Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer.

Cyclin-dependent kinases (CDKs) are a broad family of proteins involved in the cell cycle and transcriptional regulation. In this article, we explore the antitumoral activity of a novel proteolysis-targeting chimera (PROTAC) compound against CDK9. Breast cancer cell lines from different subtypes were used. Transcriptomic mapping of CDKs in breast cancer demonstrated that the expression of CDK9 predicted a detrimental outcome in basal-like tumors (HR = 1.51, CI = 1.08-2.11, p = 0.015) and, particularly, in the luminal B subtype with HER2+ expression (HR = 1.82, CI = 1.17-2.82, p = 0.0069). The novel CDK9 PROTAC, THAL-SNS-032, displayed a profound inhibitory activity in MCF7, T47D, and BT474 cells, with less effect in SKBR3, HCC1569, HCC1954, MDA-MB-231, HS578T, and BT549 cells. The three cell lines with HER2 overexpression and no presence of ER, SKBR3, HCC1569, and HCC1954 displayed an EC50 three times higher compared to ER-positive and dual ER/HER2-positive cell lines. BT474-derived trastuzumab-resistant cell lines displayed a particular sensitivity to THAL-SNS-032. Western blot analyses showed that THAL-SNS-032 caused a decrease in CDK9 levels in BT474, BT474-RH, and BT474-TDM1R cells, and a significant increase in apoptosis. Experiments in animals demonstrated an inverse therapeutic index of THAL-SNS-032, with doses in the nontherapeutic and toxic range. The identified toxicity was mainly due to an on-target off-tumor effect of the compound in the gastrointestinal epithelium. In summary, the potent and efficient antitumoral properties of the CDK9 PROTAC THAL-SNS-032 opens the possibility of using this type of compound in breast cancer only if specifically delivered to cancer cells, particularly in ER/HER2-positive and HER2-resistant tumors.

Pharmacological screening and transcriptomic functional analyses identify a synergistic interaction between dasatinib and olaparib in triple-negative breast cancer.

Identification of druggable vulnerabilities is a main objective in triple-negative breast cancer (TNBC), where no curative therapies exist. Gene set enrichment analyses (GSEA) and a pharmacological evaluation using a library of compounds were used to select potential druggable combinations. MTT and studies with semi-solid media were performed to explore the activity of the combinations. TNBC cell lines (MDAMB-231, BT549, HS-578T and HCC3153) and an additional panel of 16 cell lines were used to assess the activity of the two compounds. Flow cytometry experiments and biochemical studies were also performed to explore the mechanism of action. GSEA were performed using several data sets (GSE21422, GSE26910, GSE3744, GSE65194 and GSE42568), and more than 35 compounds against the identified functions were evaluated to discover druggable opportunities. Analyses done with the Chou and Talalay algorithm confirmed the synergy of dasatinib and olaparib. The combination of both agents significantly induced apoptosis in a caspase-dependent manner and revealed a pleotropic effect on cell cycle: Dasatinib arrested cells in G0/G1 and olaparib in G2/M. Dasatinib inhibited pChk1 and induced DNA damage measured by pH2AX, and olaparib increased pH3. Finally, the effect of the combination was also evaluated in a panel of 18 cell lines representative of the most frequent solid tumours, observing a particularly synergism in ovarian cancer. Breast cancer, triple negative, dasatinib, olaparib, screening.

Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer.

Basal-like breast cancer is an incurable disease with limited therapeutic options, mainly due to the frequent development of anti-cancer drug resistance. Therefore, identification of druggable targets to improve current therapies and overcome these resistances is a major goal. Targeting DNA repair mechanisms has reached the clinical setting and several strategies, like the inhibition of the CHK1 kinase, are currently in clinical development. Here, using a panel of basal-like cancer cell lines, we explored the synergistic interactions of CHK1 inhibitors (rabusertib and SAR020106) with approved therapies in breast cancer and evaluated their potential to overcome resistance. We identified a synergistic action of these inhibitors with agents that produce DNA damage, like platinum compounds, gemcitabine, and the PARP inhibitor olaparib. Our results demonstrated that the combination of rabusertib with these chemotherapies also has a synergistic impact on tumor initiation, invasion capabilities, and apoptosis in vitro. We also revealed a biochemical effect on DNA damage and caspase-dependent apoptosis pathways through the phosphorylation of H2AX, the degradation of full-length PARP, and the increase of caspases 3 and 8 activity. This agent also demonstrated synergistic activity in a platinum-resistant cell line, inducing an increase in cell death in response to cisplatin only when combined with rabusertib, while no toxic effect was found on non-tumorigenic breast tissue-derived cell lines. Lastly, the combination of CHK1 inhibitor with cisplatin and gemcitabine resulted in more activity than single or double combinations, leading to a higher apoptotic effect. In conclusion, in our study we identify therapeutic options for the clinical development of CHK1 inhibitors, and confirm that the inhibition of this kinase can overcome acquired resistance to cisplatin.

Syndemic factors associated with drinking patterns among Latino men and Latina transgender women who have sex with men in New York City.

Alcohol consumption is a significant public health concern among Latino men and Latina transgender women who have sex with men. However, characteristics and behaviors associated with alcohol consumption in this population, particularly in regard to the complex influence of syndemic factors, remain understudied. The purpose of this study was to examine predictors of high-risk alcohol consumption (i.e. binge or heavy drinking). Between January and March of 2014, 176 Latino men and Latina transgender women in New York City completed an interviewer-administered questionnaire. We developed a syndemics scale to reflect the total number of syndemic factors - clinically significant depression, childhood sexual abuse, intimate partner violence, and discrimination - reported by each participant. We also carried out a multinomial logistic regression model predicting binge and heavy drinking. Forty-seven percent of participants reported high-risk alcohol consumption in the past 30 days (21% binge and 26% heavy). Approximately 16% of participants reported no syndemic factors, 27% reported one factor, 39% reported two factors, and 18% reported three or four. In the multinomial logistic regression model, our syndemic factors scale was not significantly associated with binge drinking. However, participants who reported three or four factors were significantly more likely to report heavy drinking. In addition, having multiple sexual partners was associated with an increased risk of binge and heavy drinking; involvement in a same-sex relationship was associated with binge drinking. Further work is needed to develop effective prevention intervention approaches for high-risk alcohol consumption within this population.

The guanine exchange factor SWAP70 mediates vGPCR-induced endothelial plasticity.

BACKGROUND: The viral G protein-coupled receptor (vGPCR) is proposed to act as one of the predominant mediators of Kaposi's sarcoma (KS), a human herpes virus 8 (HHV8)-elicited disease. The actions of vGPCR manifest pathogenesis, in part, through increased permeability of endothelial cells. Endothelial cell-cell junctions have indeed emerged as an instrumental target involved in the vasculature defects observed within the tumor microenvironment. The pathway leading to adherens junction destabilization has been shown to involve the activation of the small GTPase Rac, in the context of either latent infection or the sole expression of vGPCR. However, the precise molecular mechanisms governed by vGPCR in vascular leakage require further elucidation. FINDINGS: Guanine exchange factors (GEFs) function as critical molecular switches that control the activation of small GTPases. We therefore screened the effects of 80 siRNAs targeting GEFs on vGPCR-driven endothelial permeability and identified switch-associated protein 70 (SWAP70) as necessary for its elevating effects. Pull-down experiments further showed that Rac activation by vGPCR was dependent on SWAP70. Examination of tissues and cells from HHV8-positive patients revealed that SWAP70 was ubiquitously expressed. Furthermore, SWAP70 was found to be crucial for vGPCR-driven endothelial tube formation and endothelial sprouting in vitro. CONCLUSIONS: SWAP70 appears to act as a molecular intermediate between vGPCR and endothelial activation. Because of the important role of vGPCR-mediated endothelial plasticity in KS pathogenesis, inhibition of SWAP70 function could be of interest for blocking vGPCR-driven activities in HHV8-defined diseases.

Intimate partner violence and sexual health: voices and images of Latina immigrant survivors in southwestern United States.

Intimate partner violence (IPV), which describes physical and/or sexual assault of a spouse or sexually intimate companion, is a common health care issue across the globe. However, existing health outcomes studies are limited. Additionally, no study to our knowledge has specifically focused on the relationship between IPV and sexual health among Latina immigrants in southwestern United States. Through the use of photovoice methodology and a community-based participatory research approach, we assessed these types of relationships drawing on data gathered from 22 Latina survivors of IPV and 20 community stakeholders in El Paso, Texas. Participants identified two major themes: the different expressions of domestic violence and the need for access to sexual and reproductive health services. Community stakeholders and participants identified practical and achievable recommendations and actions including the development of a promotora training program on IPV and sexual health. This assessment extends beyond HIV and STI risk behaviors and highlights disease prevention within a wellness and health promotion framework.

Decision-making deficits in pathological gambling: the role of executive functions, explicit knowledge and impulsivity in relation to decisions made under ambiguity and risk.

BACKGROUND: A variety of cognitive and emotional processes influence the decision-making deficits observed in pathological gambling (PG). This study investigated the role of immediate/delayed sensitivity to reward and punishment, executive functions, impulsivity and explicit knowledge in relation to decision-making performance on the original Iowa Gambling Task (IGT-ABCD) and a variant (IGT-EFGH). METHODS: We assessed 131 consecutive patients with a diagnosis of PG by using executive functioning and decision-making tasks, self-report measures of impulsivity and explicit knowledge. RESULTS: The majority of pathological gamblers (PGs) showed deficits in decision-making, characterized mainly by myopia for the future. Decisions made under risk showed different predictors. Performance on the IGT-ABCD for decisions made under risk was predicted by medium and high levels of explicit knowledge of the task, as well as by scores on the Disorderliness subscale and the degree of Stroop interference. By contrast, IGT-EFGH results were only associated with self-report impulsivity measures. CONCLUSIONS: Decision making in PG involves distinct patterns of deficits, and the predictors differ depending on the reinforcement schedule. Decisions made under risk on the IGT-ABCD are associated with explicit knowledge, executive functions and impulsivity traits related to conscious awareness and control processes. On the IGT-EFGH, however, only impulsivity traits predict decision making.

Tuberculosis stigma and perceptions in the US-Mexico border.

OBJECTIVE: To examine the experiences and perspectives on the disease and stigma from the vantage point of the persons affected by TB in El Paso, Texas, and Juárez, México to inform research on health-related stigma and interventions. MATERIALS AND METHODS: Semi-structured interviews to study TB-related stigma and the impact on access and health-seeking behaviors with 30 Mexican-origin adults (18 years and older) undergoing TB treatment. RESULTS: Barriers to accessing health services for TB; emotional distress due to their deteriorated physical and emotional condition; reactions ranging from depression, sadness; doubt, anger, and fear of rejection; distancing, fear of contagion, stigma, and feeling of discriminated against, and isolation from loved ones were reported. CONCLUSION: Stigma associated with TB is a barrier to health care access and to quality of life in tuberculosis management. Stigma adversely shapes the experience of treatment and recovery. Stigma is not a naturally occurring phenomenon, but something created by people and as such it can be "un-done" by those people as part of a collective which comprises society.

Addressing knowledge gaps: the key role of community health workers and healthcare providers in human papillomavirus prevention and vaccine uptake in a border community.

The Human Papillomavirus (HPV) is the most common sexually transmitted infection and nearly every person who is sexually active will get HPV at some point in their lifetime without having the HPV vaccine. Healthcare Providers (HCPs) and Community Health Workers (CHWs) play an essential role in promoting the HPV vaccine and providing education about HPV in communities. Three focus groups with CHWs (n = 17) and HCPs (n = 7) were conducted and led by trained facilitators. In addition to participating in the focus group, CHWs and HCPs completed a brief questionnaire. Focus groups were voice recorded and transcribed for qualitative analysis. Independent coders conducted content analysis to identify the salient themes of the focus groups. Several important findings emerged from this study highlighting the barriers to HPV knowledge, gaps in the self-perceived role of HPV cancer prevention, and opportunities to action. Financial, knowledge, patriarchy, behaviors, attitudes, and fears were identified as the perceived patient-related barriers to promoting HPV cancer prevention. Both CHWs and HCPs explained that their female patients are often discouraged by their husbands from seeking out sexual health-related healthcare. Finding suggest the need for community tailored education on HPV and "best practice" trainings for HPV prevention that is applicable to both CHWs and HCPs.

Hispanic Survivors and Caregivers of Human Papillomavirus-Associated Cancers: Lived Experiences in a U.S.-Mexico Border Community.

Although human papillomavirus (HPV)-associated cancers are preventable and treatable at early stages, health disparities in HPV-associated cancer outcomes continue to exist among Hispanic populations. Hispanics residing along the U.S.-Mexico border face barriers distinct from other geographically dispersed populations within the United States. The current research aimed to explore perspectives and lived experiences of survivors and caregivers of HPV-associated cancers in El Paso, Texas, to inform intervention development and health practices to increase preventive services among populations residing on the U.S.-Mexico border region. A mixed-method approach was employed using a semi-structured interview guide with Quality of Life (QOL) scales with (N = 29) survivors and caregivers of HPV-associated cancers. Content analysis was used to extract themes and descriptive statistics were reported for quality of life. Five major themes were identified: (1) barriers to preventive services and treatment; (2) role of health care providers in diagnosis and care; (3) treatment challenges, support systems, and challenges associated with caregiving; and (4) HPV prevention and health recommendations from survivors and caregivers. Finally, given the context of the COVID-19 pandemic, an additional theme was explored on accessibility to health and human services. QOL scales suggested better overall physical health and spiritual well-being in survivors and fear of reoccurrence among caregivers and survivors. The current research highlights the role of health care providers and human service professionals in the promotion of health practices of at-risk populations by increasing health literacy among cancer patients and caregivers, and exploring experiences, challenges, and messages caregivers and survivors had regarding HPV prevention.

Hear my voice: understanding how community health workers in the Peruvian Amazon expanded their roles to mitigate the impact of the COVID-19 pandemic through community-based participatory research.

INTRODUCTION: The COVID-19 pandemic led to the collapse of the Peruvian health system, disrupting healthcare access for indigenous communities in the Amazon. Our study analysed how community health workers (CHWs) from indigenous communities in the Peruvian Amazon expanded their roles to mitigate the effects of the COVID-19 pandemic. METHODS: Fourteen CHWs from Loreto, Peru, participated in a community-based participatory research project using Photovoice, a technique encouraging vulnerable groups to take photos and develop stories illustrating their lived experiences. Participants were recruited from Mamás del Río, a local university-based programme, through purposive sampling. CHWs were asked to photograph how the pandemic affected their lives and work. Participants met four times over 5 months to share photos and develop action items. Data were organised into key themes using thematic analysis. CHWs shared photo galleries with policy-makers in Loreto and Lima. RESULTS: CHWs produced 36 photos with 33 texts highlighting their roles during COVID-19. Three core themes emerged: the (1) collapse of health infrastructure, (2) use of medicinal plants versus pharmaceuticals and (3) community adaptations and struggles. The leadership of CHWs emerged as a cross-cutting theme as CHWs supported COVID-19 efforts without government training or resources. CHWs asked policy-makers for formal integration into the health system, standardisation of training and management of community pharmacies. CONCLUSION: CHWs demonstrated their leadership and expanded their roles during the pandemic with little to no training from the government. Global investment in robust CHW programmes can fortify healthcare delivery.

TACkling Cancer by Targeting Selective Protein Degradation.

Targeted protein degradation has emerged as an alternative therapy against cancer, offering several advantages over traditional inhibitors. The new degrader drugs provide different therapeutic strategies: they could cross the phospholipid bilayer membrane by the addition of specific moieties to extracellular proteins. On the other hand, they could efficiently improve the degradation process by the generation of a ternary complex structure of an E3 ligase. Herein, we review the current trends in the use of TAC-based technologies (TACnologies), such as PROteolysis TArgeting Chimeras (PROTAC), PHOtochemically TArgeting Chimeras (PHOTAC), CLIck-formed Proteolysis TArgeting Chimeras (CLIPTAC), AUtophagy TArgeting Chimeras (AUTAC), AuTophagosome TEthering Compounds (ATTEC), LYsosome-TArgeting Chimeras (LYTAC), and DeUBiquitinase TArgeting Chimeras (DUBTAC), in experimental development and their progress towards clinical applications.

The Use of Photovoice Methodology to Assess Health Needs and Identify Opportunities Among Migrant Transgender Women in the U.S.-Mexico Border.

Psychosocial, social and structural conditions have rarely been studied among transgender women in the U.S.-Mexico Border. This study used Photovoice methodology to empower migrant transgender women of color (TWC) to reflect on realities from their own perspectives and experiences and promote critical dialogue, knowledge, and community action. Sixteen participants documented their daily experiences through photography, engaged in photo-discussions to assess needs and identify opportunities, and developed a community-informed Call to Action. Four major themes emerged from the participants' photographs, discussions, and engagement: (1) mental health, (2) migration experiences and challenges, (3) stigma, discrimination, and resiliency, and (4) impact of the COVID-19 pandemic. Through active community engagement, a Call to Action was developed. A binational advisory committee of decision makers and scholars reviewed a set of recommendations to better respond to the needs of TWC in the U.S.-Mexico Border. Photovoice served as an empowerment tool for TWC to assess the myriad of syndemic conditions, including mental health, stigma, discrimination and COVID-19, affecting them daily and identify initiatives for change.

Analysis of Cancer Knowledge, Attitudes, and Practices in Adolescents and Young Adults in Two Texas Rural Communities.

The Youth and Young Adults Cancer Knowledge Attitudes and Practices (C-KAP) exploratory study in 2 rural underserved areas in a border community. C-KAP is an interdisciplinary research pilot project led by university scholars in psychology and social work in partnership with community partners. The exploratory cross-sectional mix-method study recruited 141 (n=141) youth and young adults (ages 18-39). This study was informed on empirical research and a bilingual online questionnaire was field-tested, and data was collected via QuestionPro Software. Quantitative analysis was conducted using SPSS version 27. Descriptive statistics and frequency analysis were used for demographics and basic statistics. Chi square tests and Fisher's exact tests between variables were ran to find statistically significant associations. For the qualitative data, independent coders conducted recurrent content analysis to identify themes. Salient themes include knowledge about cancer types; access to health care; prevention; and the perceived impact of COVID-19 pandemic. Findings highlight a lack of knowledge and orientation on cancer in youth and young adults suggesting the need for community tailored education and screening interventions. Other findings reflect gender differences in knowledge and practices, which indicates that a gender-specific lens is needed when delivering education.

Food and housing security at a US Hispanic-Serving Institution: An examination before and during the COVID-19 pandemic.

University students occupy a socially marginal position and therefore are often underserved by academic and service institutions. This article analyzes food and housing security among students at The University of Texas at El Paso, a Hispanic-Serving Institution located in the U.S.-Mexico Border region. Findings of a sample of n = 7,633 university students are presented in the first cross-sectional, two-year food and housing security study on campus administered via platform Campus Labs Baseline. The first sample in 2019 consisted of n = 2,615 students representing 10.4% of student enrollment (25,177 total 2019 enrollment), and the second sample in 2020 was n = 5,018 representing 20.2% of student enrollment (24,879 total 2020 enrollment). To measure food security, the six-item short form of the U.S. Department of Agriculture (USDA) Household Food Security Survey Module was used. To document housing security, we created questions informed by student input. In this study, survey results are reported, and tests are conducted to assess the relationships between various student characteristics and food and housing security. Student characteristics significantly impacting food and housing security are probed further using data visualizations and subpopulation analysis with a focus on analyzing factors impacted by the COVID-19 pandemic. Results indicate that employment status, consistent employment status, hours per week, academic level, number of dependents, and gender are all factors associated with food security during the pandemic but not prior to the pandemic. Other factors, including, college affiliation, ethnicity/race, having any dependents and being head of household, living alone, mode of campus transportation and mode of the transportation, household income, and age, all were associated with food security in both academic years. Using these results, a critical analysis of past interventions addressing food and housing security is presented with a focus on changes made during the pandemic. Recommendations are made for further data-driven interventions and future steps.

Effect of executive functioning, decision-making and self-reported impulsivity on the treatment outcome of pathologic gambling.

BACKGROUND: Impairments in self-regulatory behaviour reflect a deficit in executive functioning and decision-making, as well as higher levels of self-reported impulsivity, and may be involved in the development and maintenance of addictive disorders. We sought to explore the association between self-reported impulsivity and neurocognitive measures, and their association with treatment outcome in pathologic gambling. METHODS: We assessed patients with pathologic gambling using executive functioning and decision-making tests and self-report measures of impulsivity. Patients underwent cognitive-behavioural therapy (CBT) for pathologic gambling. RESULTS: We included 88 patients (8% women) in our study. High self-reported extravagance was associated with poor performance in the Iowa Gambling Task (IGT)-ABCD version. High impulsiveness, low disorderliness, high exploratory excitability (trend), poor backward block span and poor IGT-EFGH scores (trend) predicted dropout. We observed no self-reported or neurocognitive predictors of relapse or number of treatment sessions attended. LIMITATIONS: Most participants were slot-machine gamblers seeking treatment. No follow-up data and no control group were included in the study. The missing sample (i.e., individuals who were recruited and assessed in the pretreatment stage but who chose not to begin treatment) had higher extravagance scores than the final sample. CONCLUSION: Neurocognitive reward sensitivity was related to self-reported overspending behaviour. Self-regulatory impairments (especially rash impulsiveness and punishment sensitivity) and executive dysfunction predicted only dropout of CBT in participants with pathologic gambling. Different neurocognitive processes and personality traits might mediate treatment response to psychological therapy of pathologic gambling according to the specific target variable assessed.

Photovoice: Integrating Course-Based Research in Undergraduate and Graduate Social Work Education.

Research skills are vital to students' professional careers and must be cultivated in the social work curriculum. While students and faculty may hesitate to participate in a course-based research project, the authors believe that the Photovoice method is easily adapted to a variety of class and student needs. Photovoice is a field-oriented and qualitative research method that visually documents and communicates community assets and needs. The first purpose of this article is to offer Photovoice as a potential model for instructors to implement a course-based research project. The second purpose is to quantitatively assess changes in students' reported confidence in social work topics and research activities. Data revealed that the students reported increased confidence in the majority of the content and research evaluated; content examples include economic justice and determinants of social inequalities; research examples include analysing data for patterns and identifying the limitations of research methods. The data illustrate the pedagogical power of Photovoice.

The Impact of Restrictive Policies on Mexican Immigrant Parents and Their Children's Access to Health Care.

Background: This study assessed whether policies that limit Mexican immigrants' access to care affects their children's access to a regular source of care, health insurance, and timely preventive health visits. Method: This was a cross-sectional study among Mexican immigrant parents who attended a health promotion program in Texas, Nevada, New York, and Illinois. A sociodemographic survey, including parental and child variables, was administered. Results: Children of parents without health insurance were almost four times more likely to be uninsured and eight times more likely to lack a regular source of care. Children of parents without a regular source of care were less than half as likely to have their own regular source of care than children whose parents had a regular source of care. Discussion: Findings suggest when parents are uninsured/lack a regular source of care, a child's health disparity is created. Reducing disparities in health care coverage, affecting foreign-born parents, positively impacts their children's access to care. Clinical Trial Registration number: NCT03209713.

Genomic Correlates of DNA Damage in Breast Cancer Subtypes.

Among the described druggable vulnerabilities, acting on the DNA repair mechanism has gained momentum, with the approval of PARP inhibitors in several indications, including breast cancer. However, beyond the mere presence of BRCA1/BRCA2 mutations, the identification of additional biomarkers that would help to select tumors with an extreme dependence on DNA repair machinery would help to stratify therapeutic decisions. Gene set enrichment analyses (GSEA) using public datasets evaluating expression values between normal breast tissue and breast cancer identified a set of upregulated genes. Genes included in different pathways, such as ATM/ATR, BARD1, and Fanconi Anemia, which are involved in the DNA damage response, were selected and confirmed using molecular alterations data contained at cBioportal. Nineteen genes from these gene sets were identified to be amplified and upregulated in breast cancer but only five of them NBN, PRKDC, RFWD2, UBE2T, and YWHAZ meet criteria in all breast cancer molecular subtypes. Correlation of the selected genes with prognosis (relapse free survival, RFS, and overall survival, OS) was performed using the KM Plotter Online Tool. In last place, we selected the best signature of genes within this process whose upregulation can be indicative of a more aggressive phenotype and linked with worse outcome. In summary, we identify genomic correlates within DNA damage pathway associated with prognosis in breast cancer.

Pathogenic Microenvironment from Diabetic-Obese Visceral and Subcutaneous Adipocytes Activating Differentiation of Human Healthy Preadipocytes Increases Intracellular Fat, Effect of the Apocarotenoid Crocetin.

In diabetes mellitus type 2 (DM2), developed obesity is referred to as diabesity. Implementation of a healthy diet, such as the Mediterranean, prevents diabesity. Saffron is frequently used in this diet because of its bioactive components, such as crocetin (CCT), exhibit healthful properties. It is well known that obesity, defined as an excessive accumulation of fat, leads to cardiometabolic pathology through adiposopathy or hypertrophic growth of adipose tissue (AT).This is related to an impaired adipogenic process or death of adipocytes by obesogenic signals. We aimed to evaluate the effect of the pathogenic microenvironment and CCT, activating differentiation of healthy preadipocytes (PA). For this, we used human cryopreserved PA from visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) depots obtained from healthy and obese-DM2 donors. We studied the effect of a metabolically detrimental (diabesogenic) environment, generated by obese-DM2 adipocytes from VAT (VdDM) or SAT (SdDM), on the viability and accumulation of intracellular fat of adipocytes differentiated from healthy PA, in the presence or absence of CCT (1 or 10 µM). Intracellular fat was quantified by Oil Red O staining. Cytotoxicity was measured using the MTT assay. Our results showed that diabesogenic conditions induce cytotoxicity and provide a proadipogenic environment only for visceral PA. CCT at 10 µM acted as an antiadipogenic and cytoprotective compound.