Lipid Abnormalities Research Articles

Association of ADIPOQ Gene Polymorphisms with Type 2 Diabetes and Obesity Risk in the Kazakh Population: A Case-Control and Population-Based Study.

Type 2 diabetes mellitus (T2DM) is a socially significant disease with increasing prevalence worldwide. It is characterized by heterogeneous metabolic disorders and is associated with various risk factors, including BMI, abnormal lipid levels, hypertension, smoking, dietary preferences, physical inactivity, sedentary lifestyle, family history of diabetes, prediabetes or gestational diabetes, inflammation, intrauterine environment, age, sex, ethnicity, and socioeconomic status. Assessing the genetic risk of developing T2DM in specific populations remains relevant. The ADIPOQ gene, encoding adiponectin, is directly related to the risk of developing T2DM, obesity, and cardiovascular diseases. Our study demonstrated significant associations of ADIPOQ gene polymorphisms with the risk of developing T2DM and obesity, as well as with fasting glucose levels and BMI, in the Kazakh population. Specifically, rs266729 was significantly associated with T2DM and obesity in the Kazakh population, while other studied polymorphisms (rs1501299, rs2241766, and rs17846866) did not show a significant association. These findings suggest that ADIPOQ gene polymorphisms may influence T2DM risk factors and highlight the importance of genetic factors in T2DM development. However, further research in larger cohorts is needed to confirm these associations.

Identification and validation of lipid metabolism-related key genes as novel biomarkers in acute myocardial infarction and pan-cancer analysis.

Acute myocardial infarction (AMI) is associated with high morbidity and mortality, and is associated with abnormal lipid metabolism. We identified lipid metabolism related genes as biomarkers of AMI, and explored their mechanisms of action. Microarray datasets were downloaded from the GEO database and lipid metabolism related genes were obtained from Molecular Signatures Database. WGCNA was performed to identify key genes. We evaluated differential expression and performed ROC and ELISA analyses. We also explored the mechanism of AMI mediated by key genes using gene enrichment analysis. Finally, immune infiltration and pan-cancer analyses were performed for the identified key genes. TRL2, S100A9, and HCK were identified as key genes related to lipid metabolism in AMI. Internal and external validation (including ELISA) showed that these were good biomarkers of AMI. In addition, the results of gene enrichment analysis showed that the key genes were enriched in inflammatory response, immune system process, and tumor-related pathways. Finally, the results of immune infiltration showed that key genes were concentrated in neutrophils and macrophages, and pan-cancer analysis showed that the key genes were highly expressed in most tumors and were associated with poor prognosis. TLR2, S100A9, and HCK were identified as lipid metabolism related novel diagnostic biomarkers of AMI. In addition, AMI and tumors may be related through the inflammatory immune response.

Targeting antioxidant factor Nrf2 by raffinose ameliorates lipid dysmetabolism-induced pyroptosis, inflammation and fibrosis in NAFLD

BackgroundNon-alcoholic fatty liver disease (NAFLD) is a persistent liver condition that affects both human health and animal productive efficiency on a global scale. A number of naturally occurring compounds activate nuclear factor erythroid 2-related factor 2 (Nrf2) as a transcription factor with important protective effects against many liver diseases, including NAFLD. Raffinose (Ra), an oligosaccharide extracted from several plants, exhibits diverse biological functions. However, the uncertainty lies in determining whether the activation of Nrf2 by Ra can provide a preventive effect on liver lipotoxicity. PurposeThe aim of this study was to shed light on the molecular pathways by which Ra possesses its protective benefits against NAFLD. MethodsExperimental protocols were established using WT and Nrf2-null (Nrf2−/−) mice. Liver samples from each group were collected for Western blot, RT-qPCR, H & E, Sirius red and Oil red O staining. Additionally, serums were processed for ELISA. ALM12 cells were gathered for Western blot and immunofluorescence. Moreover, to elucidate the molecular mechanism of Ra, molecular docking was performed. ResultsOur results indicated that Ra remarkably alleviated liver lipotoxic in vivo and in vitro. Ra treatment effectively corrected hepatic steatosis, the release of AST, ALT, TG, and TC, as well as the depletion of HDL and LDL. Meanwhile, Ra efficiently prevented inflammation by inhibiting the TLR4-MyD88-NF-κB pathway and pyroptosis. Additionally, these findings implied that Ra reduced the production of fibrosis-related proteins, which enhanced collagen deposition. Molecular docking revealed that Ra possessed the ability to bind specific regions of Nrf2, resulting in the enhancement of Nrf2 activation and nuclear translocation. Ra treatment restored serum redox factors and antioxidant enzymes to normal levels; however, these alterations were clearly reversed in Nrf2−/− mice. ConclusionThis study reveals novel information on Ra's protective benefits against liver injury caused by abnormal lipid metabolism; these effects are mostly mediated by Nrf2 activation, suggesting a potential new medicine or treatment strategy for NAFLD.

Inositol and taurine ameliorate abnormal liver lipid metabolism induced by high sucrose intake

Previous attempts to limit fat intake failed to reduce metabolic syndrome incidence, spotlighting excessive sucrose consumption phenomenon. Recent studies challenge the traditional belief, actually fructose is predominantly metabolized in the small intestine, not just the liver. Evidence supports sucrose overconsumption leads to hepatic lipid accumulation via gut microbiome modulation, but the mechanisms and prevention strategies remain unclear. This study investigates the impact of osmolytes inositol and taurine, which are abundant in citrus fruits and seafood respectively, on lipid metabolism in rats consuming excessive sucrose. Five-week-old male Wistar rats fed with control diet, high sucrose diet, and high sucrose diet with inositol or taurine for 28 days. High sucrose diet-induced accumulation of hepatic triglyceride level was reduced only by inositol. Both inositol and taurine decreased hepatic SREBP1, ChREBP, lipogenesis enzymes mRNA levels increased by a high sucrose diet. Taurine also significantly increased the fatty acid uptake major player CD36 mRNA levels in liver. Expression of genes related to fatty acid degradation and transport remained unchanged. In cecal microbiome, high sucrose diet groups showed a decrease in alpha diversity and diverged in beta diversity from the starch diet group, while inositol and taurine did not significantly affect these aspects. Ten bacterial features including genera such as Bacteroides, Parabacteroides, Odoribacter, Streptococcus, etc., were filtered out related to the ameliorative effects of inositol and taurine on lipid metabolism. Overall, both inositol and taurine modulated hepatic lipogenesis and microbiome. However, due to taurine's enhancement of fatty acid uptake, only inositol improved steatosis in high sucrose diet rats.

Transcriptomic Analysis of Lipid Metabolism Genes in Alzheimer's Disease: Highlighting Pathological Outcomes and Compartmentalized Immune Status.

The dysregulation of lipid metabolism has been strongly associated with Alzheimer's disease (AD) and has intricate connections with various aspects of disease progression, such as amyloidogenesis, bioenergetic deficit, oxidative stress, neuroinflammation, and myelin degeneration. Here, a comprehensive bioinformatic assessment was conducted on lipid metabolism genes in the brains and peripheral blood of AD-derived transcriptome datasets, characterizing the correlation betweendifferentially expressed genes (DEGs) of lipid metabolism and disease pathologies, as well as immune cell preferences. Through the application of weighted geneco-expression network analysis (WGCNA),modules eigengenes related to lipid metabolism were pinpointed, and the examination oftheir molecular functions within biological processes, molecular pathways, andtheir associations with pathological phenotypes and molecular networkshas been characterized. Analysis of biological networks indicates notable discrepancies in the expression patterns of the DEGs between neuronal and immune cells, as well as variations in cell type enrichments within both brain tissue and peripheral blood. Additionally, drugs targeting the DEGs from central and peripheral and a diagnostic model for hub genes from the blood were retrieved and assessed, some of which were shown to be useful for therapeutic and diagnostic.These results revealed the distinctive pattern of transcriptionally abnormal lipid metabolism in central, peripheral, and immune cell activation, providing valuable insight into lipid metabolism for diagnosing and guiding more effectivetreatment forAD.

Evaluation of Secondary Dyslipidemia in Obese Children

Objective: This study was conducted to determine the frequency of dyslipidemia secondary to childhood obesity, a recently emerging clinical entity, and to compare serum lipid profiles in obese and non-obese children. Material and Methods: After screening children with an obese appearance, a group of 119 obese children aged between 2 to 16 years with a body mass index above the 95th percentile and a control group of 124 children in a similar age range were compared in terms of serum lipid profile. Results: An abnormal lipid profile was determined in 62.6% of obese children, and serum levels of total cholesterol and triglycerides were higher in this group. It was found that Childhood obesity was associated with higher levels of total cholesterol (44.5%), triglycerides (48.7%), LDL (38.7%), and lower levels of HDL (23.5%). Conclusion: Obese children have a higher risk of secondary dyslipidemia and associated comorbidities. In order to prevent childhood obesity and its dangerous consequences, effective measures must be implemented in terms of screening, early diagnosis and appropriate treatment.

The Effects of Sustained Immunosuppression Withdrawal After Liver Transplantation on Metabolic Syndrome.

Liver transplant (LT) recipients often experience adverse effects of immunosuppressive (IS) drugs, especially on metabolic profiles. Selected LT recipients can achieve successful IS withdrawal; however, its effects on metabolic syndrome (MS) are unknown. This is a retrospective single-center study investigating the incidence and/or regression of MS in 75 selected LT recipients who were previously enrolled in prospective IS withdrawal trials between 1999 and 2017. Patients who were transplanted due to nonalcoholic steatohepatitis/metabolic-associated fatty liver disease were excluded, as well as those with a follow-up <3 y after IS weaning. Forty-four patients (58.7%) achieved sustained withdrawal or minimization of immunosuppression (WMIS) and 31 patients (41.3%) required reintroduction of immunosuppression (no-WMIS). Among LT recipients who were metabolically healthy (n = 52, 69.3%) before the start of IS weaning, there was a significantly lower rate of de novo MS in WMIS patients compared with no-WMIS patients after 5 y (8.3% and 47.8%, respectively, P = 0.034). Of 23 LT recipients (30.7%) who had MS at the time of commencing IS withdrawal, complete regression of MS was observed in 47.1% of WMIS patients and in none (0%) of the no-WMIS patients after 5 y (P = 0.054). Furthermore, individual components of MS were better controlled in IS-weaned patients, such as arterial hypertension and abnormal serum lipids. Achievement of sustained IS withdrawal reduces the incidence of de novo MS development in metabolically healthy patients and increases the likelihood of MS regression in patients with established MS. The foreseeable long-term beneficial effects of these favorable metabolic changes on morbidity and mortality of LT recipients require further investigation.

Association of Apolipoprotein E (APOE) Polymorphisms With Serological Lipid and Inflammatory Markers.

Background The study aims to assess the association of apolipoprotein E (APOE) gene polymorphisms with serological lipid and inflammatory markers to determine their potential role in predicting the risk of cardiovascular diseases (CVDs) and Alzheimer's disease (AD). Methodology A total of 915 individuals underwent testing for lipid and inflammatory biomarkers at Vibrant America Clinical Laboratory. Clinical data, blood lipid and inflammatory profiles, and APOE genotyping were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results Compared to the E3/E3 genotype, individuals with E2/E3 genotypes showed higher levels of high-density lipoprotein (HDL), triglycerides, apolipoprotein A (APOA), high-sensitivity C-reactive protein (hs-CRP), and myeloperoxidase (MPO). E2/E4 genotype carriers had higher levels of HDL, triglycerides, Lp(a), and N-terminal pro b-type natriuretic peptide (BNPNT). E3/E4 genotypes were associated with elevated levels of total cholesterol, LDL, Lp(a), hs-CRP, small-density low-density lipoprotein (SDLDL), oxidized LDL (OXLDL), MPO, LDL-CAL, PLAC, and APOB. The E4/E4 group displayed higher concentrations of total cholesterol, LDL, APOB, Lp(a), hs-CRP, SDLDL, OXLDL, MPO, LDLCAL, and PLAC compared to E3/E3 carriers. These findings highlight the potential atherogenic effect of the ε4 allele and the protective effect of the ε2 allele based on lipid and inflammatory marker profiles. Conclusions This study provides strong evidence linking APOE gene polymorphism to abnormal serum lipid and inflammatory profiles. Individuals carrying the ε4 alleles exhibited dysregulated lipid metabolism and abnormal inflammatory markers, increasing their risk of CVD and AD. Early detection and prompt diagnosis are crucial for implementing therapeutic, dietary, and lifestyle interventions to mitigate risks and prevent or delay lipid and inflammation-related disorders.

Independent relationship between sleep apnea-specific hypoxic burden and glucolipid metabolism disorder: a cross-sectional study.

Obstructive sleep apnea (OSA) is associated with abnormal glucose and lipid metabolism. However, whether there is an independent association between Sleep Apnea-Specific Hypoxic Burden (SASHB) and glycolipid metabolism disorders in patients with OSA is unknown. We enrolled 2,173 participants with suspected OSA from January 2019 to July 2023 in this study. Polysomnographic variables, biochemical indicators, and physical measurements were collected from each participant. Multiple linear regression analyses were used to evaluate independent associations between SASHB, AHI, CT90 and glucose as well as lipid profile. Furthermore, logistic regressions were used to determine the odds ratios (ORs) for abnormal glucose and lipid metabolism across various SASHB, AHI, CT90 quartiles. The SASHB was independently associated with fasting blood glucose (FBG) (β = 0.058, P = 0.016), fasting insulin (FIN) (β = 0.073, P < 0.001), homeostasis model assessment of insulin resistance (HOMA-IR) (β = 0.058, P = 0.011), total cholesterol (TC) (β = 0.100, P < 0.001), total triglycerides (TG) (β = 0.063, P = 0.011), low-density lipoprotein cholesterol (LDL-C) (β = 0.075, P = 0.003), apolipoprotein A-I (apoA-I) (β = 0.051, P = 0.049), apolipoprotein B (apoB) (β = 0.136, P < 0.001), apolipoprotein E (apoE) (β = 0.088, P < 0.001) after adjustments for confounding factors. Furthermore, the ORs for hyperinsulinemia across the higher SASHB quartiles were 1.527, 1.545, and 2.024 respectively, compared with the lowest quartile (P < 0.001 for a linear trend); the ORs for hyper-total cholesterolemia across the higher SASHB quartiles were 1.762, 1.998, and 2.708, compared with the lowest quartile (P < 0.001 for a linear trend) and the ORs for hyper-LDL cholesterolemia across the higher SASHB quartiles were 1.663, 1.695, and 2.316, compared with the lowest quartile (P < 0.001 for a linear trend). Notably, the ORs for hyper-triglyceridemia{1.471, 1.773, 2.099} and abnormal HOMA-IR{1.510, 1.492, 1.937} maintained a consistent trend across the SASHB quartiles. We found SASHB was independently associated with hyperinsulinemia, abnormal HOMA-IR, hyper-total cholesterolemia, hyper-triglyceridemia and hyper-LDL cholesterolemia in Chinese Han population. Further prospective studies are needed to confirm that SASHB can be used as a predictor of abnormal glycolipid metabolism disorders in patients with OSA. ChiCTR1900025714 { http://www.chictr.org.cn/ }; Prospectively registered on 6 September 2019; China.

Metabolomic analysis reveals the molecular mechanism related to leg abnormality in broilers

AbstractRapid body weight gain in broilers overloads the metabolic system of the organism, resulting in leg abnormalities, which seriously affects animal welfare and industry economics. In this study, broilers with normal and deformed leg bones were examined. Serum biochemical indices showed that the serum calcium to phosphorus ratio was extremely decreased in leg deformed group. In addition, abnormal serum lipid levels suggested a disruption in lipid metabolism. Based on widely targeted metabonomic analysis of serum and cartilage tissues, a total of nine differential metabolites (DMs) significantly associated with leg abnormalities and serum calcium and phosphorus levels were screened, including carnitine C16:0, carnitine C18:1, 3‐hydroxymethyl‐L‐tyrosine, cis‐4‐hydroxy‐D‐proline, cis‐L‐3‐hydroxyproline, trans‐4‐hydroxy‐L‐proline, and so on. Pathway analysis revealed that fatty acid degradation and arachidonic acid metabolism were enriched. Analysis of DMs in these two pathways showed that prostaglandin D2, prostaglandin J2, prostaglandin A2, 15‐keto prostaglandin F2α, and Δ12‐prostaglandin J2 significantly differed between the normal and abnormal groups. It was hypothesized that these important metabolic pathways and metabolites were involved in the metabolic regulation of leg abnormalities.

Nardosinone relieves metabolic-associated fatty liver disease and promotes energy metabolism through targeting CYP2D6

BackgroundNardosinone, a major extract of Rhizoma nardostachyos, plays a vital role in sedation, neural stem cell proliferation, and protection of the heart muscle. However, the huge potential of nardosinone in regulating lipid metabolism and gut microbiota has not been reported, and its potential mechanism has not been studied. PurposeTo explore the regulation of nardosinone on liver lipid metabolism and gut microbiota. MethodsIn this study, the role of nardosinone in lipid metabolism was investigated in vitro and in vivo by adding it to mouse feed and HepG2 cell culture medium. And 16S rRNA gene sequencing was used to explore its regulatory effect on gut microbiota. ResultsResults showed that nardosinone could improve HFD-induced liver injury and abnormal lipid metabolism by promoting mitochondrial energy metabolism in hepatocytes, alleviating oxidative stress damage, and regulating the composition of the gut microbiota. Mechanistically, combined with network pharmacology and reverse docking analysis, it was predicted that CYP2D6 was the target of nardosinone, and the binding was verified by cellular thermal shift assay (CETSA). ConclusionsThis study highlights a novel mechanism function of nardosinone in regulating lipid metabolism and gut microbiota. It also predicts and validates CYP2D6 as a previously unknown regulatory target, which provides new possibilities for the application of nardosinone and the treatment of metabolic-associated fatty liver disease.

Exploring the Therapeutic Potential of β-Hydroxybutyrate (BHB) in Clear Cell Renal Cell Carcinoma: A Journey into Fat Browning, Autophagy, and Tumor Slimming

This study delves into the therapeutic potential of β-hydroxybutyrate (BHB) in clear cell renal cell carcinoma (ccRCC), a cancer known for its complex pathogenesis and resistance to conventional treatments. The research specifically explores the impact of BHB on cell viability, autophagy induction, and lipid metabolism in Caki-1 cells. The findings reveal that BHB significantly reduces ccRCC cell viability, particularly under low-glucose conditions. The combination of glucose and BHB treatment activates autophagy pathways, as evidenced by increased expression of autophagy-related genes (Beclin-1, LC3IIβ, and ATG5) and decreased expression of P62 after 48 and 72 hours. Moreover, the combined therapy enhances lipid metabolism, as indicated by elevated expression of PGC-1α and UCP-1, along with upregulation of ACSL3 and CPT1A, which are associated with lipid droplet formation and facilitate lipid breakdown within cells. The study concludes that BHB holds promise as a therapeutic agent for ccRCC, targeting abnormal lipid metabolism, inducing autophagy-mediated cell death, and promoting fat browning. The results suggest potential avenues for precision-guided nutritional therapies in ccRCC treatment, highlighting the innovative role of BHB in addressing the challenges posed by this cancer.

Longitudinal analysis of vitamin D levels considering sunshine duration and suggestion for a standardised approach for vitamin D supplementation in children and adolescents with obesity

BackgroundChildren with obesity have low 25 hydroxy-vitamin D (25-OH-D3) levels compared to lean children. Recommendations on when to start vitamin D supplementation differ largely between countries. Longitudinal data on 25-OH-D3 levels to guide treatment decisions are scarce since they are largely influenced by solar radiation and are difficult to compare.MethodsWe carried out a retrospective analysis of multiple 25-OH-D3 and parathyroid hormone (PTH) measurements in a cohort of 543 patients without vitamin D supplementation. All measurements were taken at the local paediatric obesity clinic as documented in the German-Austrian-Swiss APV (Prospective Documentation of Overweight Children and Adolescents) registry from 2009 to 2019. Serial 25-OH-D3 and PTH levels were adjusted for sunshine duration over the last 30 days to account for seasonal variation, as well as for sex and body mass index (BMI). We further performed an exploratory analysis of the association of sunshine duration, sex, BMI SDS (standard deviation score), abnormal lipid levels or dysglycemia with the 25-OH-D3 trend.Results229 obese patients (mean BMI SDS: 2,58 (± 0,56), 53% females, mean age: 12 (± 3) years, range: 2–21 years) with two, 115 with three and 96 with four repeated 25-OH-D3 measurements were identified. Mean adjusted 25-OH-D3 (48.2 nmol/l) and PTH (34.9 ng/l) levels remained stable over 120 weeks. 5% of the patients had an elevated PTH > 65 ng/l. High total cholesterol ≥ 200 mg/dl and high triglycerides ≥ 130 mg/dl were associated with higher 25-OH-D3 levels.ConclusionWe propose a simple method to include sunshine duration in the analysis of 25-OH-D3 levels to minimise the bias of seasonal variation. Based on our data we established the pragmatic strategy of limiting vitamin D supplementation to patients with biochemical signs of mineralisation disorders such as elevated PTH and alkaline phosphatase (AP). In children with normal PTH and AP we recommend adjustment of calcium intake and increase of outdoor activity instead.

Glycemic Index, Glycemic Load and Dyslipidemia in Adolescents from Chiapas, Mexico.

Cardiovascular disease risk throughout the life course is increased by abnormal blood lipid levels in youth. The dietary glycemic index (GI) and glycemic load (GL) during adolescence might be related to abnormal blood lipids. This study aimed to analyze the association between dietary GI, GL and dyslipidemia in adolescents from two marginalized regions of Chiapas, Mexico. A cross-sectional study was conducted with 213 adolescents. Food intake was assessed using 24 h recalls. The association between dyslipidemia and dietary GI or GL was tested by using logistic regression models. Low HDL-c was the most prevalent risk factor (47.4%), followed by hypertriglyceridemia (25.4%). In this population, overall dietary GI was not associated with dyslipidemia. A high dietary GL was associated with 2.39 higher odds of low HDL-c (95% CI: 1.21-4.74) when compared to low GL. Female adolescents with high dietary GL had 3.20 higher odds of hypertriglyceridemia (95% CI: 1.03-9.88), whereas no association was found for males. No associations were observed between overall dietary GL and total cholesterol or LDL-c. In adolescents from urban and rural communities in Chiapas, a high dietary GL was associated with a detrimental effect on HDL-c. In female adolescents, high GL was associated with hypertriglyceridemia.

Risk factors and lipid metabolism characteristics of early-onset male androgenetic alopecia: A pilot study.

Male androgenetic alopecia (MAA) is a multifactorial disease, with patients presenting at a younger age, which is a risk factor for many metabolic diseases. To explore the risk factors associated with early-onset of MAA and its metabolic characteristics. Forty patients with MAA and 45 healthy controls were collected. The serum levels of fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total testosterone (TT), uric acid (UA), and 25-hydroxyvitamin D (25(OH)D) were measured. Meanwhile, lipid metabolites were detected by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). 37.50% MAA patients had metabolic syndrome, compared to 17.78% in control group (p < 0.05). The levels of HDL-C, UA, and 25(OH)D were decreased in patients with MAA compared to healthy controls (p < 0.05). However, there was no significant difference in the level of TT between the two groups. Additionally, there were no significant differences in the levels of HDL-C, UA, 25(OH)D, and TT among different grades of hair loss (p > 0.05). The lipid profile of early-onset MAA differed significantly from healthy controls. In early-onset MAA, the levels of ceramide (Cer) and sphingomyelin (SM) were significantly lower. Cer(d38:5) and TG(15:0/18:1/18:1) may be the biomarkers. Low HDL-C, UA, and 25(OH)D may be the independent risk factors for early-onset MAA. Abnormal lipid metabolism was observed in early-onset MAA, wherein Cer and SM may serve as protective factors.

Amphiregulin secreted by umbilical cord multipotent stromal cells protects against ferroptosis of macrophages via the activating transcription factor 3-CD36 axis to alleviate endometrial fibrosis.

Endometrium fibrosis is the leading cause of uterine infertility. Macrophages participated in the occurrence and development of endometrial fibrosis. We previously reported that human umbilical cord multipotent stromal cells (hUC-MSCs) exerted their therapeutic effect in a macrophage-dependent manner in endometrial fibrosis. However precise mechanisms by which hUC-MSCs may influence macrophages in endometrial fibrosis remain largely unexplored. Here, we demonstrated that abnormal iron and lipid metabolism occurred in patients with intrauterine adhesions (IUA) and murine models. Ferroptosis has been proven to contribute to the progression of fibrotic diseases. Our results revealed that pharmacological activation of ferroptosis by Erastin aggravated endometrial fibrosis, while inhibition of ferroptosis by Ferrostatin-1 ameliorated endometrial fibrosis in vivo. Moreover, ferroptosis of macrophages was significantly upregulated in endometria of IUA murine models. Of note, transcriptome profiles revealed that CD36 gene expression was significantly increased in patients with IUA and immunofluorescence analysis showed CD36 protein was mainly located in macrophages. Silencing CD36 in macrophages could reverse cell ferroptosis. Dual luciferase reporter assay revealed that CD36 was the direct target of activation transcription factor 3 (ATF3). Furthermore, through establishing coculture system and IUA murine models, we found that hUC-MSCs had a protective role against macrophage ferroptosis and alleviated endometrial fibrosis related to decreased CD36 and ATF3. The effect of hUC-MSCs on macrophage ferroptosis was attributed to the upregulation of amphiregulin (AREG). Our data highlighted that macrophage ferroptosis occurred in endometrial fibrosis via the ATF3-CD36 pathway and hUC-MSCs protected against macrophage ferroptosis to alleviate endometrial fibrosis via secreting AREG. These findings provided a potential target for therapeutic implications of endometrial fibrosis.

The association between pregnancy levels of blood lipids and the risk of preterm birth

Preterm labor, a condition associated with various risk factors such as a history of prior preterm birth (PTB) and multiple pregnancies, has recently seen an increasing focus on its potential link with dyslipidemia. This study aims to investigate the relationship between dyslipidemia in expectant mothers and the risks of PTB. We studied 6963 mothers who gave birth at the International Peace Maternal and Child Health Hospital of Shanghai Jiaotong University School of Medicine in 2020, among which, 437 women had PTB. We extracted clinical and lipid data from electronic records, using multivariable logistic regression and restricted cubic spline models to explore the link between lipid concentrations (by quartiles) in pregnancy stages and PTB risk. The PTB rate was 6.3%. Early pregnancy in the PTB group showed elevated ApoA, ApoB, CHOL, LDL, and TG levels compared to controls (all P < 0.05). Late pregnancy showed no notable lipid differences. Multivariable analysis revealed elevated ApoA, TG, higher age, BMI ≥ 28 kg/m2, hypertension, assisted reproductive technology and gestational diabetes as PTB risk factors (all P < 0.05). After adjustments, higher ApoA, ApoB, CHOL and TG levels correlated with increased PTB risk. Using the lowest quartile, the adjusted ORs for early pregnancy's highest quartile of ApoA, ApoB, CHOL and TG were 1.348, 1.442, 1.442 and 2.156, respectively. Our findings indicate that dyslipemia in early pregnancy, including elevated levels of ApoA, ApoB, CHOL and TG, are associated with PTB. Managing lipid abnormalities during pregnancy may help reduce the risk of PTB.

Blocking H1R signal aggravates atherosclerosis by promoting inflammation and foam cell formation.

Atherosclerosis (AS) is a chronic inflammatory arterialdisease, in which abnormal lipid metabolism and foam cell formation play key roles. Histamine is a vital biogenic amine catalyzed by histidine decarboxylase (HDC) from L-histidine. Histamine H1receptor (H1R)antagonist is a commonly encountered anti-allergic agent in theclinic. However, the role and mechanism of H1R in atherosclerosis have not been fully elucidated. Here, we explored the effect of H1R on atherosclerosis using ApolipoproteinE-knockout (ApoE-/-)mice with astemizole (AST, a long-acting H1R antagonist) treatment. The results showed that AST increased atherosclerotic plaque area and hepatic lipid accumulation in mice. The result of microarray study identified a significant change of endotheliallipase (LIPG) in CD11b+ myeloid cells derived from HDC-knockout (HDC-/-) mice compared to WT mice. Blocking H1R promoted the formation of foam cells from bone marrow-derived macrophages (BMDMs) of mice by up-regulating p38mitogen-activatedproteinkinase (p38 MAPK) and LIPG signalingpathway. Taken together, these findings demonstrate that blocking H1R signal aggravates atherosclerosis by promoting abnormal lipid metabolism and macrophage-derived foam cell formation via p38 MAPK-LIPG signalingpathway. KEY MESSAGES: Blocking H1R signal with AST aggravated atherosclerosis and increased hepatic lipid accumulation in high-fatdiet (HFD)-fed ApoE-/- mice. Blocking H1R signal promoted macrophage-derived foam cell formation via p38 MAPK-LIPG signalingpathway.

The cardiovascular toxicity of polystyrene microplastics in rats: based on untargeted metabolomics analysis.

Polystyrene microplastics (PS-MPs) exhibit multi-target, multi-dimensional, chronic, and low toxicity to the cardiovascular system. They enter the bloodstream through the gastrointestinal tract and respiratory system, altering blood parameters and conditions, inducing thrombotic diseases, and damaging myocardial tissue through the promotion of oxidative stress and inflammatory responses in myocardial cells. However, many of the links and mechanisms remain unclear. In this study, 48 wistar rats were randomly divided into four groups and exposed to different concentrations of PS-MPs: control group (0mg/kg/d), low dose group (0.5mg/kg/d), middle dose group (5mg/kg/d) and high dose group (50mg/kg/d), with 12 rats in each group. After 90 consecutive days of intragastric administration of PS-MPs, biochemical markers in myocardium, aorta and blood were detected, and HE staining was performed to observe the toxic effects of PS-mps on cardiovascular system. Furthermore, non-targeted metabolomics methods were used to analyze the effect of PS-MPs exposure on the metabolism of cardiovascular system in rats, and to explore its potential molecular mechanism. The results revealed no pathological changes in the heart and aorta following PS-MPs exposure. However, the myocardial enzyme levels in the high dose PS-MPs group of rats showed a significant increase. Moreover, exposure to polystyrene microplastics caused a disorder in lipid metabolism in rats, and led to an increase in indicators of inflammation and oxidative stress in myocardial and aortic tissues, but resulted in a decrease in the level of IL-6. Untargeted metabolomics results showed that metabolites with antioxidant and anti-inflammatory effects, including equol and 4-hydroxybenzoic acid, were significantly upregulated. These results suggest that long-term exposure to high concentrations of PS-MPs may lead to abnormal lipid metabolism and cardiovascular system damage. The mechanism may be related to oxidative stress and inflammatory response. Exogenous antioxidants and changes in own metabolites may have a protective effect on the injury. Therefore, understanding the toxicological mechanism of PS-MPs not only helps to elucidate its pathogenesis, but also provides new ideas for the treatment of chronic diseases.

Identification of potential hub genes and regulatory networks of smoking-related endothelial dysfunction in atherosclerosis using bioinformatics analysis.

Endothelial dysfunction, the earliest stage of atherosclerosis, can be caused by smoking, but its molecular mechanism requires further investigation. This study aimed to use bioinformatics analysis to identify potential mechanisms involved in smoking-related atherosclerotic endothelial dysfunction. The transcriptome data used for this bioinformatics analysis were obtained from the Gene Expression Omnibus (GEO) database. The GSE137578 and GSE141136 datasets were used to identify common differentially expressed genes (co-DEGs) in endothelial cells treated with oxidized low-density lipoprotein (ox-LDL) and tobacco. The co-DEGs were annotated using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomics (KEGG) databases. Additionally, a protein-protein interaction (PPI) network was constructed to visualize their interactions and screen for hub genes. GSE120521 dataset was used to verify the expression of hub genes in unstable plaques. The miRNA expression profile GSE137580 and online databases (starBase 2.0, TargetScan 8.0 and DGIdb v4.2.0) were used to predict the related non-coding RNAs and drugs. A total of 232 co-DEGs were identified, including 113 up-regulated genes and 119 down-regulated genes. These DEGs were primarily enriched in detrimental autophagy, cell death, transcription factors, and cytokines, and were implicated in ferroptosis, abnormal lipid metabolism, inflammation, and oxidative stress pathways. Ten hub genes were screened from the constructed PPI network, including up-regulated genes such as FOS, HMOX1, SQSTM1, PTGS2, ATF3, DDIT3, and down-regulated genes MCM4, KIF15, UHRF1, and CCL2. Importantly, HMOX1 was further up-regulated in unstable plaques (p= 0.034). Finally, a regulatory network involving lncRNA/circRNA-miRNA-hub genes and drug-hub genes was established. Atherosclerotic endothelial dysfunction is associated with smoking-induced injury. Through bioinformatics analysis, we identified potential mechanisms and provided potential therapeutic targets.