The molecular mechanisms underlying hypercholesterolemia in nephrotic syndrome (NS) remain incompletely understood. Previous studies have shown that patients with NS exhibit increased hepatic expression and circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), which contribute to hypercholesterolemia by promoting hepatic low-density lipoprotein receptor (LDLR) degradation and reducing low-density lipoprotein (LDL) clearance. However, the relationships among circulating PCSK9, renal PCSK9 expression, and hypercholesterolemia in primary nephrotic syndrome (PNS) remain unclear. To investigate the associations of circulating PCSK9 with renal PCSK9 expression and hypercholesterolemia in PNS, we enrolled 56 patients with PNS and 48 patients with isolated hematuria (IH). Serum PCSK9 levels were significantly higher in patients with PNS than in those with IH [11.46 (9.31–13.76) ng/mL vs. 6.61 (4.50–8.31) ng/mL, P < 0.0001]. Immunohistochemical analysis further demonstrated increased PCSK9 expression in renal tubular epithelial cells of patients with PNS compared with the IH group. Furthermore, only in patients with PNS were circulating PCSK9 levels positively correlated with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and 24-hour urinary protein excretion (24 h-UPQ), a potential stimulus for renal PCSK9 expression. These findings suggest that hypercholesterolemia and elevated serum PCSK9 levels in PNS patients may be partially explained by increased renal PCSK9 expression, which may be associated with the stimulation of proteinuria on renal tubules.

Deep vein thrombosis (DVT) is a serious complication following gastrointestinal surgery. While D-dimer is a widely used biomarker for thrombosis, its postoperative specificity is limited due to inflammatory interference. This study introduces a novel cumulative metric—7-day D-dimer exposure (7dDDE)—to quantify perioperative coagulation burden. We retrospectively analyzed 525 patients undergoing gastrointestinal surgery, performed propensity score matching, and constructed a multivariable logistic regression model incorporating 7dDDE and other clinical variables. Model performance was evaluated using ROC curves, decision curve analysis, calibration plots, SHAP values, and a nomogram. Additionally, a linear mixed-effects model assessed D-dimer trajectories over time. The results demonstrated that 7dDDE was independently associated with postoperative DVT and was the most influential predictor in the model. The model showed good discrimination and clinical utility. Longitudinal analysis further revealed significant differences in D-dimer dynamics between DVT and non-DVT groups, even after adjustment for confounders. These findings support the use of 7dDDE as a robust biomarker for thrombotic risk stratification and highlight the importance of integrating temporal biomarker patterns into perioperative DVT prediction.

Background: Type 2 diabetes mellitus (T2DM) is a major global health issue, with significant complications impacting patients’ quality of life, including neuropathy, ophthalmic issues, nephropathy, and peripheral vascular complications. Although dietary factors influence T2DM risk, the specific impact of cheese consumption remains unclear. This study uses a two‐sample Mendelian randomization (MR) approach to investigate the causal relationship between cheese intake and T2DM, along with specific complications, including ophthalmic and peripheral vascular issues. Methods: Using summary‐level data from large‐scale genome‐wide association studies, we applied a two‐sample MR approach. Genetic variants associated with cheese consumption were selected as instrumental variables, following criteria for genome‐wide significance, linkage disequilibrium checks, and exclusion of pleiotropic effects. Robustness was assessed through various MR methods, including inverse variance weighted (IVW) and MR‐Egger. Results: The MR analysis found that increased cheese consumption was significantly associated with a reduced risk of T2DM (OR = 0.639, 95% CI: 0.482–0.847, and p value = 0.002) and its ophthalmic complications (OR = 0.386, 95% CI: 0.196–0.759, and p value = 0.015). No significant associations were found with other complications, including neuropathy, nephropathy, and peripheral vascular complications. Sensitivity analyses confirmed minimal heterogeneity and pleiotropy, supporting the reliability of these findings. Conclusion: This study suggests a protective role of cheese intake in reducing T2DM risk and its ophthalmic complications, potentially informing dietary recommendations for T2DM management.

Apolipoprotein O (APOO) plays a critical intracellular role in regulating lipid metabolism. Here, we investigated the roles of APOO in metabolism and atherogenesis in mice. Hepatic APOO expression was increased in response to hyperlipidemia but was inhibited after simvastatin treatment. Using a novel APOO global knockout (Apoo -/- ) model, it was found that APOO depletion aggravated diet-induced obesity and elevated plasma cholesterol levels. Upon crossing with low-density lipoprotein receptor (LDLR) and apolipoprotein E (APOE) knockout hyperlipidemic mouse models, Apoo -/- Apoe -/- and Apoo -/- Ldlr -/- mice exhibited elevated plasma cholesterol levels, with more severe atherosclerotic lesions than littermate controls. This indicated the effects of APOO on cholesterol metabolism independent of LDLR and APOE. Moreover, APOO deficiency reduced cholesterol excretion through bile and feces while decreasing phospholipid unsaturation by inhibiting NRF2 and CYB5R3. Restoration of CYB5R3 expression in vivo by adeno-associated virus (AAV) injection reversed the reduced degree of phospholipid unsaturation while decreasing blood cholesterol levels. This represents the first in vivo experimental validation of the role of APOO in plasma cholesterol metabolism independent of LDLR and elucidates a previously unrecognized cholesterol metabolism pathway involving NRF2/CYB5R3. APOO may be a metabolic regulator of total-body cholesterol homeostasis and a target for atherosclerosis management.Apolipoprotein O (APOO) regulates plasma cholesterol levels and atherosclerosis through a pathway involving CYB5R3 that regulates biliary and fecal cholesterol excretion, independently of the LDL receptor. In addition, down-regulation of APOO may lead to impaired mitochondrial function, which in turn aggravates diet-induced obesity and fat accumulation.

BackgroundRecent studies have revealed a significant decrease in serum fetuin-A levels in atherosclerotic aneurysms, indicating that fetuin-A may play a protective role in the progression of arterial calcification. However, the specific mechanism behind this phenomenon remains unclear. We aimed to examine the association between fetuin-A levels in thoracic aortic aneurysms (TAAs) and risk of TAAs and to evaluate whether this association was causal.MethodsA total of 26 SNPs were selected as instrumental variables for fetuin-A in 9,055 participants of European ancestry from the CHARGE consortium, and their effects on thoracic aortic aneurysm and decreased descending thoracic aortic diameter were separately estimated in 353,049 and 39,688 individuals from FinnGen consortium. We used two-sample Mendelian randomization (MR) analysis to examine the causal association. At the same time, we employed various methods, including random-effects inverse variance weighting, weighted median, MR Egger regression, and MR PRESSO, to ensure the robustness of causal effects. We assessed heterogeneity using Cochran’s Q value and examined horizontal pleiotropy through MR Egger regression and retention analysis.ResultsFetuin-A level was associated with a significantly decreasing risk of thoracic aortic aneurysm (odds ratio (OR) 0.64, 95% CI 0.47 - 0.87, P = 0.0044). Genetically predicted fetuin-A was also correlated with the decreased descending thoracic aortic diameter (β = -0.086, standard error (SE) 0.036, P = 0.017).ConclusionsSerum fetuin-A level was negatively associated with risk of TTAs and correlated with the decreased descending thoracic aortic diameter. Mendelian randomization provides support for the potential causal relationship between fetuin-A and thoracic aortic aneurysm.

BackgroundThyroid nodules, increasingly prevalent globally, pose a risk of malignant transformation. Early screening is crucial for management, yet current models focus mainly on ultrasound features. This study explores machine learning for screening using demographic and biochemical indicators.MethodsAnalyzing data from 6,102 individuals and 61 variables, we identified 17 key variables to construct models using six machine learning classifiers: Logistic Regression, SVM, Multilayer Perceptron, Random Forest, XGBoost, and LightGBM. Performance was evaluated by accuracy, precision, recall, F1 score, specificity, kappa statistic, and AUC, with internal and external validations assessing generalizability. Shapley values determined feature importance, and Decision Curve Analysis evaluated clinical benefits.ResultsRandom Forest showed the highest internal validation accuracy (78.3%) and AUC (89.1%). LightGBM demonstrated robust external validation performance. Key factors included age, gender, and urinary iodine levels, with significant clinical benefits at various thresholds. Clinical benefits were observed across various risk thresholds, particularly in ensemble models.ConclusionMachine learning, particularly ensemble methods, accurately predicts thyroid nodule presence using demographic and biochemical data. This cost-effective strategy offers valuable insights for thyroid health management, aiding in early detection and potentially improving clinical outcomes. These findings enhance our understanding of the key predictors of thyroid nodules and underscore the potential of machine learning in public health applications for early disease screening and prevention.

ABSTRACT:In vitro investigations have established metformin's capacity to downregulate proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, suggesting a potential beneficial effect on atherogenic lipoprotein particles when combined with metformin therapy. Our objective was to assess whether metformin could mitigate statin-induced adverse effects on PCSK9, thereby improving lipid profiles in patients with coronary artery disease (CAD) but without diabetes. Employing an open-label, placebo-controlled, randomized trial, we randomized patients with CAD but without diabetes into CLA (cholesterol-lowering agents alone: atorvastatin ± ezetimibe, n = 38) and Met + CLA groups (metformin plus CLA, n = 33) in a 1:1 ratio. The primary end point was the therapeutic impact of 1-month metformin combination treatment on low-density lipoprotein cholesterol (LDL-C) and PCSK9 levels. Baseline LDL-C and PCSK9 levels were 76.18 mg·dL -1 and 80.54 ng·mL -1 , respectively. After 1 month, metformin significantly reduced LDL-C (-20.81%, P < 0.001), enabling 72% of patients to attain guideline-recommended LDL-C goals. Noteworthy reductions in PCSK9 levels (-15.03%, P < 0.001) were observed. Moreover, Met + CLA markedly reduced LDL particle number more than CLA alone (-10.65% vs. 1.45%, P = 0.009), primarily due to diminished small-dense LDL particle count. Mechanistically, our study demonstrated metformin's inhibition of statin-induced PCSK9 expression in human hepatocellular cells. In summary, a 1-month metformin combination regimen reduced LDL-C levels in patients with CAD but without diabetes by inhibiting PCSK9 expression. TRIAL REGISTRATION:Chinese Clinical Trial Registry identifier: ChiCTR1900026925 (26/10/2019).

In vitro investigations have established metformin's capacity to downregulate PCSK9 expression, suggesting a potential beneficial effect on atherogenic lipoprotein particles when combined with metformin therapy. Our objective was to assess whether metformin could mitigate statin-induced adverse effects on PCSK9, thereby improving lipid profiles in patients with coronary artery disease (CAD) but without diabetes. Employing an open-label, placebo-controlled, randomized trial, we randomized patients with CAD but without diabetes into CLA (Cholesterol-Lowering Agents alone: atorvastatin+/-ezetimibe, n=38) and Met+CLA groups (metformin plus CLA, n=33) at a 1:1 ratio. The primary endpoint was the therapeutic impact of one-month metformin combination treatment on LDL-C and PCSK9 levels. Baseline LDL-C and PCSK9 levels were 76.18 mg·dL-1 and 80.54 ng·mL-1, respectively. After one month, metformin significantly reduced LDL-C (-20.81%, P<0.001), enabling 72% of patients to attain guideline-recommended LDL-C goals. Noteworthy reductions in PCSK9 levels (-15.03%, P<0.001) were observed. Moreover, Met+CLA markedly reduced LDL particle number more than CLA alone (-10.65% vs 1.45%, P=0.009), primarily due to diminished small-dense LDL particle count. Mechanistically, our study demonstrated metformin's inhibition of statin-induced PCSK9 expression in human hepatocellular cells. In summary, a one-month metformin combination regimen reduced LDL-C levels in patients with CAD but without diabetes by inhibiting PCSK9 expression.

BackgroundSubstantial evidence suggests an association between psychiatric disorders and chronic heart failure. However, further investigation is needed to confirm the causal relationship between these psychiatric disorders and chronic heart failure. To address this, we evaluated the potential effects of five psychiatric disorders on chronic heart failure using two-sample Mendelian Randomization (MR).MethodsWe selected single nucleotide polymorphisms (SNPs) associated with chronic heart failure and five psychiatric disorders (Attention-Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Major Depression, Bipolar Disorder and Schizophrenia (SCZ)). Univariable (UVMR) and multivariable two-sample Mendelian Randomization (MVMR) were employed to assess causality between these conditions. Ever smoked and alcohol consumption were controlled for mediating effects in the multivariable MR. The inverse variance weighting (IVW) and Wald ratio estimator methods served as the primary analytical methods for estimating potential causal effects. MR-Egger and weighted median analyses were also conducted to validate the results. Sensitivity analyses included the funnel plot, leave-one-out, and MR-Egger intercept tests. Additionally, potential mediators were investigated through risk factor analyses.ResultsGenetically predicted heart failure was significantly associated with ADHD (odds ratio (OR), 1.12; 95% CI, 1.04–1.20; p = 0.001), ASD (OR, 1.29; 95% CI, 1.07–1.56; p = 0.008), bipolar disorder (OR, 0.89; 95% CI, 0.83–0.96; p = 0.001), major depression (OR, 1.15; 95% CI, 1.03–1.29; p = 0.015), SCZ (OR, 1.04; 95% CI, 1.00–1.07; p = 0.024). Several risk factors for heart failure are implicated in the above cause-and-effect relationship, including ever smoked and alcohol consumption.ConclusionOur study demonstrated ADHD, ASD, SCZ and major depression may have a causal relationship with an increased risk of heart failure. In contrast, bipolar disorder was associated with a reduced risk of heart failure, which could potentially be mediated by ever smoked and alcohol consumption. Therefore, prevention strategies for heart failure should also incorporate mental health considerations, and vice versa.

Diabetes is a significant independent risk factor for atherosclerotic cardiovascular disease (ASCVD), with dyslipidemia playing a critical role in the initiation and progression of ASCVD in diabetic patients. In China, the current prevalence of dyslipidemia in diabetes is high, but the control rate remains low. Therefore, to enhance lipid management in patients with diabetes, the Endocrinology and Metabolism Physician Branch of the Chinese Medical Doctor Association, in collaboration with the Experts' Committee of the National Society of Cardiometabolic Medicine, has convened experts to develop a consensus on the management of dyslipidemia in patients with type 1 or type 2 diabetes. The development of this consensus is informed by existing practices in lipid management among Chinese diabetic patients, incorporating contemporary evidence-based findings and guidelines from national and international sources. The consensus encompasses lipid profile characteristics, the current epidemiological status of dyslipidemia, ASCVD risk stratification, and lipid management procedures in diabetic patients. For the first time, both low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol have been recommended as primary targets for lipid intervention in diabetic patients. The consensus also includes a summary and recommendations for lipid management strategies in special diabetic populations, including children and adolescents, individuals aged 75 years and older, patients with chronic kidney disease, metabolic-associated fatty liver disease, and those who are pregnant. This comprehensive consensus aims to improve cardiovascular outcomes in diabetic patients by contributing to the dissemination of key clinical advancements and guiding clinical practice.

Background: Ischemic stroke is a significant global health issue, imposing substantial social and economic burdens. Carotid artery plaques (CAP) serve as an important risk factor for stroke, and early screening can effectively reduce stroke incidence. However, China lacks nationwide data on carotid artery plaques. Machine learning (ML) can offer an economically efficient screening method. This study aimed to develop ML models using routine health examinations and blood markers to predict the occurrence of carotid artery plaques. Methods: This study included data from 5,211 participants aged 18-70, encompassing health check-ups and biochemical indicators. Among them, 1,164 participants were diagnosed with carotid artery plaques through carotid ultrasound. We constructed six ML models by employing feature selection with elastic net regression, selecting 13 indicators. Model performance was evaluated using accuracy, sensitivity, specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV), F1 score, kappa value, and Area Under the Curve (AUC) value. Feature importance was assessed by calculating the root mean square error (RMSE) loss after permutations for each variable in every model. Results: Among all six ML models, LightGBM achieved the highest accuracy at 91.8%. Feature importance analysis revealed that age, Low-Density Lipoprotein Cholesterol (LDL-c), and systolic blood pressure were important predictive factors in the models. Conclusion: LightGBM can effectively predict the occurrence of carotid artery plaques using demographic information, physical examination data and biochemistry data.

Background: Triggering receptor expressed on myeloid cells 2 (TREM2) is a unique receptor expressed by macrophages in atherosclerotic plaque and is involved in the progression of atherosclerosis. Whether serum soluble TREM2 (sTREM2) levels has a relationship with coronary heart disease (CHD) remains unclear.Methods: The cross-sectional study included 86 patients with CHD and 86 controls matched with age and sex. Demographic information, medication history, and laboratory data were collected. sTREM2 concentrations were detected by enzyme-linked immunosorbent assay. We compared the sTREM2 levels in two groups and constructed stepwise linear regression analysis for factors related to the sTREM2 level in patients with CHD; we further used the logistic regression model to evaluate the relationship between sTREM2 and CHD. The diagnostic value of sTREM2 and other biomarkers in CHD was evaluated by the receiver operating characteristic curve (ROC).Results: The serum level of sTREM2 in CHD patients is higher than that in controls. In CHD patients, the stepwise linear regression analysis found that sTREM2 levels were correlated with triglyceride (TG), high-density lipoprotein cholesterols (HDL-C), apolipoprotein B (ApoB) and smoking status. Logistic regression models showed that sTREM2 was associated independently with CHD after adjusted confounders. The ROC curve showed a sensitivity of 59.3% and specificity of 81.4% with an area under the curve of 0.781 (95% CI: 0.711-0.852) for the diagnosis of CHD with serum sTREM2 at a cut-off value of > 1104.894 pg/ml, indicating a higher diagnostic value than high sensitivity C reaction protein (hs-CRP) and apolipoprotein B (ApoB).Conclusion: In this study, we provide evidence that sTREM2 levels are elevated in CHD patients and are associated with various cardiovascular risk factors. Additionally, sTREM2 demonstrates better diagnostic performance compared to traditional indicators in identifying CHD. These findings suggest that sTREM2 may serve as a potential biomarker for coronary heart disease.

Background Mitochondrial dysfunction and aberrant structure in adipose tissue occur in obesity and obesity-linked brown adipose tissue (BAT) whitening; however, whether this aberrant architecture contributes to or is the result of obesity is unknown. Apolipoprotein O (APOO) is a constitutive protein of the mitochondrial cristae organizing system complex. This study aimed to characterize the physiological consequences of APOO deficiency in vivo. Methods APOO expression was analyzed in different human and murine adipose depots, and mice lacking APOO in adipocytes (ApooACKO) are developed to examine the metabolic consequences of adipocyte-specific APOO ablation in vitro and in vivo. Results Results showed that APOO expression is reduced in BAT from both diet-induced and leptin-deficient obese mice. APOO-knockout mice showed increased adiposity, BAT dysfunction and whitening, reduced non-shivering thermogenesis, and blunted responses to cold stimuli. APOO deficiency disrupted mitochondrial structure in brown adipocytes and impaired oxidative phosphorylation, thereby inducing a shift from oxidative to glycolytic metabolism, increasing lipogenic enzyme levels and BAT whitening. APOO inactivation inhibited thermogenesis in BAT by reducing mitochondrial long-chain fatty acid oxidation. It also disturbed peroxisomal biogenesis and very long-chain fatty acid oxidation via peroxisome proliferator-activated receptor α. Conclusions Altogether, APOO deficiency in adipocytes aggravates BAT whitening and diet-induced obesity; thus, APOO could be a therapeutic target for obesity.

Background: Fatty liver disease (FLD) is an important risk factor for liver cancer and cardiovascular disease and can lead to significant social and economic burden. However, there is currently no nationwide epidemiological survey for FLD in China, making early FLD screening crucial for the Chinese population. Unfortunately, liver biopsy and abdominal ultrasound, the preferred methods for FLD diagnosis, are not practical for primary medical institutions. Therefore, the aim of this study was to develop machine learning (ML) models for screening individuals at high risk of FLD, and to provide a new perspective on early FLD diagnosis. Methods: This study included a total of 30,574 individuals between the ages of 18 and 70 who completed abdominal ultrasound and the related clinical examinations. Among them, 3474 individuals were diagnosed with FLD by abdominal ultrasound. We used 11 indicators to build eight classification models to predict FLD. The model prediction ability was evaluated by the area under the curve, sensitivity, specificity, positive predictive value, negative predictive value, and kappa value. Feature importance analysis was assessed by Shapley value or root mean square error loss after permutations. Results: Among the eight ML models, the prediction accuracy of the extreme gradient boosting (XGBoost) model was highest at 89.77%. By feature importance analysis, we found that the body mass index, triglyceride, and alanine aminotransferase play important roles in FLD prediction. Conclusion: XGBoost improves the efficiency and cost of large-scale FLD screening.

The efficacy of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition has broadened lipid-lowering therapy thus providing decreased risk in atherosclerotic cardiovascular disease. Unfortunately, the widespread use of PCSK9 inhibitors (PCSK9i), ie, monoclonal antibodies, has led to the findings of unusual responsiveness, ie, a phenomenon defined as an LDL-C reduction of <30% vs the average LDL-C reduction efficacy of 50-60%. This unusual responsiveness to PCSK9i is attributable to several factors, ie, lack of adherence, impaired absorption, poor distribution or early elimination as well as abnormal effects of PCSK9i in the presence of anti-antibodies or mutations in PCSK9 and LDLR. Unexpectedly increased lipoprotein (Lp)(a) also appear to contribute to the unusual responsiveness scenario. Identification of these responses and mechanisms underlying them are essential for effective management of LDL-C and cardiovascular risk. In this review, we describe plausible reasons underlying this phenomenon supported by findings of clinical trials. We also elaborate on the need for education and regular follow-up to improve adherence. Collectively, the review provides a summary of the past, present, and future of mechanisms and countermeasures revolving around unusual responses to PCSK9i therapy.

The incidence of heart failure with preserved ejection fraction is increasing in patients with obesity, diabetes, hypertension, and in the aging population. However, there is a lack of adequate clinical treatment. Patients with obesity-related heart failure with preserved ejection fraction display unique pathophysiological and phenotypic characteristics, suggesting that obesity could be one of its specific phenotypes. There has been an increasing recognition that overnutrition in obesity causes adipose tissue expansion and local and systemic inflammation, which consequently exacerbates cardiac remodeling and leads to the development of obese heart failure with preserved ejection fraction. Furthermore, overnutrition leads to cellular metabolic reprogramming and activates inflammatory signaling cascades in various cardiac cells, thereby promoting maladaptive cardiac remodeling. Growing evidence indicates that the innate immune response pathway from the NLRP3 inflammasome, to interleukin-1 to interleukin-6, is involved in the generation of obesity-related systemic inflammation and heart failure with preserved ejection fraction. This review established the existence of obese heart failure with preserved ejection fraction based on structural and functional changes, elaborated the inflammation mechanisms of obese heart failure with preserved ejection fraction, proposed that NLRP3 inflammasome activation may play an important role in adiposity-induced inflammation, and summarized the potential therapeutic approaches.

Organophosphorus compounds were proposed to impair immune surveillance and increase the total burden of pathogens. However, scarce attention has been paid to the effects of organophosphate flame retardants (OPFRs) on neutrophils. Previous literature outlined that neutrophil extracellular traps (NETs) death (NETosis) is associated with autophagy-related signaling. Here we found that 20 μM diphenyl phosphate (DPHP) could promote NETs formation via assessing markers of NETs and the morphological changes. Concurrently, flow cytometry and western blot analysis revealed that DPHP-triggered NETs formation was associated with reactive oxygen species (ROS) burst and activation of extracellular signal-regulated kinase (ERK) and p38. Additionally, the results revealed that autophagy occurred in DPHP-triggered NETs formation, manifested as enhanced LC3B protein expressions and reduced p62 protein expressions. Mechanism dissection revealed that inhibition of autophagy by 3-methyladenine (3-MA) alleviated the ROS burst and subsequent NETosis caused by DPHP. Conversely, autophagy enhancer Rapamycin (Rapa) augmented the above effects of DPHP, including the generation of ROS and NETosis. Collectively, these data suggested ERK/p38 signaling and ROS burst might be an important cause of DPHP-triggered NETs formation, while suppression of excessive autophagy could rescue these actions. These observations provided a theoretical basis for the treatment and prevention of OPFRs-induced immunotoxicity.

Hexavalent chromium [Cr(VI)] is a proven toxin, carcinogen and environmental pollutant. Oral intake of Cr(VI) has been shown to lead to an increasing incidence of primary hepatic carcinoma in the population. Cellular senescence is thought to be a natural barrier to malignant transformation of cells, but senescence-associated secretory phenotype (SASP) is secreted and regulated by senescent cells links cellular senescence to malignant transformation in a dynamic way. In the present research, we demonstrated novel mechanisms of premature hepatocytes senescence induced by Cr(VI). Continuous Cr(VI) stimulation led to DNA damaged in hepatocytes, and DNA damage response (DDR) signals were transmitted by ataxia telangiectasia-mutated gene (ATM)/ataxia telangiectasia and Rad-3-related protein (ATR), resulting in zinc finger transcription factor GATA4 escaping p62-mediated selective autophagy, thereby regulating nuclear factor kappa-B (NF-κB) to induce premature senescence in hepatocytes. In contrast to the classical senescence pathway p53-p21WAF1 /CIP1 and Rb/p16INK4a, GATA4 can directly regulate the secretion of SASP during premature senescence. The results will provide valuable clues for targeted prevention and further individualized treatment of Cr(VI)-associated cancers.

Background:Although the available evidence has indicated a link between elevated serum uric acid (SUA) level and dyslipidemia, the potential contribution of SUA on lipid profiles remains unclear. Experimental and clinical studies have revealed several mechanisms through which high serum angiopoietin-like protein 4 (ANGPTL4) level exerts deleterious effects on lipid metabolism, but the role of ANGPTL4 in SUA-associated dyslipidemia has not been well studied, so far.Methods:A total of 80 subjects were classified into high SUA group (n = 40) and low SUA group (n = 40) by the median value of SUA in the whole study population. Serum ANGPTL4 levels were determined by enzyme-linked immunosorbent assays.Results:In our study, we observed that not only serum triglyceride level [1.03 (0.78, 1.50) mmol/L vs. 1.59 (1.18, 2.37) mmol/L, p = 0.001] but also serum triglyceride-rich lipoprotein cholesterol (TRL-C) level [0.38 (0.32, 0.45) mmol/L vs. 0.46 (0.34, 0.54) mmol/L, p = 0.012] were significantly elevated in high SUA group. Additionally, serum ANGPTL4 in high SUA group was higher than in low SUA group [15.81 (11.88, 20.82) ng/ml vs. 22.13 (17.88, 32.09) ng/ml, p = 0.000]. Moreover, in all subjects, TRL-C levels were positively associated with SUA (r = 0.26, p = 0.023, n = 80) and ANGPTL4 levels (r = 0.24, p = 0.036, n = 80). Using stepwise multiple regression analysis to adjust for potential confounders, SUA was discovered to be an independent contributor to serum ANGPTL4 (p = 0.023). At the same time, serum ANGPTL4 was an independent contributor to the level of TRL-C (p = 0.000). However, the correlation between SUA and TRL-C disappeared after controlling for ANGPTL4 level.Conclusion:Serum uric acid was positively correlated to TRL-C. ANGPTL4 may be an interplay between SUA and associated elevation of TRL-C.

Migraine is a complex neurological disorder with a high disability rate. Although the precipitating factors of migraine remain unclear, previous studies suggest that when there is excess nitrogen dioxide (NO2) pollution in the atmosphere, the medical demand due to migraine attacks increases sharply. However, the main role of NO2 as a trigger for migraine is not yet well understood. The purpose of this study was to explore the relationship between NO2 exposure and the occurrence of migraine as well as the possible underlying mechanisms. We first investigated whether repeated short-term NO2 exposure could induce behavioural and biological migraine phenotypes in rats. Next, capsazepine (CZP) was used to block transient receptor potential cation channel subfamily V member 1 (TRPV1) in vivo, and CZP and vitamin E (VE) were used to verify the role of reactive oxygen species (ROS)-TRPV1 signalling in NO2-induced migraine in primary trigeminal neurones in vitro. We demonstrated that short-term repeated NO2 exposure can significantly induce migraine in rats, and its key molecular mechanism may be related to ROS burst and its downstream TRPV1 channel activation. The findings of this study will enhance the understanding of the neurotoxic mechanism of NO2, provide new clues for identifying the aetiology of migraine, and lay a new experimental basis for implementing migraine-related preventive and therapeutic control measures.