Perfluoroalkyl/Polyfluoroalkyl Substances: Links to Cardiovascular Disease Risk.

Conservative estimates by the World Health Organization suggest that at least a quarter of global cardiovascular diseases are attributable to environmental exposures. Associations between air pollution and cardiovascular risk have garnered the most headlines and are strong, but less attention has been paid to other omnipresent toxicants in our ecosystem. Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are man-made chemicals that are extensively used in industrial and consumer products worldwide and in aqueous film-forming foam utilized in firefighting. As such, our exposure to PFAS is essentially ubiquitous. Given the long half-lives of these degradation-resistant chemicals, virtually, all people are carrying a body burden of PFAS. Health concerns related to PFAS are growing such that the National Academies of Sciences, Engineering and Medicine has recommended standards for clinical follow-up of individuals with high PFAS blood levels, including prioritizing screening for dyslipidemia. The link between PFAS and dyslipidemia has been extensively investigated, and evidence for associations is compelling. However, dyslipidemia is not the only cardiovascular risk factor with which PFAS is associated. Here, we review the epidemiological evidence for links between PFAS of concern identified by the National Academies of Sciences, Engineering and Medicine and risk factors for cardiovascular disease, including overweight/obesity, glucose intolerance, hypertension, dyslipidemia, and hyperuricemia. Moreover, we review the potential connections of PFAS with vascular disease and atherosclerosis. While observational data support associations between the National Academies of Sciences, Engineering and Medicine PFAS and selected cardiac risk factors, additional research is needed to establish causation and better understand how exposure to PFAS leads to the development of these conditions.

Associations between change in BMI and the risk of hypertension and dyslipidaemia in people receiving integrase strand-transfer inhibitors, tenofovir alafenamide, or both compared with other contemporary antiretroviral regimens: a multicentre, prospective observational study from the RESPOND consortium cohorts.

BACKGROUND: Integrase strand-transfer inhibitors (INSTIs) and tenofovir alafenamide have been associated with weight gain in several clinical trials and observational cohorts. However, whether weight gain associated with INSTIs and tenofovir alafenamide confers a higher risk of weight-related clinical events is unclear. We aimed to assess whether changes in BMI differentially increase hypertension or dyslipidaemia risk in people with HIV receiving INSTIs, tenofovir alafenamide, or both versus other contemporary regimens. METHODS: This multicentre, prospective observational study analysed prospective data from RESPOND, an international consortium of HIV cohorts for which recruitment began in 2017 and is still ongoing from HIV clinics and hospitals in 37 European countries and Australia. Participants were eligible if they were aged 18 years or older, receiving INSTI-containing antiretroviral therapy (ART) regimens or a contemporary non-INSTI, did not have hypertension or dyslipidaemia at baseline, and had baseline and at least two follow-up BMI, lipid, and blood pressure measurements. We excluded participants without baseline CD4 or HIV RNA results and those receiving non-ART medications associated with weight changes, including antipsychotics and mood stabilisers, corticosteroids, insulin, and insulin secretagogues. They were followed up from baseline until the earliest hypertension or dyslipidaemia event, their last visit, or Dec 31, 2021, whichever was earlier. The primary outcomes were incidence of hypertension and dyslipidaemia, for which we used multivariable Poisson regression adjusted for time-updated BMI to determine unadjusted and adjusted incidence rate ratios (IRRs) of hypertension and dyslipidaemia in people receiving INSTIs, tenofovir alafenamide, or both, and tested for interaction between time-updated ART regimen and BMI. FINDINGS: Of the 35 941 RESPOND participants, 9704 (7327 [75·5 %] male and 2377 [24·5%] female) were included in the hypertension analysis and 5231 (3796 [72·6%] male and 1435 [27·4%] female) were included in the dyslipidaemia analysis. In the univariable model, hypertension was more common in individuals receiving an INSTI with tenofovir alafenamide (IRR 1·70, 95% CI 1·54-1·88) or an INSTI without tenofovir alafenamide (1·41, 1·30-1·53) compared with those receiving neither INSTIs nor tenofovir alafenamide. Adjustment for time-updated BMI and confounders attenuated risk in participants receiving an INSTI with (IRR 1·48, 1·31-1·68) or without (1·25, 1·13-1·39) tenofovir alafenamide. Similarly, dyslipidaemia was more common in participants using tenofovir alafenamide with an INSTI (IRR 1·24, 1·10-1·40) and tenofovir alafenamide alone (1·22, 1·03-1·44) than in participants using neither INSTI nor tenofovir alafenamide. Adjustment for BMI and confounders attenuated the risk in participants receiving tenofovir alafenamide with an INSTI (adjusted IRR 1·21, 1·07-1·37), whereas the risk in those receiving tenofovir alafenamide alone became non-significant (1·15, 0·96-1·38). The associations between increasing BMI and risk of hypertension and dyslipidaemia did not differ between participants receiving different ART regimens (pinteraction=0·46 for hypertension; pinteraction=0·31 for dyslipidaemia). INTERPRETATION: Although residual confounding cannot be entirely excluded, the use of INSTIs was associated with incident hypertension, and the use of tenofovir alafenamide was associated with dyslipidaemia, with the latter association partly mediated by weight gain. These results reiterate the need for hypertension and dyslipidaemia screening in people with HIV. FUNDING: The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The Brighton HIV Cohort, The National Croatian HIV Cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort, The University of Cologne HIV Cohort, Merck Life Sciences, ViiV Healthcare, and Gilead Sciences.

Long-term Bisphenol S exposure induced gut microbiota dysbiosis, obesity, hepatic lipid accumulation, intestinal lesions and dyslipidemia in mice.

Bisphenol S (BPS) is a commonly detected chemical raw material in water, which poses significant threats to both the ecological environment and human health. Despite being recognized as a typical endocrine disruptor and a substitute for Bisphenol A, the toxicological effects of BPS remain nonnegligible. In order to comprehensively understand the health impacts of BPS, a long-term (154 days) exposure experiment was conducted on mice, during which the physiological indicators of the liver, intestine, and blood were observed. The findings revealed that exposure to BPS resulted in dysbiosis of the gut microbiota, obesity, hepatic lipid accumulation, intestinal lesions, and dyslipidemia. Furthermore, there exists a significant correlation between gut microbiota and indicators of host health. Consequently, the identification of specific gut microbiota can be considered as potential biomarkers for the evaluation of risk associated with BPS. This study will effectively address the deficiency in toxicological data pertaining to BPS. The novel BPS data obtained from this research can serve as a valuable reference for professionals in the field.

Associations of bisphenol A exposure with metabolic syndrome and its components: A systematic review and meta-analysis.

Mounting evidence shows that bisphenol A (BPA) is associated with metabolic risk factors. The aim of this study was to review related epidemiologic studies and conduct a meta-analysis to quantitatively estimate the association between BPA and metabolic syndrome. Four electronic databases were systematically searched to identify suitable articles. A total of 47 published studies were finally included. Two studies involved metabolic syndrome. Of the 17, 17, 14, and 13 studies on the relationship between BPA with abdominal obesity, blood pressure, fasting plasma glucose, and dyslipidemia, 10, 6, 3, and 4 studies were included in the meta-analysis, respectively. The results showed that the risk of abdominal obesity increased with the increase of BPA exposure, especially in the group with higher BPA exposure levels (Quartile 2 vs. Quartile 1, pooled OR = 1.16, 95%CI: 1.01, 1.33; Q3 vs. Q1, pooled OR = 1.31, 95%CI: 1.13, 1.51; Q4 vs. Q1, pooled OR = 1.40, 95%CI: 1.21, 1.61). However, there was no significant correlation between BPA exposure and metabolic syndrome components including hypertension, abnormal fasting plasma glucose, and dyslipidemia. The present study found that BPA exposure is significantly associated with a higher risk of abdominal obesity. However, the relationship between BPA with metabolic syndrome and its other components needs further longitudinal studies to verify.

Associations of polychlorinated biphenyls exposure, lifestyle, and genetic susceptibility with dyslipidemias: Evidence from a general Chinese population.

Polychlorinated biphenyls (PCBs) are endocrine-disrupting chemicals that have been associated with various adverse health conditions. Herein we explored the associations of PCBs with dyslipidemia and further assessed the modification effect of genetic susceptibility and lifestyle factors. Six serum PCBs (PCB-28, 101, 118, 138, 153, 180) were determined in 3845 participants from the Wuhan-Zhuhai cohort. Dyslipidemia, including hyper-total cholesterol (HyperTC), hyper-triglyceride (HyperTG), hyper-low density lipoprotein cholesterol (HyperLDL-C), and hypo-high density lipoprotein cholesterol (HypoHDL-C) were determined, and lipid-specific polygenic risk scores (PRS) and healthy lifestyle score were constructed. We found that all six PCB congeners were positively associated with the prevalence of dyslipidemias, and ΣPCB level was associated with HyperTC, HyperTG, and HyperLDL-C in dose-response manners. Compared with the lowest tertiles of ΣPCB, the odds ratios (95% confidence intervals) in the highest tertiles were 1.490 (1.258, 1.765) for HyperTC, 1.957 (1.623, 2.365) for HyperTG, and 1.569 (1.316, 1.873) for HyperLDL-C, respectively. Compared with those with low ΣPCB, healthy lifestyle, and low genetic risk, participants with high ΣPCB, unfavorable lifestyle, and high genetic risk had the highest odds of HyperTC, HyperTG, and HyperLDL-C. Our study provided evidence that high PCB exposure exacerbated the association of genetic risk and unhealthy lifestyle with dyslipidemia.

Monoclonal antibodies for dyslipidemia in adults: a focus on vulnerable patients groups.

INTRODUCTION: Dyslipidemia significantly contributes to atherosclerotic cardiovascular disease (ASCVD). Patients with lipid-rich vulnerable plaques are particularly susceptible to cardiovascular complications. Despite available lipid-lowering therapies (LLTs), challenges in effective lipid management remain. AREAS COVERED: This article reviews monoclonal antibody (mAb) therapy in dyslipidemia, particularly focusing on vulnerable plaques and patients. We have reviewed the definitions of vulnerable plaques and patients, outlined the efficacy of traditional LLTs, and discussed in-depth the mAbs targeting PCSK9. We extensively discuss the potential mechanisms, intracoronary imaging, and clinical evidence of PCSK9mAbs in vulnerable plaques and patients. A brief overview of promising mAbs targeting other targets such as ANGPTL3 is also provided. EXPERT OPINION: Research consistently supports the potential of mAb therapies in treating adult dyslipidemia, particularly in vulnerable patients. PCSK9mAbs are effective in regulating lipid parameters, such as LDL-C and Lp(a), and exhibit anti-inflammatory and anti-thrombotic properties. These antibodies also maintain endothelial and smooth muscle health, contributing to the stabilization of vulnerable plaques and reduction in adverse cardiovascular events. Future research aims to further understand PCSK9 and other targets like ANGPTL3, focusing on vulnerable groups. Overall, mAbs are emerging as a promising and superior approach in dyslipidemia management and cardiovascular disease prevention.

Long-term exposure to PM1 is associated with increased prevalence of metabolic diseases: evidence from a nationwide study in 123 Chinese cities.

Exposure to particulate matter (PM) has been linked to metabolic diseases. However, the effects of PM with an aerodynamic diameter ≤ 1.0 µm (PM1) on metabolic diseases remain unclear. This study is aimed at assessing the associations of PM1 with metabolic disease risk and quantifying the concentration-response (C-R) relationship of PM1 with metabolic disease risk. A national cross-sectional study was conducted, including 12,495 middle-aged and older adults in 123 Chinese cities. The two-year average concentration of PM1 was evaluated using satellite-based spatiotemporal models. Metabolic diseases, including abdominal obesity, diabetes, hypertension, dyslipidemia, and metabolic syndrome, were identified based on physical examination, blood standard biochemistry examination, and self-reported disease histories. Generalized linear models and C-R curves were used to evaluate the associations of PM1 with metabolic diseases. A total of 12,495 participants were included in this study, with a prevalence of 45.73% for abdominal obesity, 20.22% for diabetes, 42.46% for hypertension, 41.01% for dyslipidemia, and 33.78% for metabolic syndrome. The mean ± standard deviation age of participants was 58.79 ± 13.14 years. In addition to dyslipidemia, exposure to PM1 was associated with increased risks of abdominal obesity, diabetes, hypertension, and metabolic syndrome. Each 10 µg/m3 increase in PM1 concentrations was associated with 39% (odds ratio (OR) = 1.39, 95% confidence interval (CI) 1.33, 1.46) increase in abdominal obesity, 18% (OR = 1.18, 95%CI 1.12, 1.25) increase in diabetes, 11% (OR = 1.11, 95%CI 1.06, 1.16) increase in hypertension, and 25% (OR = 1.25, 95%CI 1.19, 1.31) in metabolic syndrome, respectively. C-R curves showed that the OR values of abdominal obesity, diabetes, hypertension, and metabolic syndrome were increased gradually with the increase of PM1 concentrations. Subgroup analysis indicated that exposure to PM1 was associated with increased metabolic disease risks among participants with different lifestyles and found that solid fuel users were more susceptible to PM1 than clean fuel users. This national cross-sectional study indicated that exposure to higher PM1 might increase abdominal obesity, diabetes, hypertension, and metabolic syndrome risk, and solid fuel use might accelerate the adverse effects of PM1 on metabolic syndrome risk. Further longitudinal cohort studies are warranted to establish a causal inference between PM1 exposure and metabolic disease risk.

A systematic review and meta-analysis of tolerability, cardiac safety and efficacy of inclisiran for the therapy of hyperlipidemic patients.

BACKGROUND: Dyslipidaemia is a crucial risk factor for cardiovascular morbidity and mortality. A short interfering RNA called inclisiran diminishes circulating levels of PCSK9 and LDL-C by hindering PCSK9 translation in the liver. METHODS: RCTs were electronically searched on PubMed, Cochrane Central, and Clinicaltrials.gov to assess the safety and efficacy of inclisiran. Cochrane Review Manager 5 was used to conduct the pooled analysis. Risk of bias was assessed and GRADE pro-GDT was utilized, respectively, to estimate the methodological quality and overall quality of evidence. RESULTS: Of 218 records screened, four studies were included with 2203 participants in inclisiran and 1949 participants in the placebo group. Inclisiran was related to non-significant elevated risk of total adverse events[RR = 1.05(0.98,1.12), p = 0.16; I2 = 53%], non-serious adverse events[RR = 1.09(0.97,1.22),p = 0.15;I2 = 61%] and all-cause mortality[RR = 1.01(0.60,1.70),p = 0.97;I2 = 0%] whereas a lower risk of serious adverse events[RR = 0.94(0.70,1.25),p = 0.67;I2 = 73%], cardiac disorders [RR = 0.87(0.66,1.15),p = 0.33;I2 = 42%] and Major adverse cardiovascular events(MACE)[RR = 0.79(0.62,1.00),p = 0.05; I2 = 0%] as compared to placebo. Inclisiran was also linked to a substantial decline in the percentage of LDL-C, PCSK9, total cholesterol, and Apo B. CONCLUSION: The pooled analysis of the existing evidence shows that inclisiran showed reduced risk of MACE along with excellent efficacy in managing dyslipidemia. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers are NCT03399370, NCT03397121, NCT03400800, and NCT02597127.

Elevated cholesterol levels have been found to be associated with a high risk of heart disease and associated deaths. There are various classes of drugs used to control high low-density lipoprotein cholesterol (LDL-C) levels in blood yet appropriate control and patient compliance, to regular cholesterol-lowering drugs have been an issue. Inclisiran, a novel drug for reducing the LDL-C levels in serum can be given every six months as an effective therapy to minimize the levels of LDL-C in serum. This study was designed to assess the safety and effectiveness of inclisiran in patients with hyperlipidemia. Inclisiran was found to have a non-significant elevated risk of total adverse events, non-serious adverse events, and all-cause mortality. The majority of the adverse events seem to be non-serious and tolerable. There was an observed non-significant lower risk of serious adverse events, cardiac disorders, and significantly reduced risk of major adverse cardiovascular events when compared to placebo. Inclisiran was also linked to a significant decline in the percentage of LDL-C, PCSK9, total cholesterol, and Apo B in patients with hyperlipidemia. With the evidence available at present, inclisiran seems an efficacious and well-tolerated therapeutic strategy to manage elevated cholesterol and LDL-C levels. However, long-term, large cardiovascular outcome trials are required to conclude on the drug's cardiovascular and overall safety.

Bempedoic acid: new evidence and recommendations on use.

PURPOSES OF REVIEW: Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity worldwide. Recognizing the importance of dyslipidemia treatment in the prevention of cardiovascular events has become a part of standard clinical practice. Desired values of LDL cholesterol (LDL-C) have become lower and lower in the last few decades, as evidenced by the most recent guidelines. Therefore, efforts to lower LDL cholesterol concentrations with conventional therapies and combinations of lipid-lowering therapy may not be successful in a high proportion of patients. RECENT FINDINGS: Bempedoic acid is a novel agent, first in-class ATP Citrate Lyase (ACL) inhibitor, which targets biosynthesis of the cholesterol in the liver. Considering the results of phase 3 studies, it has been approved for sole use for dyslipidemia treatment for patients who are statin-intolerant or in combination with statin-ezetimibe for those suffering from familial hypercholesterolemia or ASCVD and unable to reach targeted LDL-C values. SUMMARY: Bempedoic acid has proven beneficial for further reduction of LDL cholesterol for targeted groups of patients. It is not only efficient but also a well tolerated, affordable, and available agent whose place in lipid-lowering management is yet to be fully understood with new data collected from ongoing clinical research. In this review we suggest the place of bempedoic acid in lipid-lowering management.

Risk Factors for Relapse and/or Prolonged Glucocorticoid Therapy in Polymyalgia Rheumatica: Multicenter Study in 185 Patients.

BACKGROUND: In polymyalgia rheumatica (PMR) relapses and long-term GC dependency are common. We assessed risk factors for higher relapse rate and/or prolonged glucocorticoid therapy in PMR patients. METHODS: A multicenter and observational study (chart review) of PMR patients seen between 2006 and 2021 who had at least a 3-month follow-up period after starting GCs was performed. Results were expressed as median and interquartile range 25th-75th or mean ± standard deviation for numerical variables and percentage for categorical ones. Relapse versus nonrelapse groups were compared using Cox proportional analysis. Hazards ratios (HRs) with 95% confidence intervals (CIs) are reported. In all cases, a p value <0.05 was considered to indicate statistical significance. RESULTS: We included 185 patients (69.1% female). The median follow-up time was 17.1 months (interquartile range, 6.8-34.7). Incidence of relapses was 1.2 per 100 persons/month. In univariate analysis, PMR patients with a previous history of dyslipidemia had a lower risk of relapse (HR, 0.55; 95% CI, 0.33-0.94; p = 0.03); high-dose GC (HR, 2.35; 95% CI, 1.42-3.87; p = 0.001) and faster GC dose reduction had higher risk of relapse (HR, 3.04; 95% CI, 1.77-5.21; p = 0.001). In multivariate analysis, a previous history of dyslipidemia had a lower risk of relapse (HR, 0.54; 95% CI, 0.32-0.92; p = 0.023), and high dose of GC (HR, 2.46; 95% CI, 1.49-4.08; p = 0.001) remained the only risk factors for relapse. CONCLUSIONS: Lower doses of corticosteroids and a slow rate of reduction are critical to avoid relapse in PMR. Risk factors for higher relapse rate rely on therapy more than clinical characteristics of the patients at the time of diagnosis of PMR.

High-salt diet induces dyslipidemia through the SREBP2/PCSK9 pathway in dahl salt-sensitive rats.

A high-salt diet is known to increase serum cholesterol levels; however, the underlying mechanism of salt-induced dyslipidemia in patients with salt-sensitivity remains poorly understood. We aimed to investigate whether high-salt diet (HSD) can induce dyslipidemia and elucidate the underlying mechanism of salt-induced dyslipidemia in Dahl salt-sensitive (SS) rats. Metabolomic and biochemical analyses revealed that the consumption of an HSD (8 % NaCl) significantly increased the serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in SS rats. The enzyme-linked immunosorbent assay demonstrated an increase in circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, accompanied by a decrease in hepatic low-density lipoprotein receptor (LDLR) levels due to HSD consumption. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis revealed that HSD consumption activated sterol regulatory element-binding protein-2 (SREBP2) expression in the liver and kidney, resulting in upregulation of PCSK9 at the transcriptional level in the liver and at the translational level in the kidney, ultimately increasing circulating PCSK9 levels. The combined effects of HSD on the liver and kidney contributed to the development of hypercholesterolemia. Furthermore, an in vitro assay confirmed that high-salt exposure led to an increase in the protein expression of SREBP2 and PCSK9 secretion, thereby reducing low-density lipoprotein (LDL) uptake. This study, for the first time, shows that an HSD induces dyslipidemia through activation of the SREBP2/PCSK9 pathway, providing new insights into the prevention and treatment of dyslipidemia in patients with salt sensitivity.

Activation of the PERK-CHOP signaling pathway during endoplasmic reticulum stress contributes to olanzapine-induced dyslipidemia.

Olanzapine (OLZ) is a widely prescribed antipsychotic drug with a relatively ideal effect in the treatment of schizophrenia (SCZ). However, its severe metabolic side effects often deteriorate clinical therapeutic compliance and mental rehabilitation. The peripheral mechanism of OLZ-induced metabolic disorders remains abstruse for its muti-target activities. Endoplasmic reticulum (ER) stress is implicated in cellular energy metabolism and the progression of psychiatric disorders. In this study, we investigated the role of ER stress in the development of OLZ-induced dyslipidemia. A cohort of 146 SCZ patients receiving OLZ monotherapy was recruited, and blood samples and clinical data were collected at baseline, and in the 4th week, 12th week, and 24th week of the treatment. This case-control study revealed that OLZ treatment significantly elevated serum levels of endoplasmic reticulum (ER) stress markers GRP78, ATF4, and CHOP in SCZ patients with dyslipidemia. In HepG2 cells, treatment with OLZ (25, 50 µM) dose-dependently enhanced hepatic de novo lipogenesis accompanied by SREBPs activation, and simultaneously triggered ER stress. Inhibition of ER stress by tauroursodeoxycholate (TUDCA) and 4-phenyl butyric acid (4-PBA) attenuated OLZ-induced lipid dysregulation in vitro and in vivo. Moreover, we demonstrated that activation of PERK-CHOP signaling during ER stress was a major contributor to OLZ-triggered abnormal lipid metabolism in the liver, suggesting that PERK could be a potential target for ameliorating the development of OLZ-mediated lipid dysfunction. Taken together, ER stress inhibitors could be a potentially effective intervention against OLZ-induced dyslipidemia in SCZ.

Association of hair polychlorinated biphenyls and multiclass pesticides with obesity, diabetes, hypertension and dyslipidemia in NESCAV study.

Obesity, diabetes, hypertension and dyslipidemia are well-established risk factors for cardiovascular diseases (CVDs), and have been associated with exposure to persistent organic pollutants. However, studies have been lacking as regards effects of non-persistent pesticides on CVD risk factors. Here, we investigated whether background chronic exposure to polychlorinated biphenyls (PCBs) and multiclass pesticides were associated with the prevalence of these CVD risk factors in 502 Belgian and 487 Luxembourgish adults aged 18-69 years from the Nutrition, environment and cardiovascular health (NESCAV) study 2007-2013. We used hair analysis to evaluate the chronic internal exposure to three PCBs, seven organochlorine pesticides (OCs) and 18 non-persistent pesticides. We found positive associations of obesity with hexachlorobenzene (HCB), ß-hexachlorocyclohexane (ß-HCH) and chlorpyrifos, diabetes with pentachlorophenol (PCP), fipronil and fipronil sulfone, hypertension with PCB180 and chlorpyrifos, and dyslipidemia with diflufenican and oxadiazon, among others. However, we also found some inverse associations, such as obesity with PCP, diabetes with γ-HCH, hypertension with diflufenican, and dyslipidemia with chlorpyrifos. These results add to the existing evidence that OC exposure may contribute to the development of CVDs. Additionally, the present study revealed associations between CVD risk factors and chronic environmental exposure to currently used pesticides such as organophosphorus and pyrethroid pesticides.

Association between blood arsenic concentration and dyslipidemia: Mediating effect of lipid peroxidation in the elderly.

BACKGROUND: The earlier investigations have revealed heavy metals exposure is implicated in the pathogenesis of dyslipidemia. The goal was to evaluated the relationship of blood arsenic (As) concentration with dyslipidemia in the elderly through a cross-sectional study. METHODS: The entire 360 elderly population were selected. Fasting blood specimens, demographic information, and clinical characteristics were obtained. The concentration of blood As was detected using ICP-MS. Serum 8-iso-PGF2α, a biomarker of lipid peroxidation, was measured by ELISA. RESULTS: Pearson correlative analysis hinted there were strong relationships of blood As with liver function indices in the elderly. Besides, blood As was positively associated with total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C), and apolipoprotein A-I (ApoA I). Further multivariate linear and logistic regression suggested that the incidences of TC and LDL-C elevation were upregulated with the rising tertiles of blood As. Blood As was positively related with the prevalence of dyslipidemia (OR=3.609; 95%CI: 1.353, 6.961). Additionally, serum 8-iso-PGF2α was dramatically and positively linked to the levels of blood As and lipid profiles. Mediation analyses verified that 8-iso-PGF2α partially mediated the correlations between blood As with TC (36.63%) and LDL-C (34.03%). CONCLUSION: Blood As concentration is positively related to lipid profiles in the elderly. Higher blood As concentration elevates the prevalence of dyslipidemia. Lipid peroxidation partially mediates the correlation of As exposure with dyslipidemia.

Blood glucose level and serum lipid profiles among people living with HIV on dolutegravir-based versus efavirenz-based cART; a comparative cross-sectional study.

BACKGROUND: Antiretroviral therapy-linked metabolic abnormalities have become a growing concern among people living with HIV. There is limited data regarding the effects of dolutegravir-based treatment on blood glucose levels and serum lipid profiles in people living with HIV in Ethiopia. Thus, this study aimed to assess blood glucose levels and serum lipid profiles among people living with HIV on dolutegravir-based versus efavirenz-based therapy. METHOD AND MATERIALS: An institutional-based comparative cross-sectional study was conducted from 30 June 2021 to 30 August 2021. A total of 128 participants (64 in the dolutegravir-based group and 64 in the efavirenz-based group) were enrolled in the study. The Chi-square, independent t-test, Mann-Whitney U-test, and logistic regression were used as appropriate statistical tests using SPSS Version 26.0 for this study. A p-value of <0.05 was considered statistically significant. RESULT: The prevalence of hyperglycemia and dyslipidemia were 17.2% (11/64) and 79.7% (51/64) in the dolutegravir group, and 9.4% (6/64) and 75% (48/64) in the efavirenz group, respectively. The efavirenz group had significantly higher mean values of total cholesterol (190.73 ± 44.13 vs. 175.27 ± 37.67 mg/dl, p = 0.035) and high-density lipoprotein (47.53 ± 14.25 vs. 40.92 ± 13.17 mg/dl, p = 0.007) than the dolutegravir group. For a Kg/m2 increase in BMI and for each month's increase in the duration of HIV, the patients were 66% (AOR = 1.66, 95% CI: 1.13, 2.44), and 13% (AOR = 1.13, 95% CI: 1.03, 1.23) more likely to have hyperglycemia, respectively. In contrast, female patients were 3.04 times more likely to have dyslipidemia (AOR = 3.03, 95% CI: 1.14, 8.05) as compared to male patients, and with an increase in CD4 cell count of 1 cell/mm3, the odds of dyslipidemia increased by 0.3% (AOR = 1.003, 95% CI: 1.001, 1.006). CONCLUSION: Efavirenz-based therapy resulted in higher mean values of total cholesterol and high-density lipoprotein as compared with dolutegravir-based therapy. It is important to consider and evaluate high-density lipoprotein levels in HIV patients on dolutegravir-based therapy, and total cholesterol levels in people living with HIV on efavirenz-based therapy.

The long-term use of ART is thought to be one of the potential causes of metabolic abnormalities such as dysregulation of glucose and lipid metabolism.The burden of DTG-based cART-related metabolic abnormalities in resource-limited settings has not been well characterized.This study aimed to address these gaps by assessing blood glucose levels and serum lipid profiles among people living with HIV on DTG-based versus EFV-based regimens and identifying factors associated with hyperglycemia and dyslipidemia.

Synergism of mechanisms underlying early-stage changes in retina function in male hyperglycemic db/db mice in the absence and presence of chemically-induced dyslipidemia.

The study was designed to quantify retina function in a spontaneous mutation mouse model of diabetes, in which sustained dyslipidemia was induced chemically. The goal of the study was to identify if dyslipidemia in the presence of hyperglycemia resulted in either a synergistic, or a merely additive, exacerbation of retinal and visual dysfunctions in diabetes. Two cohorts of mice, male C57BL/6 and C57BL/KsJ-db/db mice were divided into two groups each. One group of each strain received the triblock copolymer, poloxamer 407 (P-407), administered by intraperitoneal injection ("WT P-407" and "db/db P-407" groups) with saline as a control in the remaining two groups ("WT" and "db/db" groups). Blood glucose, total cholesterol (TC) and total triglyceride (TG) levels were quantified using enzyme-based colorimetric assays. Retina function was measured using electroretinography (ERG) and visual acuity was determined by behaviorally assessing parameters of the optomotor reflex. TC and TG levels were normal in both saline controls (WT) and db/db mice but were significantly elevated in the WT P-407 group (p < 0.01 for TC; p < 0.001 for TG), while levels of the same lipids were further elevated in the db/db P-407 group when compared to the WT P-407 group levels (p < 0.001 for both TC and TG). Behavioral assessment of the optomotor reflex indicated reduced visual acuity for the db/db P-407 group when compared to either the WT P-407 or the db/db groups (p < 0.001, p < 0.0001). ERG measurements of scotopic retina function showed a significant decline in the scotopic b-wave amplitude of the WT P-407 animals (p < 0.01) and a further reduction for the db/db P-407 group when compared to controls (p < 0.0001). Very significant, strong correlations between scotopic b-wave amplitude and implicit time to TC (r = - 0.8376, p = < 0.0001 and r = 0.7069, p = 0.0022, respectively) and TG levels (r = - 0.8554, p = < 0.0001 and r = 0.7150, p = 0.0019, respectively) were found. Dyslipidemia in the presence of hyperglycemia synergistically exacerbated the severity of retinal dysfunction in diabetes. P-407 administration significantly elevated plasma TC and TG levels in male wild-type (WT) and diabetic mice (db/db), but the resulting hyperlipidemia was more significantly pronounced in the diabetic mice. While elevated plasma lipid and blood glucose levels were individually correlated with a decline in retinal function, the combination of both exacerbated retinal dysfunction. This model of combined hyperglycemia and dyslipidemia can be used to dissect individual contributions of features of the metabolic syndrome to the pathogenesis of retinal dysfunction in diabetes.

Vitamin D Receptor Activation Attenuates Olanzapine-Induced Dyslipidemia in Mice Through Alleviating Hepatic Endoplasmic Reticulum Stress.

The involvement of vitamin D (VD) signaling in atypical antipsychotics (AAPs)-induced metabolic disturbances has been previously established. This study aims to elucidate the role of VD in maintaining endoplasmic reticulum (ER) homeostasis and its impact on AAPs-induced metabolic adverse effects. Female C57BL/6 mice receive either calcitriol or vehicle one week prior to co-treatment with olanzapine (OLZ) for an additional four weeks. Metabolic parameters, hepatic ER homeostasis, and the SREBPs pathway are assessed through biochemical assays and protein expression profiling. HepG2 cells are transfected with vitamin D receptor (VDR) siRNA for VDR knockdown. OLZ-treated HepG2 cells are exposed to calcitriol to examine its effects on SREBPs and the unfolded protein response (UPR) pathways. VDR activation by calcitriol reduces OLZ-induced hepatic ER stress, leading to decreased SREBPs activity and lipid accumulation. Conversely, the knockdown of VDR in HepG2 cells diminishes the protective effects of calcitriol against OLZ-induced ER stress and SREBPs activation. This resulted in sustained UPR activation, elevated cleaved SREBPs levels, and increased lipid accumulation. These findings highlight an essential role of VDR signaling in the beneficial effects of VD on OLZ-induced metabolic side effects. Targeting VDR to resolve ER stress is likely an applicable therapeutic strategy for AAPs-induced metabolic disturbances.

CircFOXN2 alleviates glucocorticoid- and tacrolimus-induced dyslipidemia by reducing FASN mRNA stability by binding to PTBP1 during liver transplantation.

We aimed to examine impacts and functional mechanism of circular RNA forkhead box N2 (FOXN2) in tacrolimus (TAC)- and dexamethasone (Dex)-induced lipid metabolism disorders. RNA level and protein contents in TAC, Dex, or combined TAC- plus Dex-treated patients and Huh-7 cells were measured utilizing quantitative real-time (qRT)-PCR and western blotting assays measured the formation of lipid droplet. Total cholesterol (TC) and triglyceride (TG) levels were determined using corresponding commercial kits and Oil red O staining. RNA immunoprecipitation and RNA pull-down verified the binding relationship among circFOXN2, polypyrimidine tract binding protein 1 (PTBP1) and fatty acid synthase (FASN). Male C57BL/6 mice were used to establish a dyslipidemia mouse model to validate the discoveries at the cellular level. Dex treatment significantly promoted TAC-mediated increase of TC and TG in serum samples and Huh-7 cells. Moreover, circFOXN2 was reduced but FASN was elevated in TAC-treated Huh-7 cells, and these expression trends were markedly enhanced by Dex cotreatment. Overexpression of circFOXN2 could reverse the accumulation of TC and TG and the upregulation of FASN and sterol regulatory element binding transcription factor 2 (SREBP2) mediated by Dex and TAC cotreatment. Mechanistically, circFOXN2 reduced FASN mRNA stability by recruiting PTBP1. The protective roles of circFOXN2 overexpression on lipid metabolism disorders were weakened by FASN overexpression. In vivo finding also disclosed that circFOXN2 greatly alleviated the dysregulation of lipid metabolism triggered by TAC plus Dex. CircFOXN2 alleviated the dysregulation of lipid metabolism induced by the combination of TAC and Dex by modulating the PTBP1/FASN axis.NEW & NOTEWORTHY Collectively, our experiments revealed for the first time that circFOXN2 alleviated the Dex- and TAC-induced dysregulation of lipid metabolism by regulating the PTBP1/FASN axis. These findings suggested that circFOXN2 and FASN might be candidate targets for the treatment of Dex- and TAC-induced metabolic disorders.