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
Muscle atrophy can be induced by high doses or prolonged use of glucocorticoids.Kaempferol(Kae)is a naturally occurring flavonoid with a variety of biological activities and the effect of Kae on dexamethasone(Dex)indu...Muscle atrophy can be induced by high doses or prolonged use of glucocorticoids.Kaempferol(Kae)is a naturally occurring flavonoid with a variety of biological activities and the effect of Kae on dexamethasone(Dex)induced muscle atrophy in animals has not been elucidated.To explore this issue,the present experiments used a computationally assisted drug design scheme combining network pharmacology,molecular docking and in vivo experiments to investigate the mechanism of Kae against muscle atrophy.Network pharmacological analyses revealed 275 potential targets for Kae and 12294 potential targets for muscle atrophy,with a total of 228 crosstargets for Kae and muscle atrophy.GO and KEGG analyses were performed based on the protein-protein interaction(PPI)network of muscle atrophy and Kae component targets.The GO results showed that the biological processes were mainly related to the metabolic process of reactive oxygen species,and the response to oxidative stress;the cellular components were mainly focused on membrane microdomains,and membrane regions;the molecular functions mainly worked on phosphatase binding;and the KEGG pathway enrichment analyses identified the pathways of interaction between Kae and muscle atrophy.Finally,as verified by in vivo experiments,Kae may reduce the onset of muscle atrophy by activating the PI3K/AKT/m TOR/signalling pathway,inhibiting Foxo1/Foxo3 activity,and inhibiting downstream production of the ubiquitination 3 ligases Atrogin1 and Mu RF1;Kae also promotes the expression of NRF2/HO-1/KEAP1 signalling pathway,enhances muscle antioxidant capacity,inhibits the release of COX-2 and TNF-αinflammatory factors,and reduces the damage caused by oxidative stress and inflammatory factors to muscles.Therefore,there may be a synergistic effect of PI3K/AKT/m TOR and NRF2/HO-1/KEAP1 in Kae working together to prevent muscle atrophy.The binding energy and stability of Kae to potential targets were examined by molecular docking and molecular dynamics simulations,implying that Kae could be used for the prevention and treatment of muscle atrophy in patients.展开更多
Taohong Siwu Decoction(THSWD), a traditional Chinese medicinal formulation, has been demonstrated to significantly modulate key signaling pathways implicated in atherosclerosis(AS). This review examines the complex me...Taohong Siwu Decoction(THSWD), a traditional Chinese medicinal formulation, has been demonstrated to significantly modulate key signaling pathways implicated in atherosclerosis(AS). This review examines the complex mechanisms through which THSWD influences critical pathways, including nuclear factor kappa-B(NF-κB), phosphatidylinositol 3-kinase(PI3K)/serine-threonine kinase(AKT), Toll-like receptor 4(TLR4), mitogen-activated protein kinase(MAPK), and mammalian target of rapamycin(mTOR), that play pivotal roles in AS pathogenesis. By synthesizing experimental evidence and existing literature, the review summarizes how THSWD and its bioactive constituents regulate these signaling cascades to ameliorate AS. Furthermore, it highlights the distinctive therapeutic advantages of traditional Chinese medicine(TCM) compounds in managing chronic diseases driven by multi-target and multifactorial mechanisms. Analyzing disease targets from the perspective of signaling pathways enhances the scientific validation of clinical efficacy for such formulations, thereby offering novel insights for future research.展开更多
Bone resorption is a vital physiological process that enables skeletal remodeling,maintenance,and adaptation to mechanical forces throughout life.While tightly regulated under the physiological state,its dysregulation...Bone resorption is a vital physiological process that enables skeletal remodeling,maintenance,and adaptation to mechanical forces throughout life.While tightly regulated under the physiological state,its dysregulation contributes to pathological conditions such as osteoporosis,rheumatoid arthritis,and periodontitis.Periodontitis is a highly prevalent chronic inflammatory disease driven by dysbiotic biofilms that disrupt the oral microbiome,leading to the progressive breakdown of the periodontal ligament,cementum,and alveolar bone and ultimately resulting in tooth loss.This review outlines the molecular and cellular mechanisms underlying periodontitis,focusing on osteoclastogenesis,the differentiation and activation of osteoclasts,the primary mediators of bone resorption.Key transcriptional regulators,including NFATc1,c-Fos,and c-Src are discussed alongside major signaling pathways such as Mitogen Activated Protein Kinase(MAPK),Janus Tyrosine Kinase/Signal Transducer and Activator of Transcription(JAK/STAT),Nuclear Factor Kappa B(NF-κB),and Phosphoinositide 3-kinase(PI3K)/Akt,to elucidate their roles in the initiation and progression of periodontal bone loss.These pathways orchestrate the inflammatory response and osteoclast activity,underscoring their relevance in periodontitis and other osteolytic conditions.Hallmark features of periodontitis,including chronic inflammation,immune dysregulation,and tissue destruction are highlighted,with emphasis on current and emerging therapeutic strategies targeting these molecular pathways.Special attention is given to small molecules,biologics,and natural compounds that have the potential to modulate key signaling pathways.Although advances in understanding these mechanisms have identified promising therapeutic targets,translation into effective clinical interventions remains challenging.Continued research into regulating bone-resorptive signaling pathways is essential for developing more effective treatments for periodontitis and related inflammatory bone 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:Hepatocellular carcinoma(HCC)is a highly lethal malignancy driven by both intrinsic oncogenic pathways and immune microenvironmental regulation.Emerging evidence suggests that DNASE1L3 may influence tumor b...Background:Hepatocellular carcinoma(HCC)is a highly lethal malignancy driven by both intrinsic oncogenic pathways and immune microenvironmental regulation.Emerging evidence suggests that DNASE1L3 may influence tumor biology and immune responses;however,its specific roles in HCC progression and macrophage-mediated regulation remain unclear.This study aimed to elucidate the biological functions of DNASE1L3 in HCC and to determine how it modulates tumor behavior and immune interactions.Methods:Bioinformatics analyses of the GSE41804 and Cancer Genome Atlas-Liver Hepatocellular Carcinoma(TCGA-LIHC)datasets were used to identify hub genes.Functional assays assessed the impact of DNASE1L3 on HCC cell proliferation,migration,invasion,and cell cycle progression.The effects of DNASE1L3 on macrophage polarization and the Wnt/β-catenin signaling pathway were examined using a co-culture system.An HCC organoid model was established to further validate its regulatory function.Results:Eight prognostic signature genes were identified,with deoxyribonuclease I-like 3(DNase I-like 3)selected as the hub gene.DNASE1L3 overexpression suppressed HCC cell growth,inhibited migration and invasion,induced G1 arrest,and modulated epithelial-mesenchymal transition(EMT)markers.DNASE1L3 knockdown promoted M2-like macrophage polarization.Mechanistically,DNASE1L3 interacted withβ-catenin to enhance its ubiquitination and degradation,thereby inhibiting Wnt/β-catenin signaling and reducing PD-L1 expression.DNASE1L3 overexpression similarly restricted organoid growth and suppressed pathway activity.Conclusion:DNASE1L3 acts as a negative regulator of HCC progression by targeting the Wnt/β-catenin pathway and reducing PD-L1 expression,thereby influencing both tumor cell behavior and macrophage-mediated immune responses.展开更多
Tumors are defined by uncontrolled cell proliferation(Hariharan and Bilder,2006).Benign tumors are typically slow-growing and localized,while malignant ones are invasive and aggressive.The nuclear receptor Eip75B(E75)...Tumors are defined by uncontrolled cell proliferation(Hariharan and Bilder,2006).Benign tumors are typically slow-growing and localized,while malignant ones are invasive and aggressive.The nuclear receptor Eip75B(E75),a heme-binding protein responsive to ecdysone signaling,encodes three major isoforms,E75A,E75B,and E75C(Bialecki et al.,2002),among them,only E75A and E75C contain zinc finger domains that enable DNA binding.展开更多
The ErbB signaling network has recently emerged as a key modulator of central nervous system responses to injury.This review provides a comprehensive overview of ErbB receptors and their ligands,highlighting canonical...The ErbB signaling network has recently emerged as a key modulator of central nervous system responses to injury.This review provides a comprehensive overview of ErbB receptors and their ligands,highlighting canonical and non-canonical signaling mechanisms relevant to brain damage.We explore how ErbB signaling is dynamically regulated following injury and how it orchestrates processes such as neuroinflammation,gliosis,and neural repair.Special attention is given to its interplay with other critical pathways,including Notch signaling,and its roles within adult neurogenic niches,where it modulates neural stem cell behavior in response to damage.Based on accumulating preclinical evidence,we propose two therapeutic strategies for targeting ErbB signaling in brain injury:(1)dampening neuroinflammation through ErbB inhibition and(2)promoting neuroprotection and neurogenesis via neuregulin-1-mediated activation.The first strategy is supported by studies,which demonstrate that inhibition of ErbB1 limits neuroinflammation and supports neural repair in preclinical models.The latter strategy is supported by emerging studies demonstrating the significant potential of novel protein kinase C activating diterpenes in modulating ErbB signaling pathways through the regulation of neuregulin-1 release.Diterpenes,by influencing the ErbB pathway,may uniquely bridge the gap between neuroprotection and regeneration.Their potential to modulate inflammation and promote pro-regenerative cellular environments positions them as promising tools in the development of targeted therapies.By dissecting these mechanisms,we aim to shed light on the translational potential of ErbB-targeted therapies and their capacity to enhance endogenous repair processes in the injured brain.展开更多
Objectives The discovery of novel molecular targets to enhance the osteogenesis of human bone marrow-derived mesenchymal stem cells(H-BMSCs)represents a promising strategy for preventing and treating osteoporosis.Thus...Objectives The discovery of novel molecular targets to enhance the osteogenesis of human bone marrow-derived mesenchymal stem cells(H-BMSCs)represents a promising strategy for preventing and treating osteoporosis.Thus,the primary objective of this study is to elucidate the mechanisms by which long non-coding RNA FOXD2-AS1(lncRNA FOXD2-AS1)regulates early osteogenic differentiation in H-BMSCs,thereby identifying potential therapeutic targets.Methods Lentivirus-mediated vectors were constructed to either overexpress or silence FOXD2-AS1 in H-BMSCs.The effects of FOXD2-AS1 on osteogenesis were subsequently assessed by analyzing osteogenic marker expression and alkaline phosphatase(ALP)staining.To clarify the role of the Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)pathway in this process,AG490 inhibitor(a JAK2/STAT3 pathway inhibitor)and knockdown of STAT3 were used to investigate the mechanisms of FOXD2-AS1.Results FOXD2-AS1 overexpression increased ALP activity and osteogenic marker expression,while its knockdown had the opposite effects.From a mechanistic perspective,FOXD2-AS1 overexpression promoted JAK2 and STAT3 phosphorylation,whereas its suppression attenuated their activation.Also,the osteogenic increase induced by FOXD2-AS1 overexpression was reversed by AG490 treatment or STAT3 silencing,indicating that the pathway plays a role in this process.Conclusion FOXD2-AS1 was identified as a novel genetic switch driving osteogenic commitment via JAK2/STAT3 activation,revealing a new regulatory mechanism and a potential therapeutic target for osteoporosis.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
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
Tooth morphogenesis is orchestrated by a complex interplay of signaling pathways and transcription factors that control cell proliferation,apoptosis,and differentiation,with the Wnt/β-catenin signaling pathway playin...Tooth morphogenesis is orchestrated by a complex interplay of signaling pathways and transcription factors that control cell proliferation,apoptosis,and differentiation,with the Wnt/β-catenin signaling pathway playing a pivotal role.However,the comprehensive regulatory mechanisms of Wnt/β-catenin signaling remain largely unclear.Smad7,a key antagonist of the TGF-βsuperfamily,is essential for maintaining tissue homeostasis and ensuring proper cellular function.Our previous study has demonstrated that Smad7 knockout in mice leads to impaired proliferative property of tooth germ cells,resulting in small molars.Here,we identified SMAD7 expression in human dental papilla and dental pulp,colocalized with β-CATENIN and cell proliferationrelated proteins.RNA sequencing analysis revealed a significant reduction in Wnt signaling activity in Smad7-deficient mouse tooth germs.Using lentivirus transfection,we established SMAD7-knockdown human dental papilla stem cells,which manifested remarkably blunt proliferation rate,along with diminished Wnt signaling activity.In vivo transplantation investigations further revealed the indispensable role of SMAD7 in dentin formation.Mechanistically,we revealed that β-CATENIN interacts with P-SMAD2/3 and SMAD7 through co-immunoprecipitation and yeast two-hybrid assays.Inhibition of TGF-β pathway or disruption of SMAD7/β-CATENIN transcription factor complex formation potently impacted Wnt/β-catenin activities,indicating both direct and indirect regulatory mechanisms.These findings highlight the critical role of SMAD7 in the proliferation and diffe rentiation of human dental stem cells,which could contribute to dental tissue regeneration and engineering.展开更多
Background:Lung adenocarcinoma(LUAD),the most prevalent histological subtype of lung cancer,remains a leading cause of cancer-related mortality due to late diagnosis,metastasis,and therapy resistance.The aim of the st...Background:Lung adenocarcinoma(LUAD),the most prevalent histological subtype of lung cancer,remains a leading cause of cancer-related mortality due to late diagnosis,metastasis,and therapy resistance.The aim of the study is to investigate the role of Kinetochore Scaffold 1(KNL1)in promoting LUAD progression and its underlying molecular regulatory mechanisms.Methods:KNL1 mRNA expression levels across 33 cancer types were analyzed using bioinformatics analysis based on the TCGA database.Immunohistochemistry(IHC)was used to assess KNL1 expression in LUAD and normal tissues.Stable KNL1-knockdown and KNL1-overexpressing LUAD cell lines were established using lentiviral infection.Western blotting(WB)was used to measure epithelial-mesenchymal transition(EMT)markers and ferroptosis-related protein expression.Cell migration was evaluated via scratch wound healing assays.The thiobarbituric acid(TBA)method was employed for the detection of malondialdehyde.a fluorescent probe was utilized to determine ferrous ion content.WB determined the phosphorylation ratios of AMP-activated protein kinase(AMPK)and mammalian target of rapamycin(mTOR)proteins.Results:1.KNL1 was highly expressed in 31 cancer types,including LUAD.Kaplan-Meier curves showed significantly shorter median survival in patients with high KNL1 expression.IHC confirmed upregulated KNL1 expression in LUAD tissues.2.KNL1 overexpression significantly promoted LUAD cell migration and increased mesenchymal marker expression,whereas KNL1 knockdown exerted opposite effects.3.KNL1 overexpression significantly reduced MDA content and Fe^(2+)levels in RSL3-treated LUAD cells while increasing the expression of key ferroptosis defense proteins;conversely,it markedly increased the accumulation of MDA and Fe^(2+)and downregulated these proteins.KNL1 overexpression significantly increased phosphorylated AMPK(p-AMPK)expression but decreased phosphorylated mTOR(p-mTOR)expression in RSL3-treated LUAD cells;conversely,it inhibited p-AMPK expression and activated p-mTOR.Conclusion:KNL1 promotes lung adenocarcinoma progression by suppressing ferroptosis through regulation of the AMPK-mTOR signaling pathway.展开更多
Osteogenesis is the process of bone formation mediated by the osteoblasts,participating in various bone-related physiological processes including bone development,bone homeostasis and fracture healing.It exhibits temp...Osteogenesis is the process of bone formation mediated by the osteoblasts,participating in various bone-related physiological processes including bone development,bone homeostasis and fracture healing.It exhibits temporal and spatial interconnectivity with angiogenesis,constructed by multiple forms of cell communication occurring between bone and vascular endothelial cells.Molecular regulation among different cell types is crucial for coordinating osteogenesis and angiogenesis to facilitate bone remodeling,fracture healing,and other bone-related processes.The transmission of signaling molecules and the activation of their corresponding signal pathways are indispensable for various forms of cell communication.This communication acts as a“bridge”in coupling osteogenesis to angiogenesis.This article reviews the modes and processes of cell communication in osteogenesisangiogenesis coupling over the past decade,mainly focusing on interactions among bone-related cells and vascular endothelial cells to provide insights into the mechanism of cell communication of osteogenesis-angiogenesis coupling in different bone-related contexts.Moreover,clinical relevance and applications are also introduced in this review.展开更多
Recently,Tian et al.published a research paper with significant breakthroughs in Cell[1].The study found that targeting the signalling pathways named Serpine2-lowdensity lipoprotein receptor-related protein 1(Lrp1)and...Recently,Tian et al.published a research paper with significant breakthroughs in Cell[1].The study found that targeting the signalling pathways named Serpine2-lowdensity lipoprotein receptor-related protein 1(Lrp1)and ectonucleoside triphosphate diphosphohydrolase 1(CD39)-adenosine A_(3)receptor(A_(3)AR)is a promising strategy for the treatment of vascular dementia.The Serpine2-Lrp1 signalling pathway primarily exerts its therapeutic effects on myelin regeneration by regulating the differentiation of oligodendrocyte precursor cells.Serpine2 is a secretory serine protease inhibitor regulates proteolytic homeostasis.It may also bind to cell surface receptors such as Lrp1 to directly activate signalling pathways.As a transmembrane glycoprotein receptor,Lrpl mediates the endocytic clearance of ligands.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
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
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
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
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funded by Yunnan Youth Top-notch Talent Support Program(YNWR-QNBJ2018-173)Agricultural Joint project of Yunnan Provincial S&T Programs(202301BD070001-195)+2 种基金S&T project of Yunnan provincial finance(K212020001-01)supported by Yunnan Province Education Department’s Engineering Research Center of Eco-friendly Products from Yunnan Characteristic Edible FungiYunnan Province Yongsheng County Farmer Academician Technology service station.
文摘Muscle atrophy can be induced by high doses or prolonged use of glucocorticoids.Kaempferol(Kae)is a naturally occurring flavonoid with a variety of biological activities and the effect of Kae on dexamethasone(Dex)induced muscle atrophy in animals has not been elucidated.To explore this issue,the present experiments used a computationally assisted drug design scheme combining network pharmacology,molecular docking and in vivo experiments to investigate the mechanism of Kae against muscle atrophy.Network pharmacological analyses revealed 275 potential targets for Kae and 12294 potential targets for muscle atrophy,with a total of 228 crosstargets for Kae and muscle atrophy.GO and KEGG analyses were performed based on the protein-protein interaction(PPI)network of muscle atrophy and Kae component targets.The GO results showed that the biological processes were mainly related to the metabolic process of reactive oxygen species,and the response to oxidative stress;the cellular components were mainly focused on membrane microdomains,and membrane regions;the molecular functions mainly worked on phosphatase binding;and the KEGG pathway enrichment analyses identified the pathways of interaction between Kae and muscle atrophy.Finally,as verified by in vivo experiments,Kae may reduce the onset of muscle atrophy by activating the PI3K/AKT/m TOR/signalling pathway,inhibiting Foxo1/Foxo3 activity,and inhibiting downstream production of the ubiquitination 3 ligases Atrogin1 and Mu RF1;Kae also promotes the expression of NRF2/HO-1/KEAP1 signalling pathway,enhances muscle antioxidant capacity,inhibits the release of COX-2 and TNF-αinflammatory factors,and reduces the damage caused by oxidative stress and inflammatory factors to muscles.Therefore,there may be a synergistic effect of PI3K/AKT/m TOR and NRF2/HO-1/KEAP1 in Kae working together to prevent muscle atrophy.The binding energy and stability of Kae to potential targets were examined by molecular docking and molecular dynamics simulations,implying that Kae could be used for the prevention and treatment of muscle atrophy in patients.
基金supported by the National Natural Science Foundation of China (Nos. 82104430 and 82274133)the Shanghai Sailing Program (No. 21YF1447600)the Future Plan for Traditional Chinese Medicine Development of Science and Technology of Shanghai Municipal Hospital of Traditional Chinese Medicine (No. WL-HBQN-2022002K)。
文摘Taohong Siwu Decoction(THSWD), a traditional Chinese medicinal formulation, has been demonstrated to significantly modulate key signaling pathways implicated in atherosclerosis(AS). This review examines the complex mechanisms through which THSWD influences critical pathways, including nuclear factor kappa-B(NF-κB), phosphatidylinositol 3-kinase(PI3K)/serine-threonine kinase(AKT), Toll-like receptor 4(TLR4), mitogen-activated protein kinase(MAPK), and mammalian target of rapamycin(mTOR), that play pivotal roles in AS pathogenesis. By synthesizing experimental evidence and existing literature, the review summarizes how THSWD and its bioactive constituents regulate these signaling cascades to ameliorate AS. Furthermore, it highlights the distinctive therapeutic advantages of traditional Chinese medicine(TCM) compounds in managing chronic diseases driven by multi-target and multifactorial mechanisms. Analyzing disease targets from the perspective of signaling pathways enhances the scientific validation of clinical efficacy for such formulations, thereby offering novel insights for future research.
基金supported by grant provided by the Sao Paulo Research Foundation-FAPESP.Grant#2023/15750-7。
文摘Bone resorption is a vital physiological process that enables skeletal remodeling,maintenance,and adaptation to mechanical forces throughout life.While tightly regulated under the physiological state,its dysregulation contributes to pathological conditions such as osteoporosis,rheumatoid arthritis,and periodontitis.Periodontitis is a highly prevalent chronic inflammatory disease driven by dysbiotic biofilms that disrupt the oral microbiome,leading to the progressive breakdown of the periodontal ligament,cementum,and alveolar bone and ultimately resulting in tooth loss.This review outlines the molecular and cellular mechanisms underlying periodontitis,focusing on osteoclastogenesis,the differentiation and activation of osteoclasts,the primary mediators of bone resorption.Key transcriptional regulators,including NFATc1,c-Fos,and c-Src are discussed alongside major signaling pathways such as Mitogen Activated Protein Kinase(MAPK),Janus Tyrosine Kinase/Signal Transducer and Activator of Transcription(JAK/STAT),Nuclear Factor Kappa B(NF-κB),and Phosphoinositide 3-kinase(PI3K)/Akt,to elucidate their roles in the initiation and progression of periodontal bone loss.These pathways orchestrate the inflammatory response and osteoclast activity,underscoring their relevance in periodontitis and other osteolytic conditions.Hallmark features of periodontitis,including chronic inflammation,immune dysregulation,and tissue destruction are highlighted,with emphasis on current and emerging therapeutic strategies targeting these molecular pathways.Special attention is given to small molecules,biologics,and natural compounds that have the potential to modulate key signaling pathways.Although advances in understanding these mechanisms have identified promising therapeutic targets,translation into effective clinical interventions remains challenging.Continued research into regulating bone-resorptive signaling pathways is essential for developing more effective treatments for periodontitis and related inflammatory bone 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.
基金funded by Shanghai Science and Technology Innovation Action Plan Project(22140901100)Shanghai Key Laboratory of Molecular Imaging(18DZ2260400)Shanghai University of Medicine and Health Science Seed Fund(SSF-24-21-01).
文摘Background:Hepatocellular carcinoma(HCC)is a highly lethal malignancy driven by both intrinsic oncogenic pathways and immune microenvironmental regulation.Emerging evidence suggests that DNASE1L3 may influence tumor biology and immune responses;however,its specific roles in HCC progression and macrophage-mediated regulation remain unclear.This study aimed to elucidate the biological functions of DNASE1L3 in HCC and to determine how it modulates tumor behavior and immune interactions.Methods:Bioinformatics analyses of the GSE41804 and Cancer Genome Atlas-Liver Hepatocellular Carcinoma(TCGA-LIHC)datasets were used to identify hub genes.Functional assays assessed the impact of DNASE1L3 on HCC cell proliferation,migration,invasion,and cell cycle progression.The effects of DNASE1L3 on macrophage polarization and the Wnt/β-catenin signaling pathway were examined using a co-culture system.An HCC organoid model was established to further validate its regulatory function.Results:Eight prognostic signature genes were identified,with deoxyribonuclease I-like 3(DNase I-like 3)selected as the hub gene.DNASE1L3 overexpression suppressed HCC cell growth,inhibited migration and invasion,induced G1 arrest,and modulated epithelial-mesenchymal transition(EMT)markers.DNASE1L3 knockdown promoted M2-like macrophage polarization.Mechanistically,DNASE1L3 interacted withβ-catenin to enhance its ubiquitination and degradation,thereby inhibiting Wnt/β-catenin signaling and reducing PD-L1 expression.DNASE1L3 overexpression similarly restricted organoid growth and suppressed pathway activity.Conclusion:DNASE1L3 acts as a negative regulator of HCC progression by targeting the Wnt/β-catenin pathway and reducing PD-L1 expression,thereby influencing both tumor cell behavior and macrophage-mediated immune responses.
基金supported by the National Natural Science Foundation of China(32170824 and 32322027 to X.M.)HRHI program of Westlake Laboratory of Life Sciences and Biomedicine(1011103360222B1 to X.M.)+1 种基金"Pioneer"and"Leading Goose"R&D Program of Zhejiang(2024SSYS0034)State Key Laboratory of Gene Expression.
文摘Tumors are defined by uncontrolled cell proliferation(Hariharan and Bilder,2006).Benign tumors are typically slow-growing and localized,while malignant ones are invasive and aggressive.The nuclear receptor Eip75B(E75),a heme-binding protein responsive to ecdysone signaling,encodes three major isoforms,E75A,E75B,and E75C(Bialecki et al.,2002),among them,only E75A and E75C contain zinc finger domains that enable DNA binding.
基金supported by the I+D+i(PID2022-142418OB-C21)grant funded by MICIU/AEI/10.13039/501100011033 and by ERDF/UE.
文摘The ErbB signaling network has recently emerged as a key modulator of central nervous system responses to injury.This review provides a comprehensive overview of ErbB receptors and their ligands,highlighting canonical and non-canonical signaling mechanisms relevant to brain damage.We explore how ErbB signaling is dynamically regulated following injury and how it orchestrates processes such as neuroinflammation,gliosis,and neural repair.Special attention is given to its interplay with other critical pathways,including Notch signaling,and its roles within adult neurogenic niches,where it modulates neural stem cell behavior in response to damage.Based on accumulating preclinical evidence,we propose two therapeutic strategies for targeting ErbB signaling in brain injury:(1)dampening neuroinflammation through ErbB inhibition and(2)promoting neuroprotection and neurogenesis via neuregulin-1-mediated activation.The first strategy is supported by studies,which demonstrate that inhibition of ErbB1 limits neuroinflammation and supports neural repair in preclinical models.The latter strategy is supported by emerging studies demonstrating the significant potential of novel protein kinase C activating diterpenes in modulating ErbB signaling pathways through the regulation of neuregulin-1 release.Diterpenes,by influencing the ErbB pathway,may uniquely bridge the gap between neuroprotection and regeneration.Their potential to modulate inflammation and promote pro-regenerative cellular environments positions them as promising tools in the development of targeted therapies.By dissecting these mechanisms,we aim to shed light on the translational potential of ErbB-targeted therapies and their capacity to enhance endogenous repair processes in the injured brain.
基金supported by the Natural Science Foundation of Hubei Province of China(Grant No.2023AFB671)the National Natural Science Foundation of China(Grant Nos.82360177 and 82560182)+1 种基金the Key Project of Jiangxi Provincial Natural Science Foundation(Grant No.20224ACB206011)“Xuncheng Talents”Project in Jiujiang City,Jiangxi Province(Grant No.JJXC2023071).
文摘Objectives The discovery of novel molecular targets to enhance the osteogenesis of human bone marrow-derived mesenchymal stem cells(H-BMSCs)represents a promising strategy for preventing and treating osteoporosis.Thus,the primary objective of this study is to elucidate the mechanisms by which long non-coding RNA FOXD2-AS1(lncRNA FOXD2-AS1)regulates early osteogenic differentiation in H-BMSCs,thereby identifying potential therapeutic targets.Methods Lentivirus-mediated vectors were constructed to either overexpress or silence FOXD2-AS1 in H-BMSCs.The effects of FOXD2-AS1 on osteogenesis were subsequently assessed by analyzing osteogenic marker expression and alkaline phosphatase(ALP)staining.To clarify the role of the Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)pathway in this process,AG490 inhibitor(a JAK2/STAT3 pathway inhibitor)and knockdown of STAT3 were used to investigate the mechanisms of FOXD2-AS1.Results FOXD2-AS1 overexpression increased ALP activity and osteogenic marker expression,while its knockdown had the opposite effects.From a mechanistic perspective,FOXD2-AS1 overexpression promoted JAK2 and STAT3 phosphorylation,whereas its suppression attenuated their activation.Also,the osteogenic increase induced by FOXD2-AS1 overexpression was reversed by AG490 treatment or STAT3 silencing,indicating that the pathway plays a role in this process.Conclusion FOXD2-AS1 was identified as a novel genetic switch driving osteogenic commitment via JAK2/STAT3 activation,revealing a new regulatory mechanism and a potential therapeutic target for osteoporosis.
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 Key Research and Development Program of China to W.Tian (2022YFA1104400)the National Natural Science Foundation of China to T.Chen (82100959)a grant from the Sichuan Science and Technology Program to Z.Liu (2024YFFK0068)。
文摘Tooth morphogenesis is orchestrated by a complex interplay of signaling pathways and transcription factors that control cell proliferation,apoptosis,and differentiation,with the Wnt/β-catenin signaling pathway playing a pivotal role.However,the comprehensive regulatory mechanisms of Wnt/β-catenin signaling remain largely unclear.Smad7,a key antagonist of the TGF-βsuperfamily,is essential for maintaining tissue homeostasis and ensuring proper cellular function.Our previous study has demonstrated that Smad7 knockout in mice leads to impaired proliferative property of tooth germ cells,resulting in small molars.Here,we identified SMAD7 expression in human dental papilla and dental pulp,colocalized with β-CATENIN and cell proliferationrelated proteins.RNA sequencing analysis revealed a significant reduction in Wnt signaling activity in Smad7-deficient mouse tooth germs.Using lentivirus transfection,we established SMAD7-knockdown human dental papilla stem cells,which manifested remarkably blunt proliferation rate,along with diminished Wnt signaling activity.In vivo transplantation investigations further revealed the indispensable role of SMAD7 in dentin formation.Mechanistically,we revealed that β-CATENIN interacts with P-SMAD2/3 and SMAD7 through co-immunoprecipitation and yeast two-hybrid assays.Inhibition of TGF-β pathway or disruption of SMAD7/β-CATENIN transcription factor complex formation potently impacted Wnt/β-catenin activities,indicating both direct and indirect regulatory mechanisms.These findings highlight the critical role of SMAD7 in the proliferation and diffe rentiation of human dental stem cells,which could contribute to dental tissue regeneration and engineering.
基金supported by grants from Natural Science Foundation of Hunan Province(No.2022JJ50158).
文摘Background:Lung adenocarcinoma(LUAD),the most prevalent histological subtype of lung cancer,remains a leading cause of cancer-related mortality due to late diagnosis,metastasis,and therapy resistance.The aim of the study is to investigate the role of Kinetochore Scaffold 1(KNL1)in promoting LUAD progression and its underlying molecular regulatory mechanisms.Methods:KNL1 mRNA expression levels across 33 cancer types were analyzed using bioinformatics analysis based on the TCGA database.Immunohistochemistry(IHC)was used to assess KNL1 expression in LUAD and normal tissues.Stable KNL1-knockdown and KNL1-overexpressing LUAD cell lines were established using lentiviral infection.Western blotting(WB)was used to measure epithelial-mesenchymal transition(EMT)markers and ferroptosis-related protein expression.Cell migration was evaluated via scratch wound healing assays.The thiobarbituric acid(TBA)method was employed for the detection of malondialdehyde.a fluorescent probe was utilized to determine ferrous ion content.WB determined the phosphorylation ratios of AMP-activated protein kinase(AMPK)and mammalian target of rapamycin(mTOR)proteins.Results:1.KNL1 was highly expressed in 31 cancer types,including LUAD.Kaplan-Meier curves showed significantly shorter median survival in patients with high KNL1 expression.IHC confirmed upregulated KNL1 expression in LUAD tissues.2.KNL1 overexpression significantly promoted LUAD cell migration and increased mesenchymal marker expression,whereas KNL1 knockdown exerted opposite effects.3.KNL1 overexpression significantly reduced MDA content and Fe^(2+)levels in RSL3-treated LUAD cells while increasing the expression of key ferroptosis defense proteins;conversely,it markedly increased the accumulation of MDA and Fe^(2+)and downregulated these proteins.KNL1 overexpression significantly increased phosphorylated AMPK(p-AMPK)expression but decreased phosphorylated mTOR(p-mTOR)expression in RSL3-treated LUAD cells;conversely,it inhibited p-AMPK expression and activated p-mTOR.Conclusion:KNL1 promotes lung adenocarcinoma progression by suppressing ferroptosis through regulation of the AMPK-mTOR signaling pathway.
基金supported by central government-guided major science and technology project of Hebei province 236Z7709G(M.C.Q.)Tangshan science and technology project 23130216E(M.C.Q.)+8 种基金key research projects of North China University of Science and Technology ZD-YG-202309(M.C.Q.)National Natural Science Foundations of China 82230030 and 81871492(Y.L.)Beijing International Science and Technology Cooperation Project Z221100002722003(Y.L.)Beijing Natural Science Foundation L234017(Y.L.)Peking University Medicine plus X Pilot Program-Key Technologies R&D Project 2024YXXLHGG004(Y.L.)Key R&D Plan of Ningxia Hui Autonomous Region 2020BCG01001(Y.L.)First-Class Discipline Team of Kunming Medical University 2024XKTDTS08(Y.L.)Innovative Research Team of High-level Local Universities in Shanghai SHSMU-ZLCX20212402(Y.L.)Postdoctoral Fellowship Program of CPSF under Grant Number GZB20240038(X.J.C.).
文摘Osteogenesis is the process of bone formation mediated by the osteoblasts,participating in various bone-related physiological processes including bone development,bone homeostasis and fracture healing.It exhibits temporal and spatial interconnectivity with angiogenesis,constructed by multiple forms of cell communication occurring between bone and vascular endothelial cells.Molecular regulation among different cell types is crucial for coordinating osteogenesis and angiogenesis to facilitate bone remodeling,fracture healing,and other bone-related processes.The transmission of signaling molecules and the activation of their corresponding signal pathways are indispensable for various forms of cell communication.This communication acts as a“bridge”in coupling osteogenesis to angiogenesis.This article reviews the modes and processes of cell communication in osteogenesisangiogenesis coupling over the past decade,mainly focusing on interactions among bone-related cells and vascular endothelial cells to provide insights into the mechanism of cell communication of osteogenesis-angiogenesis coupling in different bone-related contexts.Moreover,clinical relevance and applications are also introduced in this review.
基金support from the Sichuan Science and Technology Program(2024JDHJ0043 and 2025YFHZ0121).
文摘Recently,Tian et al.published a research paper with significant breakthroughs in Cell[1].The study found that targeting the signalling pathways named Serpine2-lowdensity lipoprotein receptor-related protein 1(Lrp1)and ectonucleoside triphosphate diphosphohydrolase 1(CD39)-adenosine A_(3)receptor(A_(3)AR)is a promising strategy for the treatment of vascular dementia.The Serpine2-Lrp1 signalling pathway primarily exerts its therapeutic effects on myelin regeneration by regulating the differentiation of oligodendrocyte precursor cells.Serpine2 is a secretory serine protease inhibitor regulates proteolytic homeostasis.It may also bind to cell surface receptors such as Lrp1 to directly activate signalling pathways.As a transmembrane glycoprotein receptor,Lrpl mediates the endocytic clearance of ligands.
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.
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 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.
