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PMC11277217_p30
|
PMC11277217
|
sec[3]/sec[8]/p[0]
|
4.9. Reporter Assay
| 4.109375 |
biomedical
|
Study
|
[
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[
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Primary epiphyseal chondrocytes isolated from RARγ null or hetero mice were subjected to reverse transfection with the reporter constructs on the Cignal Finder 45-Pathway Reporter Array plate (Qiagen) at a density of 3.0 × 10 4 cells/cm 2 following the manufacturer’s protocol, except for the use of Lipofectamine 3000 (Thermo Fisher Scientific) instead of Attractene. The next day, the cells were treated with 100 nM NRX204647 for 24 h. Luciferase assay was performed using the Dual-Glo Luciferase Assay System (Promega, Madison, WI, USA).
|
[
"Sonia A. Garcia",
"Kimberly Wilson",
"Ningfeng Tang",
"Hongying Tian",
"Takeshi Oichi",
"Aruni T. Gunawardena",
"Michael Chorny",
"Ivan S. Alferiev",
"John E. Herzenberg",
"Vincent Y. Ng",
"Masahiro Iwamoto",
"Motomi Enomoto-Iwamoto"
] |
https://doi.org/10.3390/ijms25147610
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277217_p31
|
PMC11277217
|
sec[3]/sec[9]/p[0]
|
4.10. Statistics
| 2.873047 |
biomedical
|
Study
|
[
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[
0.9716796875,
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0.00034165382385253906
] |
The results were analyzed using Prism 10 version 10.0.1 (GraphPad Software, Boston, MA, USA). To compare two groups, Mann–Whitney U test was used. To compare multiple groups, Kruskal–Wallis test was used. The threshold for significance for all tests was set at p < 0.05. The relevant descriptive statistics were shown in Supplementary Tables S1–S4 .
|
[
"Sonia A. Garcia",
"Kimberly Wilson",
"Ningfeng Tang",
"Hongying Tian",
"Takeshi Oichi",
"Aruni T. Gunawardena",
"Michael Chorny",
"Ivan S. Alferiev",
"John E. Herzenberg",
"Vincent Y. Ng",
"Masahiro Iwamoto",
"Motomi Enomoto-Iwamoto"
] |
https://doi.org/10.3390/ijms25147610
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277229_p0
|
PMC11277229
|
sec[0]/p[0]
|
1. Introduction
| 3.734375 |
biomedical
|
Review
|
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Tobacco use is the most preventable cause of disability and death worldwide as more than eight million people die annually, and 80% of these deaths occur in low- and middle-income countries (LMICs) . In 2003, World Health Organization (WHO) Member States adopted the WHO Framework Convention on Tobacco Control (FCTC), a global health treaty that places obligations on parties to reduce the supply and demand of tobacco . Since coming into effect in 2005, the WHO FCTC has helped accelerate the adoption of evidence-based best practices aimed at reducing tobacco use, nicotine addiction, and exposure to secondhand tobacco smoke including establishing smoke-free public places and workplaces (Article 8), banning tobacco advertising, promotion, and sponsorship (TAPS) (Article 13), and requiring pictorial health warning labels (HWLs) (Article 11) .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277229_p1
|
PMC11277229
|
sec[0]/p[1]
|
1. Introduction
| 1.736328 |
other
|
Other
|
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[
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The adoption of WHO FCTC-based policies has significantly progressed in the Latin America and Caribbean (LAC) region. As of May 2024, all 33 LAC countries, except 4 (Argentina, Cuba, Dominican Republic, and Haiti), have ratified the FCTC . Twenty-two countries require pictorial HWLs printed on cigarette packages , nine have adopted comprehensive TAPS bans , and twenty-six countries, including the entire sub-region of South America, has adopted 100% smoke-free indoor public places .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277229_p2
|
PMC11277229
|
sec[0]/p[2]
|
1. Introduction
| 3.974609 |
biomedical
|
Study
|
[
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] |
[
0.9990234375,
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Despite this success, the focus of the literature analyzing the adoption of WHO FCTC policies has primarily focused on high-income countries (HICs) in analyzing facilitators and barriers to policy adoption . While recently published studies have begun to assess policy adoption and implementation of WHO FCTC-based best practices in LMICs, significant knowledge gaps remain . In particular, there is a lack of analyzing LMIC case studies to understand how tobacco control initiatives reach policy agendas and are ultimately passed into law. This is especially the case in Mexico, which is the second most populous LAC country, home to over 130 million people. In 2008, the Mexican government adopted a weak federal tobacco control law, the General Law for Tobacco Control (LGCT, la Ley General para el Control del Tabaco) that, among other measures, required designated smoking areas in public places . Following a decade of numerous failed attempts to either pass a new FCTC-based law or amend the LGCT, on 17 February 2022, an amendment to the LGCT was officially published, which established 100% smoke-free public places including outdoor spaces and for electronic cigarettes and heated tobacco products, and completely prohibited TAPS ( Table 1 ). Given the repeated failures to amend the LGCT, this represents the first known study that attempts to understand the process of adoption of a WHO FCTC-based national tobacco control law in Mexico. In doing so, this study hopes to provide lessons for other LMICs, especially in LAC, working to adopt policies aligned with the WHO FCTC and its implementation guidelines.
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277229_p3
|
PMC11277229
|
sec[1]/sec[0]/sec[0]/p[0]
|
Interviews with Key Informants
| 2.529297 |
biomedical
|
Study
|
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Between December 2023 and March 2024, we invited via email 24 key stakeholders that had been involved in tobacco control in Mexico between 2008 and 2020, to participate in an in-depth interview. Interviewees were identified through media searches, the authors’ networks, and snowball sampling. Fourteen agreed to be interviewed, six denied our requests, and four never responded after five requests. The interviewees included public health advocates (n = 5), academic researchers (n = 2), Mexican policymakers and government officials (n = 5), and inter-governmental organization officials (n = 2). The interviewees were emailed semi-structured interview questions and agreed through verbal consent to participate in the study in accordance with a protocol approved by the University of Nevada, Reno Committee on Human Research ( Appendix A ). Interviews were conducted and recorded via Zoom and lasted approximately 45–60 min. Interviewees also provided 14 public documents (e.g., draft legislation, health advocacy reports, press conferences) to provide further documentation and context for this study.
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277229_p4
|
PMC11277229
|
sec[2]/p[0]
|
3. Data Analysis
| 1.104492 |
other
|
Other
|
[
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[
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Given that Mexico had failed to amend the LGCT for more than a decade, we adopted Kingdon’s Multiple Streams Framework (MSF) to understand how the policy eventually made its way onto the policy agenda setting stage and was ultimately passed . MSF is used to highlight why particular policy issues make the agenda of policymakers while others fail. The MSF hypothesizes that a policy problem is more likely to gain attention from policymakers when it is “coupled” with a policy solution under a supportive political environment . In particular, the MSF examines three semi-independent “streams” that travel through the policy process: the problem stream, policy stream, and politics stream . The problem stream relates to how policymakers, the media, and the public define or frame a problem as this can constrain the types of policy solutions that policymakers consider. This can occur when accumulating factors lead to increased attention to a policy problem, when there is a focusing event (e.g., disaster), or if there appears to be a feasible or effective solution in a given political context. The policy stream focuses on the generation of policy solutions that have risen or are expected to rise on the political agenda. Policy entrepreneurs, or individuals willing “to invest their resources-time, energy, reputation, and sometimes money”, advocate for specific policy solutions and often work to build coalitions that increase support for their desired policy solutions . Finally, the politics stream focuses on the broader socio-political environment where problems and solutions are defined and connected. This can include factors such as public mood, advocacy campaigns, and election results, where policy entrepreneurs can judiciously navigate the political landscape to connect their desired policies with significant problems .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277229_p5
|
PMC11277229
|
sec[2]/p[1]
|
3. Data Analysis
| 1.267578 |
other
|
Study
|
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[
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0.002414703369140625,
0.001476287841796875
] |
Given these three streams, the MSF hypothesis suggests that an “issue’s chances of gaining agenda status dramatically increase when all three streams—problems, policies, and politics—are coupled in a single package” . In other words, the opening of a policy window determines the likelihood that an issue will become a policy agenda item. This mostly occurs when a policy window opens in the problem or politics stream that emphasizes the need for policy action . While policy windows are particularly opportune moments for agenda setting, they are not always pathways for policy change. Instead, a “problem must be coupled with a solution in a way that is attractive and coherent to receptive policymakers and, potentially, the public while the window is open” . Then, policymakers must enter into the policymaking process to formulate, negotiate, and adopt a specific policy . This study analyzes the data through the MSF to understand how initiatives to reform LGCT made their way onto the political agenda and ultimately passed.
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277229_p6
|
PMC11277229
|
sec[3]/sec[0]/p[0]
|
4.1. Previous Efforts Failing to Reform the LGCT
| 1.717773 |
other
|
Study
|
[
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[
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] |
Between 2008 and 2020, over 100 initiatives were introduced to either amend the LGCT or introduce a new tobacco control law. All participants that were interviewed for this study claimed that these failures stemmed from (1) a lack of political will, (2) tobacco industry political influence with policymakers, and (3) a lack of health advocacy coordination ( Table 2 ).
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277229_p7
|
PMC11277229
|
sec[3]/sec[1]/p[0]
|
4.2. Lack of Political Will
| 1.175781 |
other
|
Other
|
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[
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] |
Since the LGCT was passed in 2008, the Mexican government was led by President Felipe Calderón of the conservative right-wing National Action Party (PAN, Partido Acción Nacional) and Enrique Peña Nieto of the center-right Institutional Revolutionary Party (PRI, Partido Revolucionario Institucional). Between 2008 and 2018, these political parties also made up the majority in both chambers of the National Congress. Several interviewees claimed that both the PAN and PRI favored economic interests over health , and some mentioned that even representatives from the Health Minister at times did not want to move any tobacco control initiatives forward . One health advocate stated that anything that had to do with health hardly came out of the health committee . When there was support from a PAN member of the health committee to amend the LGCT, the Health Minister from the PRI did not support it . Furthermore, there was no political champion to lead tobacco control efforts during this time period .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277229_p8
|
PMC11277229
|
sec[3]/sec[2]/p[0]
|
4.3. Tobacco Industry Political Influence
| 1.222656 |
other
|
Other
|
[
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[
0.00237274169921875,
0.99609375,
0.00089263916015625,
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] |
Although several policymakers lacked political will to amend the LGCT, the tobacco industry in Mexico played a significant role in influencing these policymakers . Tobacco companies, including Philip Morris International and British American Tobacco, have been powerful in Mexico , establishing close relations with policymakers, mostly PAN and PRI policymakers in high profile positions . A couple of health advocates claimed that any progress would be stalled once it reached high levels such as the Health Minister , who at times has been caught negotiating and receiving funding and gifts from the industry . Others advocate that the industry was opportune to consistently influence committee presidents to block any tobacco control initiatives from being discussed so they would not reach the plenary for further discussion . When discussion occurred, the industry strategically visited legislators and their legislative advisors to review technical issues to influence them to voice or vote against any proposals so they would not progress out of committee .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277229_p9
|
PMC11277229
|
sec[3]/sec[3]/p[0]
|
4.4. Lack of Health Advocacy Coordination
| 1.296875 |
other
|
Other
|
[
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0.97509765625
] |
[
0.0098876953125,
0.98779296875,
0.0019102096557617188,
0.0005803108215332031
] |
While local tobacco control groups worked together with international health organizations, several interviewees mentioned that efforts were not as consolidated and coordinated during the late 2000s and 2010s . Some health advocates mentioned that previous efforts were ‘isolated’ and did not go anywhere . Other advocates claimed they did not have the physical infrastructure and human resources to carry out particular operations . Furthermore, others claimed that the coordination was more informal, leading to a lack of consensus and urgency in advocating for certain legislative bills .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277229_p10
|
PMC11277229
|
sec[4]/p[0]
|
5. Problem Stream
| 1.110352 |
other
|
Other
|
[
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0.99267578125
] |
[
0.0172576904296875,
0.9794921875,
0.00255584716796875,
0.0008440017700195312
] |
This section of the policymaking process examines how defining and framing the problem evolved over time led to increased attention to a policy problem that policymakers would consider policy solutions ( Table 2 ).
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277229_p11
|
PMC11277229
|
sec[4]/sec[0]/p[0]
|
5.1. Indicators/Statistics
| 3.908203 |
biomedical
|
Study
|
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[
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0.00031280517578125
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In defining the severity of the problem of tobacco use in Mexico, health advocates and government officials relied on local and international indicators and statistics. Several interviewees claimed that a lot of support came from annual nationwide surveys on smoking prevalence conducted by the National Institute of Public Health (INSP, Instituto Nacional de Salud Pública). Additionally, the INSP participated in a study with the University of Washington International Health Metric Evaluation program in assessing tobacco control policies in 32 Mexican states and its implications on tobacco consumption and health effects, which helped inform policy debates . This was complemented by the Global Adult Tobacco Survey (GATS), which was conducted three times in Mexico . This provided national representative data to measure the magnitude of smoking, which helped illustrate the lack of progress in areas such as youth smoking . Additionally, the GATS surveys provided significant policy feedback using the WHO MPOWER, a package of six evidence-based demand reduction measures contained in the WHO FCTC, which allowed the advocates to fully monitor the population . These surveys helped define the problem with “great precision” to identify policies that needed to be adopted . Over time, these surveys also highlighted tobacco use consumption state by state , and how public support was growing for tobacco control policies such as smoke-free environments and TAPS restrictions .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277229_p12
|
PMC11277229
|
sec[4]/sec[1]/p[0]
|
5.2. Feedback from Other Policies
| 2.027344 |
other
|
Other
|
[
0.44970703125,
0.0036163330078125,
0.546875
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[
0.06939697265625,
0.916015625,
0.01393890380859375,
0.0006442070007324219
] |
In addition to collecting important data and evidence in Mexico, important feedback was given about progress and success occurring in Latin America. Several interviewees claimed that, over time, countries such as Brazil, Uruguay, and Panama adopted WHO FCTC-based policies and experienced great success, decreasing smoking prevalence levels, altering social norms regarding smoking, lowering youth smoking initiation rates, and reducing the burden of death due to tobacco use . Health advocates and government officials in Mexico also attended regional tobacco control conferences in Mexico and abroad to learn about best practices . These conferences were important networking opportunities that enabled leaders from other countries to visit Mexico to further educate policymakers in Mexico about the progress and success in their own country . Over time, this helped build capacity in Mexico but also created increased urgency as Mexico began to lag behind other countries in adopting WHO FCTC-based policies . For example, by 2021 , all of South America had established 100% smoke-free environments, whereas Mexico was still lagging behind .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277229_p13
|
PMC11277229
|
sec[4]/sec[2]/p[0]
|
5.3. Framing the Issue
| 2.373047 |
other
|
Other
|
[
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[
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Given the success in collecting and generating evidence along with important regional feedback, health advocates began to frame the issue more with urgency, targeting industry, youth protection, and adoption of WHO FCTC-based policies. A few health advocates mentioned that for years without data and these successes from other countries, framing tobacco control issues focused more on the smokers and the habit of smoking . As a result, the focus tended to concentrate heavily on treatment and assisting smokers to quit smoking , yet these efforts were still underfunded and limited at the time. Over time, the framing changed to concentrate more on prevention and risk factors associated with non-communicable diseases. In particular, advocates would connect risk factors with policy interventions and use collected data to illustrate how many lives could be saved if the government adopted smoke-free policies and TAPS bans . These approaches also zeroed in on protecting youth who were more susceptible to industry targeted marketing . This framing connected with a renewed focus on industry, highlighting industry political and marketing practices . Given past struggles with the Ministry of Economy and lessons learned elsewhere, advocates also increasingly framed these issues as economic issues (life and medical care costs) , development issues (meeting United Nations Sustainable Development Goals) , and legal issues (Mexico’s constitution Article 4 establishes the right to the protection of health) . This evidence, lessons from other countries, and framing helped generate momentum to amend the LGCT.
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277229_p14
|
PMC11277229
|
sec[5]/p[0]
|
6. Policy Stream
| 1.053711 |
other
|
Other
|
[
0.0017881393432617188,
0.0007719993591308594,
0.99755859375
] |
[
0.003215789794921875,
0.99365234375,
0.0021762847900390625,
0.0009684562683105469
] |
This section of the policymaking process analyzes the various policy solutions that have risen to the political agenda and how policy entrepreneurs have worked to build coalitions to increase support for amending the LGCT.
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277229_p15
|
PMC11277229
|
sec[5]/sec[0]/p[0]
|
6.1. Policy Entrepreneurs
| 1.749023 |
other
|
Other
|
[
0.08905029296875,
0.00244903564453125,
0.90869140625
] |
[
0.007312774658203125,
0.9814453125,
0.01058197021484375,
0.0004634857177734375
] |
Throughout the late 2000s and 2010s, tobacco control coalitions and coordination continued to grow and expand both within the country and regionally. According to some health advocates, the earlier generation of leaders were overcommitted and at times were forced to work in isolation as more emphasis was placed on individual experts to help . However, this capacity changed when there was more investment in training and projects that came from inter-governmental organizations such as the Pan American Health Organization (PAHO) and international public health organizations such as the Campaign for Tobacco-Free Kids (CTFK) and the International Union Against Tuberculosis and Cancer (the Union) . This support helped place more emphasis on the group as a transnational tobacco control network and fueled stronger coalition building and coordination among local and national public health groups in Mexico and regionally, producing high levels of cooperation and collaboration . This collaboration and coordination continued with the media as, according to one advocate, it “extended to journalists who trusted us and looked for us” . Another health advocate discussed becoming more aggressive in approach, stating that previously, they would not call out political parties, worrying about the consequences, but then experienced greater freedom in pressuring policymakers . Finally, one health advocate stated that even during down times politically, when there was a lack of political will, it was “a period rich in research and collaboration” .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277229_p16
|
PMC11277229
|
sec[5]/sec[0]/p[1]
|
6.1. Policy Entrepreneurs
| 1.379883 |
other
|
Other
|
[
0.01032257080078125,
0.0008687973022460938,
0.98876953125
] |
[
0.00698089599609375,
0.99072265625,
0.0017309188842773438,
0.0005087852478027344
] |
Meanwhile, despite failed attempts to amend the LGCT at the national level, important advocacy and policy adoption occurred at the state and local levels throughout the 2010s. Following the Supreme Court’s decision regarding Mexico City’s 2008 smoke-free law to allow subnational governments the authority to adopt stronger policies than the LGCT, some of the largest and most populated states such as Mexico, Tabasco, Tamaulipas, and Oaxaca adopted 100% smoke-free laws . By 2020, 15 states had adopted 100% smoke-free laws, covering more than 60% of the entire population of Mexico . Several interviewees claimed that this progress at the subnational level helped continue to expand tobacco control coalitions and build momentum to amend the LGCT by using successful local evidence to lobby national policymakers . Others claimed that this positioned health advocates to be more active locally, helping build supportive public health narratives to expand the capacity of journalists in the local media to gain more earned media coverage . Furthermore, local health groups such as Salud Justa, CODICE, and Refleacciona helped map out local capabilities and achievements, which in turn helped generate more consensus and expand coalitions across the country, recruiting support from local universities, media companies, and political champions .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277229_p17
|
PMC11277229
|
sec[5]/sec[1]/p[0]
|
6.2. Approaching Policymakers
| 1.308594 |
other
|
Other
|
[
0.01194000244140625,
0.0009870529174804688,
0.9873046875
] |
[
0.004779815673828125,
0.99365234375,
0.0013093948364257812,
0.000400543212890625
] |
While there continued to be a lack of political will during the 2010s, tobacco control advocates relentlessly continued to attempt to convince policymakers to advance tobacco control. This was a time period of strategically identifying and cultivating relationships with key policymakers who may support or oppose tobacco control initiatives in the future . As one health advocate explained, “this was a time of sowing seeds and cultivating relationships with key actors in the legislature”, which is “politically profitable as media will seek them out” . Another interviewee mentioned the importance of political mapping and identifying loud opposing voices such as a legislator from Nayarit, a tobacco-growing state in Mexico, that strongly supported tobacco farming and opposed tobacco control initiatives . These efforts were also attempts to gain positioning around the problem and work within the priorities of different political agendas .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277229_p18
|
PMC11277229
|
sec[5]/sec[2]/p[0]
|
6.3. Policy Alternatives
| 1.477539 |
other
|
Other
|
[
0.02685546875,
0.0014867782592773438,
0.9716796875
] |
[
0.0266876220703125,
0.96533203125,
0.006984710693359375,
0.0008502006530761719
] |
Throughout the 2010s, health advocates also gained experience in learning which policy solutions were more feasible than others. Given the local success surrounding 100% smoke-free environments and to a lesser extent with TAPS restrictions, several interviewees claimed that this momentum over time had an effect of policymakers being more willing to accept these policy solutions . One government official noted that “smoke-free became more acceptable due to social norm change as you would now go to a restaurant and increasingly see smokers know to go outside and smoke” . Other interviewees claimed that surveys from the INSP and GATS also showcased how other countries were passing 100% smoke-free laws and TAPS restrictions and experiencing great success . Other policy solutions such as tobacco standardized packaging and tobacco flavor bans appeared to meet more resistance . In particular, some claimed that the industry aggressively argued against these proposals and brought a lot of economic and legal pressure, forcing policymakers and government officials to avoid further discussions for these proposals . Despite these setbacks, health advocates mentioned that by testing their arguments over many years, they had a better idea of which ones were more persuasive and which helped in terms of positioning tobacco control .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277229_p19
|
PMC11277229
|
sec[6]/p[0]
|
7. Politics Stream
| 1.086914 |
other
|
Other
|
[
0.00426483154296875,
0.0007867813110351562,
0.9951171875
] |
[
0.003223419189453125,
0.99462890625,
0.0017175674438476562,
0.0006465911865234375
] |
This section of the policymaking process examines how an election and administrative turnover combined with public health pressure campaigns helped lead to an opening of the political opportunity window to finally reform the LGCT despite continued industry opposition.
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277229_p20
|
PMC11277229
|
sec[6]/sec[0]/p[0]
|
7.1. Administrative or Legislative Turnover
| 1.182617 |
other
|
Other
|
[
0.005603790283203125,
0.0007691383361816406,
0.99365234375
] |
[
0.006801605224609375,
0.99169921875,
0.0009403228759765625,
0.0005817413330078125
] |
All interviewees claimed that the election of President Andrés Manuel López Obrador of the leftist political party the National Regeneration Movement (MORENA, Movimiento Regeneración Nacional) and a majority of MORENA elected officials in 2018 played a critical role in the amendment of the LGCT . This elective and administrative change was a key turning point that led to a fundamental shift in prioritizing public health . Several interviewees mentioned that political will change was noticeable immediately as there was a greater sense of responsibility . According to interviewees, President López Obrador’s leadership and commitment to advancing public health trickled down to all institutions involved in tobacco-related issues, and his political agenda was carried out by policymakers in congress . In particular, this change included the leadership of Dr. Hugo López-Gatell, Undersecretariat of Prevention and Health Promotion in the Health Ministry, and later, political champions Dr. Carmen Medel Palma, president of the Chamber of Deputies health committee, and Ernesto Pérez Astorga, member of the Senate Health Committee . One government official claimed that these political changes “made necessary negotiations possible in the legislature” and “helped achieve consensus politically” , while another noted that each of these leaders had “very close access to President López Obrador” .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277229_p21
|
PMC11277229
|
sec[6]/sec[1]/p[0]
|
7.2. Pressure Group Campaigns
| 1.788086 |
other
|
Other
|
[
0.05963134765625,
0.002925872802734375,
0.9375
] |
[
0.02386474609375,
0.97216796875,
0.0034961700439453125,
0.000583648681640625
] |
While the new government came in with a fresh approach and openness to address various public health and societal issues , health advocates still had to meet with policymakers and government officials to convince them of the importance of addressing tobacco use . Interviewees again discussed the value of informing new policymakers about tobacco control and identifying key allies where they could “plant seeds” for future assistance once tobacco control initiatives reached the political agenda . One government official claimed health advocates “developed close relationships right away with the new government” . In particular, health advocates identified and worked closely with Undersecretariat López-Gatell and Deputy Medel, who were immediately interested in the topic and eager to work with health groups and convince policymakers to put tobacco control on the political agenda . All interviewees claimed that the decades’ worth of evidence collected, successful regional experiences, and an increased focus on prevention were packaged in policy briefs and reports that were used to provide technical support to government officials . This initially consisted of health advocates providing technical and legal support to Undersecretariat López-Gatell and Deputy Medel, who would be in position to further lobby “within” the administration and congress about the importance of tobacco control . As a result, they organized several sessions with policymakers, especially health committee members, and government officials, especially from the Economic Ministry, aimed at convincing them that tobacco reforms would be good for the country . Using material prepared by health advocates and inter-governmental organizations such as PAHO, both repeatedly warned policymakers about tobacco industry interference, referenced international success stories and progress, and focused on prevention, especially among youth . They also cited strong public support for several tobacco control measures including 90% public support for 100% smoke-free environments in Mexico, which were well received by policymakers, especially those in the health committee .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277229_p22
|
PMC11277229
|
sec[6]/sec[1]/p[1]
|
7.2. Pressure Group Campaigns
| 1.624023 |
other
|
Other
|
[
0.051605224609375,
0.0022945404052734375,
0.9462890625
] |
[
0.026092529296875,
0.97021484375,
0.0032901763916015625,
0.000606536865234375
] |
Meanwhile, health advocates simultaneously operated outside these channels to directly inform policymakers with similar well-coordinated framing and messaging. This initially focused on briefing policymakers about WHO FCTC Article 5.3, which rejects tobacco industry partnerships and participating in tobacco control policymaking . A few interviewees mentioned that on separate occasions, there were members of the Health Ministry and policymakers within both chambers of congress that had planned to meet with industry officials or were invited to industry-sponsored events but rejected these invitations after they were briefed about WHO FCTC Article 5.3 . Health advocates also used regional reports and other evidence to stress the increasingly strong public support, a rise in youth consumption that was preventable, and that while Mexico was the first country in the region to ratify the WHO FCTC, it was falling behind other countries . One advocate stated “all of this helped to establish the urgency” of addressing tobacco use , while one government official explained, “civil society put pressure from the outside, while we lobbied on the inside but we were coordinated with the same messaging throughout the process” .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277229_p23
|
PMC11277229
|
sec[6]/sec[2]/p[0]
|
7.3. Industry Interference
| 1.18457 |
other
|
Other
|
[
0.00609588623046875,
0.0009527206420898438,
0.9931640625
] |
[
0.0024738311767578125,
0.99609375,
0.001110076904296875,
0.0005016326904296875
] |
The tobacco industry was also very active in attempting to meet with and lobby various policymakers and government officials to prevent any tobacco control legislation from surfacing. Policymakers and government officials stated that they had found out later that industry officials had attempted to meet with newly elected policymakers, offering them gifts, vacations, and financial support in return for rejecting any tobacco control initiative to be introduced and discussed . While these industry efforts ultimately failed, interviewees claimed that the industry was aggressive as always, and if not for a majority in MORENA policymakers in the health committee, tobacco control legislation may have not moved, thereby reiterating the importance of political and administrative change .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277229_p24
|
PMC11277229
|
sec[7]/p[0]
|
8. Decision Window: Introduction and Adoption of LGCT Reforms
| 1.128906 |
other
|
Other
|
[
0.0047454833984375,
0.0008482933044433594,
0.99462890625
] |
[
0.0019292831420898438,
0.99658203125,
0.0009322166442871094,
0.0004987716674804688
] |
As the three streams (problems, policies and politics) aligned, there emerged an opening of a policy window to finally couple everything together to put tobacco control initiatives on the political agenda and eventually amend the LGCT. This final section examines the policymaking process of tobacco control entering the political agenda in 2019 and ending with the amendment of the LGCT in 2022.
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277229_p25
|
PMC11277229
|
sec[7]/sec[0]/p[0]
|
8.1. Entering the Political Agenda
| 1.274414 |
other
|
Other
|
[
0.01313018798828125,
0.0009608268737792969,
0.98583984375
] |
[
0.0102996826171875,
0.98779296875,
0.0014677047729492188,
0.0005307197570800781
] |
According to interviewees in late 2019 and early 2020, tobacco control appeared to not only enter the political agenda but also receive significant support and attention as a priority from President López Obrador. Health advocates often engaged with President López Obrador’s advisory team through close relations with the Undersecretariat Dr. Lopez-Gatell . Several interviewees claimed that tobacco made its way onto the political agenda because they could reach the president through his morning press conferences . In particular, health advocates would work with journalists to ask direct questions to the president or president’s secretary, which “forced them to address the issue” and helped “position the topic of tobacco on the political agenda” . This motivated other journalists to ask questions, which sparked further coordination with journalists through built trust, leading to tobacco control being discussed in various media outlets and “reaching the highest level of the political agenda” . One advocate mentioned they tailored their messaging along with President López Obrador, stating, “if the president said there was ‘inequality’ then we focused on the inequality of smokers” .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277229_p26
|
PMC11277229
|
sec[7]/sec[1]/p[0]
|
8.2. Introduction of Initiatives
| 1.364258 |
other
|
Other
|
[
0.01727294921875,
0.0012969970703125,
0.9814453125
] |
[
0.00824737548828125,
0.990234375,
0.0010576248168945312,
0.0004968643188476562
] |
While tobacco control initiatives had been discussed in the past, the origin and initial draft of the eventually approved legislation to amend the LGCT was introduced in the Chamber of Deputies health committee on 3 March 2020 by Deputy Manuel Huerta ( Table 1 ). This initial draft included several provisions that aligned with the FCTC, including 100% smoke-free environments and a TAPS ban, among others. While this initial initiative was supported by health advocates, it did not gain traction in the health committee. Between September and November 2020, a series of tobacco control initiatives were introduced first by Deputy Medel and then by Deputy Frida Esparza, which again were supported by health advocates and attempted to align with the FCTC . While all these bills were discussed in the health committee, none of them were voted on and, as a result, they remained pending in committee and not a priority. A few interviewees stated that the health committee president at the time, Deputy Miroslava Sànchez Galván, was not as supportive and, similar to the past, was more like a gatekeeper despite increased political will and support from the MORENA party and López Obrador administration.
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277229_p27
|
PMC11277229
|
sec[7]/sec[1]/p[1]
|
8.2. Introduction of Initiatives
| 1.149414 |
other
|
Other
|
[
0.003231048583984375,
0.00119781494140625,
0.99560546875
] |
[
0.0029315948486328125,
0.99560546875,
0.0007963180541992188,
0.0007395744323730469
] |
Despite these political setbacks, on 10 February 2021, Deputy Medel was appointed Chamber health committee president. Several interviewees agreed this was another key turning point that further strengthened their position and provided another opportunity for the political window to open . As committee president, Deputy Medel wasted no time in holding public sessions, attempting to secure a vote in committee on some piece of legislation that amended the LGCT. Throughout the discussions of various initiatives, each of the provisions were carefully examined. Several interviewees claimed that given past experiences, there was a consensus to prioritize 100% smoke-free environments and a TAPS ban . Other provisions including tobacco standardized packaging and a tobacco flavor ban were supported but reached strong resistance among policymakers . Given previous political struggles, intensive negotiations, and a closing political window opportunity, policymakers with support of health advocates decided to drop these other provisions and prioritize 100% smoke-free environments and a TAPS ban . Some interviewees claimed the other provisions had “less support” , were “too risky” , and acknowledged that negotiations can be quite difficult and sometimes you have to “prioritize” and “sacrifice” other parts to ensure that the main components can advance forward . One government official stated, “sometimes you cannot win everything” , while another stated, “we needed this to advance otherwise we may have missed the political opportunity” . Following these changes, on 25 March 2021, the health committee unanimously voted to approve Deputy Medel’s LGCT amendment bill .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277229_p28
|
PMC11277229
|
sec[7]/sec[2]/p[0]
|
8.3. Pressure Group Campaigns
| 1.165039 |
other
|
Other
|
[
0.005664825439453125,
0.0010042190551757812,
0.9931640625
] |
[
0.0012845993041992188,
0.99755859375,
0.0006327629089355469,
0.00040459632873535156
] |
Throughout the legislative process, health advocates continued to relentlessly support the LGCT amendment through further coordination and key communication messaging, developing a paid media campaign, producing earned media through advocacy campaigns and participating in key political activities.
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
PMC11277229_p29
|
PMC11277229
|
sec[7]/sec[2]/sec[0]/p[0]
|
8.3.1. Continued Coordination and Key Communication Messaging
| 1.557617 |
other
|
Other
|
[
0.024566650390625,
0.0022144317626953125,
0.97314453125
] |
[
0.0048980712890625,
0.9931640625,
0.0013513565063476562,
0.0004146099090576172
] |
Health advocates developed a communication strategy with compelling and engaging messages that was supported by increased collaboration and coordination . Strong coordination consisted of planning and consensus building internally and then framing these issues with consistent arguments and messaging repeatedly across different platforms . In particular, when industry actors or opposing policymakers argued against or acted in opposition to the policy proposals, health advocates were quick and coordinated in their responses. This included supporting policymakers when they asked for advice and then communicating and coordinating which expert(s) were best positioned within the advocacy network to respond and then provide the correct political, economic, and legal advice necessary to address the opposition . One policymaker claimed to receive a lot of help from both local and international health groups and stated “without their help we would have not done anything” and “they always approached me wanting to fight this issue [tobacco] together” . Another policymaker stated, “the truth is, they never left me alone and that was great help” . These policymakers further went on to state that they appreciated how the transnational tobacco control network was very coordinated with many years of experience, would help to intervene at every possible moment, and offered recommendations and assistance quickly and concisely .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277229_p30
|
PMC11277229
|
sec[7]/sec[2]/sec[0]/p[1]
|
8.3.1. Continued Coordination and Key Communication Messaging
| 1.381836 |
other
|
Other
|
[
0.0274658203125,
0.001224517822265625,
0.97119140625
] |
[
0.024810791015625,
0.97265625,
0.0020580291748046875,
0.0006489753723144531
] |
Several interviewees also claimed that COVID-19 played a key role as a significant focusing event that contributed to the success of LGCT reforms . This initially began with health advocates internally collecting and reviewing data and connecting COVID-19 to smoking by demonstrating that smoking was a key risk factor in contracting COVID-19. Health advocates then worked closely with Undersecretary Lopez-Gatell to produce key messaging and frame the tobacco issue around COVID-19 to President López Obrador, who further supported this in morning press conferences . Other interviewees claimed this had a ripple effect as government announcements continued to highlight how COVID-19 was worse for those who smoke, which helped further position tobacco control support from more policymakers and journalists . One advocate stated this “helped institutionalize the issue as they wanted to engage with us more” . While some interviewees did not believe COVID-19 played a big role in helping amend the LGCT, they acknowledged that COVID-19 did allow them to have more direct access to policymakers through virtual zoom meetings . Other advocates claimed this access allowed them to be more informed about policymaker positions, more connected across virtual meetings, and more coordinated in their messaging .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277229_p31
|
PMC11277229
|
sec[7]/sec[2]/sec[1]/p[0]
|
8.3.2. Media Advocacy
| 1.400391 |
other
|
Other
|
[
0.01387786865234375,
0.0011224746704101562,
0.98486328125
] |
[
0.0109100341796875,
0.98681640625,
0.0014925003051757812,
0.0006103515625
] |
Health advocates participated in several paid and earned media campaigns to help support the LGCT reforms. This consisted of paid advertisement spots in various media platforms including newspapers, television, radio, billboards, and social media. For example, local advocacy group Reflecciona, with CTFK support and participation of the entire transnational tobacco control network through Mexico SaludHable, implemented an advertising campaign called “Es por todos” (It is for everyone), which consisted of three phases: (1) raising awareness to amend the LGCT , (2) promoting the reforms in congress , and (3) creating community support and triggering conversations on social networks . The campaign produced powerful images, rich infographics, and captivating messages focused on youth that were employed in various media platforms including newspapers, radio, television, billboards, subway stations, buses, and social media . Furthermore, some of these advertisements exposed industry interference and targeted policymakers to help support passage of the LGCT reforms. This included tagging policymakers on Twitter and posting social media graphics with their faces asking them what side they were on (public health or with industry), and distributing personalized boxes with pictures of their faces . Other efforts consisted of gaining earned media coverage, which included the morning president press conferences as already discussed and holding press conferences of their own at critical junctures of the legislative process. For example, on 27 January 2021, local health group Salud Justa with support from CTFK and PAHO organized a press conference titled “South America is already 100% smoke-free, what about Mexico?”, which created further urgency and helped propel the Medel bill to be finally introduced in the health committee in March 2021 . On 16 March 2021, Salud Justa organized another press conference to denounce PRI Deputy Fernando Galindo for colluding with the tobacco companies to delay the vote in the health committee . Five days later, health groups also joined Deputy Medel in another press conference to further denounce the Chamber of Deputies economic committee for not collaborating in the discussion of amending the LGCT . These efforts led to several published articles, interviews, and op-eds that helped the health committee unanimously vote to approve the Medel bill on 25 March 2021 .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277229_p32
|
PMC11277229
|
sec[7]/sec[2]/sec[2]/p[0]
|
8.3.3. Political Activities
| 1.261719 |
other
|
Other
|
[
0.00652313232421875,
0.0014715194702148438,
0.9921875
] |
[
0.0024318695068359375,
0.99609375,
0.0008625984191894531,
0.0005097389221191406
] |
Health advocates continued to participate in public hearings and debates and proactively identify and educate policymakers to support the LGCT reforms. Understanding that the eventual initiatives may reach the senate, health advocates identified and worked closely with Senate Health Committee member Ernesto Pérez Astorga, who became another political champion to help support and facilitate the approval of the LGCT amendment in the senate . One health advocate recalled that despite being a strong businessman supportive of business practices, Senator Pérez Astorga told him “that it was better to defend the right to health because it was for the general well-being than to defend the economic right of a few” . In August 2021, a month before the senate resumed sessions, health advocates also worked proactively to send senators the Healthy Legislative Agenda, which included a petition to the senate to approve the LGCT reform . Health advocates continued to use data from surveys, regional reports, and local subnational progress in Mexico to create infographics, fact sheets, and policy briefs on smoking prevalence rates, especially among youth, the benefits of smoke-free environments and banning TAPS, and conflicts of interest with industry, among others, to educate policymakers . On 13 October 2021, health advocates participated in a senate virtual forum hosted by Senator Pérez Astorga, in which they continued to express their support for the LGCT amendment . Health advocates followed up with this session, sending letters to senators in late October further requesting that the senate approve the LGCT amendment . These efforts led to the Senate Health Committee also unanimously approving the LGCT amendment on 3 November 2021 and the senate legislative studies committee approving it on 2 December 2021.
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277229_p33
|
PMC11277229
|
sec[7]/sec[3]/p[0]
|
8.4. Industry Interference
| 1.258789 |
other
|
Other
|
[
0.01025390625,
0.0006175041198730469,
0.9892578125
] |
[
0.0140838623046875,
0.98388671875,
0.0015993118286132812,
0.0005950927734375
] |
Throughout the political process, the industry continued to relentlessly oppose LGCT reforms. The tobacco industry continued to lobby policymakers to prevent or delay the process of amending the LGCT. Tobacco companies and restaurant associations also continued to iterate that the LGCT amendment would result in important economic losses for the country, including loses in economic revenue and impacting employment, as tobacco companies argued they were an important source of employment, providing thousands of jobs to workers, most notably tobacco farmers . According to interviewees, the officials that appeared to be coopted by the industry seemed to mostly regurgitate industry economic talking points . Tobacco companies also leveraged support from policymakers and tobacco farmers from tobacco-growing states such as Nayarit and Veracruz, who were also vocal throughout the process in opposing the LGCT reforms . However, according to interviewees, this opposition did not gain much traction because the industry used the same recycled arguments from the past, so the health advocates were well prepared in their counterarguments . This included arguing that most of the tobacco in Mexico is imported from other countries , thousands of cigarettes are produced every hour, which is more technical and not really using labor , and the tobacco that is grown in Mexico relies on industry taking advantage of child labor, paying them low wages and exposing them to pesticides that also contaminate the environment .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277229_p34
|
PMC11277229
|
sec[7]/sec[3]/p[1]
|
8.4. Industry Interference
| 1.125 |
other
|
Other
|
[
0.00370025634765625,
0.000820159912109375,
0.99560546875
] |
[
0.0045318603515625,
0.99365234375,
0.0009188652038574219,
0.0007166862487792969
] |
Given the industry’s struggle and failure to halt the progression of the LGCT, the industry resorted to scare tactics and threatened health advocates and government officials. This included standard legal threats to initially oppose standardized packaging proposals, but as the Medel bill focused on a TAPS ban, industry legal threats centered on how a TAPS ban was a violation of the Mexican constitution and international trade agreements . This also included personal threats that largely came after a health advocacy opinion letter to the health committee that was shared with the economic committee was leaked to the industry and vaping associations . Personal attacks were first launched against health advocates, claiming that particular members of international health groups were interfering with Mexican legislation, calling it a “form of colonialism” . Further personal attacks were launched against policymakers and their assistants, as one policymaker claimed that she received threats from industry groups that had pictures of her son . Another policymaker claimed that industry groups held demonstrations outside of their offices, arguing they did not represent them and were taking jobs away . When these threats did not gain much ground with policymakers, they threatened their legislative assistants and their families . Despite these personal threats and attacks to health advocates, policymakers, and their assistants, they all powered through and maintained their support for the Medel bill.
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277229_p35
|
PMC11277229
|
sec[7]/sec[4]/p[0]
|
8.5. Perfect Storm
| 1.161133 |
other
|
Other
|
[
0.0031948089599609375,
0.0008416175842285156,
0.99609375
] |
[
0.004302978515625,
0.99365234375,
0.0012731552124023438,
0.0006656646728515625
] |
Following a decade of attempts to reform the LGCT, the Mexican government finally approved the amendment on 14 December 2021, which was published in the official gazette on 17 February 2022 . When asked why the LGCT was finally amended, all interviewees claimed that it was a combination of continued and increasingly coordinated health advocacy support to define and frame the problem to policymakers and the media (problem stream), continued efforts to refine and modify proposals for support (policy stream), and strong political will (political stream) that provided a window of opportunity to introduce and amend the LGCT . Several interviewees claimed that all of these elements and efforts came together to create a “perfect storm” , which allowed the amendment to be introduced and then ultimately passed. Furthermore, some claimed that even though political will is key, “you still need to take advantage of the political opportunity” , “you have to be prepared and coordinated for when the moment does arise” , and years of experience and increased coordination and collaboration, which “can take many years to build” , significantly helped to accomplish this.
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277229_p36
|
PMC11277229
|
sec[8]/p[0]
|
9. Discussion
| 1.094727 |
other
|
Other
|
[
0.0047149658203125,
0.0005664825439453125,
0.99462890625
] |
[
0.0155487060546875,
0.982421875,
0.0011548995971679688,
0.000946044921875
] |
The Mexican case study illustrates how the persistent effort of the policy entrepreneurs resulted in the convergence of the problem, policy solution, and political process streams at the policy window. The policy window, opened by an institutionalized event (presidential election) and the activities of the persistent health advocates, ultimately led to policy adoption.
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277229_p37
|
PMC11277229
|
sec[8]/p[1]
|
9. Discussion
| 2.496094 |
biomedical
|
Study
|
[
0.71630859375,
0.0020923614501953125,
0.281494140625
] |
[
0.88232421875,
0.11480712890625,
0.002292633056640625,
0.0005736351013183594
] |
The case of Mexico further illustrates the importance of a transnational tobacco control network comprising local health groups, international health organizations, and inter-governmental organizations collectively working together to help adopt FCTC-based policies. Similar to other tobacco control case studies in LMICs , the financial and technical support from international groups helped fuel and support local efforts. Unlike other case studies that typically provide short snap shots of successes and failures during the policy process , this study examined these efforts over time, demonstrating the growth of this network from individual and isolated efforts to increased coordination and collaboration. While resources continue to play a critical role in supporting local health advocacy efforts, long-term knowledge and experience , as showcased in Mexico, can further institutionalize and sustain local efforts .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277229_p38
|
PMC11277229
|
sec[8]/p[2]
|
9. Discussion
| 1.614258 |
other
|
Other
|
[
0.08392333984375,
0.0012874603271484375,
0.9150390625
] |
[
0.0201263427734375,
0.97705078125,
0.00241851806640625,
0.0004444122314453125
] |
The Mexican case also illustrates the importance of subnational efforts in contributing to the success of national policy reforms. Similar to other larger countries with federally structured governments, it can be quite challenging to make federal changes, especially amidst strong tobacco industry opposition . Despite failed efforts at the national level throughout the 2010s, significant progress was made at the state and local levels to produce effective subnational tobacco control policies that helped change social norms, a key ingredient that has been shown to alter public attitudes surrounding tobacco use and contribute to nationwide tobacco control policy efforts . This case study is a reminder that local governments remain important laboratories for experimentation and advancing tobacco control that can have a profound effect on scaling-up efforts nationally .
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277229_p39
|
PMC11277229
|
sec[8]/p[3]
|
9. Discussion
| 1.640625 |
other
|
Other
|
[
0.050872802734375,
0.0011453628540039062,
0.94775390625
] |
[
0.094482421875,
0.90283203125,
0.0019474029541015625,
0.0008544921875
] |
The Mexican case study also highlights the importance of seizing political opportunities when they arise and operating through short political windows to adopt WHO FCTC-based policies. Similar to other successful facilitators of WHO FCTC policy adoption , health advocates were coordinated and proactive to identify and target potential supportive policymakers before political opportunities opened. This included developing close relations with policymakers in key positions who later became political champions to leverage support for tobacco control initiatives, a key facilitator in policy adoption . This approach also recognized the importance of political timing and ensuring the initiative was approved in the health committee during a tight political window; otherwise, this could have been a missed political opportunity as demonstrated in other failed cases . With the recent election of MORENA presidential candidate Claudia Sheinbaum, there could be an important political opportunity to accomplish this given the political party’s recent leadership in tobacco control.
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277229_p40
|
PMC11277229
|
sec[8]/sec[0]/p[0]
|
Limitations
| 1.826172 |
biomedical
|
Study
|
[
0.626953125,
0.0020503997802734375,
0.370849609375
] |
[
0.79833984375,
0.1976318359375,
0.00321197509765625,
0.0007901191711425781
] |
Although we reached out to 24 individuals, only 14 agreed to be interviewed. Furthermore, most of the interviewees work in public health, so there is an inherent bias towards efforts and support to improve public health. However, a strength of this paper is the diversity of viewpoints, as interviewees included representatives from academia, advocacy, and government. These interviewees were also integrally involved in the policy process and provided an added level of insight to help contextualize our documented findings.
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277229_p41
|
PMC11277229
|
sec[9]/p[0]
|
10. Conclusions
| 1.212891 |
other
|
Other
|
[
0.01500701904296875,
0.0012502670288085938,
0.98388671875
] |
[
0.00128936767578125,
0.998046875,
0.0004749298095703125,
0.0002841949462890625
] |
The Mexican experience illustrates the importance of continued health advocacy and political will in adopting FCTC-based policies. Other countries should follow Mexico’s lead by collecting and sharing data through coordinating efforts in order to be prepared to seize political opportunity windows when strong political will is present.
|
[
"Eric Crosbie",
"Sara Perez",
"Adriana Rocha Camarena",
"Valentina Ochoa Vivanco",
"Gianella Severini",
"Patricia Gutkowski",
"Patricia Sosa",
"Ernesto M. Sebrié"
] |
https://doi.org/10.3390/ijerph21070917
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p0
|
PMC11277241
|
sec[0]/p[0]
|
1. Introductory Overview—Diabetes as a Risk Factor for Encephalopathy
| 4.152344 |
biomedical
|
Review
|
[
0.99755859375,
0.00177764892578125,
0.0008730888366699219
] |
[
0.060150146484375,
0.045562744140625,
0.892578125,
0.0019102096557617188
] |
Diabetes mellitus (DM) is a heterogeneous, chronic metabolic disease characterized by elevated blood glucose levels. Hyperglycemia in DM is a consequence of defects in insulin secretion, tissue resistance to insulin or a combination of both these factors . Clinically, two types of diabetes are most commonly diagnosed: type 1 (T1D) and type 2 (T2D). In T1D, the deficiency or lack of insulin is caused by a chronic, progressive autoimmune process that destroys the beta cells of the pancreatic islets of Langerhans, whereas in T2D, tissue insulin resistance occurs, often despite hyperinsulinemia .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p1
|
PMC11277241
|
sec[0]/p[1]
|
1. Introductory Overview—Diabetes as a Risk Factor for Encephalopathy
| 4.042969 |
biomedical
|
Review
|
[
0.98828125,
0.007076263427734375,
0.004558563232421875
] |
[
0.0033893585205078125,
0.001262664794921875,
0.99462890625,
0.00054931640625
] |
Over time, individuals with glucose metabolism disorders, especially poorly controlled diabetes, are predisposed to serious complications, including cardiovascular disease, kidney disease, blindness, neuropathy, lower-extremity amputation, and diabetic encephalopathy (DE), which is the subject of this review . DE is a chronic complication of DM that affects the central nervous system (CNS) and is characterized by cognitive impairment and motor dysfunctions . Therefore, patients with DE are at greater risk of both dementia and postural perturbations (e.g., balance disorders) . Moreover, considering the prevalence of diabetes, mainly type 2 diabetes, which is largely influenced by the obesity pandemic, DE has become a common CNS complication of DM, with no effective therapies currently available . Recent studies have indicated that damage to synaptic mitochondria may play an important role in the pathomechanism of DE, but the nature of this phenomenon remains unclear .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277241_p2
|
PMC11277241
|
sec[0]/sec[0]/p[0]
|
1.1. Consequences of the Lack of or Insufficient Action of Insulin
| 4.632813 |
biomedical
|
Study
|
[
0.9990234375,
0.0005431175231933594,
0.00037598609924316406
] |
[
0.80078125,
0.0033893585205078125,
0.1951904296875,
0.0007371902465820312
] |
The central actions of insulin appear to support cognitive functions by regulating neurotransmitter release, synaptic transmission, and neuronal glucose uptake . Disturbed brain glucose metabolism and hippocampal insulin resistance may impair cognitive functions and contribute to neurodegeneration . In addition, the deficiency of central insulin may reduce cerebral blood flow and blood supply to the cerebral cortex, which can also result in cognitive impairment . Moreover, such deficiency of insulin, resulting either from absolute insulin deficiency or from brain insulin resistance, may promote the accumulation of Aβ aggregates and the hyperphosphorylation of tau proteins because the physiological effects of insulin can oppose these processes . Advanced glycation end products (AGEs) can stimulate receptors for advanced glycation end products (RAGEs) and Toll-like receptor 4 (TLR4), which may result in neuroinflammation, the stimulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-dependent signaling pathways, and the release of proinflammatory cytokines . Therefore, neuroinflammation is a constant component of the pathophysiology of DE .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
PMC11277241_p3
|
PMC11277241
|
sec[0]/sec[1]/p[0]
|
1.2. The Damaging Effects of Chronic Hyperglycemia
| 4.519531 |
biomedical
|
Study
|
[
0.9990234375,
0.0007262229919433594,
0.00041365623474121094
] |
[
0.63916015625,
0.0028362274169921875,
0.357177734375,
0.0008716583251953125
] |
Moreover, chronic hyperglycemia may damage the blood–brain barrier (BBB), mainly through its pro-oxidative effects . All these effects cause diabetes, a pathological condition associated with insulin deficiency, to promote neurodegeneration and the occurrence of cognitive deficits, recapitulating to some extent the same pathomechanisms that underlie other neurodegenerative diseases, such as Alzheimer’s disease . This may justify the introduction of DE, defined as the sum of the effects of insufficient insulin on the CNS. The pathomechanisms of cognitive deficits occurring in DE largely overlap with the pathomechanisms of other neurodegenerative diseases, resulting in neuronal loss . The duration of diabetes increases the incidence of both diabetic neuropathy and DE, which do not immediately appear at the onset of the disease, especially when patients’ blood glucose levels are well stabilized . In patients with diabetes diagnosed less than 12 months prior, the incidence of diabetic neuropathy equals approximately 10%, increasing to 50% 25 years after diagnosis . The most common symptoms of diabetic peripheral neuropathy include paresthesia, numbness, and a burning sensation .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277241_p4
|
PMC11277241
|
sec[0]/sec[2]/p[0]
|
1.3. The Importance of Chemokine Dysfunction in Diabetes
| 4.335938 |
biomedical
|
Study
|
[
0.99951171875,
0.0004591941833496094,
0.00027251243591308594
] |
[
0.673828125,
0.0030956268310546875,
0.322509765625,
0.0007224082946777344
] |
In humans, the chemokine (or chemotactic cytokine) family includes over 50 small proteins produced by various cells, including those in brain tissue (i.e., astrocytes, microglia, and neurons) . These secreted proteins interact with metabotropic receptors, also known as G protein-coupled receptors (GPCRs), on the surface of target cells and transmit numerous chemotactic and immunoregulatory signals . Since the recruitment of immune cells to the site of inflammation and their subsequent activation and regulation are essential conditions for an effective inflammatory immune response, the chemokine system is a key element in maintaining immune homeostasis . Consequently, chemokines are involved in all protective or destructive immune and inflammatory responses, including neuroinflammation . In diabetes, changes in chemokine concentrations, activities, and profiles have been demonstrated, mainly involving an increase in pro-inflammatory and neurotoxic effects .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277241_p5
|
PMC11277241
|
sec[0]/sec[2]/p[1]
|
1.3. The Importance of Chemokine Dysfunction in Diabetes
| 3.363281 |
biomedical
|
Other
|
[
0.998046875,
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[
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Chemokine CX3CL1 (fractalkine) is commonly found throughout the brain, particularly in neural cells, and its receptor is known to be present on microglial cells . As a signaling molecule, CX3CL1 facilitates neuronal glial crosstalk .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277241_p6
|
PMC11277241
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sec[0]/sec[2]/p[2]
|
1.3. The Importance of Chemokine Dysfunction in Diabetes
| 3.8125 |
biomedical
|
Review
|
[
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[
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This review presents the neuroprotective and neurotoxic effects of fractalkine, which may manifest themselves in diabetes and influence the course of DE. Because DE is rarely diagnosed in isolated form (as pure DE), other neurodegenerative diseases that most often co-occur with DE are mentioned.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277241_p7
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PMC11277241
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sec[1]/sec[0]/p[0]
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2.1. Structure
| 4.660156 |
biomedical
|
Study
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[
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C-X3-C motif chemokine ligand 1 (CX3CL1), also known as fractalkine or neurotactin, is the only member of the δ subfamily of chemokines and seems to bind to only one receptor, CX3CR1, a transmembrane Gi protein-coupled receptor . Many other substances belonging to the chemokine family show less specific binding activity than CX3CL1 . The full-length CX3CL1 molecule is larger than most other chemokines and has two forms. The 95-kDa full-length membrane-bound molecule contains a 76-amino-acid N-terminal chemokine domain, a 241-amino-acid mucin-like glycosylated stalk, a 19-amino-acid hydrophobic transmembrane region (α helix), and a 37-amino-acid intracellular C-terminal domain . Another form is a soluble molecule of approximately 70 kDa that contains an N-terminal chemokine domain and an extracellular mucin-like stalk . The soluble domain of CX3CL1 acts as a signaling molecule (chemoattractant) and can bind to CX3CR1 receptors expressed on microglia . In contrast, its transmembrane mucin-like stalk may act as an adhesion molecule for microglia and infiltrate leukocytes during the inflammatory response . The molecular structures of both forms of FKN are shown in Figure 1 .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277241_p8
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PMC11277241
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sec[1]/sec[1]/p[0]
|
2.2. CX3CL1 in the CNS
| 3.990234 |
biomedical
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Study
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[
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[
0.88134765625,
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In the CNS, CX3CL1 is constitutively expressed in neurons, especially in hippocampal neurons , while in astrocytes, its expression can be induced by TNF-α and interferon gamma (IFN-γ) . CX3CR1 receptor activation is associated with several intracellular second messengers. In the brain, CX3CR1 expression is limited to microglia .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p9
|
PMC11277241
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sec[1]/sec[1]/p[1]
|
2.2. CX3CL1 in the CNS
| 4.355469 |
biomedical
|
Study
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[
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[
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The activation of the CX3CL1-CX3CR1 signaling pathway in microglia, both by the soluble form of CX3CL1 and by its membrane-bound form, inhibits lipopolysaccharide (LPS)-induced major histocompatibility complex class II (MHC2) and cluster of differentiation 40 (CD40) mRNA biosynthesis and the level of interleukin-1 beta (IL-1β) expression, and these anti-inflammatory effects depend on the activation of protein kinase B (Akt) and phosphoinositide 3-kinase (PI3K) .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p10
|
PMC11277241
|
sec[1]/sec[1]/p[2]
|
2.2. CX3CL1 in the CNS
| 4.546875 |
biomedical
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Study
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[
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[
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The activation of the CX3CL1-CX3CR1 axis also stimulates Akt activation in microglia in a dose- and time-dependent manner. The treatment of primary cocultures of glial cells and neurons with fractalkine results in the transient phosphorylation of Akt within 10 min and extracellular signal-regulated kinase 1/2 (ERK1/2) within 1 min of exposure to CX3CL1 . Moreover, CX3CL1 significantly inhibits neuronal calcium influx induced by N-methyl-D-aspartate (NMDA) receptor activation, and this effect can be abrogated by the inhibition of the ERK1/2-dependent signaling pathway. CX3CL1 also inhibits NMDA-dependent apoptosis through Akt- and ERK1/2-dependent signaling pathways . This effect is likely mediated by the activation of microglia rather than by a direct effect of CX3CL1 on neurons. The treatment of hippocampal neuron cultures with the soluble form of CX3CL1 activates cyclic adenosine monophosphate (cAMP)/Ca 2+ response element binding protein (CREB), a transcription factor, and ERK1/2 kinase but not kinases such as cJun NH(2)-terminal kinase (JNK) or mitogen-activated protein kinases P38 (P38 MAPK) .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277241_p11
|
PMC11277241
|
sec[1]/sec[1]/p[3]
|
2.2. CX3CL1 in the CNS
| 4.105469 |
biomedical
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Study
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[
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[
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In addition, it induces the translocation of the NF-κB p65 subunit to the cell nucleus. A specific PI3K inhibitor abrogated the translocation of the NF-κB p65 subunit to the cell nucleus, suggesting that CX3CL1-CX3CR1-dependent signaling activates NF-κB via Akt . These results, however, have not been confirmed in other experimental models and could have been due to the specific cell culture system used, e.g., the contamination of the culture with microglia.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p12
|
PMC11277241
|
sec[1]/sec[1]/p[4]
|
2.2. CX3CL1 in the CNS
| 4.160156 |
biomedical
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Study
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[
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By acting on the CX3CR1 receptor, CX3CL1 modulates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor phosphorylation, increasing calcium influx and inhibiting excitatory postsynaptic potentials and long-term potentiation (LTP) .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277241_p13
|
PMC11277241
|
sec[1]/sec[1]/p[5]
|
2.2. CX3CL1 in the CNS
| 4.589844 |
biomedical
|
Study
|
[
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[
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0.00040435791015625
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CX3CL1 may also enhance inhibitory postsynaptic currents, possibly by increasing neuronal responsiveness to γ-aminobutyric acid (GABA) and GABA-dependent chloride anion influx into cells . CX3CL1 can activate the CX3CR1 receptor on microglia with the subsequent release of adenosine, which may, in turn, activate adenosine (A)3 (R) receptors on neurons, inducing a signaling cascade that results in the modulation of GABA-A receptors, increasing their sensitivity to GABA . Adenosine may also activate adenosine A2AR receptors on microglia, inducing the release of D-serine, which acts as a coagonist of the NMDA receptor, increasing calcium influx into cells through NMDA receptor activation . Microglia-derived adenosine may also exert a neuroprotective effect by activating the A1R adenosine receptor in neurons .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p14
|
PMC11277241
|
sec[1]/sec[1]/p[6]
|
2.2. CX3CL1 in the CNS
| 4.378906 |
biomedical
|
Study
|
[
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[
0.998046875,
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Several studies have shown that CX3CL1 inhibits LPS-induced microglial activation by reducing the production of nitric oxide (NO), interleukin-6 (IL-6), and TNF-α and inhibits the neurotoxic effects of LPS-activated microglia in vitro by limiting the release of proinflammatory mediators . These data suggest that high levels of endogenous CX3CL1 expressed in adult CNS neurons lead to the tonic activation of CX3CR1 on microglia and act as a neuronal signal maintaining microglia in a quiescent state , thus contributing to the neuroprotective role of CX3CL1-CX3CR1-dependent signaling. In contrast, in mixed cultures of neuronal and glial cells collected from CX3CR1 −/− mice, as well as in microglial murine BV-2 cells with silenced CX3CR1 production, the LPS-induced release of TNF-α, NO, and superoxide molecules is reduced in comparison to cells from wild-type (WT) mice , suggesting that CX3CL1 is also involved in the release of proinflammatory mediators from activated microglia.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277241_p15
|
PMC11277241
|
sec[2]/sec[0]/p[0]
|
3.1. Main CX3CL1-CX3CR1 Signaling Pathways
| 4.527344 |
biomedical
|
Study
|
[
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[
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The attachment of the CX3CL1 molecule to the extracellular determinants of CX3CR1 causes conformational rearrangements preceding the activation of heterotrimeric G proteins (the Gαβγ heterotrimer) of the G protein complex associated with CX3CR1 . The Gα subunit interacts with G protein regulatory (GPR) domain-containing proteins and synembryn (RIC8), a nonreceptor guanine-nucleotide exchange factor for Gα subunits, to exchange the guanosine-5’-triphosphate (GTP) molecule for guanosine-5’-diphosphate (GDP) . The presence of active GTP-bound Gα in the G protein complex leads to its dissociation into Gαi-GTP and a GβGγ dimer. Activated Gαi interacts with downstream effectors .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277241_p16
|
PMC11277241
|
sec[2]/sec[0]/p[1]
|
3.1. Main CX3CL1-CX3CR1 Signaling Pathways
| 4.160156 |
biomedical
|
Study
|
[
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[
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The emerging CX3CL1-CX3CR1 signaling axis utilizes several well-described pathways to activate numerous transcription factors, such as signal transducer and activator of transcription protein (STAT), NF-κβ, and CREB, while inhibiting other factors (e.g., members of the class O forkhead box transcription factor [FOXO]) .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277241_p17
|
PMC11277241
|
sec[2]/sec[0]/p[2]
|
3.1. Main CX3CL1-CX3CR1 Signaling Pathways
| 4.414063 |
biomedical
|
Study
|
[
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[
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Most CX3CR1-related signaling pathways have been shown to involve other chemokine receptors. These include, among others, the following: Stimulating the mobilization of calcium ions from intracellular resources through the phospholipase C (PLC)/protein kinase C (PKC) pathway ; The activation of appropriate kinases with subsequent downstream signaling within the following pathways: (a) The Janus kinase (JAK)/STAT pathway; (b) The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/IkappaBeta (Iκβ) kinase (IKK)/Iκβ/NF-κβ pathway; (c) Ras kinases (Ras)/Raf kinases (Raf)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK); (d) MEK kinase (MEKK)/cJun NH(2)-terminal kinase (JNK)/CREB or MEKK/mito-gen-activated protein kinase (P38)/CREB pathways .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p18
|
PMC11277241
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sec[2]/sec[0]/p[3]
|
3.1. Main CX3CL1-CX3CR1 Signaling Pathways
| 1.999023 |
biomedical
|
Study
|
[
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[
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The above signaling pathways are shown in Figure 2 .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p19
|
PMC11277241
|
sec[2]/sec[0]/p[4]
|
3.1. Main CX3CL1-CX3CR1 Signaling Pathways
| 4.667969 |
biomedical
|
Study
|
[
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[
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The sCX3CL1 molecule is created by cutting off (marked with scissors) extracellular structures (N-terminal chemokine domain and mucin-like stalk) from the membrane form of fractalkine (mCX3CL1) after the action of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), tumor necrosis factor alpha (TNF-α) converting enzyme (TACE or ADAM17), matrix metalloproteinase-2 (MMP-2), or cathepsins (CTS). Neuronal sCX3CL1 stimulates transmembrane metabotropic CX3CR1 on microglial cells, causing conformational changes with subsequent G protein activation. During the nucleotide exchange of the guanosine-5’-triphosphate (GDP) for the guanosine-5’-diphosphate (GTP), the activated alpha subunit (Gαi) dissociates from the G protein Gαβγ heterotrimer. Changes in gene transcription after CX3CR1 activation are accompanied by the release of intracellularly stored calcium ions (Ca 2+ ) due to the activation of the phospholipase C (PLC)/inositol-1,4,5-triphosphate (IP3)/protein kinase C (PKC) pathway.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p20
|
PMC11277241
|
sec[2]/sec[0]/p[5]
|
3.1. Main CX3CL1-CX3CR1 Signaling Pathways
| 2.730469 |
biomedical
|
Other
|
[
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[
0.006610870361328125,
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Other abbreviations: Akt—protein kinase B; ERK—extracellular signal-regulated kinase; IκB—inhibitory protein of NF-κB; IKK—IkappaBeta (Iκβ) kinase; JAK—Janus kinase; MEK—mitogen-activated protein kinase kinase; MEKK—MEK kinase; P38—mitogen-activated protein kinases; PI3K—phosphoinositide 3-kinase; Raf—Raf kinases; Ras—Ras kinases.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.714283 |
PMC11277241_p21
|
PMC11277241
|
sec[2]/sec[1]/p[0]
|
3.2. Physiological Action of CX3CL1-CX3CR1 Signaling in Brain Tissue
| 4.363281 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.99853515625,
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Under physiological conditions, the CX3CL1-CX3CR1 signaling pathway is involved in various brain functions during development and adulthood. Recently, a key role was attributed to synaptic pruning dependent on microglia, which phagocytize inactive synapses during the postnatal maturation of the brain . CX3CR1 GFP/GFP mice, in which microglia synthesize green fluorescent protein (GFP) instead of the CX3CR1 receptor, have more synapses than WT mice, at least until the third week of life . In the hippocampal CA1 region, CX3CR1-deficient (CX3CR1 −/− ) mice also exhibit reduced numbers of microglia during postnatal development, suggesting that CX3CL1-dependent signaling may exert a chemotactic effect on microglia in the brain . Therefore, the genetic ablation of the CX3CR1 receptor may cause microglia to become unresponsive to the chemotactic effects of CX3CL1, thereby reducing the number of microglia in the brain. As a result, a greater density of synapses in CX3CR1 −/− mice can be explained by a lower number of microglia.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p22
|
PMC11277241
|
sec[2]/sec[1]/p[1]
|
3.2. Physiological Action of CX3CL1-CX3CR1 Signaling in Brain Tissue
| 4.527344 |
biomedical
|
Study
|
[
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[
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CX3CL1 also inhibits neuronal migration by increasing neuronal binding to the extracellular matrix . However, CX3CL1 has the opposite effect on microglia. Blocking CX3CR1 inhibits microglial cell migration in response to CX3CL1 . This finding supports the hypothesis that CX3CL1-CX3CR1 signaling may act as a pathway guide for microglia, promoting their colonization of the CNS. Moreover, the migration of microglia into the centers of the developing somatosensory cortex, which usually occurs around postnatal day 5, is delayed by several days in CX3CR1 −/−/GFP/GFP mice, even if no differences are detected at postnatal day 9 . The absence of CX3CR1 also delays the maturation of functional glutamate receptors . Microglia affect synapse maturation during individual development, which is generally promoted by the CX3CL1-CX3CR1 signaling pathway. CX3CL1 produced by neurons in the adult brain likely maintains microglia in a quiescent, inactivated state. Microglial activation occurs when CX3CL1 release is reduced, e.g., in the hippocampus of aging rats . Such “homeostatic” effects on microglia may play a significant role in the CX3CL1-CX3CR1 signaling pathway.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p23
|
PMC11277241
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sec[2]/sec[1]/p[2]
|
3.2. Physiological Action of CX3CL1-CX3CR1 Signaling in Brain Tissue
| 4.445313 |
biomedical
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Study
|
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[
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A strong activation of microglia in response to the intraperitoneal administration of LPS in CX3CR1 −/−/GFP/GFP mice has been observed, and apart from that, the transplantation of such activated microglia into WT mice produces completely different effects than the transplantation of microglia collected from CX3CR1 +/− mice . Microglia from CX3CR1 +/− mice rapidly migrate from the administration site and mainly infiltrate white matter tracts, whereas microglia from CX3CR1 −/− mice remain at the site of administration. Moreover, neuronal loss surrounding activated GFP + microglia collected from CX3CR1 −/− mice is more significant and more persistent than that in the brains of WT mice that received microglia collected from CX3CR1 +/− mice, probably due to increased IL-1β release from microglia collected from CX3CR1 −/− mice . In a mouse model of Parkinson’s disease, CX3CR1 −/− mice showed more pronounced cell death in the pars compacta of the substantia nigra than did CX3CR1 +/+ mice, and similar results were obtained for CX3CL1 −/− mice. These findings suggest that the CX3CL1-CX3CR1 signaling pathway modulates the activity of microglia and that disruptions in this pathway may result in their impaired function .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277241_p24
|
PMC11277241
|
sec[2]/sec[1]/p[3]
|
3.2. Physiological Action of CX3CL1-CX3CR1 Signaling in Brain Tissue
| 3.888672 |
biomedical
|
Study
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Citing the results of studies on CX3CL1-CX3CR1 signaling in Parkinson’s disease may provide some approximation to DE, which may be helpful in the absence of studies on animal models regarding such signaling in DE. This is justified by the fact that epidemiological data and clinical trial results suggest that insulin resistance, diabetes, and chronic inflammation contribute to the overlapping etiologies of DE and Parkinson’s disease. Consequently, people with diabetes are around 40% more likely to develop Parkinson’s than those without diabetes .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p25
|
PMC11277241
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sec[2]/sec[1]/p[4]
|
3.2. Physiological Action of CX3CL1-CX3CR1 Signaling in Brain Tissue
| 4.199219 |
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|
Study
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In another rat model of Parkinson’s disease , CX3CL1 was shown to have a neuroprotective effect and prevented neuronal death in the striatum. Indeed, the administration of CX3CL1 to the striatum of rats is neuroprotective and causes a significant decrease in activated microglia. Similarly, when glial cells and hippocampal neurons were cocultured in vitro, neuronal death was detected when microglia were previously exposed to LPS, and this effect was partially abrogated by the administration of CX3CL1 . The activation of microglia with LPS changes their phenotype from quiescent to phagocytic and neurotoxic.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277241_p26
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PMC11277241
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sec[3]/p[0]
|
4. The Role of CX3CL1-CX3CR1 Signaling in CNS Pathology
| 4.519531 |
biomedical
|
Study
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The CX3CL1-CX3CR1-dependent signaling pathway plays a vital role in autoimmune and inflammatory CNS diseases. Multiple sclerosis is a typical autoimmune CNS disease characterized by inflammation and focal demyelination within the spinal cord and brain . An animal model of experimentally induced autoimmune encephalomyelitis represents a disease closely related to multiple sclerosis , in which the expression of CX3CL1 and CX3CR1 changes within the sites of demyelination. Indeed, the accumulation of microglia expressing CX3CR1 receptors has been found in brain damage and inflammation in rats with experimentally induced autoimmune encephalomyelitis without any alterations in the neuronal expression of CX3CL1 . However, an increase in CX3CL1 expression has been found in astrocytes located near regions affected by inflammation, which may indicate that astrocytes are the source of excessive CX3CL1 release and attract microglia to these regions . Another aspect refers to the increased expression of CX3CL1 in microglia of rats with experimentally induced encephalomyelitis . In this context, the increase in CX3CL1 expression may be a process by which microglia attempt to return to a quiescent phenotype and inhibit their excessive activation.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277241_p27
|
PMC11277241
|
sec[3]/p[1]
|
4. The Role of CX3CL1-CX3CR1 Signaling in CNS Pathology
| 4.558594 |
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Study
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Moreover, the disease course of CX3CR1 −/− mice with experimentally induced encephalomyelitis is more severe than that of WT mice. These mice also show a more significant expression of proinflammatory cytokines, such as TNF-α and IL-17, than do WT mice . Conversely, concentrations of the anti-inflammatory cytokine IL-10 are significantly greater in WT mice affected by experimentally induced encephalomyelitis than in CX3CR1 −/− mice affected by this disease . These results indicate a close correlation between CX3CL1 and CX3CR1 in the regulation of the autoimmune response. An autoimmune response within the CNS may result in the excessive activation of microglia. However, while there is considerable evidence that microglial activation contributes to neuronal damage in multiple sclerosis, there is also evidence that microglia also have essential reparative functions. Microglia can increase the expression of CX3CL1 and CX3CR1, which may constitute a mechanism by which they attempt to prevent hyperactivation and restore the quiescent phenotype in adjacent microglia. Depending on the effectiveness of this autoregulation, microglia may generally acquire a neurotoxic or neuroprotective phenotype. Consistent with this, in the course of multiple sclerosis, one of the polymorphic variants of CX3CR1, namely, CX3CR1 I249/T280 , affects the affinity of CX3CL1 for its receptor and the expression of the receptor itself.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p28
|
PMC11277241
|
sec[3]/p[2]
|
4. The Role of CX3CL1-CX3CR1 Signaling in CNS Pathology
| 4.320313 |
biomedical
|
Study
|
[
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Spinal cord injury significantly damages neurons and completely disrupts axonal continuity, leading to inflammation and neurodegeneration at and around the site of injury , which then results in the recruitment of microglia and monocyte-derived macrophages . Microglia and macrophages promote the formation of the glial scar, which reduces the chance of recovering the function of damaged neurons and, thus, the chance of survival of the organism as a whole . CX3CR1 −/− mice have a specific subpopulation of macrophages that are not present in WT mice. These macrophages infiltrate the damaged spinal cord and possess unique properties compared to those of macrophages found in WT mice. Microglia in CX3CR1 −/− mice produce lower amounts of inducible nitric oxide synthase (iNOS) and IL-6 mRNA after spinal cord injury.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277241_p29
|
PMC11277241
|
sec[3]/p[3]
|
4. The Role of CX3CL1-CX3CR1 Signaling in CNS Pathology
| 4.371094 |
biomedical
|
Study
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Moreover, in CX3CR1 −/− mice, functional recovery after spinal cord injury occurs faster and to a greater extent, suggesting that the relationship between neurons and microglia is in dynamic equilibrium during neuronal regeneration. Therefore, after spinal cord injury, microglia in CX3CR1 +/+ (WT) mice may release factors that activate astrocytes and promote glial scar formation, inhibiting functional axonal regeneration. The pharmacological blockade of CX3CR1 in an appropriate time window after spinal cord injury may serve as a novel method to inhibit microglial activation and promote neural regeneration. Despite the undoubtedly neuroprotective functions of the CX3CL1-CX3CR1 signaling pathway in the CNS, CX3CL1 may do more harm than good under certain circumstances. Studies conducted in CX3CL1 −/− mice to investigate the role of CX3CL1 immediately after ischemic injury suggest that CX3CL1 expression inhibits recovery from ischemic CNS injury . Similar studies in CX3CL1 −/− and CX3CR1 −/− mice have shown that in both strains of mice, the volume of infarcted tissue after ischemia is lower, and the administration of exogenous CX3CL1 to WT mice reduces the total volume of tissue affected by ischemic infarction. CX3CL1 administration has no effect on CX3CR1 −/− mice.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p30
|
PMC11277241
|
sec[3]/p[4]
|
4. The Role of CX3CL1-CX3CR1 Signaling in CNS Pathology
| 4.261719 |
biomedical
|
Study
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Furthermore, in an in vitro glucose and oxygen deprivation model that reflects in vivo ischemic conditions, CX3CL1 reduced TNF-α release from CX3CR1 −/− microglia. These results may explain why administering exogenous CX3CL1 to CX3CR1 −/− mice increases the total volume of infarcted tissues, considering the neuroprotective effects of TNF-α . CX3CL1 did not affect TNF-α release in microglia collected from WT mice. Moreover, in CX3CR1 −/− mice, the infarct area after ischemia was smaller than that in the WT and heterozygous mice. Greater IL-1β expression has been observed in the astrocytes of CX3CR1 +/− mice than in those of CX3CR1 −/− mice. This finding suggests that, under stressful conditions, such as during an ischemic episode, CX3CR1 −/− microglia acquire an astrocyte function-altering phenotype by default .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p31
|
PMC11277241
|
sec[3]/p[5]
|
4. The Role of CX3CL1-CX3CR1 Signaling in CNS Pathology
| 4.113281 |
biomedical
|
Study
|
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Studies on the sex-specific effects of CX3CL1-CX3CR1 signaling have shown that, within 12 weeks of an ischemic event in WT and CX3CR1 −/− mice, female WT mice recover more functions than female CX3CR1 −/− mice , while no difference has been found in males. This finding suggests that, for unknown reasons, signaling dependent on the activation of the CX3CR1 receptor has a more significant neuroprotective effect in the event of ischemic episodes in females than in males.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277241_p32
|
PMC11277241
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sec[3]/sec[0]/p[0]
|
4.1. CX3CL1-CX3CR1 Pathway in Aging Microglia
| 4.878906 |
biomedical
|
Study
|
[
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Increasing amounts of data are emerging regarding the role of CX3CL1/CX3CR1 signaling in the aged brain. A significant amount of data suggest that the expression of CX3CL1 in the brain of young rodents is high and decreases with age, which reduces the number of ramified microglia and promotes the release of neuroinflammation markers . Moreover, in old mice exposed to peripheral LPS, the microglial response is enhanced , which may confirm the anti-inflammatory and neuroprotective effects of CX3CL1 in young mice. Interestingly, LPS exposure also reduces CX3CR1 expression in old brains more than in young brains, resulting in a long-term decrease in the expression of these receptors on microglia . Recent studies have confirmed these results and have shown that, while the expression of CX3CR1 on microglia returns to normal within 24 h of exposure to LPS in young mice, this does not occur in old mice . This failure to return regular CX3CR1 expression is accompanied by increased IL-1β release, often exacerbating existing CNS diseases. Taken together, the reduced expression of CX3CL1, CX3CR1, or both proteins in aged brains significantly alters the effectiveness of the signaling axis dependent on these proteins, resulting in both morphological and functional alterations in microglial cell phenotypes, as well as the impairment of microglial function. It is known that neurogenesis in the hippocampus decreases during aging. The pharmacological blockade or genetic ablation of CX3CR1 has a similar effect on the dentate gyrus of the mouse hippocampus, with a subsequent IL-1β-dependent decrease in the survival and proliferation rate of neuronal stem cells . In this context, the attenuation of CX3CL1-dependent signaling may contribute to the excessive activation of microglia . It remains to be determined whether the same phenomenon occurs in humans. Considering the reduced neurogenesis in the hippocampus during cognitive impairment and aging, further studies are recommended to determine the involvement of the CX3CL1/CX3CR1 signaling pathway in the pathologies mentioned above in humans. The activation of the CX3CR1 receptor in microglia regulates PI3K activity, reducing IL-1β production . Since aging is characterized by a chronic increase in IL-1β levels in the hippocampus and IL-1β inhibits the cell cycle in neuronal progenitor cells , the impaired activation of CX3CR1 receptor-dependent signaling may contribute to the reduced rate of neurogenesis in aged brains, especially because the blockade of IL-1β abrogates these effects .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p33
|
PMC11277241
|
sec[3]/sec[0]/p[1]
|
4.1. CX3CL1-CX3CR1 Pathway in Aging Microglia
| 4.382813 |
biomedical
|
Study
|
[
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Recent studies have also clarified the role of IL-1β. Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD + )-dependent protein deacetylase, has been associated with neuroprotective effects, which are partially dependent on the inactivation of the p65 subunit of NF-κB by SIRT1 and, therefore, on the inhibition of the expression of IL-1β, a protein upregulated by NF-κB . However, the activated CX3CR1 receptor can inhibit the activity of protein kinase A (PKA); thus, the deletion of this receptor may facilitate the activation of PKA and, therefore, the activation of NF-κB, which is also dependent on this kinase . In CX3CR1 −/− microglia, SIRT1 activity increases, which likely helps to prevent the excessive activation of NF-κB, but in old brains, it is insufficient to prevent the excessive expression of genes promoted by NF-κB, including the IL-1β-encoding gene .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277241_p34
|
PMC11277241
|
sec[3]/sec[0]/p[2]
|
4.1. CX3CL1-CX3CR1 Pathway in Aging Microglia
| 4.472656 |
biomedical
|
Study
|
[
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Previous studies on various animal models of neurodegeneration have shown that the loss of neuronal interactions with microglia caused by damage to the CX3CL1-CX3CR1 signaling pathway results in a more significant neurotoxic activity of microglia and, therefore, in a more severe course of neurodegenerative diseases . However, it is unknown whether the impaired functioning of the CX3CL1-CX3CR1 signaling pathway occurs as a result or as a cause of the increased activation of microglia, while both scenarios may occur during brain aging or diabetic encephalopathy. No differences in CX3CL1 mRNA expression were detected in hippocampal neurons collected from old rats compared with those collected from young rats, which indicates that posttranslational mechanisms are responsible for the decreased CX3CL1 activity . The administration of exogenous CX3CL1 restores physiological levels of neurogenesis. Moreover, a slight decrease in CX3CL1 expression was observed in middle-aged rats. However, they do not have such an inhibitory effect on the function of the CX3CL1-CX3CR1-dependent signaling axis, as observed in old rats, proving the direct role of aging in the significant inhibition of CX3CL1 expression. In other words, the apparent physiological decline in CX3CL1 expression that occurs during aging may be compensated for during the early but not late stage of this process.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p35
|
PMC11277241
|
sec[3]/sec[0]/p[3]
|
4.1. CX3CL1-CX3CR1 Pathway in Aging Microglia
| 4.253906 |
biomedical
|
Study
|
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When looking at the interindividual genetic variation in the CX3CR1 coding regions, two single nucleotide polymorphisms (SNPs) can be detected. Interestingly, these polymorphisms are associated with an increased risk of age-related macular degeneration (AMD) and a reduced risk of atherosclerosis . Moreover, plasma-soluble CX3CR1 levels are significantly greater in people with mild to moderate Alzheimer’s disease than in people with severe disease. If we assume that the severity of Alzheimer’s disease progresses with age, such observations are consistent with the hypothesis that CX3CL1-CX3CR1 signaling plays a neuroprotective role . Notably, in old mice, voluntary physical exercise increases the CX3CL1 concentration in the brain and, therefore, neurogenesis in the hippocampus , which leads to improved hippocampal function . Combined, this suggests that decreased physical activity with age may contribute to a decrease in CX3CL1 levels in the brain.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p36
|
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|
sec[3]/sec[1]/p[0]
|
4.2. Common Denominators of Brain Aging, Alzheimer’s Disease, and Diabetic Encephalopathy
| 4.613281 |
biomedical
|
Study
|
[
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In the course of both Alzheimer’s disease and untreated diabetes, microglia may be excessively activated by factors such as oxidative stress and neuroinflammation. In Alzheimer’s disease, microglia may be directly activated by extracellular deposits of Aβ aggregates, while in DE, they can be activated by AGEs. Furthermore, damage to the blood–brain barrier occurring in the course of diabetes makes it permeable to substances not generally found in the brain, which may promote neuroinflammation. The pattern of microglial cell activation depends on microglial interactions with neurons, while CX3CL1-CX3CR1 signaling plays a significant role in these interactions. Many studies have indicated that CX3CL1-CX3CR1 signaling may exert a neuroprotective effect by preventing the hyperactivation of microglia and thus the neuroinflammatory response . However, other studies have suggested that CX3CL1-CX3CR1 activation can be harmful in slightly different contexts . Therefore, the modulation of CX3CL1-CX3CR1 signaling may have different effects depending on the metabolic context . However, much evidence indicates that, in the course of diabetic encephalopathy, the activation of this pathway can exert a neuroprotective effect since it takes part in the inhibition of microglial hyperactivation by neurons, which can prevent neuroinflammation, thus lowering the risk of dementia as a long-term complication of diabetes.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277241_p37
|
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sec[3]/sec[2]/p[0]
|
4.3. Neuroinflammation and Neurodegeneration in diabetic Encephalopathy
| 4.894531 |
biomedical
|
Study
|
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The symptoms of DE consist mainly of cognitive deficits resulting from neuroinflammation and neurodegeneration. One of the possible mechanisms underlying these complications of diabetes is persistent inflammation resulting from the pronounced secretion of proinflammatory mediators and pro-oxidant substances . Proinflammatory mediators are predominantly released from glia, including microglia, astrocytes, and oligodendroglia, in the brain . The most common microglia-related function is immune surveillance—both in the healthy brain and in the brain affected by various diseases. Microglia constantly explore their microenvironment by extending and retracting their highly motile processes . This property is essential for achieving a rapid response to infections or injuries that lead to the activation of microglia, changing their phenotype from quiescent to activated. At the same time, however, the chronic excessive activation of microglia in the course of diabetes, e.g., due to hyperglycemia, may adversely affect the brain, leading to chronic neuroinflammation. The activation of microglia may occur in response to the disruption of neuronal function, e.g., by excess glycation end products or reactive oxygen species (ROS), and is associated with immunoreactive, morphological, proliferative, and migratory changes in microglial phenotypes . The activation of microglia allows the elimination of pathogens and debris from other cells during acute inflammatory reactions, which is a beneficial phenomenon. However, the same activation may have an unfavorable effect on chronic inflammatory reactions, contributing to neurodegeneration . Chronic inflammation within the CNS may result in the excessive activation of microglia, which, under such conditions, may excessively release proinflammatory cytokines and undergo oxidative and nitrosative stress . Activated microglia can proliferate and migrate to sites of brain tissue damage, where they undergo morphological changes and alterations in gene expression resulting from interactions among various signaling pathways .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277241_p38
|
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|
sec[3]/sec[2]/p[1]
|
4.3. Neuroinflammation and Neurodegeneration in diabetic Encephalopathy
| 4.355469 |
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|
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[
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The main pathomechanism of DE comprises dysglycemia-related phenomena, i.e., complications of abnormal plasma glucose concentrations—both too high and too low . Hyperglycemia may result in BBB damage through its pro-oxidative effects, as well as pro-inflammatory actions dependent on AGE-RAGE signaling . Therefore, chronic hyperglycemia—both in the course of type I and type II diabetes—can lead to the hyperactivation of microglial cells, although this effect may be prevented to some extent by CX3CL1–CX3CR1-dependent signaling , as already mentioned above.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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|
4.3. Neuroinflammation and Neurodegeneration in diabetic Encephalopathy
| 4.222656 |
biomedical
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Review
|
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0.0009412765502929688
] |
At the same time, it is noteworthy that hypoglycemia can also be a complication of diabetes, or—to be more precise—of its treatment. Hypoglycemia may occur as a result of insulin overdosage in the treatment of type I diabetes, or as a result of sulphonylurea derivative use in the treatment of type II diabetes. Hypoglycemia may insult the CNS in a completely different way than chronic hyperglycemia, resulting in an acute glucose depletion in neurons and ATP deficiency which may even lead to neuronal death. Thus, hypoglycemia can induce irreversible cognitive dysfunction due to neuronal necrosis, directly independent of inflammatory mediators . Fortunately, new medications used in the treatment of type II diabetes, such as glucagon-like peptide 1 (GLP-1) analogs, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, and the long-known metformin, are much less likely to induce hypoglycemia, since they do not unconditionally stimulate insulin secretion . On the other hand, hypoglycemia as a complication of type I diabetes treatment can be averted by meticulous measuring plasma glucose concentration and through the precise adjustment of insulin doses.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277241_p40
|
PMC11277241
|
sec[3]/sec[2]/sec[0]/p[0]
|
Diabetic Encephalopathy—Focus on Microglia
| 4.902344 |
biomedical
|
Study
|
[
0.99853515625,
0.0008521080017089844,
0.0004901885986328125
] |
[
0.9765625,
0.00197601318359375,
0.0209197998046875,
0.0006451606750488281
] |
Much evidence indicates that microglia-dependent inflammation within the CNS plays an important role in the pathogenesis of DE. For example, extracellular nucleotides, particularly adenosine triphosphate (ATP), which act through purinergic metabotropic (e.g., P2Y) and purinergic ionotropic (e.g., P2X) receptors, are critical modulators of microglia–neuron communication . Therefore, microglia may affect the course of DE, among other processes, through interactions with neurons. First, neurons become hyperactive in response to neurotoxic factors, hyperglycemia and hyperlipidemia, after which they release slow-acting microglial activators, such as matrix metalloproteinase-9 (MMP-9), ATP, and chemokines, mainly monocyte chemoattractant protein-1 (MCP-1, also known as chemokine CCL2), and CX3CL1 (fractalkine). Second, the activation of p38 mitogen-activated protein kinases, a class of MAPKs in microglia, produces mediators such as neurotrophins and substances that regulate synaptic transmission and the intensity of inflammation. Microglial inflammation may also result from blocking the interaction between the immunomodulatory molecule CD200 and its receptor CD200R. The CD200/CD200R signaling pathway is responsible for immunosuppressive mechanisms involving the inhibition of macrophages, the induction of regulatory T cells, the switching of cytokine profiles from Th1 to Th2, the inhibition of tumor-specific T-cell immunity, and the induction of myeloid-derived suppressor cells (MDSCs) . The inflammatory response in microglia also occurs due to the activation of signaling pathways related to pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), a microglial receptor–adaptor complex known as triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12), as well as AGE-RAGE signaling . Despite having transporters for the three main energy substrates (glucose, fatty acids, and glutamine), during an acute inflammatory response, microglia may experience an energy deficit because microglial energy consumption is dependent on their degree of activity . Because neuronal hyperactivity caused by neurotoxic factors has a feedback-activating effect on microglia, including through the production of CX3CL1, the microglia–neuron interaction in the DE is a vicious cycle .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277241_p41
|
PMC11277241
|
sec[3]/sec[2]/sec[0]/p[1]
|
Diabetic Encephalopathy—Focus on Microglia
| 4.039063 |
biomedical
|
Study
|
[
0.99951171875,
0.00011545419692993164,
0.00017845630645751953
] |
[
0.9755859375,
0.0120086669921875,
0.0119781494140625,
0.00023627281188964844
] |
Therefore, regulating the activity of some signaling pathways within microglia by inhibiting the activation of receptors for ATP (e.g., the purinergic ionotropic receptors P2X4 and P2X7), MMP-9, chemokines (CX3CL1 and CCL2), p38 mitogen-activated protein kinases (a class of mitogen-activated protein kinases (MAPKs)), interleukins (IL-1β, IL-6), and tumor necrosis factor alpha (TNF-α) may contribute to the development of novel treatments for DE .
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277241_p42
|
PMC11277241
|
sec[4]/p[0]
|
5. Concluding Remarks
| 4.5 |
biomedical
|
Review
|
[
0.99853515625,
0.000972747802734375,
0.0006914138793945312
] |
[
0.3046875,
0.0022411346435546875,
0.6923828125,
0.0008625984191894531
] |
DE is a common long-term and chronic complication of DM. Therefore, with the high and constantly increasing incidence of diabetes, DE contributes significantly to cognitive impairment and motor dysfunctions. A constant component of the DE pathomechanism is neuroinflammation, which is caused by a complete lack of insulin (e.g., in T1D) or the ineffective action of insulin due to insulin resistance (e.g., in type T2D, which most often co-occurs with obesity). In addition to the lack of homeostatic glucose and the anti-inflammatory effects of insulin, which limit NF-κB activation and subsequent proinflammatory cytokine expression, chronic hyperglycemia also contributes to neurodegenerative processes mainly through its pro-oxidative effects, which damage blood–brain barrier integrity and increase neuronal loss. The observed clinical diversity of DE forms can be explained by the fact that aging is the primary factor for most neurodegenerative diseases and that, in many cases, the pathomechanisms of several neurodegenerative diseases overlap (e.g., Alzheimer’s disease and Parkinson’s disease).
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277241_p43
|
PMC11277241
|
sec[4]/p[1]
|
5. Concluding Remarks
| 3.859375 |
biomedical
|
Study
|
[
0.99951171875,
0.00012600421905517578,
0.00020623207092285156
] |
[
0.970703125,
0.007419586181640625,
0.021697998046875,
0.00028133392333984375
] |
Although patients with T2D usually have higher plasma concentrations of CX3CL1 than healthy individuals, due to general pro-inflammatory phenotypes related to a high-carbohydrate hypercaloric diet, there are no research studies that allow verifying if this peripheral CX3CL1 acts on the CNS and thus makes any difference in reference to the course of DE . However, it seems that dysglycemia is the main and fundamental pathomechanism underlying DE.
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277241_p44
|
PMC11277241
|
sec[4]/p[2]
|
5. Concluding Remarks
| 4.558594 |
biomedical
|
Review
|
[
0.998046875,
0.0010976791381835938,
0.0008063316345214844
] |
[
0.240234375,
0.002742767333984375,
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0.0009331703186035156
] |
Fractalkine is an intriguing chemokine with the unique properties of an adhesion molecule (mCX3CL1) and chemoattractant (sCX3CL1), that plays a central role in the nervous system. While neurons constitutively express CX3CL1 in the CNS and it can be induced by TNF-α and IFN-γ in astrocytes, CX3CR1 expression in the brain is limited to microglia. This finding highlights the direction of action of the CX3CL1-CX3CR1 signaling axis, which regulates the level of microglial activity in response to brain injury or inflammation. However, knowledge about the role of CX3CL1 in DE, as well as in other neurodegenerative diseases, remains surprisingly incomplete and controversial. Depending on the clinical context, CX3CL1 may have neuroprotective effects by inhibiting the inflammatory process in microglia or, conversely, maintaining/intensifying inflammation and neurotoxicity. The impact of comorbidities, including CNS aging, should be considered because, as mentioned above, DE does not occur in an isolated form. Therapeutic actions in DE aimed at limiting neuronal hyperactivity, causing impaired synaptic plasticity, should focus on interrupting the vicious cycle within the microglia–neuron interaction involving the CX3CL1–CX3CR1 signaling pathway. This can be achieved both by restoring neural homeostasis and by limiting the inflammatory response of microglia. There is a high probability that influencing the activity of the CX3CL1–CX3CR1 axis may also be beneficial in patients suffering from other diseases predisposing to dysglycemia (e.g., hyperadrenocorticism or chronic autoimmune and inflammatory diseases treated with corticosteroids).
|
[
"Mateusz Wątroba",
"Anna D. Grabowska",
"Dariusz Szukiewicz"
] |
https://doi.org/10.3390/ijms25147527
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277253_p0
|
PMC11277253
|
sec[0]/p[0]
|
1. Introduction
| 4.097656 |
biomedical
|
Review
|
[
0.99755859375,
0.001556396484375,
0.0009045600891113281
] |
[
0.04815673828125,
0.004669189453125,
0.9462890625,
0.0006709098815917969
] |
Acute pulmonary hypertension is a complex, potentially life-threatening disorder, which may occur both in newborns and adults. Severe pulmonary infection might be associated with pulmonary hypertension as a part of acute lung injury and concomitant hypoxia. Likewise, Coronavirus Disease 2019 (COVID-19) might lead to acute respiratory distress syndrome associated with hypoxia-induced pulmonary vasoconstriction related to generalized inflammation of the endothelium . Inhaled pulmonary vasodilators, such as nitric oxide (iNO) and prostacyclins, are widely used in the treatment of hospitalized patients with elevated pulmonary arterial pressure, since these agents provide pulmonary vasodilation and thereby improve oxygenation in critically ill patients . Inhaled pulmonary vasodilators (IPVs) can reduce pulmonary vascular resistance (PVR) and improve right ventricular function with minimal systemic effects. Therefore, inhalation therapy has been the subject of several clinical studies and industrial development projects.
|
[
"Attila Oláh",
"Bálint András Barta",
"Mihály Ruppert",
"Alex Ali Sayour",
"Dávid Nagy",
"Tímea Bálint",
"Georgina Viktória Nagy",
"István Puskás",
"Lajos Szente",
"Levente Szőcs",
"Tamás Sohajda",
"Endre Zima",
"Béla Merkely",
"Tamás Radovits"
] |
https://doi.org/10.3390/ijms25147981
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277253_p1
|
PMC11277253
|
sec[0]/p[1]
|
1. Introduction
| 3.974609 |
biomedical
|
Review
|
[
0.998046875,
0.0010557174682617188,
0.0007228851318359375
] |
[
0.2110595703125,
0.01120758056640625,
0.77734375,
0.0006241798400878906
] |
The standard therapy, NO inhalation, is permitted and reimbursed only in dedicated hospitalized patients and must be controlled by professional medical staff. The main disadvantages of iNO therapy include the extreme instability and dosing difficulties due to rapid inactivation. Additionally, overdosing of iNO might result in methemoglobinemia, toxicity, acute lung injury, and hypoxia as well . To avoid the above-mentioned difficulties, numerous investigations have been launched to compare the effects of parenteral administration of NO donor drugs to apply these therapies for short- and long-term treatment . Currently, IPV drug selection always depends on hospital rules and regulations, experience and preferences, and expenses. However, limited and inadequate studies have reported a mortality benefit of IPVs in different patients . Therefore, more research on IPVs is needed to determine management strategies including time, dose, and duration.
|
[
"Attila Oláh",
"Bálint András Barta",
"Mihály Ruppert",
"Alex Ali Sayour",
"Dávid Nagy",
"Tímea Bálint",
"Georgina Viktória Nagy",
"István Puskás",
"Lajos Szente",
"Levente Szőcs",
"Tamás Sohajda",
"Endre Zima",
"Béla Merkely",
"Tamás Radovits"
] |
https://doi.org/10.3390/ijms25147981
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277253_p2
|
PMC11277253
|
sec[0]/p[2]
|
1. Introduction
| 4.085938 |
biomedical
|
Study
|
[
0.9990234375,
0.0008006095886230469,
0.00023162364959716797
] |
[
0.99853515625,
0.0009608268737792969,
0.0002465248107910156,
0.00013458728790283203
] |
An alternative to iNO therapy has been developed by Cyclolab R&D Ltd. (Budapest, Hungary). SIN-1A (N-nitroso-N-morpholino-amino-acetonitrile), the unstable active metabolite of the orally administered prodrug molsidomine and linsidomine (SIN-1), has been stabilized by a cyclodextrin derivative in a new drug formulation. This cyclodextrin derivative might facilitate the administration and proper dosing of SIN-1A by inhalation. In this experimental study, we aimed to investigate the hemodynamic effect of inhalative SIN-1A administration under physiological and pathological conditions in a large animal model and compare its efficacy to the standard iNO inhalation therapy. According to our hypothesis, SIN-1A administration might be an effective option to resolve acute pulmonary hypertension with the advantage of ease of administration.
|
[
"Attila Oláh",
"Bálint András Barta",
"Mihály Ruppert",
"Alex Ali Sayour",
"Dávid Nagy",
"Tímea Bálint",
"Georgina Viktória Nagy",
"István Puskás",
"Lajos Szente",
"Levente Szőcs",
"Tamás Sohajda",
"Endre Zima",
"Béla Merkely",
"Tamás Radovits"
] |
https://doi.org/10.3390/ijms25147981
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277253_p3
|
PMC11277253
|
sec[1]/sec[0]/p[0]
|
2.1. Pharmacodynamics
| 4.105469 |
biomedical
|
Study
|
[
0.99951171875,
0.000324249267578125,
0.00017976760864257812
] |
[
0.9990234375,
0.0005435943603515625,
0.0004336833953857422,
0.00008338689804077148
] |
SIN-1A administration showed a similar, rapid effect on pulmonary artery pressure as iNO inhalation . The greatest relative change in pulmonary artery pressure values was reached after approximately ten minutes and remained relatively unchanged during further administration. Larger doses of SIN-1A (SIN-1A-10) were comparable to iNO-related PAP alterations.
|
[
"Attila Oláh",
"Bálint András Barta",
"Mihály Ruppert",
"Alex Ali Sayour",
"Dávid Nagy",
"Tímea Bálint",
"Georgina Viktória Nagy",
"István Puskás",
"Lajos Szente",
"Levente Szőcs",
"Tamás Sohajda",
"Endre Zima",
"Béla Merkely",
"Tamás Radovits"
] |
https://doi.org/10.3390/ijms25147981
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277253_p4
|
PMC11277253
|
sec[1]/sec[1]/p[0]
|
2.2. Hemodynamic Alterations after Inhalation Therapy—Physiological Conditions
| 4.136719 |
biomedical
|
Study
|
[
0.9990234375,
0.0007319450378417969,
0.00018799304962158203
] |
[
0.9990234375,
0.0003266334533691406,
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0.00010710954666137695
] |
Baseline hemodynamic data were compared to measurements collected after inhalational therapy of each drug . PAP and PVR showed a tendentious decrease due to all of these drugs and SIN-1A-10 had a similar effect as iNO. While iNO did not influence SAP and SVR, SIN-1A administration was associated with decreased SAP and SVR values. Moreover, this effect seemed to be dose-dependent: higher doses of SIN-1A had a more pronounced effect . As a result of these alterations, the PVR/SVR ratio decreased in the iNO group, while it remained unchanged in the SIN-1A-5 and SIN-1A-10 groups. HR and CO were not significantly altered.
|
[
"Attila Oláh",
"Bálint András Barta",
"Mihály Ruppert",
"Alex Ali Sayour",
"Dávid Nagy",
"Tímea Bálint",
"Georgina Viktória Nagy",
"István Puskás",
"Lajos Szente",
"Levente Szőcs",
"Tamás Sohajda",
"Endre Zima",
"Béla Merkely",
"Tamás Radovits"
] |
https://doi.org/10.3390/ijms25147981
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277253_p5
|
PMC11277253
|
sec[1]/sec[2]/p[0]
|
2.3. Hemodynamic Alterations after Inhalation Therapy—Pulmonary Hypertension (U46619)
| 4.136719 |
biomedical
|
Study
|
[
0.99951171875,
0.0004591941833496094,
0.00020253658294677734
] |
[
0.9990234375,
0.00022852420806884766,
0.0005121231079101562,
0.00008040666580200195
] |
The observed alterations after inhalation therapy were similar under pathological conditions . iNO markedly decreased the PAP and PVR values. The SIN-1A-10 dose had a similar impact on PAP as iNO, while SIN-1A-5 inhalation was associated with a moderate decrement (~20%). Both SIN-1A doses were associated with decreased PVR, although the larger dose showed only a strong tendency. SIN-1A-5 and SIN-1A-10 also reduced systemic blood pressure and vascular resistance (SAP and SVR), while these parameters remained unchanged in the iNO group. Consequently, iNO markedly decreased the PVR/SVR ratio, showing the strong selectivity of its vasodilating effect on the pulmonary circulation. In contrast, SIN-1A was associated with an unchanged PVR/SVR ratio. We could not detect any significant alterations in CO and HR.
|
[
"Attila Oláh",
"Bálint András Barta",
"Mihály Ruppert",
"Alex Ali Sayour",
"Dávid Nagy",
"Tímea Bálint",
"Georgina Viktória Nagy",
"István Puskás",
"Lajos Szente",
"Levente Szőcs",
"Tamás Sohajda",
"Endre Zima",
"Béla Merkely",
"Tamás Radovits"
] |
https://doi.org/10.3390/ijms25147981
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277253_p6
|
PMC11277253
|
sec[1]/sec[3]/p[0]
|
2.4. Other Parameters
| 4.101563 |
biomedical
|
Study
|
[
0.99951171875,
0.0004172325134277344,
0.00018477439880371094
] |
[
0.99951171875,
0.0002396106719970703,
0.0003666877746582031,
0.0000826120376586914
] |
The core temperature and the parameters of blood gas analysis were considered physiological throughout our experiments. Inhalation therapies did not significantly influence platelet aggregation (using ADP reagent, Table 2 ) under physiological conditions. SIN-1A inhalation tended to decrease the AUC values in the case of U46619-induced pulmonary hypertension, indicating a possible beneficial inhibitory effect on platelet aggregation under pathological conditions.
|
[
"Attila Oláh",
"Bálint András Barta",
"Mihály Ruppert",
"Alex Ali Sayour",
"Dávid Nagy",
"Tímea Bálint",
"Georgina Viktória Nagy",
"István Puskás",
"Lajos Szente",
"Levente Szőcs",
"Tamás Sohajda",
"Endre Zima",
"Béla Merkely",
"Tamás Radovits"
] |
https://doi.org/10.3390/ijms25147981
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277253_p7
|
PMC11277253
|
sec[2]/p[0]
|
3. Discussion
| 4.105469 |
biomedical
|
Study
|
[
0.9990234375,
0.0009417533874511719,
0.00015401840209960938
] |
[
0.99853515625,
0.0006246566772460938,
0.0006785392761230469,
0.0001875162124633789
] |
In this study, we provided a direct comparison of the short-term pulmonary and systemic effects of the new inhaled SIN-1A formulation and compared it to the gold standard pulmonary vasodilator iNO therapy in a porcine model of acute pulmonary hypertension. According to our data, SIN-1A might be an effective therapeutic option in acute pulmonary hypertension.
|
[
"Attila Oláh",
"Bálint András Barta",
"Mihály Ruppert",
"Alex Ali Sayour",
"Dávid Nagy",
"Tímea Bálint",
"Georgina Viktória Nagy",
"István Puskás",
"Lajos Szente",
"Levente Szőcs",
"Tamás Sohajda",
"Endre Zima",
"Béla Merkely",
"Tamás Radovits"
] |
https://doi.org/10.3390/ijms25147981
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277253_p8
|
PMC11277253
|
sec[2]/p[1]
|
3. Discussion
| 4.511719 |
biomedical
|
Study
|
[
0.9990234375,
0.0007524490356445312,
0.00028777122497558594
] |
[
0.82666015625,
0.009979248046875,
0.1619873046875,
0.0013675689697265625
] |
Pulmonary hypertension is a characteristic and important feature of acute respiratory distress syndrome (ARDS). The early phase of ARDS involves the pathological processes of pulmonary vasoconstriction, thromboembolism of the small and large vessels, and lung interstitial edema . These pathophysiologic mechanisms are also associated with severe COVID-19 pneumonia, promoting the sequence of acute pulmonary hypertension . Not only the micro- and macro-embolization in the pulmonary circulation, but also the generalized injury of the endothelium plays a pivotal role in pulmonary injury by losing the active paracrine, endocrine, and autocrine vasodilative function of the vascular endothelium . The production of vasodilators, such as nitric oxide and prostacyclin, might be severely impaired, promoting vasoconstriction of the pulmonary vessels. These factors set the stage for the development of acute pulmonary hypertension and associated problems, such as right ventricular strain and failure .
|
[
"Attila Oláh",
"Bálint András Barta",
"Mihály Ruppert",
"Alex Ali Sayour",
"Dávid Nagy",
"Tímea Bálint",
"Georgina Viktória Nagy",
"István Puskás",
"Lajos Szente",
"Levente Szőcs",
"Tamás Sohajda",
"Endre Zima",
"Béla Merkely",
"Tamás Radovits"
] |
https://doi.org/10.3390/ijms25147981
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277253_p9
|
PMC11277253
|
sec[2]/p[2]
|
3. Discussion
| 4.214844 |
biomedical
|
Study
|
[
0.9990234375,
0.0006251335144042969,
0.00015592575073242188
] |
[
0.998046875,
0.0004665851593017578,
0.0012912750244140625,
0.0001423358917236328
] |
We found similar pharmacodynamics of SIN-1A and iNO . Compared with other routes of drug administration, inhalation therapy delivers medication directly to the lung, enabling higher pulmonary drug concentrations and less systemic adverse effects. Indeed, the velocity of the effect is comparable to other inhaled pulmonary vasodilators such as iloprost, a prostacyclin analog . The route of inhalation has a number of attractive features for the treatment of pulmonary hypertension, including the delivery of the drug directly to the target organ, thus enhancing pulmonary specificity and reducing systemic adverse effects . Intravenous vasodilator agents might lead to an increase in intrapulmonary shunting and systemic hypotension, which can limit their therapeutic use . Nitric oxide as an endogenous vasodilatory substance is of particular interest in pulmonary hypertension, considering its selective pulmonary action . Although iNO therapy has not been associated with improved survival rates in adult intensive care patients, the application of iNO inhalation can serve as a salvage therapy for ARDS in adults, as it temporarily improves arterial oxygenation . SIN-1A (3-morpholino-syndnonimine) is the active metabolite of the orally administered prodrug molsidomine stabilized by cyclodextrin. Therefore, its stability allows us to provide inhalation therapy without a complicated delivery system. In our experiment, iNO therapy was provided as the standard dose for therapy (20 ppm) that might be associated with the optimized benefit–risk ratio by providing significant hemodynamic impact with less probability of adverse effects .
|
[
"Attila Oláh",
"Bálint András Barta",
"Mihály Ruppert",
"Alex Ali Sayour",
"Dávid Nagy",
"Tímea Bálint",
"Georgina Viktória Nagy",
"István Puskás",
"Lajos Szente",
"Levente Szőcs",
"Tamás Sohajda",
"Endre Zima",
"Béla Merkely",
"Tamás Radovits"
] |
https://doi.org/10.3390/ijms25147981
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277253_p10
|
PMC11277253
|
sec[2]/p[3]
|
3. Discussion
| 4.28125 |
biomedical
|
Study
|
[
0.99951171875,
0.0004792213439941406,
0.00015437602996826172
] |
[
0.99609375,
0.0003407001495361328,
0.0035114288330078125,
0.00016057491302490234
] |
Inhalation of NO was associated with a significant reduction in PAP and PVR (approximately 30–40% decrease in pressure) and its effect was comparable to other studies, where iNO therapy was provided in pathological conditions in human and animal models . With the potential toxicity, rebound phenomenon, high cost, and unsatisfactory response rate associated with iNO, alternative treatment options have been tested. Inhaled prostacyclin showed similar efficacy compared to iNO therapy . SIN-1A therapy was also associated with a significant reduction in PAP. Oral administration of the NO donor molsidomine might attenuate hypoxia-related PH syndrome by enhancing the NO-cGMP pathway in experimental settings and in human cases . Therefore, inhalation of molsidomine-derived pharmacological agents might result in an effective local treatment in alveoli, where pulmonary vasoconstriction is the primary cause of ventilation–perfusion mismatch. We could also observe the dose-dependent impact of SIN-1A: while 5 mg could not lead to the same pronounced effect as iNO, SIN-1A-10 therapy was associated with a similar impact on the pulmonary circulation . This is an important feature as other promising drugs could not reach the same effect in previous studies as iNO . We should also mention that SIN-1A-10 showed similar pharmacodynamics to iNO regarding pulmonary resistance, reaching its maximal effect after 15 min . The lack of delay in effect might be a crucial characteristic in the setting of acute PH, especially in the case of ARDS caused by fulminant pulmonary infection.
|
[
"Attila Oláh",
"Bálint András Barta",
"Mihály Ruppert",
"Alex Ali Sayour",
"Dávid Nagy",
"Tímea Bálint",
"Georgina Viktória Nagy",
"István Puskás",
"Lajos Szente",
"Levente Szőcs",
"Tamás Sohajda",
"Endre Zima",
"Béla Merkely",
"Tamás Radovits"
] |
https://doi.org/10.3390/ijms25147981
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
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