Sodium taurocholate cotransporting polypeptide(NTCP)is identified as the functional receptor for HBV entry,which is responsible for upregulated HBV transcription in the HBV life cycle.Besides,NTCP is also implicated i...Sodium taurocholate cotransporting polypeptide(NTCP)is identified as the functional receptor for HBV entry,which is responsible for upregulated HBV transcription in the HBV life cycle.Besides,NTCP is also implicated in the progression of HBV-induced hepatocellular carcinoma(HCC).Thereby,NTCP-targeting entry inhibitors are proposed to suppress HBV infection and replication in HBV-induced hepatoma therapy.Herein,we integrated in silico screening and chemical synthesis to obtain a small-molecule NTCP inhibitor B7,which exhibited moderate anti-proliferative activities against HepG2 cells and anti-HBV activity in vitro.Additionally,CETSA assay,molecular docking,and MD simulation validated that B7 could bind to NTCP.Furthermore,western blot analysis demonstrated that B7 induced apoptosis with an increased expression of Bax and caspase 3 cleaving as well as a decreasing expression of Bcl-2 in HepG2 cells.Taken together,our study identified B7 as a novel NTCP inhibitor with anti-proliferation activities which might provide a new opportunity for HCC therapy.展开更多
Dear Editor,Chronic hepatitis B virus(HBV)is a global health problem closely associated with a spectrum of liver diseases.Current clinical treatment options for HBV infection are generally not curative,highlighting th...Dear Editor,Chronic hepatitis B virus(HBV)is a global health problem closely associated with a spectrum of liver diseases.Current clinical treatment options for HBV infection are generally not curative,highlighting the need for the development of novel therapeutics.Sodium taurocholate cotransporting polypeptide(NTCP)was identified as a functional receptor for HBV entry,making it a promising therapeutic target for developing novel anti-HBV agents.展开更多
The kidneys play a critical role in maintaining glucose homeostasis.Under normal renal tubular function,most of the glucose filtered from the glomeruli is re-absorbed in the proximal tubules,leaving only trace amounts...The kidneys play a critical role in maintaining glucose homeostasis.Under normal renal tubular function,most of the glucose filtered from the glomeruli is re-absorbed in the proximal tubules,leaving only trace amounts in the urine.Glycosuria can occur as a symptom of generalized proximal tubular dysfunction or when the reabsorption threshold is exceeded or the glucose threshold is reduced,as seen in familial renal glycosuria(FRG).FRG is characterized by persistent glycosuria despite normal blood glucose levels and tubular function and is primarily associated with mutations in the sodium/glucose cotransporter 5A2 gene,which encodes the sodium-glucose cotransporter(SGLT)2.Inhibiting SGLTs has been proposed as a novel treatment strategy for diabetes,and since FRG is often considered an asymptomatic and benign condition,it has inspired preclinical and clinical studies using SGLT2 inhibitors in type 2 diabetes.However,patients with FRG may exhibit clinical features such as lower body weight or height,altered systemic blood pressure,diaper dermatitis,amino-aciduria,decreased serum uric acid levels,and hypercalciuria.Further research is needed to fully understand the pathophysiology,molecular genetics,and clinical manifestations of renal glucosuria.展开更多
To achieve an unmanned rice farm,in this study,a cotransporter system was developed using a tracked rice harvester and transporter for autonomous harvesting,unloading,and transportation.Additionally,two unloading and ...To achieve an unmanned rice farm,in this study,a cotransporter system was developed using a tracked rice harvester and transporter for autonomous harvesting,unloading,and transportation.Additionally,two unloading and transportation modes—harvester waiting for unloading(HWU)and transporter fol-lowing for unloading(TFU)—were proposed,and a harvesting-unloading-transportation(HUT)strategy was defined.By breaking down the main stages of the collaborative operation,designing module-state machines(MSMs),and constructing state-transition chains,a HUT collaborative operation logic frame-work suitable for the embedded navigation controller was designed using the concept and method of the finite-state machine(FSM).This method addresses the multiple-stage,nonsequential,and complex processes in HUT collaborative operations.Simulations and field-harvesting experiments were performed to evaluate the applicability of this proposed strategy and system.The experimental results showed that the HUT collaborative operation strategy effectively integrated path planning,path-tracking control,inter-vehicle communication,collaborative operation control,and implementation control.The cotrans-porter system completed the entire process of harvesting,unloading,and transportation.The field-harvesting experiment revealed that a harvest efficiency of 0.42 hm^(2)·h^(−1) was achieved.This study can provide insight into collaborative harvesting and solutions for the harvesting process of unmanned farms.展开更多
This article discusses the study by GrubićRotkvićet al on the mechanisms of action of sodium-glucose cotransporter 2 inhibitors(SGLT2i)in patients with type 2 diabetes mellitus(T2DM)and heart failure(HF).T2DM and HF a...This article discusses the study by GrubićRotkvićet al on the mechanisms of action of sodium-glucose cotransporter 2 inhibitors(SGLT2i)in patients with type 2 diabetes mellitus(T2DM)and heart failure(HF).T2DM and HF are highly comorbid,with a significantly increased prevalence of HF in patients with T2DM.SGLT2i exhibit potential in reducing hospitalization rates for HF and cardiovascular mortality through multiple mechanisms,including improving blood glucose control,promoting urinary sodium excretion,reducing sympathetic nervous system activity,lowering both preload and afterload on the heart,alleviating inflammation and oxidative stress,enhancing endothelial function,improving myocardial energy metabolism,and stabilizing cardiac ion homeostasis.Further research and clinical practice will help optimize the use of SGLT2i in HF patients.展开更多
BACKGROUND Mizagliflozin(MIZ)is a specific inhibitor of sodium-glucose cotransport protein 1(SGLT1)originally developed as a medication for diabetes.AIM To explore the impact of MIZ on diabetic nephropathy(DN).METHODS...BACKGROUND Mizagliflozin(MIZ)is a specific inhibitor of sodium-glucose cotransport protein 1(SGLT1)originally developed as a medication for diabetes.AIM To explore the impact of MIZ on diabetic nephropathy(DN).METHODS Diabetic mice were created using db/db mice.They were administered either a low dose(0.5 mg/kg)or a high dose(1.0 mg/kg)of the SGLT1 inhibitor MIZ via stomach gavage for 8 weeks.Subsequently,mesangial cells(MCs)were isolated and subjected to high glucose conditions in culture to assess the effects of MIZ on DN.RESULTS The results showed that low doses of MIZ significantly reduced albuminuria to a level comparable to that achieved with high doses in db/db mice.High doses of MIZ led to a substantial increase in body weight in mice,along with decreased blood glucose levels and food intake.Moreover,the intervention with high-dose MIZ notably decreased the expression of extracellular matrix genes,such as collagen type 1 alpha 1 mRNA levels.While the expression of SGLT1 increased after exposure to high glucose,it decreased following treatment with MIZ.Furthermore,MIZ intervention was more effective in improving lactate dehydrogenase levels in MCs induced by high glucose compared to canagliflozin.MIZ also significantly elevated levels of antioxidant enzymes superoxide dismutase,catalase,and glutathione,while reducing malondialdehyde levels.CONCLUSION These findings indicate that MIZ can ameliorate DN by inhibiting SGLT1,inflammation,and oxidative stress.展开更多
Heart failure(HF),which falls outside of the historical macrovascular or microvascular categorizations of diabetes complications,has been overlooked for long time in diabetic patients,despite its increasing prevalence...Heart failure(HF),which falls outside of the historical macrovascular or microvascular categorizations of diabetes complications,has been overlooked for long time in diabetic patients,despite its increasing prevalence and mortality.As originally stated in the Framingham studies,diabetes is associated with an increased risk of HF.Subsequent studies not only corroborated these findings but also identified HF as the most frequent first onset of cardiovascular involvement.The paramount role of proper management of common modifiable risk factors such as hypertension,obesity,dyslipidemia and smoking,became rapidly clear.Conversely,the impact of intensive glycemic control was more contentious.A large meta-analysis of randomized controlled trials reported a lack of effect of strict glycemic control as compared to standard care on HF-related outcomes.The considerable heterogeneity of the effect estimate and the higher risk conferred by thiazolidinediones suggested that mechanism of action of antidiabetic drugs played a key role.Furthermore,the safety concerns of pioglitazone led Food and Drug Administration to release a guidance for drug manufacturers stating that cardiovascular risk should be comprehensively evaluated during drug development.Surprisingly,in just a few years,large cardiovascular outcome trials established the beneficial cardiovascular effects of sodium-glucose cotransporter 2 inhibitors.These effects were consistent regardless diabetes and ejection fraction.Therefore,scientific community started to question the glucose-lowering and diuretic properties of sodium-glucose cotransporter 2 inhibitors as the unique mechanisms for improved outcomes.A plenty of preclinical and clinical studies identified several mechanisms besides glucose-lowering effects.However,these mechanistic studies focused on animal models and patients with established HF.If the same mechanisms account for beneficial effects in patients at risk for or with pre-HF is unknown.Grubić Rotkvićet al published an interesting work adding data in early stages HF.展开更多
In real soil environments,humus,colloids and other components significantly affect pollutant migration behavior.Investigating Tl(I)and kaolinite colloids’cotransport in quartz sand media containing sodium humate(HA-N...In real soil environments,humus,colloids and other components significantly affect pollutant migration behavior.Investigating Tl(I)and kaolinite colloids’cotransport in quartz sand media containing sodium humate(HA-Na)is vital for comprehending Tl(I)migration underground.This study examined the migration of Tl(I)and kaolinite colloids across varying pH levels(5,7),ionic strengths(ISs)(1,5,50 mmol/L),and kaolinite colloid concentra-tions.Results indicate that lower IS and pH promote Tl(I)migration when transported alone.In cotransport system,kaolinite promotes Tl(I)migration under acidic conditions but inhibits it under neutral conditions,except at high kaolinite concentrations,where the effect shifts from inhibition to promotion.This is primarily due to changes in the zeta potential of quartz sand,HA-Na,and kaolinite,as well as Tl(I)adsorption after HA-Na and kaolinite occupy binding sites.Competitive adsorption between cations and Tl(I)also plays a significant role.Conversely,in individual system,higher IS and pH inhibit kaolinite migration,while increased kaolinite concentration promotes it.In cotransport system,Tl(I)promotes kaolinite migration under acidic conditions but inhibits it under neutral conditions,except at low kaolinite concentrations.This relates to changes in the zeta potential between kaolinite and the medium,as well as the retention of HA-Na in the column and its adsorption onto kaolinite.Competitive adsorption and binding site saturation also have an impact.This study enhances understanding of Tl(I)migration by revealing the dual effect of kaolinite colloids under different environmental conditions,contributing to better knowledge of Tl(I)fate and transport in natural environments.展开更多
In this editorial,we discussed the article published in the recent issue of the World Journal of Diabetes.To understand the effect of mizagliflozin on kidney injury induced by diabetes,we focused on the mechanisms by ...In this editorial,we discussed the article published in the recent issue of the World Journal of Diabetes.To understand the effect of mizagliflozin on kidney injury induced by diabetes,we focused on the mechanisms by which high glucose triggers oxidative stress and contributes to kidney injury in diabetes.The high level of unmetabolized glucose reaching the kidney triggers glucose reabsorption by renal tubules,which elevates the cellular glucose level of renal cells.High glucose induces lactate dehydrogenase overexpression and thus shifts glucose metabolism,which causes mitochondrial dysfunction.Mitochondria generate approximately 90%of the reactive oxygen species in cells,whose dysfunction further alters glucose metabolism and enhances reactive oxygen species generation.Oxidative stress stimulates proinflammatory factor production and kidney inflammatory injury.Mizagliflozin decreases glucose reabsorption and thus ameliorates diabetes-induced kidney injury.展开更多
Sodium-glucose cotransporter 2(SGLT2)inhibitors compete with the SGLT2 protein for glucose binding in the renal tubules,reducing glucose reabsorption in the kidneys.This in turn leads to increased excretion of glucose...Sodium-glucose cotransporter 2(SGLT2)inhibitors compete with the SGLT2 protein for glucose binding in the renal tubules,reducing glucose reabsorption in the kidneys.This in turn leads to increased excretion of glucose,sodium,and water into the urine.These inhibitors,initially developed for diabetes management,have shown potential benefits beyond glycemic control,impacting liver health through various mechanisms.They have emerged as promising agents in managing liver conditions,including fatty liver disease,cirrhosis,and the prevention of hepatocellular carcinoma(HCC).They modulate processes like oxidative stress,inflammation,and autophagy,which are implicated in metabolic dysfunction-associated steatotic liver disease pathogenesis,potentially reducing steatosis and inflammation and preventing progression to more severe liver conditions.In patients with liver cirrhosis,SGLT2 inhibitors have been associated with a reduced need for large-volume paracentesis and lower mortality rates,indicating their potential in managing diuretic-resistant ascites.SGLT2 inhibitors have shown potential in modulating molecular pathways involved in HCC,such as inflammatory responses and oxidative stress,that could justify their use in the prevention of HCC and improving survival in patients with HCC.The present review synthesized findings from multiple studies to elucidate the role of SGLT2 inhibitors in these liver conditions.展开更多
The study by Lin et al delves into the clinical impact of dapagliflozin,a repre-sentative sodium-glucose cotransporter 2(SGLT2)inhibitor,on chronic heart failure complicated by hyperuricemia.This investigation highlig...The study by Lin et al delves into the clinical impact of dapagliflozin,a repre-sentative sodium-glucose cotransporter 2(SGLT2)inhibitor,on chronic heart failure complicated by hyperuricemia.This investigation highlights dapagliflo-zin’s efficacy in lowering serum uric acid levels,enhancing cardiac function,and reducing cardiovascular events.This work not only provides a comprehensive analysis of dapagliflozin’s sustained benefits in these patients but also introduces novel insights for managing chronic heart failure exacerbated by elevated uric acid.Furthermore,this review examines the potential role of SGLT2 inhibitor in the context of gout,evaluating its mechanisms and clinical application prospects in the management of hyperuricemia,thereby further enriching the medical community’s understanding of SGLT2 inhibitor.展开更多
BACKGROUND The use of sodium-glucose cotransporter 2(SGLT2)inhibitor in heart failure(HF)patients is increasing significantly,regardless of whether they have a history of diabetes.The effects of SGLT2 inhibitor on HF ...BACKGROUND The use of sodium-glucose cotransporter 2(SGLT2)inhibitor in heart failure(HF)patients is increasing significantly,regardless of whether they have a history of diabetes.The effects of SGLT2 inhibitor on HF are likely mediated through multiple mechanisms,including suppression of the renin-angiotensin-aldosterone system(RAAS),reduction in oxidative stress leading to enhanced myocardial efficiency,and attenuation of adverse cardiac remodeling by preventing fibrosis.These pathways are fundamental to reducing mortality,improving patients'quality of life,and alleviating the burden on the United States healthcare system by decreasing HF-related hospitalizations.AIM To evaluate SGLT2 inhibitor effects on HF,focusing on hospitalization for HF(HHF),cardiovascular(CV)deaths,and all-cause mortality.METHODS A comprehensive search was conducted in PubMed for randomized controlled trials(RCTs)evaluating the effects of SGLT2 inhibitor in HF patients compared to placebo,covering the period from January 1,2014,to January 1,2025.The primary outcomes assessed were HHF,CV deaths,and all-cause mortality.RevMan Web 5.4.1 was used to assess the risk of bias heterogeneity and to perform the statistical analyses.A random-effects model was employed for all statistical evaluations.RESULTS A total of nine RCTs were included in this analysis:DELIVER,DECLARE-TIMI 58,DAPA-HF,EMPA-REG OUTCOME,EMPEROR-Reduced,EMPEROR-Preserved,SOLOIST-WHF,EMPULSE,and VERTIS-CV.For HHF,eight trials(excluding the SOLOIST-WHF;n=25906)were pooled,while CV deaths were assessed using data from eight trials(excluding the EMPULSE;n=26598).Compared to placebo,SGLT2 inhibitor significantly reduced the risk of HHF(relative risk:0.74;95%CI:0.71-0.77;P<0.00001)and CV death(odds ratio:0.88;95%CI:0.83-0.92;P=0.0006).All nine trials(n=27128)were included in the analysis of all-cause mortality.SGLT2 inhibitor were associated with a statistically significant reduction in all-cause mortality compared to placebo(OR:0.91;95%CI:0.84-0.98;P=0.02).CONCLUSION These results suggest that SGLT2 inhibitor significantly reduce the risk of hospitalization for HF,CV deaths,and all-cause mortality.展开更多
Objective:Preventing the transition from acute to chronic pain(pain transition)is a new strategy for treating chronic pain.The present study aimed to investigate the role of K+-Cl−Cotransporter Isoform 2(KCC2)andγ-am...Objective:Preventing the transition from acute to chronic pain(pain transition)is a new strategy for treating chronic pain.The present study aimed to investigate the role of K+-Cl−Cotransporter Isoform 2(KCC2)andγ-aminobutyric acid receptor type A(GABAAR)in the spinal cord dorsal horn(SCDH)in pain transition and the intervention effect of electroacupuncture(EA),and to understand the mechanism of EA in preventing acute and chronic pain transition in the spinal center.Methods:A rat model of hyperalgesic priming(HP)was established by injecting carrageenan(Car)into the plantar area of rats,followed by the injection of prostaglandin E2(PGE2)into the dorsal foot 7 days later.The GABAAR agonist(muscimol)and KCC2 activator(CLP257)were intrathecally injected for three consecutive days after PGE2 injection.EA was applied at a frequency of 2/100 Hz to the bilateral foot Zusanli(ST36)and Kunlun(BL60).A von Frey filament was used to detect the pain threshold in each group of rats.Western blotting(WB)and immunofluorescence(IF)were used to detect GABAAR and KCC2 expression in each rats group.By combining EA intervention with a KCC2 inhibitor(VU0240551),we explored the mechanism of pain transition of EA regulation of GABAAR and KCC2 expression in SCDH.Results:The HP model was established by injecting mice with Car/PGE2.Compared to the normal saline(NS)+NS and NS+PGE2 groups,the pain threshold of the Car+PGE2 group decreased significantly 48 hours after PGE2 injection(P<0.01).The WB results indicated that intrathecal injection of a GABAAR agonist upregulated GABAAR expression in the SCDH of HP model rats(P<0.05).WB and IF results revealed that intrathecal injection of the KCC2 activator significantly increased GABAAR and KCC2 expression in the SCDH of HP model rats(P<0.01)and that GABAAR and KCC2 were co-expressed in the same SCDH cells.Compared to the Car+PGE2 group,EA intervention significantly increased MWTs from 48 to 72 hours after the first injection and 4,24,and 48 hours after the second injection(P<0.01).EA upregulated GABAAR and KCC2 expression in the SCDH of rats with HP(P<0.05).Intrathecal injection of the KCC2 inhibitor blocked the analgesic effect of EA in HP model rats(P<0.01).Conclusions:In SCDH,KCC2 expression was downregulated,causing downregulation of GABAAR expression and resulting in pain transition.EA upregulates KCC2 and GABAAR expression and prevents pain transition.展开更多
Diabetes mellitus is a major contributor to kidney failure,with diabetic nephro-pathy being a common microvascular complication.The increasing prevalence of diabetes and its complications suggests a rise in associated...Diabetes mellitus is a major contributor to kidney failure,with diabetic nephro-pathy being a common microvascular complication.The increasing prevalence of diabetes and its complications suggests a rise in associated morbidity and mortality.Recent studies highlight increased mortality related to diabetic kidney disease,with disparities across demographic and geographic groups.Novel pharmacological treatments,including sodium-glucose cotransporter 2 inhibitors,non-steroidal mineralocorticoid receptor antagonists,and glucagon-like peptide-1 agonists,offer promise in slowing disease progression and reducing renal mortality.However,the growing epidemics of obesity and diabetes necessitate prioritizing public health policies focused on primary and secondary prevention,along with comprehensive multidisciplinary care.展开更多
The global prevalence of diabetes has surged in recent years,with diabetic kidney disease(DKD)emerging as a major complication.Traditional therapies have had limited success in slowing progression to end-stage kidney ...The global prevalence of diabetes has surged in recent years,with diabetic kidney disease(DKD)emerging as a major complication.Traditional therapies have had limited success in slowing progression to end-stage kidney disease.However,novel therapies,particularly sodium-glucose cotransporter 2(SGLT2)inhibitors and glucagon-like peptide-1(GLP-1)receptor agonists,which were initially developed for hyperglycemia management,have transformed the treatment of obesity,heart failure,cardiovascular disease,and more recently,DKD.SGLT2 inhibitors have consistently and significantly reduced cardiovascular events,albuminuria,and glomerular filtration rate,highlighting their efficacy across diverse clinical presentations for patients with kidney impairment.Although fewer studies have specifically investigated GLP-1 receptor agonists in patients with kidney disease,existing evidence underscores their potential to slow renal disease progression,reduce albuminuria,and improve clinically relevant outcomes.However,further research is needed to better identify patients most likely to benefit from treatment.Together,these therapies represent valuable advancements for DKD,offering significant reductions in morbidity and mortality and shifting the management of the disease by becoming essential pillars for the treatment of these patients.展开更多
Heart failure(HF)with preserved ejection fraction(HFpEF)has exceeded HF with reduced ejection fraction(HFrEF),becoming the most common type of HF.Unlike HFrEF,HFpEF is primarily a chronic low-grade inflammatory proces...Heart failure(HF)with preserved ejection fraction(HFpEF)has exceeded HF with reduced ejection fraction(HFrEF),becoming the most common type of HF.Unlike HFrEF,HFpEF is primarily a chronic low-grade inflammatory process closely associated with metabolic disorders.The coexistence of HFpEF and metabolic dysfunction-associated steatotic liver disease(MASLD)presents significant clinical challenges due to shared metabolic pathophysiology and complex inter-play.Management strategies for HFpEF and MASLD remain challenging.Sodium-glucose cotransporter 2 inhibitors have shown benefits in managing both conditions.Additionally,glucagon-like peptide-1 receptor agonists are being actively investigated for their potential benefits,particularly in MASLD.A comprehensive,patient-centered approach that combines metabolic and cardiova-scular care is essential for improving outcomes in patients with HFpEF and MASLD,addressing the global metabolic health challenges.展开更多
Type 2 diabetes markedly elevates fracture risk despite normal or high bone mineral density,a paradox reflecting qualitative skeletal deficits rather than loss of mass.Chronic hyperglycemia fosters the accumulation of...Type 2 diabetes markedly elevates fracture risk despite normal or high bone mineral density,a paradox reflecting qualitative skeletal deficits rather than loss of mass.Chronic hyperglycemia fosters the accumulation of advanced glycation end products in bone;their nonenzymatic crosslinks stiffen type I collagen,impair mineralization,and erode mechanical strength.By engaging the receptor for advanced glycation end products,these adducts activate nuclear factorκB and mitogen-activated protein kinase cascades,amplifying oxidative stress,inflammation,osteoblast dysfunction,and osteoclastogenesis.This review synthesizes epidemiological data from type 1 and type 2 diabetes,highlights the limits of densitybased skeletal assessment,and details the molecular pathology of the glycation-collagen axis.It also appraises antiglycation therapies,including formation inhibitors,crosslink breakers and receptor antagonists,with a particular focus on sodium-glucose cotransporter 2 inhibitors that couple glycemic control with modulation of the glycation pathway.By integrating recent basic and clinical advances,we propose a mechanistic framework for diabetic bone disease and outline strategies to mitigate glycationdriven skeletal fragility.展开更多
Feasible and effective cell models for hepatitis B virus(HBV) infection are required for investigating the complete lifecycle of this virus, including the early steps of viral entry. Resistance to dimethyl sulfoxide/p...Feasible and effective cell models for hepatitis B virus(HBV) infection are required for investigating the complete lifecycle of this virus, including the early steps of viral entry. Resistance to dimethyl sulfoxide/polyethylene glycol(DMSO/PEG), h NTCP expression, and a differentiated state are the limiting factors for successful HBV infection models. In the present study, we used a hepatoma cell line(Hu7^(hDNTCPh)) to overcome these limiting factors so that it exhibits excellent susceptibility to HBV infection. To achieve this goal, different hepatoma cell lines were tested with 2.5% DMSO/4%PEG8000, and one resistant cell line(Huh7 D) was used to construct a stable h NTCP-expressing cell line(Hu7^(hDNTCPh)) using a recombinant lentivirus system. Then, the morphological characteristics and differentiation molecular markers of Hu7^(hDNTCPh) cells with or without DMSO treatment were characterized. Finally, the susceptibility of Hu7^(hDNTCPh) cells to HBV infection was assessed. Our results showed that Huh7 D cells were resistant to 2.5% DMSO/4% PEG8000, whereas the others were not. Hu7^(hDNTCPh) cells were established to express a high level of h NTCP compared to liver extracts, and Hu7^(hDNTCPh) cells rapidly transformed into a non-dividing, well-differentiated polarized phenotype under DMSO treatment. Hu7^(hDNTCPh) cells fully supported the entire lifecycle of HBV infection. This cell culture system will be useful for the analysis of host-virus interactions, which should facilitate the discovery of antiviral drugs and vaccines.展开更多
Currently, hepatitis B virus(HBV), upon attaching to human hepatocytes, is considered to interact first with heparan sulfate proteoglycan(HSPG) via an antigenic loop of HBV envelope S protein. Then, it is promptly tra...Currently, hepatitis B virus(HBV), upon attaching to human hepatocytes, is considered to interact first with heparan sulfate proteoglycan(HSPG) via an antigenic loop of HBV envelope S protein. Then, it is promptly transferred to the sodium taurocholate cotransporting polypeptide(NTCP) via the myristoylated N-terminal sequence of pre-S1 region(from Gly-2 to Gly-48, HBV genotype D), and it finally enters the cell by endocytosis. However, it is not clear how HSPG passes HBV to NTCP and how NTCP contributes to the cellular entry of HBV. Owing to the poor availability and the difficulty of manipulations, including fluorophore encapsulation, it has been nearly impossible to perform biochemical and cytochemical analyses using a substantial amount of HBV. A bio-nanocapsule(BNC), which is a hollow nanoparticle consisting of HBV envelope L protein, was efficiently synthesized in Saccharomyces cerevisiae. Since BNC could encapsulate payloads(drugs, genes, proteins) and specifically enter human hepatic cells utilizing HBV-derived infection machinery, it could be used as a model of HBV infection to elucidate the early infection machinery. Recently, it was demonstrated that the N-terminal sequence of pre-S1 region(from Asn-9 to Gly-24) possesses low p H-dependent fusogenic activity, which might play a crucial role in the endosomal escape of BNC payloads and in the uncoating process of HBV. In this minireview, we describe a model in which each domain of the HBV L protein contributes to attachment onto human hepatic cells through HSPG, initiation of endocytosis, interaction with NTCP in endosomes, and consequent provocation of membrane fusion followed by endosomal escape.展开更多
Hepatitis B virus(HBV)is a primary cause of chronic liver diseases in humans.HBV infection exhibits strict host and tissue tropism.HBV core promoter(Cp)drives transcription of pregenomic RNA(pg RNA)and plays a key rol...Hepatitis B virus(HBV)is a primary cause of chronic liver diseases in humans.HBV infection exhibits strict host and tissue tropism.HBV core promoter(Cp)drives transcription of pregenomic RNA(pg RNA)and plays a key role in the viral life cycle.Hepatocyte nuclear factor 4α(HNF4α)acts as a major transcriptional factor that stimulates Cp.In this work,we reported that BEL7404 cell line displayed a high efficiency of DNA transfection and high levels of HBV antigen expression after transfection of HBV replicons without prominent viral replication.The introduction of exogenous HNF4αand human sodium taurocholate cotransporting polypeptide(h NTCP)expression into BEL7404made it permissive for HBV replication and susceptible to HBV infection.BEL7404-derived cell lines with induced HBV permissiveness and susceptibility were constructed by stable co-transfection of h NTCP and Tet-inducible HNF4αfollowed by limiting dilution cloning.HBV replication in such cells was sensitive to inhibition by nucleotide analog tenofovir,while the infection was inhibited by HBV entry inhibitors.This cell culture system provides a new and additional tool for the study of HBV replication and infection as well as the characterization of antiviral agents.展开更多
基金supported by National Science and Technology Major Project of the Ministry of Science and Technology of China(No.2018ZX09735005)the National Natural Science Foundation of China(Nos.81922064,81874290,81673290,81803347 and 81903502)+1 种基金the Natural Science Foundation of Guangdong Province(No.2018A030313707)Post-Doctor Research Project,West China Hospital,Sichuan University(No.2019HXBH034)。
文摘Sodium taurocholate cotransporting polypeptide(NTCP)is identified as the functional receptor for HBV entry,which is responsible for upregulated HBV transcription in the HBV life cycle.Besides,NTCP is also implicated in the progression of HBV-induced hepatocellular carcinoma(HCC).Thereby,NTCP-targeting entry inhibitors are proposed to suppress HBV infection and replication in HBV-induced hepatoma therapy.Herein,we integrated in silico screening and chemical synthesis to obtain a small-molecule NTCP inhibitor B7,which exhibited moderate anti-proliferative activities against HepG2 cells and anti-HBV activity in vitro.Additionally,CETSA assay,molecular docking,and MD simulation validated that B7 could bind to NTCP.Furthermore,western blot analysis demonstrated that B7 induced apoptosis with an increased expression of Bax and caspase 3 cleaving as well as a decreasing expression of Bcl-2 in HepG2 cells.Taken together,our study identified B7 as a novel NTCP inhibitor with anti-proliferation activities which might provide a new opportunity for HCC therapy.
基金supported by the National Key R&D Program of China(2022YFA1303600)National Natural Science Foundation of China[No.22137002 to Y.D.,No.92353303,22277010 and 22477013 to Z.G.,No.U23A20472 and 82273423 to J.C.,No.82302507 to H.Y.]+5 种基金Ministry of Human Resources and Social Security Funding Scheme for High-Level Overseas Chinese Students’Return of China[to Z.G.]China Postdoctoral Science Foundation[No.2021T140784 and 2020M683638XB to J.H.]Natural Science Foundation of Chongqing[No.CSTB2022NSCQ-MSX1061 to Z.G.]Chongqing Postdoctoral Science Foundation[No.CSTB2022NSCQ-BHX0616 to J.H.]CQMU Program for Youth Innovation in Future Medicine[No.W0074 to Z.G.]Joint Project of Pinnacle Disciplinary Group of the Second Affiliated Hospital of Chongqing Medical University.
文摘Dear Editor,Chronic hepatitis B virus(HBV)is a global health problem closely associated with a spectrum of liver diseases.Current clinical treatment options for HBV infection are generally not curative,highlighting the need for the development of novel therapeutics.Sodium taurocholate cotransporting polypeptide(NTCP)was identified as a functional receptor for HBV entry,making it a promising therapeutic target for developing novel anti-HBV agents.
文摘The kidneys play a critical role in maintaining glucose homeostasis.Under normal renal tubular function,most of the glucose filtered from the glomeruli is re-absorbed in the proximal tubules,leaving only trace amounts in the urine.Glycosuria can occur as a symptom of generalized proximal tubular dysfunction or when the reabsorption threshold is exceeded or the glucose threshold is reduced,as seen in familial renal glycosuria(FRG).FRG is characterized by persistent glycosuria despite normal blood glucose levels and tubular function and is primarily associated with mutations in the sodium/glucose cotransporter 5A2 gene,which encodes the sodium-glucose cotransporter(SGLT)2.Inhibiting SGLTs has been proposed as a novel treatment strategy for diabetes,and since FRG is often considered an asymptomatic and benign condition,it has inspired preclinical and clinical studies using SGLT2 inhibitors in type 2 diabetes.However,patients with FRG may exhibit clinical features such as lower body weight or height,altered systemic blood pressure,diaper dermatitis,amino-aciduria,decreased serum uric acid levels,and hypercalciuria.Further research is needed to fully understand the pathophysiology,molecular genetics,and clinical manifestations of renal glucosuria.
基金the National Key Research and Development Program of China(2021YFD2000600)the National Natural Science Foundation of China(32071914)+1 种基金the Modern Agricultural Industry Technology System of China(CARS-170405)the Key Research and Development Program(Science and Technology Demonstration Project)project of Shandong Province(2022SFGC0202).
文摘To achieve an unmanned rice farm,in this study,a cotransporter system was developed using a tracked rice harvester and transporter for autonomous harvesting,unloading,and transportation.Additionally,two unloading and transportation modes—harvester waiting for unloading(HWU)and transporter fol-lowing for unloading(TFU)—were proposed,and a harvesting-unloading-transportation(HUT)strategy was defined.By breaking down the main stages of the collaborative operation,designing module-state machines(MSMs),and constructing state-transition chains,a HUT collaborative operation logic frame-work suitable for the embedded navigation controller was designed using the concept and method of the finite-state machine(FSM).This method addresses the multiple-stage,nonsequential,and complex processes in HUT collaborative operations.Simulations and field-harvesting experiments were performed to evaluate the applicability of this proposed strategy and system.The experimental results showed that the HUT collaborative operation strategy effectively integrated path planning,path-tracking control,inter-vehicle communication,collaborative operation control,and implementation control.The cotrans-porter system completed the entire process of harvesting,unloading,and transportation.The field-harvesting experiment revealed that a harvest efficiency of 0.42 hm^(2)·h^(−1) was achieved.This study can provide insight into collaborative harvesting and solutions for the harvesting process of unmanned farms.
文摘This article discusses the study by GrubićRotkvićet al on the mechanisms of action of sodium-glucose cotransporter 2 inhibitors(SGLT2i)in patients with type 2 diabetes mellitus(T2DM)and heart failure(HF).T2DM and HF are highly comorbid,with a significantly increased prevalence of HF in patients with T2DM.SGLT2i exhibit potential in reducing hospitalization rates for HF and cardiovascular mortality through multiple mechanisms,including improving blood glucose control,promoting urinary sodium excretion,reducing sympathetic nervous system activity,lowering both preload and afterload on the heart,alleviating inflammation and oxidative stress,enhancing endothelial function,improving myocardial energy metabolism,and stabilizing cardiac ion homeostasis.Further research and clinical practice will help optimize the use of SGLT2i in HF patients.
文摘BACKGROUND Mizagliflozin(MIZ)is a specific inhibitor of sodium-glucose cotransport protein 1(SGLT1)originally developed as a medication for diabetes.AIM To explore the impact of MIZ on diabetic nephropathy(DN).METHODS Diabetic mice were created using db/db mice.They were administered either a low dose(0.5 mg/kg)or a high dose(1.0 mg/kg)of the SGLT1 inhibitor MIZ via stomach gavage for 8 weeks.Subsequently,mesangial cells(MCs)were isolated and subjected to high glucose conditions in culture to assess the effects of MIZ on DN.RESULTS The results showed that low doses of MIZ significantly reduced albuminuria to a level comparable to that achieved with high doses in db/db mice.High doses of MIZ led to a substantial increase in body weight in mice,along with decreased blood glucose levels and food intake.Moreover,the intervention with high-dose MIZ notably decreased the expression of extracellular matrix genes,such as collagen type 1 alpha 1 mRNA levels.While the expression of SGLT1 increased after exposure to high glucose,it decreased following treatment with MIZ.Furthermore,MIZ intervention was more effective in improving lactate dehydrogenase levels in MCs induced by high glucose compared to canagliflozin.MIZ also significantly elevated levels of antioxidant enzymes superoxide dismutase,catalase,and glutathione,while reducing malondialdehyde levels.CONCLUSION These findings indicate that MIZ can ameliorate DN by inhibiting SGLT1,inflammation,and oxidative stress.
文摘Heart failure(HF),which falls outside of the historical macrovascular or microvascular categorizations of diabetes complications,has been overlooked for long time in diabetic patients,despite its increasing prevalence and mortality.As originally stated in the Framingham studies,diabetes is associated with an increased risk of HF.Subsequent studies not only corroborated these findings but also identified HF as the most frequent first onset of cardiovascular involvement.The paramount role of proper management of common modifiable risk factors such as hypertension,obesity,dyslipidemia and smoking,became rapidly clear.Conversely,the impact of intensive glycemic control was more contentious.A large meta-analysis of randomized controlled trials reported a lack of effect of strict glycemic control as compared to standard care on HF-related outcomes.The considerable heterogeneity of the effect estimate and the higher risk conferred by thiazolidinediones suggested that mechanism of action of antidiabetic drugs played a key role.Furthermore,the safety concerns of pioglitazone led Food and Drug Administration to release a guidance for drug manufacturers stating that cardiovascular risk should be comprehensively evaluated during drug development.Surprisingly,in just a few years,large cardiovascular outcome trials established the beneficial cardiovascular effects of sodium-glucose cotransporter 2 inhibitors.These effects were consistent regardless diabetes and ejection fraction.Therefore,scientific community started to question the glucose-lowering and diuretic properties of sodium-glucose cotransporter 2 inhibitors as the unique mechanisms for improved outcomes.A plenty of preclinical and clinical studies identified several mechanisms besides glucose-lowering effects.However,these mechanistic studies focused on animal models and patients with established HF.If the same mechanisms account for beneficial effects in patients at risk for or with pre-HF is unknown.Grubić Rotkvićet al published an interesting work adding data in early stages HF.
基金supported by the National Natural Science Foundation of China(Nos.52070029 and 51878092)the National Key Research and Development Program of China(No.2023YFC3904103).
文摘In real soil environments,humus,colloids and other components significantly affect pollutant migration behavior.Investigating Tl(I)and kaolinite colloids’cotransport in quartz sand media containing sodium humate(HA-Na)is vital for comprehending Tl(I)migration underground.This study examined the migration of Tl(I)and kaolinite colloids across varying pH levels(5,7),ionic strengths(ISs)(1,5,50 mmol/L),and kaolinite colloid concentra-tions.Results indicate that lower IS and pH promote Tl(I)migration when transported alone.In cotransport system,kaolinite promotes Tl(I)migration under acidic conditions but inhibits it under neutral conditions,except at high kaolinite concentrations,where the effect shifts from inhibition to promotion.This is primarily due to changes in the zeta potential of quartz sand,HA-Na,and kaolinite,as well as Tl(I)adsorption after HA-Na and kaolinite occupy binding sites.Competitive adsorption between cations and Tl(I)also plays a significant role.Conversely,in individual system,higher IS and pH inhibit kaolinite migration,while increased kaolinite concentration promotes it.In cotransport system,Tl(I)promotes kaolinite migration under acidic conditions but inhibits it under neutral conditions,except at low kaolinite concentrations.This relates to changes in the zeta potential between kaolinite and the medium,as well as the retention of HA-Na in the column and its adsorption onto kaolinite.Competitive adsorption and binding site saturation also have an impact.This study enhances understanding of Tl(I)migration by revealing the dual effect of kaolinite colloids under different environmental conditions,contributing to better knowledge of Tl(I)fate and transport in natural environments.
基金Supported by The Basic Research Project of Wenzhou Municipal Science and Technology Bureau,No.Y20240008The Medical Health Science and Technology Project of Zhejiang Provincial Health Commission,No.2024KY138The Key Laboratory of School of Laboratory Medicine and Life Sciences,Wenzhou Medical University of China,No.JS2023003。
文摘In this editorial,we discussed the article published in the recent issue of the World Journal of Diabetes.To understand the effect of mizagliflozin on kidney injury induced by diabetes,we focused on the mechanisms by which high glucose triggers oxidative stress and contributes to kidney injury in diabetes.The high level of unmetabolized glucose reaching the kidney triggers glucose reabsorption by renal tubules,which elevates the cellular glucose level of renal cells.High glucose induces lactate dehydrogenase overexpression and thus shifts glucose metabolism,which causes mitochondrial dysfunction.Mitochondria generate approximately 90%of the reactive oxygen species in cells,whose dysfunction further alters glucose metabolism and enhances reactive oxygen species generation.Oxidative stress stimulates proinflammatory factor production and kidney inflammatory injury.Mizagliflozin decreases glucose reabsorption and thus ameliorates diabetes-induced kidney injury.
文摘Sodium-glucose cotransporter 2(SGLT2)inhibitors compete with the SGLT2 protein for glucose binding in the renal tubules,reducing glucose reabsorption in the kidneys.This in turn leads to increased excretion of glucose,sodium,and water into the urine.These inhibitors,initially developed for diabetes management,have shown potential benefits beyond glycemic control,impacting liver health through various mechanisms.They have emerged as promising agents in managing liver conditions,including fatty liver disease,cirrhosis,and the prevention of hepatocellular carcinoma(HCC).They modulate processes like oxidative stress,inflammation,and autophagy,which are implicated in metabolic dysfunction-associated steatotic liver disease pathogenesis,potentially reducing steatosis and inflammation and preventing progression to more severe liver conditions.In patients with liver cirrhosis,SGLT2 inhibitors have been associated with a reduced need for large-volume paracentesis and lower mortality rates,indicating their potential in managing diuretic-resistant ascites.SGLT2 inhibitors have shown potential in modulating molecular pathways involved in HCC,such as inflammatory responses and oxidative stress,that could justify their use in the prevention of HCC and improving survival in patients with HCC.The present review synthesized findings from multiple studies to elucidate the role of SGLT2 inhibitors in these liver conditions.
文摘The study by Lin et al delves into the clinical impact of dapagliflozin,a repre-sentative sodium-glucose cotransporter 2(SGLT2)inhibitor,on chronic heart failure complicated by hyperuricemia.This investigation highlights dapagliflo-zin’s efficacy in lowering serum uric acid levels,enhancing cardiac function,and reducing cardiovascular events.This work not only provides a comprehensive analysis of dapagliflozin’s sustained benefits in these patients but also introduces novel insights for managing chronic heart failure exacerbated by elevated uric acid.Furthermore,this review examines the potential role of SGLT2 inhibitor in the context of gout,evaluating its mechanisms and clinical application prospects in the management of hyperuricemia,thereby further enriching the medical community’s understanding of SGLT2 inhibitor.
文摘BACKGROUND The use of sodium-glucose cotransporter 2(SGLT2)inhibitor in heart failure(HF)patients is increasing significantly,regardless of whether they have a history of diabetes.The effects of SGLT2 inhibitor on HF are likely mediated through multiple mechanisms,including suppression of the renin-angiotensin-aldosterone system(RAAS),reduction in oxidative stress leading to enhanced myocardial efficiency,and attenuation of adverse cardiac remodeling by preventing fibrosis.These pathways are fundamental to reducing mortality,improving patients'quality of life,and alleviating the burden on the United States healthcare system by decreasing HF-related hospitalizations.AIM To evaluate SGLT2 inhibitor effects on HF,focusing on hospitalization for HF(HHF),cardiovascular(CV)deaths,and all-cause mortality.METHODS A comprehensive search was conducted in PubMed for randomized controlled trials(RCTs)evaluating the effects of SGLT2 inhibitor in HF patients compared to placebo,covering the period from January 1,2014,to January 1,2025.The primary outcomes assessed were HHF,CV deaths,and all-cause mortality.RevMan Web 5.4.1 was used to assess the risk of bias heterogeneity and to perform the statistical analyses.A random-effects model was employed for all statistical evaluations.RESULTS A total of nine RCTs were included in this analysis:DELIVER,DECLARE-TIMI 58,DAPA-HF,EMPA-REG OUTCOME,EMPEROR-Reduced,EMPEROR-Preserved,SOLOIST-WHF,EMPULSE,and VERTIS-CV.For HHF,eight trials(excluding the SOLOIST-WHF;n=25906)were pooled,while CV deaths were assessed using data from eight trials(excluding the EMPULSE;n=26598).Compared to placebo,SGLT2 inhibitor significantly reduced the risk of HHF(relative risk:0.74;95%CI:0.71-0.77;P<0.00001)and CV death(odds ratio:0.88;95%CI:0.83-0.92;P=0.0006).All nine trials(n=27128)were included in the analysis of all-cause mortality.SGLT2 inhibitor were associated with a statistically significant reduction in all-cause mortality compared to placebo(OR:0.91;95%CI:0.84-0.98;P=0.02).CONCLUSION These results suggest that SGLT2 inhibitor significantly reduce the risk of hospitalization for HF,CV deaths,and all-cause mortality.
基金supported by the Natural Science Foundation of Zhejiang Province(No.LY23H270007)。
文摘Objective:Preventing the transition from acute to chronic pain(pain transition)is a new strategy for treating chronic pain.The present study aimed to investigate the role of K+-Cl−Cotransporter Isoform 2(KCC2)andγ-aminobutyric acid receptor type A(GABAAR)in the spinal cord dorsal horn(SCDH)in pain transition and the intervention effect of electroacupuncture(EA),and to understand the mechanism of EA in preventing acute and chronic pain transition in the spinal center.Methods:A rat model of hyperalgesic priming(HP)was established by injecting carrageenan(Car)into the plantar area of rats,followed by the injection of prostaglandin E2(PGE2)into the dorsal foot 7 days later.The GABAAR agonist(muscimol)and KCC2 activator(CLP257)were intrathecally injected for three consecutive days after PGE2 injection.EA was applied at a frequency of 2/100 Hz to the bilateral foot Zusanli(ST36)and Kunlun(BL60).A von Frey filament was used to detect the pain threshold in each group of rats.Western blotting(WB)and immunofluorescence(IF)were used to detect GABAAR and KCC2 expression in each rats group.By combining EA intervention with a KCC2 inhibitor(VU0240551),we explored the mechanism of pain transition of EA regulation of GABAAR and KCC2 expression in SCDH.Results:The HP model was established by injecting mice with Car/PGE2.Compared to the normal saline(NS)+NS and NS+PGE2 groups,the pain threshold of the Car+PGE2 group decreased significantly 48 hours after PGE2 injection(P<0.01).The WB results indicated that intrathecal injection of a GABAAR agonist upregulated GABAAR expression in the SCDH of HP model rats(P<0.05).WB and IF results revealed that intrathecal injection of the KCC2 activator significantly increased GABAAR and KCC2 expression in the SCDH of HP model rats(P<0.01)and that GABAAR and KCC2 were co-expressed in the same SCDH cells.Compared to the Car+PGE2 group,EA intervention significantly increased MWTs from 48 to 72 hours after the first injection and 4,24,and 48 hours after the second injection(P<0.01).EA upregulated GABAAR and KCC2 expression in the SCDH of rats with HP(P<0.05).Intrathecal injection of the KCC2 inhibitor blocked the analgesic effect of EA in HP model rats(P<0.01).Conclusions:In SCDH,KCC2 expression was downregulated,causing downregulation of GABAAR expression and resulting in pain transition.EA upregulates KCC2 and GABAAR expression and prevents pain transition.
文摘Diabetes mellitus is a major contributor to kidney failure,with diabetic nephro-pathy being a common microvascular complication.The increasing prevalence of diabetes and its complications suggests a rise in associated morbidity and mortality.Recent studies highlight increased mortality related to diabetic kidney disease,with disparities across demographic and geographic groups.Novel pharmacological treatments,including sodium-glucose cotransporter 2 inhibitors,non-steroidal mineralocorticoid receptor antagonists,and glucagon-like peptide-1 agonists,offer promise in slowing disease progression and reducing renal mortality.However,the growing epidemics of obesity and diabetes necessitate prioritizing public health policies focused on primary and secondary prevention,along with comprehensive multidisciplinary care.
基金Supported by Industrial Technological Initiation Scholarship of National Council for Scientific and Technological Development,CNPq,Brazil,No.0932204294929829 and No.7414780530977345the Scientific Initiation Scholarship Programme(PIBIC)of National Council for Scientific and Technological Development,CNPq,Brazil,No.5763023359532159,No.6472982965854452,and No.7340128440641417the CNPq Research Productivity Fellow,No.4357511882624145.
文摘The global prevalence of diabetes has surged in recent years,with diabetic kidney disease(DKD)emerging as a major complication.Traditional therapies have had limited success in slowing progression to end-stage kidney disease.However,novel therapies,particularly sodium-glucose cotransporter 2(SGLT2)inhibitors and glucagon-like peptide-1(GLP-1)receptor agonists,which were initially developed for hyperglycemia management,have transformed the treatment of obesity,heart failure,cardiovascular disease,and more recently,DKD.SGLT2 inhibitors have consistently and significantly reduced cardiovascular events,albuminuria,and glomerular filtration rate,highlighting their efficacy across diverse clinical presentations for patients with kidney impairment.Although fewer studies have specifically investigated GLP-1 receptor agonists in patients with kidney disease,existing evidence underscores their potential to slow renal disease progression,reduce albuminuria,and improve clinically relevant outcomes.However,further research is needed to better identify patients most likely to benefit from treatment.Together,these therapies represent valuable advancements for DKD,offering significant reductions in morbidity and mortality and shifting the management of the disease by becoming essential pillars for the treatment of these patients.
基金Supported by Wenzhou Science Technology Bureau Foundation,No.2022Y0726.
文摘Heart failure(HF)with preserved ejection fraction(HFpEF)has exceeded HF with reduced ejection fraction(HFrEF),becoming the most common type of HF.Unlike HFrEF,HFpEF is primarily a chronic low-grade inflammatory process closely associated with metabolic disorders.The coexistence of HFpEF and metabolic dysfunction-associated steatotic liver disease(MASLD)presents significant clinical challenges due to shared metabolic pathophysiology and complex inter-play.Management strategies for HFpEF and MASLD remain challenging.Sodium-glucose cotransporter 2 inhibitors have shown benefits in managing both conditions.Additionally,glucagon-like peptide-1 receptor agonists are being actively investigated for their potential benefits,particularly in MASLD.A comprehensive,patient-centered approach that combines metabolic and cardiova-scular care is essential for improving outcomes in patients with HFpEF and MASLD,addressing the global metabolic health challenges.
基金Supported by Clinical Medical Research Fund of the Zhejiang Medical Association,No.2025ZYC-Z32Henan Provincial Key Research and Development Program,No.231111311000+1 种基金Henan Provincial Science and Technology Research Project,No.232102310411Clinical Medical Research Fund of the Zhejiang Medical Association,2024ZYC-Z30.
文摘Type 2 diabetes markedly elevates fracture risk despite normal or high bone mineral density,a paradox reflecting qualitative skeletal deficits rather than loss of mass.Chronic hyperglycemia fosters the accumulation of advanced glycation end products in bone;their nonenzymatic crosslinks stiffen type I collagen,impair mineralization,and erode mechanical strength.By engaging the receptor for advanced glycation end products,these adducts activate nuclear factorκB and mitogen-activated protein kinase cascades,amplifying oxidative stress,inflammation,osteoblast dysfunction,and osteoclastogenesis.This review synthesizes epidemiological data from type 1 and type 2 diabetes,highlights the limits of densitybased skeletal assessment,and details the molecular pathology of the glycation-collagen axis.It also appraises antiglycation therapies,including formation inhibitors,crosslink breakers and receptor antagonists,with a particular focus on sodium-glucose cotransporter 2 inhibitors that couple glycemic control with modulation of the glycation pathway.By integrating recent basic and clinical advances,we propose a mechanistic framework for diabetic bone disease and outline strategies to mitigate glycationdriven skeletal fragility.
基金supported by the National Natural Science Foundation of China (Grant number: 81601760, 31621061 and 81461130019)General Financial Grant from the China Postdoctoral Science Foundation (Grant number: 2016M602587)+1 种基金the Shenzhen Foundation of Science and Technology (Grant number: JCYJ20160425 104534335)supported by the Youth Innovation Promotion Association CAS (No.201603)
文摘Feasible and effective cell models for hepatitis B virus(HBV) infection are required for investigating the complete lifecycle of this virus, including the early steps of viral entry. Resistance to dimethyl sulfoxide/polyethylene glycol(DMSO/PEG), h NTCP expression, and a differentiated state are the limiting factors for successful HBV infection models. In the present study, we used a hepatoma cell line(Hu7^(hDNTCPh)) to overcome these limiting factors so that it exhibits excellent susceptibility to HBV infection. To achieve this goal, different hepatoma cell lines were tested with 2.5% DMSO/4%PEG8000, and one resistant cell line(Huh7 D) was used to construct a stable h NTCP-expressing cell line(Hu7^(hDNTCPh)) using a recombinant lentivirus system. Then, the morphological characteristics and differentiation molecular markers of Hu7^(hDNTCPh) cells with or without DMSO treatment were characterized. Finally, the susceptibility of Hu7^(hDNTCPh) cells to HBV infection was assessed. Our results showed that Huh7 D cells were resistant to 2.5% DMSO/4% PEG8000, whereas the others were not. Hu7^(hDNTCPh) cells were established to express a high level of h NTCP compared to liver extracts, and Hu7^(hDNTCPh) cells rapidly transformed into a non-dividing, well-differentiated polarized phenotype under DMSO treatment. Hu7^(hDNTCPh) cells fully supported the entire lifecycle of HBV infection. This cell culture system will be useful for the analysis of host-virus interactions, which should facilitate the discovery of antiviral drugs and vaccines.
文摘Currently, hepatitis B virus(HBV), upon attaching to human hepatocytes, is considered to interact first with heparan sulfate proteoglycan(HSPG) via an antigenic loop of HBV envelope S protein. Then, it is promptly transferred to the sodium taurocholate cotransporting polypeptide(NTCP) via the myristoylated N-terminal sequence of pre-S1 region(from Gly-2 to Gly-48, HBV genotype D), and it finally enters the cell by endocytosis. However, it is not clear how HSPG passes HBV to NTCP and how NTCP contributes to the cellular entry of HBV. Owing to the poor availability and the difficulty of manipulations, including fluorophore encapsulation, it has been nearly impossible to perform biochemical and cytochemical analyses using a substantial amount of HBV. A bio-nanocapsule(BNC), which is a hollow nanoparticle consisting of HBV envelope L protein, was efficiently synthesized in Saccharomyces cerevisiae. Since BNC could encapsulate payloads(drugs, genes, proteins) and specifically enter human hepatic cells utilizing HBV-derived infection machinery, it could be used as a model of HBV infection to elucidate the early infection machinery. Recently, it was demonstrated that the N-terminal sequence of pre-S1 region(from Asn-9 to Gly-24) possesses low p H-dependent fusogenic activity, which might play a crucial role in the endosomal escape of BNC payloads and in the uncoating process of HBV. In this minireview, we describe a model in which each domain of the HBV L protein contributes to attachment onto human hepatic cells through HSPG, initiation of endocytosis, interaction with NTCP in endosomes, and consequent provocation of membrane fusion followed by endosomal escape.
基金the National Natural Science Foundation of China(81971921,81971931)the National base cultivation project(20DZ2210404)the Major science and technology project for the prevention and treatment of major infectious diseases(2018ZX10301208)。
文摘Hepatitis B virus(HBV)is a primary cause of chronic liver diseases in humans.HBV infection exhibits strict host and tissue tropism.HBV core promoter(Cp)drives transcription of pregenomic RNA(pg RNA)and plays a key role in the viral life cycle.Hepatocyte nuclear factor 4α(HNF4α)acts as a major transcriptional factor that stimulates Cp.In this work,we reported that BEL7404 cell line displayed a high efficiency of DNA transfection and high levels of HBV antigen expression after transfection of HBV replicons without prominent viral replication.The introduction of exogenous HNF4αand human sodium taurocholate cotransporting polypeptide(h NTCP)expression into BEL7404made it permissive for HBV replication and susceptible to HBV infection.BEL7404-derived cell lines with induced HBV permissiveness and susceptibility were constructed by stable co-transfection of h NTCP and Tet-inducible HNF4αfollowed by limiting dilution cloning.HBV replication in such cells was sensitive to inhibition by nucleotide analog tenofovir,while the infection was inhibited by HBV entry inhibitors.This cell culture system provides a new and additional tool for the study of HBV replication and infection as well as the characterization of antiviral agents.
