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Objective To investigate the effects of sterol regulatory element binding protein 1c (SREBP1c) deficiency on the intestinal microbiota in mice. Methods SREBP1c knockout (SREBP1c-KO) mice were used as research objects, and the feces of homozygous SREBP1c-KO mice and wild-type littermates (WT) were collected. Subsequently, the fecal genomic DNA was analyzed by 16S rDNA sequencing. The differences of gut microbial composition between the SREBP1c-KO and WT mice were detected and compared using species taxonomy analysis, diversity index analysis, cluster analysis, and principal component analysis (PCA). Moreover, the discrepancies of liver lipid anabolism and intestinal barrier were also investigated between the 2 groups. Results Under conventional feeding, SREBP1c knockout had no significant effect on the body weight and total cholesterol (TC) content in the liver of mice, but notably decreased the content of triglyceride (TG) in the liver. α diversity index (Sobs index) analysis showed that the gut microbiota diversity of SREBP1c-KO mice was greatly lower than that of the WT counterparts (P < 0.01), and PCA analysis indicated that the gut microbial composition was different between the 2 groups of mice. At the phylum level, the ratio of Firmicutes to Bacteroides presented an upward trend in the intestine of SREBP1c-KO mice, but there was no statistical difference. At the genus level, as compared with the WT group, the relative abundance of Rikenella was significantly reduced in SREBP1c-KO mice (P < 0.05). Additionally, the expression levels of intestinal barrier associated genes Reg3γ and Occludin were obviously down-regulated in SREBP1c-KO mice. Conclusion The deletion of SREBP1c, an important regulator of lipid metabolism, reduces the diversity of intestinal microbiota and the relative abundance of Rikenella in mice, which may be related to the weakening of intestinal barrier.

Objective To explore the role and underlying mechanism of microfibrillar associated protein 5 (MFAP5) in the treatment of overweight polycystic ovary syndrome (PCOS) with metformin combined with glucagon-like peptide-1 receptor agonist (GLP-1RA), liraglutides, by analyzing the correlation of the molecule alteration with improvement of metabolic indexes. Methods Twenty-three overweight or obese PCOS patients who were treated with metformin combined with liraglutide for 12 weeks in our hospital during December 2019 and February 2021 were retrospectively enrolled. According to body mass index (BMI), the subjects were divided into obese group (n=12) and overweight group (n=11). They were all given oral administration of metformin hydrochloride enteric-coated tablet (0.5 g, 3 times/day) and subcutaneous injection of liraglutide injection (primarily, 0.6 mg, once/day, and then increased to 1.2 mg, once/day, 1 week later, with the maximum dose of 1.8 mg). Physical measurement indicators, metabolic and inflammatory related indicators and sex hormone levels of the 2 groups were collected before and after 12 weeks of treatment. Plasma MFAP5 level was detected by ELISA. Results After 12 weeks of treatment, physical measurement indicators, glucose and lipid metabolism indicators, inflammatory indicators and sex hormone levels were all improved in both groups (P < 0.05). Correlation analysis showed that the alteration of plasma MFAP5 level in all patients were positively correlated with the changes of body weight (r=0.520, P=0.011), BMI (r=0.469, P=0.024), waist circumference (r=0.634, P=0.001), hip circumference (r=0.587, P=0.001), fasting insulin (r=0.602, P=0.002) and triglyceride (r=0.556, P=0.002). For the patients form the overweight group, their change of plasma MFAP5 level had a positive correlation with the changes of glucolipid metabolism related indicators, including insulin at 60 min in insulin releasing test (r=0.602, P=0.002) and triglyceride (r=0.655, P=0.029). In the obese group, the change of plasma MFAP5 level was positively correlated with the changes of waist circumference (r=0.495, P=0.002), hip circumference (r=0.508, P=0.010), glucolipid metabolism related indicators, such as fasting insulin (r=0.578, P=0.001), insulin at 180 min (r=0.656, P=0.021), HOMA-IR (r=0.497, P=0.012), triglyceride (r=0.595, P=0.041), and sex hormone. Conclusion In overweight PCOS patients, plasma MFAP5 level is related to the improvement of glucolipid metabolism. MFAP5 may be a related molecule involved in the treatment of overweight PCOS with liraylutide combined with metformin, and may serve as a reliable indicator in monitoring of therapeutic efficacy.

Since the 1950s, when the Turing Test was introduced, there has been notable progress in machine language intelligence. Language modeling, crucial for AI development, has evolved from statistical to neural models over the last two decades. Recently, transformer-based Pre-trained Language Models (PLM) have excelled in Natural Language Processing (NLP) tasks by leveraging large-scale training corpora. Increasing the scale of these models enhances performance significantly, introducing abilities like context learning that smaller models lack. The advancement in Large Language Models, exemplified by the development of ChatGPT, has made significant impacts both academically and industrially, capturing widespread societal interest. This survey provides an overview of the development and prospects from Large Language Models (LLM) to Large Multimodal Models (LMM). It first discusses the contributions and technological advancements of LLMs in the field of natural language processing, especially in text generation and language understanding. Then, it turns to the discussion of LMMs, which integrates various data modalities such as text, images, and sound, demonstrating advanced capabilities in understanding and generating cross-modal content, paving new pathways for the adaptability and flexibility of AI systems. Finally, the survey highlights the prospects of LMMs in terms of technological development and application potential, while also pointing out challenges in data integration, cross-modal understanding accuracy, providing a comprehensive perspective on the latest developments in this field. [ABSTRACT FROM AUTHOR]

Mitochondrial dynamics is the process of mitochondrial fusion and division to maintain dynamic balance. In recent years, it has been found that this dynamic change plays an important role in regulating mitochondrial morphology and quantity, mitochondrial oxidative metabolism, membrane potential and energy production. In diabetes, hyperglycemia significantly interferes with the dynamic balance of mitochondrial fusion and division process, and affects the quantity, morphology and function of mitochondria. And ultimately, the dynamic change of mitochondria is closely related to many chronic complications of diabetes, but the specific mechanism remains unclear. Our research group has long been committed to exploring the roles and mechanisms of mitochondrial dynamics in a variety of diabetic complications. This review summarizes the research progress and potential mechanisms of mitochondrial dynamics in diabetic ulcers, diabetic nephropathy and diabetic cardiomyopathy.

Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons. The hypothalamus is essential for energy regulation, with POMC neurons crucial for controlling food intake and energy balance. Here, the authors show that AZGP1 improves leptin sensitivity in POMC neurons, aiding in weight loss and energy use by altering leptin-JAK2-STAT3 signalling. [ABSTRACT FROM AUTHOR]

Podocytes are particularly sensitive to lipid accumulation, which has recently emerged as a crucial pathological process in the progression of proteinuric kidney diseases like diabetic kidney disease and focal segmental glomerulosclerosis. However, the underlying mechanism remains unclear. Here, podocytes predominantly expressed protein dedicator of cytokinesis 5 (Dock5) is screened to be critically related to podocyte lipid lipotoxicity. Its expression is reduced in both proteinuric kidney disease patients and mouse models. Podocyte‐specific deficiency of Dock5 exacerbated podocyte injury and glomeruli pathology in proteinuric kidney disease, which is mainly through modulating fatty acid uptake by the liver X receptor α (LXRα)/scavenger receptor class B (CD36) signaling pathway. Specifically, Dock5 deficiency enhanced CD36‐mediated fatty acid uptake of podocytes via upregulating LXRα in an m6A‐dependent way. Moreover, the rescue of Dock5 expression ameliorated podocyte injury and proteinuric kidney disease. Thus, the findings suggest that Dock5 deficiency is a critical contributor to podocyte lipotoxicity and may serve as a promising therapeutic target in proteinuric kidney diseases. [ABSTRACT FROM AUTHOR]

High-sensitivity optical imaging can be achieved through improving upconversion photoluminescence (UCPL) efficiency of localized surface plasmon resonance (LSPR)-enhanced excitation and emission. Herein, we report a type of UCPL nanoprobe, Au nanospheres assemblage@Gd2O3:Yb3+/Ln3+ (Ln = Er, Ho, Tm), which exhibits emission enhancements from 46- to 96-fold as compared with its Au-free counterparts. The aggregation and interaction among Au nanospheres embedded inside the nanoprobe brings about three characteristic LSPR peaks in visible and near-infrared regions according to simulated and experimental absorption spectra, resulting in both excitation and emission fields simultaneously intensified all through the entire nanoprobe. We addressed a characteristic wavelength dependence on emission amplifications, which could be elucidated by a LSPR-enhanced UCPL mechanism and relevant rate equations that we addressed. The nanoprobe was verified to have a superior capability for optical bio-imaging with a negligible toxicity in vitro and in vivo. This study realizes a synchronous double-field-enhanced upconversion of optical nanoprobe in situ, and may gain an insight into its mechanism underlying for LSPR-induced UCPL enhancement. [ABSTRACT FROM AUTHOR]

Background: Diabetic cardiomyopathy (DbCM) is defined as the existence of abnormal myocardial structure and functions in the absence of other cardiac diseases, such as coronary artery disease, hypertension, and significant valvular disease, in individuals with diabetes. Although abundant epidemic evidence demonstrates that diabetes is independently associated with the risk of developing heart failure, DbCM is not normally diagnosed in clinical practices due to its exclusive diagnosis, and no diagnostic biomarker was applied in a clinical test.Methods: To detect the concentrations of serum Annexin A2 in non-diabetic subjects, type 2 diabetic (T2DM) patients with or without DbCM, and analyzed its relationship to parameters of cardiac functions, glucose, lipid metabolism, and renal functions. 266 eligible participants were included and were divided into 3 groups including non-diabetic subjects (NGR), T2DM patients without DbCM (T2DM group), and the DbCM group. Echocardiography, coronary computed tomography angiography, electrocardiogram, blood pressure, thyroid function, and clinical and other biochemical parameters were measured in all participants.Results: Serum Annexin A2 concentrations were higher in DbCM (P < 0.05) and T2DM (P < 0.05) groups compared with the NGR group, especially in DbCM patients. Correlation analysis showed that serum Annexin A2 levels were negatively associated with left ventricular (LV) ejection fraction (EF), LV fractional shortening (FS), the ratio of early (E-wave) and late (A-wave) LV diastolic filling velocities (E/A ratio), and estimated glomerular filtration rate (eGFR), and were positively correlated with age, blood urea nitrogen (BUN) and creatinine (Cr) (all P < 0.05). Multiple logistical regression analyses revealed that serum in both the second and the third tertiles of Annexin A2 concentration were significantly associated with DbCM. E/A ratio is the independent factor for Annexin A2 concentration when adjusted for LV FS%, BUN, and Cr.Conclusions: Circulating Annexin A2 concentrations might be induced in DbCM patients and were negatively associated with cardiac systolic and diastolic functions, which suggested it might be a predictor of early diagnosis in DbCM and might be a potential therapeutic target for DbCM. [ABSTRACT FROM AUTHOR]

Non-healing diabetic wounds and ulcer complications, with persistent cell dysfunction and obstructed cellular processes, are leading causes of disability and death in patients with diabetes. Currently, there is a lack of guideline-recommended hypoglycemic drugs in clinical practice, likely due to limited research and unclear mechanisms. In this study, it is demonstrated that liraglutide significantly accelerates wound closure in diabetic mouse models (db/db mice and streptozotocin-induced mice) by improving re-epithelialization, collagen deposition, and extracellular matrix remodeling, and enhancing the proliferation, migration, and adhesion functions of keratinocytes. However, these effects of improved healing by liraglutide are abrogated in dedicator of cytokinesis 5 (Dock5) keratinocyte-specific knockout mice. Mechanistically, liraglutide induces cellular function through stabilization of unconventional myosin 1c (Myo1c). Liraglutide directly binds to Myo1c at arginine 93, enhancing the Myo1c/Dock5 interaction by targeting Dock5 promoter and thus promoting the proliferation, migration, and adhesion of keratinocytes. Therefore, this study provides insights into liraglutide biology and suggests it may be an effective treatment for diabetic patients with wound-healing pathologies., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Fish oil (FO), a mixture of omega-3 fatty acids mainly comprising docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), has been recommended for patients with type 2 diabetes (T2D) and hypertriglyceridemia. However, its effects on lipidomic profiles and gut microbiota and the factors influencing triglyceride (TG) reduction remain unclear., Methods: We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 309 Chinese patients with T2D with hypertriglyceridemia (ClinicalTrials.gov: NCT03120299). Participants were randomly assigned (1:1) to receive either 4 g FO or corn oil for 12 weeks. The primary outcome was changes in serum TGs and the lipidomic profile, and the secondary outcome included changes in the gut microbiome and other metabolic variables., Findings: The FO group had significantly better TG reduction (mean [95% confidence interval (CI)]: -1.51 [-2.01, -1.01] mmol/L) compared to the corn oil group (-0.66 [-1.15, -0.16] mmol/L, p = 0.02). FO significantly altered the serum lipid profile by reducing low-unsaturated TG species and increasing those containing DHA or EPA. FO had minor effects on gut microbiota, while baseline microbial features predicted the TG response to FO better than phenotypic or lipidomic features, potentially mediated by specific lipid metabolites. A total of 9 lipid metabolites significantly mediated the link between 4 baseline microbial variables and the TG response to FO supplementation., Conclusions: Our findings demonstrate differential impacts of omega-3 fatty acids on lipidomic and microbial profiles in T2D and highlight the importance of baseline gut microbiota characteristics in predicting the TG-lowering efficacy of FO., Funding: This study was funded by the National Nature Science Foundation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: It is uncertain whether intravenous methylprednisolone improves outcomes for patients with acute ischemic stroke due to large-vessel occlusion (LVO) undergoing endovascular thrombectomy., Objective: To assess the efficacy and adverse events of adjunctive intravenous low-dose methylprednisolone to endovascular thrombectomy for acute ischemic stroke secondary to LVO., Design, Setting, and Participants: This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 82 hospitals in China, enrolling 1680 patients with stroke and proximal intracranial LVO presenting within 24 hours of time last known to be well. Recruitment took place between February 9, 2022, and June 30, 2023, with a final follow-up on September 30, 2023., Interventions: Eligible patients were randomly assigned to intravenous methylprednisolone (n = 839) at 2 mg/kg/d or placebo (n = 841) for 3 days adjunctive to endovascular thrombectomy., Main Outcomes and Measures: The primary efficacy outcome was disability level at 90 days as measured by the overall distribution of the modified Rankin Scale scores (range, 0 [no symptoms] to 6 [death]). The primary safety outcomes included mortality at 90 days and the incidence of symptomatic intracranial hemorrhage within 48 hours., Results: Among 1680 patients randomized (median age, 69 years; 727 female [43.3%]), 1673 (99.6%) completed the trial. The median 90-day modified Rankin Scale score was 3 (IQR, 1-5) in the methylprednisolone group vs 3 (IQR, 1-6) in the placebo group (adjusted generalized odds ratio for a lower level of disability, 1.10 [95% CI, 0.96-1.25]; P = .17). In the methylprednisolone group, there was a lower mortality rate (23.2% vs 28.5%; adjusted risk ratio, 0.84 [95% CI, 0.71-0.98]; P = .03) and a lower rate of symptomatic intracranial hemorrhage (8.6% vs 11.7%; adjusted risk ratio, 0.74 [95% CI, 0.55-0.99]; P = .04) compared with placebo., Conclusions and Relevance: Among patients with acute ischemic stroke due to LVO undergoing endovascular thrombectomy, adjunctive methylprednisolone added to endovascular thrombectomy did not significantly improve the degree of overall disability., Trial Registration: ChiCTR.org.cn Identifier: ChiCTR2100051729.

The activity of proteinase is reported to correlate with the development and progression of nonalcoholic fatty liver disease (NAFLD). Puromycin-sensitive aminopeptidase (PSA/NPEPPS) is an integral nontransmembrane enzyme that functions to catalyze the cleavage of amino acids near the N-terminus of polypeptides. A previous study suggested that this enzyme acts as a regulator of neuropeptide activity; however, the metabolic function of this enzyme in the liver has not been explored. Here, we identified the novel role of PSA in hepatic lipid metabolism. Specifically, PSA expression was lower in fatty livers from NAFLD patients and mice (HFD, ob/ob, and db/db). PSA knockdown in cultured hepatocytes exacerbated diet-induced triglyceride accumulation through enhanced lipogenesis and attenuated fatty acid β-oxidation. Moreover, PSA mediated activation of the master regulator of antioxidant response, nuclear factor erythroid 2-related factor 2 (NRF2), by stabilizing NRF2 protein expression, which further induced downstream antioxidant enzymes to protect the liver from oxidative stress and lipid overload. Accordingly, liver-specific PSA overexpression attenuated hepatic lipid accumulation and steatosis in ob/ob mice. Furthermore, in human liver tissue samples, decreased PSA expression correlated with the progression of NAFLD. Overall, our findings suggest that PSA is a pivotal regulator of hepatic lipid metabolism and its antioxidant function occurs by suppressing NRF2 ubiquitination. Moreover, PSA may be a potential biomarker and therapeutic target for treating NAFLD., (© The Author(s) (2021). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.)