An abnormal metabolism-related gene, ALG3, is a potential diagnostic and prognostic biomarker for lung adenocarcinoma.

BACKGROUND: To explore the abnormal metabolism-related genes that affect the prognosis of patients with lung adenocarcinoma (LUAD), and analyze the relationship with immune infiltration and competing endogenous RNA (ceRNA) network. METHODS: Transcriptome data of LUAD were downloaded from the Cancer Genome Atlas database. Abnormal metabolism-related differentially expressed genes in LUAD were screened by the R language. Cox analysis was used to construct LUAD prognostic risk model. Kaplan-Meier test, ROC curve and nomograms were used to evaluate the predictive ability of metabolic related gene prognostic model. CIBERSORT algorithm was used to analyze the relationship between risk score and immune infiltration. The starBase database constructed a regulatory network consistent with the ceRNA hypothesis. IHC experiments were performed to verify the differential expression of ALG3 in LUAD and paracancerous samples. RESULTS: In this study, 42 abnormal metabolism-related differential genes were screened. After survival analysis, the final 5 metabolism-related genes were used as the construction of prognosis model, including ALG3, COL7A1, KL, MST1, and SLC52A1. In the model, the survival rate of LUAD patients in the high-risk subgroup was lower than that in the low-risk group. In addition, the risk score of the constructed LUAD prognostic model can be used as an independent prognostic factor for patients. According to the analysis of CIBERSORT algorithm, the risk score is related to the infiltration of multiple immune cells. The potential ceRNA network of model genes in LUAD was constructed through the starBase database. IHC experiments revealed that ALG3 expression was upregulated in LUAD. CONCLUSION: The prognostic model of LUAD reveals the relationship between metabolism and prognosis of LUAD, and provides a novel perspective for diagnosis and research of LUAD.

Association between weekend warrior physical activity pattern and all-cause mortality among adults living with type 2 diabetes: a prospective cohort study from NHANES 2007 to 2018.

BACKGROUND: It is uncertain whether the weekend warrior pattern is associated with all-cause mortality among adults living with type 2 diabetes. This study explored how the 'weekend warrior' physical activity (PA) pattern was associated with all-cause mortality among adults living with type 2 diabetes. METHODS: This prospective cohort study investigated US adults living with type 2 diabetes in the National Health and Nutrition Examination Survey (NHANES). Mortality data was linked to the National Death Index. Based on self-reported leisure-time and occupational moderate-to-vigorous PA (MVPA), participants were categorized into 3 groups: physically inactive (< 150 min/week of MVPA), weekend warrior (≥ 150 min/week of MVPA in 1 or 2 sessions), and physically active (≥ 150 min/week of MVPA in 3 or more sessions). RESULTS: A total of 6067 participants living with type 2 diabetes [mean (SD) age, 61.4 (13.5) years; 48.0% females] were followed for a median of 6.1 years, during which 1206 deaths were recorded. Of leisure-time and occupational activity, compared with inactive individuals, hazard ratios (HRs) for all-cause mortality were 0.49 (95% CI 0.26-0.91) and 0.57 (95% CI 0.38-0.85) for weekend warrior individuals, and 0.55 (95% CI 0.45-0.67) and 0.64 (95% CI 0.53-0.76) for regularly active individuals, respectively. However, when compared leisure-time and occupational weekend warrior with regularly active participants, the HRs were 0.82 (95% CI 0.42-1.61) and 1.00 (95% CI 0.64-1.56) for all-cause mortality, respectively. CONCLUSIONS: Weekend warrior PA pattern may have similar effects on lowering all-cause mortality as regularly active pattern among adults living with type 2 diabetes, regardless of leisure-time or occupational activity. Therefore, weekend warrior PA pattern may be sufficient to reduce all-cause mortality for adults living with type 2 diabetes.

Construction and validation of a prognostic model for esophageal cancer based on prognostic-related RNA-binding protein.

BACKGROUND: Construction of a prognostic model for esophageal cancer (ESCA) based on prognostic RNA-binding proteins (RBPs) and preliminary evaluation of RBP function. METHODS: RNA-seq data of ESCA was downloaded from The Cancer Genome Atlas database and mRNA was extracted to screen differentially expressed genes using R. After screening RBPs in differentially expressed genes, R packages clusterProfiler and pathview were used to analyze the RBPs for Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway. Based on the prognosis-related RBPs, COX regression was used to establish the prognostic risk model of ESCA. Risk model predictive ability was assessed using calibration analysis, receiver operating characteristic curves, Kaplan-Meier curves, decision curve analysis, and Harrell consistency index (C-index). A nomogram was established by combining the risk model with clinicopathological features. RESULTS: A total of 105 RBPs were screened from ESCA. A prognostic risk model consisting of 6 prognostic RBPs (ARHGEF28, BOLL, CIRBP, DKC1, SNRPB, and TRIT1) was constructed by COX regression analysis. The prognosis was worse in the high-risk group, and the receiver operating characteristic curve showed (area under the curve = 0.90) that the model better predicted patients' 5-year survival. In addition, 6 prognostic RBPs had good diagnostic power for ESCA. In addition, a total of 39 mRNAs were identified as predicted target molecules for DKC1. CONCLUSION: ARHGEF28, BOLL, CIRBP, DKC1, SNRPB, and TRIT1, as RBPs, are associated with the prognosis of ESCA, which may provide new ideas for targeted therapy of ESCA.

Lipopolysaccharide-induced bacterial infection model: microRNA-370-3p participates in the anti-infection response by targeting the macrophage TLR4-NLRP3 caspase-1 cellular pyroptosis pathway.

OBJECTIVE: To explore the effect of miR-370-3p on LPS triggering, in particular its involvement in disease progression by targeting the TLR4-NLRP3-caspase-1 cellular pyroptosis pathway in macrophages. METHODS: Human macrophage RAW264.7 was divided into 6 groups: control, LPS, LPS + inhibitor-NC, LPS + miR-370-3p inhibitor, LPS + mimics-NC and LPS + miR-370-3p mimics. RT-qPCR was used to detect the expression level of miR-370-3p and analyzed comparatively. CCK-8 and flow cytometry assays were used to detect cell viability and apoptosis. ELISA assay was used to detect the levels of IL-1ß and TNF-α in the supernatant of the cells. The WB assay was used to detect TLR4, NLRP3, Caspase-1 and GSDMD levels. RESULTS: After LPS induction, macrophage miR-370-3p levels decreased, cell viability decreased, and apoptosis increased. At the same time, the levels of TLR4, NLRP3, Caspase-1 and GSDMD increased in the cells, and the levels of IL-1ß and TNF-α increased in the cell supernatant. Compared with the LPS group, the significantly higher expression level of miR-370-3p in the cells of the LPS + miR-370-3p mimics group was accompanied by significantly higher cell viability, significantly lower apoptosis rate, significantly lower levels of TLR4, NLRP3, Caspase-1, and GSDMD in the cells, and significantly lower levels of IL-1ß and TNF-α in the cell supernatant. CONCLUSION: MiR-370-3p may be involved in anti-infective immune responses by targeting and inhibiting the macrophage TLR4-NLRP3-caspase-1 cellular pyroptosis pathway.

Credibility of the evidence on green space and human health: an overview of meta-analyses using evidence grading approaches.

BACKGROUND: Green space is an important part of the human living environment, with many epidemiological studies estimating its impact on human health. However, no study has quantitatively assessed the credibility of the existing evidence, impeding their translations into policy decisions and hindering researchers from identifying new research gaps. This overview aims to evaluate and rank such evidence credibility. METHODS: Following the PRISMA guideline, we systematically searched PubMed, Web of Science, and Embase databases for systematic reviews with meta-analyses concerning green spaces and health outcomes published up to January 15, 2024. We categorized the credibility of meta-analytical evidence from interventional studies into four levels (i.e., high, moderate, low, and very low) using the Grading of Recommendation, Assessment, Development and Evaluations framework, based on five domains including risk of bias, inconsistency, indirectness, imprecision, and publication bias. Further, we recalculated all the meta-analyses from observational studies and classified evidence into five levels (i.e., convincing, highly suggestive, suggestive, weak, and non-significant) by considering stringent thresholds for P-values, sample size, robustness, heterogeneity, and testing for biases. FINDINGS: In total, 154 meta-analysed associations (interventional = 44, observational = 110) between green spaces and health outcomes were graded. Among meta-analyses from interventional studies, zero, four (wellbeing, systolic blood pressure, negative affect, and positive affect), 20, and 20 associations between green spaces and health outcomes were graded as high, moderate, low, and very low credibility evidence, respectively. Among meta-analyses from observational studies, one (cardiovascular disease mortality), four (prevalence/incidence of diabetes mellitus, preterm birth, and small for gestational age infant, and all-cause mortality), 12, 22, and 71 associations were categorized as convincing, highly suggestive, suggestive, weak, and non-significant evidence, respectively. INTERPRETATION: The current evidence largely confirms beneficial associations between green spaces and human health. However, only a small subset of these associations can be deemed to have a high or convincing credibility. Hence, future better designed primary studies and meta-analyses are still needed to provide higher quality evidence for informing health promotion strategies. FUNDING: The National Natural Science Foundation of China of China; the Guangzhou Science and Technology Program; the Guangdong Medical Science and Technology Research Fund; the Research Grant Council of the Hong Kong SAR; and Sino-German mobility program.

The adiponectin-derived peptide ALY688 protects against the development of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the severe form of non-alcoholic fatty liver disease which has a high potential to progress to cirrhosis and hepatocellular carcinoma, yet adequate effective therapies are lacking. Hypoadiponectinemia is causally involved in the pathogenesis of MASH. This study investigated the pharmacological effects of adiponectin replacement therapy with the adiponectin-derived peptide ALY688 (ALY688-SR) in a mouse model of MASH. Human induced pluripotent stem (iPS) cell-derived hepatocytes were used to test cytotoxicity and signaling of unmodified ALY688 in vitro. High-fat diet with low methionine and no added choline (CDAHF) was used to induce MASH and test the effects of ALY688-SR in vivo. Histological MASH activity score (NAS) and fibrosis score were determined to assess the effect of ALY688-SR. Transcriptional characterization of mice through RNA sequencing was performed to indicate potential molecular mechanisms involved. In cultured hepatocytes, ALY688 efficiently induced adiponectin-like signaling, including the AMP-activated protein kinase and p38 mitogen-activated protein kinase pathways, and did not elicit cytotoxicity. Administration of ALY688-SR in mice did not influence body weight but significantly ameliorated CDAHF-induced hepatic steatosis, inflammation, and fibrosis, therefore effectively preventing the development and progression of MASH. Mechanistically, ALY688-SR treatment markedly induced hepatic expression of genes involved in fatty acid oxidation, whereas it significantly suppressed the expression of pro-inflammatory and pro-fibrotic genes as demonstrated by transcriptomic analysis. ALY688-SR may represent an effective approach in MASH treatment. Its mode of action involves inhibition of hepatic steatosis, inflammation, and fibrosis, possibly via canonical adiponectin-mediated signaling.

Islet-Resident Memory T Cells Orchestrate the Immunopathogenesis of Type 1 Diabetes through the FABP4-CXCL10 Axis.

Type 1 diabetes (T1D) is a chronic disease characterized by self-destruction of insulin-producing pancreatic ß cells by cytotoxic T cell activity. However, the pathogenic mechanism of T cell infiltration remains obscure. Recently, tissue-resident memory T (TRM) cells have been shown to contribute to cytotoxic T cell recruitment. TRM cells are found present in human pancreas and are suggested to modulate immune homeostasis. Here, the role of TRM cells in the development of T1D is investigated. The presence of TRM cells in pancreatic islets is observed in non-obese diabetic (NOD) mice before T1D onset. Mechanistically, elevated fatty acid-binding protein 4 (FABP4) potentiates the survival and alarming function of TRM cells by promoting fatty acid utilization and C-X-C motif chemokine 10 (CXCL10) secretion, respectively. In NOD mice, genetic deletion of FABP4 or depletion of TRM cells using CD69 neutralizing antibodies resulted in a similar reduction of pancreatic cytotoxic T cell recruitment, a delay in diabetic incidence, and a suppression of CXCL10 production. Thus, targeting FABP4 may represent a promising therapeutic strategy for T1D.

Myocardial infarction accelerates the progression of MASH by triggering immunoinflammatory response and induction of periosti.

Patients with metabolic dysfunction-associated steatotic liver disease (MASLD), especially advanced metabolic dysfunction-associated steatohepatitis (MASH), have an increased risk of cardiovascular diseases (CVDs). Whether CVD events will, in turn, influence the pathogenesis of MASLD remains unknown. Here, we show that myocardial infarction (MI) accelerates hepatic pathological progression of MASLD. Patients with MASLD who experience CVD events after their diagnosis exhibit accelerated liver fibrosis progression. MI promotes hepatic fibrosis in mice with MASH, accompanied by elevated circulating Ly6Chi monocytes and their recruitment to damaged liver tissues. These adverse effects are significantly abrogated when deleting these cells. Meanwhile, MI substantially increases circulating and cardiac periostin levels, which act on hepatocytes and stellate cells to promote hepatic lipid accumulation and fibrosis, finally exacerbating hepatic pathological progression of MASH. These preclinical and clinical results demonstrate that MI alters systemic homeostasis and upregulates pro-fibrotic factor production, triggering cross-disease communication that accelerates hepatic pathological progression of MASLD.

Experimental and Numerical Study of Membrane Residual Stress in Q690 High-Strength Steel Welded Box Section Compressed Member.

High-strength steel (HSS) members with welded sections exhibit a notably lower residual compressive stress ratio compared with common mild steel (CMS) members. Despite this difference, current codes often generalize the findings from CMS members to HSS members, and the previous unified residual stress models are generally conservative. This study focuses on the membrane residual stress distribution in Q690 steel welded box sections. By leveraging experimental results, the influence of section sizes and welding parameters on membrane residual stress was delved into. A larger plate size correlates with a decrease in the residual compressive stress across the section, with a more pronounced reduction observed in adjacent plates. Additionally, augmenting the number of welding passes tends to diminish residual stresses across the section. Results showed that membrane residual stress adhered to the section's self-equilibrium, while the self-equilibrium in the plates was not a uniform pattern. A reliable residual stress simulation method for Q690 steel welded box sections was established using a three-dimensional thermal-elastic-plastic finite element model (3DTEFEM) grounded in experimental data. This method served as the cornerstone for parameter analysis in this study and set the stage for subsequent research. As a result, an accurate unified residual stress model for Q690 steel welded box sections was derived.

Metabolic Dysfunction-Associated Steatohepatitis Detected by Neutrophilic Crown-Like Structures in Morbidly Obese Patients: A Multicenter and Clinicopathological Study.

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), and closely associated with a high risk of liver-related morbidity and mortality. Although enhanced neutrophil infiltration of the liver is a histological hallmark of MASH, the morphological pattern of hepatic neutrophils and their relevance to the definition of MASH remain unknown. This clinicopathological study aimed to determine the association of neutrophilic crown-like structures (CLSs) in liver biopsies and evaluate their relevance to the histological diagnosis of MASH. A total of 483 morbidly obese adults who underwent bariatric surgery were recruited. Neutrophilic CLSs in liver biopsies were detected by immunohistochemistry for neutrophil elastase and proteinase 3. All participants were classified into 4 histological subgroups: no MASLD (118, 24.4%), MASLD (76, 15.7%), borderline MASH (185, 38.3%), and definite MASH (104, 21.5%). In the discovery cohort (n = 379), the frequency of neutrophilic CLSs increased in line with the severity of liver disease. The number of neutrophilic CLSs was positively correlated with established histological characteristics of MASH. At a cutoff value of <0.3 per 20× microscopic field, the number of neutrophilic CLSs yielded a robust diagnostic accuracy to discriminate no MASLD and MASLD from borderline MASH and definite MASH; a cutoff at >1.3 per 20× microscopic field exhibited a statistically significant accuracy to distinguish definite MASH from other groups (no MASLD, MASLD, and borderline MASH). The significance of neutrophilic CLSs in identifying borderline MASH and definite MASH was confirmed in an external validation cohort (n = 104). The frequency of neutrophilic CLSs was significantly higher than that of macrophagic CLSs. In conclusion, neutrophilic CLSs in the liver represent a typical histological characteristic of MASH and may serve as a promising indicator to improve the diagnostic accuracy of MASH during histological assessment of liver biopsies.

Association between sleep patterns and galectin-3 in a Chinese community population.

BACKGROUND: Irregular sleep patterns have been associated with inflammation. Galectin-3, a novel biomarker, plays an important role in inflammation. We investigated the relationship between sleep patterns and galectin-3 in a Chinese population. METHODS: A total of 1,058 participants from the Shenzhen-Hong Kong United Network on Cardiovascular Disease study were included in the analysis. Age and sex-adjusted linear regression models were employed to investigate the relationship between galectin-3 level and traditional metabolic biomarkers. Logistic regression models were used to estimate the association among sleep disturbance, nighttime sleep duration, and daytime napping duration and elevated galectin-3, with elevated galectin-3 defined as galectin-3 level > 65.1 ng/ml. RESULTS: Of study participants, the mean age was 45.3 years and 54.3% were women. Waist circumference, natural logarithm (ln)-transformed triglyceride, and ln-transformed high sensitivity C-reactive protein were positively associated with galectin-3 level (age and sex-adjusted standardized ß [95% confidence interval (CI)], 0.12 [0.04, 0.21], 0.11 [0.05, 0.17], and 0.08 [0.02, 0.14], respectively). Sleep disturbance was associated with elevated galectin-3 (odds ratio [95% CI], 1.68 [1.05, 2.68], compared to those without sleep disturbance) after adjusting for traditional metabolic biomarkers. No interaction was observed between galectin-3 and age, sex, obesity, hypertension, and diabetes on sleep disturbance. No association was found between nighttime sleep duration or daytime napping duration and elevated galectin-3. CONCLUSIONS: Our study provides evidence of a significant association between sleep disturbance and elevated galectin-3 level, independent of traditional metabolic biomarkers. Screening and interventions on galectin-3 could assist in preventing sleep disturbance-induced inflammatory disease.

Glucose regulation of adipose tissue browning by CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF.

Glucose is required for generating heat during cold-induced nonshivering thermogenesis in adipose tissue, but the regulatory mechanism is largely unknown. CREBZF has emerged as a critical mechanism for metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD). We investigated the roles of CREBZF in the control of thermogenesis and energy metabolism. Glucose induces CREBZF in human white adipose tissue (WAT) and inguinal WAT (iWAT) in mice. Lys208 acetylation modulated by transacetylase CREB-binding protein/p300 and deacetylase HDAC3 is required for glucose-induced reduction of proteasomal degradation and augmentation of protein stability of CREBZF. Glucose induces rectal temperature and thermogenesis in white adipose of control mice, which is further potentiated in adipose-specific CREBZF knockout (CREBZF FKO) mice. During cold exposure, CREBZF FKO mice display enhanced thermogenic gene expression, browning of iWAT, and adaptive thermogenesis. CREBZF associates with PGC-1α to repress thermogenic gene expression. Expression levels of CREBZF are negatively correlated with UCP1 in human adipose tissues and increased in WAT of obese ob/ob mice, which may underscore the potential role of CREBZF in the development of compromised thermogenic capability under hyperglycemic conditions. Our results reveal an important mechanism of glucose sensing and thermogenic inactivation through reversible acetylation.

Coin-sized, fully integrated, and minimally invasive continuous glucose monitoring system based on organic electrochemical transistors.

Continuous glucose monitoring systems (CGMs) are critical toward closed-loop diabetes management. The field's progress urges next-generation CGMs with enhanced antinoise ability, reliability, and wearability. Here, we propose a coin-sized, fully integrated, and wearable CGM, achieved by holistically synergizing state-of-the-art interdisciplinary technologies of biosensors, minimally invasive tools, and hydrogels. The proposed CGM consists of three major parts: (i) an emerging biochemical signal amplifier, the organic electrochemical transistor (OECT), improving the signal-to-noise ratio (SNR) beyond traditional electrochemical sensors; (ii) a microneedle array to facilitate subcutaneous glucose sampling with minimized pain; and (iii) a soft hydrogel to stabilize the skin-device interface. Compared to conventional CGMs, the OECT-CGM offers a high antinoise ability, tunable sensitivity and resolution, and comfort wearability, enabling personalized glucose sensing for future precision diabetes health care. Last, we discuss how OECT technology can help push the limit of detection of current wearable electrochemical biosensors, especially when operating in complicated conditions.

Propofol and salvianolic acid A synergistically attenuated cardiac ischemia-reperfusion injury in diabetic mice via modulating the CD36/AMPK pathway.

Background: Prevention of diabetic heart myocardial ischemia-reperfusion (IR) injury (MIRI) is challenging. Propofol attenuates MIRI through its reactive oxygen species scavenging property at high doses, while its use at high doses causes hemodynamic instability. Salvianolic acid A (SAA) is a potent antioxidant that confers protection against MIRI. Both propofol and SAA affect metabolic profiles through regulating Adenosine 5'-monophosphate-activated protein kinase (AMPK). The aim of this study was to investigate the protective effects and underlying mechanisms of low doses of propofol combined with SAA against diabetic MIRI. Methods: Diabetes was induced in mice by a high-fat diet followed by streptozotocin injection, and MIRI was induced by coronary artery occlusion and reperfusion. Mice were treated with propofol at 46 mg/kg/h without or with SAA at 10 mg/kg/h during IR. Cardiac origin H9c2 cells were exposed to high glucose (HG) and palmitic acid (PAL) for 24 h in the absence or presence of cluster of differentiation 36 (CD36) overexpression or AMPK gene knockdown, followed by hypoxia/reoxygenation (HR) for 6 and 12 h. Results: Diabetes-exacerbated MIRI is evidenced as significant increases in post-ischemic infarction with reductions in phosphorylated (p)-AMPK and increases in CD36 and ferroptosis. Propofol moderately yet significantly attenuated all the abovementioned changes, while propofol plus SAA conferred superior protection against MIRI to that of propofol. In vitro, exposure of H9c2 cells under HG and PAL decreased cell viability and increased oxidative stress that was concomitant with increased levels of ferroptosis and a significant increase in CD36, while p-AMPK was significantly reduced. Co-administration of low concentrations of propofol and SAA at 12.5 µM in H9c2 cells significantly reduced oxidative stress, ferroptosis and CD36 expression, while increasing p-AMPK compared to the effects of propofol at 25 µM. Moreover, either CD36 overexpression or AMPK silence significantly exacerbated HR-induced cellular injuries and ferroptosis, and canceled propofol- and SAA-mediated protection. Notably, p-AMPK expression was downregulated after CD36 overexpression, while AMPK knockdown did not affect CD36 expression. Conclusions: Combinational usage of propofol and SAA confers superior cellular protective effects to the use of high-dose propofol alone, and it does so through inhibiting HR-induced CD36 overexpression to upregulate p-AMPK.

Hormone-based pharmacotherapy for metabolic dysfunction-associated fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has reached epidemic proportions globally in parallel to the rising prevalence of obesity. Despite its significant burden, there is no approved pharmacotherapy specifically tailored for this disease. Many potential drug candidates for MAFLD have encountered setbacks in clinical trials, due to safety concerns or/and insufficient therapeutic efficacy. Nonetheless, several investigational drugs that mimic the actions of endogenous metabolic hormones, including thyroid hormone receptor ß (THRß) agonists, fibroblast growth factor 21 (FGF21) analogues, and glucagon-like peptide-1 receptor agonists (GLP-1RAs), showed promising therapeutic efficacy and excellent safety profiles. Among them, resmetirom, a liver-targeted THRß-selective agonist, has met the primary outcomes in alleviation of metabolic dysfunction-associated steatohepatitis (MASH), the advanced form of MAFLD, and liver fibrosis in phase-3 clinical trials. These hormone-based pharmacotherapies not only exhibit varied degrees of therapeutic efficacy in mitigating hepatic steatosis, inflammation and fibrosis, but also improve metabolic profiles. Furthermore, these three hormonal agonists/analogues act in a complementary manner to exert their pharmacological effects, suggesting their combined therapies may yield synergistic therapeutic benefits. Further in-depth studies on the intricate interplay among these metabolic hormones are imperative for the development of more efficacious combination therapies, enabling precision management of MAFLD and its associated comorbidities.

Shared genetic architecture between periodontal disease and type 2 diabetes: a large scale genome-wide cross-trait analysis.

PURPOSE: To investigate the relationship between abnormal glucose metabolism, type 2 diabetes (T2D), and periodontal disease (PER) independent of Body Mass Index (BMI), we employed a genome-wide cross-trait approach to clarify the association. METHODS: Our study utilized the most extensive genome-wide association studies conducted for populations of European ancestry, including PER, T2D, fasting glucose, fasting insulin, 2-hour glucose after an oral glucose challenge, HOMA-ß, HOMA-IR (unadjusted or adjusted for BMI) and HbA1c. RESULTS: With this approach, we were able to identify pleiotropic loci, establish expression-trait associations, and quantify global and local genetic correlations. There was a significant positive global genetic correlation between T2D (rg = 0.261, p = 2.65 × 10-13), HbA1c (rg = 0.182, p = 4.14 × 10-6) and PER, as well as for T2D independent of BMI (rg = 0.158, p = 2.34 × 10-6). A significant local genetic correlation was also observed between PER and glycemic traits or T2D. We also identified 62 independent pleiotropic loci that impact both PER and glycemic traits, including T2D. Nine significant pathways were identified between the shared genes between T2D, glycemic traits and PER. Genetically liability of HOMA-ßadjBMI was causally associated with the risk of PER. CONCLUSION: Our research has revealed a genetic link between T2D, glycemic traits, and PER that is influenced by biological pleiotropy. Notably, some of these links are not related to BMI. Our research highlights an underlying link between patients with T2D and PER, regardless of their BMI.

Liver-specific adiponectin gene therapy suppresses microglial NLRP3-inflammasome activation for treating Alzheimer's disease.

Adiponectin (APN) is an adipokine which predominantly expresses in adipocytes with neuroprotective and anti-inflammatory effects. We have recently indicated that circulatory trimeric APN can enter the brain by crossing the blood-brain barrier (BBB) and modulate microglia-mediated neuroinflammation. Here, we found that the microglial NLR family pyrin domain containing 3 (NLRP3)-inflammasome activation was exacerbated in APN-/-5xFAD mice in age-dependent manner. The focus of this study was to develop a new and tractable therapeutic approach for treating Alzheimer's disease (AD)-related pathology in 5xFAD mice using peripheral APN gene therapy. We have generated and transduced adeno-associated virus (AAV2/8) expressing the mouse mutated APN gene (APNC39S) into the liver of 5xFAD mice that generated only low-molecular-weight trimeric APN (APNTri). Single dose of AAV2/8-APNC39S in the liver increased circulatory and cerebral APN levels indicating the overexpressed APNTri was able to cross the BBB. Overexpression of APNTri decreased both the soluble and fibrillar Aß in the brains of 5xFAD mice. AAV2/8-APNTri treatment reduced Aß-induced IL-1ß and IL-18 secretion by suppressing microglial NLRP3-inflammasome activation. The memory functions improved significantly in AAV-APNTri-treated 5xFAD mice with reduction of dystrophic neurites. These findings demonstrate that peripheral gene delivery to overexpress trimeric APN can be a potential therapy for AD.

Exploring the therapeutic potential of tetrahydrobiopterin for heart failure with preserved ejection fraction: A path forward.

A large number of patients are affected by classical heart failure (HF) symptomatology with preserved ejection fraction (HFpEF) and multiorgan syndrome. Due to high morbidity and mortality rate, hospitalization and mortality remain serious socioeconomic problems, while the lack of effective pharmacological or device treatment means that HFpEF presents a major unmet medical need. Evidence from clinical and basic studies demonstrates that systemic inflammation, increased oxidative stress, and impaired mitochondrial function are the common pathological mechanisms in HFpEF. Tetrahydrobiopterin (BH4), beyond being an endogenous co-factor for catalyzing the conversion of some essential biomolecules, has the capacity to prevent systemic inflammation, enhance antioxidant resistance, and modulate mitochondrial energy production. Therefore, BH4 has emerged in the last decade as a promising agent to prevent or reverse the progression of disorders such as cardiovascular disease. In this review, we cover the clinical progress and limitations of using downstream targets of nitric oxide (NO) through NO donors, soluble guanylate cyclase activators, phosphodiesterase inhibitors, and sodium-glucose co-transporter 2 inhibitors in treating cardiovascular diseases, including HFpEF. We discuss the use of BH4 in association with HFpEF, providing new evidence for its potential use as a pharmacological option for treating HFpEF.