Idiopathic pulmonary fibrosis（IPF） is characterized by progressive lung scarring, reduced median survival, poor prognosis and limited therapeutic options, leading to great need for new pharmacologic therapies. In re...Idiopathic pulmonary fibrosis（IPF） is characterized by progressive lung scarring, reduced median survival, poor prognosis and limited therapeutic options, leading to great need for new pharmacologic therapies. In recent years, researchers have found that Rho-ROCK signaling pathway may be a new drug target in the prevention of IPF. This article reviewed the role of Rho-ROCK pathway in pulmonary fibrosis and the application of ROCK inhibitors in experimental models of IPF. Multiple lines of evidence therefore indicated that ROCK inhibition has great potential to be a powerful therapeutic tool in the prevention and treatment of IPF in clinic.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
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
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
BACKGROUND Simulated microgravity environment can lead to gastrointestinal motility disturbance.The pathogenesis of gastrointestinal motility disorders is closely related to the stem cell factor(SCF)/c-kit signaling p...BACKGROUND Simulated microgravity environment can lead to gastrointestinal motility disturbance.The pathogenesis of gastrointestinal motility disorders is closely related to the stem cell factor(SCF)/c-kit signaling pathway associated with intestinal flora and Cajal stromal cells.Moreover,intestinal flora can also affect the regulation of SCF/c-kit signaling pathway,thus affecting the expression of Cajal stromal cells.Cajal cells are the pacemakers of gastrointestinal motility.AIM To investigate the effects of Bifidobacterium lactis(B.lactis)BLa80 on the intestinal flora of rats in simulated microgravity and on the gastrointestinal motility-related SCF/c-kit pathway.METHODS The internationally recognized tail suspension animal model was used to simulate the microgravity environment,and 30 rats were randomly divided into control group,tail suspension group and drug administration tail suspension group with 10 rats in each group for a total of 28 days.The tail group was given B.lactis BLa80 by intragastric administration,and the other two groups were given water intragastric administration,the concentration of intragastric administration was 0.1 g/mL,and each rat was 1 mL/day.Hematoxylin&eosin staining was used to observe the histopathological changes in each segment of the intestine of each group,and the expression levels of SCF,c-kit,extracellular signal-regulated kinase(ERK)and p-ERK in the gastric antrum of each group were detected by Western blotting and PCR.The fecal flora and mucosal flora of rats in each group were detected by 16S rRNA.RESULTS Simulated microgravity resulted in severe exfoliation of villi of duodenum,jejunum and ileum in rats,marked damage,increased space between villi,loose arrangement,shortened columnar epithelium of colon,less folds,narrower mucosal thickness,reduced goblet cell number and crypts,and significant improvement after probiotic intervention.Simulated microgravity reduced the expressions of SCF and c-kit,and increased the expressions of ERK and P-ERK in the gastric antrum of rats.However,after probiotic intervention,the expressions of SCF and ckit were increased,while the expressions of ERK and P-ERK were decreased,with statistical significance(P<0.05).In addition,simulated microgravity can reduce the operational taxonomic unit(OTU)of the overall intestinal flora of rats,B.lactis BLa80 can increase the OTU of rats,simulated microgravity can reduce the overall richness and diversity of stool flora of rats,increase the abundance of firmicutes in stool flora of rats,and reduce the abundance of Bacteroides in stool flora of rats,most of which are mainly beneficial bacteria.Simulated microgravity can increase the overall richness and diversity of mucosal flora,increase the abundance of Bacteroides and Desulphurides in the rat mucosal flora,and decrease the abundance of firmicutes,most of which are proteobacteria.After probiotics intervention,the overall Bacteroidetes trend in simulated microgravity rats was increased.CONCLUSION B.lactis BLa80 can ameliorate intestinal mucosal injury,regulate intestinal flora,inhibit ERK expression,and activate the SCF/c-kit signaling pathway,which may have a facilitating effect on gastrointestinal motility in simulated microgravity rats.展开更多
Netrin-1 and its receptors play crucial roles in inducing axonal growth and neuronal migration during neuronal development.Their profound impacts then extend into adulthood to encompass the maintenance of neuronal sur...Netrin-1 and its receptors play crucial roles in inducing axonal growth and neuronal migration during neuronal development.Their profound impacts then extend into adulthood to encompass the maintenance of neuronal survival and synaptic function.Increasing amounts of evidence highlight several key points:(1)Diminished Netrin-1 levels exacerbate pathological progression in animal models of Alzheimer’s disease and Parkinson’s disease,and potentially,similar alterations occur in humans.(2)Genetic mutations of Netrin-1 receptors increase an individuals’susceptibility to neurodegenerative disorders.(3)Therapeutic approaches targeting Netrin-1 and its receptors offer the benefits of enhancing memory and motor function.(4)Netrin-1 and its receptors show genetic and epigenetic alterations in a variety of cancers.These findings provide compelling evidence that Netrin-1 and its receptors are crucial targets in neurodegenerative diseases.Through a comprehensive review of Netrin-1 signaling pathways,our objective is to uncover potential therapeutic avenues for neurodegenerative disorders.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
BACKGROUND Excessive endoplasmic reticulum(ER)stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier,activate the signal transducer and activator of transcription 3(STAT3)/nuclear f...BACKGROUND Excessive endoplasmic reticulum(ER)stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier,activate the signal transducer and activator of transcription 3(STAT3)/nuclear factor kappa B(NF-κB)signaling pathway,and exacerbate the inflammatory response,thus participating in the pathogenesis of ulcerative colitis(UC).Mesalazine is a commonly used drug in the clinical treatment of UC.However,further studies are needed to determine whether mesalazine regulates the ER stress of intestinal epithelial cells,downregulates the STAT3/NF-κB pathway to play a role in the treatment of UC.AIM To study the therapeutic effects of mesalazine on spontaneous colitis in interleukin-10(IL-10)-/-mice.METHODS The 24-week-old IL-10-/-mice with spontaneous colitis were divided into the model group and the 5-amino salicylic acid group.Littermates of wild-type mice of the same age group served as the control.There were eight mice in each group,four males and four females.The severity of symptoms of spontaneous colitis in IL-10-/-mice was assessed using disease activity index scores.On day 15,the mice were sacrificed.The colon length was measured,and the histopathological changes and ultrastructure of colonic epithelial cells were detected.The protein expressions of STAT3,p-STAT3,NF-κB,IκB,p-IκB,and glucoseregulated protein 78 were identified using Western blotting.The STAT3 and NF-κB mRNA expressions were identified using real-time polymerase chain reaction.The glucose-regulated protein 78 and C/EBP homologous protein expressions in colon sections were detected using immunofluorescence.RESULTS Mesalazine reduced the symptoms of spontaneous colitis in IL-10 knockout mice and the histopathological damage of colonic tissues,and alleviated the ER stress in epithelial cells of colitis mice.Western blotting and quantitative real-time polymerase chain reaction results showed that the STAT3/NF-κB pathway in the colon tissue of model mice was activated,suggesting that this pathway was involved in the pathogenesis of UC and might become a potential therapeutic target.Mesalazine could down-regulate the protein expressions of p-STAT3,NF-κB and p-IκB,and down-regulate the mRNA expression of STAT3 and NF-κB.CONCLUSION Mesalazine may play a protective role in UC by reducing ER stress by regulating the STAT3/NF-κB signaling pathway.展开更多
Objective:To examine the protective effect of saikosaponin D against streptozotocin(STZ)-induced gestational diabetes mellitus in female rats.Methods:Intraperitoneal administration of STZ(40 mg/kg)was used for the ind...Objective:To examine the protective effect of saikosaponin D against streptozotocin(STZ)-induced gestational diabetes mellitus in female rats.Methods:Intraperitoneal administration of STZ(40 mg/kg)was used for the induction of diabetes in pregnant rats,and rats orally received sikosaponin D(10,20,and 40 mg/kg).The body weight,placental weight,fetal weight,fetal index,and various biochemical parameters,including antioxidant,glucose level,cytokines,and apoptosis parameters,were estimated.The expression levels of various mRNAs were also analyzed.Results:Saikosaponin D increased body weight and fetal weight while decreasing placental weight and placental index.Saikosaponin D significantly altered various biochemical parameters such as fasting blood glucose,glycated hemoglobin(HbA1c),hemoglobin,hepatic glycogen,advanced glycation end products,lipid parameters(total cholesterol,triglyceride,low density lipoprotein,high density lipoprotein,very low density lipoprotein),antioxidant parameters(superoxide dismutase,glutathione,glutathione peroxidase,malonaldehyde,catalase),inflammatory cytokines(tumor necrosis factor-α,interleukin-6,interleukin-1β,interleukin-10),apoptosis parameters(Bcl-2,Bax,caspase-3),resistin,adiponectin,leptin,intercellular adhesion molecule 1,vascular cell adhesion molecule-1,and monocyte chemotactic protein-1.Furthermore,saikosaponin D modulated the mRNA expression of TLR4,MyD88,NF-κB,NLRP3,TNF-α,IL-6,CRP,SIRT1,and MAPK.Conclusions:Saikosaponin D exhibits a protective effect against STZinduced gestational diabetes mellitus in rats via regulation of TLR4/MyD88/NF-κB and MAPK signaling pathways.展开更多
The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enh...The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis.The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites,which activates the vagus nerve and modulates the immune and neuroendocrine systems.Conversely,alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota,creating a dynamic network of microbial-host interactions.This reciprocal regulation affects neurodevelopment,neurotransmitter control,and behavioral traits,thus playing a role in the modulation of neurological diseases.The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation,mitochondrial dysfunction,abnormal energy metabolism,microglial activation,oxidative stress,and neurotransmitter release,which collectively influence the onset and progression of neurological diseases.This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway,along with its implications for potential therapeutic interventions in neurological diseases.Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders.This can be achieved through various methods such as dietary modifications,probiotic supplements,Chinese herbal extracts,combinations of Chinese herbs,and innovative dosage forms.These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.展开更多
Pulpitis is a common infective oral disease in clinical situations.The regulatory mechanisms of immune defense in pulpitis are still being investigated.Osteomodulin(OMD)is a small leucine-rich proteoglycan family memb...Pulpitis is a common infective oral disease in clinical situations.The regulatory mechanisms of immune defense in pulpitis are still being investigated.Osteomodulin(OMD)is a small leucine-rich proteoglycan family member distributed in bones and teeth.It is a bioactive protein that promotes osteogenesis and suppresses the apoptosis of human dental pulp stem cells(hDPSCs).In this study,the role of OMD in pulpitis and the OMD-induced regulatory mechanism were investigated.The OMD expression in normal and inflamed human pulp tissues was detected via immunofluorescence staining.Intriguingly,the OMD expression decreased in the inflammatory infiltration area of pulpitis specimens.The cellular experiments demonstrated that recombined human OMD could resist the detrimental effects of lipopolysaccharide(LPS)-induced inflammation.A conditional Omd knockout mouse model with pulpal inflammation was established.LPS-induced inflammatory impairment significantly increased in conditional Omd knockout mice,whereas OMD administration exhibited a protective effect against pulpitis.Mechanistically,the transcriptome alterations of OMD overexpression showed significant enrichment in the nuclear factor-κB(NF-κB)signaling pathway.Interleukin-1 receptor 1(IL1R1),a vital membrane receptor activating the NF-κB pathway,was significantly downregulated in OMD-overexpressing hDPSCs.Additionally,the interaction between OMD and IL1R1 was verified using co-immunoprecipitation and molecular docking.In vivo,excessive pulpal inflammation in Omd-deficient mice was rescued using an IL1R antagonist.Overall,OMD played a protective role in the inflammatory response via the IL1R1/NF-κB signaling pathway.OMD may optimize the immunomodulatory functions of hDPSCs and can be used for regenerative endodontics.展开更多
Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis,leading to a notably low five-year survival rate.This study offers a d...Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis,leading to a notably low five-year survival rate.This study offers a detailed exploration of epidemiological trends in pancreatic cancer and key molecular drivers,such as mutations in CDKN2A,KRAS,SMAD4,and TP53,along with the influence of cancer-associated fibroblasts(CAFs)on disease progression.In particular,we focused on the pivotal roles of signaling pathways such as the transforming growth factor-βand Wnt/β-catenin pathways in the development of pancreatic cancer and investigated their application in emerging therapeutic strategies.This study provides new scientific perspectives on pancreatic cancer treatment,especially in the development of precision medicine and targeted therapeutic strategies,and demonstrates the importance of signaling pathway research in the development of effective therapeutic regimens.Future studies should explore the subtypes of CAFs and their specific roles in the tumor microenvironment to devise more effective therapeutic methods.展开更多
AIM:To evaluate the function and mechanisms of forskolin in treating ataxia-like behavior in Celsr3 conditional knockout(cKO)mice.METHODS:The efficiency of intraperitoneally administered forskolin was evaluated by beh...AIM:To evaluate the function and mechanisms of forskolin in treating ataxia-like behavior in Celsr3 conditional knockout(cKO)mice.METHODS:The efficiency of intraperitoneally administered forskolin was evaluated by behavioral tests,and the molecular mechanisms were investigated by patch-clamp experiments.RESULTS:The loss of Celsr3 led to ataxia-like behavior,accompanied by impaired miniature excitatory postsynaptic currents(mEPSCs)and postsynaptic long-term potentiation(LTP)in PCs.The cAMP activator forskolin ameliorated ataxia-like behavior and abrogated the mEPSCs impairment and LTP in model mice.Interestingly,the effects of forskolin could be blocked by SQ22536(a cAMP antagonist)and ESI-08(exchange protein activated by cAMP antagonist;Epac)but the H89(a PKA antagonist)could not block the effects.CONCLUSION:Celsr3 plays an important role in motor coordination by modulating synaptic function,and forskolin may be a valuable therapeutic drug for certain types of inherited cerebellar ataxia.展开更多
OBJECTIVE To explore hypoglycemic effect of 95%ethanol fraction of Nitraria roborowskii Kom(NRK-C)and its possible mechanism evaluated in the type 2 diabetes mellitus(T2DM)mice.METHODS The body weight,organ indices,bl...OBJECTIVE To explore hypoglycemic effect of 95%ethanol fraction of Nitraria roborowskii Kom(NRK-C)and its possible mechanism evaluated in the type 2 diabetes mellitus(T2DM)mice.METHODS The body weight,organ indices,blood glucose levels,serum biochemical indexes,as well as HE/PAS histopathological section were all analyzed to assess the hypoglycemic effect of NRK-C in T2DM mice induced by a high-fat diet(HFD)combined with six intraperitoneal injections of 35 mg·kg^(-1)of streptozotocin(STZ).The Western blotting and immunofluorescence were further applied to determine the regulatory effect of NRK-C on key signaling proteins.RESULTS The fasting blood glucose levels were significantly reduced after 7 weeks of administration of NRK-C.In addition,NRK-C could also significantly improve glucose tolerance,hepatic glycogen levels,and lipid levels(total cholesterol,triglyceride,low density lipoprotein and high density lipoprotein),and significantly reduced insulin resistance of diabetic mice,which played an important role in the antidiabetic effects.Further mechanism research demonstrated that phosphorylated PI3K expression was up-regulated and p-GSK3βexpression was up-regulated after NRK-C intervention,indicating that NRK-C might exert a potential antidiabetic effect by modulating the PI3K/AKT signaling pathway.CONCLUSION All these results suggested that NRK-C might improve T2DM and had the potential to be used as an adjunctive therapy.展开更多
BACKGROUND Recent studies have shown that liraglutide,a glucagon-like peptide-1 receptor agonist,has unexpected cardioprotective effects.However,the distinctive effects of liraglutide on diabetic cardiomyopathy(DCM),p...BACKGROUND Recent studies have shown that liraglutide,a glucagon-like peptide-1 receptor agonist,has unexpected cardioprotective effects.However,the distinctive effects of liraglutide on diabetic cardiomyopathy(DCM),particularly its effect on mitophagy,have not been fully elucidated.AIM To investigate the effects of liraglutide on cardiac damage and mitophagy in DCM rats.METHODS A high-fat diet and streptozotocin were used to induce DCM in rats.After 12 weeks of liraglutide treatment,rats underwent assessments of cardiac function,serum biochemical parameters,histological changes,apoptosis index,and protein levels.Furthermore,neonatal rat cardiomyocytes(NRCMs)were exposed to 25 mmol/L glucose plus 250μmol/L palmitate(high glucose+palmitic acid),with or without 200 nmol/L liraglutide,to investigate the effects of liraglutide on cardiomyocyte injury and the underlying mechanisms.RESULTS Liraglutide improved myocardial function and ameliorated cardiac damage in DCM rats,as indicated by reduced myocardial apoptosis,hypertrophy,and interstitial fibrosis(P<0.05).In NRCMs,Liraglutide alleviated mitochondrial morphological and functional damage as well as oxidative stress,improved mitophagic defects,and reduced cell apoptosis(P<0.05).Mechanistically,liraglutide alleviated NRCMs damage by enhancing mitophagy mediated by the adenosine monophosphate-activated protein kinase(AMPK)-Parkin signaling pathway,which was evidenced by the reversal of its effects upon compound C treatment.CONCLUSION Liraglutide exerted cardioprotective effects in DCM rats by inhibiting cardiomyocyte apoptosis and promoting mitophagy mediated by the AMPK-Parkin signaling pathway.展开更多
Background:Neurodegenerative diseases(NDs),including Alzheimer‘s disease,Parkinson‘s disease,and Huntington‘s disease,are complex and challenging due to their intricate pathophysiology and limited treatment options...Background:Neurodegenerative diseases(NDs),including Alzheimer‘s disease,Parkinson‘s disease,and Huntington‘s disease,are complex and challenging due to their intricate pathophysiology and limited treatment options.Methods:This review systematically sourced articles related to neurodegenerative diseases,neurodegeneration,quercetin,and clinical studies from primary medical databases,including Scopus,PubMed,and Web of Science.Results:Recent studies have included quercetin to impact the cellular and molecular pathways involved in neurodegeneration.Quercetin,a flavonoid abundant in vegetables and fruits,is gaining attention for its antioxidant,anti-inflammatory,and antiapoptotic properties.It regulates signaling pathways such as nuclear factor-κB(NF-κB),sirtuins,and phosphatidylinositol 3-kinase/protein kinase B(PI3K/Akt).These pathways are essential for cellular survival,inflammation regulation,and apoptosis.Preclinical and clinical studies have shown that quercetin improves symptoms and pathology in neurodegenerative models,indicating promising outcomes.Conclusions:The study explores the potential of incorporating laboratory research into practical medical treatment,focusing on quercetin‘s neuroprotective effects on NDs and its optimal dosage.展开更多
Steroidal alkaloids are the main active components in many medicinal plants and exhibit diverse biological activities.Axillaridine A(AA)is a newly discovered steroidal alkaloid.However,whether AA could suppress osteoc...Steroidal alkaloids are the main active components in many medicinal plants and exhibit diverse biological activities.Axillaridine A(AA)is a newly discovered steroidal alkaloid.However,whether AA could suppress osteoclastogenesis and alleviate ovariectomy-induced bone loss in mice remains unknown.In vitro,AA significantly suppressed the receptor activator of nuclear factor-κB(NF-κB)ligand(RANKL)-induced osteoclast differentiation via downregulating the expression of osteoclastogenesis-related marker genes,proteins,and transcriptional regulators,including tartrate-resistant acid phosphatase(TRAP),c-Src,matrix metallopeptidase-9(MMP-9),cathepsin K,nuclear factor of activated T cells,cytoplasmic 1(NFATc1),and c-Fos.This was achieved by blocking RANKL-RANK interaction and inhibiting RANKL-mediated RANK signaling pathways,including NF-κB,AKT,and mitogen-activated protein kinases(MAPKs)in osteoclast precursors.In vivo,AA significantly inhibited the ovariectomized(OVX)-induced body weight gain and blood glucose increase in mice.AA did not adversely affect the histomorphologies,weights,and indices of the kidney and liver in OVX mice.AA effectively ameliorated bone loss in OVX mice by inhibiting osteoclastogenesis.AA significantly inhibited the serum levels of tartrate-resistant acid phosphatase 5b(TRACP-5b)and C-telopeptide of type I collagen(CTX-I).AA significantly inhibited the OVX-induced expression of osteoclastogenesis-related marker genes and proteins in the femur.In summary,AA alleviates ovariectomy-induced bone loss in mice by suppressing osteoclastogenesis via inhibition of RANKL-mediated RANK signaling pathways and could be potentially used for the prevention and treatment of osteoclastrelated diseases such as osteoporosis.展开更多
Dear Editor,Sleep and memory are highly linked across species.Sleep gates and stabilizes memory,critical for memory processing.Insufficient sleep impairs cognition acutely/chronically,in vertebrates and invertebrates[...Dear Editor,Sleep and memory are highly linked across species.Sleep gates and stabilizes memory,critical for memory processing.Insufficient sleep impairs cognition acutely/chronically,in vertebrates and invertebrates[1,2].While key elements are characterized[3,4],how a single molecule integrates sleep and memory remains unknown.展开更多
[Objectives]To investigate the anti-hepatic fibrosis mechanism of lavandulyl flavonoid Kurarinol A(KA)from Sophora flavescens through the TGF/Smad signaling pathway.[Methods]A hepatic fibrosis model was established by...[Objectives]To investigate the anti-hepatic fibrosis mechanism of lavandulyl flavonoid Kurarinol A(KA)from Sophora flavescens through the TGF/Smad signaling pathway.[Methods]A hepatic fibrosis model was established by TGF-β1-induced activation of human hepatic stellate cells LX-2.Western blot and RT-qPCR techniques were employed to study the anti-fibrotic mechanism of KA through the TGF/Smad signaling pathway.[Results]KA exerted anti-hepatic fibrosis effects by significantly reducing the gene expression levels of TGF-β1,Smad2,Smad3,and Smad4,as well as markedly decreasing the protein expression levels of TGF-β1,p-Smad2/3/Smad2/3,and Smad4.[Conclusions]KA demonstrates significant anti-hepatic fibrosis activity and alleviates liver fibrosis through the TGF/Smad signaling pathway.展开更多
Breast cancer(BC)is one of the most prevalent malignant tumors affecting women worldwide,with its incidence rate continuously increasing.As a result,treatment strategies for this disease have received considerable att...Breast cancer(BC)is one of the most prevalent malignant tumors affecting women worldwide,with its incidence rate continuously increasing.As a result,treatment strategies for this disease have received considerable attention.Research has highlighted the crucial role of the Hedgehog(Hh)signaling pathway in the initiation and progression of BC,particularly in promoting tumor growth and metastasis.Therefore,molecular targets within this pathway represent promising opportunities for the development of novel BC therapies.This study aims to elucidate the therapeutic mechanisms by which natural compounds modulate the Hh signaling pathway in BC.By conducting a comprehensive review of various natural compounds,including polyphenols,terpenes,and alkaloids,we reveal both common and unique regulatory mechanisms that influence this pathway.This investigation represents the first comprehensive analysis of five distinct mechanisms through which natural compounds modulate key molecules within the Hh pathway and their impact on the aggressive behaviors of BC.Furthermore,by exploring the structure-activity relationships between these compounds and their molecular targets,we shed light on the specific structural features that enable natural compounds to interact with various components of the Hh pathway.These novel insights contribute to advancing the development and clinical application of natural compound-based therapeutics.Our thorough review not only lays the groundwork for exploring innovative BC treatments but also opens new avenues for leveraging natural compounds in cancer therapy.展开更多
基金Zhejiang Provincial Natural Science Foundation of China(Grant No.LQ15H280007)National Natural Science Foundation of China(Grant No.81202977)project of Traditional Chinese Medicine Science of Zhejiang province(Grant No.2013ZA026 and 2016ZA042)
文摘Idiopathic pulmonary fibrosis（IPF） is characterized by progressive lung scarring, reduced median survival, poor prognosis and limited therapeutic options, leading to great need for new pharmacologic therapies. In recent years, researchers have found that Rho-ROCK signaling pathway may be a new drug target in the prevention of IPF. This article reviewed the role of Rho-ROCK pathway in pulmonary fibrosis and the application of ROCK inhibitors in experimental models of IPF. Multiple lines of evidence therefore indicated that ROCK inhibition has great potential to be a powerful therapeutic tool in the prevention and treatment of IPF in clinic.
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 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.
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.
文摘BACKGROUND Simulated microgravity environment can lead to gastrointestinal motility disturbance.The pathogenesis of gastrointestinal motility disorders is closely related to the stem cell factor(SCF)/c-kit signaling pathway associated with intestinal flora and Cajal stromal cells.Moreover,intestinal flora can also affect the regulation of SCF/c-kit signaling pathway,thus affecting the expression of Cajal stromal cells.Cajal cells are the pacemakers of gastrointestinal motility.AIM To investigate the effects of Bifidobacterium lactis(B.lactis)BLa80 on the intestinal flora of rats in simulated microgravity and on the gastrointestinal motility-related SCF/c-kit pathway.METHODS The internationally recognized tail suspension animal model was used to simulate the microgravity environment,and 30 rats were randomly divided into control group,tail suspension group and drug administration tail suspension group with 10 rats in each group for a total of 28 days.The tail group was given B.lactis BLa80 by intragastric administration,and the other two groups were given water intragastric administration,the concentration of intragastric administration was 0.1 g/mL,and each rat was 1 mL/day.Hematoxylin&eosin staining was used to observe the histopathological changes in each segment of the intestine of each group,and the expression levels of SCF,c-kit,extracellular signal-regulated kinase(ERK)and p-ERK in the gastric antrum of each group were detected by Western blotting and PCR.The fecal flora and mucosal flora of rats in each group were detected by 16S rRNA.RESULTS Simulated microgravity resulted in severe exfoliation of villi of duodenum,jejunum and ileum in rats,marked damage,increased space between villi,loose arrangement,shortened columnar epithelium of colon,less folds,narrower mucosal thickness,reduced goblet cell number and crypts,and significant improvement after probiotic intervention.Simulated microgravity reduced the expressions of SCF and c-kit,and increased the expressions of ERK and P-ERK in the gastric antrum of rats.However,after probiotic intervention,the expressions of SCF and ckit were increased,while the expressions of ERK and P-ERK were decreased,with statistical significance(P<0.05).In addition,simulated microgravity can reduce the operational taxonomic unit(OTU)of the overall intestinal flora of rats,B.lactis BLa80 can increase the OTU of rats,simulated microgravity can reduce the overall richness and diversity of stool flora of rats,increase the abundance of firmicutes in stool flora of rats,and reduce the abundance of Bacteroides in stool flora of rats,most of which are mainly beneficial bacteria.Simulated microgravity can increase the overall richness and diversity of mucosal flora,increase the abundance of Bacteroides and Desulphurides in the rat mucosal flora,and decrease the abundance of firmicutes,most of which are proteobacteria.After probiotics intervention,the overall Bacteroidetes trend in simulated microgravity rats was increased.CONCLUSION B.lactis BLa80 can ameliorate intestinal mucosal injury,regulate intestinal flora,inhibit ERK expression,and activate the SCF/c-kit signaling pathway,which may have a facilitating effect on gastrointestinal motility in simulated microgravity rats.
基金supported by the National Natural Science Foundation of China(Youth Science Fund Project),No.81901292(to GC)the National Key Research and Development Program of China,No.2021YFC2502100(to GC)the National Natural Science Foundation of China,No.82071183(to ZZ).
文摘Netrin-1 and its receptors play crucial roles in inducing axonal growth and neuronal migration during neuronal development.Their profound impacts then extend into adulthood to encompass the maintenance of neuronal survival and synaptic function.Increasing amounts of evidence highlight several key points:(1)Diminished Netrin-1 levels exacerbate pathological progression in animal models of Alzheimer’s disease and Parkinson’s disease,and potentially,similar alterations occur in humans.(2)Genetic mutations of Netrin-1 receptors increase an individuals’susceptibility to neurodegenerative disorders.(3)Therapeutic approaches targeting Netrin-1 and its receptors offer the benefits of enhancing memory and motor function.(4)Netrin-1 and its receptors show genetic and epigenetic alterations in a variety of cancers.These findings provide compelling evidence that Netrin-1 and its receptors are crucial targets in neurodegenerative diseases.Through a comprehensive review of Netrin-1 signaling pathways,our objective is to uncover potential therapeutic avenues for neurodegenerative disorders.
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 Xi’an Science and Technology Plan Project,No.23YXYJ0162Shaanxi Province Traditional Chinese Medicine Research and Innovation Talent Plan Project,No.TZKN-CXRC-16+2 种基金Project of Shaanxi Administration of Traditional Chinese Medicine,No.SZYKJCYC-2025-JC-010Shaanxi Province Key Research and Development Plan Project-Social Development Field,No.S2025-YF-YBSF-0391the Science and Technology Innovation Cultivation Program of Longhua Hospital affiliated to Shanghai University of Chinese Medicine,No.YD202220。
文摘BACKGROUND Excessive endoplasmic reticulum(ER)stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier,activate the signal transducer and activator of transcription 3(STAT3)/nuclear factor kappa B(NF-κB)signaling pathway,and exacerbate the inflammatory response,thus participating in the pathogenesis of ulcerative colitis(UC).Mesalazine is a commonly used drug in the clinical treatment of UC.However,further studies are needed to determine whether mesalazine regulates the ER stress of intestinal epithelial cells,downregulates the STAT3/NF-κB pathway to play a role in the treatment of UC.AIM To study the therapeutic effects of mesalazine on spontaneous colitis in interleukin-10(IL-10)-/-mice.METHODS The 24-week-old IL-10-/-mice with spontaneous colitis were divided into the model group and the 5-amino salicylic acid group.Littermates of wild-type mice of the same age group served as the control.There were eight mice in each group,four males and four females.The severity of symptoms of spontaneous colitis in IL-10-/-mice was assessed using disease activity index scores.On day 15,the mice were sacrificed.The colon length was measured,and the histopathological changes and ultrastructure of colonic epithelial cells were detected.The protein expressions of STAT3,p-STAT3,NF-κB,IκB,p-IκB,and glucoseregulated protein 78 were identified using Western blotting.The STAT3 and NF-κB mRNA expressions were identified using real-time polymerase chain reaction.The glucose-regulated protein 78 and C/EBP homologous protein expressions in colon sections were detected using immunofluorescence.RESULTS Mesalazine reduced the symptoms of spontaneous colitis in IL-10 knockout mice and the histopathological damage of colonic tissues,and alleviated the ER stress in epithelial cells of colitis mice.Western blotting and quantitative real-time polymerase chain reaction results showed that the STAT3/NF-κB pathway in the colon tissue of model mice was activated,suggesting that this pathway was involved in the pathogenesis of UC and might become a potential therapeutic target.Mesalazine could down-regulate the protein expressions of p-STAT3,NF-κB and p-IκB,and down-regulate the mRNA expression of STAT3 and NF-κB.CONCLUSION Mesalazine may play a protective role in UC by reducing ER stress by regulating the STAT3/NF-κB signaling pathway.
文摘Objective:To examine the protective effect of saikosaponin D against streptozotocin(STZ)-induced gestational diabetes mellitus in female rats.Methods:Intraperitoneal administration of STZ(40 mg/kg)was used for the induction of diabetes in pregnant rats,and rats orally received sikosaponin D(10,20,and 40 mg/kg).The body weight,placental weight,fetal weight,fetal index,and various biochemical parameters,including antioxidant,glucose level,cytokines,and apoptosis parameters,were estimated.The expression levels of various mRNAs were also analyzed.Results:Saikosaponin D increased body weight and fetal weight while decreasing placental weight and placental index.Saikosaponin D significantly altered various biochemical parameters such as fasting blood glucose,glycated hemoglobin(HbA1c),hemoglobin,hepatic glycogen,advanced glycation end products,lipid parameters(total cholesterol,triglyceride,low density lipoprotein,high density lipoprotein,very low density lipoprotein),antioxidant parameters(superoxide dismutase,glutathione,glutathione peroxidase,malonaldehyde,catalase),inflammatory cytokines(tumor necrosis factor-α,interleukin-6,interleukin-1β,interleukin-10),apoptosis parameters(Bcl-2,Bax,caspase-3),resistin,adiponectin,leptin,intercellular adhesion molecule 1,vascular cell adhesion molecule-1,and monocyte chemotactic protein-1.Furthermore,saikosaponin D modulated the mRNA expression of TLR4,MyD88,NF-κB,NLRP3,TNF-α,IL-6,CRP,SIRT1,and MAPK.Conclusions:Saikosaponin D exhibits a protective effect against STZinduced gestational diabetes mellitus in rats via regulation of TLR4/MyD88/NF-κB and MAPK signaling pathways.
基金supported by the National Natural Science Foundation of China,No.82003965the Science and Technology Research Project of Sichuan Provincial Administration of Traditional Chinese Medicine,No.2024MS167(to LH)+2 种基金the Xinglin Scholar Program of Chengdu University of Traditional Chinese Medicine,No.QJRC2022033(to LH)the Improvement Plan for the'Xinglin Scholar'Scientific Research Talent Program at Chengdu University of Traditional Chinese Medicine,No.XKTD2023002(to LH)the 2023 National Project of the College Students'Innovation and Entrepreneurship Training Program at Chengdu University of Traditional Chinese Medicine,No.202310633028(to FD)。
文摘The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis.The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites,which activates the vagus nerve and modulates the immune and neuroendocrine systems.Conversely,alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota,creating a dynamic network of microbial-host interactions.This reciprocal regulation affects neurodevelopment,neurotransmitter control,and behavioral traits,thus playing a role in the modulation of neurological diseases.The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation,mitochondrial dysfunction,abnormal energy metabolism,microglial activation,oxidative stress,and neurotransmitter release,which collectively influence the onset and progression of neurological diseases.This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway,along with its implications for potential therapeutic interventions in neurological diseases.Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders.This can be achieved through various methods such as dietary modifications,probiotic supplements,Chinese herbal extracts,combinations of Chinese herbs,and innovative dosage forms.These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.
基金supported by grants from the National Natural Science Foundation of China (82071104)Science and Technology Commission of Shanghai Municipality (23XD1434200/22Y21901000)+9 种基金Shanghai Hospital Development Center(SHDC12022120)National Clinical Research Center for Oral Diseases (NCRCO2021-omics-07)Shanghai Clinical Research Center for Oral Diseases (19MC1910600)Major and Key Cultivation Projects of Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine (JYZP006)Shanghai’s Top Priority Research Center (2022ZZ01017)CAMS Innovation Fund for Medical Sciences (2019-I2M-5-037)Fundamental research program funding of Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine(JYZZ237)Eastern Talent Plan Leading Project (BJZH2024001)partly supported by the Shanghai Ninth People’s Hospital affiliated with Shanghai Jiao Tong University,School of Medicine(JYJC202223)Shanghai Key Laboratory of Translational Medicine on Ear and Nose diseases (14DZ2260300)
文摘Pulpitis is a common infective oral disease in clinical situations.The regulatory mechanisms of immune defense in pulpitis are still being investigated.Osteomodulin(OMD)is a small leucine-rich proteoglycan family member distributed in bones and teeth.It is a bioactive protein that promotes osteogenesis and suppresses the apoptosis of human dental pulp stem cells(hDPSCs).In this study,the role of OMD in pulpitis and the OMD-induced regulatory mechanism were investigated.The OMD expression in normal and inflamed human pulp tissues was detected via immunofluorescence staining.Intriguingly,the OMD expression decreased in the inflammatory infiltration area of pulpitis specimens.The cellular experiments demonstrated that recombined human OMD could resist the detrimental effects of lipopolysaccharide(LPS)-induced inflammation.A conditional Omd knockout mouse model with pulpal inflammation was established.LPS-induced inflammatory impairment significantly increased in conditional Omd knockout mice,whereas OMD administration exhibited a protective effect against pulpitis.Mechanistically,the transcriptome alterations of OMD overexpression showed significant enrichment in the nuclear factor-κB(NF-κB)signaling pathway.Interleukin-1 receptor 1(IL1R1),a vital membrane receptor activating the NF-κB pathway,was significantly downregulated in OMD-overexpressing hDPSCs.Additionally,the interaction between OMD and IL1R1 was verified using co-immunoprecipitation and molecular docking.In vivo,excessive pulpal inflammation in Omd-deficient mice was rescued using an IL1R antagonist.Overall,OMD played a protective role in the inflammatory response via the IL1R1/NF-κB signaling pathway.OMD may optimize the immunomodulatory functions of hDPSCs and can be used for regenerative endodontics.
基金Supported by National Key Research and Development Program Project,No.2017YFC1700601Shaanxi Provincial Key Research and Development Program Project,No.2018SF-350Leading Talents in Scientific and Technological Innovation of the Shaanxi Province Special Support Plan,No.00518。
文摘Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis,leading to a notably low five-year survival rate.This study offers a detailed exploration of epidemiological trends in pancreatic cancer and key molecular drivers,such as mutations in CDKN2A,KRAS,SMAD4,and TP53,along with the influence of cancer-associated fibroblasts(CAFs)on disease progression.In particular,we focused on the pivotal roles of signaling pathways such as the transforming growth factor-βand Wnt/β-catenin pathways in the development of pancreatic cancer and investigated their application in emerging therapeutic strategies.This study provides new scientific perspectives on pancreatic cancer treatment,especially in the development of precision medicine and targeted therapeutic strategies,and demonstrates the importance of signaling pathway research in the development of effective therapeutic regimens.Future studies should explore the subtypes of CAFs and their specific roles in the tumor microenvironment to devise more effective therapeutic methods.
基金Supported by the Natural Science Foundation of Chongqing Municipality,China(No.CSTB2022NSCQ-BHX0725)the National Natural Science Foundation of China(No.82401728).
文摘AIM:To evaluate the function and mechanisms of forskolin in treating ataxia-like behavior in Celsr3 conditional knockout(cKO)mice.METHODS:The efficiency of intraperitoneally administered forskolin was evaluated by behavioral tests,and the molecular mechanisms were investigated by patch-clamp experiments.RESULTS:The loss of Celsr3 led to ataxia-like behavior,accompanied by impaired miniature excitatory postsynaptic currents(mEPSCs)and postsynaptic long-term potentiation(LTP)in PCs.The cAMP activator forskolin ameliorated ataxia-like behavior and abrogated the mEPSCs impairment and LTP in model mice.Interestingly,the effects of forskolin could be blocked by SQ22536(a cAMP antagonist)and ESI-08(exchange protein activated by cAMP antagonist;Epac)but the H89(a PKA antagonist)could not block the effects.CONCLUSION:Celsr3 plays an important role in motor coordination by modulating synaptic function,and forskolin may be a valuable therapeutic drug for certain types of inherited cerebellar ataxia.
文摘OBJECTIVE To explore hypoglycemic effect of 95%ethanol fraction of Nitraria roborowskii Kom(NRK-C)and its possible mechanism evaluated in the type 2 diabetes mellitus(T2DM)mice.METHODS The body weight,organ indices,blood glucose levels,serum biochemical indexes,as well as HE/PAS histopathological section were all analyzed to assess the hypoglycemic effect of NRK-C in T2DM mice induced by a high-fat diet(HFD)combined with six intraperitoneal injections of 35 mg·kg^(-1)of streptozotocin(STZ).The Western blotting and immunofluorescence were further applied to determine the regulatory effect of NRK-C on key signaling proteins.RESULTS The fasting blood glucose levels were significantly reduced after 7 weeks of administration of NRK-C.In addition,NRK-C could also significantly improve glucose tolerance,hepatic glycogen levels,and lipid levels(total cholesterol,triglyceride,low density lipoprotein and high density lipoprotein),and significantly reduced insulin resistance of diabetic mice,which played an important role in the antidiabetic effects.Further mechanism research demonstrated that phosphorylated PI3K expression was up-regulated and p-GSK3βexpression was up-regulated after NRK-C intervention,indicating that NRK-C might exert a potential antidiabetic effect by modulating the PI3K/AKT signaling pathway.CONCLUSION All these results suggested that NRK-C might improve T2DM and had the potential to be used as an adjunctive therapy.
基金Supported by National Natural Science Foundation of China,No.81370221 and No.82172334PUMC Youth Fund,No.3332018200+1 种基金National Science and Technology Major Project of the Ministry of Science and Technology of China,No.2024ZD0522005CAMS Innovation Fund for Medical Science,No.2016-CXGC05-4 and No.2021-I2M-1-008.
文摘BACKGROUND Recent studies have shown that liraglutide,a glucagon-like peptide-1 receptor agonist,has unexpected cardioprotective effects.However,the distinctive effects of liraglutide on diabetic cardiomyopathy(DCM),particularly its effect on mitophagy,have not been fully elucidated.AIM To investigate the effects of liraglutide on cardiac damage and mitophagy in DCM rats.METHODS A high-fat diet and streptozotocin were used to induce DCM in rats.After 12 weeks of liraglutide treatment,rats underwent assessments of cardiac function,serum biochemical parameters,histological changes,apoptosis index,and protein levels.Furthermore,neonatal rat cardiomyocytes(NRCMs)were exposed to 25 mmol/L glucose plus 250μmol/L palmitate(high glucose+palmitic acid),with or without 200 nmol/L liraglutide,to investigate the effects of liraglutide on cardiomyocyte injury and the underlying mechanisms.RESULTS Liraglutide improved myocardial function and ameliorated cardiac damage in DCM rats,as indicated by reduced myocardial apoptosis,hypertrophy,and interstitial fibrosis(P<0.05).In NRCMs,Liraglutide alleviated mitochondrial morphological and functional damage as well as oxidative stress,improved mitophagic defects,and reduced cell apoptosis(P<0.05).Mechanistically,liraglutide alleviated NRCMs damage by enhancing mitophagy mediated by the adenosine monophosphate-activated protein kinase(AMPK)-Parkin signaling pathway,which was evidenced by the reversal of its effects upon compound C treatment.CONCLUSION Liraglutide exerted cardioprotective effects in DCM rats by inhibiting cardiomyocyte apoptosis and promoting mitophagy mediated by the AMPK-Parkin signaling pathway.
基金financially supporting this work through the Large Research Group Project under grant number R.G.P.2/510/45。
文摘Background:Neurodegenerative diseases(NDs),including Alzheimer‘s disease,Parkinson‘s disease,and Huntington‘s disease,are complex and challenging due to their intricate pathophysiology and limited treatment options.Methods:This review systematically sourced articles related to neurodegenerative diseases,neurodegeneration,quercetin,and clinical studies from primary medical databases,including Scopus,PubMed,and Web of Science.Results:Recent studies have included quercetin to impact the cellular and molecular pathways involved in neurodegeneration.Quercetin,a flavonoid abundant in vegetables and fruits,is gaining attention for its antioxidant,anti-inflammatory,and antiapoptotic properties.It regulates signaling pathways such as nuclear factor-κB(NF-κB),sirtuins,and phosphatidylinositol 3-kinase/protein kinase B(PI3K/Akt).These pathways are essential for cellular survival,inflammation regulation,and apoptosis.Preclinical and clinical studies have shown that quercetin improves symptoms and pathology in neurodegenerative models,indicating promising outcomes.Conclusions:The study explores the potential of incorporating laboratory research into practical medical treatment,focusing on quercetin‘s neuroprotective effects on NDs and its optimal dosage.
基金supported by the grants from the National Natural Science Foundation of China(82404638)the Xingdian Talent Plan of Yunnan Province(XDYC-QNRC-2023-0427 and XDYC-YLXZ2022-0025)the Natural Science Foundation of Yunnan Province(202101BD070001-034,202101BD070001-049,202201AT070267,and 202201AU070183)。
文摘Steroidal alkaloids are the main active components in many medicinal plants and exhibit diverse biological activities.Axillaridine A(AA)is a newly discovered steroidal alkaloid.However,whether AA could suppress osteoclastogenesis and alleviate ovariectomy-induced bone loss in mice remains unknown.In vitro,AA significantly suppressed the receptor activator of nuclear factor-κB(NF-κB)ligand(RANKL)-induced osteoclast differentiation via downregulating the expression of osteoclastogenesis-related marker genes,proteins,and transcriptional regulators,including tartrate-resistant acid phosphatase(TRAP),c-Src,matrix metallopeptidase-9(MMP-9),cathepsin K,nuclear factor of activated T cells,cytoplasmic 1(NFATc1),and c-Fos.This was achieved by blocking RANKL-RANK interaction and inhibiting RANKL-mediated RANK signaling pathways,including NF-κB,AKT,and mitogen-activated protein kinases(MAPKs)in osteoclast precursors.In vivo,AA significantly inhibited the ovariectomized(OVX)-induced body weight gain and blood glucose increase in mice.AA did not adversely affect the histomorphologies,weights,and indices of the kidney and liver in OVX mice.AA effectively ameliorated bone loss in OVX mice by inhibiting osteoclastogenesis.AA significantly inhibited the serum levels of tartrate-resistant acid phosphatase 5b(TRACP-5b)and C-telopeptide of type I collagen(CTX-I).AA significantly inhibited the OVX-induced expression of osteoclastogenesis-related marker genes and proteins in the femur.In summary,AA alleviates ovariectomy-induced bone loss in mice by suppressing osteoclastogenesis via inhibition of RANKL-mediated RANK signaling pathways and could be potentially used for the prevention and treatment of osteoclastrelated diseases such as osteoporosis.
基金supported by the National Natural Science Foundation of China(32371063,82341248,and 32071009)Guangdong Basic and Applied Basic Research Foundation(2024A1515011500)the Shenzhen Science and Technology Program(ZDSYS20200811142401005).
文摘Dear Editor,Sleep and memory are highly linked across species.Sleep gates and stabilizes memory,critical for memory processing.Insufficient sleep impairs cognition acutely/chronically,in vertebrates and invertebrates[1,2].While key elements are characterized[3,4],how a single molecule integrates sleep and memory remains unknown.
基金Supported by Guizhou Provincial Science and Technology Project(2024-023ZK2024-047,2024-015)+3 种基金the Innovation and Entrepreneurship Training Program for Undergraduates from China(202310660082,S2024106601432X)University Engineering Research Center for the Prevention and Treatment of Chronic Diseases by Authentic Medicinal Materials in Guizhou Province(2023-035)Administration of Traditional Chinese Medicine of Guizhou Province(QZYY-2024-134)Science Foundation of the Health Commission of Guizhou Province(gzwkj2025-538).
文摘[Objectives]To investigate the anti-hepatic fibrosis mechanism of lavandulyl flavonoid Kurarinol A(KA)from Sophora flavescens through the TGF/Smad signaling pathway.[Methods]A hepatic fibrosis model was established by TGF-β1-induced activation of human hepatic stellate cells LX-2.Western blot and RT-qPCR techniques were employed to study the anti-fibrotic mechanism of KA through the TGF/Smad signaling pathway.[Results]KA exerted anti-hepatic fibrosis effects by significantly reducing the gene expression levels of TGF-β1,Smad2,Smad3,and Smad4,as well as markedly decreasing the protein expression levels of TGF-β1,p-Smad2/3/Smad2/3,and Smad4.[Conclusions]KA demonstrates significant anti-hepatic fibrosis activity and alleviates liver fibrosis through the TGF/Smad signaling pathway.
基金supported by the National Natural Science Foundation of China(Grant No.:82174222)Shandong Province Natural Science Foundation,China(Grant No.:ZR2021LZY015).
文摘Breast cancer(BC)is one of the most prevalent malignant tumors affecting women worldwide,with its incidence rate continuously increasing.As a result,treatment strategies for this disease have received considerable attention.Research has highlighted the crucial role of the Hedgehog(Hh)signaling pathway in the initiation and progression of BC,particularly in promoting tumor growth and metastasis.Therefore,molecular targets within this pathway represent promising opportunities for the development of novel BC therapies.This study aims to elucidate the therapeutic mechanisms by which natural compounds modulate the Hh signaling pathway in BC.By conducting a comprehensive review of various natural compounds,including polyphenols,terpenes,and alkaloids,we reveal both common and unique regulatory mechanisms that influence this pathway.This investigation represents the first comprehensive analysis of five distinct mechanisms through which natural compounds modulate key molecules within the Hh pathway and their impact on the aggressive behaviors of BC.Furthermore,by exploring the structure-activity relationships between these compounds and their molecular targets,we shed light on the specific structural features that enable natural compounds to interact with various components of the Hh pathway.These novel insights contribute to advancing the development and clinical application of natural compound-based therapeutics.Our thorough review not only lays the groundwork for exploring innovative BC treatments but also opens new avenues for leveraging natural compounds in cancer therapy.
