A novel subpopulation of monocytes with a strong interferon signature indicated by SIGLEC-1 is present in patients with in recent-onset type 1 diabetes.

AIMS/HYPOTHESIS: Type 1 diabetes is a T cell-mediated autoimmune disease characterised by pancreatic beta cell destruction. In this study, we explored the pathogenic immune responses in initiation of type 1 diabetes and new immunological targets for type 1 diabetes prevention and treatment. METHODS: We obtained peripheral blood samples from four individuals with newly diagnosed latent autoimmune diabetes in adults (LADA) and from four healthy control participants. Single-cell RNA-sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells to uncover transcriptomic profiles of early LADA. Validation was performed through flow cytometry in a cohort comprising 54 LADA, 17 adult-onset type 2 diabetes, and 26 healthy adults, matched using propensity score matching (PSM) based on age and sex. A similar PSM method matched 15 paediatric type 1 diabetes patients with 15 healthy children. Further flow cytometry analysis was performed in both peripheral blood and pancreatic tissues of non-obese diabetic (NOD) mice. Additionally, cell adoptive transfer and clearance assays were performed in NOD mice to explore the role of this monocyte subset in islet inflammation and onset of type 1 diabetes. RESULTS: The scRNA-seq data showed that upregulated genes in peripheral T cells and monocytes from early-onset LADA patients were primarily enriched in the IFN signalling pathway. A new cluster of classical monocytes (cluster 4) was identified, and the proportion of this cluster was significantly increased in individuals with LADA compared with healthy control individuals (11.93% vs 5.93%, p=0.017) and that exhibited a strong IFN signature marked by SIGLEC-1 (encoding sialoadhesin). These SIGLEC-1+ monocytes expressed high levels of genes encoding C-C chemokine receptors 1 or 2, as well as genes for chemoattractants for T cells and natural killer cells. They also showed relatively low levels of genes for co-stimulatory and HLA molecules. Flow cytometry analysis verified the elevated levels of SIGLEC-1+ monocytes in the peripheral blood of participants with LADA and paediatric type 1 diabetes compared with healthy control participants and those with type 2 diabetes. Interestingly, the proportion of SIGLEC-1+ monocytes positively correlated with disease activity and negatively with disease duration in the LADA patients. In NOD mice, the proportion of SIGLEC-1+ monocytes in the peripheral blood was highest at the age of 6 weeks (16.88%), while the peak occurred at 12 weeks in pancreatic tissues (23.65%). Adoptive transfer experiments revealed a significant acceleration in diabetes onset in the SIGLEC-1+ group compared with the SIGLEC-1- or saline control group. CONCLUSIONS/INTERPRETATION: Our study identified a novel group of SIGLEC-1+ monocytes that may serve as an important indicator for early diagnosis, activity assessment and monitoring of therapeutic efficacy in type 1 diabetes, and may also be a novel target for preventing and treating type 1 diabetes. DATA AVAILABILITY: RNA-seq data have been deposited in the GSA human database ( https://ngdc.cncb.ac.cn/gsa-human/ ) under accession number HRA003649.

EMC10 modulates hepatic ER stress and steatosis in an isoform-specific manner.

BACKGROUND & AIMS: Endoplasmic reticulum (ER) membrane protein complex subunit 10 (EMC10) has been implicated in obesity. Here we investigated the roles of the two isoforms of EMC10, including a secreted isoform (scEMC10) and an ER membrane-bound isoform (mEMC10), in metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: Manifold steatotic mouse models and HepG2 cells were employed to investigate the role of EMC10 in the regulation of hepatic PERK-eIF2α-ATF4 signaling and hepatosteatosis. The therapeutic effect of scEMC10-neutralizing antibody on mouse hepatosteatosis was explored. Associations of MASLD with serum scEMC10 and hepatic mEMC10 were determined in two cohorts of participants with MASLD. RESULTS: scEMC10 promoted, while mEMC10 suppressed, the activation of hepatic PERK-eIF2α-ATF4 signaling. Emc10 gene knockout exacerbated, while hepatic overexpression of mEMC10 ameliorated, hepatic ER stress and steatosis in mice challenged with either a methionine- and choline-deficient diet or tunicamycin, highlighting a direct, suppressive role of mEMC10 in MASLD via modulation of hepatic ER stress. Overexpression of scEMC10 promoted, whereas neutralization of circulating scEMC10 prevented, hepatosteatosis in mice with fatty liver, suggesting a role of scEMC10 in MASLD development. Clinically, serum scEMC10 was increased, while hepatic mEMC10 was decreased, in participants with MASLD. Correlative analysis indicated that serum scEMC10 positively, whereas hepatic mEMC10 negatively, correlated with liver fat content and serum ALT, AST, and GGT. CONCLUSIONS: These findings demonstrate a novel isoform-specific role for EMC10 in the pathogenesis of MASLD and identify the secreted isoform as a tractable therapeutic target for MASLD via antibody-based neutralization. IMPACT AND IMPLICATIONS: We have shown the role of EMC10 in the regulation of energy homeostasis and obesity. In this study, we determine the distinct roles of the two isoforms of EMC10 in the regulation of hepatic endoplasmic reticulum stress and steatosis in mice, and report on the associations of the different EMC10 isoforms with metabolic dysfunction-associated steatotic liver disease in humans. Our findings delineate a novel regulatory axis for hepatosteatosis and identify EMC10 as a modulator of the PERK-eIF2α-ATF4 signaling cascade that may be of broad physiological significance. Moreover, our pre-clinical and clinical studies provide evidence of the therapeutic potential of targeting scEMC10 in MASLD.

sAPPα Peptide Promotes Damaged Microglia to Clear Alzheimer's Amyloid-ß via Restoring Mitochondrial Function.

Alzheimer's disease (AD) is an age-related neurodegenerative disease with amyloid-ß (Aß) deposition as the main pathological feature. It's an important challenge to find new ways to clear Aß from the brain. The soluble amyloid precursor protein α (sAPPα) is a neuroprotective protein and can attenuate neuronal damage, including toxic Aß. However, the regulatory role of sAPPα in non-neuronal cells, such as microglia, is less reported and controversial. Here, we showed that sAPPα promoted the phagocytosis and degradation of Aß in both normal and damaged microglia. Moreover, the function of damaged microglia was improved by the sAPPα through normalizing mitochondrial function. Furthermore, the results of molecular docking simulation showed that sAPPα had a good affinity with Aß. We preliminarily reveal that sAPPα is similar to antibodies and can participate in the regulation of microglia phagocytosis and degradation of Aß after binding to Aß. sAPPα is expected to be a mild and safe peptide drug or drug carrier for AD.

Niobium Modification of CeO2 Tuning Electron Density of Nickel-Ceria Interfacial Sites for Enhanced CO2 Methanation.

CO2 methanation has attracted considerable attention as a promising strategy for recycling CO2 and generating valuable methane. This study presents a niobium-doped CeO2-supported Ni catalyst (Ni/NbCe), which demonstrates remarkable performance in terms of CO2 conversion and CH4 selectivity, even when operating at a low temperature of 250 °C. Structural analysis reveals the incorporation of Nb species into the CeO2 lattice, resulting in the formation of a Nb-Ce-O solid solution. Compared with the Ni/CeO2 catalyst, this solid solution demonstrates an improved spatial distribution. To comprehend the impact of the Nb-Ce-O solid solution on refining the electronic properties of the Ni-Ce interfacial sites, facilitating H2 activation, and accelerating the hydrogenation of CO2* into HCOO*, in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) analysis and density functional theory (DFT) calculations were conducted. These investigations shed light on the mechanism through which the activity of CO2 methanation is enhanced, which differs from the commonly observed CO* pathway triggered by oxygen vacancies (OV). Consequently, this study provides a comprehensive understanding of the intricate interplay between the electronic properties of the catalyst's active sites and the reaction pathway in CO2 methanation over Ni-based catalysts.

Theoretical study of transition metal-doped ß12 borophene as a new single-atom catalyst for carbon dioxide electroreduction.

The electrocatalytic carbon dioxide reduction reaction (CO2RR) presents a viable and cost-effective approach for the elimination of CO2 by transforming it into valuable products. Nevertheless, this process is impeded by the absence of exceptionally active and stable catalysts. Herein, a new type of electrocatalyst of transition metal (TM)-doped ß12-borophene (TM@ß12-BM) is investigated via density functional theory (DFT) calculations. Through comprehensive screening, two promising single-atom catalysts (SACs), Sc@ß12-BM and Y@ß12-BM, are successfully identified, exhibiting high stability, catalytic activity and selectivity for the CO2RR. The C1 products methane (CH4) and methanol (CH3OH) are synthesized with limiting potentials (UL) of -0.78 V and -0.56 V on Sc@ß12-BM and Y@ß12-BM, respectively. Meanwhile, CO2 is more favourable for reduction into the C2 product ethanol (CH3CH2OH) compared to ethylene (C2H4) via C-C coupling on these two SACs. More importantly, the dynamic barriers of the key C-C coupling step are 0.53 eV and 0.73 eV for the "slow-growth" sampling approach in the explicit water molecule model. Furthermore, Sc@ß12-BM and Y@ß12-BM exhibit higher selectivity for producing C1 compounds (CH4 and CH3OH) than C2 (CH3CH2OH) in the CO2RR. Compared with Sc@ß12-BM, Y@ß12-BM demonstrates superior inhibition of the competitive hydrogen evolution reaction (HER) in the liquid phase. These results not only demonstrate the great potential of SACs for direct reduction of CO2 to C1 and C2, but also help in rationally designing high-performance SACs.

Tophi and carotid atherosclerosis in gout patients: Role of insulin resistance.

BACKGROUND AND AIM: Gout and cardiovascular disease are closely related, but the mechanism linking them is still unknown. Gout may affect the insulin signaling pathway inducing insulin resistance (IR). The study aims to evaluate the association between tophi and carotid atherosclerosis, considering the potential role of IR. METHODS AND RESULTS: A total of 595 patients with gout aged 18 to 80 were enrolled in this study. Carotid intima-media thickness, plaques and tophi were evaluated by B-mode ultrasonography. IR was assessed by the HOMA index (hepatic IR) and Gutt index (peripheral IR). Multivariable logistic regression and interaction analysis were used to examine the association between tophi and IR and its impact on carotid atherosclerosis. Among these participants, the average age was 55.4 (±12.54) years, and 94.6 % were male. Tophi were associated with increased odds of carotid atherosclerosis and burden after adjustment for confounders (P < 0.05). Tophi and IR synergically interacted for inducing carotid atherosclerosis. The interaction between peripheral IR with tophi was more pronounced than hepatic IR with tophi. CONCLUSIONS: Tophi were independently associated with carotid atherosclerosis risk. IR mediated a significant amount of the effect of tophi on the development of carotid atherosclerosis. Peripheral IR probably plays a more important role than hepatic IR does.

Untargeted metabolomic profiling identifies serum metabolites associated with type 2 diabetes in a cross-sectional study of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.

Type 2 diabetes (T2D) is a complex chronic disease with substantial phenotypic heterogeneity affecting millions of individuals. Yet, its relevant metabolites and etiological pathways are not fully understood. The aim of this study is to assess a broad spectrum of metabolites related to T2D in a large population-based cohort. We conducted a metabolomic analysis of 4,281 male participants within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. The serum metabolomic analysis was performed using an LC-MS/GC-MS platform. Associations between 1,413 metabolites and T2D were examined using linear regression, controlling for important baseline risk factors. Standardized ß-coefficients and standard errors (SEs) were computed to estimate the difference in metabolite concentrations. We identified 74 metabolites that were significantly associated with T2D based on the Bonferroni-corrected threshold (P < 3.5 × 10-5). The strongest signals associated with T2D were of carbohydrates origin, including glucose, 1,5-anhydroglucitol (1,5-AG), and mannose (ß = 0.34, -0.91, and 0.41, respectively; all P < 10-75). We found several chemical class pathways that were significantly associated with T2D, including carbohydrates (P = 1.3 × 10-11), amino acids (P = 2.7 × 10-6), energy (P = 1.5 × 10-4), and xenobiotics (P = 1.2 × 10-3). The strongest subpathway associations were seen for fructose-mannose-galactose metabolism, glycolysis-gluconeogenesis-pyruvate metabolism, fatty acid metabolism (acyl choline), and leucine-isoleucine-valine metabolism (all P < 10-8). Our findings identified various metabolites and candidate chemical class pathways that can be characterized by glycolysis and gluconeogenesis metabolism, fructose-mannose-galactose metabolism, branched-chain amino acids, diacylglycerol, acyl cholines, fatty acid oxidation, and mitochondrial dysfunction.NEW & NOTEWORTHY These metabolomic patterns may provide new additional evidence and potential insights relevant to the molecular basis of insulin resistance and the etiology of T2D.

Pt-Loaded Nb─W Metal Composite Oxide for Selective Cleavage of Secondary C─O Bonds.

Selective hydrogenolysis of glycerol to 1,3-propanediol (1,3-PDO) is recognized as one of the most promising reactions for the valorization of biomass. Precise activation of C─O bonds of glycerol molecule is the key step to realize the high yield of catalytic conversion. Here, a Pt-loaded Nb-W composite oxides with crystallographic shear phase for the precise activation and cleavage of secondary C─O (C(2)─O) bonds are first reported. The developed Nb14 W3 O44 with uniform structure possesses arrays of W-O-Nb active sites that totally distinct from individual WOx or NbOx species, which is superior to the adsorption and activation of C(2)─O bonds. The Nb14 W3 O44 support with rich reversible redox couples also promotes the electron feedback ability of Pt and enhances its interaction with Pt nanoparticles, resulting in high activity for H2 dissociation and hydrogenation. All these favorable factors confer the Pt/Nb14 W3 O44 excellent performance for selective hydrogenolysis of glycerol to 1,3-PDO with the yield of 75.2% exceeding the record of 66%, paying the way for the commercial development of biomass conversion. The reported catalysts or approach can also be adopted to create a family of Nb-W metal composite oxides for other catalytic reactions requiring selective C─O bond activation and cleavage.

Comparison of Bisphosphonates Versus Teriparatide in Therapy of the Glucocorticoid-Induced Osteoporosis (GIOP): A Meta-Analysis of Randomized Controlled Trials.

Osteoporosis (OP) is characterized as decreased bone mineral density (BMD) and increased risk of bone fracture. Secondary OP resulting from excess endogenous or exogenous glucocorticoid is defined as glucocorticoid-induced osteoporosis (GIOP). Current therapeutic strategies for GIOP are similar to menopausal osteoporosis, including calcium and vitamin D supplementation, bisphosphonates, and parathyroid hormone (PTH) analogues (teriparatide). Previously, several published meta-analyses compared anti-osteoporotic agents for the menopausal or aging-dependent OP. However, the physiopathologic bone metabolism of GIOP is different. In this study, we investigated the efficacy of BMD enhancement, bone fracture rate and safety of bisphosphonates versus teriparatide in the therapy of GIOP. We searched databases including PubMed, Embase, and the Cochrane Library until Jan 2023, and selected ten random clinical trials (RCT)s that compared the efficacy and/or safety of bisphosphonate versus teriparatide for GIOP patients. Teriparatide therapy increased lumber spinal BMD by 3.96% (95% CI 3.01-4.9%, p<0.00001), 1.23% (95% CI 0.36-2.1%, p=0.006) at total hip, and 1.45% (95% CI 0.31-2.58%, p=0.01) at femoral neck, respectively, compared to bisphosphonates at 18-month therapy for GIOP. Teriparatide also reduced bone fracture especially in vertebral bone (p=0.0001, RR 6.27, 95% CI 2.44-16.07), and increased bone formation and resorption marker levels. There was no difference in the incidence of adverse effects in bisphosphonate and teriparatide groups. Teriparatide showed better performance over bisphosphonate in BMD enhancement, bone fracture reduction, and bone remodeling improvement, without increasing the incidence of adverse effects.

Association between serum free fatty acid levels and tophus in patients with gout: a cross-sectional study.

OBJECTIVES: To explore the relationship between serum free fatty acid (FFA) and tophus in gout patients, and to investigate whether FFA increases the risk of tophus deposition by lowering urine pH. METHODS: A total of 595 patients with gout aged 18 to 80 were enrolled between June 2018 and August 2021. The subjects were divided into four groups according to FFA. Logistic regression was used to analyse the association between serum FFA and tophus. Receiver operating curves (ROC) were plotted to explore the predictive value of FFA on the occurrence of tophus. RESULTS: Accompanying the increase of FFA levels, the prevalence of tophus in groups Q3 and Q4 was significantly higher than in groups Q1 and Q2 (33.6%, 36.5% vs. 6.3%, 19.6%, p<0.001). According to the Spearman correlation, serum FFA levels were positively correlated with tophus while negatively with urine pH (p<0.001). FFA had a significant interaction with urine pH on tophus risk. Multivariate logistic regression showed that participants in Q2-Q4 had a higher OR of tophus than those in Q1 (OR were 2.770, 5.878 and 7.958 in Q2-Q4, respectively). ROC showed the best cut-off value of serum FFA level in predicting the onset of tophus was 0.46 mmol/L. Serum FFA had a great discriminant ability to predict tophus. CONCLUSIONS: High FFA levels are independently associated with tophus risk and FFA may promote tophi deposition by lowering urine pH. Serum FFA levels have a great screening value to identify tophus.

Covalent Organic Framework/g-C3N4 van der Waals Heterojunction toward H2 Production.

Photocatalytic water splitting into H2 is the most economic and environmentally friendly strategy for H2 production, and rationally constructing a heterojunction retains enormous influence on a photocatalytic system. Herein, 2D/2D covalent organic framework/graphitic carbon nitride (COF/CN) van der Waals heterojunctions were readily prepared via an ultrasonic method for high-efficiency visible-light photocatalytic H2 production. The photocatalytic H2 production performance of optimized COF/CN composites can reach up to 449.64 µmol·h-1, which is approximately 5 times that of pure CN (89.08 µmol·h-1). The characterization and experimental studies reveal that the synergistic effect between COF and CN contributes to promoting the interfacial migration and spatial separation of photoinduced e--h+ pairs, further boosting the photocatalytic hydrogen production activity. This work may open a new window to design and fabricate effective heterojunction photocatalysts for photocatalytic energy conversion.

Changes in the salivary metabolome in patients with chronic erosive gastritis.

INTRODUCTION: Chronic erosive gastritis (CEG) is closely related to gastric cancer, which requires early diagnosis and intervention. The invasiveness and discomfort of electronic gastroscope have limited its application in the large-scale screening of CEG. Therefore, a simple and noninvasive screening method is needed in the clinic. OBJECTIVES: The aim of this study is to screen potential biomarkers that can identify diseases from the saliva samples of CEG patients using metabolomics. METHODS: Saliva samples from 64 CEG patients and 30 healthy volunteers were collected, and metabolomic analysis was performed using UHPLC-Q-TOF/MS in the positive and negative ion modes. Statistical analysis was performed using both univariate (Student's t-test) and multivariate (orthogonal partial least squares discriminant analysis) tests. Receiver operating characteristic (ROC) analysis was conducted to determine significant predictors in the saliva of CEG patients. RESULTS: By comparing the saliva samples from CEG patients and healthy volunteers, 45 differentially expressed metabolites were identified, of which 37 were up-regulated and 8 were down-regulated. These differential metabolites were related to amino acid, lipid, phenylalanine metabolism, protein digestion and absorption, and mTOR signaling pathway. In the ROC analysis, the AUC values of 7 metabolites were greater than 0.8, among which the AUC values of 1,2-dioleoyl-sn-glycoro-3-phosphodylcholine and 1-stearoyl-2-oleoyl-sn-glycoro-3-phospholine (SOPC) were greater than 0.9. CONCLUSIONS: In summary, a total of 45 metabolites were identified in the saliva of CEG patients. Among them, 1,2-dioleoyl-sn-glycoro-3-phosphorylcholine and 1-stearoyl-2-oleoyl-sn-glycoro-3-phosphorine (SOPC) might have potential clinical application value.

Sinensetin ameliorates high glucose-induced diabetic nephropathy via enhancing autophagy in vitro and in vivo.

Diabetic nephropathy (DN) affects around 40% of people with diabetes, the final outcome of which is end-stage renal disease. The deficiency of autophagy and excessive oxidative stress have been found to participate in the pathogenesis of DN. Sinensetin (SIN) has been proven to have strong antioxidant capability. However, the effect of SIN on DN has not been studied. We examined the effect of SIN on cell viability and autophagy in the podocyte cell line, MPC5 cells, treated with high glucose (HG). For in vivo studies, DN mice models were established by intraperitoneal injected with streptozotocin (40 mg/kg) for 5 consecutive days and fed with a 60% high-fat diet, and SIN was given (10, 20, and 40 mg/kg) for 8 weeks via intraperitoneal injection. The results showed that SIN could protect MPC5 cells against HG-induced damage and significantly improve the renal function of DN mice. Moreover, SIN remarkably restored the autophagy activity of MPC5 cells which was inhibited under HG conditions. Consistent with this, SIN efficiently improved autophagy in the kidney tissue of DN mice. In brief, our findings demonstrated the protective effect of SIN on DN via restoring the autophagic function, which might provide a basis for drug development.

Electroencephalogram-Based Brain Connectivity Analysis in Prolonged Disorders of Consciousness.

Background: Prolonged disorders of consciousness (pDOC) are common in neurology and place a heavy burden on families and society. This study is aimed at investigating the characteristics of brain connectivity in patients with pDOC based on quantitative EEG (qEEG) and extending a new direction for the evaluation of pDOC. Methods: Participants were divided into a control group (CG) and a DOC group by the presence or absence of pDOC. Participants underwent magnetic resonance imaging (MRI) T1 three-dimensional magnetization with a prepared rapid acquisition gradient echo (3D-T1-MPRAGE) sequence, and video EEG data were collected. After calculating the power spectrum by EEG data analysis tool, DTABR ((δ + θ)/(α + ß) ratio), Pearson's correlation coefficient (Pearson r), Granger's causality, and phase transfer entropy (PTE), we performed statistical analysis between two groups. Finally, receiver operating characteristic (ROC) curves of connectivity metrics were made. Results: The proportion of power in frontal, central, parietal, and temporal regions in the DOC group was lower than that in the CG. The percentage of delta power in the DOC group was significantly higher than that in the CG, the DTABR in the DOC group was higher than that in the CG, and the value was inverted. The Pearson r of the DOC group was higher than that of CG. The Pearson r of the delta band (Z = -6.71, P < 0.01), theta band (Z = -15.06, P < 0.01), and alpha band (Z = -28.45, P < 0.01) were statistically significant. Granger causality showed that the intensity of directed connections between the two hemispheres in the DOC group at the same threshold was significantly reduced (Z = -82.43, P < 0.01). The PTE of each frequency band in the DOC group was lower than that in the CG. The PTE of the delta band (Z = -42.68, P < 0.01), theta band (Z = -56.79, P < 0.01), the alpha band (Z = -35.11, P < 0.01), and beta band (Z = -63.74, P < 0.01) had statistical significance. Conclusion: Brain connectivity analysis based on EEG has the advantages of being noninvasive, convenient, and bedside. The Pearson r of DTABR, delta, theta, and alpha bands, Granger's causality, and PTE of the delta, theta, alpha, and beta bands can be used as biological markers to distinguish between pDOC and healthy people, especially when behavior evaluation is difficult or ambiguous; it can supplement clinical diagnosis.

The Preparation of Golgi Apparatus-Targeted Polymer Dots Encapsulated with Carbon Nanodots of Bright Near-Infrared Fluorescence for Long-Term Bioimaging.

As a vital organelle in eukaryotic cells, the Golgi apparatus is responsible for processing and transporting proteins in cells. Precisely monitoring the status of the Golgi apparatus with targeted fluorescence imaging technology is of enormous importance but remains a dramatically challenging task. In this study, we demonstrate the construction of the first Golgi apparatus-targeted near-infrared (NIR) fluorescent nanoprobe, termed Golgi-Pdots. As a starting point of our investigation, hydrophobic carbon nanodots (CNDs) with bright NIR fluorescence at 674 nm (fluorescence quantum yield: 12.18%), a narrow emission band of 23 nm, and excellent stability were easily prepared from Magnolia Denudata flowers using an ultrasonic method. Incorporating the CNDs into a polymer matrix modified with Golgi-targeting molecules allowed for the production of the water-soluble Golgi-Pdots, which showed high colloidal stability and similar optical properties compared with pristine CNDs. Further studies revealed that the Golgi-Pdots showed good biocompatibility and Golgi apparatus-targeting capability. Based on these fascinating merits, utilizing Golgi-Pdots for the long-term tracking of the Golgi apparatus inside live cells was immensely successful.

Resveratrol Enhances Wound Healing in Type 1 Diabetes Mellitus by Promoting the Expression of Extracellular Vesicle-Carried MicroRNA-129 Derived from Mesenchymal Stem Cells.

Recent studies have shown the promotive effect of resveratrol on wound healing. This study aims to explore the underlying molecular mechanism of resveratrol in type 1 diabetes mellitus (T1DM) through microRNA (miR)-129-containing extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) based on in silico analysis. The rat model of T1DM was established by intraperitoneal injection of sodium citrate containing streptozotocin, and the wound was made around the deep fascia. Rat MSCs were isolated and treated with resveratrol (SRT501), and the corresponding EVs (SRT501-EVs) were isolated, where the expression of miR-129 was determined. By performing function experiments, the effect of SRT501-EVs and miR-129 on the biological functions of human umbilical vein endothelial cells (HUVECs) was determined. Finally, the binding relationship between miR-129 and tumor necrosis factor receptor-associated factor 6 (TRAF6) was also determined by the dual-luciferase reporter gene assay. miR-129 was shown as a candidate related to both resveratrol and wound healing in T1DM. SRT501-EVs promoted the skin wound healing of T1DM rats and also further improved the proliferative, migratory, and tube formation potentials of HUVECs. Resveratrol inhibited the expression of TRAF6 in HUVECs stimulated by MSC-conditioned medium and promoted the transfer of miR-129 via EVs, while TRAF6 was confirmed as a target gene of miR-129. Furthermore, inhibition of miR-129 attenuated the proangiogenic effect of resveratrol on HUVECs. Resveratrol exerts promotive role in wound healing in T1DM through downregulation of TRAF6 via MSC-EV-carried miR-129, suggesting a regulatory network involved in the wound healing process in T1DM.

hUCMSCs carrying exenatide prevent T1DM by improving intestinal microflora composition and islet tissue damage repair.

BACKGROUND: Exenatide is a stable analogue of glucagon-like peptide 1 that can reduce postprandial hyperglycemia and has been utilized as adjunctive therapy for type 1 diabetes mellitus (T1DM). The human umbilical cord is a rich source of MSCs, and human umbilical cord mesenchymal stem cells (hUCMSCs) also show potential to enhance insulin secretion. Here, we aimed to explore the effects of hUCMSCs carrying exenatide in T1DM and further identify the possible mechanisms involved. METHODS: hUCMSCs were isolated from human umbilical cord tissues, identified, and transduced with recombinant lentivirus carrying exenatide to obtain exenatide-carrying hUCMSCs (hUCMSCs@Ex-4). RESULTS: The results showed that hUCMSCs@Ex-4 restored the blood glucose levels and body weight of NOD mice, and repressed immune cell infiltration and islet tissue changes. Additionally, in T1DM mice, treatment with hUCMSCs@Ex-4 reduced the blood glucose levels and promoted repair of islet tissue damage. Moreover, hUCMSCs@Ex-4 attenuated renal tissue lesions in T1DM mice. Applying bioinformatic analysis, the effects of hUCMSCs@Ex-4 were suggested to correlate with decreased abundance of pro-inflammatory intestinal bacteria and increased abundance of anti-inflammatory intestinal bacteria. CONCLUSION: Overall, the study indicated that hUCMSCs carrying exenatide might improve beneficial intestinal microflora abundance and promote islet tissue damage repair, thereby alleviating T1DM.

The role of mitochondrial fission factor in podocyte injury in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most important complications of diabetes mellitus (DM) and has become the second cause of end-stage renal disease (ESRD). This study intends to investigate the molecular mechanism of increased mitochondrial fission in podocytes under the effect of high glucose (HG), and to preliminarily study the role of mitochondrial fission factor (MFF)-mediated mitochondrial fission in podocyte injury of DN. In vitro studies, we found that HG induced increased mitochondrial fission and podocyte damage. At the same time MFF mRNA and protein levels was increased, suggesting that MFF was transcriptional upregulated under HG conditions. Consistent with this, in vivo studies found that mitochondrial fission was also significantly increased in podocytes of diabetic nephropathy mice, and MFF expression was up-regulated. Therefore, our study proves that mitochondrial fission increases in podocytes under DM both in vitro and in vivo, and the up-regulation of MFF expression may be one of the reasons for the increase of mitochondrial fission. After inhibiting the expression of MFF, the survival rate of podocytes was significantly decreased under HG conditions, suggesting that MFF may play a protective role in podocyte injury in DN.

C-peptide, glycaemic control, and diabetic complications in type 2 diabetes mellitus: A real-world study.

OBJECTIVE: To explore the relationship between C-peptide and glycaemic control rate and diabetic complications (microvascular complication and cerebral infarction) and provide evidence for stratified treatment of type 2 diabetes mellitus (T2DM)-based C-peptide. METHOD: This is a cross-sectional real-world observational study. According to the inclusion and exclusion criteria, we studied 1377 patients with T2DM, grouped by fasting C-peptide and HOMA-IR. Blood samples were collected after fasting overnight. Logistic regression was used to analyse the relationship among fasting C-peptide, HOMA-IR, C2/C0 ratio (the ratio of 2 h postprandial C-peptide to fasting C-peptide), glycaemic control rate, and occurrence of diabetic complications. Restricted cubic spline (RCS) curves based on logistic regression were used to evaluate the relationship between C-peptide, glycaemic control rate, and diabetic kidney disease (DKD). RESULTS: Patients were subdivided according to their fasting C-peptide in 4 groups (Q1,Q2,Q3,Q4). Patients of group Q3 (1.71 ≤ C-peptide < 2.51 ng/ml) showed the lowest incidence of DKD, diabetic retinopathy (DR), and rate of insulin absorption as welll as higher glycaemic control rate. Logistic regression shows that the probability of reaching glycemic control increased with higher levels of C-peptide, compared with group Q1, after adjusting for age, gender, duration of diabetes, body mass index, systolic blood pressure, diastolic blood pressure, creatinine, low-density lipoprotein, triglyceride, total cholesterol, and high-density lipoprotein. RCS curve shows that, when C-peptide is ≤2.68 ng/ml, the incidence of not reaching glycaemic control decreases with increasing C-peptide. The possibility of not reaching glycaemic control decreased with increasing C2/C0, when C-peptide is ≥1.71 ng/ml. RCS curve shows that the relationship between C-peptide and DKD follows a U-style curve. When C-peptide is <2.84 ng/ml, the incidence of DKD decreased with increasing C-peptide. With the increase in the C2/C0 ratio, the incidence of DKD, DR, and fatty liver did not decrease. CONCLUSION: When C-peptide is ≥ 1.71 and < 2.51 ng/ml, patients with T2DM had a higher glycemic control rate. Excessive C-peptide plays different roles in DKD and DR; C-peptide may promote the incidence of DKD but protects patients from DR. Higher C2/C0 ratio is important for reaching glycaemic control but cannot reduce the risk of DKD, DR, and fatty liver.

The Negative Association Between NAFLD Severity and CKD in a Non-Diabetic Gouty Population.

Nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) share common pathogenic mechanisms and risk factors. We aim to evaluate the association between NAFLD and CKD in a non-diabetic gouty population. The retrospective cross sectional study was performed on 1049 non-diabetic gouty participants, who were hospitalized between 2014 and 2020, across 4 districts in Shandong, China. Demographic and clinical characteristics of the study population were collected. The odds ratios (OR) and corresponding 95% confidence intervals (CI) about the NAFLD severity determined by ultrasonography were obtained by multiple logistic regression analysis. An unexpectedly inverse relationship was found between NAFLD severity and the risk of CKD in people with gout. Multivariate logistic regression analysis demonstrated that a higher degree of NAFLD severity is independently associated with a lower risk of CKD in people with gout, after adjusted for age, sex, smoking, gout duration, and metabolic risk factors including obesity, hypertension, hyperglycemia, hyperuricemia, and dyslipidemia, with OR 0.392 (95% CI 0.248-0.619, p<0.001), 0.379 (95% CI 0.233-0.616, p<0.001) and 0.148 (95% CI 0.043-0.512, p=0.003) in participants with mild, moderate, and severe NAFLD, respectively, compared to those without NAFLD. We also observed a weakened association of serum uric acid (SUA) with metabolic risk factors and NAFLD under circumstances of CKD in people with gout (r=-0.054, p=0.466). In conclusion, the presence and severity of NAFLD were negatively associated with the risk of CKD in the non-diabetic gouty population.