BackgroundPolycystic ovary syndrome (PCOS) is associated with increased cardiovascular disease (CVD) risk, but differences across phenotypes in Chinese women remain unclear. This study aimed to characterize clinical profiles of PCOS phenotypes, predict CVD risks, and evaluate associations between phenotypes and CVD risk.MethodsA total of 206 women with PCOS were included from an initial cohort of 211 and classified into four phenotypes according to Rotterdam criteria. Clinical data, laboratory results, and imaging measurements were collected. CVD risks were estimated using the China-PAR model. One-way ANOVA and the Kruskal-Wallis test were used for continuous variables, and Pearson’s chi-square or Fisher’s exact test for categorical variables. Firth logistic regression was employed to assess the association between PCOS phenotypes and CVD risk, and mediation analysis detected the indirect effects.ResultsAmong 206 patients with PCOS, 104 (50.5%), 36 (17.5%), 19 (9.2%) and 47 (22.8%) were classified as phenotype A, B, C and D. BMI, WC, SBP, and DBP were significantly higher in phenotypes A, B, and C than in D (P<0.05). UA, LDL-C, TG, and HOMA-IR were significantly higher in phenotypes A and B than in D, while HDL-C and ISI-Matsuda were significantly lower (P<0.05). Lifetime CVD risk scores were significantly higher in phenotypes A, B, and C compared with D (P< 0.05), with values of 15.55%, 17.65%, 17.30%, and 9.90%. After adjusting for diet, physical activity, and medication use, phenotypes A (OR 3.18, 95% CI: 1.30-8.84, P = 0.010), B (OR 4.90, 95% CI: 1.58-16.44, P = 0.006), and C (OR 4.67, 95% CI: 1.39-16.64, P = 0.013) were significantly associated with higher odds of high lifetime CVD risk compared with D. The mediating effects of BMI, HOMA-IR, and UA were significant (P< 0.05), with BMI exhibiting the largest mediating effect, accounting for 94.7%, 70.9%, and 42.9% of the total effect in phenotypes A, B, and C compared with D.ConclusionsOur results demonstrated that more adverse clinical abnormalities and significantly higher CVD risk in women with phenotypes A, B, and C compared with D. BMI, HOMA-IR, and UA play a significantly mediating role between phenotypes and CVD risk. This study suggests that it may be necessary to conduct regular CVD risk assessments for patients with different phenotypes of PCOS, in order to guide early individualized treatment strategies, with a focus on weight and metabolic management.

BACKGROUND:Complete 17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a rare autosomal recessive form of congenital adrenal hyperplasia caused by CYP17A1 variants. Large-scale studies integrating clinical, genetic, and functional data remain limited. METHODS:We recruited 113 genetically confirmed 17-OHD patients from 107 unrelated families. Comprehensive clinical manifestations, hormonal, and imaging examination data were collected. CYP17A1 variants were identified by Sanger sequencing, whole-exome sequencing or long-read sequencing. In vitro functional studies including enzyme activity assays and minigene splicing assays were performed to verify the pathogenicity of the variants. RESULTS:All patients presented as phenotypic females, with a median diagnostic age of 17 years. Hypertension (93.58%) and hypokalemia (74.31%) were the dominant clinical features, and 91.26% exhibited Tanner stage I breast development. We identified 50 pathogenic CYP17A1 variants, including 6 novel ones (c.286C>G, c.436+1G>T, c.1241C>T, c.1300C>T, c.1348C>T, c.1433G>T). The mutation spectrum was dominated by a founder hotspot, c.985_987delinsAA, accounting for 59.29% of alleles, with mutations clustering in exons 6 and 8. In vitro enzyme activity assays confirmed near-complete loss of both 17α-hydroxylase and 17,20-lyase activities in all variants except p.Val236Gly, which retained minimal residual activity. Notably, 5 variants (including 2 missense changes, c.1084C>T and c.1085G>A) were shown to disrupt normal pre-mRNA splicing in minigene assays, revealing a dual molecular mechanism of pathogenicity involving both protein dysfunction and aberrant RNA processing. CONCLUSION:This study defines the most comprehensive CYP17A1 variant spectrum for complete 17-OHD in China, identifies 6 novel pathogenic variants, and uncovers splicing disruption as an under-recognized mechanism in missense mutations. These findings expand the molecular and clinical understanding of 17-OHD, highlight the founder effect of c.985_987delinsAA in the Chinese population, and provide critical insights for genetic diagnosis and counseling.

Hyperuricemia (HUA) is primarily attributed to insufficient uric acid (UA) excretion. 6'‑O‑Caffeoylarbutin (CA), the primary bioactive constituent of anti‑gout herbal tea (Que Zui tea), has demonstrated potential urate‑lowering effects; however, its underlying mechanisms require further elucidation. In the present study, a hypoxanthine (HX) and potassium oxonate (PO) induced hyperuricemia (HUA) mouse model was established to assess the effects of different doses of CA. Biochemical analyses, histopathological examination, western blotting and 16S rRNA gene sequencing were conducted to explore the underlying mechanisms. Notably, CA markedly reduced serum uric acid (SUA), serum creatinine (SCr) and blood urea nitrogen (BUN) levels and alleviated renal and intestinal histopathological damage. In the kidney, CA upregulated ATP‑binding cassette sub‑family G member 2 (ABCG2), and downregulated glucose transporter 9 (GLUT9) and urate transporter 1 expression (URAT1). In the intestine, CA increased ABCG2, PDZ domain containing 1 (PDZK1) and tight junction protein expression, while decreasing GLUT9, suggesting improved urate excretion and barrier integrity. 16S ribosomal RNA sequencing revealed that CA was associated with increased gut microbial diversity and reduced abundance of potentially harmful bacteria, including Desulfovibrio. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States‑based prediction suggested accompanying shifts in microbial functions related to transport and metabolism. In conclusion, these findings suggested that CA may exert beneficial effects on HUA involving regulation of renal and intestinal urate transport, improvement of intestinal barrier function and favorable modulation of gut microbiota. CA may therefore serve as a potential candidate for functional food development or therapeutic strategies against HUA.

Objective:Previous Mendelian randomization (MR) studies have suggested an association between the gut microbiome and metabolic-associated fatty liver disease (MAFLD). However, the reliance on 16S rRNA sequencing data has led to inconsistent findings and limited species-level insights. To address this, we conducted a de novo MR analysis using species-level shotgun metagenomic data, combined it with a meta-analysis to consolidate the existing evidence, and explored metabolite-mediated pathways. Methods:Bidirectional MR analyses were performed between 883 gut microbiota taxa (derived from shotgun metagenomic genome-wide association study) and MAFLD. Published MR studies (up to December 1, 2024) were identified using PubMed, Embase, Web of Science, and the Cochrane Library for meta-analysis. Multivariable MR (MVMR) and mediation analyses were applied to assess the mediating effects of 1,400 blood metabolites. Results:The de novo MR identified 25 MAFLD-associated microbial taxa. Integration with 7 published studies revealed 34 causal taxa, including 10 at the species level. Among the 1,400 metabolites, 53 showed causal links with MAFLD. MVMR and mediation analyses identified deoxycholate as a mediator of the effect of Bifidobacterium on MAFLD risk (22.06% mediation proportion). Conclusion:This study elucidated the connections between species-level gut microbiota and MAFLD, highlighting the interplay between microbiota, metabolites, and disease pathogenesis. These findings provide novel insights into the potential therapeutic targets for MAFLD.

AIM:To report two cases of immune-mediated severe hyperinsulinemia-Type B Insulin Resistance Syndrome (TBIRS) and Exogenous Insulin Antibody Syndrome (EIAS)-and to highlight the clinical clues for differential diagnosis and the divergent therapeutic strategies. METHODS:Detailed clinical, biochemical, and immunological evaluations of two patients with extreme hyperinsulinemia (>350 µU/ml) and refractory hyperglycemia were performed, including polyethylene glycol (PEG) precipitation and insulin recovery assays. RESULTS:Patient 1, a 59-year-old woman with type 2 diabetes and pulmonary tuberculosis, had insulin levels exceeding 1000 µU/ml with positive anti-insulin receptor antibodies, confirming TBIRS. Active tuberculosis contraindicated immunosuppression and hyperglycemia persisted. Patient 2, a 61-year-old man with type 2 diabetes, had insulin levels of 767.7-833.9 µU/ml with strongly positive anti-insulin antibodies. PEG precipitation revealed an insulin recovery of 28.6% and a free-to-total insulin ratio of 6.8%, confirming EIAS. Insulin discontinuation and corticosteroids achieved glycemic control. CONCLUSION:TBIRS and EIAS, though both presenting with extreme hyperinsulinemia, require fundamentally different management strategies. Comorbidities such as active tuberculosis may preclude immunosuppressive therapy in TBIRS, creating therapeutic dilemmas. In EIAS, when initial insulin modification fails to resolve glycemic instability, timely escalation to glucocorticoid therapy can achieve sustained immunological remission and durable glycemic control.

Introduction and Objective: Genetic susceptibility to obesity is well-known. However, the impact of physical activity (PA) on metabolic health in genetically predisposed individuals remains unclear. We aim to explore how PA interacts with obesity polygenic risk scores (PRS) in children, focusing on the modulation of adipose tissue endocrine function and the underlying mechanisms using multi-omics data. Methods: We enrolled 3,280 schoolchildren from the Beijing Children and Adolescents Metabolic Syndrome Study (BCAMS). PA and lifestyle factors were assessed through questionnaires. Fasting insulin and five adipokines (leptin, adiponectin, RBP-4, FGF21, SPARC) were measured. Genetic risk was assessed via genotyping 14 obesity-related SNPs. Mediation analysis examined the role of adipokine levels in the relationship between exercise-regulated PRS and metabolic risk. Multi-omics data integration included publicly available eQTL, multi-tissue transcriptomics, epigenomics, and proteomics data. Results: Significant interactions existed between the 14-SNP PRS and PA scores on BMI, metabolic health, and adipokine levels (p = 0.001-0.05). Key loci responsive to exercise were identified as ADCY3, GNPDA2, PEPD, MAP2K5, and MC4R. Regular MVPA diminished the predictive effect of the PRS on obesity phenotypes (p> 0.05). The leptin/adiponectin ratio significantly mediates the regulation of genetic risk by exercise (p< 0.05). Multi-omics integration revealed that MAP2K5, GNPDA2, and PEPD increase obesity risk, while ADCY3 provides protection. Moreover, the influence of these genes on weight metrics varied significantly with exercise adjustments; exercise enhances metabolic health by altering gene expression and epigenetic states, influencing adipokine secretion. Conclusion: This study elucidates how PA mitigates the genetic obesity risk via the leptin-adiponectin axis. These insights provide a foundation for precision exercise interventions in childhood obesity management. Disclosure M. Li: None. H. Zhu: None. S. Gao: None. Funding the National Natural Science Foundation of China (82270924, 81970732); National High Level Hospital Clinical Research Funding (2025-PUMCH-C-041, 2022-PUMCH-C-014); Capital's Funds for Health Improvement and Research (2020-2Z-40117); the CAMS Innovation Fund for Medical Sciences (CIFMS 2021-I2M-1-016); key program of Beijing Municipal Science & Technology Commission (D111100000611001, D111100000611002).

ObjectiveAlthough an insulin-to-C-peptide molar ratio greater than 1 has traditionally been considered suggestive of insulin autoimmune syndrome (IAS), its diagnostic value remains controversial, and the optimal cutoff is unclear. This study aimed to evaluate the diagnostic performance of the insulin-to-C-peptide molar ratio for distinguishing IAS and exogenous insulin antibody syndrome (EIAS) from insulinoma and to identify the optimal diagnostic cutoff.MethodsWe retrospectively collected clinical and biochemical data from 19 patients with IAS, 33 with EIAS, and 70 control patients with pathologically confirmed insulinoma. Receiver-operating-characteristic (ROC) curve analysis was performed separately for IAS versus insulinoma and EIAS versus insulinoma to assess the diagnostic performance of the insulin-to-C-peptide molar ratio in the fasting state and during hypoglycemic episodes.ResultsThe insulin-to-C-peptide molar ratio was significantly higher in IAS and EIAS than in insulinoma at both fasting and during hypoglycemic episodes. During hypoglycemic episodes, the area under the ROC curve (AUC) was 0.970 for IAS versus insulinoma and 0.944 for EIAS versus insulinoma, with optimal cutoffs of 0.382 and 0.552, respectively. In the fasting state, the corresponding AUCs were 0.916 and 0.961, with optimal cutoffs of 0.309 and 0.386. Compared with the conventionally used cutoff of 1, the optimal cutoffs substantially improved sensitivity while maintaining high specificity, particularly for IAS. Insulin concentration alone also showed good diagnostic performance for distinguishing IAS from insulinoma, with AUCs of 0.985 and 0.943 and optimal cutoffs of 83.1 and 58.86 μIU/mL during hypoglycemic episodes and in the fasting state, respectively, but was less informative for EIAS, with AUCs of 0.853 and 0.729 and optimal cutoffs of 67.85 and 71.94 μIU/mL, respectively.ConclusionThe insulin-to-C-peptide molar ratio, measured either during hypoglycemic episodes or in the fasting state, showed good diagnostic performance for distinguishing IAS and EIAS from insulinoma. The conventionally used cutoff of 1 appears to be too high, and lower cutoffs may provide better sensitivity while preserving specificity. Validation in larger cohorts is needed.

>Childhood obesity has become a global epidemic.It has been shown that nearly 55% of children with obesity will remain with obesity during adolescence and about 80% of adolescents with obesity will still suffer from this condition in the adulthood [1] . This increase leads to a myriad of health risks, such as type 2 diabetes（T2D）, cardiovascular diseases, and various metabolic disorders [1] .

Objective:Most patients with insulinoma are overweight or obese. Ghrelin levels in insulinoma have been linked to both obesity and hyperinsulinemia. Liver-expressed antimicrobial peptide 2 (LEAP2), a novel hormone and endogenous antagonist of the ghrelin receptor, is associated with obesity; however, its relationship with obesity and hyperinsulinemia in insulinoma, and its expression within tumor tissue, remains unknown. Methods:Serum LEAP2, insulin, and ghrelin levels were measured by ELISA in patients with insulinoma and in age-, sex-, and BMI-matched controls. LEAP2 expression was examined in insulinoma tissue and paired adjacent pancreatic specimens by immunohistochemical staining. Results:Serum LEAP2 levels were significantly higher in patients with insulinoma than in controls (P = 0.028) and positively correlated with serum insulin levels (r = 0.408, P < 0.001) while negatively correlated with ghrelin levels (r = -0.551, P < 0.01). In controls, serum LEAP2 levels were significantly associated with BMI (P = 0.047), whereas in patients, the correlation did not reach statistical significance (P = 0.067). Immunostaining showed that LEAP2 peptide was expressed in insulinoma tissue. Conclusion:Serum LEAP2 levels are elevated in insulinoma and correlate with hyperinsulinemia and BMI. LEAP2 is expressed in insulinoma tissue, suggesting a potential role in the metabolic profile of these patients.

Dynamic interactions between genetic predispositions and environmental exposures significantly shape the escalating prevalence of childhood obesity. This systematic review synthesizes observational and clinical trial evidence on the gene-environment interplays influencing childhood obesity, highlighting the role of genetic variants and environmental moderators such as dietary habits, physical activity, sleep durations, parental behaviors, socioeconomic status, ethnicity, gender, as well as lifestyle interventions. We conducted an exhaustive search across 5 databases (Medline, PubMed, EMBASE, Web of Science, and Cochrane Library), adhering to PRISMA guidelines. We ultimately included 147 studies that investigated these interplays in diverse populations. Specifically, 83 studies focused on gene-diet interplays, 23 on gene-physical activity, 5 on sedentary behavior, 3 on screen time, 7 on sleep duration, 10 on parental behavior, 4 on socioeconomic status, 16 on gender, 8 on age, 7 on ethnicity, and 13 on the effects of lifestyle interventions. Notably, we meta-analyzed energy expenditure and macronutrient consumption, including carbohydrates, proteins, and fats, as well as the proportion of energy supplied by each nutrient between carriers and noncarriers of the FTO effect allele, revealing that carriers consumed a higher proportion of fat calories, with no other significant differences noted. This review demonstrates that genetic risk variants, particularly in FTO (e.g., rs9939609) and MC4R (e.g., rs17782313), amplify the adverse effects of obesogenic behaviors, offering insights into the intricate pathophysiology of childhood obesity and suggesting the potential for personalized interventions based on genetic profiles.

BACKGROUND:Upregulation or delay of acute inflammation at any stage limits fat graft survival. Active endogenous inflammation resolution mechanisms and mediators are novel therapeutic tools for inflammation. This study explored the effects of supplementation of omega-3 polyunsaturated fatty acids (PUFAs) deriving specialized proresolving mediators on postoperative inflammation and graft survival in vivo. METHODS:Fish oil (or saline for the control group) was administered intragastrically in the C57BL/6N mouse fat graft model for a week before and after transplantation. The mice were euthanized at 3, 7, 14, 30, or 90 days after transplantation. Serum C-reactive protein concentration was determined by enzyme-linked immunosorbent assay. Gene expression levels of inflammatory factors, perilipin-1, and vascular endothelial growth factor in the grafts were analyzed by quantitative real-time polymerase chain reaction. Hematoxylin and eosin, Masson trichrome, immunohistochemistry, and immunofluorescence staining were performed. RESULTS:Omega-3 PUFAs reduced the serum C-reactive protein concentration. In addition, in the grafts of the fish oil group, expression of proinflammatory factors was reduced, and expression of anti-inflammatory factors was increased. CD11b+ immunofluorescence intensity at days 14 and 30 was reduced, and the F4/80+/CD11b+ ratio at days 3 and 7 and the CD206+/F4/80+ ratio at days 7, 14, and 30 were increased, consistent with the results of immunohistochemical control staining (CD11b, F4/80, and CD206). Gene expression of vascular endothelial growth factor at day 14 and perilipin-1 at days 30 and 90 were increased. Perilipin-1+ percentage area and CD31+ percentage area at day 90 were increased. Inflammatory cell infiltration and fibrosis were decreased. CONCLUSION:Omega-3 PUFAs can enhance inflammation resolution and angiogenesis and promote fat graft survival in a controlled mouse model. CLINICAL RELEVANCE STATEMENT:The authors' findings suggest the effectiveness of using inflammatory resolution mechanisms to promote fat graft survival and provide a fundamental support for clinical use of omega-3 PUFAs in autologous fat transplantation.

BACKGROUND:Childhood obesity poses a global health threat, with emerging evidence suggesting distinct adipocyte senescence patterns compared to adult-onset obesity. We systematically explored whether childhood obesity may be causally associated with age-related diseases through a meta-analysis of Mendelian randomization (MR) evidence. METHODS:We screened six databases (MEDLINE, PubMed, EMBASE, Web of Science, Cochrane Library and CNKI) and identified 45 MR articles examining paediatric adiposity and major age-related diseases. For each disease, we performed a meta-analysis using results from published MR studies and conducted de novo analyses based on genetic data from UK Biobank (n = 453 169), FinnGen (n > 200 000) and other large consortiums. RESULTS:The meta-analysis examined 44 diseases across 9 systems, revealing suggestive associations between genetically determined childhood obesity and increased risk of 16 age-related diseases, including hypertension, atrial fibrillation, coronary artery disease, stroke and myocardial infarction; colorectal, endometrial and pancreatic cancers; nonalcoholic fatty liver disease, type 2 diabetes, diabetic nephropathy; multiple sclerosis and gout; Alzheimer's disease; depression and asthma. Three of these associations were marginal (p = 0.03-0.05). Paradoxical inverse associations emerged for breast cancer and ulcerative colitis. CONCLUSION:The findings from this meta-analysis underscore associations between childhood adiposity and multisystem age-related pathologies, underscoring the imperative for early obesity prevention.

Sleep disturbance is increasingly common and has been linked to adverse metabolic outcomes. This study investigated whether sleep recovery (SR) mitigates the effects of chronic sleep fragmentation (SF) on glucose metabolism, with a focus on gut microbiota and inguinal white adipose tissue (iWAT) transcriptomics. Mice were subjected to 8 weeks of SF followed by SR. After 2 weeks of SR (SF 8w-SR 2w), glucose intolerance persisted, accompanied by significant alterations in gut microbiota composition and iWAT gene expression. Key hub genes (Ncapg, Cenpe, Ttk) and glucose metabolism-related genes (Lnpep, Pten, Apoe, Cebpb, Ido1, Ahsg) were identified. Bacterial genera were significantly altered and associated with glucose metabolism. After 8 weeks of SR (SF 8w-SR 8w), glucose tolerance was restored, although alterations in gut microbiota composition persisted. Notably, Rikenellaceae_RC9_gut_group and Defluviitaleaceae_UCG-011 remained persistently altered. These findings indicate that short-term SR is insufficient to reverse SF-induced glucose intolerance, which is associated with changes in the gut microbiota and iWAT transcriptome. Although prolonged SR improves glucose metabolism, persistent microbial alterations suggest a lasting impact of SF, underscoring the potential role of gut dysbiosis in metabolic dysfunction following sleep disturbances.

Childhood obesity may induce epigenetic changes, affecting long-term cardiac health. However, empirical evidence remains scarce. Leveraging the prospective cohort of Beijing Child and Adolescent Metabolic Syndrome study (BCAMS), we investigated the blood DNA methylation signatures associated with childhood obesity and the future risk of cardiac hypertrophy in young adults, confirming causality with Mendelian randomization (MR). The BCAMS study followed children into adulthood. Data including blood DNA methylation profiles, along with lifestyles, blood levels of 7 adipokines and 32 amino acids were collected at baseline. Echocardiographic measurements were assessed at the 10-year follow-up. Enrichment and correlation analyses were performed, and two-sample MR analyses involving 105,268 participants from European biobanks were employed to infer causality. Cross-sectionally, we identified 376 differentially methylated sites between children with obesity and normal-weight controls (n=25), particularly within genes enriched in the cardiomyopathy pathway. Longitudinally, 11 childhood obesity-associated methylation sites, especially cg25835058 (KAZN), cg01362389 (TDH) and cg12099423 (SLC17A9), showed strong correlations with left ventricular index (LVMI) at the 10-year follow-up (P<.0017). Additionally, these sites were associated with traditional risk factors, notably glutamine, which displayed strongest protective association with LVMI (-1.72g/m2.7 per 1SD increase, P<.001) when validated with the entire cohort (n=326). MR analysis confirmed the significant correlation between cg12099423 methylation levels and SLC17A9 expression, and the causality between gene expression levels (KAZN, TDH, SLC17A9) and LVMI. Methylation associated with childhood obesity, particularly SLC17A9, may function as an epigenetic mechanism impacting long-term cardiac health later in life, emphasizing the significance of early intervention.

BACKGROUND:Poor sleep quality (PSQ) is associated with cardiovascular disease, but the key intermediate variables underlying this relationship in youths remain unclear. We aimed to explore the relationship between PSQ and adverse cardiac structure in Chinese youths with elevated cardiometabolic risk, focusing on the roles of appetite adipokines and insulin resistance. METHODS:We utilized cross-sectional data from the Beijing Children and Adolescents Metabolic Syndrome (BCAMS) Study Cohort (n = 559, mean age = 20.2 years). Participants underwent echocardiographic assessments, a sleep quality questionnaire, an oral glucose tolerance test, and plasma levels of insulin and five appetite adipokines. RESULTS:Elevated PSQ scores were associated with adverse left ventricular mass index (LVMI) (0.64 g/m2.7 per unit increase in PSQ score), altered appetite adipokines, including 8.3 % higher leptin, 1.9 % higher retinol-binding protein 4 (RBP4), and 3.2 % lower high-molecular-weight adiponectin (HMW-adiponectin), as well as impaired insulin sensitivity, reflected by 6.6 % higher fasting insulin levels, 6.7 % higher homeostasis model assessment of insulin resistance (HOMA-IR), and 4.9 % lower insulin sensitivity index (Matsuda Index) (ISIMatsuda), per point increase in PSQ score (all p < 0.05). In mediation analyses, leptin significantly mediated 28.5 % of the PSQ-LVMI association (p < 0.001), and insulin-related indices explained 13.6 %-23.6 % (p < 0.05); HMW-adiponectin showed a marginal mediating effect (8.1 %, p = 0.077). Furthermore, interaction analysis revealed that insulin resistance amplified the adverse impact of PSQ on LVMI (pinteraction = 0.04 for HOMA-IR; 0.029 for ISIMatsuda), with high PSQ-related elevations in LVMI more pronounced among youths with higher insulin resistance. CONCLUSIONS:PSQ is associated with early adverse cardiac remodeling in youths with cardiometabolic risk, potentially driven by elevated leptin and insulin resistance. Targeting sleep quality, adipokine signaling, and insulin sensitivity, may offer synergistic strategies for early cardiovascular prevention in at-risk youths.

BACKGROUND:Doxorubicin (DOX) has significant toxic side effects on cardiomyocytes, and existing preventive drug dexrazoxane has serious side effects. Therefore, in-depth research on drugs that can enhance the antitumor effect of DOX and simultaneously reduce its cardiotoxicity is of crucial significance. Our study explored the regulatory role of Erianin in DOX-induced cardiotoxicity and the specific molecular mechanism. METHODS:In this study, we constructed a myocardial injury model in mice with DOX. The toxic side effects of DOX on the organism were determined by recording the weight changes of the mice and calculating the spleen index and heart-tibia ratio of the mice. The degree of myocardial injury in mice was evaluated by methods such as echocardiography and Sirius red staining. Further in vivo experiments were conducted to verify whether the silencing of Nrf2 could block the protective effect of Erianin on myocardial cells. RESULTS:We found Erianin significantly alleviated DOX-induced cardiomyocyte injury (p < 0.0001), increased heart tissue pumping efficiency and contractility (p < 0.001), and reduced myocardial cell fibrosis. Mechanism study showed that Erianin can bind to Keap1, promote its ubiquitination and autophagic degradation, increase the acetylation of lysine 599 site in Nrf2 protein, and activate the antioxidant stress response. CONCLUSIONS:Taken together, our study had for the first time elucidated the molecular mechanism by which Erianin alleviated DOX-induced myocardial injury by activating the Keap1-Nrf2 signaling pathway. It provides a theoretical basis for the development of Erianin as a potential protective drug for DOX-induced cardiotoxicity. It has very important clinical application and translational value.

Abstract Background Mounting evidence supports a significant correlation between the stress hyperglycemia ratio (SHR) and both short- and long-term prognoses in patients with acute coronary syndrome (ACS). Nevertheless, research examining the association between the SHR and the complexity of coronary artery disease (CAD) is scarce. Therefore, this study aimed to explore the association between the SHR and CAD complexity, as assessed by the SYNTAX score, in patients with ACS. Methods A total of 4715 patients diagnosed with ACS were enrolled and divided into five groups according to the quintiles of the SHR. CAD complexity was assessed using the SYNTAX score and categorized as low (≤ 22) or mid/high (> 22) levels. Logistic regression was utilized to examine the association between the SHR and CAD severity (mid-/high SYNTAX score). Restricted cubic spline (RCS) curves were generated to assess the association between the SHR and CAD severity. Subgroup analyses were conducted to stratify outcomes based on age, sex, diabetes mellitus (DM) status, and clinical presentation. Results Among the total ACS population, 503 (10.7%) patients had mid/high SYNTAX scores. Logistic regression analysis revealed that the SHR was an independent risk factor for mid/high SYNTAX scores in a U-shaped pattern. After adjusting for confounding variables, Q1 and Q5 demonstrated elevated odds ratios (ORs) relative to the reference category Q3, with ORs of 1.61 (95% CI: 1.19 ∼ 2.19) and 1.68 (95% CI: 1.24 ∼ 2.29), respectively. Moreover, the ORs for Q2 (1.02, 95% CI: 0.73 ∼ 1.42) and Q4 (1.18, 95% CI: 0.85 ∼ 1.63) resembled that of Q3. Compared with the merged Q2-4 group, the ORs were 1.52 (95% CI: 1.21 ∼ 1.92) for Q1 group and 1.58 (95% CI: 1.25 ∼ 2) for the Q5 group. Subgroup analysis revealed that the U-shaped association between the SHR and mid/high SYNTAX score was attenuated in DM patients (P for interaction = 0.045). Conclusions There were U-shaped associations between the SHR and CAD complexity in ACS patients, with an SHR ranging from 0.68 to 0.875 indicating a relatively lower OR for mid/high SYNTAX scores. Further studies are necessary to both evaluate the predictive value of the SHR in ACS patients and explore the underlying mechanisms of the observed U-shaped associations.

Sleep disorders have emerged as a widespread public health concern, primarily due to their association with an increased risk of developing cardiovascular diseases. Our previous research indicated a potential direct impact of insufficient sleep duration on cardiac remodeling in children and adolescents. Nevertheless, the underlying mechanisms behind the link between sleep fragmentation (SF) and cardiac abnormalities remain unclear. In this study, we aimed to investigate the effects of SF interventions at various life stages on cardiac structure and function, as well as to identify genes associated with SF-induced cardiac dysfunction. To achieve this, we established mouse models of chronic SF and two-week sleep recovery (SR). Our results revealed that chronic SF significantly compromised left ventricular contractile function across different life stages, leading to alterations in cardiac structure and ventricular remodeling, particularly during early life stages. Moreover, microarray analysis of mouse heart tissue identified two significant modules and nine hub genes (Ddx60, Irf9, Oasl2, Rnf213, Cmpk2, Stat2, Parp14, Gbp3, and Herc6) through protein-protein interaction analysis. Notably, the interactome predominantly involved innate immune responses. Importantly, all hub genes lost significance following SR. The second module primarily consisted of circadian clock genes, and real-time PCR validation demonstrated significant upregulation of Arntl, Dbp, and Cry1 after SF, while subsequent SR restored normal Arntl expression. Furthermore, the expression levels of four hub genes (Ddx60, Irf9, Oasl2, and Cmpk2) and three circadian clock genes (Arntl, Dbp, and Cry1) exhibited correlations with structural and functional echocardiographic parameters. Overall, our findings suggest that SF impairs left ventricular contractile function and ventricular remodeling during early life stages, and this may be mediated by modulation of the innate immune response and circadian rhythm. Importantly, our findings suggest that a short period of SR can alleviate the detrimental effects of SF on the cardiac immune response, while the influence of SF on circadian rhythm appears to be more persistent. These findings underscore the importance of good sleep for maintaining cardiac health, particularly during early life stages.

AbstractBackgroundResearch has established connection between gut microbiome and the risk of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the causal relationships and the roles of potential mediating factors, such as blood metabolites, remain unclear.MethodsWe conducted a bidirectional and mediation Mendelian randomization (MR) study using the genome-wide summary statistics of gut microbial taxa (Dutch Microbiome Project, n = 7,738), blood lipids (UK Biobank, n =8,299), and the largest MAFLD GWAS data (1,483 cases and 17,781 controls). We used the inverse-variance weighted estimation method as our primary approach. The multivariable Mendelian randomization (MVMR) and two-step MR approaches were used to prioritize the most likely causal metabolites as mediators. Additionally, we conducted linkage disequilibrium score regression (LDSC) analyses to assess genetic correlations, and downstream gene-based analyses to investigate the shared biological mechanism.ResultsBy testing the causal effects of 205 bacterial pathways and 207 taxa on MAFLD, we identified 5 microbial taxa causally associated with MAFLD, notably the species Parabacteroides merdae (OR [95%CI] = 1.191[1.022-1.388],p= 0.025). Among 1,399 blood metabolites, 53 showed causal associations with MAFLD, with pregnenetriol sulfate identified as a mediator for genus Parabacteroides on MAFLD (proportion mediated = 16.30%). LDSC analysis also provided suggestive evidence for a potential genetic correlation between them (rg= 2.124,p=0.009).ConclusionsThe study suggested a novel causal relationship between gut microbial taxa and MAFLD, especially the genus Parabacteroides merdae and blood metabolite pregnenetriol sulfate might mediate this relationship.ImportanceOur study reveals novel insights into how the intersection of microorganisms living in the human gut, known as the gut microbiome, influences the development of Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD), a condition increasingly recognized as a major global health concern. By identifying specific gut microbiome taxa and metabolites that contribute to the onset and progression of MAFLD, our findings enhance comprehension of this prevalent condition and unveil promising prospects for its prevention and intervention. We discovered that certain gut bacteria can affect the levels of blood metabolites, which in turn impact the liver’s health. This work carries significant implications for novel strategies for MAFLD prevention and treatment, including interventions aimed at modifying the gut microbiome. Our research underscores the gut-liver connection and its implications for metabolic diseases, contributing to future therapeutic developments that could improve public health worldwide.Graphic abstract