Metformin accelerates bone fracture healing by promoting type H vessel formation through inhibition of YAP1/TAZ expression

Due to increasing morbidity worldwide,fractures are becoming an emerging public health concern.This study aimed to investigate the effect of metformin on the healing of osteoporotic as well as normal fractures.Type H vessels have recently been identified as a bone-specific vascular subtype that supports osteogenesis.Here,we show that metformin accelerated fracture healing in both osteoporotic and normal mice.Moreover,metformin promoted angiogenesis in vitro under hypoxia as well as type H vessel formation throughout fracture healing.Mechanistically,metformin increased the expression of HIF-1α,an important positive regulator of type H vessel formation,by inhibiting the expression of YAP1/TAZ in calluses and hypoxia-cultured human microvascular endothelial cells(HMECs).The results of HIF-1αor YAP1/TAZ interference in hypoxia-cultured HMECs using si RNA further suggested that the enhancement of HIF-1αand its target genes by metformin is primarily through YAP1/TAZ inhibition.Finally,overexpression of YAP1/TAZ partially counteracted the effect of metformin in promoting type H vessel-induced angiogenesis-osteogenesis coupling during fracture repair.In summary,our findings suggest that metformin has the potential to be a therapeutic agent for fractures by promoting type H vessel formation through YAP1/TAZ inhibition.

Self-assembled carbon monoxide nanogenerators managing sepsis through scavenging multiple inflammatory mediators

Sepsis,a life-threatening syndrome of organ damage resulting from dysregulated inflammatory response,is distinguished by overexpression of inflammatory cytokines,excessive generation of reactive oxygen/nitrogen species(RONS),heightened activation of pyroptosis,and suppression of autophagy.However,current clinical symptomatic supportive treatment has failed to reduce the high mortality.Herein,we developed self-assembled multifunctional carbon monoxide nanogenerators(Nano CO),as sepsis drug candidates,which can release CO in response to ROS,resulting in clearing bacteria and activating the heme oxygenase-1/CO system.This activation strengthened endogenous protection and scavenged multiple inflammatory mediators to alleviate the cytokine storm,including scavenging RONS and cfDNA,inhibiting macrophage activation,blocking pyroptosis and activating autophagy.Animal experiments show that Nano CO has a good therapeutic effect on mice with LPSinduced sepsis,which is manifested in hypothermia recovery,organ damage repair,and a 50%decrease in mortality rates.Taken together,these results illustrated the efficacy of multifunctional Nano CO to target clearance of multiple mediators in sepsis treatment and act against other refractory inflammation-related diseases.

Cold-Induced Reprogramming of Subcutaneous White Adipose Tissue Assessed by Single-Cell and Single-Nucleus RNA Sequencing

Adipose browning has demonstrated therapeutic potentials in several diseases.Here,by conducting transcriptomic profiling at the single-cell and single-nucleus resolution,we reconstituted the cellular atlas in mouse inguinal subcutaneous white adipose tissue(iWAT)at thermoneutrality or chronic cold condition.All major nonimmune cells within the iWAT,including adipose stem and progenitor cells(ASPCs),mature adipocytes,endothelial cells,Schwann cells,and smooth muscle cells,were recovered,allowing us to uncover an overall and detailed blueprint for transcriptomes and intercellular cross-talks and the dynamics during white adipose tissue brown remodeling.Our findings also unravel the existence of subpopulations in mature adipocytes,ASPCs,and endothelial cells,as well as new insights on their interconversion and reprogramming in response to cold.The adipocyte subpopulation competent of major histocompatibility complex class Ⅱ(MHCⅡ)antigen presentation is potentiated.Furthermore,a subcluster of ASPC with CD74 expression was identified as the precursor of this MHCⅡ^(+)adipocyte.Beige adipocytes are transdifferented from preexisting lipid generating adipocytes,which exhibit developmental trajectory from de novo differentiation of amphiregulin cells(Aregs).Two distinct immune-like endothelial subpopulations are present in iWAT and are responsive to cold.Our data reveal fundamental changes during cold-evoked adipose browning.

Isolated ileal perforation due to cytomegalovirus reactivation during management of terbinafine hypersensitivity

We report a case of 71-year-old man who developed a hypersensitivity syndrome associated with terbinafine. He was placed on terbinafine (250 mg/d) for the treatment of tinea pedis due to diabetes mellitus. Following the treatment with terbinafine, he developed druginduced hypersensitivity syndrome (DIHS). Systemic corticosteroid led to transient improvement of his clinical manifestations. Three months after disease onset, he presented with panperitonitis due to ileal perforation, and underwent an emergency operation. The affected ileum was resected and ileostomy was performed in the terminal ileum. Cytomegalovirus (CMV)-specific IgG antibodies were significantly increased, high-titer CMV antigenemia was detected, and pathological examination of the resected ileum confirmed CMV infection. Based onthese observations, we strongly recommend that physicians monitor reactivation of the family of herpesvirus other than herpesvirus 6, to manage DIHS properly.

Meta-analysis of therapy of Kang’ai injection combined with chemotherapy in the treatment of non-small cell lung cancer

Objective:To compare the safety and efficacy of Kang’ai injection combined with chemotherapy and chemotherapy alone in the treatment of non-small cell lung cancer.Methods:The related control and randomized studies from 1966 to October 01,2022,were retrieved in the following databases:China National Knowledge Infrastructure,Wanfang databases,Value In Paper,SinoMed,PubMed,Embase and Cochrane Library.A comprehensive literature search was conducted in 7 electronic databases identifying all the relevant randomized controlled trials.Cochrane handbook 5.2.3 was applied to evaluate the quality of included trials,and the RevMan 5.3 software was used to analyze data and assess the publication bias.Results:From the 16 studies reviewed,a total of 1,398 patients were included.Compared with docetaxel+cis-platinum chemotherapy alone,Kang’ai injection combined with docetaxel+cis-platinum chemotherapy showed significant effects in improving clinical response rate(RR:1.40,95%confidence interval(CI)(1.25,1.58)),quality of life score(Karnofsky score)(RR:1.53,95%CI(1.32,1.78)),traditional Chinese medicine syndrome(RR:2.01,95%CI(1.43,2.83))and safety(RR:0.62,95%CI(0.54,0.71)),the differences were statistically significant.Conclusion:Kang’ai injection may increase the therapeutic effectiveness,improve the quality of life,and reduce the toxicity of chemotherapy in patients with non-small cell lung cancer.These results require confirmation by further rigorously designed randomized controlled trials(PROSPERO registration number:CRD42020176917).

New insight of obesity-associated NAFLD: Dysregulated “crosstalk” between multi-organ and the liver?

Obesity plays a crucial role in the development of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism for the pathogenesis of obesity-associated NAFLD remains largely obscure. Although the “multiple hit” theory provides a more accurate explanation of NAFLD pathogenesis, it still cannot fully explain precisely how obesity causes NAFLD. The liver is the key integrator of the body's energy needs, receiving input from multiple metabolically active organs. Thus, recent studies have advocated the “multiple crosstalk” hypothesis, highlighting that obesity-related hepatic steatosis may be the result of dysregulated “crosstalk” among multiple extra-hepatic organs and the liver in obesity. A wide variety of circulating endocrine hormones work together to orchestrate this “crosstalk”. Of note, with deepening understanding of the endocrine system, the perception of hormones has gradually risen from the narrow sense (i.e. traditional hormones) to the broad sense of hormones as organokines and exosomes. In this review, we focus on the perspective of organic endocrine hormones (organokines) and molecular endocrine hormones (exosomes), summarizing systematically how the two types of new hormones mediate the dialogue between extra-hepatic organs and liver in the pathogenesis of obesity-related NAFLD.

Combination therapy with saxagliptin and vitamin D for the preservation ofβ-cell function in adult-onset type 1 diabetes:a multi-center,randomized,controlled trial

Disease modifying therapies aiming to preserveβ-cell function in patients with adult-onset autoimmune type 1 diabetes are lacking.Here,we conducted a multi-centre,randomized,controlled trial to assess theβ-cell preservation effects of saxagliptin alone and saxagliptin combined with vitamin D as adjunctive therapies in adult-onset autoimmune type 1 diabetes.In this 3-arm trial,301 participants were randomly assigned to a 24-month course of the conventional therapy(metformin with or without insulin)or adjunctive saxagliptin or adjunctive saxagliptin plus vitamin D to the conventional therapy.The primary endpoint was the change from baseline to 24 months in the fasting C-peptide.The secondary endpoints included the area under the concentration-time curve(AUC)for C-peptide level in a 2-h mixed-meal tolerance test,glycemic control,total daily insulin use and safety,respectively.The primary endpoint was not achieved in saxagliptin plus vitamin D group(P=0.18)and saxagliptin group(P=0.26).However,compared with the conventional therapy,2-h C-peptide AUC from 24 months to baseline decreased less with saxagliptin plus vitamin D(-276 pmol/L vs.-419 pmol/L;P=0.01),and not to the same degree with saxagliptin alone(-314 pmol/L;P=0.14).Notably,for participants with higher glutamic acid decarboxylase antibody(GADA)levels,the decline ofβ-cell function was much lower in saxagliptin plus vitamin D group than in the conventional therapy group(P=0.001).Insulin dose was significantly reduced in both active treatment groups than in the conventional therapy group despite all groups having similar glycemic control.In conclusion,the combination of saxagliptin and vitamin D preserves pancreaticβ-cell function in adult-onset autoimmune type 1 diabetes,an effect especially efficacious in individuals with higher GADA levels.Our results provide evidence for a novel adjunct to insulin and metformin as potential initial treatment for adult-onset type 1 diabetes.(ClinicalTrials.gov identifier:NCT02407899).

Individualized coefficient of variability cut-off values for reducing the risk of hypoglycemia in Chinese type 1 diabetes mellitus(T1DM)patients

To the Editor:Type 1 diabetes mellitus(T1DM)is a progressive disease caused by severe islet b-cell function impairment,resulting in high glucose variability(GV)in patients.[1]While intensive insulin treatment enabled T1DM patients to achieve near-normal glucose,reflected by reduced hemoglobin A1c(HbA1c)levels,stricter HbA1c targets were associated with an increased risk of hypoglycemia,which would compromise patients’quality of life and survival.[2]Recent studies suggest that GV reflects hypoglycemia better than HbA1c alone,and continuous glucose monitoring(CGM)provides a more comprehensive glycemic profile for better glucose indices assessment.[3]Therefore,we aimed to explore the relationship between the coefficient of variability(CV)of blood glucose and hypoglycemia in T1DM patients with different HbA1c levels and to identify the optimal cut-off values of CV for reducing the hypoglycemia risk in Chinese T1DM patients.

Implications of glycemic risk index across different levels of glycated hemoglobin(HbA1c)in type 1 diabetes

To the Editor:Glycemic control in individuals with type 1 diabetes(T1D)is challenging and requires multidimensional evaluation and precise management.Glycated hemoglobin(HbA1c)is currently the gold standard for assessing glucose control and predicting diabetes prognosis.However,it exhibits limitations in terms of accuracy,which is influenced by clinical factors,^([1])and its inability to reflect information about hypoglycemia and glycemic variability.[2]Continuous glucose monitoring(CGM)has revolutionized glycemic profile evaluation by introducing novel glycemic variables that surpass conventional parameters and offer insights into critical areas for improving glycemic control.

Vascular wall microenvironment:Endothelial cells original exosomes mediated melatonin-suppressed vascular calcification and vascular ageing in a m6A methylation dependent manner

Vascular calcification and vascular ageing are“silent”diseases but are highly prevalent in patients with end stage renal failure and type 2 diabetes,as well as in the ageing population.Melatonin(MT)has been shown to induce cardiovascular protection effects.However,the role of MT on vascular calcification and ageing has not been well-identified.In this study,the aortic transcriptional landscape revealed clues for MT related cell-to-cell communication between endothelial cells(ECs)and vascular smooth muscle cells(VSMCs)in vascular calcification and vascular ageing.Furthermore,we elucidated that it was exosomes that participate in the information transportation from ECs to VSMCs.The exosomes secreted from melatonin-treated ECs(MT-ECs-Exos)inhibited calcification and senescence of VSMCs.Mechanistically,miR-302d-5p was highly enriched in MT-ECs-Exos,while depletion of miR-302d-5p blocked the ability of MT-ECs-Exos to suppress VSMC calcification and senescence.Notably,Wnt3 was a bona fide target of miR-302d-5p and modulated VSMC calcification and senescence.Furthermore,we found that maturation of endothelial derived exosomal miR-302d-5p was promoted by WTAP in an N^(6)-methyladenosine(m^(6)A)-dependent manner.Interestingly,MT alleviated vascular calcification and ageing in 5/6-nephrectomy(5/6 NTP)mice,a chronic kidney disease(CKD)induced vascular calcification and vascular ageing mouse model.MT-ECs-Exos was absorbed by VSMCs in vivo and effectively prevented vascular calcification and ageing in 5/6 NTP mice.ECs-derived miR-302d-5p mediated MT induced anti-calcification and anti-ageing effects in 5/6 NTP mice.Our study suggests that MT-ECs-Exos alleviate vascular calcification and ageing through the miR-302d-5p/Wnt3 signaling pathway,dependent on m^(6)A methylation.

cGAS-STING signaling and function in metabolism and kidney diseases

The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway senses the presence of cytosolic DNA and,in turn,triggers downstream signaling to induce the expression of inflammatory and type I interferon genes in immune cells.Whereas the innate immune function of the cGAS-STING pathway is well studied over the past years,emerging evidence suggests that this signaling pathway may have additional functions beyond innate immune surveillance.Consistent with this notion,dysregulation of the cGAS-STING signaling pathway in adipocytes,hepatocytes,and renal proximal tubule epithelial cells are associated with metabolic dysfunction,impaired energy homeostasis,and kidney diseases.In this review,we summarize current understanding of the cGAS-STING pathway in several metabolic diseases such as obesity,insulin resistance,alcoholic and nonalcoholic fatty liver diseases,as well as acute kidney injury and chronic kidney disease.We also review the interaction between the cGAS-STING pathway and lipid metabolism.Lastly,we discuss potential mechanisms by which cGAS-STING signaling regulates metabolism and point toward future avenues of research targeting the cGAS-STING pathway as possible means to treat common metabolic disorders.

Associations of insulin resistance and beta-cell function with abnormal lipid profile in newly diagnosed diabetes

Background:Abnormal lipids are strong predictors of cardiovascular disease in type 1 diabetes mellitus(T1DM)and type 2 diabetes mellitus(T2DM).However,the potential associations of insulin resistance(IR)and beta-cell function(BCF)with abnormal lipids in newly diagnosed T1DM or T2DM patients are not fully understood.Methods:A cross-sectional survey of 15,928 participants was conducted.Homeostasis model assessment and postprandial C-peptide levels were used to estimate IR and BCF.A restricted cubic spline(RCS)nested in binary logistic regression was used to examine the associations of IR and BCF with abnormal lipids.Results:High triglyceride(TG),low high-density lipoprotein cholesterol,and high low-density lipoprotein cholesterol(LDL-C)accounted for 49.7%,47.8%,and 59.2%of the participants,respectively.In multivariable analysis,high IR was associated with an increased risk of high TGs(P for trend<0.001)in T1DM and is associated with an elevated risk of high TG and low HDL-C(all P for trend<0.01)in T2DM.Low BCF was not associated with risks of dyslipidemia in patients with T1DM or T2DM after adjustment for potential confounders.Conclusion:High IR had different associations with the risk of dyslipidemia in newly diagnosed T1DM and T2DM patients,suggesting that early treatment that improves IR may benefit abnormal lipid metabolism.

Common and distinct regulation of human and mouse brown and beige adipose tissues： a promising therapeutic target for obesity

Obesity, which underlies various metabolic and cardio- vascular diseases, is a growing public health challenge for which established therapies are inadequate. Given the current obesity epidemic, there is a pressing need for more novel therapeutic strategies that will help adult individuals to manage their weight. One promising therapeutic intervention for reducing obesity is to enhance energy expenditure. Investigations into human brown fat and the recently discovered beige/brite fat have galvanized intense research efforts during the past decade because of their pivotal roles in energy dissi- pation. In this review, we summarize the evolution of human brown adipose tissue （hBAT） research and dis- cuss new in vivo methodologies for evaluating energy expenditure in patients. We highlight the differences between human and mouse BAT by integrating and comparing their cellular morphology, function, and gene expression profiles. Although great advances in hBAT biology have been achieved in the past decade, more cellular models are needed to acquire a better under- standing of adipose-specific processes and molecular mechanisms. Thus, this review also describes the development of a human brown fat cell line, which could provide promising mechanistic insights into hBAT function, signal transduction, and development. Finally, we focus on the therapeutic potential and current limi- tations of hBAT as an anti-glycemic, anti-lipidemic, and weight loss-inducing ＇metabolic panacea＇.

T cell metabolism in obesity and beyond:comments on‘DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-y production’

T cells have long been known as the core of adaptive immunity and play piv-otal roles in host defense(Zhu et al.,2010).There are two main types of T cells in our body,cytotoxic T cells(CD8^(+))and helper T(Th)cells(CD4^(+)),the latter comprised of Th1,Th2,Th17,and Treg subsets.Increasing evidence supports that metabolic reprogramming of T cells leads to dramatic changes in tissue microenvironments,which may alter whole-body energy homeostasis and metabolism,beyond their roles in adaptive immunity(Varanasi et al.,2020).

COVID-19 and diabetes:the contributions of hyperglycemia

Coronavirus disease 2019(COVID-19)caused by coronavirus SARS-CoV-2 infec-tion has now evolved into a worldwide cri-sis that triggers substantial morbidity and mortality.COVID-19 occurS more fre-quently and has more serious complica-tions in patients with diabetes mellitus,but the underlying mechanisms remain largely elusive.

Epigenetic regulation in metabolic diseases:mechanisms and advances in clinical study

Epigenetics regulates gene expression and has been confirmed to play a critical role in a variety of metabolic diseases,such as diabetes,obesity,non-alcoholic fatty liver disease(NAFLD),osteoporosis,gout,hyperthyroidism,hypothyroidism and others.The term‘epigenetics’was firstly proposed in 1942 and with the development of technologies,the exploration of epigenetics has made great progresses.There are four main epigenetic mechanisms,including DNA methylation,histone modification,chromatin remodelling,and noncoding RNA(ncRNA),which exert different effects on metabolic diseases.Genetic and non-genetic factors,including ageing,diet,and exercise,interact with epigenetics and jointly affect the formation of a phenotype.Understanding epigenetics could be applied to diagnosing and treating metabolic diseases in the clinic,including epigenetic biomarkers,epigenetic drugs,and epigenetic editing.In this review,we introduce the brief history of epigenetics as well as the milestone events since the proposal of the term‘epigenetics’.Moreover,we summarise the research methods of epigenetics and introduce four main general mechanisms of epigenetic modulation.Furthermore,we summarise epigenetic mechanisms in metabolic diseases and introduce the interaction between epigenetics and genetic or non-genetic factors.Finally,we introduce the clinical trials and applications of epigenetics in metabolic diseases.

Prevalence of maturity-onset diabetes of the young in phenotypic type 2 diabetes in young adults:a nationwide,multi-center,cross-sectional survey in China

Background:Maturity-onset diabetes of the young(MODY)is the most common monogenic diabetes.The aim of this study was to assess the prevalence of MODY in phenotypic type 2 diabetes(T2DM)among Chinese young adults.Methods:From April 2015 to October 2017,this cross-sectional study involved 2429 consecutive patients from 46 hospitals in China,newly diagnosed between 15 years and 45 years,with T2DM phenotype and negative for standardized glutamic acid decarboxylase antibody at the core laboratory.Sequencing using a custom monogenic diabetes gene panel was performed,and variants of 14 MODY genes were interpreted as per current guidelines.Results:The survey determined 18 patients having genetic variants causing MODY(6 HNF1A,5 GCK,3 HNF4A,2 INS,1 PDX1,and 1 PAX4).The prevalence of MODY was 0.74%(95%confidence interval[CI]:0.40-1.08%).The clinical characteristics of MODY patients were not specific,72.2%(13/18)of them were diagnosed after 35 years,47.1%(8/17)had metabolic syndrome,and only 38.9%(7/18)had a family history of diabetes.No significant difference in manifestations except for hemoglobin A1c levels was found between MODY and non-MODY patients.Conclusion:The prevalence of MODY in young adults with phenotypic T2DM was 0.74%,among which HNF1A-,GCK-,and HNF4A-MODY were the most common subtypes.Clinical features played a limited role in the recognition of MODY.

The composition,function,and regulation of adipose stem and progenitor cells

White adipose tissue(WAT)is a highly plastic organ that plays a central role in regulating whole-body energy metabolism.Adipose stem and progenitor cells(ASPCs)are essential components of the stromal vascular fraction(SVF)of adipose tissue.They give rise to mature adipocytes and play a critical role in maintaining adipose tissue function.However,the molecular heterogeneity and functional diversity of ASPCs are still poorly understood.Recently,single-cell RNA sequencing(scRNA-seq)analysis has identified distinct subtypes of ASPCs in murine and human adipose tissues,providing new insights into the cellular complexity of ASPCs among multiple fat depots.This review summarizes the current knowledge on ASPC populations,including their markers,functions,and regulatory mechanisms.Targeting one or several of these cell populations may ameliorate metabolic disorders by promoting adaptive hyperplastic adipose growth.

Chemokine CCL1 as a therapeutic target for pulmonary fibrosis: comments on ‘The chemokine CCL1 triggers an AMFR‒SPRY1 pathway that promotes differentiation of lung fibroblasts into myofibroblasts and drives pulmonary fibrosis’

Pulmonary fibrosis(PF)is a type of chronic and progressive respiratory diseases characterized by excessive extracellular matrix(ECM)deposition,interstitial fibrotic lesions,and architectural distortion.Patients with PF suffer from pulmonary function decline and progressive worsening of dyspnea with poor prognosis(Wilson and Wynn,2009).Although recent progress provides mechanistic insights into the pathogenesis of PF,no effective treatment against PF is available other than lung transplantation.Therefore,a better understanding of the molecular and cellular mechanisms of PF is crucial for the discovery of new therapeutic targets for safe and effective anti-PF drugs.

Schistosoma japonicum Eggs Exerts Protective Effects in an Experimental Ulcerative Colitis Model

Ulcerative colitis(UC)is a chronic inflammatory disease affecting the colon,with an increasing incidence worldwide.Disease pathogenesis is multifactorial and involves genetic predisposition,epithelial barrier defects,dysregulated immune responses,and environmental factors[1,2].