0007643699645996094
] |
[ 123 I]BMIPP might be useful for colon cancer imaging. However, [ 123 I]BMIPP binds to >99% of serum albumin, causing its retention in the blood, and imaging of lung cancer, liver cancer, and other types of cancer would be difficult because of the large [ 123 I]BMIPP accumulation in the heart, blood, and other trunk tissues. Therefore, new imaging radiotracers based on the chemical structure analog of [ 123 I]BMIPP are needed to enable fatty acid metabolism imaging of various types of cancer.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277422_p18
|
PMC11277422
|
sec[3]/p[0]
|
4. Materials and Methods
| 1.30957 |
biomedical
|
Other
|
[
0.9912109375,
0.0018796920776367188,
0.00695037841796875
] |
[
0.1632080078125,
0.8310546875,
0.0021514892578125,
0.0035114288330078125
] |
[ 123 I]BMIPP was purchased from Nihon Medi-Physics Co., Ltd. (Tokyo, Japan). [ 18 F]FDG was synthesized at the PET facility of Kanazawa University.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277422_p19
|
PMC11277422
|
sec[3]/sec[0]/p[0]
|
4.1. Using Cancer Cell Lines
| 4.09375 |
biomedical
|
Study
|
[
0.99951171875,
0.00019443035125732422,
0.00022554397583007812
] |
[
0.9990234375,
0.00040841102600097656,
0.00029349327087402344,
0.00005137920379638672
] |
The human-derived lung adenocarcinoma cancer cell lines H441 (American Type Culture Collection, Manassas, VA, USA) and PC-14 (RIKEN Cell Bank, Tsukuba, Japan), and the human-derived colon cancer cell lines LS180 and DLD-1 (American Type Culture Collection, Manassas, VA, USA) were selected in this study because lung cancer and colon cancer have the number one and number two cancer mortality rates in the world, respectively . H441 was cultured in the RPMI-1640 medium (FUJIFILM Wako Chemical, Osaka, Japan). PC-14 and DLD-1 were cultured in Dulbecco’s Modified Eagle’s Medium (FUJIFILM Wako Chemicals, Tsukuba, Japan), and LS180 was cultured in Eagle’s Minimum Essential Medium (E-MEM, FUJIFILM Wako Chemicals, Tokyo, Japan). All cell lines were cultured at 37 °C in a 5% CO 2 atmosphere. In addition, all culture media were mixed with 10% fetal bovine serum and 1% sodium pyruvate.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277422_p20
|
PMC11277422
|
sec[3]/sec[1]/p[0]
|
4.2. Accumulation of [ 123 I]BMIPP and [ 18 F]FDG in Cancer Cells
| 4.109375 |
biomedical
|
Study
|
[
0.99951171875,
0.00040435791015625,
0.0001634359359741211
] |
[
0.9990234375,
0.0004940032958984375,
0.000335693359375,
0.00008279085159301758
] |
Each cancer cell was seeded in a 12-well plastic plate at a density of 1.0 × 10 5 cells/well. Approximately 1 day after seeding, the cells were preincubated in phosphate-buffered saline (PBS, pH 7.4) for approximately 5 min and then incubated with [ 123 I]BMIPP (37 kBq/well, 1.08 fmol/kBq) and [ 18 F]FDG (370 kBq/well, 0.35 fmol/kBq) for 5, 10, 30, and 60 min at 37 °C ( n = 4). After incubation, the cancer cells were washed twice with PBS and lysed with 0.1 M NaOH. Intracellular radioactivity was measured using a gamma counter . The measurement results were expressed as the percentage injected dose (%ID)/mg protein using the amount of intracellular protein measured with a protein assay kit (Thermo Fisher Scientific, Waltham, MA, USA).
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277422_p21
|
PMC11277422
|
sec[3]/sec[2]/p[0]
|
4.3. Accumulation of [ 123 I]BMIPP in Cancer Cells Using a Fatty Acid Transporter Inhibitor
| 4.109375 |
biomedical
|
Study
|
[
0.99951171875,
0.0002684593200683594,
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] |
[
0.9990234375,
0.00057220458984375,
0.0002574920654296875,
0.0000623464584350586
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Each cancer cell was seeded in a 12-well plastic plate at a density of 1.0 × 10 5 cells/well. Approximately 1 day after seeding, the cells were preincubated in PBS for approximately 5–10 min and then incubated with [ 123 I]BMIPP (37 kBq/well, 40 fmol/37 kBq) and 1.0 mM sulfosuccinimidyl oleate (SSO, Cayman Chemical, Ann Arbor, MI, USA), an inhibitor of CD36 , or 1.0 mM lipofermata (Cayman Chemical, Ann Arbor, MI, USA), an inhibitor of fatty acid transport proteins (FATPs) , for 5 min, at which transporters are active ( n = 4). Subsequent procedures followed the method outlined in Section 4.2 .
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277422_p22
|
PMC11277422
|
sec[3]/sec[3]/p[0]
|
4.4. Accumulation of [ 123 I]BMIPP in Cancer Cells under Low-Temperature Conditions
| 4.085938 |
biomedical
|
Study
|
[
0.99951171875,
0.00040531158447265625,
0.00019478797912597656
] |
[
0.9990234375,
0.0007724761962890625,
0.0002455711364746094,
0.00008505582809448242
] |
Each cancer cell was seeded in a 12-well plastic plate at a density of 1.0 × 10 5 cells/well. Approximately one day after seeding, the cells were preincubated in ice-cold PBS for approximately 5 min and then incubated with [ 123 I]BMIPP (37 kBq/well, 1.08 fmol/kBq) for 5, 10, 30, and 60 min under ice-cold conditions at 4 °C ( n = 4). Subsequent procedures followed the method outlined in Section 4.2 .
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277422_p23
|
PMC11277422
|
sec[3]/sec[4]/p[0]
|
4.5. Accumulation of [ 123 I]BMIPP in Cancer Cells Using a Fatty Acid Oxidation Inhibitor
| 4.09375 |
biomedical
|
Study
|
[
0.99951171875,
0.00033926963806152344,
0.00019824504852294922
] |
[
0.9990234375,
0.0005669593811035156,
0.00023818016052246094,
0.00007134675979614258
] |
Each cancer cell was seeded in a 12-well plastic plate at a density of 1.0 × 10 5 cells/well. Approximately 1 day after seeding, the cells were preincubated in PBS for approximately 5 min and then incubated with [ 123 I]BMIPP (37 kBq/well, 1.08 fmol/kBq) and 1.0 mM etomoxir, an inhibitor of FAO , for 60 min ( n = 4). Subsequent procedures followed the method outlined in Section 4.2 .
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277422_p24
|
PMC11277422
|
sec[3]/sec[5]/p[0]
|
4.6. Biological Distribution of [ 123 I]BMIPP in Tumor-Bearing Mice
| 4.117188 |
biomedical
|
Study
|
[
0.99951171875,
0.0003619194030761719,
0.0001659393310546875
] |
[
0.9990234375,
0.00035953521728515625,
0.0003082752227783203,
0.00008296966552734375
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All animal experiments conducted in this study were performed in compliance with the ethical standards of Kanazawa University , international standards for animal welfare, and institutional guidelines. LS180 was adjusted to a concentration of 5.0 × 10 6 cells/100 µL using serum-free E-MEM and transplanted under the skin of the right thigh of BALB/c male mice (4 weeks old, SLC Inc., Hamamatsu, Japan). Tumor-bearing mice (with a cancer diameter of 0.5–1.0 cm) approximately 2 weeks after transplantation were used in the experiments. The mice were made to fast for 6 h before the experiment and then injected with [ 123 I]BMIPP (37 kBq/mouse, 1.08 fmol/kBq) and [ 18 F]FDG (370 kBq/mouse, 0.35 fmol/kBq) through the tail vein. After 5, 10, 30, and 60 min of [ 123 I]BMIPP administration ( n = 3), blood samples were drawn from the hearts of the mice under isoflurane anesthesia (FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan), and the mice were euthanized by cervical dislocation. Several organs (the brain, thyroid, heart, lungs, pancreas, liver, stomach, spleen, kidney, small intestine, large intestine, and muscle) and the tumor were collected, and their radioactivity was measured using a gamma counter. The results for the brain, heart, lungs, pancreas, liver, spleen, kidney, small intestine, large intestine, muscle, and tumor were normalized to the weight of the respective organs using an electronic balance (AUX220, Shimadzu Corporation, Kyoto, Japan) and expressed as %ID/g. The results for the thyroid, stomach, small intestine, and large intestine are expressed as %ID, and the large intestine is expressed as both. The intestine was averaged for the small and large intestines.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277422_p25
|
PMC11277422
|
sec[3]/sec[6]/p[0]
|
4.7. Statistical Analysis
| 2.931641 |
biomedical
|
Study
|
[
0.99853515625,
0.00034689903259277344,
0.0011072158813476562
] |
[
0.8330078125,
0.1641845703125,
0.002044677734375,
0.0006718635559082031
] |
The p -values were calculated using a two-tailed paired Student’s t -test for comparisons between the two groups using GraphPad Prism 8 statistical software (GraphPad Software, Inc., La Jolla, CA, USA). A p -value of 0.01 or 0.05 was considered statistically significant.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277422_p26
|
PMC11277422
|
sec[4]/p[0]
|
5. Conclusions
| 4.136719 |
biomedical
|
Study
|
[
0.99951171875,
0.0001398324966430664,
0.00013768672943115234
] |
[
0.99658203125,
0.0016012191772460938,
0.0019502639770507812,
0.00010275840759277344
] |
[ 123 I]BMIPP accumulates highly in cancer cells compared to [ 18 F]FDG in vitro, and the colon cancer-to-large-intestine ratio exceeds 1.0 during the 30 min that follows [ 123 I]BMIPP administration in vivo. As the accumulation mechanism, [ 123 I]BMIPP is mainly taken up by cancer cells via the fatty acid transporters CD36 and FATPs and incorporated into mitochondria via CPT1. Therefore, [ 123 I]BMIPP may be useful for imaging cancers with activated fatty acid metabolism, such as colon cancer. However, novel imaging radiotracers based on the chemical structure analog of [ 123 I]BMIPP are needed.
|
[
"Kakeru Sato",
"Yuka Hirayama",
"Asuka Mizutani",
"Jianwei Yao",
"Jinya Higashino",
"Yuto Kamitaka",
"Yuka Muranaka",
"Kana Yamazaki",
"Ryuichi Nishii",
"Masato Kobayashi",
"Keiichi Kawai"
] |
https://doi.org/10.3390/ijms25147747
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
39057285_p0
|
39057285
|
sec[0]/p[0]
|
1. Introduction
| 3.873047 |
biomedical
|
Study
|
[
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[
0.876953125,
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Aphids (Hemiptera: Aphididae) are a diverse group of insects, encompassing around 5600 species divided into 24 subfamilies . They are widespread in temperate regions, with some species exhibiting seasonal alternation between unrelated groups of host plants, including angiosperms, gymnosperms and herbaceous plants . Their life cycles, involving both sexual and asexual reproduction driven by adaptive radiation, contribute to their variable phenotypic features . This great diversity makes aphids a fascinating research model with a complex role in ecosystems. On the one hand, aphids produce honeydew and engage in mutualistic relationships with ants . They also contribute to bioaccumulating chemical elements from plants and contaminated soil . However, they are significant crop and ornamental plant pests, causing damage through direct feeding or the transfer of plant pathogens .
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057285_p1
|
39057285
|
sec[0]/p[1]
|
1. Introduction
| 4.140625 |
biomedical
|
Study
|
[
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[
0.9873046875,
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The subfamily Drepanosiphinae is a widely distributed group of aphids, currently containing 40 species belonging to five genera. Research on the systematics of Drepanosiphinae has mainly focused on the external morphology and molecular biology of the genera Drepanosiphoniella Davatchi, Hille Ris Lambers and Remaudière, 1957 ; Drepanosiphum Koch, 1855 ; Yamatocallis Matsumura, 1917 ; and Shenahweum Hottes & Frison, 1931 . The genus Drepanaphis Del Guercio, 1909 , is the most numerous genus within the subfamily, here revised to include 18 species with 44 known morphs. Species from this genus are characterised by distinct dorsal tubercles on the abdominal segments, very long antennae and reduced legs chaetotaxy. All Drepanaphis species are regarded as Nearctic, with D. acerifoliae also introduced to Europe . Most species in this genus are similar in the body size and wax arrangement of the dominant morph, alate viviparous females, making them difficult to distinguish. Species of this genus are mostly monophagous, feeding primarily on different maple trees ( Acer spp.), although some are oligophagous. Exceptionally, the host plant of D. monelli is buckeye ( Aesculus glabra ).
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057285_p2
|
39057285
|
sec[0]/p[2]
|
1. Introduction
| 2.900391 |
other
|
Other
|
[
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0.54296875
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[
0.292236328125,
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Thomas described the first species of the current genus Drepanaphis in 1878 as Siphonophora acerifoliae . At the end of the description of the new species, he included the following sentence: “It is possible that this Aphis should be placed in Drepanosiphum , or a new genus be formed for its reception”. Just a year later, in 1879, Monell classified S. acerifoliae in the genus Drepanosiphum , changing the species name to Drepanosiphum acerifolii . For years, most researchers hesitated to determine whether this species also belonged to the genus Drepanosiphum . Finally, on 15 September 1909, Del Guercio , in “Revista di Patologia Vegetale”, proposed a new genus for S. acerifoliae — Drepanaphis . At the same time, in September 1909, Davis proposed the genus Phymatosiphum for the same species in the “Annals of the Entomological Society of America”. Davis referred to the suggestions of H. Schouteden and H. F. Wilson that this was not a representative of Drepanosiphum . Interestingly, Del Guercio described the new genus from material he received from Davis himself. His footnote at the end of the article proves this: “Gli insetti esaminati ed in base ai quali ho stabilito il genere indicato mi sono stati spediti gentilmente dal chiaro collega J. J. Davis, al quale porgo anche in questa occasione sentiti ringraziamenti.” [transl. “The insects examined and on the basis of which I established the indicated genus were kindly sent to me by my good colleague J. J. Davis, to whom I also offer heartfelt thanks on this occasion.”]. Therefore, if Davis had not shared the material mentioned with Del Guercio, we would probably now be discussing the genus Phymatosiphum . Nevertheless, according to the International Code of Zoological Nomenclature (ICZN), Art. 21.3, Del Guercio was the first to describe the genus because its publication date is specified to the day.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057285_p3
|
39057285
|
sec[0]/p[3]
|
1. Introduction
| 4.140625 |
biomedical
|
Review
|
[
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[
0.462158203125,
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Once the systematic position of this genus was established, new species were subsequently described. Davis described Phymatosiphum monelli , which Gillette synonymised as Drepanaphis monelli . In 1931, Granovsky described D. keshenae ; in 1937, Miller proposed D. sabrinae . In 1941, Smith described D. carolinensis , D. kanzensis , D. nigricans , D. parvus , D. rubrum and D. spicata . However, in 1943, Smith and Knowlton described two more species— D. granovskyi and D. utahensis —and at the same time concluded that D. rubrum is a synonym of D. parvus . Smith described two additional species— D. tissoti in 1944 and D. simpsoni in 1959 . Then, in 1968, Smith and Dillery carried out the first revision of the genus Drepanaphis , describing four more new species— D. choanotricha , D. idahoensis , D. knowltoni and D. saccharini . The last species, described by Richards in 1969, was D. pallida .
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999993 |
39057285_p4
|
39057285
|
sec[0]/p[4]
|
1. Introduction
| 3.865234 |
biomedical
|
Study
|
[
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[
0.9462890625,
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As already mentioned, this genus was revised by Smith and Dillery in 1968 , and since then, this has been the most reliable source of information about the Drepanaphis species. The publication provided important information about the morphology of winged viviparous females, but little attention was given to the descriptions of oviparous females and males. The authors primarily studied interspecific relationships and categorised morphological groups to represent differences between species within a genus. However, they focused extensively on the features of the nymphs without considering the morphological characteristics of the adults. Due to the high similarity of winged forms and the lack of distinct morphological characters between species, the species identity of D. nigricans and D. tissoti has been questioned, as has that of D. pallida and D. simpsoni .
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
39057285_p5
|
39057285
|
sec[0]/p[5]
|
1. Introduction
| 4.226563 |
biomedical
|
Study
|
[
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[
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Therefore, the aim of this study is to perform a comprehensive revision of the genus Drepanaphis that considers the variability in species across different regions of North America. This study seeks to document the sexual morphs of 15 species for the first time, including the description of all oviparous females, and to provide comprehensive identification keys for all known species and morphs. A principal components analysis (PCA) is utilised to elucidate relationships among species within the various morphological groups identified in the genus, clarifying the status of the most similar species. Additionally, by examining museum specimens, a new species is described, Drepanaphis robinsoni sp. nov., which was previously confused with two other species. It also aims to correct numerous misidentifications of specimens previously mislabelled. Lastly, this study intends to present updated range maps for all species and provide images of key morphological features using light and scanning electron microscopy, thereby contributing to a more complete understanding of this historically understudied genus.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057285_p6
|
39057285
|
sec[1]/sec[0]/p[0]
|
2.1. Study Material and Light Microscopy
| 3.904297 |
biomedical
|
Study
|
[
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A total of 652 microscopic slides and 1382 individuals were examined . Freshly collected samples were preserved in 70% ethanol. Insects were slide mounted using the method of Wieczorek ; examined using light microscopes: a Nikon Ni-U, equipped with a phase contrast system and a Leica DM 3000 LED; and photographed using a Leica MC 190 HD camera (Leica Microsystems GmbH, Wetzlar, Germany). The measurements were taken according to Ilharco and van Harten and are given in millimetres. Voucher specimens were deposited in the entomological collection of the University of Silesia in Katowice, Poland (DZUS). Actual host plant names are given according to the WFO Plant List . Final figure processing was performed using Photoscape X 4.2 . The drawings were prepared manually and then scanned and processed in Photoscape. The dimensions are the average value of several/dozen measurements of individual appendages.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057285_p7
|
39057285
|
sec[1]/sec[0]/p[1]
|
2.1. Study Material and Light Microscopy
| 3.169922 |
biomedical
|
Other
|
[
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[
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The following abbreviations (in the descriptions, re-descriptions, tables and Supplementary Materials ) were used: ABD—abdominal tergite or tergites; ANT—antennae or their lengths; ANT I–VI—antennal segments from I to VI or their lengths (ratios between antennal segments are given as “III/IV”); BASE—basal part of the last antennal segment or its length; BL—body length; DAT—dorsal abdominal tubercles; FEMUR I—fore femur length; FEMUR II—middle femur length; FEMUR III—hind femur length; HW—head width across compound eyes; HT II—second segment of hind tarsus or its length; PT—processus terminalis of the last antennal segment or its length; SIPH—siphunculi sclerite width; TIBIA III—hind tibia length; URS—ultimate segments of rostrum (IV + V) or their lengths.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057285_p8
|
39057285
|
sec[1]/sec[0]/p[2]
|
2.1. Study Material and Light Microscopy
| 0.838867 |
other
|
Other
|
[
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[
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The material studied was loaned from the following depositories: Biologické centrum IECA—The Biology Centre of the Czech Academy of Sciences; INHS Insect Collection—Illinois Natural History Survey Champaign, Illinois; MNHN—Muséum national d’Histoire naturelle, Paris, France; MZLU—Museum of Zoology, Lund University, Sweden; MZPW—Museum of the Zoological Institute of the Polish Academy of Sciences, Warsaw; NHMUK—Natural History Museum, London, United Kingdom; USNM—United States National Museum, Smithsonian Institution, Washington, DC, United States; ZMUC—Zoological Museum, University of Copenhagen, Copenhagen, Denmark; A. Jensen’s private collection.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057285_p9
|
39057285
|
sec[1]/sec[0]/p[3]
|
2.1. Study Material and Light Microscopy
| 0.934082 |
other
|
Other
|
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[
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] |
The holotype of the new species is deposited at the NHMUK. Paratypes will be deposited at the NHMUK and DZUS.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057285_p10
|
39057285
|
sec[1]/sec[0]/p[4]
|
2.1. Study Material and Light Microscopy
| 1.18457 |
other
|
Other
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[
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[
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Quoting the labels of the specimens, a double slash (//) is used to divide data on different labels. Notes and information about the collection are in square brackets [ ].
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057285_p11
|
39057285
|
sec[1]/sec[1]/p[0]
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2.2. Scanning Electron Microscopy
| 4.105469 |
biomedical
|
Study
|
[
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[
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Specimens for scanning electron microscopy (SEM) analysis (five individuals) were preserved in 70% ethanol. The samples were dehydrated using serial baths of 80%, 90% and 96% ethanol—20 min for 80% ethanol, 15 min for 90% ethanol, 10 min for 96% ethanol and two baths of absolute alcohol for 10 min each. Dehydrated samples were dried using a Leica EM CPD300 automated critical point dryer (Leica Microsystems, Vienna, Austria). Dry samples were mounted on aluminium stubs with double-sided adhesive carbon tape and sputter coated with a 30 nm gold layer in a Safematic CCU-010 high-vacuum sputter coater (Safematic GmbH, Zizers, Switzerland). The specimens were imaged with Hitachi SU8010 (Hitachi High-Technologies Corporation, Tokyo, Japan) and Phenom XL (Phenom-World B.V., Eindhoven, The Netherlands) field emission scanning electron microscopes. Final figure processing was performed using Photoscape X 4.2 .
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057285_p12
|
39057285
|
sec[1]/sec[2]/p[0]
|
2.3. Statistical Analysis
| 4.125 |
biomedical
|
Study
|
[
0.9970703125,
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[
0.99951171875,
0.00018024444580078125,
0.00019443035125732422,
0.00003820657730102539
] |
A principal components analysis (PCA) was conducted based on the data recorded from individual specimens. Data sets ( Tables S1 and S2 ) with morphometric variables, morphometric ratios and morphological characters for alate viviparous females (52 characters), males (51 characters) and oviparous females (46 characters) were tested with multiple correlation analysis, and the variables with the lowest redundancy values were finally selected. Six morphometric variables, ten morphometric ratios and eight morphological characters were selected for the 213 alate viviparous females of the genus Drepanaphis (see Table S3 for details). For the 30 males (see Table S4 for more information), four morphometric variables, 11/12 morphometric ratios and nine morphological characters were selected. In turn, for the 43 oviparous females (see Table S4 for more information), five morphometric variables, 13 morphometric ratios and six morphological characters were selected (all variables are listed in Tables S1 and S2 ). Before the PCA, each character was converted to zero mean and unit standard deviation within reduced data sets, so the same weight was given to all of them. The PAST software ver. 4.13 was used for multivariate analyses. Since we have already analysed distinctiveness at the generic level with representatives of Drepanaphis and the closely related genera Drepanosiphum and Drepanosiphoniella , we will not repeat it here and will refer to the previous publication .
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057285_p13
|
39057285
|
sec[1]/sec[3]/p[0]
|
2.4. Occurrence Data and Preparation of Maps
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biomedical
|
Study
|
[
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[
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0.0005636215209960938
] |
The occurrence data were obtained from the scientific literature, specimens studied in museum collections, fieldwork in the USA in September 2022, iNaturalist and biodiversity databases . Museum curators were asked to provide information about their collections (photographs of the preparations were provided). Some specimens were also examined in the collections during the personal stay of the first author. Databases were searched based on keywords, i.e., the name of the species and its synonyms. All records with unspecified or unknown localities were excluded.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057285_p14
|
39057285
|
sec[1]/sec[3]/p[1]
|
2.4. Occurrence Data and Preparation of Maps
| 2.134766 |
biomedical
|
Study
|
[
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[
0.740234375,
0.25732421875,
0.0014600753784179688,
0.0007171630859375
] |
All localities of the studied species were georeferenced using Google Earth ver. 10.38.0.0 (Google Inc. , Mountain View, CA, USA) (geographical projection, decimal degrees, datum: WGS84). The ranges of host plants were based on data obtained from http://databasin.org , accessed on 12 June 2024 (Conservation Biology Institute (CBI) ; the maps are a digital representation of the tree species range maps from the Atlas of the United States Trees by Little ). Maps were prepared using Quantum GIS ver. 3.30.1 (QGIS Development Team ) using the WGS84 datum and EPSG: 4326 or 3857 (Web Mercator). The data on the distribution of individual species will be published in the GBIF.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057285_p15
|
39057285
|
sec[2]/sec[0]/p[0]
|
3.1. Taxonomy
| 4.277344 |
biomedical
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Study
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[
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Body slender, pale, with various pigmentation patterns on legs. Head separated from pronotum, abdominal segments not separated from one another. Head with little-developed antennal tubercles, with postero-dorsal, latero-dorsal and fronto-orbital setae . Compound eyes with numerous ommatidia and well-developed triommatidia . Rostrum ends between fore and middle coxae. Ultimate rostral segments with two pairs of primary setae and four to seven pairs of accessory setae, variable within species . Antennae six-segmented. Antennal segment II shortest; antennal segments IV and V similar in length; processus terminalis longest. Antennae covered with pointed, short, colourless setae. On ANT I–II 0.01–0.02 mm long (on ANT I more abundant on apical part of segment); on ANT III–VI 0.005–0.01 mm long. ANT I with 8–12 setae, ANT II with 2–5 setae, ANT III with 40–50 setae, ANT IV with 12–18 setae, ANT V with 7–9 setae, BASE with 2–3 setae (type I trichoid sensilla), PT with 2 subapical and 1 apical setae (type II trichoid sensilla). ANT III with 2–22 rounded secondary rhinaria . Apical part of antennal segment V with one primary rhinarium . Base of antennal segment VI with 1 primary (major) rhinarium (big multiporous placoid sensillum) and 4–11 accessory rhinaria (small multiporous placoid sensilla) adhering to primary rhinarium, number of which may vary between species. Above and below major rhinarium, additional primary rhinaria present . All rhinaria with ciliated cuticle edges . Fore wings with radius strongly curved, media twice branched. Hind wings with media present. Dorsal abdominal tubercles with trichoid sensilla type I at ends . Dorsal setae pointed, blunt or forked. Siphunculi flask-shaped or tubular . Apex of siphunculi with well-developed, strong flange and well-developed operculum on siphuncular pore . Fore femora dark dorsally or pale, hind femora pale, smudged or with dark stripes on distal parts. Legs covered by not numerous, 0.01–0.05 mm long, fine setae with pointed apices. Femora with smaller amount of setae, and tibiae with more abundant setae, especially at end . First tarsal segments 4:4:4, empodial setae spatulate . Cauda knobbed, with 4–6 long, fine and pointed setae . Anal plate and genital plate covered by numerous fine and pointed setae.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057285_p16
|
39057285
|
sec[2]/sec[0]/p[1]
|
3.1. Taxonomy
| 2.957031 |
biomedical
|
Study
|
[
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[
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Body pear-shaped or oval with elongated end of abdomen. Dorsal abdominal tubercles absent. ANT III without or with single, small, rounded secondary rhinaria. BASE with 1 rounded primary rhinarium with ciliated edge and 6–7 very small accessory rhinaria, adhering to primary rhinarium. Dorsal setae arranged in marginal, pleural and spinal rows. ABD I–VI with blunt setae distributed on well-developed sclerites. ABD VII–VIII with pointed setae. Hind tibiae with rounded pseudosensoria, mostly arranged along almost their entire lengths. Cauda knobbed with numerous setae.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057285_p17
|
39057285
|
sec[2]/sec[0]/p[2]
|
3.1. Taxonomy
| 3.548828 |
biomedical
|
Study
|
[
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[
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General characters like in alate viviparous females. ANT III–V with numerous, small, rounded secondary rhinaria. BASE with 1 rounded primary rhinarium with ciliated edge and 4–5 very small accessory rhinaria, adhering to primary rhinarium. Abdomen with well-developed dorsal sclerotisation, especially on ABD IV–V. Dorsal abdominal tubercles smaller and less visible than in alate viviparous females. In some species inconspicuous. Cauda more or less knobbed, with five long, fine, pointed setae. Genitalia dusky, except for D. granovskyi , with genitalia distinctly darkly pigmented. In all known males parameres large, lobate, except D. simpsoni , with parameres much smaller and elongated. Parameres and basal part of phallus covered with numerous short setae. Distal part of sclerotised arms rather long and thin, whereas proximal part shorter and wider.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057285_p18
|
39057285
|
sec[2]/sec[4]/p[0]
|
3.5. Results of the Statistical Analysis
| 4.078125 |
biomedical
|
Study
|
[
0.98291015625,
0.0005402565002441406,
0.0166778564453125
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[
0.99951171875,
0.0002830028533935547,
0.00021731853485107422,
0.000042319297790527344
] |
Based on the morphological and morphometric data, in the PCA results for the group consisting of the 213 alate viviparous females representing all species of the genus Drepanaphis , the first two axes of the PCA represent 70.8% of the total variance (the first three axes represent 80.9%). The first component (axis 1) is characterised mostly by the fore femora colour and the arrangement of conspicuous dorsal abdominal tubercles. The second component (axis 2) reflects the characteristics of the presence of stripes on the hind femora, dorsal sclerites and siphunculi colour . In the case of all analysed morphs, qualitative features were decisive due to the fact that metric features often overlap, and there is no single clear feature that would allow for distinguishing individual species from each other.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057285_p19
|
39057285
|
sec[2]/sec[4]/p[1]
|
3.5. Results of the Statistical Analysis
| 4.128906 |
biomedical
|
Study
|
[
0.98828125,
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[
0.99951171875,
0.00037097930908203125,
0.0002448558807373047,
0.00004965066909790039
] |
For 30 males representing 12 species of the genus Drepanaphis , the first two axes of the PCA represent 67.3% of the total variance (the first three axes represent 75.8%) in the variant where the antennal segment ratio VI PT/BASE variable is not used. When this characteristic is used, then the value increases to 86.9% (the first three axes represent 91.2%). The first component (axis 1) is characterised by the fore femora colour, the presence of the stripes on the hind femora and the antenna colour. The second component (axis 2) reflects mainly the length-to-height ratio in the middle part of the siphunculi, the number of frontal setae and the visible appearance of a third pair of tubercles on the abdomen segment . In the analysis where the ratio of the length of the processus terminalis of the last antennal segment to that of its basal part was also used, this feature is dominant in the characterisation for axis 1 .
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057285_p20
|
39057285
|
sec[2]/sec[4]/p[2]
|
3.5. Results of the Statistical Analysis
| 3.910156 |
biomedical
|
Study
|
[
0.9794921875,
0.00048661231994628906,
0.0200347900390625
] |
[
0.99853515625,
0.0010986328125,
0.0001957416534423828,
0.00006103515625
] |
For 43 oviparous females representing 14 species of the genus Drepanaphis , the first two axes of the PCA represent 91.3% of the total variance (the first three axes represent 94.4%). The first component (axis 1) is characterised by the ratio of the length of the processus terminalis of the last antennal segment to that of its basal part. The second component (axis 2) reflects mainly the colour of antennae, fore tibiae, dorsal sclerites and siphunculi .
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057285_p21
|
39057285
|
sec[2]/sec[4]/p[3]
|
3.5. Results of the Statistical Analysis
| 4.214844 |
biomedical
|
Study
|
[
0.99169921875,
0.0005559921264648438,
0.007537841796875
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[
0.99951171875,
0.00025844573974609375,
0.0003314018249511719,
0.000048279762268066406
] |
The PCA results confirm the full species status of D. tissoti within the genus Drepanaphis . Moreover, according to previously proposed species groups by Smith and Dillery , most of these proposals are justified. In the genus under study, we can distinguish the “ acerifoliae ” group, characterised by four clearly visible pairs of dorsal abdominal tubercles in alate viviparous females. Originally, species such as D. acerifoliae , D. carolinensis and D. sabrinae were included here. However, D. sabrinae has a unique tubercle pattern, its siphunculi are light brown and unlike the other two species, which have four accessory rhinaria each, this species has five to six of them. This species is plotted for alate viviparous females at the far end of axis 1, but for oviparous females, it is shown close to D. acerifoliae and D. carolinensis . Species in the “ monelli ” group have only the third pair of tubercles visible and dark stripes on the hind femora. This group includes D. keshenae , D. knowltoni , D. monelli and D. spicata . Smith and Dillery also proposed D. kanzensis here, although they also indicated some doubts about its position in this group. Based on the morphological analysis of this species, we propose not assigning it to any existing group, similar to the approach taken with D. sabrinae . The position of D. kanzensis outside the previously designated group is confirmed in the analyses of all generations—alate viviparous females and sexuales, oviparous females and males. In the case of sexual generation, species from the “ acerifoliae ” and “ monelli ” groups partially overlap, which is primarily due to the very similar metric ratio of the analysed characters and, especially in the case of males, the inability to measure some features in D. acerifoliae and D. carolinensis individuals . For the correct analysis of the results, it is also important to mention that in oviparous females, the measurement values of the processus terminalis (ANT VI PT) for two individuals from D. acerifoliae and two from D. monelli were lower than those in the others, which resulted in some disturbance in the analyses and the separation of these individuals on the plot. This is the only reason for this situation.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057285_p22
|
39057285
|
sec[2]/sec[4]/p[4]
|
3.5. Results of the Statistical Analysis
| 2.658203 |
biomedical
|
Study
|
[
0.68798828125,
0.0007567405700683594,
0.31103515625
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[
0.7509765625,
0.2471923828125,
0.00127410888671875,
0.0005269050598144531
] |
The remaining groups coincide with the previous proposal. Therefore, we have a “ nigricans ” group, with D. choanotricha , D. nigricans and D. tissoti , mostly characterised by very long antennae; a “ parva ” group, where all species have a light-coloured front femora, i.e., D. idahoensis , D. parva , D. robinsoni sp. nov. and D. saccharini ; and a fifth “ utahensis ” group, with D. granovskyi , D. simpsoni and D. utahensis , where all species have two pairs of frontal setae on the head.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057285_p23
|
39057285
|
sec[3]/sec[0]/p[0]
|
4.1. Morphological Groups within the Genus Drepanaphis
| 4.289063 |
biomedical
|
Study
|
[
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The most significant character of species belonging to the genus Drepanaphis is the presence of distinctive tubercles on dorsal abdominal tergites I–IV. The size and shape of dorsal abdominal tubercles have great importance in the systematics of this group of aphids. Smith and Dillery pointed out the importance of this feature for distinguishing species belonging to five morpho-groups. However, in their original descriptions, they did not consider qualitative features such as the colour of the fore femora or the shape of the siphunculi. Additionally, when determining the groups, the authors paid great attention to the characteristics of the nymphs and the host plant associations, which may not provide sufficient information about the morphological similarities within the designated groups. They also did not consider the characteristics of the sexual generation, which were relatively poorly known. By analysing the morphological characters in the genus Drepanaphis , five distinct species groups can be distinguished. Species with four distinct pairs of dorsal abdominal tubercles, with the third pair being the largest, first femora dark around the edges and four accessory rhinaria are characteristic of the “ acerifoliae ” group, consisting of D. acerifoliae and D. carolinensis . The original division also included D. sabrinae , but due to different proportions of tubercles (the second and third pairs of equal length) and five accessory rhinaria, this species is not classified into any group. Additionally, D. sabrinae is the only species with an ultimate rostral segment 0.12–0.14 mm long. The second group of species morphologically similar to each other and distinguished by having only a third pair of tubercles is the “ monelli ” group ( D. keshenae , D. knowltoni , D. monelli and D. spicata ). Species in this group are very similar and are often incorrectly marked in museum collections; e.g., D. knowltoni was marked incorrectly as D. monelli and vice versa; D. knowltoni and D. spicata are also frequently confused species. In the case of this group, similarly to the “ acerifoliae ” group, another species, D. kanzensis , was originally included. Variability resulting from the colour of the fore femora and the lack of black stripes on the third pair of hind femora means that this species is also not classified into any group. A group of individuals characterised by relatively small body size, long antennae and a variable number of accessory rhinaria creates the “ nigricans ” group ( D. choanotricha , D. nigricans , D. tissoti ). Remaudière and Remaudière , after personal communication from Quednau, established the synonymisation of D. tissoti with D. nigricans , but our analysis indicates differences between them. A significant feature was the number of rhinaria, both secondary ( D. nigricans with more than 11, D. tissoti never with more than 11) and accessory ( D. nigricans always with 4, D. tissoti with 5–11). Species belonging to the “ parva ” group ( D. idahoensis , D. parva , D. robinsoni sp. nov., D. saccharini ) differ by pale fore femora. Drepanaphis parva and D. robinsoni sp. nov. have wing veins with slightly dusky areas. Apart from the similarity in the smudge on the wings, they differ in the presence of sclerotisation on the abdomen or the different shapes of the dorsal abdominal tubercles . Representatives with two frontal setae in adults belong to the “ utahensis ” group ( D. granovskyi , D. simpsoni , D. utahensis ). Drepanaphis granovskyi and D. utahensis are light-coloured species with relatively small tubercles, which in the case of D. simpsoni are larger, and this species is the only one with the first pair of tubercles, the largest concerning the remaining pairs.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057285_p24
|
39057285
|
sec[3]/sec[1]/p[0]
|
4.2. Morphometric Similarities in the Genus Drepanaphis
| 4.371094 |
biomedical
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0.00008660554885864258
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The phenomenon of morphological similarity in aphids is common and can be distinguished in many genera of hemipterans. An example is the genus Aphis L., where the species generally appear very similar due to convergence toward particular morphological types . To distinguish some of them ( A. glycines , A. gossypii , A. rhamnicola ), it is necessary to use DNA barcoding because morphological comparative studies are insufficient . While species in the Drepanaphis genus may initially appear different, primarily due to the varied arrangement of dorsal abdominal tubercles, and constitute a distinct group within the subfamily Drepanosiphinae , the morphometric features of most species overlap, making it impossible to establish clear differentiation ranges. The range of sizes of individuals in the genus is very wide, especially considering that the specimens analysed encompass forms from each season (from early spring to late autumn), which may vary substantially in body size. Additionally, the morphological plasticity of aphids can affect a wide spectrum of ranges of dimensions. The morphometric feature that often carries significant taxonomic information is the length of the appropriate segments of the antennae. In some species of the genus Drepanaphis , the length of the processus terminalis of the last antennal segment may serve as a distinguishing feature, visible in well-preserved specimens. However, in the case of most mounted specimens, the last segment is often broken or destroyed, which can lead to erroneous conclusions regarding interspecies differences based on this feature . Another qualitative feature is the number of rhinaria on antennal segment III, which should be relatively constant. In the case of some species, such as D. choanotricha , the number of rhinaria is small, which facilitates initial verification. However, the ranges of rhinaria numbers overlap for many species, rendering this feature less significant for identification purposes. The number of setae on the ultimate rostral segment is also a questionable diagnostic character.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057285_p25
|
39057285
|
sec[3]/sec[1]/p[1]
|
4.2. Morphometric Similarities in the Genus Drepanaphis
| 4.132813 |
biomedical
|
Study
|
[
0.98828125,
0.00042557716369628906,
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[
0.9931640625,
0.00293731689453125,
0.00374603271484375,
0.00010442733764648438
] |
Although SEM can provide excellent imaging of detailed morphological features in aphids , this method does not enable accurate counting of this character . Therefore, we included ranges of numerical intervals in the key rather than specific values in this case. Although quantitative features such as the number of accessory rhinaria on the base of antennal segment VI may differentiate species like D. choanotricha , D. sabrinae and D. tissoti , most morphometric features overlap. When verifying individuals in this genus, attention should primarily be given to qualitative features, which can aid in identifying living specimens. These features include dark-bordered wings in the case of D. acerifoliae and D. keshenae and the colour of the fore femora. When analysing individuals using light microscopy, the qualitative features that hold the greatest diagnostic importance are the shape and size of the dorsal abdominal tubercles. Although in some species, their shape and size may be distorted by the incorrect positioning of individuals on the mounted specimen , this feature remains valuable, especially in morphologically very similar species.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057285_p26
|
39057285
|
sec[3]/sec[2]/p[0]
|
4.3. Host Plant Ambiguity
| 4.285156 |
biomedical
|
Study
|
[
0.99560546875,
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0.0038890838623046875
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[
0.9990234375,
0.0002856254577636719,
0.00064849853515625,
0.00006395578384399414
] |
After analysing specimens from various entomological collections, it was found that Drepanaphis species are associated with a much broader range of host plant species than previously believed. This applies in particular to species that were classified as monophagous. Drepanaphis monelli is the only species in this genus that feeds on Aesculus glabra ; the remaining species feed on maples. Host plant associations were also used as a diagnostic feature in the key and differentiated the examined specimens. Among the analysed specimens of this species in the INHS collection, a series of specimens of Drepanaphis monelli were also found on A. saccharum and A. saccharinum . Following thorough analysis, the taxonomic identity of this species was confirmed, thereby rejecting the possibility of mislabelling the specimens. In this case, we suspect two phenomena: (I) accidental drift from a host plant to a neighbouring tree species or (II) a genuinely broader species range of the host plant. While we do not discount the possibility of drift, which is common in groups of small insects , it has been observed accidentally in other species within this genus, such as on ferns ( D. acerifoliae ) and mosses ( D. utahensis ). However, we are more inclined to claim that the number of host plant species is greater than expected, a conclusion supported by numerous other examples. Drepanaphis kanzensis , which mainly occurs on A. saccharum , may also appear on A. rubrum or A. saccharinum . It is noteworthy that the sexual generation of this species primarily occurs on A. saccharinum rather than A. saccharum , contrary to common assumption. The question arises of whether the sexual generation in this genus is so difficult to collect because of the omission of host plants. An interesting example is the new species D. robinsoni sp. nov., initially misidentified as both D. choanotricha , associated with A. saccharum , and D. parva , which primarily feeds on A. rubrum . In this case, we face difficulties in determining the primary host plant of the new species. Although designating a single host plant facilitates initial verification and provides a reliable source of information about the species , the analysis of a representative number of specimens from the genus Drepanaphis reveals that they are more narrowly oligophagous than monophagous. This fact should be considered when using the identification key.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057285_p27
|
39057285
|
sec[3]/sec[3]/p[0]
|
4.4. Distribution
| 3.566406 |
biomedical
|
Study
|
[
0.80810546875,
0.0007948875427246094,
0.1912841796875
] |
[
0.99365234375,
0.005615234375,
0.0006732940673828125,
0.0001373291015625
] |
Among all identified Drepanaphis species, D. granovskyi , D. idahoensis and D. utahensis stand out most prominently due to their distribution. They are the only ones associated exclusively with the western part of North America, and they all feed on Acer grandidentatum . However, morphological analysis indicates that D. idahoensis is less similar to other species. A similar distinction can be observed with D. knowltoni , which also inhabits the same geographical area and feeds on A. grandidentatum but exhibits distinct morphological characteristics. The case of D. spicata is also noteworthy. Representatives of this species occur in the northernmost part of the continent among all those analysed (with only D. acerifoliae also recorded above latitude 49°). Similar to D. knowltoni , D. spicata shows range fragmentation, although further field confirmation of these findings is necessary.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057285_p28
|
39057285
|
sec[3]/sec[3]/p[1]
|
4.4. Distribution
| 1.480469 |
other
|
Other
|
[
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0.001506805419921875,
0.64208984375
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[
0.0880126953125,
0.908203125,
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0.0010805130004882812
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The ranges of the other species overlap, corresponding to the natural ranges of their host plants. There are strong indications that the original habitat of the first representatives of this genus was the eastern part of North America, and their evolution is closely linked to the spread of trees within the Acer genus .
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057285_p29
|
39057285
|
sec[4]/p[0]
|
5. Conclusions
| 2.740234 |
biomedical
|
Study
|
[
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0.13623046875
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[
0.923828125,
0.0706787109375,
0.0049285888671875,
0.0006608963012695312
] |
The study of the genus Drepanaphis highlights its taxonomic complexity and the diverse host plant associations among its species. Morphological analyses reveal distinctiveness even among closely related species, underscoring the importance of comprehensive revision and accurate species identification tools. The geographical distribution patterns suggest evolutionary ties to the Acer genus, particularly in eastern North America.
|
[
"Kamila Malik",
"Agnieszka Bugaj-Nawrocka",
"Karina Wieczorek"
] |
https://doi.org/10.3390/insects15070553
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277452_p0
|
PMC11277452
|
sec[0]/p[0]
|
1. Introduction
| 4.1875 |
biomedical
|
Review
|
[
0.9697265625,
0.0224456787109375,
0.00801849365234375
] |
[
0.0041656494140625,
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Heart failure (HF) represents a complex and multifaceted clinical syndrome with a substantial global health burden worldwide . An estimated 64.3 million people are currently dealing with heart failure . In Western countries, the prevalence of this condition is around 1% and 2% but is estimated to continuously increase in the next few decades, especially because of an increasing and aging population. Coronary artery disease (CAD) is still the leading cause underlying HF in Western countries . However, while more attention has traditionally been devoted to epicardial CAD, emerging research underscores the pivotal role of coronary microvascular dysfunction (CMD) in the pathogenesis and evolution of this clinical syndrome, especially heart failure with preserved ejection fraction (HFpEF) . CMD refers to a spectrum of changes in the structure and function of coronary microcirculation, causing reduced coronary blood flow (CBF) and ultimately resulting in myocardial ischemia, fibrosis and remodeling . Despite the emerging pathophysiological and prognostic role of CMD, there is no specific treatment to date addressing this condition. Moreover, the invasive and non-invasive diagnosis of CMD is still challenging. This narrative review aims to explore the molecular mechanisms underlying CMD, and its distinct manifestations across the spectrum of HF pathology, discussing novel therapeutic targets and remaining knowledge gaps in the field.
|
[
"Giulia La Vecchia",
"Isabella Fumarulo",
"Andrea Caffè",
"Mario Chiatto",
"Rocco A. Montone",
"Nadia Aspromonte"
] |
https://doi.org/10.3390/ijms25147628
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277452_p1
|
PMC11277452
|
sec[1]/p[0]
|
2. Pathophysiology of CMD
| 5.085938 |
biomedical
|
Study
|
[
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[
0.93359375,
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The coronary tree is composed of different interacting compartments with decreasing size and distinct capacitance and resistance functions. The proximal territory is composed of the epicardial coronary vessels, which offer a predominant capacitance function and little resistance to CBF . Going more distally, the intermediate compartment includes the pre-arteriolar vessels (500 to 100 µm diameter), which are more sensitive to pressure and flow changes, displaying significant resistance to blood flow. Arterioles are the main contributors to the metabolic regulation of CBF by being more responsive to changes in the intramyocardial concentration of metabolites with direct vasoactive properties on the coronary endothelium . Coronary microvascular dysfunction encompasses a combination of different structural and functional abnormalities at the microcirculatory level, involving pre-arterioles, arterioles, and capillaries . Functional mechanisms may be due to impaired dilation and/or an increased constriction of coronary microcirculation (microvascular spasm) . Reduced vasodilation can be due to mechanisms that are either dependent on or independent of the endothelium . Endothelial-dependent mechanisms include the reduced production and/or enhanced degradation of endothelial-derived relaxation molecules, such as prostaglandins, nitric oxide (NO) and endothelium-derived hyperpolarizing factor(s) (EDHFs), as well as the enhanced release of vasoconstrictor mediators, such as endothelin-1 (ET-1) . In this regard, chronic inflammation and free radical overproduction are considered key pathogenetic mechanisms driving the reduced bioavailability of coronary vasodilators. Preclinical studies showed that an increased concentration of intracellular reactive oxygen species (ROS) promotes the transformation of NO into free radicals by switching the NO synthetase from a NO to a ROS-producing enzyme, thus resulting in reduced vasodilation mediated by nitric oxide (NO) and the increased vasoconstriction activity of ET-1 through the activation of the RhoA/Rho-kinase pathway . Endothelial-independent mechanisms are still not well known, but impaired vasodilator properties and enhanced susceptibility to normal vasoconstrictor stimuli of the vascular smooth muscle cells (VSMCs) at the microcirculatory level, as well as abnormal autonomic activity, are thought to be involved in this condition . Beyond functional alterations, CMD may be due to structural abnormalities of the coronary microcirculation. Hence, vascular “remodeling” at the microcirculatory levels with hypertrophic inward remodeling (mainly due to smooth muscle hypertrophy and increased collagen deposition) and luminal narrowing of the arterioles and capillaries lead to pathological changes such as perivascular fibrosis, microvascular rarefaction, and myocardial stiffness that contribute to altered coronary physiology and reduced CBF . These phenomena are extensively documented in clinical conditions characterized by an increased myocardial mass, such as in hypertensive heart disease and hypertrophic cardiomyopathy, where these pathological abnormalities extend beyond the vascular level toward the left ventricle, contributing to chronic myocardial ischemia, interstitial fibrosis, and progression to HF and increasing the risk of adverse cardiovascular outcomes .
|
[
"Giulia La Vecchia",
"Isabella Fumarulo",
"Andrea Caffè",
"Mario Chiatto",
"Rocco A. Montone",
"Nadia Aspromonte"
] |
https://doi.org/10.3390/ijms25147628
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277452_p2
|
PMC11277452
|
sec[2]/p[0]
|
3. CMD across the Spectrum of Heart Failure Pathology
| 3.984375 |
biomedical
|
Review
|
[
0.99462890625,
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0.0015010833740234375
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[
0.01094818115234375,
0.0279693603515625,
0.9599609375,
0.00135040283203125
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HF is a clinical syndrome characterized by symptoms and signs arising from impaired cardiac function. The cardiac dysfunction may be due to either structural or functional abnormalities leading to elevated pressures within the heart chambers and/or insufficient blood output at rest or during exertion, which are responsible for the clinical symptoms and raised biomarkers of cardiac dysfunction . The underlying causes of HF can vary. In developed countries, CAD and hypertension are the most frequent, followed by valvular heart disease, arrhythmias, cardiomyopathies, systemic disease (i.e., neuromuscular, autoimmune, endocrine), and therapy-related issues (i.e., chemotherapy, radiotherapy) .
|
[
"Giulia La Vecchia",
"Isabella Fumarulo",
"Andrea Caffè",
"Mario Chiatto",
"Rocco A. Montone",
"Nadia Aspromonte"
] |
https://doi.org/10.3390/ijms25147628
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277452_p3
|
PMC11277452
|
sec[2]/p[1]
|
3. CMD across the Spectrum of Heart Failure Pathology
| 3.958984 |
biomedical
|
Study
|
[
0.99951171875,
0.00036263465881347656,
0.00016057491302490234
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[
0.7705078125,
0.01763916015625,
0.210693359375,
0.0009236335754394531
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CMD may be present across the entire spectrum of HF, from HF with reduced ejection fraction (HFrEF) defined by a left ventricular ejection fraction (LVEF) < 40%, to HF with mildly reduced ejection fraction (HFmrEF) with an LVEF between 40% and 50%, to HF with preserved ejection fraction (HFpEF) with an LVEF > 50% ( Table 1 ).
|
[
"Giulia La Vecchia",
"Isabella Fumarulo",
"Andrea Caffè",
"Mario Chiatto",
"Rocco A. Montone",
"Nadia Aspromonte"
] |
https://doi.org/10.3390/ijms25147628
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.857143 |
PMC11277452_p4
|
PMC11277452
|
sec[2]/p[2]
|
3. CMD across the Spectrum of Heart Failure Pathology
| 4.496094 |
biomedical
|
Review
|
[
0.99609375,
0.0023059844970703125,
0.00160980224609375
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[
0.0650634765625,
0.0014896392822265625,
0.9326171875,
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] |
Nevertheless, the pathophysiological role of CMD seems to be essential, especially in the latter group of patients, those affected by HFpEF, who account for half of all heart failure presentations . HFpEF usually affects patients who are typically older and more often female compared to those with HFrEF and HFmrEF. Also, they usually suffer from several comorbidities, both cardiovascular, such as atrial fibrillation (AF), hypertension, and stroke, and non-cardiovascular, such as diabetes mellitus (DM), obesity, and chronic kidney disease (CDK) . Diastolic dysfunction is the key clinical feature of HFpEF, a multifaced process due to chronic inflammation, cardiometabolic dysfunction, and extracellular fibrosis . More recently, HFpEF has been redefined as a systemic disease that affects more than just the heart. It is now recognized to involve multiple organs, with systemic inflammation, extracellular fibrosis, and microvascular dysfunction . In this regard, comorbidities such as hypertension, diabetes mellitus, obesity, and kidney disease play a pivotal role in contributing to the pro-inflammatory milieu underlying HFpEF and are independent risk factors for this clinical condition . Over the past few years, a significant association between HFpEF and CMD has been found and CMD-HFpEF is turning out to be a prevalent endotype of HFpEF that seems to be associated with a poor cardiovascular prognosis .
|
[
"Giulia La Vecchia",
"Isabella Fumarulo",
"Andrea Caffè",
"Mario Chiatto",
"Rocco A. Montone",
"Nadia Aspromonte"
] |
https://doi.org/10.3390/ijms25147628
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277452_p5
|
PMC11277452
|
sec[2]/p[3]
|
3. CMD across the Spectrum of Heart Failure Pathology
| 4.570313 |
biomedical
|
Study
|
[
0.99853515625,
0.0008707046508789062,
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[
0.8447265625,
0.0011816024780273438,
0.1534423828125,
0.00064849853515625
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The PROMIS-HFpEF (prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction) study evaluated the prevalence and the prognostic significance of CMD, defined as a coronary flow reserve (CFR) < 2.5 measured non-invasively with adenosine stress transthoracic Doppler echocardiography, among 202 patients with a diagnosis of HFpEF . The authors proved that nearly 75% of all patients with HFpEF showed evidence of CMD in the absence of significant epicardial CAD . Moreover, worse CFR values were seen to be associated with risk markers of HF severity, such as higher N-terminal pro–B-type natriuretic peptide [NT-proBNP] levels and evidence of RV dysfunction (assessed by tricuspid annular plane systolic excursion (TAPSE) and right ventricular free wall strain) ( p < 0.05) . Recently, a meta-analysis by Lin at al., including results derived from 10 studies and involving 1267 patients, documented a prevalence of CMD around 71% in patients with HFpEF . Again, Yang et al. documented a similar prevalence of CMD among HFpEF patients, with nearly the same proportion of endothelium-dependent and -independent CMD . These results have been strengthened by the following studies evaluating the association between CMD and HFpEF by using either invasive assessment (e.g., coronary angiography) and non-invasive testing (e.g., cardiac magnetic resonance [CMR] with stress perfusion imaging and coronary vasodilator agents administration) . Paolisso et al. investigated the presence of CMD, assessed invasively by continuous intracoronary thermodilution, in 56 patients with de novo HF and nonobstructive CAD . According to the study results, 29 individuals (52% of the study population) were affected by CMD, with a similar prevalence across the spectrum of HFrEF and HFpEF pathology. However, different hemodynamic properties and phenotype characteristics were found in patients with HFrEF compared to those with HFpEF. Indeed, in the HFrEF group, CMD was described as a “functional” alteration, characterized by lower absolute microvascular resistance and higher absolute coronary flow values at rest. Conversely, in the HFpEF group, CMD was classified as a “structural” pathology, characterized by higher absolute microvascular resistance and lower absolute coronary flow during hyperemia . These findings may suggest that the correlation between CMD and HFpEF has to be sought in diastolic dysfunction and its interdependence with capillary rarefaction, which is actually “structural” CMD. Strengthening this hypothesis, an autopsy study conducted by Mohammed et al. reported the presence of a significant capillary rarefaction in patients affected by HFpEF, which also correlated with the presence and extension of myocardial fibrosis . The patients with HFpEF also had more cardiac hypertrophy and epicardial CAD compared to the controls, which may contribute to the left ventricular diastolic dysfunction typical of HFpEF . Capillary rarefaction has also been documented using non-invasive techniques. Arnold et al. reported lower myocardial perfusion reserve (MPR) values assessed by CMR in HFpEF patients compared to healthy controls . On the other hand, the authors did not find a significant correlation between reduced MPR, suggestive of CMD and capillary rarefaction, and myocardial fibrosis.
|
[
"Giulia La Vecchia",
"Isabella Fumarulo",
"Andrea Caffè",
"Mario Chiatto",
"Rocco A. Montone",
"Nadia Aspromonte"
] |
https://doi.org/10.3390/ijms25147628
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277452_p6
|
PMC11277452
|
sec[2]/p[4]
|
3. CMD across the Spectrum of Heart Failure Pathology
| 4.003906 |
biomedical
|
Review
|
[
0.96533203125,
0.030364990234375,
0.00434112548828125
] |
[
0.005046844482421875,
0.05194091796875,
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0.002719879150390625
] |
Despite the clinically and epidemiologically significant association between CMD and HF, the European Society of Cardiology (ESC) guidelines do not recommend a routinary assessment of CMD in HF patients and only provide a class IIa recommendation for invasive testing (guidewire-based CFR and/or microcirculatory resistance measurements) and a class IIb recommendation for non-invasive testing (transthoracic Doppler of the left anterior descending (LAD), CMR, and positron emission tomography (PET)) in the context of chronic coronary syndromes (CCSs) . However, invasive testing of CMD is increasingly adopted in clinical practice, and its use is expected to become widespread in catheterization laboratories over the next few years.
|
[
"Giulia La Vecchia",
"Isabella Fumarulo",
"Andrea Caffè",
"Mario Chiatto",
"Rocco A. Montone",
"Nadia Aspromonte"
] |
https://doi.org/10.3390/ijms25147628
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277452_p7
|
PMC11277452
|
sec[3]/p[0]
|
4. Chronic Inflammation, Endothelial Dysfunction and HF
| 4.917969 |
biomedical
|
Study
|
[
0.99755859375,
0.0015649795532226562,
0.0010328292846679688
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[
0.93359375,
0.00162506103515625,
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As mentioned, chronic low-grade inflammation significantly contributes to the development of CMD . Concordantly, endothelium-dependent CMD, assessed by a blunted microvascular response to acetylcholine (ACh), has been associated with increased inflammatory markers such as high-sensitivity C reactive protein (hs-CRP) and soluble urokinase-type plasminogen activator receptor (suPAR) . Inflammatory conditions, particularly in the presence of cardiovascular risk factors, are responsible for increased superoxide production by NAD(P)H oxidase (Nox), and consequent endothelial dysfunction though oxidative stress . In detail, Nox activity is enhanced by inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and is able to induce p66 Shc, a pro-apoptotic mitochondrial adapter which, in turn, favors ROS production and further upregulates Nox in a vicious cycle . Endothelial dysfunction in the context of ROS vascular accumulation results from reduced NO bioavailability due to its conversion to peroxynitrite radicals and endothelial NO synthetase (eNOS) uncoupling . Other endothelium-derived relaxing factors are involved in coronary microvascular tone regulation, such as H 2 O 2 , which derives from superoxide released by endothelial cells in response to shear stress . Superoxide synthesis and its subsequent rapid dismutation to H 2 O 2 represent a physiological pathway for arteriolar flow-induced vasodilation, as long as the Nox system is not hyperactivated, a condition in which excessive ROS production may precipitate oxidative stress and endothelial dysfunction . Nox enzyme isoform upregulation can result from metabolic disturbances and/or impaired hemodynamic homeostasis, which are associated with traditional cardiovascular risk factors . Furthermore, p66 Shc expression is positively modulated at the epigenetic level in diabetic patients, favoring persistent inflammation and unremitting endothelial dysfunction (the “hyperglycemic memory” phenomenon) . Aside from classical cardiovascular risk factors, microvascular and epicardial endothelial dysfunction may also arise from long-term air pollutant exposure, specifically, particulate matter (PM), which has been proven to enhance the pro-inflammatory response leading to systemic oxidative stress . In this regard, Montone et al. provided evidence that higher exposure to air pollutants, such as 2.5 (PM2.5) and PM10, can drive a higher risk of developing coronary events, including coronary vasomotor disorders in the absence of obstructive CAD, by enhancing systemic and local inflammatory processes .
|
[
"Giulia La Vecchia",
"Isabella Fumarulo",
"Andrea Caffè",
"Mario Chiatto",
"Rocco A. Montone",
"Nadia Aspromonte"
] |
https://doi.org/10.3390/ijms25147628
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
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