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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 β (THRβ) 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 THRβ-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.

The blood-brain barrier (BBB) is a critical interface that maintains the central nervous system homeostasis by controlling the exchange of substances between the blood and the brain. Disruption of the BBB plays a vital role in the development of neuroinflammation and neurological dysfunction in sepsis, but the mechanisms by which the BBB becomes disrupted during sepsis are not well understood. Here, we induced endotoxemia, a major type of sepsis, in mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS acutely increased BBB permeability, activated microglia, and heightened inflammatory responses in brain endothelium and parenchyma. Concurrently, LPS or proinflammatory cytokines activated the NF-κB pathway, inhibiting Wnt/β-catenin signaling in brain endothelial cells in vitro and in vivo. Cell culture study revealed that NF-κB p65 directly interacted with β-catenin to suppress Wnt/β-catenin signaling. Pharmacological NF-κB pathway inhibition restored brain endothelial Wnt/β-catenin signaling activity and mitigated BBB disruption and neuroinflammation in septic mice. Furthermore, genetic or pharmacological activation of brain endothelial Wnt/β-catenin signaling substantially alleviated LPS-induced BBB leakage and neuroinflammation, while endothelial conditional ablation of the Wnt7a/7b co-receptor Gpr124 exacerbated the BBB leakage caused by LPS. Mechanistically, Wnt/β-catenin signaling activation rectified the reduced expression levels of tight junction protein ZO-1 and transcytosis suppressor Mfsd2a in brain endothelial cells of mice with endotoxemia, inhibiting both paracellular and transcellular permeability of the BBB. Our findings demonstrate that endotoxemia-associated systemic inflammation decreases endothelial Wnt/β-catenin signaling through activating NF-κB pathway, resulting in acute BBB disruption and neuroinflammation. Targeting the endothelial Wnt/β-catenin signaling may offer a promising therapeutic strategy for preserving BBB integrity and treating neurological dysfunction in sepsis. [ABSTRACT FROM AUTHOR]

M1 macrophages induce protective immunity against infection, but also contribute to metabolic and inflammatory diseases. Here we show that the E3 ubiquitin ligase, MDM2, promotes the glycolytic and inflammatory activities of M1 macrophage by increasing the production of IL-1β, MCP-1 and nitric oxide (NO). Mechanistically, MDM2 triggers the ubiquitination and degradation of E3 ligase, SPSB2, to stabilize iNOS and increases production of NO, which s-nitrosylates and activates HIF-1α for triggering the glycolytic and pro-inflammatory programs in M1 macrophages. Myeloid-specific haplodeletion of MDM2 in mice not only blunts LPS-induced endotoxemia and NO production, but also alleviates obesity-induced adipose tissue-resident macrophage inflammation. By contrast, MDM2 haplodeletion induces higher mortality, tissue damage and bacterial burden, and also suppresses M1 macrophage response, in the cecal ligation and puncture-induced sepsis mouse model. Our findings thus identify MDM2 as an activator of glycolytic and inflammatory responses in M1 macrophages by connecting the iNOS-NO and HIF-1α pathways. Proinflammatory macrophages mediate protective immunity but also contribute to inflammatory diseases. Here the authors show that the E3 ligase, MDM2, induces nitric oxide from macrophage, potentially triggering the s-nitrosylation and activation of HIF-1α for the production of inflammatory cytokines, to protect mice from sepsis but aggravate obesity-induced inflammation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a chronic disease characterized by self‐destruction of insulin‐producing pancreatic β 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. [ABSTRACT FROM AUTHOR]

Background and Purpose: Adipocyte fatty acid‐binding protein (A‐FABP) exacerbates cerebral ischaemia injury by disrupting the blood–brain barrier (BBB) through inducing expression of MMP‐9. Circulating A‐FABP levels positively correlate with infarct size in stroke patients. We hypothesized that targeting circulating A‐FABP by a neutralizing antibody would alleviate ischaemic stroke outcome. Experimental Approach: Monoclonal antibodies (mAbs) against A‐FABP were generated using mouse hybridoma techniques. Binding affinities of a generated mAb named 6H2 towards various FABPs were determined using Biacore. Molecular docking studies were performed to characterize the 6H2‐A‐FABP complex structure and epitope. The therapeutic potential and safety of 6H2 were evaluated in mice with transient middle cerebral artery occlusion (MCAO) and healthy mice, respectively. Key Results: Replenishment of recombinant A‐FABP exaggerated the stroke outcome in A‐FABP‐deficient mice. 6H2 exhibited nanomolar to picomolar affinities to human and mouse A‐FABP, respectively, with minimal cross‐reactivities with heart and epidermal FABPs. 6H2 effectively neutralized JNK/c‐Jun activation elicited by A‐FABP and reduced MMP‐9 production in macrophages. Molecular docking suggested that 6H2 interacts with the "lid" of the fatty acid binding pocket of A‐FABP, thus likely hindering the binding of its substrates. In mice with transient MCAO, 6H2 significantly attenuated BBB disruption, cerebral oedema, infarction, neurological deficits, and decreased mortality associated with reduced cytokine and MMP‐9 production. Chronic 6H2 treatment showed no obvious adverse effects in healthy mice. Conclusion and Implications: These results establish circulating A‐FABP as a viable therapeutic target for ischaemic stroke, and provide a highly promising antibody drug candidate with high affinity and specificity. [ABSTRACT FROM AUTHOR]

Objective: Baseline circulating thrombospondin‐2 (TSP2) level was identified as a potential novel hepatic fibrosis biomarker that associates with development and progression of hepatic fibrosis in patients with nonalcoholic fatty liver disease and type 2 diabetes. Here, we investigated whether circulating TSP2 levels changed with improvement in liver stiffness (LS), which reflects liver fibrosis on transient elastography. Design: Serum TSP2 levels were measured in participants from a randomized, open‐label intervention study, at baseline and after 24‐weeks treatment of either dapagliflozin 10 mg (N = 30) or sitagliptin 100 mg daily (N = 30). Vibration‐controlled transient elastography was performed to evaluate the severity of hepatic fibrosis and steatosis using LS and controlled attenuation parameter (CAP), respectively. Patients and Measurements: Among all 60 participants with similar clinical characteristics at baseline (mean HbA1c 8.9%, CAP 289 dB/m and LS 5.8 kPa), despite similar HbA1c lowering, treatment with dapagliflozin, but not sitagliptin, led to significant improvements in body weight (BW) (p =.012), CAP (p =.015) and LS (p =.011) after 24 weeks. Results: Serum TSP2 level decreased significantly from baseline in dapagliflozin‐treated participants (p =.035), whereas no significant change was observed with sitagliptin. In correlation analysis, change in serum TSP2 levels only positively correlated with change in LS (r =.487, p =.006), but not with changes in BW, CAP or HbA1c after dapagliflozin treatment. Conclusions: Serum TSP2 level decreased with LS after dapagliflozin treatment, and was independent of improvements in BW, glycemic control and hepatic steatosis, further supporting the potential of serum TSP2 level as a novel hepatic fibrosis biomarker in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: To explore the effect of HPV16 E7 targeted cGAS-STING signaling pathway on immune function of cervical cancer cells. Methods: HPV16 E7 overexpression and interference plasmids were constructed in vitro and transfected into SiHa cells. mRNA expression level of HPV16 E7 was detected by qPCR, and expressions of CD95, MICA/B, CD73, CD39, CTLA-4 and CD25 were detected by flow cytometry. On this basis, cGAS-siRNA and STING-siRNA were transfected into SiHa cells respectively. Cell viability was detected by CCK8, and cell apoptosis was detected by flow cytometry. mRNA and protein expressions of cGAS, STING, IFN-I and HPV16 E7 were detected by qPCR and Western blot respectively. Expressions of CD95, MICA/B, CD73, CD39, CTLA-4 and CD25 were detected by flow cytometry. Results: Levels of CD95 and MICA/B were decreased in STING-siRNA+HPV16 E7 overexpression group (P<0.05), while levels of CD73, CD39, CTLA-4 and CD25 were increased (P<0.05) . Protein expression levels of cGAS, STING and IFN-I were decreased (P<0.05). Results of STING-siRNA+HPV16 E7 interference group were opposite. Conclusion: HPV16 E7 inhibits the immune function of cervical cancer cells by targeting cGAS-STING signaling pathway. [ABSTRACT FROM AUTHOR]

Aims: Autophagy is an important cellular process for maintaining physiological homeostasis and is known to protect against cardiovascular diseases including ischemia reperfusion (I/R) injury. The underlying mechanisms behind its protection require further characterization., Materials and Methods: Atg7 knock out (AKO) mice were generated and subjected to I/R injury, complemented by Atg7 KO in a H9c2 cardiomyoblast cellular model ± hypoxia-reoxygenation. Subsequently, in both models, inflammation and cell death were studied., Key Findings: We confirmed that Atg7 KO led to autophagy, including mitophagy, deficiency. Upon H/R, Atg7 KO cells exhibited increased cell death compared to WT cells. Notably, we found that autophagy deficiency increased stress-induced mitochondrial fission, release of mitochondrial DNA, and sterile inflammation, namely activation of a STING/IRF3 axis leading to elevated interferon-α. Following I/R injury, AKO mice showed elevated cell death which correlated with a gene expression profile indicative of decreased anti-inflammatory responses., Significance: Autophagy deficiency in the cardiomyocyte setting results in detrimental effects during I/R injury in mice or H/R injury in cells, mediated in part via mtDNA/IRF3/STING pathway. As such, modulation of this pathway may yield novel and promising therapeutics to treat or prevent I/R injury., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gary Sweeney reports financial support was provided by the Heart & Stroke Foundation of Canada. Gary Sweeney reports a relationship with Allysta Pharmaceuticals Inc. that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Mycobacterium tuberculosis (Mtb), the main pathogen responsible for the high mortality and morbidity of tuberculosis (TB) worldwide, primarily targets and invades macrophages. Infected macrophages activate a series of immune mechanisms to clear Mtb, however, Mtb evades host immune surveillance through subtle immune escape strategies to create a microenvironment conducive to its own proliferation, growth, and dissemination, while inducing immune cell death. The course of TB is strongly correlated with the form of cell death, including apoptosis, pyroptosis, and necrosis. Recent studies have revealed that ferroptosis, a novel type of programmed cell death characterized by iron-dependent lipid peroxidation, is closely linked to the regulatory mechanisms of TB. The central role of ferroptosis in the pathologic process of TB is increasingly becoming a focal point for exploring new therapeutic targets in this field. This paper will delve into the dynamic game between Mtb and host immune cells, especially the role of ferroptosis in the pathogenesis of TB. At the same time, this paper will analyze the regulatory pathways of ferroptosis and provide unique insights and innovative perspectives for TB therapeutic strategies based on the ferroptosis mechanism. This study not only expands the theoretical basis of TB treatment, but also points out the direction of future drug development, providing new possibilities for overcoming this global health problem., Competing Interests: Declaration of competing interest The authors declare no financial or personal conflicts of interest in this study., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Understanding how childhood psychosocial adjustment (CPA) influences later life health outcomes is crucial for developing interventions to mitigate the long-term risk of cardiometabolic diseases (CMDs)., Aims: To investigate the association between CPA and incident CMDs in mid-life, and the mediating roles of educational attainment, smoking habits and depression during young adulthood., Method: A prospective cohort study utilised data from the 1958 National Child Development Study (NCDS; 1958-2013) and the 1970 British Cohort Study (BCS70; 1970-2018), encompassing 22 012 participants assessed for CPA in childhood, who were subsequently evaluated for educational attainment, smoking habits and depression in young adulthood, followed by assessments for CMDs in mid-life. CPA was assessed using the Bristol Social Adjustment Guides in the NCDS and the Rutter Child Behaviour Scale in the BCS70, with higher scores indicating poorer psychosocial adjustment. The primary outcomes were the mid-life incidences of hypertension, diabetes and obesity., Results: Compared with children in the lowest tertile for CPA scores, those in the middle tertile had an adjusted odds ratio for hypertension of 0.98 (95% CI 0.90-1.06), whereas those in the highest tertile had an odds ratio of 1.17 (95% CI 1.08-1.26). For diabetes, the corresponding odds ratios (95% CI) were 1.15 (0.98-1.35) and 1.39 (1.19-1.62). For obesity, the corresponding odds ratios (95% CI) were 1.08 (1.00-1.16) and 1.18 (1.09-1.27). These associations were partially mediated by educational attainment (2.4-13.9%) and depression during young adulthood (2.5-14.9%)., Conclusions: Poorer CPA is correlated with the development of hypertension, diabetes and obesity in mid-life. Interventions aimed at improving CPA may help in reducing the burden of these diseases in later life.

Background: BMP9 (bone morphogenetic protein 9) is a member of the TGF-β (transforming growth factor β) family of cytokines with pleiotropic effects on glucose metabolism, fibrosis, and lymphatic development. However, the role of BMP9 in myocardial infarction (MI) remains elusive., Methods: The expressional profiles of BMP9 in cardiac tissues and plasma samples of subjects with MI were determined by immunoassay or immunoblot. The role of BMP9 in MI was determined by evaluating the impact of BMP9 deficiency and replenishment with adeno-associated virus-mediated BMP9 expression or recombinant human BMP9 protein in mice., Results: We show that circulating BMP9 and its cardiac levels are markedly increased in humans and mice with MI and are negatively associated with cardiac function. It is important to note that BMP9 deficiency exacerbates left ventricular dysfunction, increases infarct size, and augments cardiac fibrosis in mice with MI. In contrast, replenishment of BMP9 significantly attenuates these adverse effects. We further demonstrate that BMP9 improves lymphatic drainage function, thereby leading to a decrease of cardiac edema. In addition, BMP9 increases the expression of mitochondrial DECR1 (2,4-dienoyl-CoA reductase 1), a rate-limiting enzyme involved in β-oxidation, which, in turn, promotes cardiac mitochondrial bioenergetics and mitigates MI-induced cardiomyocyte injury. Moreover, DECR1 deficiency exacerbates MI-induced cardiac damage in mice, whereas this adverse effect is restored by the treatment of adeno-associated virus-mediated DECR1. Consistently, DECR1 deletion abrogates the beneficial effect of BMP9 against MI-induced cardiomyopathy and cardiac damage in mice., Conclusions: These results suggest that BMP9 protects against MI by fine-tuning the multiorgan cross-talk among the liver, lymph, and the heart.

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., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

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., Competing Interests: Competing interests: The authors declare that they have no competing interests., (Copyright © 2024 Mengqi Fan et al.)

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 β [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., (© 2024. The Author(s).)

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.

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., Competing Interests: Competing interests statement:The authors declare no competing interest.

Introduction: Metabolic disturbances are major contributors to the onset and progression of non-alcoholic fatty liver disease (NAFLD), which includes a histological spectrum ranging from single steatosis (SS) to non-alcoholic steatohepatitis (NASH). This study aimed to identify serum metabolites and lipids enriched in different histological stages of NAFLD and to explore metabolites/lipids as non-invasive biomarkers in risk prediction of NAFLD and NASH in obese Chinese., Methods: Serum samples and liver biopsies were obtained from 250 NAFLD subjects. Untargeted metabolomic and lipidomic profiling were performed using Liquid Chromatography-Mass Spectrometry. Significantly altered metabolites and lipids were identified by MaAsLin2. Pathway enrichment was conducted with MetaboAnalyst and LIPEA. WGCNA was implemented to construct the co-expression network. Logistic regression models were developed to classify different histological stages of NAFLD., Results: A total of 263 metabolites and 550 lipid species were detected in serum samples. Differential analysis and pathway enrichment analysis revealed the progressive patterns in metabolic mechanisms during the transition from normal liver to SS and to NASH, including N-palmitoyltaurine, tridecylic acid, and branched-chain amino acid signaling pathways. The co-expression network showed a distinct correlation between different triglyceride and phosphatidylcholine species with disease severity. Multiple models classifying NAFLD versus normal liver and NASH versus SS identified important metabolic features associated with significant improvement in disease prediction compared to conventional clinical parameters., Conclusion: Different histological stages of NAFLD are enriched with distinct sets of metabolites, lipids, and metabolic pathways. Integrated algorithms highlight the important metabolic and lipidomic features for diagnosis and staging of NAFLD in obese individuals., Competing Interests: None., (© 2024 The Authors.)

The lipid synthesis of fatty acid (FA) represents a significant hallmark in the occurrence and progression of malignant tumor, which are associated with lymph node (LN) metastasis. Elucidation of the molecular mechanisms underlying LN metastasis could provide therapeutic strategies for cervical cancer (CCa). N6-Methyladenosine (m 6 A), the most prevalent and abundant RNA modification, exerts specific regulatory control over a series of oncogene expressions. This study demonstrated a clinical correlation between the upregulation of the m 6 A reader YTHDF3 and LN metastasis, thereby contributing to poor overall survival probability (OS) among CCa patients. The mechanistic investigation revealed that SREBF1 transcriptionally activated YTHDF3 expression by binding to its promoter. Functional experiments demonstrated that the upregulation of YTHDF3 significantly enhanced the in vitro proliferative, migratory, and invasive capacities of CCa cells, while also promoting lymphangiogenesis and facilitating LN metastasis in vivo . Mechanistically, the upregulation of LRP6 through YTHDF3-mediated m 6 A modification resulted in increased expression of FASN and ACC1, leading to both lipolysis of lipid droplets and synthesis of free fatty acid. Ultimately, this promoted fatty acid metabolism and enhanced LN metastasis by activating the LRP6-YAP-VEGF-C axis, which could induce lymphangiogenesis in CCa. Our study highlighted that YTHDF3 can serve as a promising therapeutic target and predictive biomarker for CCa patients with LN metastasis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: The importance of gut microbes in mediating the benefits of lifestyle intervention is increasingly recognized. However, compared to the bacterial microbiome, the role of intestinal fungi in exercise remains elusive. With our established randomized controlled trial of exercise intervention in Chinese males with prediabetes ( n  = 39, ClinicalTrials.gov:NCT03240978), we investigated the dynamics of human gut mycobiome and further interrogated their associations with exercise-elicited outcomes using multi-omics approaches., Methods: Clinical variations and biological samples were collected before and after training. Fecal fungal composition was analyzed using the internal transcribed spacer 2 (ITS2) sequencing and integrated with paired shotgun metagenomics, untargeted metabolomics, and Olink proteomics., Results: Twelve weeks of exercise training profoundly promoted fungal ecological diversity and intrakingdom connection. We further identified exercise-responsive genera with potential metabolic benefits, including Verticillium, Sarocladium, and Ceratocystis. Using multi-omics approaches, we elucidated comprehensive associations between changes in gut mycobiome and exercise-shaped metabolic phenotypes, bacterial microbiome, and circulating metabolomics and proteomics profiles. Furthermore, a machine-learning algorithm built using baseline microbial signatures and clinical characteristics predicted exercise responsiveness in improvements of insulin sensitivity, with an area under the receiver operating characteristic (AUROC) of 0.91 (95% CI: 0.85-0.97) in the discovery cohort and of 0.79 (95% CI: 0.74-0.86) in the independent validation cohort ( n  = 30)., Conclusions: Our findings suggest that intense exercise training significantly remodels the human fungal microbiome composition. Changes in gut fungal composition are associated with the metabolic benefits of exercise, indicating gut mycobiome is a possible molecular transducer of exercise. Moreover, baseline gut fungal signatures predict exercise responsiveness for diabetes prevention, highlighting that targeting the gut mycobiome emerges as a prospective strategy in tailoring personalized training for diabetes prevention.

Adaptive thermogenesis is a vital physiological process for small endotherms. Female animals usually are more sensitive to cold temperature due to anatomical differences. Whether there is a sex difference at a molecular level is unclear. Stress granules (SGs) are dynamic organelles in which untranslated mRNAs reside during cellular stress. We hypothesize that the prompt response of SGs to cold stress can reveal the molecular difference between sexes. By analyzing the content in SGs of brown adipose tissue (BAT) at the early phase of cold stress for both sexes, we found more diverse mRNAs docked in the SGs in male mice and these mRNAs representing an extensive cellular reprogramming including apoptosis process and cold-induced thermogenesis. In female mice, the mRNAs in SGs dominantly were comprised of genes regulating ribonucleoprotein complex biogenesis. Conversely, the proteome in SGs was commonly characterized as structure molecules and RNA processing for both sexes. A spectrum of eukaryotic initiation factors (eIFs) was detected in the SGs of both female and male BAT, while those remained unchanged upon cold stress in male mice, various eIF3 and eIF4G isoforms were found reduced in female mice. Taken together, the unique features in SGs of male BAT reflected a prompt uncoupling protein-1 (UCP1) induction which was absent in female, and female, by contrast, were prepared for long-term transcriptional and translational adaptations. NEW & NOTEWORTHY The proteome analysis reveals that stress granules are the predominant form of cytosolic messenger ribonucleoproteins of brown adipose tissue (BAT) at the early phase of cold exposure in mice for both sexes. The transcriptome of stress granules of BAT unveils a sex difference of molecular response in early phase of cold exposure in mice, and such difference prepares for a prompt response to cold stress in male mice while for long-term adaptation in female mice.