α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively dete...α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively determined.The expression of low-density lipoprotein receptor–related protein 1,which is abundantly expressed in neurons and considered to be a multifunctional endocytic receptor,is elevated in the neurons of patients with Parkinson's disease.However,whether there is a direct link between low-density lipoprotein receptor–related protein 1 andα-synuclein aggregation and propagation in Parkinson's disease remains unclear.Here,we established animal models of Parkinson's disease by inoculating monkeys and mice withα-synuclein pre-formed fibrils and observed elevated low-density lipoprotein receptor–related protein 1 levels in the striatum and substantia nigra,accompanied by dopaminergic neuron loss and increasedα-synuclein levels.However,low-density lipoprotein receptor–related protein 1 knockdown efficiently rescued dopaminergic neurodegeneration and inhibited the increase inα-synuclein levels in the nigrostriatal system.In HEK293A cells overexpressingα-synuclein fragments,low-density lipoprotein receptor–related protein 1 levels were upregulated only when the N-terminus ofα-synuclein was present,whereas anα-synuclein fragment lacking the N-terminus did not lead to low-density lipoprotein receptor–related protein 1 upregulation.Furthermore,the N-terminus ofα-synuclein was found to be rich in lysine residues,and blocking lysine residues in PC12 cells treated withα-synuclein pre-formed fibrils effectively reduced the elevated low-density lipoprotein receptor–related protein 1 andα-synuclein levels.These findings indicate that low-density lipoprotein receptor–related protein 1 regulates pathological transmission ofα-synuclein from the striatum to the substantia nigra in the nigrostriatal system via lysine residues in theα-synuclein N-terminus.展开更多
BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis th...BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis through binding to dif-ferent ligands.AIM To evaluate the correlation between single nucleotide polymorphisms(SNPs)of ACVR1C and susceptibility to esophageal squamous cell carcinoma(ESCC)in Chinese Han population.METHODS In this hospital-based cohort study,1043 ESCC patients and 1143 healthy controls were enrolled.Five SNPs(rs4664229,rs4556933,rs77886248,rs77263459,rs6734630)of ACVR1C were assessed by the ligation detection reaction method.Hardy-Weinberg equilibrium test,genetic model analysis,stratified analysis,linkage disequi-librium test,and haplotype analysis were conducted.RESULTS Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC,and those with rs77886248 TA mutant were related with higher risk,especially in older male smokers.In the haplotype analysis,ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC,while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC.CONCLUSION ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC,which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.展开更多
Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0...Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.展开更多
Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has b...Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.展开更多
OBJECTIVE:To explore if Hewei Jiangni granule(和胃降逆颗粒,HWJNG)could regulate esophageal hypersensitivity via stromal interaction molecule 1(STIM1)/transient receptor potential vanilloid subfamily member 1(TRPV1)pat...OBJECTIVE:To explore if Hewei Jiangni granule(和胃降逆颗粒,HWJNG)could regulate esophageal hypersensitivity via stromal interaction molecule 1(STIM1)/transient receptor potential vanilloid subfamily member 1(TRPV1)pathway.METHODS:Qualitative analysis of HWJNG was analysis by high performance of liquid and gas chromatography.In vivo,animal model of non-erosive reflux disease(NERD)was established by fructose intake and restraint stress.HWJNG and Omeprazole were administered by gavage to the drug intervention group.Reflux and visceral hypersensitivity were analyzed by pathological changes,PH value test,mechanical paw withdrawal threshold,thermal withdrawal latency and mast cells(MCs)degranulation.In vitro,substance P(SP)-induced P815 cells and dorsal root ganglion(DRG)cells were cocultured.Expression in both mice and cells of STIM1,TRPV1,and esophageal visceral hypersensitivity-related gastrointestinal neurochemicals were validated by enzyme linked immunosorbent assays,quantitative realtime polymerase chain reaction(qRT-PCR)and Western blot.Moreover,overexpression and small interfering RNA against STIM1 were utilized to verify of the role of HWJNG in DRG cells.RESULTS:HWJNG significantly suppressed intercellular space widening,injury of mitochondrial,MCs degranulation,mechanical allodynia and heat neuropathic sensory and increased pH value of esophageal mucosa in NERD mice.HWJNG inhibited expression of visceral hypersensitivityrelated gastrointestinal neurochemicals in esophageal mucosa and activated P815 cells,and expression of the STIM1,TRPV1 and related neurotransmitters in DRG and DRG cells.STIM1 siRNA and HWJNG both reduced P815 cells adhesion to DRGs cells and Ca2+flow into the cytoplasmic space of DRG cells.Furthermore,HWJNG could reversed STIM1 overexpression induced upregulation of TRPV1.CONCLUSION:HWJNG suppressed intercellular space widening in NERD mice,stabilized MCs and restored neuronal hyperexcitability by regulating visceral hypersensitivity via STIM1/TRPV1 pathway.展开更多
Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially...Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially among patients with poor functional outcomes.ICH is often accompanied by decreased consciousness and limb dysfunction.This seriously affects patients’ability to live independently.Although rapid advances in neurosurgery have greatly improved patient survival,there remains insufficient evidence that surgical treatment significantly improves long-term outcomes.With in-depth pathophysiological studies after ICH,increasing evidence has shown that secondary injury after ICH is related to long-term prognosis and that the key to secondary injury is various immune-mediated neuroinflammatory reactions after ICH.In basic and clinical studies of various systemic inflammatory diseases,triggering receptor expressed on myeloid cells 1/2(TREM-1/2),and the TREM receptor family is closely related to the inflammatory response.Various inflammatory diseases can be upregulated and downregulated through receptor intervention.How the TREM receptor functions after ICH,the types of results from intervention,and whether the outcomes can improve secondary brain injury and the long-term prognosis of patients are unknown.An analysis of relevant research results from basic and clinical trials revealed that the inhibition of TREM-1 and the activation of TREM-2 can alleviate the neuroinflammatory immune response,significantly improve the long-term prognosis of neurological function in patients with cerebral hemorrhage,and thus improve the ability of patients to live independently.展开更多
Chemotherapy-induced nausea and vomiting(CINV)is common in patients receiving moderately or highly emetogenic chemotherapy and is caused by the activation of peripheral and central nervous system pathways,with the neu...Chemotherapy-induced nausea and vomiting(CINV)is common in patients receiving moderately or highly emetogenic chemotherapy and is caused by the activation of peripheral and central nervous system pathways,with the neurokinin-1 receptor playing a central role in delayed CINV.Neurokinin-1 receptor antagonists(NK1RAs)in combination with other antiemetic agents are recommended in international and Chinese guidelines for the prevention of acute and delayed CINV.Therefore,a summary of current data for NK1RAs would be of great clinical utility.This article summarizes the available clinical and real-world data on the use of NK1RAs in CINV prophylaxis,with a focus on evidence from China,where three NK1RAs,aprepitant,fosaprepitant and netupitant,are currently approved.NK1RAs have demonstrated efficacy and favorable safety in the prevention of acute and delayed CINV.Further research is required to determine the optimal use of these drugs and to identify strategies for CINV management in specific patient populations.展开更多
Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and ...Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and sigma-1 receptor(Sig-1R)-mediated mitochondrial apoptosis in human proximal tubule epithelial-originated kidney-2(HK-2)cells.However,the involvement of Sig-1R in OTA-induced nephrotoxicity,encompassing other forms of regulated cell death like ferroptosis,remains unexplored.In this research,cell viability,apoptotic rate,cholesterol levels,mitochondrial glutathione(mGSH)levels,reactive oxygen species(ROS)levels,and protein expressions in HK-2 cells treated with OTA and/or blarcamesine hydrochloride(Anavex 2-73)were evaluated.The results suggest that OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,subsequently promoting sterol regulatory element-binding protein 2,3-hydroxy-3-methylglutaryl-CoA reductase,GRAM domain-containing protein 1B,steroidogenic acute regulatory protein,mitochondrial,78 kDa glucose-regulated protein,CCAAT/enhancer-binding protein homologous protein,cyclophilin D,cleaved-caspase-3,B-cell lymphoma-2-associated X protein,and long-chain fatty acid-CoA ligase 4,inhibiting tumor necrosis factor receptor-associated protein 1,mitochondrial 2-oxoglutarate/malate carrier protein,B-cell lymphoma-2-like protein 1,and glutathione peroxidase 4,reducing mGSH levels,and increasing total cholesterol,mitochondrial cholesterol,and ROS levels.In conclusion,OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,thereby disrupting redox and cholesterol homeostasis in vitro.The regulation of cholesterol homeostasis by Sig-1R and its involvement in OTA-induced mitochondrial apoptosis and ferroptosis are reported here for the first time.展开更多
The study of ligand-receptor interactions is of great significance in food flavor perception.In this study,a computer simulation method was used to investigate the mechanism of interaction between umami peptides and T...The study of ligand-receptor interactions is of great significance in food flavor perception.In this study,a computer simulation method was used to investigate the mechanism of interaction between umami peptides and T1R1/T1R3-Venus-flytrap domain(VFT)receptor.The binding site,conformational changes,and binding free energy between umami peptides and T1R1/T1R3-VFT were analyzed through molecular modeling,molecular docking,and molecular dynamics simulations.The receptor model constructed using AlphaFold2 has the best rationality.The molecular docking results showed that umami peptides primarily bound to T1R1-VFT through hydrogen bonding,with key binding residues such as Thr149,Arg151,and Asp108.The binding of umami peptides led to a more stable complex system,and the positively charged amino acids contributed positively to the overall binding free energy.This study provides theoretical support for the development of a better understanding of the interaction between umami substances and the umami receptor.展开更多
Obesity is a global pandemic that has been threatening the worldwide population.It has been reported to be associated with an increase in the risk of chronic diseases such as type 2 diabetes mellitus(T2DM),cardiovascu...Obesity is a global pandemic that has been threatening the worldwide population.It has been reported to be associated with an increase in the risk of chronic diseases such as type 2 diabetes mellitus(T2DM),cardiovascular disease,and other diseases,including some malignancies.Currently,the first line of management includes lifestyle modifications.However,recently,bariatric surgeries were introduced to combat obesity.The previous modalities of management are always challenging since lifestyle could have limited long-term effectiveness and difficulty to achieve,and surgeries are invasive and also require a lifestyle modification and commitment.Glucagon-like peptide-1 receptor agonists(GLP-1RAs)were initially introduced as a rising star for managing T2DM,with patients benefiting from the control of blood sugar and weight loss.These medications work by enhancing feelings of fullness,slowing down digestion,and ultimately reducing calorie intake.However,GLP-1RAs are not without side effects and have some costs.Common side effects include gastrointestinal(GI)adverse events such as nausea,vomiting,diarrhea,and a lack of GI motility,which is the main mechanism through which the drug induces a feeling of fullness and promotes weight loss,potentially resulting in treatment discontinuation.More serious,though less frequent,risks include pancreatitis,gallbladder diseases,and,rarely,thyroid Ccell cancers.This review aimed to discuss the globally emerging role of GLP-1RAs in obesity management and highlight some safety considerations for patients taking these drugs.展开更多
The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia.Therefore,macrophage-based therapeutic targets need to be explored for ischemic disease.In the current st...The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia.Therefore,macrophage-based therapeutic targets need to be explored for ischemic disease.In the current study,we found that the mRNA levels of scavenger receptor A1(Sr-a1)were elevated in patients with critical limb ischemia,based on an analysis of the Gene Expression Omnibus data.We then investigated the role and underlying mechanisms of macrophage SR-A1 in a mouse hindlimb ischemia(HLI)model.Compared with the Sr-a1^(fl/fl)mice,the Lyz^(Cre+)/Sr-a1^(flox/flox)(Sr-a1~(ΔMΦ))mice showed significantly reduced laser Doppler blood flow in the ischemic limb on day seven after HLI.Consistently,histological analysis revealed that the ischemic limb of the Sr-a1~(ΔMΦ)mice exhibited more severe and prolonged necrotic morphology,inflammation,fibrosis,decreased vessel density,and delayed regeneration than that of the control Sr-a1~(fl/fl)mice.Furthermore,restoring wild-type myeloid cells to the Sr-a1 knockout mice effectively improved the Doppler perfusion in the ischemic limb and mitigated skeletal muscle damage seven days after HLI.Consistent with these in vivo findings,co-cultivating macrophages with the mouse myoblast cell line C2C12 revealed that the Sr-a1^(-/-)bone marrow macrophages significantly inhibited myoblast differentiation in vitro.Mechanistically,SR-A1 enhanced the skeletal muscle regeneration in response to HLI by inhibiting oncostatin M production via suppression of the NF-κB signaling activation.These findings indicate that SR-A1 may be a promising candidate protein to improve tissue repair and regeneration in peripheral ischemic arterial disease.展开更多
BACKGROUND Atrial fibrillation(AF)stands as the most prevalent type of arrhythmia,affecting approximately 60 million individuals world-wide.Although antiarrhythmic drugs(AADs)remain the gold standard for AF treatment,...BACKGROUND Atrial fibrillation(AF)stands as the most prevalent type of arrhythmia,affecting approximately 60 million individuals world-wide.Although antiarrhythmic drugs(AADs)remain the gold standard for AF treatment,glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are arising as potential therapeutic alternatives.AIM To evaluate the impact of GLP-1 RAs on the incidence of AF.METHODS Inclusion criteria included systematic reviews(SRs)that based their analyses on clinical trials,observational studies,controlled trials and network meta-analyses.A total of 8 SRs were selected for data extraction,focusing on semaglutide,liraglutide and dulaglutide.Additionally,the effects of GLP-1 RAs on AF incidence were compared with those of sodium-glucose co-transporter 2(SGLT2)inhibitors.RESULTS Findings indicate that semaglutide,evaluated in the largest patient cohort across the 8 SRs,consistently reduced AF incidence.However,dulaglutide and liraglutide exhibited inconsistent effects.Notably,as opposed to variable outcomes associated with GLP-1 RAs,SGLT2 inhibitors a class of antidiabetic agents with weight-reducing properties exhibit significant cardiovascular benefits,including reductions in both AF and atrial flutter.CONCLUSION GLP-1 RAs emerge as a promising and potential alternative for AADs in reduction of incidence of AF.However,further research is required to fully determine their therapeutic potential and long-term cardiovascular effects.展开更多
BACKGROUND Yes-associated protein 1(YAP1),a downstream transcriptional coactivator regulated by the Hippo signaling pathway,has been shown to be involved in liver fibrosis.YAP activity is modulated by G-protein couple...BACKGROUND Yes-associated protein 1(YAP1),a downstream transcriptional coactivator regulated by the Hippo signaling pathway,has been shown to be involved in liver fibrosis.YAP activity is modulated by G-protein coupled receptors,including Gαs-coupled protein dopamine receptor D1(DRD1).Levodopa,a dopamine precursor,activates DRD1 on cell surface,triggering its downstream signaling pathway.AIM To investigate the therapeutic effect of levodopa and the downstream mechanism on carbon tetrachloride(CCl_(4))-induced liver fibrosis,including liver DRD1 expression.METHODS SD rats were intraperitoneally injected with 40%CCl_(4)for 8 weeks to induce liver fibrosis,followed by treatment with varying doses of levodopa for 2 weeks.Serum aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels were measured,and liver pathology was assessed using hematoxylin and eosin and Masson's staining.Alpha-smooth muscle actin(α-SMA)content,along with the expressions of DRD1,YAP,and phosphorylated protein,was analyzed by Western blot,immunohistochemistry,and reverse transcription-quantitative real-time polymerase chain reaction.RESULTS Compared with the controls,levodopa-treated rats showed a decrease in the proportion of collagen in the liver and a recovery from liver fibrosis(P=0.0007).Western blot and immunohistochemistry indicated that DRD1 was upregulated in the fibrotic liver of rats treated with levodopa,showing an increase in DRD1 Level(P<0.0001).In addition,the upregulation of DRD1 activated the Hippo signaling pathway,manifested as increased YAP phosphorylation(P<0.05).CONCLUSION This was the first study to demonstrate that levodopa attenuates CCl_(4)-induced liver fibrosis by inhibiting the Hippo/YAP signaling pathways.展开更多
This editorial discusses Christodoulidis et al's article,which appeared in the most recent edition.The clinical trials have demonstrated the programmed cell death receptor 1(PD-1)inhibitor Pembrolizumab involved c...This editorial discusses Christodoulidis et al's article,which appeared in the most recent edition.The clinical trials have demonstrated the programmed cell death receptor 1(PD-1)inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer(AGC).Pembrolizumab combined with chemotherapy can enhance its sensitivity,and further eliminate tumor cells that develop resistance to chemotherapy.The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis.The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy,and the safety is controllable.PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.展开更多
基金supported by the Natural Science Foundation of Guangxi Zhuang Automomous Region,Nos.2019GXNSFDA245015(to MC),2022GXNSFBA035654(to HL)the National Natural Science Foundation of China,Nos.82360241(to MC),82304876(to HL)+1 种基金Scientific Research and Technology Development Project of Guilin City,Nos.20220139-3(to MC),20210218-5(to HL)Guangxi Medical and Health Key Discipline Construction Project(to QL)。
文摘α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively determined.The expression of low-density lipoprotein receptor–related protein 1,which is abundantly expressed in neurons and considered to be a multifunctional endocytic receptor,is elevated in the neurons of patients with Parkinson's disease.However,whether there is a direct link between low-density lipoprotein receptor–related protein 1 andα-synuclein aggregation and propagation in Parkinson's disease remains unclear.Here,we established animal models of Parkinson's disease by inoculating monkeys and mice withα-synuclein pre-formed fibrils and observed elevated low-density lipoprotein receptor–related protein 1 levels in the striatum and substantia nigra,accompanied by dopaminergic neuron loss and increasedα-synuclein levels.However,low-density lipoprotein receptor–related protein 1 knockdown efficiently rescued dopaminergic neurodegeneration and inhibited the increase inα-synuclein levels in the nigrostriatal system.In HEK293A cells overexpressingα-synuclein fragments,low-density lipoprotein receptor–related protein 1 levels were upregulated only when the N-terminus ofα-synuclein was present,whereas anα-synuclein fragment lacking the N-terminus did not lead to low-density lipoprotein receptor–related protein 1 upregulation.Furthermore,the N-terminus ofα-synuclein was found to be rich in lysine residues,and blocking lysine residues in PC12 cells treated withα-synuclein pre-formed fibrils effectively reduced the elevated low-density lipoprotein receptor–related protein 1 andα-synuclein levels.These findings indicate that low-density lipoprotein receptor–related protein 1 regulates pathological transmission ofα-synuclein from the striatum to the substantia nigra in the nigrostriatal system via lysine residues in theα-synuclein N-terminus.
基金Supported by The National Natural Science Foundation of China,No.82350127 and No.82241013the Shanghai Natural Science Foundation,No.20ZR1411600+2 种基金the Shanghai Shenkang Hospital Development Center,No.SHDC2020CR4039the Bethune Ethicon Excellent Surgery Foundation,No.CESS2021TC04Xuhui District Medical Research Project of Shanghai,No.SHXH201805.
文摘BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis through binding to dif-ferent ligands.AIM To evaluate the correlation between single nucleotide polymorphisms(SNPs)of ACVR1C and susceptibility to esophageal squamous cell carcinoma(ESCC)in Chinese Han population.METHODS In this hospital-based cohort study,1043 ESCC patients and 1143 healthy controls were enrolled.Five SNPs(rs4664229,rs4556933,rs77886248,rs77263459,rs6734630)of ACVR1C were assessed by the ligation detection reaction method.Hardy-Weinberg equilibrium test,genetic model analysis,stratified analysis,linkage disequi-librium test,and haplotype analysis were conducted.RESULTS Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC,and those with rs77886248 TA mutant were related with higher risk,especially in older male smokers.In the haplotype analysis,ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC,while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC.CONCLUSION ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC,which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.
基金supported by the National Natural Science Foundation of China,Nos.82204360(to HM)and 82270411(to GW)National Science and Technology Innovation 2030 Major Program,No.2021ZD0200900(to YL)。
文摘Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.
文摘Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.
基金National Natural Science Foundation of China:Study on the Molecular Mechanism of the Regulation of Crypt Goblet Cell Pyroptosis and Exocytosis to Repair Ulcerative Colitis Mucus Barrier by the Method of Clearing and Opening the Xuanfu from the Perspective of"Xuanfu-Crypt"(No.82305143),and National Natural Science Foundation of China:Exploring the Molecular Mechanism of"Hewei Jiangni Fang"Intervention in Non-erosive Reflux Disease Esophageal Hypersensitivity from the Perspective of Mas-related Gene X2/Stromal Interaction Molecule 1/Cell Adhesion Molecule 1 Pathway Regulation of Mast Cell/Dorsal Root Ganglion Communication based on the"Xinkai-Kujiang"Method(No.82374401)。
文摘OBJECTIVE:To explore if Hewei Jiangni granule(和胃降逆颗粒,HWJNG)could regulate esophageal hypersensitivity via stromal interaction molecule 1(STIM1)/transient receptor potential vanilloid subfamily member 1(TRPV1)pathway.METHODS:Qualitative analysis of HWJNG was analysis by high performance of liquid and gas chromatography.In vivo,animal model of non-erosive reflux disease(NERD)was established by fructose intake and restraint stress.HWJNG and Omeprazole were administered by gavage to the drug intervention group.Reflux and visceral hypersensitivity were analyzed by pathological changes,PH value test,mechanical paw withdrawal threshold,thermal withdrawal latency and mast cells(MCs)degranulation.In vitro,substance P(SP)-induced P815 cells and dorsal root ganglion(DRG)cells were cocultured.Expression in both mice and cells of STIM1,TRPV1,and esophageal visceral hypersensitivity-related gastrointestinal neurochemicals were validated by enzyme linked immunosorbent assays,quantitative realtime polymerase chain reaction(qRT-PCR)and Western blot.Moreover,overexpression and small interfering RNA against STIM1 were utilized to verify of the role of HWJNG in DRG cells.RESULTS:HWJNG significantly suppressed intercellular space widening,injury of mitochondrial,MCs degranulation,mechanical allodynia and heat neuropathic sensory and increased pH value of esophageal mucosa in NERD mice.HWJNG inhibited expression of visceral hypersensitivityrelated gastrointestinal neurochemicals in esophageal mucosa and activated P815 cells,and expression of the STIM1,TRPV1 and related neurotransmitters in DRG and DRG cells.STIM1 siRNA and HWJNG both reduced P815 cells adhesion to DRGs cells and Ca2+flow into the cytoplasmic space of DRG cells.Furthermore,HWJNG could reversed STIM1 overexpression induced upregulation of TRPV1.CONCLUSION:HWJNG suppressed intercellular space widening in NERD mice,stabilized MCs and restored neuronal hyperexcitability by regulating visceral hypersensitivity via STIM1/TRPV1 pathway.
基金Supported by Shanxi Provincial Key Research and Development Plan Project,No.2020ZDLSF01-02Doctor Foundation of the Second Affiliated Hospital of Xi’an Medical University,No.X2Y-R11.
文摘Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially among patients with poor functional outcomes.ICH is often accompanied by decreased consciousness and limb dysfunction.This seriously affects patients’ability to live independently.Although rapid advances in neurosurgery have greatly improved patient survival,there remains insufficient evidence that surgical treatment significantly improves long-term outcomes.With in-depth pathophysiological studies after ICH,increasing evidence has shown that secondary injury after ICH is related to long-term prognosis and that the key to secondary injury is various immune-mediated neuroinflammatory reactions after ICH.In basic and clinical studies of various systemic inflammatory diseases,triggering receptor expressed on myeloid cells 1/2(TREM-1/2),and the TREM receptor family is closely related to the inflammatory response.Various inflammatory diseases can be upregulated and downregulated through receptor intervention.How the TREM receptor functions after ICH,the types of results from intervention,and whether the outcomes can improve secondary brain injury and the long-term prognosis of patients are unknown.An analysis of relevant research results from basic and clinical trials revealed that the inhibition of TREM-1 and the activation of TREM-2 can alleviate the neuroinflammatory immune response,significantly improve the long-term prognosis of neurological function in patients with cerebral hemorrhage,and thus improve the ability of patients to live independently.
基金provided technical help and editorial assistance for this manuscriptsupport for this manuscript was also provided by Dr.Sharon Gladwin(Rude Health Consulting Limited)and funded by MSD Chinafunded by MSD China.
文摘Chemotherapy-induced nausea and vomiting(CINV)is common in patients receiving moderately or highly emetogenic chemotherapy and is caused by the activation of peripheral and central nervous system pathways,with the neurokinin-1 receptor playing a central role in delayed CINV.Neurokinin-1 receptor antagonists(NK1RAs)in combination with other antiemetic agents are recommended in international and Chinese guidelines for the prevention of acute and delayed CINV.Therefore,a summary of current data for NK1RAs would be of great clinical utility.This article summarizes the available clinical and real-world data on the use of NK1RAs in CINV prophylaxis,with a focus on evidence from China,where three NK1RAs,aprepitant,fosaprepitant and netupitant,are currently approved.NK1RAs have demonstrated efficacy and favorable safety in the prevention of acute and delayed CINV.Further research is required to determine the optimal use of these drugs and to identify strategies for CINV management in specific patient populations.
基金financially supported by the National Natural Science Foundation of China(3226058782060598)+4 种基金the Scientific Research Program of Guizhou Provincial Department of Education(QJJ[2023]019)the Science&Technology Program of Guizhou Province(QKHPTRC-CXTD[2022]014)the Excellent Youth Talents of Zunyi Medical University(17zy-006)the Innovation and Entrepreneurship Training Program for College Students of China(202210661140)the Innovation and Entrepreneurship Training Program for College Students of Zunyi Medical University(ZYDC2021110).
文摘Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and sigma-1 receptor(Sig-1R)-mediated mitochondrial apoptosis in human proximal tubule epithelial-originated kidney-2(HK-2)cells.However,the involvement of Sig-1R in OTA-induced nephrotoxicity,encompassing other forms of regulated cell death like ferroptosis,remains unexplored.In this research,cell viability,apoptotic rate,cholesterol levels,mitochondrial glutathione(mGSH)levels,reactive oxygen species(ROS)levels,and protein expressions in HK-2 cells treated with OTA and/or blarcamesine hydrochloride(Anavex 2-73)were evaluated.The results suggest that OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,subsequently promoting sterol regulatory element-binding protein 2,3-hydroxy-3-methylglutaryl-CoA reductase,GRAM domain-containing protein 1B,steroidogenic acute regulatory protein,mitochondrial,78 kDa glucose-regulated protein,CCAAT/enhancer-binding protein homologous protein,cyclophilin D,cleaved-caspase-3,B-cell lymphoma-2-associated X protein,and long-chain fatty acid-CoA ligase 4,inhibiting tumor necrosis factor receptor-associated protein 1,mitochondrial 2-oxoglutarate/malate carrier protein,B-cell lymphoma-2-like protein 1,and glutathione peroxidase 4,reducing mGSH levels,and increasing total cholesterol,mitochondrial cholesterol,and ROS levels.In conclusion,OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,thereby disrupting redox and cholesterol homeostasis in vitro.The regulation of cholesterol homeostasis by Sig-1R and its involvement in OTA-induced mitochondrial apoptosis and ferroptosis are reported here for the first time.
基金funded by the National Natural Science Foundation of China(32001824,31972198)supported by the Startup Fund for Young Faculty at SJTU(Shanghai Jiao Tong University)High Level Innovation Team and Distinguished Scholar Project of Guangxi Universities and Colleges(2020[6]).
文摘The study of ligand-receptor interactions is of great significance in food flavor perception.In this study,a computer simulation method was used to investigate the mechanism of interaction between umami peptides and T1R1/T1R3-Venus-flytrap domain(VFT)receptor.The binding site,conformational changes,and binding free energy between umami peptides and T1R1/T1R3-VFT were analyzed through molecular modeling,molecular docking,and molecular dynamics simulations.The receptor model constructed using AlphaFold2 has the best rationality.The molecular docking results showed that umami peptides primarily bound to T1R1-VFT through hydrogen bonding,with key binding residues such as Thr149,Arg151,and Asp108.The binding of umami peptides led to a more stable complex system,and the positively charged amino acids contributed positively to the overall binding free energy.This study provides theoretical support for the development of a better understanding of the interaction between umami substances and the umami receptor.
文摘Obesity is a global pandemic that has been threatening the worldwide population.It has been reported to be associated with an increase in the risk of chronic diseases such as type 2 diabetes mellitus(T2DM),cardiovascular disease,and other diseases,including some malignancies.Currently,the first line of management includes lifestyle modifications.However,recently,bariatric surgeries were introduced to combat obesity.The previous modalities of management are always challenging since lifestyle could have limited long-term effectiveness and difficulty to achieve,and surgeries are invasive and also require a lifestyle modification and commitment.Glucagon-like peptide-1 receptor agonists(GLP-1RAs)were initially introduced as a rising star for managing T2DM,with patients benefiting from the control of blood sugar and weight loss.These medications work by enhancing feelings of fullness,slowing down digestion,and ultimately reducing calorie intake.However,GLP-1RAs are not without side effects and have some costs.Common side effects include gastrointestinal(GI)adverse events such as nausea,vomiting,diarrhea,and a lack of GI motility,which is the main mechanism through which the drug induces a feeling of fullness and promotes weight loss,potentially resulting in treatment discontinuation.More serious,though less frequent,risks include pancreatitis,gallbladder diseases,and,rarely,thyroid Ccell cancers.This review aimed to discuss the globally emerging role of GLP-1RAs in obesity management and highlight some safety considerations for patients taking these drugs.
基金supported by the National Natural Science Foundation of China(Grant Nos.82030012,81670263,82170444,82270476,82270361,and 82100433)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(Grant No.24KJA310003)。
文摘The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia.Therefore,macrophage-based therapeutic targets need to be explored for ischemic disease.In the current study,we found that the mRNA levels of scavenger receptor A1(Sr-a1)were elevated in patients with critical limb ischemia,based on an analysis of the Gene Expression Omnibus data.We then investigated the role and underlying mechanisms of macrophage SR-A1 in a mouse hindlimb ischemia(HLI)model.Compared with the Sr-a1^(fl/fl)mice,the Lyz^(Cre+)/Sr-a1^(flox/flox)(Sr-a1~(ΔMΦ))mice showed significantly reduced laser Doppler blood flow in the ischemic limb on day seven after HLI.Consistently,histological analysis revealed that the ischemic limb of the Sr-a1~(ΔMΦ)mice exhibited more severe and prolonged necrotic morphology,inflammation,fibrosis,decreased vessel density,and delayed regeneration than that of the control Sr-a1~(fl/fl)mice.Furthermore,restoring wild-type myeloid cells to the Sr-a1 knockout mice effectively improved the Doppler perfusion in the ischemic limb and mitigated skeletal muscle damage seven days after HLI.Consistent with these in vivo findings,co-cultivating macrophages with the mouse myoblast cell line C2C12 revealed that the Sr-a1^(-/-)bone marrow macrophages significantly inhibited myoblast differentiation in vitro.Mechanistically,SR-A1 enhanced the skeletal muscle regeneration in response to HLI by inhibiting oncostatin M production via suppression of the NF-κB signaling activation.These findings indicate that SR-A1 may be a promising candidate protein to improve tissue repair and regeneration in peripheral ischemic arterial disease.
文摘BACKGROUND Atrial fibrillation(AF)stands as the most prevalent type of arrhythmia,affecting approximately 60 million individuals world-wide.Although antiarrhythmic drugs(AADs)remain the gold standard for AF treatment,glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are arising as potential therapeutic alternatives.AIM To evaluate the impact of GLP-1 RAs on the incidence of AF.METHODS Inclusion criteria included systematic reviews(SRs)that based their analyses on clinical trials,observational studies,controlled trials and network meta-analyses.A total of 8 SRs were selected for data extraction,focusing on semaglutide,liraglutide and dulaglutide.Additionally,the effects of GLP-1 RAs on AF incidence were compared with those of sodium-glucose co-transporter 2(SGLT2)inhibitors.RESULTS Findings indicate that semaglutide,evaluated in the largest patient cohort across the 8 SRs,consistently reduced AF incidence.However,dulaglutide and liraglutide exhibited inconsistent effects.Notably,as opposed to variable outcomes associated with GLP-1 RAs,SGLT2 inhibitors a class of antidiabetic agents with weight-reducing properties exhibit significant cardiovascular benefits,including reductions in both AF and atrial flutter.CONCLUSION GLP-1 RAs emerge as a promising and potential alternative for AADs in reduction of incidence of AF.However,further research is required to fully determine their therapeutic potential and long-term cardiovascular effects.
文摘BACKGROUND Yes-associated protein 1(YAP1),a downstream transcriptional coactivator regulated by the Hippo signaling pathway,has been shown to be involved in liver fibrosis.YAP activity is modulated by G-protein coupled receptors,including Gαs-coupled protein dopamine receptor D1(DRD1).Levodopa,a dopamine precursor,activates DRD1 on cell surface,triggering its downstream signaling pathway.AIM To investigate the therapeutic effect of levodopa and the downstream mechanism on carbon tetrachloride(CCl_(4))-induced liver fibrosis,including liver DRD1 expression.METHODS SD rats were intraperitoneally injected with 40%CCl_(4)for 8 weeks to induce liver fibrosis,followed by treatment with varying doses of levodopa for 2 weeks.Serum aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels were measured,and liver pathology was assessed using hematoxylin and eosin and Masson's staining.Alpha-smooth muscle actin(α-SMA)content,along with the expressions of DRD1,YAP,and phosphorylated protein,was analyzed by Western blot,immunohistochemistry,and reverse transcription-quantitative real-time polymerase chain reaction.RESULTS Compared with the controls,levodopa-treated rats showed a decrease in the proportion of collagen in the liver and a recovery from liver fibrosis(P=0.0007).Western blot and immunohistochemistry indicated that DRD1 was upregulated in the fibrotic liver of rats treated with levodopa,showing an increase in DRD1 Level(P<0.0001).In addition,the upregulation of DRD1 activated the Hippo signaling pathway,manifested as increased YAP phosphorylation(P<0.05).CONCLUSION This was the first study to demonstrate that levodopa attenuates CCl_(4)-induced liver fibrosis by inhibiting the Hippo/YAP signaling pathways.
基金Supported by Jilin Provincial Natural Science Foundation,No.YDZJ202401650ZYTS。
文摘This editorial discusses Christodoulidis et al's article,which appeared in the most recent edition.The clinical trials have demonstrated the programmed cell death receptor 1(PD-1)inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer(AGC).Pembrolizumab combined with chemotherapy can enhance its sensitivity,and further eliminate tumor cells that develop resistance to chemotherapy.The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis.The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy,and the safety is controllable.PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.
