Ischemic stroke is a major cause of neurological deficits and high disability rate.As the primary immune cells of the central nervous system,microglia play dual roles in neuroinflammation and tissue repair following a...Ischemic stroke is a major cause of neurological deficits and high disability rate.As the primary immune cells of the central nervous system,microglia play dual roles in neuroinflammation and tissue repair following a stroke.Their dynamic activation and polarization states are key factors that influence the disease process and treatment outcomes.This review article investigates the role of microglia in ischemic stroke and explores potential intervention strategies.Microglia exhibit a dynamic functional state,transitioning between pro-inflammatory(M1)and anti-inflammatory(M2)phenotypes.This duality is crucial in ischemic stroke,as it maintains a balance between neuroinflammation and tissue repair.Activated microglia contribute to neuroinflammation through cytokine release and disruption of the blood-brain barrier,while simultaneously promoting tissue repair through anti-inflammatory responses and regeneration.Key pathways influencing microglial activation include Toll-like receptor 4/nuclear factor kappa B,mitogen-activated protein kinases,Janus kinase/signal transducer and activator of transcription,and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathways.These pathways are targets for various experimental therapies aimed at promoting M2 polarization and mitigating damage.Potential therapeutic agents include natural compounds found in drugs such as minocycline,as well as traditional Chinese medicines.Drugs that target these regulatory mechanisms,such as small molecule inhibitors and components of traditional Chinese medicines,along with emerging technologies such as single-cell RNA sequencing and spatial transcriptomics,offer new therapeutic strategies and clinical translational potential for ischemic stroke.展开更多
Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microgl...Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microglia play an important role in secondary injury and can be activated in response to traumatic brain injury.In this article,we review the origin and classification of microglia as well as the dynamic changes of microglia in traumatic brain injury.We also clarify the microglial polarization pathways and the therapeutic drugs targeting activated microglia.We found that regulating the signaling pathways involved in pro-inflammatory and anti-inflammatory microglia,such as the Toll-like receptor 4/nuclear factor-kappa B,mitogen-activated protein kinase,Janus kinase/signal transducer and activator of transcription,phosphoinositide 3-kinase/protein kinase B,Notch,and high mobility group box 1 pathways,can alleviate the inflammatory response triggered by microglia in traumatic brain injury,thereby exerting neuroprotective effects.We also reviewed the strategies developed on the basis of these pathways,such as drug and cell replacement therapies.Drugs that modulate inflammatory factors,such as rosuvastatin,have been shown to promote the polarization of antiinflammatory microglia and reduce the inflammatory response caused by traumatic brain injury.Mesenchymal stem cells possess anti-inflammatory properties,and clinical studies have confirmed their significant efficacy and safety in patients with traumatic brain injury.Additionally,advancements in mesenchymal stem cell-delivery methods—such as combinations of novel biomaterials,genetic engineering,and mesenchymal stem cell exosome therapy—have greatly enhanced the efficiency and therapeutic effects of mesenchymal stem cells in animal models.However,numerous challenges in the application of drug and mesenchymal stem cell treatment strategies remain to be addressed.In the future,new technologies,such as single-cell RNA sequencing and transcriptome analysis,can facilitate further experimental studies.Moreover,research involving non-human primates can help translate these treatment strategies to clinical practice.展开更多
V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating ene...V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown.In this study,we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity(DIO)mice.Under normal chow diet feeding,overexpression of Raf1 in AgRP neurons led to obesity in mice characterized by increased body weight,fat mass,and impaired glucose tolerance.Conversely,Raf1 knockout in AgRP neurons protected against diet-induced obesity,reducing fat mass and improving glucose tolerance.Mechanistically,Raf1 activated the MAPK signaling pathway,culminating in the phosphorylation of cAMP response element-binding protein(CREB),which enhanced transcription of Agrp and Npy.Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis,highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance.Collectively,these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis,positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.展开更多
The nervous system function requires a precise but plastic neural architecture.The neuronal shape dictates how neurons interact with each other and with other cells,being the morphology of dendrites and axons the cent...The nervous system function requires a precise but plastic neural architecture.The neuronal shape dictates how neurons interact with each other and with other cells,being the morphology of dendrites and axons the central determinant of the functional properties of neurons and neural circuits.The topological and structural morphology of axons and dendrites defines and determines how synapses are conformed.The morphological diversity of axon and dendrite arborization governs the neuron’s inputs,synaptic integration,neuronal computation,signal transmission,and network circuitry,hence defining the particular connectivity and function of the different brain areas.展开更多
Banana(Musa spp.),being a globally significant fruit crop,faces a myriad of threats from various diseases,such as Fusarium wilt,Xanthomonas wilt,bunchy top disease,and weevils disease.This review provides an overview ...Banana(Musa spp.),being a globally significant fruit crop,faces a myriad of threats from various diseases,such as Fusarium wilt,Xanthomonas wilt,bunchy top disease,and weevils disease.This review provides an overview of recent advancements in molecular mechanisms and immune signaling pathways underlying disease resistance in banana.First,the review discusses the latest research advances on banana pests and diseases.Subsequently,this review explores the immune responses and signaling pathways,pattern recognition receptor-triggered immunity,effector-triggered immunity,cell death,reactive oxygen species,autophagy,hormonal pathways,and other players involved in bananaedisease interactions.Finally,the review discusses the current understanding of the genetic architecture of disease resistance in banana,focusing on the identification of defense-related genes and quantitative trait loci associated with resistance to major pathogens and offering recommendations for genetic research.The conclusion underscores the significance of research on banana immunity,specifically highlighting the crucial need to identify endogenous resistance genes and elucidate immune signaling pathways for future efforts aimed at breeding disease-resistant banana.This review offers a comprehensive perspective on the molecular mechanisms underlying disease resistance in banana and serves as a valuable reference for breeding efforts aimed at enhancing banana's resistance to pathogens.展开更多
Objective:Artemether is a semi-synthetic derivative of artemisinin and is widely used in the treatment of Plasmodium(P.)falciparum malaria.This study aimed to characterize the safety profile of artemether based on 15-...Objective:Artemether is a semi-synthetic derivative of artemisinin and is widely used in the treatment of Plasmodium(P.)falciparum malaria.This study aimed to characterize the safety profile of artemether based on 15-year data retrived from FDA adverse event reporting system(FAERS).Methods:This is a retrospective analysis on 15-year data of artemether-related adverse effects(AEs)retrieved from the FAERS.AEs were classified according to System Organ Class(SOC)and Preferred Terms(PT).Signal detection was performed using Reporting Odds Ratios(ROR),Proportional Reporting Ratios(PRR),and Empirical Bayes Geometric Mean(EBGM).Stratified analyses examined the impact of demographic factors such as sex,age,and time-to-onset.Temporal patterns and associated risk factors were also investigated.Results:Haemolytic anaemia and haemolysis emerged as the most frequently reported AEs,exhibiting significantly elevated RORs(males:ROR 381.36,95%CI 247.06-588.60;females:ROR 455.11,95%CI 286.43-723.12).Sex-specific differences were evident,with females showing a higher incidence of reproductive-related AEs,including spontaneous abortion and premature labour.Temporal trend analysis revealed that the majority of AEs occurred within the first 30 days after the initiation of artemether administration,indicating a rapid onset.The most affected SOCs were blood and lymphatic system disorders and hepatobiliary disorders.Conclusions:Artemether is associated with a notable frequency of early-onset AEs,particularly hematological and hepatobiliary disorders.The observed sex-specific vulnerability to reproductive AEs highlights the need for sex-conscious clinical approaches.Enhanced post-treatment monitoring and further investigations into the drug’s pharmacokinetics and mechanistic pathways are recommended.展开更多
Tunneling nanotubes are crucial structures for cellular communication and are observed in a variety of cell types.Glial cells,the most abundant cells in the nervous system,play a vital role in intercellular signaling ...Tunneling nanotubes are crucial structures for cellular communication and are observed in a variety of cell types.Glial cells,the most abundant cells in the nervous system,play a vital role in intercellular signaling and can show abnormal activation under pathological conditions.Our bibliometric analysis indicated a substantial increase in research on tunneling nanotubes over the past two decades,highlighting their important role in cellular communication.This review focuses on the formation of tunneling nanotubes in various types of glial cells,including astrocytes,microglia,glioma cells,and Schwann cells,as well as their roles in cellular communication and cargo transport.We found that glial cells influence the stability of the neural system and play a role in nerve regeneration through tunneling nanotubes.Tunneling nanotubes facilitate the transmission and progression of diseases by transporting pathogens and harmful substances.However,they are also involved in alleviating cellular stress by removing toxins and delivering essential nutrients.Understanding the interactions between glial cells through tunneling nanotubes could provide valuable insights into the complex neural networks that govern brain function and responses to injury.展开更多
Synaptic pruning is a crucial process in synaptic refinement,eliminating unstable synaptic connections in neural circuits.This process is triggered and regulated primarily by spontaneous neural activity and experience...Synaptic pruning is a crucial process in synaptic refinement,eliminating unstable synaptic connections in neural circuits.This process is triggered and regulated primarily by spontaneous neural activity and experience-dependent mechanisms.The pruning process involves multiple molecular signals and a series of regulatory activities governing the“eat me”and“don't eat me”states.Under physiological conditions,the interaction between glial cells and neurons results in the clearance of unnecessary synapses,maintaining normal neural circuit functionality via synaptic pruning.Alterations in genetic and environmental factors can lead to imbalanced synaptic pruning,thus promoting the occurrence and development of autism spectrum disorder,schizophrenia,Alzheimer's disease,and other neurological disorders.In this review,we investigated the molecular mechanisms responsible for synaptic pruning during neural development.We focus on how synaptic pruning can regulate neural circuits and its association with neurological disorders.Furthermore,we discuss the application of emerging optical and imaging technologies to observe synaptic structure and function,as well as their potential for clinical translation.Our aim was to enhance our understanding of synaptic pruning during neural development,including the molecular basis underlying the regulation of synaptic function and the dynamic changes in synaptic density,and to investigate the potential role of these mechanisms in the pathophysiology of neurological diseases,thus providing a theoretical foundation for the treatment of neurological disorders.展开更多
BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese med...BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese medicines.It is known for its suppression of inflammation and mitigation of oxidative stress.Its therapeutic efficacy and mechanistic underpinnings in UC remain uncharacterized.AIM To investigate the therapeutic potential and mechanisms of CE in UC.METHODS The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a dextran sulfate sodium-induced murine colitis model.Network pharmacology was employed to predict potential targets and pathways.Then molecular docking and dynamics simulations were utilized to confirm a stable interaction between CE and the toll-like receptor 4(TLR4)/myeloid differentiation factor 2(MD2)complex.The anti-inflammatory mechanisms were further verified using in vitro assays.Additionally,the gut microbiota composition was analyzed via 16S rRNA gene sequencing.RESULTS CE significantly alleviated colitis symptoms,mitigated histopathological damage,and suppressed inflammation.Moreover,CE restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins(zonula occludens 1,occludin,claudin-1).Mechanistically,CE stably bound to MD2,inhibiting lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells.This led to suppression of the downstream mitogen-activated protein kinase and nuclear factor kappa B signaling pathways,downregulating the expression of tumor necrosis factor-alpha,interleukin-1β,and interleukin-6.Gut microbiota analysis revealed that CE reversed dextran sulfate sodium-induced dysbiosis with significant enrichment of butyrogenic Christensenella minuta.CONCLUSION CE acted on MD2 to suppress proinflammatory cascades,promoting mucosal barrier reconstitution and microbiota remodeling and supporting its therapeutic use in UC.展开更多
This narrative review examines recent advances in salivary biomarkers for oral squamous cell carcinoma(OSCC),a major subtype of oral cancer with persistently low five-year survival rates due to delayed diagnosis.Saliv...This narrative review examines recent advances in salivary biomarkers for oral squamous cell carcinoma(OSCC),a major subtype of oral cancer with persistently low five-year survival rates due to delayed diagnosis.Saliva has emerged as a noninvasive diagnostic medium capable of reflecting both local tumor activity and systemic physiological changes.Various salivary biomarkers,including microRNAs,cytokines,proteins,metabolites,and exosomes,have been linked to oncogenic signaling pathways involved in tumor progression,immune modulation,and therapeutic resistance.Advances in quantitative polymerase chain reaction,mass spectrometry,and next-generation sequencing have enabled comprehensive biomarker profiling,while point-of-care detection systems and saliva-based omics platforms are accelerating clinical translation.Remaining challenges include variability in salivary composition,lack of standardized collection protocols,and insufficient validation across large patient cohorts.This review highlights the mechanistic relevance,diagnostic potential,and translational challenges of salivary biomarkers in OSCC.展开更多
Debates regarding the specific effects of general anesthesia on developing brains have persisted for over 30 years.A consensus has been reached that prolonged,repeated,high-dose exposure to anesthetics is associated w...Debates regarding the specific effects of general anesthesia on developing brains have persisted for over 30 years.A consensus has been reached that prolonged,repeated,high-dose exposure to anesthetics is associated with a higher incidence of deficits in behavior and executive function,while single exposure has a relatively minor effect on long-term neurological function.In this review,we summarize the dose-dependent neuroprotective or neurotoxic effects of gamma-aminobutyric acid type A receptor agonists,a representative group of sedatives,on developing brains or central nervous system diseases.Most preclinical research indicates that anesthetics have neurotoxic effects on the developing brain through various signal pathways.However,recent studies on low-dose anesthetics suggest that they may promote neurodevelopment during this critical period.These findings are incomprehensible for the general“dose-effect”principles of pharmacological research,which has attracted researchers'interest and led to the following questions:What is the threshold for the dual effects exerted by anesthetics such as propofol and sevoflurane on the developing brain?To what extent can their protective effects be maximized?What are the underlying mechanisms involved in these effects?Consequently,this issue has essentially become a“mathematical problem.”After summarizing the dose-dependent effects of gamma-aminobutyric acid type A receptor agonist sedatives in both the developing brain and the brains of patients with central nervous system diseases,we believe that all such anesthetics exhibit specific threshold effects unique to each drug.These effects range from neuroprotection to neurotoxicity,depending on different brain functional states.However,the exact values of the specific thresholds for different drugs in various brain states,as well as the underlying mechanisms explaining why these thresholds exist,remain unclear.Further in-depth exploration of these issues could significantly enhance the therapeutic translational value of these anesthetics.展开更多
Background:Myocardial infarction(MI)remains a major global public health challenge.Although advances in reperfusion therapy have reduced acute mortality,post-infarction cardiac remodeling continues to pose a substanti...Background:Myocardial infarction(MI)remains a major global public health challenge.Although advances in reperfusion therapy have reduced acute mortality,post-infarction cardiac remodeling continues to pose a substantial threat to long-term cardiovascular health.Oxidative stress and the ensuing inflammatory response are key drivers of this pathological process,leading to cardiomyocyte death,myocardial fibrosis,and functional impairment.Among the regulatory pathways involved,the kelch-like ECH-associated protein 1(Keap1)/nuclear factor erythroid 2-related factor 2(Nrf2)axis has emerged as a critical therapeutic target for mitigating post-MI cardiac injury.Methods:A murine MI model was established by permanent ligation of the left anterior descending coronary artery.Mice received oral Tongxinbi formula(TXB)at low,medium,or high doses(9/18/36 g/kg)once daily for 28 days.Cardiac function was assessed by echocardiography;myocardial fibrosis by Masson’s trichrome;and endothelial integrity by CD31 immunofluorescence.Plasma markers of endothelial function and inflammation were quantified.In vitro,oxidative stress was induced by H2O2 in vascular endothelial cells and cardiomyocytes,followed by treatment with TXB drug-containing serum.Western blot and RT-qPCR were used to measure components of the Keap1/Nrf2 pathway;ELISA quantified oxidative stress and inflammatory indices.Conditioned-medium experiments evaluated endothelial cell–mediated paracrine protection of cardiomyocytes.Results:TXB significantly improved cardiac function and reduced myocardial fibrosis after MI,in association with preservation of microvascular structure and systemic attenuation of oxidative stress and inflammation.In vitro,TXB activated the endothelial Keap1/Nrf2 pathway,enhanced cellular antioxidant defenses,increased VEGF secretion,and,via endothelial cell-mediated paracrine signaling,alleviated cardiomyocyte injury under oxidative stress.Conclusion:TXB exerts anti-fibrotic and cardioprotective effects by activating Nrf2 signaling and engaging endothelial-mediated paracrine mechanisms,collectively mitigating oxidative stress and inflammation in the post-MI setting.展开更多
Objective:To investigate the anti-atherosclerosis effect of chikusetsusaponinⅣ(CSⅣ)against high-fat diet-induced atherosclerosis in rats.Methods:A high-fat diet was used for the induction of atherosclerosis in rats,...Objective:To investigate the anti-atherosclerosis effect of chikusetsusaponinⅣ(CSⅣ)against high-fat diet-induced atherosclerosis in rats.Methods:A high-fat diet was used for the induction of atherosclerosis in rats,and the rats received oral CSⅣor atorvastatin.The body weight,organ weights,food intake,calorie intake,lipid parameters,3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA)/mevalonate ratio,collagen,free fatty acid,cardiac parameters,apolipoprotein(A and B),antioxidant parameters,inflammatory cytokines,and inflammatory parameters were assessed.The mRNA expressions of interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),IL-6,IL-17,PI3K,AKT,and mTOR were estimated.Results:CSⅣsignificantly modulated food intake,body weight,organ weight(liver,kidney,and heart),and calories(P<0.05).Total cholesterol,triglycerides,very low-density lipoprotein cholesterol,low-density lipoprotein cholesterol,cardiovascular risk index-1,and cardiovascular risk index-2 were decreased,while high-density lipoprotein cholesterol and anti-atherogenic index were increased significantly in the CSⅣgroup(P<0.05).Besides,CSⅣsignificantly restored the level of HMG-CoA/mevalonate ratio,collagen,free fatty acid,cardiac parameters(creatinine kinase-MB,lactate dehydrogenase,cTnT,cTnI),apolipoprotein(apolipoprotein A and apolipoprotein B),antioxidant parameters(MDA,CAT,GPx,GSH,SOD),inflammatory cytokines(TNF-α,IL-1β,IL-6,IL-10),inflammatory parameters(COX-2,TGF-β,NF-κB),intercellular adhesion molecule-1,vascular cell adhesion molecule-1,and monocyte chemoattractant protein-1.CSⅣalso decreased the mRNA expression of IL-1β,TNF-α,IL-6,IL-17,PI3K,AKT,and mTOR.Conclusions:This study showed the anti-atherosclerosis effect of CSⅣagainst high-fat diet-induced atherosclerosis in rats via alteration of NF-κB/COX-2 and PI3K/AKT/mTOR signaling pathway.展开更多
Accurate time delay estimation of target echo signals is a critical component of underwater target localization.In active sonar systems,echo signal processing is vulnerable to the effects of reverberation and noise in...Accurate time delay estimation of target echo signals is a critical component of underwater target localization.In active sonar systems,echo signal processing is vulnerable to the effects of reverberation and noise in the maritime environment.This paper proposes a novel method for estimating target time delay using multi-bright spot echoes,assuming the target’s size and depth are known.Aiming to effectively enhance the extraction of geometric features from the target echoes and mitigate the impact of reverberation and noise,the proposed approach employs the fractional order Fourier transform-frequency sliced wavelet transform to extract multi-bright spot echoes.Using the highlighting model theory and the target size information,an observation matrix is constructed to represent multi-angle incident signals and obtain the theoretical scattered echo signals from different angles.Aiming to accurately estimate the target’s time delay,waveform similarity coefficients and mean square error values between the theoretical return signals and received signals are computed across various incident angles and time delays.Simulation results show that,compared to the conventional matched filter,the proposed algorithm reduces the relative error by 65.9%-91.5%at a signal-to noise ratio of-25 dB,and by 66.7%-88.9%at a signal-to-reverberation ratio of−10 dB.This algorithm provides a new approach for the precise localization of submerged targets in shallow water environments.展开更多
Background:The development of gastric cancer(GC)encompasses precancerous conditions like chronic atrophic gastritis(CAG)and premalignant lesions of gastric cancer(PLGC).In these situations,abnormal Notch signaling res...Background:The development of gastric cancer(GC)encompasses precancerous conditions like chronic atrophic gastritis(CAG)and premalignant lesions of gastric cancer(PLGC).In these situations,abnormal Notch signaling results in mucosal impairment and the initiation of cancer.Banxia Xiexin Decoction(BXD),a well-known formula in traditional Chinese medicine(TCM),shows promise in treating gastric disorders,but its mechanisms in gastric restoration remain unclear.Methods:Using MNNG-induced CAG and PLGC rat models,BXD was administered for 12 weeks.Gastric mucosal pathology was assessed via hematoxylin-eosin staining.Proliferation(Ki-67)and angiogenesis(VEGFA)markers were evaluated by immunohistochemistry.Network pharmacology identified BXD’s targets and pathways.Notch pathway components(Notch1,Jagged1,Dll4,Hes1)were analyzed via qPCR,Western blot,and immunohistochemistry.Results:BXD significantly ameliorated mucosal atrophy,glandular structural disorder,and dysplasia in CAG and PLGC rats.Network pharmacology revealed 323 overlapping targets between BXD and PLGC,with Notch signaling as a central pathway.BXD downregulated Notch1,Jagged1,Dll4,and Hes1 expression at transcriptional and protein levels,suppressed Ki-67(proliferation)and VEGFA(angiogenesis)overexpression,and restored gastric mucosal integrity.Conclusion:BXD inhibits Notch signaling,reduces aberrant proliferation and angiogenesis,and interrupts Correa’s gastric carcinogenesis cascade.This study provides mechanistic evidence supporting BXD as a TCM-based intervention for gastric precancerous lesions.展开更多
The interleukin-17 family is the key group of cytokines and displays a broad spectrum of biological functions,including regulating the inflammatory cascade in various autoimmune and inflammatory diseases,such as multi...The interleukin-17 family is the key group of cytokines and displays a broad spectrum of biological functions,including regulating the inflammatory cascade in various autoimmune and inflammatory diseases,such as multiple sclerosis,neuromyelitis optica spectrum disorder,myasthenia gravis,Guillain–Barre syndrome,acute disseminated encephalomyelitis,diabetes,inflammatory skin diseases,joint inflammation,and cancer.Although the function of the interleukin-17 family has attracted increasing research attention over many years,the expression,function,and regulation mechanisms of different interleukin-17 members are complicated and still only partially understood.Currently,the interleukin-17A pathway is considered a critical therapeutic target for numerous immune and chronic inflammatory diseases,with several monoclonal antibodies against interleukin-17A having been successfully used in clinical practice.Whether other interleukin-17 members have the potential to be targeted in other diseases is still debated.This review first summarizes the recent advancements in understanding the physicochemical properties,physiological functions,cellular origins,and downstream signaling pathways of different members and corresponding receptors of the interleukin-17 family.Subsequently,the function of interleukin-17 in various immune diseases is discussed,and the important role of interleukin-17 in the pathological process of immune diseases is demonstrated from multiple perspectives.Then,the current status of targeted interleukin-17 therapy is summarized,and the effectiveness and safety of targeted interleukin-17 therapy are analyzed.Finally,the clinical application prospects of targeting the interleukin-17 pathway are discussed.展开更多
Type 2 diabetes mellitus has central complications:Diabetes,a metabolic disorder primarily characterized by hyperglycemia due to insufficient insulin secretion,or impaired insulin signaling,has significant central com...Type 2 diabetes mellitus has central complications:Diabetes,a metabolic disorder primarily characterized by hyperglycemia due to insufficient insulin secretion,or impaired insulin signaling,has significant central complications.Type 2 diabetes mellitus(T2DM),the most prevalent type of diabetes,affects more than 38 million individuals in the United States(approximately 1 in 10)and is defined by chronic hyperglycemia and insulin resistance,which refers to a reduced cellular response to insulin.展开更多
Protein aggregates,mitochondrial import stress and neurodegenerative disorders:A salient hallmark of several neurodegenerative diseases,including Parkinson’s disease,is the abundance of protein aggregates(Goiran et a...Protein aggregates,mitochondrial import stress and neurodegenerative disorders:A salient hallmark of several neurodegenerative diseases,including Parkinson’s disease,is the abundance of protein aggregates(Goiran et al.,2022).This molecular event is believed to lead to activation of stress pathways ultimately resulting in cellular dysfunction(Eldeeb et al.,2022).Accordingly,many lines of research investigations focused on dampening the formation of protein aggregates or augmenting the clearance of protein aggregates as a potential therapeutic strategy to counteract the progression of neurodegenerative diseases,albeit with little success(Costa-Mattioli and Walter,2020).Cell stress cues such as the accumulation of protein aggregates lead to the activation of stress response pathways that aid cells in responding to the damage.Despite the notion that the transient activation of these pathways helps cells cope with stressors,persistent activation can induce unwanted apoptosis of cells and reduce overall tissue strength as well as lead to an accumulation of aggregation-prone proteins(Hetz and Papa,2018).Mutations in proteins involved in stress signaling termination can cause conditions like ataxia and early-onset dementia(Conroy et al.,2014).Therefore,it is crucial for stress response signaling to be turned off once conditions have improved.Nevertheless,the mechanisms by which cells silence these signals are still elusive.展开更多
Dendritic spines are small protrusions along dendrites that contain most of the excitatory synapses in principal neurons,playing a crucial role in neuronal function by creating a compartmentalized environment for sign...Dendritic spines are small protrusions along dendrites that contain most of the excitatory synapses in principal neurons,playing a crucial role in neuronal function by creating a compartmentalized environment for signal transduction.The plasticity of spine morphologies provides a tunable handle to regulate calcium signal dynamics,allowing rapid regulation of protein expression necessary to establish and maintain synapses(Cornejo et al.,2022).If excitatory inputs were to be located primarily on dendritic shafts,dendrites would frequently short-circuit,preventing voltage signals from propagating(Cornejo et al.,2022).It is thus not surprising that the structural plasticity of dendritic spines is closely linked to synaptic plasticity and memory formation(Berry and Nedivi,2017).While comprehensive in vitro studies have been conducted,in vivo studies that directly tackle the mechanism of dendritic transport and translation in regulating spine plasticity spatiotemporally are limited.展开更多
Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in m...Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in mitigating intrahepatic cholestasis,the precise mechanisms underlying its therapeutic effects remain inadequately understood.This study aims to comprehensively investigate the pharmacological mechanisms underlying the therapeutic effects of ZZBPD in cholestatic liver injury(CLI).Methods:Firstly,we evaluated the hepatoprotective effects of ZZBPD on mice with CLI induced byα-naphthylisothiocyanate(ANIT),by measuring biochemical markers,inflammatory factors,and bile acid levels.Subsequently,we employed network pharmacology and single-cell RNA sequencing(scRNA-seq)to identify key targets and potential signaling pathways for the prevention and treatment of CLI.Finally,we further validated the mechanism of action of ZZBPD on these key targets through molecular docking,western blotting,and immunofluorescence techniques.Results:ZZBPD notably improved serum liver function,reduced hepatic inflammation,and restored bile acid balance.Through network pharmacology and scRNA-seq analysis,48 core targets were identified,including TNF,IL-6,and NFKB1,all of which are linked to the IL-17 and NF-κB signaling pathways,as shown by KEGG enrichment analysis.Molecular docking further confirmed stable interactions between ZZBPD’s key active components and molecules such as IL-6,IL-17,and NF-κB.Additionally,western blotting and immunofluorescence validated the downregulation of IL-17 and NF-κB protein expression in liver tissue.Conclusion:ZZBPD effectively treats CLI by activating pathways related to the bile acid receptor FXR,while also modulating the IL-17/NF-κB signaling pathway.This dual action enhances bile secretion and alleviates liver inflammation.These findings offer important insights into the pharmacological mechanisms of ZZBPD and underscore its potential as a promising therapeutic for CLI.展开更多
基金supported by the National Natural Science Foundation of China,82471345(to LC)the Key Research and Development Program for Social Development by the Jiangsu Provincial Department of Science and Technology.No.BE2022668(to LC).
文摘Ischemic stroke is a major cause of neurological deficits and high disability rate.As the primary immune cells of the central nervous system,microglia play dual roles in neuroinflammation and tissue repair following a stroke.Their dynamic activation and polarization states are key factors that influence the disease process and treatment outcomes.This review article investigates the role of microglia in ischemic stroke and explores potential intervention strategies.Microglia exhibit a dynamic functional state,transitioning between pro-inflammatory(M1)and anti-inflammatory(M2)phenotypes.This duality is crucial in ischemic stroke,as it maintains a balance between neuroinflammation and tissue repair.Activated microglia contribute to neuroinflammation through cytokine release and disruption of the blood-brain barrier,while simultaneously promoting tissue repair through anti-inflammatory responses and regeneration.Key pathways influencing microglial activation include Toll-like receptor 4/nuclear factor kappa B,mitogen-activated protein kinases,Janus kinase/signal transducer and activator of transcription,and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathways.These pathways are targets for various experimental therapies aimed at promoting M2 polarization and mitigating damage.Potential therapeutic agents include natural compounds found in drugs such as minocycline,as well as traditional Chinese medicines.Drugs that target these regulatory mechanisms,such as small molecule inhibitors and components of traditional Chinese medicines,along with emerging technologies such as single-cell RNA sequencing and spatial transcriptomics,offer new therapeutic strategies and clinical translational potential for ischemic stroke.
基金supported by the Natural Science Foundation of Yunnan Province,No.202401AS070086(to ZW)the National Key Research and Development Program of China,No.2018YFA0801403(to ZW)+1 种基金Yunnan Science and Technology Talent and Platform Plan,No.202105AC160041(to ZW)the Natural Science Foundation of China,No.31960120(to ZW)。
文摘Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microglia play an important role in secondary injury and can be activated in response to traumatic brain injury.In this article,we review the origin and classification of microglia as well as the dynamic changes of microglia in traumatic brain injury.We also clarify the microglial polarization pathways and the therapeutic drugs targeting activated microglia.We found that regulating the signaling pathways involved in pro-inflammatory and anti-inflammatory microglia,such as the Toll-like receptor 4/nuclear factor-kappa B,mitogen-activated protein kinase,Janus kinase/signal transducer and activator of transcription,phosphoinositide 3-kinase/protein kinase B,Notch,and high mobility group box 1 pathways,can alleviate the inflammatory response triggered by microglia in traumatic brain injury,thereby exerting neuroprotective effects.We also reviewed the strategies developed on the basis of these pathways,such as drug and cell replacement therapies.Drugs that modulate inflammatory factors,such as rosuvastatin,have been shown to promote the polarization of antiinflammatory microglia and reduce the inflammatory response caused by traumatic brain injury.Mesenchymal stem cells possess anti-inflammatory properties,and clinical studies have confirmed their significant efficacy and safety in patients with traumatic brain injury.Additionally,advancements in mesenchymal stem cell-delivery methods—such as combinations of novel biomaterials,genetic engineering,and mesenchymal stem cell exosome therapy—have greatly enhanced the efficiency and therapeutic effects of mesenchymal stem cells in animal models.However,numerous challenges in the application of drug and mesenchymal stem cell treatment strategies remain to be addressed.In the future,new technologies,such as single-cell RNA sequencing and transcriptome analysis,can facilitate further experimental studies.Moreover,research involving non-human primates can help translate these treatment strategies to clinical practice.
基金support from various sources,including the National Natural Science Foundation of China(Grant Nos.81570774,82070872,92049118,and 82370854)the Junior Thousand Talents Program of China,and the Nanjing Medical University Startup Fund(All awarded to J.L.)support provided by Jiangsu Province's Innovation Personal as well as Innovative and Entrepreneurial Team of Jiangsu Province(Grant No.JSSCTD2021)(All awarded to J.L.).
文摘V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown.In this study,we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity(DIO)mice.Under normal chow diet feeding,overexpression of Raf1 in AgRP neurons led to obesity in mice characterized by increased body weight,fat mass,and impaired glucose tolerance.Conversely,Raf1 knockout in AgRP neurons protected against diet-induced obesity,reducing fat mass and improving glucose tolerance.Mechanistically,Raf1 activated the MAPK signaling pathway,culminating in the phosphorylation of cAMP response element-binding protein(CREB),which enhanced transcription of Agrp and Npy.Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis,highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance.Collectively,these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis,positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.
基金supported by the Wellcome Trust(grant No.103852).
文摘The nervous system function requires a precise but plastic neural architecture.The neuronal shape dictates how neurons interact with each other and with other cells,being the morphology of dendrites and axons the central determinant of the functional properties of neurons and neural circuits.The topological and structural morphology of axons and dendrites defines and determines how synapses are conformed.The morphological diversity of axon and dendrite arborization governs the neuron’s inputs,synaptic integration,neuronal computation,signal transmission,and network circuitry,hence defining the particular connectivity and function of the different brain areas.
基金supported by the Natural Science Foundation of Guangdong Province(Grant Nos.2022A15151104922023A1515012955)Guangzhou Science and Technology Plan Project(Grant No.2023A04J0795).
文摘Banana(Musa spp.),being a globally significant fruit crop,faces a myriad of threats from various diseases,such as Fusarium wilt,Xanthomonas wilt,bunchy top disease,and weevils disease.This review provides an overview of recent advancements in molecular mechanisms and immune signaling pathways underlying disease resistance in banana.First,the review discusses the latest research advances on banana pests and diseases.Subsequently,this review explores the immune responses and signaling pathways,pattern recognition receptor-triggered immunity,effector-triggered immunity,cell death,reactive oxygen species,autophagy,hormonal pathways,and other players involved in bananaedisease interactions.Finally,the review discusses the current understanding of the genetic architecture of disease resistance in banana,focusing on the identification of defense-related genes and quantitative trait loci associated with resistance to major pathogens and offering recommendations for genetic research.The conclusion underscores the significance of research on banana immunity,specifically highlighting the crucial need to identify endogenous resistance genes and elucidate immune signaling pathways for future efforts aimed at breeding disease-resistant banana.This review offers a comprehensive perspective on the molecular mechanisms underlying disease resistance in banana and serves as a valuable reference for breeding efforts aimed at enhancing banana's resistance to pathogens.
文摘Objective:Artemether is a semi-synthetic derivative of artemisinin and is widely used in the treatment of Plasmodium(P.)falciparum malaria.This study aimed to characterize the safety profile of artemether based on 15-year data retrived from FDA adverse event reporting system(FAERS).Methods:This is a retrospective analysis on 15-year data of artemether-related adverse effects(AEs)retrieved from the FAERS.AEs were classified according to System Organ Class(SOC)and Preferred Terms(PT).Signal detection was performed using Reporting Odds Ratios(ROR),Proportional Reporting Ratios(PRR),and Empirical Bayes Geometric Mean(EBGM).Stratified analyses examined the impact of demographic factors such as sex,age,and time-to-onset.Temporal patterns and associated risk factors were also investigated.Results:Haemolytic anaemia and haemolysis emerged as the most frequently reported AEs,exhibiting significantly elevated RORs(males:ROR 381.36,95%CI 247.06-588.60;females:ROR 455.11,95%CI 286.43-723.12).Sex-specific differences were evident,with females showing a higher incidence of reproductive-related AEs,including spontaneous abortion and premature labour.Temporal trend analysis revealed that the majority of AEs occurred within the first 30 days after the initiation of artemether administration,indicating a rapid onset.The most affected SOCs were blood and lymphatic system disorders and hepatobiliary disorders.Conclusions:Artemether is associated with a notable frequency of early-onset AEs,particularly hematological and hepatobiliary disorders.The observed sex-specific vulnerability to reproductive AEs highlights the need for sex-conscious clinical approaches.Enhanced post-treatment monitoring and further investigations into the drug’s pharmacokinetics and mechanistic pathways are recommended.
基金supported by the National Natural Science Foundation of China,No.82101115(to JY)the Wuhan University Independent Innovation Fund Youth Project,No.2042021kf0094(to JY).
文摘Tunneling nanotubes are crucial structures for cellular communication and are observed in a variety of cell types.Glial cells,the most abundant cells in the nervous system,play a vital role in intercellular signaling and can show abnormal activation under pathological conditions.Our bibliometric analysis indicated a substantial increase in research on tunneling nanotubes over the past two decades,highlighting their important role in cellular communication.This review focuses on the formation of tunneling nanotubes in various types of glial cells,including astrocytes,microglia,glioma cells,and Schwann cells,as well as their roles in cellular communication and cargo transport.We found that glial cells influence the stability of the neural system and play a role in nerve regeneration through tunneling nanotubes.Tunneling nanotubes facilitate the transmission and progression of diseases by transporting pathogens and harmful substances.However,they are also involved in alleviating cellular stress by removing toxins and delivering essential nutrients.Understanding the interactions between glial cells through tunneling nanotubes could provide valuable insights into the complex neural networks that govern brain function and responses to injury.
基金supported by the National Natural Science Foundation of China,No.31760290,82160688the Key Development Areas Project of Ganzhou Science and Technology,No.2022B-SF9554(all to XL)。
文摘Synaptic pruning is a crucial process in synaptic refinement,eliminating unstable synaptic connections in neural circuits.This process is triggered and regulated primarily by spontaneous neural activity and experience-dependent mechanisms.The pruning process involves multiple molecular signals and a series of regulatory activities governing the“eat me”and“don't eat me”states.Under physiological conditions,the interaction between glial cells and neurons results in the clearance of unnecessary synapses,maintaining normal neural circuit functionality via synaptic pruning.Alterations in genetic and environmental factors can lead to imbalanced synaptic pruning,thus promoting the occurrence and development of autism spectrum disorder,schizophrenia,Alzheimer's disease,and other neurological disorders.In this review,we investigated the molecular mechanisms responsible for synaptic pruning during neural development.We focus on how synaptic pruning can regulate neural circuits and its association with neurological disorders.Furthermore,we discuss the application of emerging optical and imaging technologies to observe synaptic structure and function,as well as their potential for clinical translation.Our aim was to enhance our understanding of synaptic pruning during neural development,including the molecular basis underlying the regulation of synaptic function and the dynamic changes in synaptic density,and to investigate the potential role of these mechanisms in the pathophysiology of neurological diseases,thus providing a theoretical foundation for the treatment of neurological disorders.
基金Supported by the Provincial Key Cultivation Laboratory for Digestive Disease Research,No.2021SYS13Shanxi Province’s“Si Ge Yi Pi”Science and Technology Driven Medical Innovation Project,No.2021MX03Shanxi Provincial Basic Research Program,No.202403021222423.
文摘BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese medicines.It is known for its suppression of inflammation and mitigation of oxidative stress.Its therapeutic efficacy and mechanistic underpinnings in UC remain uncharacterized.AIM To investigate the therapeutic potential and mechanisms of CE in UC.METHODS The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a dextran sulfate sodium-induced murine colitis model.Network pharmacology was employed to predict potential targets and pathways.Then molecular docking and dynamics simulations were utilized to confirm a stable interaction between CE and the toll-like receptor 4(TLR4)/myeloid differentiation factor 2(MD2)complex.The anti-inflammatory mechanisms were further verified using in vitro assays.Additionally,the gut microbiota composition was analyzed via 16S rRNA gene sequencing.RESULTS CE significantly alleviated colitis symptoms,mitigated histopathological damage,and suppressed inflammation.Moreover,CE restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins(zonula occludens 1,occludin,claudin-1).Mechanistically,CE stably bound to MD2,inhibiting lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells.This led to suppression of the downstream mitogen-activated protein kinase and nuclear factor kappa B signaling pathways,downregulating the expression of tumor necrosis factor-alpha,interleukin-1β,and interleukin-6.Gut microbiota analysis revealed that CE reversed dextran sulfate sodium-induced dysbiosis with significant enrichment of butyrogenic Christensenella minuta.CONCLUSION CE acted on MD2 to suppress proinflammatory cascades,promoting mucosal barrier reconstitution and microbiota remodeling and supporting its therapeutic use in UC.
基金supported by the College of Oral Medicine,Taipei Medical University,Taipei,Taiwan(Grant No.TMUCOM202502)supported by Taipei Medical University Hospital,Taipei,Taiwan(Grant No.114TMUH-NE-05).
文摘This narrative review examines recent advances in salivary biomarkers for oral squamous cell carcinoma(OSCC),a major subtype of oral cancer with persistently low five-year survival rates due to delayed diagnosis.Saliva has emerged as a noninvasive diagnostic medium capable of reflecting both local tumor activity and systemic physiological changes.Various salivary biomarkers,including microRNAs,cytokines,proteins,metabolites,and exosomes,have been linked to oncogenic signaling pathways involved in tumor progression,immune modulation,and therapeutic resistance.Advances in quantitative polymerase chain reaction,mass spectrometry,and next-generation sequencing have enabled comprehensive biomarker profiling,while point-of-care detection systems and saliva-based omics platforms are accelerating clinical translation.Remaining challenges include variability in salivary composition,lack of standardized collection protocols,and insufficient validation across large patient cohorts.This review highlights the mechanistic relevance,diagnostic potential,and translational challenges of salivary biomarkers in OSCC.
文摘Debates regarding the specific effects of general anesthesia on developing brains have persisted for over 30 years.A consensus has been reached that prolonged,repeated,high-dose exposure to anesthetics is associated with a higher incidence of deficits in behavior and executive function,while single exposure has a relatively minor effect on long-term neurological function.In this review,we summarize the dose-dependent neuroprotective or neurotoxic effects of gamma-aminobutyric acid type A receptor agonists,a representative group of sedatives,on developing brains or central nervous system diseases.Most preclinical research indicates that anesthetics have neurotoxic effects on the developing brain through various signal pathways.However,recent studies on low-dose anesthetics suggest that they may promote neurodevelopment during this critical period.These findings are incomprehensible for the general“dose-effect”principles of pharmacological research,which has attracted researchers'interest and led to the following questions:What is the threshold for the dual effects exerted by anesthetics such as propofol and sevoflurane on the developing brain?To what extent can their protective effects be maximized?What are the underlying mechanisms involved in these effects?Consequently,this issue has essentially become a“mathematical problem.”After summarizing the dose-dependent effects of gamma-aminobutyric acid type A receptor agonist sedatives in both the developing brain and the brains of patients with central nervous system diseases,we believe that all such anesthetics exhibit specific threshold effects unique to each drug.These effects range from neuroprotection to neurotoxicity,depending on different brain functional states.However,the exact values of the specific thresholds for different drugs in various brain states,as well as the underlying mechanisms explaining why these thresholds exist,remain unclear.Further in-depth exploration of these issues could significantly enhance the therapeutic translational value of these anesthetics.
基金the Major Special Project of Jiangsu Administration of Traditional Chinese Medicine(Project No.ZT202116)the Key R&D Project of Jiangsu Province(Project No.BE2020727)+2 种基金the Yangzhou Science and Technology Program(Project No.YZ2021062,YZ2024143 and YZ2024194)the Third Batch of Academic Mentorship Program for Senior TCM Experts in Jiangsu Province(Project No.2019028)the 2023 Jiangsu Pharmaceutical Association–Aosaikang Hospital Pharmacy Research Project(Project No.A202333).
文摘Background:Myocardial infarction(MI)remains a major global public health challenge.Although advances in reperfusion therapy have reduced acute mortality,post-infarction cardiac remodeling continues to pose a substantial threat to long-term cardiovascular health.Oxidative stress and the ensuing inflammatory response are key drivers of this pathological process,leading to cardiomyocyte death,myocardial fibrosis,and functional impairment.Among the regulatory pathways involved,the kelch-like ECH-associated protein 1(Keap1)/nuclear factor erythroid 2-related factor 2(Nrf2)axis has emerged as a critical therapeutic target for mitigating post-MI cardiac injury.Methods:A murine MI model was established by permanent ligation of the left anterior descending coronary artery.Mice received oral Tongxinbi formula(TXB)at low,medium,or high doses(9/18/36 g/kg)once daily for 28 days.Cardiac function was assessed by echocardiography;myocardial fibrosis by Masson’s trichrome;and endothelial integrity by CD31 immunofluorescence.Plasma markers of endothelial function and inflammation were quantified.In vitro,oxidative stress was induced by H2O2 in vascular endothelial cells and cardiomyocytes,followed by treatment with TXB drug-containing serum.Western blot and RT-qPCR were used to measure components of the Keap1/Nrf2 pathway;ELISA quantified oxidative stress and inflammatory indices.Conditioned-medium experiments evaluated endothelial cell–mediated paracrine protection of cardiomyocytes.Results:TXB significantly improved cardiac function and reduced myocardial fibrosis after MI,in association with preservation of microvascular structure and systemic attenuation of oxidative stress and inflammation.In vitro,TXB activated the endothelial Keap1/Nrf2 pathway,enhanced cellular antioxidant defenses,increased VEGF secretion,and,via endothelial cell-mediated paracrine signaling,alleviated cardiomyocyte injury under oxidative stress.Conclusion:TXB exerts anti-fibrotic and cardioprotective effects by activating Nrf2 signaling and engaging endothelial-mediated paracrine mechanisms,collectively mitigating oxidative stress and inflammation in the post-MI setting.
基金funded by the Yancheng Municipal Health Commission 2024 Medical Research Project(YK2024166).
文摘Objective:To investigate the anti-atherosclerosis effect of chikusetsusaponinⅣ(CSⅣ)against high-fat diet-induced atherosclerosis in rats.Methods:A high-fat diet was used for the induction of atherosclerosis in rats,and the rats received oral CSⅣor atorvastatin.The body weight,organ weights,food intake,calorie intake,lipid parameters,3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA)/mevalonate ratio,collagen,free fatty acid,cardiac parameters,apolipoprotein(A and B),antioxidant parameters,inflammatory cytokines,and inflammatory parameters were assessed.The mRNA expressions of interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),IL-6,IL-17,PI3K,AKT,and mTOR were estimated.Results:CSⅣsignificantly modulated food intake,body weight,organ weight(liver,kidney,and heart),and calories(P<0.05).Total cholesterol,triglycerides,very low-density lipoprotein cholesterol,low-density lipoprotein cholesterol,cardiovascular risk index-1,and cardiovascular risk index-2 were decreased,while high-density lipoprotein cholesterol and anti-atherogenic index were increased significantly in the CSⅣgroup(P<0.05).Besides,CSⅣsignificantly restored the level of HMG-CoA/mevalonate ratio,collagen,free fatty acid,cardiac parameters(creatinine kinase-MB,lactate dehydrogenase,cTnT,cTnI),apolipoprotein(apolipoprotein A and apolipoprotein B),antioxidant parameters(MDA,CAT,GPx,GSH,SOD),inflammatory cytokines(TNF-α,IL-1β,IL-6,IL-10),inflammatory parameters(COX-2,TGF-β,NF-κB),intercellular adhesion molecule-1,vascular cell adhesion molecule-1,and monocyte chemoattractant protein-1.CSⅣalso decreased the mRNA expression of IL-1β,TNF-α,IL-6,IL-17,PI3K,AKT,and mTOR.Conclusions:This study showed the anti-atherosclerosis effect of CSⅣagainst high-fat diet-induced atherosclerosis in rats via alteration of NF-κB/COX-2 and PI3K/AKT/mTOR signaling pathway.
基金Supported by the State Key Laboratory of Acoustics and Marine Information Chinese Academy of Sciences(SKL A202507).
文摘Accurate time delay estimation of target echo signals is a critical component of underwater target localization.In active sonar systems,echo signal processing is vulnerable to the effects of reverberation and noise in the maritime environment.This paper proposes a novel method for estimating target time delay using multi-bright spot echoes,assuming the target’s size and depth are known.Aiming to effectively enhance the extraction of geometric features from the target echoes and mitigate the impact of reverberation and noise,the proposed approach employs the fractional order Fourier transform-frequency sliced wavelet transform to extract multi-bright spot echoes.Using the highlighting model theory and the target size information,an observation matrix is constructed to represent multi-angle incident signals and obtain the theoretical scattered echo signals from different angles.Aiming to accurately estimate the target’s time delay,waveform similarity coefficients and mean square error values between the theoretical return signals and received signals are computed across various incident angles and time delays.Simulation results show that,compared to the conventional matched filter,the proposed algorithm reduces the relative error by 65.9%-91.5%at a signal-to noise ratio of-25 dB,and by 66.7%-88.9%at a signal-to-reverberation ratio of−10 dB.This algorithm provides a new approach for the precise localization of submerged targets in shallow water environments.
基金supported by the National Natural Science Foundation of China(Grant No.82274442)the Key Research Project in Traditional Chinese Medicine of Tianjin Municipal Health Commission(Grant No.202007)the Integrated Traditional Chinese and Western Medicine Research Project of Tianjin Municipal Health Commission(Grant No.2023134).
文摘Background:The development of gastric cancer(GC)encompasses precancerous conditions like chronic atrophic gastritis(CAG)and premalignant lesions of gastric cancer(PLGC).In these situations,abnormal Notch signaling results in mucosal impairment and the initiation of cancer.Banxia Xiexin Decoction(BXD),a well-known formula in traditional Chinese medicine(TCM),shows promise in treating gastric disorders,but its mechanisms in gastric restoration remain unclear.Methods:Using MNNG-induced CAG and PLGC rat models,BXD was administered for 12 weeks.Gastric mucosal pathology was assessed via hematoxylin-eosin staining.Proliferation(Ki-67)and angiogenesis(VEGFA)markers were evaluated by immunohistochemistry.Network pharmacology identified BXD’s targets and pathways.Notch pathway components(Notch1,Jagged1,Dll4,Hes1)were analyzed via qPCR,Western blot,and immunohistochemistry.Results:BXD significantly ameliorated mucosal atrophy,glandular structural disorder,and dysplasia in CAG and PLGC rats.Network pharmacology revealed 323 overlapping targets between BXD and PLGC,with Notch signaling as a central pathway.BXD downregulated Notch1,Jagged1,Dll4,and Hes1 expression at transcriptional and protein levels,suppressed Ki-67(proliferation)and VEGFA(angiogenesis)overexpression,and restored gastric mucosal integrity.Conclusion:BXD inhibits Notch signaling,reduces aberrant proliferation and angiogenesis,and interrupts Correa’s gastric carcinogenesis cascade.This study provides mechanistic evidence supporting BXD as a TCM-based intervention for gastric precancerous lesions.
基金supported by the National Natural Science Foundational of China(Key Program),No.U24A20692(to CJZ)the National Natural Science Foundational of China,Nos.82101414(to MLJ),82371355(to CJZ)+4 种基金the National Natural Science Foundational of China for Excellent Young Scholars,No.82022019(to CJZ)Sichuan Special Fund for Distinguished Young Scholars,No.24NSFJQ0052(to CJZ)The Innovation and Entrepreneurial Team of Sichuan Tianfu Emei Program,No.CZ2024018(to CJZ)Funding for Distinguished Young Scholars of Sichuan Provincial People’s Hospital,No.30420230005(to CJZ)Funding for Distinguished Young Scholars of University of Electronic Science and Technology of China,No.A1098531023601381(to CJZ)。
文摘The interleukin-17 family is the key group of cytokines and displays a broad spectrum of biological functions,including regulating the inflammatory cascade in various autoimmune and inflammatory diseases,such as multiple sclerosis,neuromyelitis optica spectrum disorder,myasthenia gravis,Guillain–Barre syndrome,acute disseminated encephalomyelitis,diabetes,inflammatory skin diseases,joint inflammation,and cancer.Although the function of the interleukin-17 family has attracted increasing research attention over many years,the expression,function,and regulation mechanisms of different interleukin-17 members are complicated and still only partially understood.Currently,the interleukin-17A pathway is considered a critical therapeutic target for numerous immune and chronic inflammatory diseases,with several monoclonal antibodies against interleukin-17A having been successfully used in clinical practice.Whether other interleukin-17 members have the potential to be targeted in other diseases is still debated.This review first summarizes the recent advancements in understanding the physicochemical properties,physiological functions,cellular origins,and downstream signaling pathways of different members and corresponding receptors of the interleukin-17 family.Subsequently,the function of interleukin-17 in various immune diseases is discussed,and the important role of interleukin-17 in the pathological process of immune diseases is demonstrated from multiple perspectives.Then,the current status of targeted interleukin-17 therapy is summarized,and the effectiveness and safety of targeted interleukin-17 therapy are analyzed.Finally,the clinical application prospects of targeting the interleukin-17 pathway are discussed.
基金supported by grants from NIH T32(DK007260,to WC)the Steno North American Fellowship awarded by the Novo Nordisk Foundation(NNF23OC0087108,to WC)+6 种基金STI2030-Major Projects(2021ZD0202700,to HY)the National Natural Science Foundation of China(32241004,to HY)the Natural Science Foundation of Zhejiang Province of China(LR24C090001,to HY)Key R&D Program of Zhejiang Province(2024SSYS0017,to HY)CAMS Innovation Fund for Medical Sciences(2019-12M-5-057,to HY)Fundamental Research Funds for the Central Universities(226-2022-00193,to HY)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2023-PT310-01,to HY)。
文摘Type 2 diabetes mellitus has central complications:Diabetes,a metabolic disorder primarily characterized by hyperglycemia due to insufficient insulin secretion,or impaired insulin signaling,has significant central complications.Type 2 diabetes mellitus(T2DM),the most prevalent type of diabetes,affects more than 38 million individuals in the United States(approximately 1 in 10)and is defined by chronic hyperglycemia and insulin resistance,which refers to a reduced cellular response to insulin.
文摘Protein aggregates,mitochondrial import stress and neurodegenerative disorders:A salient hallmark of several neurodegenerative diseases,including Parkinson’s disease,is the abundance of protein aggregates(Goiran et al.,2022).This molecular event is believed to lead to activation of stress pathways ultimately resulting in cellular dysfunction(Eldeeb et al.,2022).Accordingly,many lines of research investigations focused on dampening the formation of protein aggregates or augmenting the clearance of protein aggregates as a potential therapeutic strategy to counteract the progression of neurodegenerative diseases,albeit with little success(Costa-Mattioli and Walter,2020).Cell stress cues such as the accumulation of protein aggregates lead to the activation of stress response pathways that aid cells in responding to the damage.Despite the notion that the transient activation of these pathways helps cells cope with stressors,persistent activation can induce unwanted apoptosis of cells and reduce overall tissue strength as well as lead to an accumulation of aggregation-prone proteins(Hetz and Papa,2018).Mutations in proteins involved in stress signaling termination can cause conditions like ataxia and early-onset dementia(Conroy et al.,2014).Therefore,it is crucial for stress response signaling to be turned off once conditions have improved.Nevertheless,the mechanisms by which cells silence these signals are still elusive.
基金supported by the National Natural Science Foundation of China(NSFC/RGC/JRF N_HKU735/21)Research Grant Council of Hong Kong,China(17102120,17108821,17103922,C1024-22GF,C7074-21G)+1 种基金Health and Medical Research Fund(HMRF 09200966)(to CSWL)FRQS Postdoctoral Fellowship(to AHKF).
文摘Dendritic spines are small protrusions along dendrites that contain most of the excitatory synapses in principal neurons,playing a crucial role in neuronal function by creating a compartmentalized environment for signal transduction.The plasticity of spine morphologies provides a tunable handle to regulate calcium signal dynamics,allowing rapid regulation of protein expression necessary to establish and maintain synapses(Cornejo et al.,2022).If excitatory inputs were to be located primarily on dendritic shafts,dendrites would frequently short-circuit,preventing voltage signals from propagating(Cornejo et al.,2022).It is thus not surprising that the structural plasticity of dendritic spines is closely linked to synaptic plasticity and memory formation(Berry and Nedivi,2017).While comprehensive in vitro studies have been conducted,in vivo studies that directly tackle the mechanism of dendritic transport and translation in regulating spine plasticity spatiotemporally are limited.
基金supported by the National Science Foundation of China(No.82405004,82474253)the Natural Science Foundation postdoctoral project of Chongqing(CSTB2022NSCQ-BHX0709)+2 种基金Chongqing Wanzhou District doctoral“through train”scientific research project(wzstc-20220124)Natural Science Foundation of Chongqing,China(No.Cstc2021jcyj-msxmX0996)Chongqing Wanzhou District Science and Health Joint Medical Research Project(wzstc-kw2023032)。
文摘Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in mitigating intrahepatic cholestasis,the precise mechanisms underlying its therapeutic effects remain inadequately understood.This study aims to comprehensively investigate the pharmacological mechanisms underlying the therapeutic effects of ZZBPD in cholestatic liver injury(CLI).Methods:Firstly,we evaluated the hepatoprotective effects of ZZBPD on mice with CLI induced byα-naphthylisothiocyanate(ANIT),by measuring biochemical markers,inflammatory factors,and bile acid levels.Subsequently,we employed network pharmacology and single-cell RNA sequencing(scRNA-seq)to identify key targets and potential signaling pathways for the prevention and treatment of CLI.Finally,we further validated the mechanism of action of ZZBPD on these key targets through molecular docking,western blotting,and immunofluorescence techniques.Results:ZZBPD notably improved serum liver function,reduced hepatic inflammation,and restored bile acid balance.Through network pharmacology and scRNA-seq analysis,48 core targets were identified,including TNF,IL-6,and NFKB1,all of which are linked to the IL-17 and NF-κB signaling pathways,as shown by KEGG enrichment analysis.Molecular docking further confirmed stable interactions between ZZBPD’s key active components and molecules such as IL-6,IL-17,and NF-κB.Additionally,western blotting and immunofluorescence validated the downregulation of IL-17 and NF-κB protein expression in liver tissue.Conclusion:ZZBPD effectively treats CLI by activating pathways related to the bile acid receptor FXR,while also modulating the IL-17/NF-κB signaling pathway.This dual action enhances bile secretion and alleviates liver inflammation.These findings offer important insights into the pharmacological mechanisms of ZZBPD and underscore its potential as a promising therapeutic for CLI.
