AIM:To examine the effects of combined treatment of oxaliplatin and phosphatidylinositol 3'-kinase inhibitor,2-(4-morpholinyl) -8-phenyl-4H-1-benzopyran-4-one(LY294002) for gastric cancer. METHODS:Cell viability w...AIM:To examine the effects of combined treatment of oxaliplatin and phosphatidylinositol 3'-kinase inhibitor,2-(4-morpholinyl) -8-phenyl-4H-1-benzopyran-4-one(LY294002) for gastric cancer. METHODS:Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide assay.Apoptotic cells were detected by flow cytometric analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay.Western blotting and immuno-precipitation were used to examine protein expression and recruitment,respectively.Nuclear factorκB(NFκB) binding activities were investigated using electrophoretic mobility shift assay.Nude mice were used to investigate tumor growth. RESULTS:Treatment with combined oxaliplatin and LY294002 resulted in increased cell growth inhibi-tion and cell apoptosis in vitro,and increased tumor growth inhibition and cell death in the tumor mass in vivo.In MKN45 and AGS cells,oxaliplatin treatment promoted both protein kinase B(Akt) and NFκB activation,while pretreatment with LY294002 significantly attenuated oxaliplatin-induced Akt activity and NFκB binding.LY294002 promoted oxaliplatin-induced Fas ligand(FasL) expression,Fas-associated death domain protein recruitment,caspase-8,Bid,and caspase-3 activation,and the short form of cellular caspase-8/FLICEinhibitory protein(c-FLIPS) inhibition.In vivo,LY294002 inhibited oxaliplatin-induced activation of Akt and NFκB,and increased oxaliplatin-induced expression of FasL,inhibition of c-FLIPS,and activation of caspase-8,Bid,and caspase-3. CONCLUSION:Combination of oxaliplatin and LY294002 was therapeutically promising for gastric cancer treatment.The enhanced sensitivity of the combined treatment was associated with the activation of the death receptor pathway.展开更多
BACKGROUND Colorectal cancer(CRC)is an extremely malignant tumor with a high mortality rate.Little is known about the mechanism by which forkhead Box q1(FOXQ1)causes CRC invasion and metastasis through the epidermal g...BACKGROUND Colorectal cancer(CRC)is an extremely malignant tumor with a high mortality rate.Little is known about the mechanism by which forkhead Box q1(FOXQ1)causes CRC invasion and metastasis through the epidermal growth factor receptor(EGFR)pathway.AIM To illuminate the mechanism by which FOXQ1 promotes the invasion and metastasis of CRC by activating the heparin binding epidermal growth factor(HB-EGF)/EGFR pathway.METHODS We investigated the differential expression and prognosis of FOXQ1 and HB-EGF in CRC using the Gene Expression Profiling Interactive Analysis(GEPIA)website(http://gepia.cancer-pku.cn/index.html).Quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting were used to detect the expression of FOXQ1 and HB-EGF in cell lines and tissues,and we constructed a stable lowexpressing FOXQ1 cell line and verified it with the above method.The expression changes of membrane-bound HB-EGF(proHB-EGF)and soluble HB-EGF(sHB-EGF)in the lowexpressing FOXQ1 cell line were detected by flow cytometry and ELISA.Western blotting was used to detect changes in the expression levels of HB-EGF and EGFR pathway-related downstream genes when exogenous recombinant human HB-EGF was added to FOXQ1 knockdown cells.Proliferation experiments,transwell migration experiments,and scratch experiments were carried out to determine the mechanism by which FOXQ1 activates the EGFR signaling pathway through HB-EGF,and then to evaluate the clinical relevance of FOXQ1 and HB-EGF.RESULTS GEPIA showed that the expression of FOXQ1 in CRC tissues was relatively high and was related to a lower overall survival rate.PCR array results showed that FOXQ1 is related to the HB-EGF and EGFR pathways.Knockdown of FOXQ1 suppressed the expression of HB-EGF,and led to a decrease in EGFR and its downstream genes AKT,RAF,KRAS expression levels.After knockdown of FOXQ1 in CRC cell lines,cell proliferation,migration and invasion were attenuated.Adding HB-EGF restored the migration and invasion ability of CRC,but not the cell proliferation ability.Kaplan–Meier survival analysis results showed that the combination of FOXQ1 and HB-EGF may serve to predict CRC survival.CONCLUSION Based on these collective data,we propose that FOXQ1 promotes the invasion and metastasis of CRC via the HB-EGF/EGFR pathway.展开更多
Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand...Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.展开更多
Objective： To investigate the effects of xanthotoxin from Apiaceae medicinal plants on cell proliferation and apoptosis, and explore its mechanism of action against human gastric carcinoma SGC-7901 cells in vitro.Met...Objective： To investigate the effects of xanthotoxin from Apiaceae medicinal plants on cell proliferation and apoptosis, and explore its mechanism of action against human gastric carcinoma SGC-7901 cells in vitro.Methods： SGC-7901, HepG-2, MCF-7, and A549 cells were treated with different concentrations of xanthotoxin（10, 20, 60, 80, 100, 120, 140, and 160 μg/mL） for 48 h, and the cell viability（IC50） was determined by MTT assay; Xanthotoxin-induced apoptosis in cells was observed by using Hoechst 33258 Staining Kit and Annexin V-FITC Apoptosis Detection Kit; Flow cytometry was used to detect apoptosis related proteins of Fas/FasL, Bid, and DR5/TRAIL proteins in human gastric carcinoma SGC-7901 cells after being treated by xanthotoxin; The influence of xanthotoxin on Caspase-8 protein expression in the cells was determined by Flouormetric Assay Kit.Results： Xanthotoxin obviously inhibited SGC-7901, HepG-2, MCF-7, and A549 cells proliferation, and its inhibition was in a concentration-dependent manner; flow cytometry results showed that in a certain concentration range, xanthotoxin can increase the expression levels of Fas/FasL and DR5/TRAIL proteins in a concentration-dependence manner. The content of Bid protein in cells was increased, and it showed concentration-dependence.Conclusion： Xanthotoxin may induce SGC-7901 cells apoptosis in a certain concentration range through the Fas/FasL protein mediated death receptor pathway, or by DR5/TRAIL mediated death receptor pathway, and increase the expression level of death receptor protein, activation Caspase-8, activating downstream effect factor, inducing cell apoptosis, or activate Caspase-8 cutting activate protein Bid, and then enter the mitochondrial pathway, induction of apoptosis.展开更多
Objective The aim of this study is to investigate whether microwave exposure would affect the N-methyI-D-aspartate receptor （NMDAR） signaling pathway to establish whether this plays a role in synaptic plasticity imp...Objective The aim of this study is to investigate whether microwave exposure would affect the N-methyI-D-aspartate receptor （NMDAR） signaling pathway to establish whether this plays a role in synaptic plasticity impairment. Methods 48 male Wistar rats were exposed to 30 mW/cm^2 microwave for 10 min every other day for three times. Hippocampal structure was observed through H＆E staining and transmission electron microscope. PC12 cells were exposed to 30 mW/cm^2 microwave for 5 min and the synapse morphology was visualized with scanning electron microscope and atomic force microscope. The release of amino acid neurotransmitters and calcium influx were detected. The expressions of several key NMDAR signaling molecules were evaluated. Results Microwave exposure caused injury in rat hippocampal structure and PC12 cells, especially the structure and quantity of synapses. The ratio of glutamic acid and gamma-aminobutyric acid neurotransmitters was increased and the intracellular calcium level was elevated in PC12 cells. A significant change in NMDAR subunits （NR1, NR2A, and NR2B） and related signaling molecules （CaZ＋/calmodulin-dependent kinase II gamma and phosphorylated cAMP-response element binding protein） were examined. Conclusion 30 mW/cm^2 microwave exposure resulted in alterations of synaptic structure, amino acid neurotransmitter release and calcium influx. NMDAR signaling molecules were closely associated with impaired synaptic plasticity.展开更多
AIM：To detect the expression of B cell receptor signaling pathway（BCRSP） in lacrimal gland benign lymphoepithelial lesions（LGBLEL）.METHODS：Gene microarray was used to compare whole-genome expression in lacrimal ...AIM：To detect the expression of B cell receptor signaling pathway（BCRSP） in lacrimal gland benign lymphoepithelial lesions（LGBLEL）.METHODS：Gene microarray was used to compare whole-genome expression in lacrimal gland tissues from LGBLEL patients to tissues from orbital cavernous hemangioma（control tissues）. Expression of BCRSP was confirmed by polymerase chain reaction（PCR） and immunohistochemistry. RESULTS：The expression of 22 genes of the BCRSP increased significantly in LGBLEL patients. PCR analysis showed that CD22, CR2, and BTK were all highly expressed in LGBLEL tissues. Immunohistochemical analysis showed that CR2 protein was present in LGBLEL, but CD22 and BTK proteins were negative. CR2, CD22, and BTK were not observed in the orbital cavernous hemangiomas with either PCR or immunohistochemistry. CONCLUSION：BCRSP might be involved in the pathogenesis of LGBLEL.展开更多
Avian infectious bronchitis virus(IBV) is a Gammacoronavirus in the family Coronaviridae and causes highly contagious respiratory disease in chickens. Innate immunity plays significant roles in host defense against IB...Avian infectious bronchitis virus(IBV) is a Gammacoronavirus in the family Coronaviridae and causes highly contagious respiratory disease in chickens. Innate immunity plays significant roles in host defense against IBV. Here, we explored the interaction between IBV and the host innate immune system. Severe histopathological lesions were observed in the tracheal mucosa at 3–5days post inoculation(dpi) and in the kidney at 8 dpi, with heavy viral loads at 1–11 and 1–28 dpi,respectively. The expression of m RNAs encoding Toll-like receptor(TLR) 3 and TLR7 were upregulated at 3–8 dpi, and that of TIR-domain-containing adapter-inducing interferon(IFN) β(TRIF) was upregulated at 21 dpi in the trachea and kidney. Myeloid differentiation primary response protein 88(My D88) was upregulated in the trachea during early infection. Tumor necrosis factor receptor-associated factor(TRAF) 3 and TRAF6 were upregulated expression in both tissues.Moreover, melanoma differentiation-associated protein 5(MDA5), laboratory of genetics and physiology 2(LGP2), stimulator of IFN genes(STING), and mitochondrial antiviral signaling protein(MAVS), as well as TANK binding kinase 1(TBK1), inhibitor of kappa B kinase(IKK) ?, IKKα, IKKβ,IFN regulatory factor(IRF) 7, nuclear factor of kappa B(NF-κB), IFN-α, IFN-β, various interleukins(ILs), and macrophage inflammatory protein-1β(MIP-1β) were significantly upregulated in the trachea and downregulated in the kidney. These results suggested that the TLR and MDA5 signaling pathways and innate immune cytokine were induced after IBV infection. Additionally,consistent responses to IBV infection were observed during early infection, with differential and complicated responses in the kidney.展开更多
Objective:MiRNAs have been recently implicated in the pathogenesis of ischemia-reperfusion(IR)injury.This study aimed to investigate the miRNA expression profiles,in the early stages after lung transplantation(LT)and ...Objective:MiRNAs have been recently implicated in the pathogenesis of ischemia-reperfusion(IR)injury.This study aimed to investigate the miRNA expression profiles,in the early stages after lung transplantation(LT)and to study the involvement of the Toll-like receptor(TLR)signaling pathway in lung IR injury following LT.Methods:We established the left LT model in mice and selected the miRNA-122 as a research target.The mice were injected with a miRNA-122-specific inhibitor,following which pathological changes in the lung tissue were studied using different lung injury indicators.In addition,we performed deep sequencing of transplanted lung tissues to identify differentially expressed(DE)miRNAs and their target genes.These target genes were used to further perform gene ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis.Results:A total of 12 DE miRNAs were selected,and 2476 target genes were identified.The GO enrichment analysis predicted 6063 terms,and the KEGG analysis predicted 1554 biological pathways.Compared with the control group,inhibiting the expression of miRNA-122 significantly reduced the lung injury and lung wet/dry ratio(P<0.05).In addition,the activity of myeloperoxidase and the expression levels of tumor necrosis factor-alpha and TLR2/4 were decreased(P<0.05);whereas the expression of interleukin-10 was increased(P<0.05).Furthermore,the inhibition of miRNA-122 suppressed the IR injury-induced activation of the TLR signaling pathway.Conclusion:Our findings showed the differential expression of several miRNAs in the early inflammatory response following LT.Of these,miRNA-122 promoted IR injury following LT,whereas its inhibition prevented IR injury in a TLR-dependent manner.展开更多
Multiple sclerosis（MS）is a chronic autoimmune disease of the central nervous system（CNS）characterized by coexisting processes of inflammation,demyelination,axonal neurodegeneration,and gliosis.It is the most commo...Multiple sclerosis（MS）is a chronic autoimmune disease of the central nervous system（CNS）characterized by coexisting processes of inflammation,demyelination,axonal neurodegeneration,and gliosis.It is the most common disabling neurological disease in young adulthood.展开更多
Whether M3 cholinergic receptor signal transduction pathway is involved in regulation of the activation of NF-κB and the expression of chemokine MOB-1, MCP-1genes in pancreatic acinar cells was investigated. Rat panc...Whether M3 cholinergic receptor signal transduction pathway is involved in regulation of the activation of NF-κB and the expression of chemokine MOB-1, MCP-1genes in pancreatic acinar cells was investigated. Rat pancreatic acinar cells were isolated, cultured and treated with carbachol, atropine and PDTC in vitro. The MOB-1 and MCP-1 mRNA expression was detected by using RT-PCR. The activation of NF-κB was monitored by using electrophoretic mobility shift assay. The results showed that as compared with control group, M3 cholinergic receptor agonist (10 -3 mol/L, 10 -4 mol/L carbachol) could induce a concentration-dependent and time-dependent increase in the expression of MOB-1, MCP-1 mRNA in pancreatic acinar cells. After treatment with 10 -3 mol/L carbachol for 2 h, the expression of MOB-1, MCP-1 mRNA was strongest. The activity of NF-κB in pancreatic acinar cells was significantly increased (P<0.01) after treated with M3 cholinergic receptor agonist (10 -3 mol/L carbachol) in vitro for 30 min. Either M3 cholinergic receptor antagonist (10 -5 mol/L atropine) or NF-κB inhibitor (10 -2 mol/L PDTC) could obviously inhibit the activation of NF-κB and the chemokine MOB-1, MCP-1 mRNA expression induced by carbachol (P<0.05). This inhibitory effect was significantly increased by atropine plus PDTC (P<0.01). The results of these studies indicated that M3 cholinergic receptor signal transduction pathway was likely involved in regulation of the expression of chemokine MOB-1 and MCP-1genes in pancreatic acinar cells in vitro through the activation of NF-κB.展开更多
The prevalence of prostate cancer in males worldwide is increasing every year.Androgen and androgen receptor drive the development of prostate cancer and are important targets for the treatment of prostate cancer.A gr...The prevalence of prostate cancer in males worldwide is increasing every year.Androgen and androgen receptor drive the development of prostate cancer and are important targets for the treatment of prostate cancer.A growing number of reports indicate that the traditional Chinese medicine has a clear advantage in the prevention and treatment of prostate cancer.This article provides an overview of the in vitro and in vivo studies of different traditional Chinese medicine monomers acting on the androgen receptor-signaling pathway in prostate cancer.展开更多
BACKGROUND Jianpi Gushen Huayu Decoction(JPGS)has been used to clinically treat diabetic nephropathy(DN)for many years.However,the protective mechanism of JPGS in treating DN remains unclear.AIM To evaluate the therap...BACKGROUND Jianpi Gushen Huayu Decoction(JPGS)has been used to clinically treat diabetic nephropathy(DN)for many years.However,the protective mechanism of JPGS in treating DN remains unclear.AIM To evaluate the therapeutic effects and the possible mechanism of JPGS on DN.METHODS We first evaluated the therapeutic potential of JPGS on a DN mouse model.We then investigated the effect of JPGS on the renal metabolite levels of DN mice using non-targeted metabolomics.Furthermore,we examined the effects of JPGS on c-Jun N-terminal kinase(JNK)/P38-mediated apoptosis and the inflammatory responses mediated by toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB)/NOD-like receptor family pyrin domain containing 3(NLRP3).RESULTS The ameliorative effects of JPGS on DN mice included the alleviation of renal injury and the control of inflammation and oxidative stress.Untargeted metabolomic analysis revealed that JPGS altered the metabolites of the kidneys in DN mice.A total of 51 differential metabolites were screened.Pathway analysis results indicated that nine pathways significantly changed between the control and model groups,while six pathways significantly altered between the model and JPGS groups.Pathways related to cysteine and methionine metabolism;alanine,tryptophan metabolism;aspartate and glutamate metabolism;and riboflavin metabolism were identified as the key pathways through which JPGS affects DN.Further experimental validation showed that JPGS treatment reduced the expression of TLR4/NF-κB/NLRP3 pathways and JNK/P38 pathway-mediated apoptosis related factors.CONCLUSION JPGS could markedly treat mice with streptozotocin(STZ)-induced DN,which is possibly related to the regulation of several metabolic pathways found in kidneys.Furthermore,JPGS could improve kidney inflammatory responses and ameliorate kidney injuries in DN mice via the TLR4/NF-κB/NLRP3 pathway and inhibit JNK/P38 pathwaymediated apoptosis in DN mice.展开更多
Non-alcoholic fatty liver disease(NAFLD),a critical global health concern,continues to challenge medical researchers with limited treatment options.This letter examines on the study by Luo et al,demonstrating that vit...Non-alcoholic fatty liver disease(NAFLD),a critical global health concern,continues to challenge medical researchers with limited treatment options.This letter examines on the study by Luo et al,demonstrating that vitamin D 1,25-dihydroxyvitamin D3[1,25(OH)2D3]improves hepatic steatosis in NAFLD by inhibiting M1 macrophage polarization via the vitamin D receptor-peroxisome proliferator-activated receptor gamma signaling pathway.This letter critically appraises these findings,comparing them to similar studies,and discusses their potential implications for treating NAFLD.Furthermore,we highlight future directions,including dose optimization and mechanistic studies.展开更多
Objective To investigate the active components and mechanisms by which Qingre Zaoshi Jiedu Recipe influences the transformation from cervical high-risk human papillomavirus(HR-HPV)-related cervicitis to cancer,utilizi...Objective To investigate the active components and mechanisms by which Qingre Zaoshi Jiedu Recipe influences the transformation from cervical high-risk human papillomavirus(HR-HPV)-related cervicitis to cancer,utilizing network pharmacology,Gene Expression Omnibus(GEO)data,and molecular docking techniques.Methods Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),HERB,and the Encyclopedia of Traditional Chinese Medicine(ETCM)databases were used to screen out the active ingredients and related targets of Qingre Zaoshi Jiedu Recipe.The GeneCards database for disease targets at different stages of HR-HPV-related cervicitis–cancer were searched.The String platform to construct a protein-protein interaction network and identify key targets was utilized.Enrichment analysis of intersecting genes was performed using the DAVID database.The GSE149763 dataset from the GEO to identify differential genes involved in the transformation from cervicitis to cervical cancer by comparing cervicitis with cervical intraepithelial neoplasia III and cervical cancer was utilized.R language to generate volcano plots,heat maps,and key target expression trend charts were employed.Molecular docking of key pathway targets and main compounds of Qingre Zaoshi Jiedu Recipe for HR-HPV-related cervicitis–cancer was performed using AutoDock Vina.Results The study identified 185 main active ingredients of Qingre Zaoshi Jiedu Recipe.The protein–protein interaction network indicates that the core targets for interfering with HR-HPV-related inflammation–cancer transformation include TNF,IL-6,IL-1β,CXCL8,IL-1α,IFN-γ,IL-10,CCL2,CCL5,and CXCL10.KEGG pathway analysis indicates that Qingre Zaoshi Jiedu Recipe primarily affects HR-HPV-related inflammation–cancer transformation via the Toll-like receptor signaling pathway.GEO analysis identified the Toll-like receptor pathway as crucial across various stages of cervicitis–cancer lesions,with CXCL10 emerging as a key target.Molecular docking analysis revealed that the primary components of Qingre Zaoshi Jiedu Recipe effectively bind to TLR4.Conclusion Qingre Zaoshi Jiedu Recipe can interfere with HR-HPV-related cervicitis–cancer transformation by acting on TLR4 through the Toll-like receptor pathway.展开更多
Background:In recent years,the rising prevalence of obesity and metabolic syndrome has led to an increased number of individuals developing metabolic dysfunction-associated steatotic liver disease(MASLD).Furthermore,g...Background:In recent years,the rising prevalence of obesity and metabolic syndrome has led to an increased number of individuals developing metabolic dysfunction-associated steatotic liver disease(MASLD).Furthermore,given the substantial global prevalence of chronic hepatitis B(CHB),instances of MASLD coexisting with CHB are becoming increasingly commonplace in clinical scenarios.Both conditions can lead to liver fibrosis,cirrhosis,and potentially hepatocellular carcinoma(HCC).However,the intrica-cies of the dual etiology,consequential outcomes,and associated risks of CHB concurrent with MASLD are still not fully understood.Data sources:A literature search was conducted on PubMed for articles published up to March 2024.The search keywords included nonalcoholic fatty liver disease,nonalcoholic steatohepatitis,chronic hepatitis B,liver fibrosis,hepatocellular carcinoma,nuclear factor erythroid 2-related factor 2,and oxidative stress.Results:This review examined recent studies on the interplay between MASLD and CHB.The coexis-tence of these conditions may facilitate the clearance of hepatitis B surface antigen from the serum and impede hepatitis B virus(HBV)replication.Conversely,individuals with coexisting CHB tend to exhibit a lower rate of hypertriglyceridemia and reduced serum triglyceride levels compared with those only having NAFLD.Nevertheless,these observations do not necessarily indicate universally positive outcomes.Indeed,MASLD and CHB may synergistically act as“co-conspirators”to exacerbate clinical manifestations,particularly liver fibrosis and HCC.Conclusions:As our understanding of the interaction between steatosis and HBV infection becomes clearer,we can better assess the risk of advanced liver disease in patients with concurrent CHB and MASLD.These insights will support the exploration of potential underlying mechanisms and may provide recommendations for improving patient outcomes.展开更多
BACKGROUND Visceral hypersensitivity is the core pathogenesis of irritable bowel syndrome(IBS)and is often accompanied by negative emotions such as anxiety or depression.Paraventricular hypothalamic nucleus(PVN)cortic...BACKGROUND Visceral hypersensitivity is the core pathogenesis of irritable bowel syndrome(IBS)and is often accompanied by negative emotions such as anxiety or depression.Paraventricular hypothalamic nucleus(PVN)corticotropin-releasing factor(CRF)is involved in the stress-related gastrointestinal dysfunction.Electroacupuncture(EA)has unique advantages for the treatment of visceral hypersensitivity and negative emotions in IBS patients.However,the underlying mechanisms remain unclear.AIM To investigate the pathological mechanisms visceral hypersensitivity and negative emotions in IBS,as well as the effect mechanism of EA.METHODS A model of diarrhoeal IBS(IBS-D)with negative emotions was prepared by chronic restraint combined with glacial acetic acid enema.The effect of EA was verified by abdominal withdrawal reflex and open-field test.PVN CRFcolonic mast cell(MC)/transient potential receptor vanilloid type 1(TRPV1)pathway was detected by immunofluorescence,Western blot,ELISA,and toluidine blue staining.Moreover,PVN CRFergic neurons were activated or inhibited by chemogenetical technique to observe the changes of effect indicator.RESULTS In the model group,IBS-D symptoms and negative emotions were successfully induced.Notably,the combination of Baihui(GV20)with Tianshu(ST25)and Dachangshu(BL25)acupoints showed the greatest efficacy in improving the negative emotions and visceral hypersensitivity in model mice.Furthermore,we found that EA inhibited overactivated PVN CRFergic neurons and the overexpression of serum CRF,colonic CRF,CRF-receptor 1(CRFR1),mast cell tryptase(MCT),protease-activated receptor 2 and TRPV1 in model mice.Moreover,we found that activating PVN CRFergic neurons induced negative emotions and visceral hypersensitivity in normal mice;however,inhibiting PVN CRFergic neurons alleviated negative emotions and intestinal symptoms in model mice and decreased the expression of colonic CRF-R1,MCT,and TRPV1.CONCLUSION This research highlights the key role of PVN CRF-MC CRF-R1 and the downstream MC/TRPV1 pathway in the pathological process of IBS-D and the mechanism of the effect of EA.展开更多
Background： Mastitis, an infection caused by Gram-positive bacteria, produces udder inflammation and oxidative injury in milk-producing mammals. Toll-like receptor 2（TLR2） is important for host recognition of invad...Background： Mastitis, an infection caused by Gram-positive bacteria, produces udder inflammation and oxidative injury in milk-producing mammals. Toll-like receptor 2（TLR2） is important for host recognition of invading Grampositive microbes. Over-expression of TLR2 in transgenic dairy goats is a useful model for studying various aspects of infection with Gram-positive bacteria, in vivo.Methods： We over-expressed TLR2 in transgenic dairy goats. Pam3CSK4, a component of Gram-positive bacteria,triggered the TLR2 signal pathway by stimulating the monocytes-macrophages from the TLR2-positive transgenic goats, and induced over-expression of activator protein-1（AP-1）, phosphatidylinositol 3-kinase（PI3K） and transcription factor nuclear factor kappa B（NF-κB） and inflammation factors downstream of the signal pathway.Results： Compared with wild-type controls, measurements of various oxidative stress-related molecules showed that TLR2, when over-expressed in transgenic goat monocytes-macrophages, resulted in weak lipid damage, high level expression of anti-oxidative stress proteins, and significantly increased m RNA levels of transcription factor NF-E2-related factor-2（Nrf2） and the downstream gene, heme oxygenase-1（HO-1）. When Pam3CSK4 was used to stimulate ear tissue in vivo the HO-1 protein of the transgenic goats had a relatively high expression level.Conclusions： The results indicate that the oxidative injury in goats over-expressing TLR2 was reduced following Pam3CSK4 stimulation. The underlying mechanism for this reduction was increased expression of the anti-oxidation gene HO-1 by activation of the Nrf2 signal pathway.展开更多
Berberine（BBR） is an isoquinoline alkaloid extracted from Rhizoma coptidis and has been used for treating type 2 diabetes mellitus（T2DM） in China. The development of T2 DM is often associated with insulin resistan...Berberine（BBR） is an isoquinoline alkaloid extracted from Rhizoma coptidis and has been used for treating type 2 diabetes mellitus（T2DM） in China. The development of T2 DM is often associated with insulin resistance and impaired glucose uptake in peripheral tissues. In this study, we examined whether BBR attenuated glucose uptake dysfunction through the cholinergic anti-inflammatory pathway in Hep G2 cells. Cellular glucose uptake, quantified by the 2-[N-（7-Nitrobenz-2-oxa-1,3-diazol-4-yl）-amino]-2-deoxy-D-glucose（2-NBDG）, was inhibited by 21% after Hep G2 cells were incubated with insulin（10-6 mol/L） for 36 h. Meanwhile, the expression of alpha7 nicotinic acetylcholine receptor（α7n ACh R） protein was reduced without the change of acetylcholinesterase（ACh E） activity. The level of interleukin-6（IL-6） in the culture supernatant, the ratio of phosphorylated I-kappa-B kinase-β（IKKβ） Ser181/IKKβ and the expression of nuclear factor-kappa B（NF-κB） p65 protein were also increased. However, the treatment with BBR enhanced the glucose uptake, increased the expression of α7n ACh R protein and inhibited ACh E activity. These changes were also accompanied with the decrease of the ratio of p IKKβ Ser181/IKKβ, NF-κB p65 expression and IL-6 level. Taken together, these results suggest that BBR could enhance glucose uptake, and relieve insulin resistance and inflammation in Hep G2 cells. The mechanism may be related to the cholinergic anti-inflammatory pathway and the inhibition of ACh E activity.展开更多
Hypoxia has become an unfavorable factor affecting the sustainable development of the large yellow croaker Larimichthys crocea,an economically important mariculture fish in China.Apoptosis is a consequence of hypoxia ...Hypoxia has become an unfavorable factor affecting the sustainable development of the large yellow croaker Larimichthys crocea,an economically important mariculture fish in China.Apoptosis is a consequence of hypoxia on fish.However,the effects of hypoxia stress on apoptosis in L.crocea remain largely unknown.We investigated the effect of environmental hypoxia on apoptosis in L.crocea.Results show that hypoxia induced apoptosis in L.crocea both in vivo and in vitro.The mitochondrial membrane potential was significantly reduced in large yellow croaker fry(LYCF)cells.The expression levels of Bcell lymphoma/leukemia-2(Bcl-2)m RNA and protein were also significantly decreased in the liver and LYCF cells during 96 h and 48 h of hypoxia stress,respectively,whereas the expression level of Bcl-2 associated X(Bax)mRNA,Casp3 mRNA,and activity of caspase-3/7/9 were significantly increased,indicating that hypoxia induced caspase-dependent intrinsic apoptosis in L.crocea.The expression level of the apoptosis-inducing factor(AIF)protein was significantly increased in the liver and LYCF cells.The level of AIF protein was significantly decreased in the cytoplasm but increased in the nuclei of L.crocea,demonstrating that hypoxia induced the AIF-mediated caspase-independent intrinsic apoptosis.In addition,the activity of caspase-8 was significantly increased,indicating that hypoxia stress induced extrinsic apoptosis in L.crocea.Therefore,hypoxia induced apoptosis in L.crocea through both the intrinsic and extrinsic pathways.The present study accumulated basic biological information to help elucidate the mechanism of hypoxia response in marine fish.展开更多
Regenerative capacity is weak after central nervous system injury because of the absence of an enhancing microenvironment and presence of an inhibitory microenvironment for neuronal and axonal repair. In addition to t...Regenerative capacity is weak after central nervous system injury because of the absence of an enhancing microenvironment and presence of an inhibitory microenvironment for neuronal and axonal repair. In addition to the Nogo receptor（Ng R）, the paired immunoglobulin-like receptor B（Pir B） is a recently discovered coreceptor of Nogo, myelin-associated glycoprotein, and myelin oligodendrocyte glycoprotein. Concurrent blocking of Ng R and Pir B almost completely eliminates the inhibitory effect of myelin-associated inhibitory molecules on axonal regeneration. Pir B participates in a key pathological process of the nervous system, specifically axonal regeneration inhibition. Pir B is an inhibitory receptor similar to Ng R, but their effects are not identical. This study summarizes the structure, distribution, relationship with common nervous system diseases, and known mechanisms of Pir B, and concludes that Pir B is also distributed in cells of the immune and hematopoietic systems. Further investigations are needed to determine if immunomodulation and blood cell migration involve inhibition of axonal regeneration.展开更多
基金Supported by The National Natural Science Foundation of China,No.30470782
文摘AIM:To examine the effects of combined treatment of oxaliplatin and phosphatidylinositol 3'-kinase inhibitor,2-(4-morpholinyl) -8-phenyl-4H-1-benzopyran-4-one(LY294002) for gastric cancer. METHODS:Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide assay.Apoptotic cells were detected by flow cytometric analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay.Western blotting and immuno-precipitation were used to examine protein expression and recruitment,respectively.Nuclear factorκB(NFκB) binding activities were investigated using electrophoretic mobility shift assay.Nude mice were used to investigate tumor growth. RESULTS:Treatment with combined oxaliplatin and LY294002 resulted in increased cell growth inhibi-tion and cell apoptosis in vitro,and increased tumor growth inhibition and cell death in the tumor mass in vivo.In MKN45 and AGS cells,oxaliplatin treatment promoted both protein kinase B(Akt) and NFκB activation,while pretreatment with LY294002 significantly attenuated oxaliplatin-induced Akt activity and NFκB binding.LY294002 promoted oxaliplatin-induced Fas ligand(FasL) expression,Fas-associated death domain protein recruitment,caspase-8,Bid,and caspase-3 activation,and the short form of cellular caspase-8/FLICEinhibitory protein(c-FLIPS) inhibition.In vivo,LY294002 inhibited oxaliplatin-induced activation of Akt and NFκB,and increased oxaliplatin-induced expression of FasL,inhibition of c-FLIPS,and activation of caspase-8,Bid,and caspase-3. CONCLUSION:Combination of oxaliplatin and LY294002 was therapeutically promising for gastric cancer treatment.The enhanced sensitivity of the combined treatment was associated with the activation of the death receptor pathway.
基金Supported by National Natural Science Foundation of China,No. 81502556Yunnan Digestive Endoscopy Clinical Medical Center Foundation for Health Commission of Yunnan Province,No. 2X2019-01-02
文摘BACKGROUND Colorectal cancer(CRC)is an extremely malignant tumor with a high mortality rate.Little is known about the mechanism by which forkhead Box q1(FOXQ1)causes CRC invasion and metastasis through the epidermal growth factor receptor(EGFR)pathway.AIM To illuminate the mechanism by which FOXQ1 promotes the invasion and metastasis of CRC by activating the heparin binding epidermal growth factor(HB-EGF)/EGFR pathway.METHODS We investigated the differential expression and prognosis of FOXQ1 and HB-EGF in CRC using the Gene Expression Profiling Interactive Analysis(GEPIA)website(http://gepia.cancer-pku.cn/index.html).Quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting were used to detect the expression of FOXQ1 and HB-EGF in cell lines and tissues,and we constructed a stable lowexpressing FOXQ1 cell line and verified it with the above method.The expression changes of membrane-bound HB-EGF(proHB-EGF)and soluble HB-EGF(sHB-EGF)in the lowexpressing FOXQ1 cell line were detected by flow cytometry and ELISA.Western blotting was used to detect changes in the expression levels of HB-EGF and EGFR pathway-related downstream genes when exogenous recombinant human HB-EGF was added to FOXQ1 knockdown cells.Proliferation experiments,transwell migration experiments,and scratch experiments were carried out to determine the mechanism by which FOXQ1 activates the EGFR signaling pathway through HB-EGF,and then to evaluate the clinical relevance of FOXQ1 and HB-EGF.RESULTS GEPIA showed that the expression of FOXQ1 in CRC tissues was relatively high and was related to a lower overall survival rate.PCR array results showed that FOXQ1 is related to the HB-EGF and EGFR pathways.Knockdown of FOXQ1 suppressed the expression of HB-EGF,and led to a decrease in EGFR and its downstream genes AKT,RAF,KRAS expression levels.After knockdown of FOXQ1 in CRC cell lines,cell proliferation,migration and invasion were attenuated.Adding HB-EGF restored the migration and invasion ability of CRC,but not the cell proliferation ability.Kaplan–Meier survival analysis results showed that the combination of FOXQ1 and HB-EGF may serve to predict CRC survival.CONCLUSION Based on these collective data,we propose that FOXQ1 promotes the invasion and metastasis of CRC via the HB-EGF/EGFR pathway.
基金supported by the National Natural Science Foundation of China(Key Program),No.11932013the National Natural Science Foundation of China(General Program),No.82272255+2 种基金Armed Police Force High-Level Science and Technology Personnel ProjectThe Armed Police Force Focuses on Supporting Scientific and Technological Innovation TeamsKey Project of Tianjin Science and Technology Plan,No.20JCZDJC00570(all to XC)。
文摘Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.
基金supported by Harbin University of Commerce Research Funding(17x072)
文摘Objective： To investigate the effects of xanthotoxin from Apiaceae medicinal plants on cell proliferation and apoptosis, and explore its mechanism of action against human gastric carcinoma SGC-7901 cells in vitro.Methods： SGC-7901, HepG-2, MCF-7, and A549 cells were treated with different concentrations of xanthotoxin（10, 20, 60, 80, 100, 120, 140, and 160 μg/mL） for 48 h, and the cell viability（IC50） was determined by MTT assay; Xanthotoxin-induced apoptosis in cells was observed by using Hoechst 33258 Staining Kit and Annexin V-FITC Apoptosis Detection Kit; Flow cytometry was used to detect apoptosis related proteins of Fas/FasL, Bid, and DR5/TRAIL proteins in human gastric carcinoma SGC-7901 cells after being treated by xanthotoxin; The influence of xanthotoxin on Caspase-8 protein expression in the cells was determined by Flouormetric Assay Kit.Results： Xanthotoxin obviously inhibited SGC-7901, HepG-2, MCF-7, and A549 cells proliferation, and its inhibition was in a concentration-dependent manner; flow cytometry results showed that in a certain concentration range, xanthotoxin can increase the expression levels of Fas/FasL and DR5/TRAIL proteins in a concentration-dependence manner. The content of Bid protein in cells was increased, and it showed concentration-dependence.Conclusion： Xanthotoxin may induce SGC-7901 cells apoptosis in a certain concentration range through the Fas/FasL protein mediated death receptor pathway, or by DR5/TRAIL mediated death receptor pathway, and increase the expression level of death receptor protein, activation Caspase-8, activating downstream effect factor, inducing cell apoptosis, or activate Caspase-8 cutting activate protein Bid, and then enter the mitochondrial pathway, induction of apoptosis.
基金supported by the National Natural Science Foundation of China(No.81172620)
文摘Objective The aim of this study is to investigate whether microwave exposure would affect the N-methyI-D-aspartate receptor （NMDAR） signaling pathway to establish whether this plays a role in synaptic plasticity impairment. Methods 48 male Wistar rats were exposed to 30 mW/cm^2 microwave for 10 min every other day for three times. Hippocampal structure was observed through H＆E staining and transmission electron microscope. PC12 cells were exposed to 30 mW/cm^2 microwave for 5 min and the synapse morphology was visualized with scanning electron microscope and atomic force microscope. The release of amino acid neurotransmitters and calcium influx were detected. The expressions of several key NMDAR signaling molecules were evaluated. Results Microwave exposure caused injury in rat hippocampal structure and PC12 cells, especially the structure and quantity of synapses. The ratio of glutamic acid and gamma-aminobutyric acid neurotransmitters was increased and the intracellular calcium level was elevated in PC12 cells. A significant change in NMDAR subunits （NR1, NR2A, and NR2B） and related signaling molecules （CaZ＋/calmodulin-dependent kinase II gamma and phosphorylated cAMP-response element binding protein） were examined. Conclusion 30 mW/cm^2 microwave exposure resulted in alterations of synaptic structure, amino acid neurotransmitter release and calcium influx. NMDAR signaling molecules were closely associated with impaired synaptic plasticity.
基金Supported by National Natural Science Fund(No.81170875No.81371052)+1 种基金Key Discipline Leading Plan in Beijing Eye Institution(No.201512)Capital of Clinical Characteristics and the Applied Research(No.Z151100004015115)
文摘AIM：To detect the expression of B cell receptor signaling pathway（BCRSP） in lacrimal gland benign lymphoepithelial lesions（LGBLEL）.METHODS：Gene microarray was used to compare whole-genome expression in lacrimal gland tissues from LGBLEL patients to tissues from orbital cavernous hemangioma（control tissues）. Expression of BCRSP was confirmed by polymerase chain reaction（PCR） and immunohistochemistry. RESULTS：The expression of 22 genes of the BCRSP increased significantly in LGBLEL patients. PCR analysis showed that CD22, CR2, and BTK were all highly expressed in LGBLEL tissues. Immunohistochemical analysis showed that CR2 protein was present in LGBLEL, but CD22 and BTK proteins were negative. CR2, CD22, and BTK were not observed in the orbital cavernous hemangiomas with either PCR or immunohistochemistry. CONCLUSION：BCRSP might be involved in the pathogenesis of LGBLEL.
基金supported by grants from the Natural Science Foundation of China (31360611 and 31160516)Guangxi Natural Science Foundation (2013GXNSFCA01 9010 and 2014GXNSFDA118011)
文摘Avian infectious bronchitis virus(IBV) is a Gammacoronavirus in the family Coronaviridae and causes highly contagious respiratory disease in chickens. Innate immunity plays significant roles in host defense against IBV. Here, we explored the interaction between IBV and the host innate immune system. Severe histopathological lesions were observed in the tracheal mucosa at 3–5days post inoculation(dpi) and in the kidney at 8 dpi, with heavy viral loads at 1–11 and 1–28 dpi,respectively. The expression of m RNAs encoding Toll-like receptor(TLR) 3 and TLR7 were upregulated at 3–8 dpi, and that of TIR-domain-containing adapter-inducing interferon(IFN) β(TRIF) was upregulated at 21 dpi in the trachea and kidney. Myeloid differentiation primary response protein 88(My D88) was upregulated in the trachea during early infection. Tumor necrosis factor receptor-associated factor(TRAF) 3 and TRAF6 were upregulated expression in both tissues.Moreover, melanoma differentiation-associated protein 5(MDA5), laboratory of genetics and physiology 2(LGP2), stimulator of IFN genes(STING), and mitochondrial antiviral signaling protein(MAVS), as well as TANK binding kinase 1(TBK1), inhibitor of kappa B kinase(IKK) ?, IKKα, IKKβ,IFN regulatory factor(IRF) 7, nuclear factor of kappa B(NF-κB), IFN-α, IFN-β, various interleukins(ILs), and macrophage inflammatory protein-1β(MIP-1β) were significantly upregulated in the trachea and downregulated in the kidney. These results suggested that the TLR and MDA5 signaling pathways and innate immune cytokine were induced after IBV infection. Additionally,consistent responses to IBV infection were observed during early infection, with differential and complicated responses in the kidney.
基金supported by grants from the National Natural Science Foundation of China(No.81600074)Hubei Natural Science Foundation(No.2017CFB473).
文摘Objective:MiRNAs have been recently implicated in the pathogenesis of ischemia-reperfusion(IR)injury.This study aimed to investigate the miRNA expression profiles,in the early stages after lung transplantation(LT)and to study the involvement of the Toll-like receptor(TLR)signaling pathway in lung IR injury following LT.Methods:We established the left LT model in mice and selected the miRNA-122 as a research target.The mice were injected with a miRNA-122-specific inhibitor,following which pathological changes in the lung tissue were studied using different lung injury indicators.In addition,we performed deep sequencing of transplanted lung tissues to identify differentially expressed(DE)miRNAs and their target genes.These target genes were used to further perform gene ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis.Results:A total of 12 DE miRNAs were selected,and 2476 target genes were identified.The GO enrichment analysis predicted 6063 terms,and the KEGG analysis predicted 1554 biological pathways.Compared with the control group,inhibiting the expression of miRNA-122 significantly reduced the lung injury and lung wet/dry ratio(P<0.05).In addition,the activity of myeloperoxidase and the expression levels of tumor necrosis factor-alpha and TLR2/4 were decreased(P<0.05);whereas the expression of interleukin-10 was increased(P<0.05).Furthermore,the inhibition of miRNA-122 suppressed the IR injury-induced activation of the TLR signaling pathway.Conclusion:Our findings showed the differential expression of several miRNAs in the early inflammatory response following LT.Of these,miRNA-122 promoted IR injury following LT,whereas its inhibition prevented IR injury in a TLR-dependent manner.
基金Dr.Mao-Draayer has served as a consultant and/or received grant support from:Acorda,Bayer Pharmaceutical,Biogen Idec,EMD Serono,Genzyme,Novartis,Questor,Teva Neuroscience and Chugai PharmaDr.Mao-Draayeris currently supported by grants from NIH NIAID Autoimmune Center of Excellence:UM1-AI110557+1 种基金NIH NINDS R01-NS080821the University of Michigan Neurology Department
文摘Multiple sclerosis（MS）is a chronic autoimmune disease of the central nervous system（CNS）characterized by coexisting processes of inflammation,demyelination,axonal neurodegeneration,and gliosis.It is the most common disabling neurological disease in young adulthood.
文摘Whether M3 cholinergic receptor signal transduction pathway is involved in regulation of the activation of NF-κB and the expression of chemokine MOB-1, MCP-1genes in pancreatic acinar cells was investigated. Rat pancreatic acinar cells were isolated, cultured and treated with carbachol, atropine and PDTC in vitro. The MOB-1 and MCP-1 mRNA expression was detected by using RT-PCR. The activation of NF-κB was monitored by using electrophoretic mobility shift assay. The results showed that as compared with control group, M3 cholinergic receptor agonist (10 -3 mol/L, 10 -4 mol/L carbachol) could induce a concentration-dependent and time-dependent increase in the expression of MOB-1, MCP-1 mRNA in pancreatic acinar cells. After treatment with 10 -3 mol/L carbachol for 2 h, the expression of MOB-1, MCP-1 mRNA was strongest. The activity of NF-κB in pancreatic acinar cells was significantly increased (P<0.01) after treated with M3 cholinergic receptor agonist (10 -3 mol/L carbachol) in vitro for 30 min. Either M3 cholinergic receptor antagonist (10 -5 mol/L atropine) or NF-κB inhibitor (10 -2 mol/L PDTC) could obviously inhibit the activation of NF-κB and the chemokine MOB-1, MCP-1 mRNA expression induced by carbachol (P<0.05). This inhibitory effect was significantly increased by atropine plus PDTC (P<0.01). The results of these studies indicated that M3 cholinergic receptor signal transduction pathway was likely involved in regulation of the expression of chemokine MOB-1 and MCP-1genes in pancreatic acinar cells in vitro through the activation of NF-κB.
基金supported by grants from the National Natural Science Foundation of China(No.81603438 and No.81802568).
文摘The prevalence of prostate cancer in males worldwide is increasing every year.Androgen and androgen receptor drive the development of prostate cancer and are important targets for the treatment of prostate cancer.A growing number of reports indicate that the traditional Chinese medicine has a clear advantage in the prevention and treatment of prostate cancer.This article provides an overview of the in vitro and in vivo studies of different traditional Chinese medicine monomers acting on the androgen receptor-signaling pathway in prostate cancer.
基金Supported by the Scientific Foundation of Administration of Traditional Chinese Medicine of Hebei Province,China,No.2023257.
文摘BACKGROUND Jianpi Gushen Huayu Decoction(JPGS)has been used to clinically treat diabetic nephropathy(DN)for many years.However,the protective mechanism of JPGS in treating DN remains unclear.AIM To evaluate the therapeutic effects and the possible mechanism of JPGS on DN.METHODS We first evaluated the therapeutic potential of JPGS on a DN mouse model.We then investigated the effect of JPGS on the renal metabolite levels of DN mice using non-targeted metabolomics.Furthermore,we examined the effects of JPGS on c-Jun N-terminal kinase(JNK)/P38-mediated apoptosis and the inflammatory responses mediated by toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB)/NOD-like receptor family pyrin domain containing 3(NLRP3).RESULTS The ameliorative effects of JPGS on DN mice included the alleviation of renal injury and the control of inflammation and oxidative stress.Untargeted metabolomic analysis revealed that JPGS altered the metabolites of the kidneys in DN mice.A total of 51 differential metabolites were screened.Pathway analysis results indicated that nine pathways significantly changed between the control and model groups,while six pathways significantly altered between the model and JPGS groups.Pathways related to cysteine and methionine metabolism;alanine,tryptophan metabolism;aspartate and glutamate metabolism;and riboflavin metabolism were identified as the key pathways through which JPGS affects DN.Further experimental validation showed that JPGS treatment reduced the expression of TLR4/NF-κB/NLRP3 pathways and JNK/P38 pathway-mediated apoptosis related factors.CONCLUSION JPGS could markedly treat mice with streptozotocin(STZ)-induced DN,which is possibly related to the regulation of several metabolic pathways found in kidneys.Furthermore,JPGS could improve kidney inflammatory responses and ameliorate kidney injuries in DN mice via the TLR4/NF-κB/NLRP3 pathway and inhibit JNK/P38 pathwaymediated apoptosis in DN mice.
基金National Natural Science Foundation of China,No.82170406 and No.81970238.
文摘Non-alcoholic fatty liver disease(NAFLD),a critical global health concern,continues to challenge medical researchers with limited treatment options.This letter examines on the study by Luo et al,demonstrating that vitamin D 1,25-dihydroxyvitamin D3[1,25(OH)2D3]improves hepatic steatosis in NAFLD by inhibiting M1 macrophage polarization via the vitamin D receptor-peroxisome proliferator-activated receptor gamma signaling pathway.This letter critically appraises these findings,comparing them to similar studies,and discusses their potential implications for treating NAFLD.Furthermore,we highlight future directions,including dose optimization and mechanistic studies.
基金supported by National Chinese Medicine Inheritance and Development Demonstration Pilot Project-Zhongshan Chinese Medicine Hospital Chinese Medicine Research Project(YN2024B005).
文摘Objective To investigate the active components and mechanisms by which Qingre Zaoshi Jiedu Recipe influences the transformation from cervical high-risk human papillomavirus(HR-HPV)-related cervicitis to cancer,utilizing network pharmacology,Gene Expression Omnibus(GEO)data,and molecular docking techniques.Methods Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),HERB,and the Encyclopedia of Traditional Chinese Medicine(ETCM)databases were used to screen out the active ingredients and related targets of Qingre Zaoshi Jiedu Recipe.The GeneCards database for disease targets at different stages of HR-HPV-related cervicitis–cancer were searched.The String platform to construct a protein-protein interaction network and identify key targets was utilized.Enrichment analysis of intersecting genes was performed using the DAVID database.The GSE149763 dataset from the GEO to identify differential genes involved in the transformation from cervicitis to cervical cancer by comparing cervicitis with cervical intraepithelial neoplasia III and cervical cancer was utilized.R language to generate volcano plots,heat maps,and key target expression trend charts were employed.Molecular docking of key pathway targets and main compounds of Qingre Zaoshi Jiedu Recipe for HR-HPV-related cervicitis–cancer was performed using AutoDock Vina.Results The study identified 185 main active ingredients of Qingre Zaoshi Jiedu Recipe.The protein–protein interaction network indicates that the core targets for interfering with HR-HPV-related inflammation–cancer transformation include TNF,IL-6,IL-1β,CXCL8,IL-1α,IFN-γ,IL-10,CCL2,CCL5,and CXCL10.KEGG pathway analysis indicates that Qingre Zaoshi Jiedu Recipe primarily affects HR-HPV-related inflammation–cancer transformation via the Toll-like receptor signaling pathway.GEO analysis identified the Toll-like receptor pathway as crucial across various stages of cervicitis–cancer lesions,with CXCL10 emerging as a key target.Molecular docking analysis revealed that the primary components of Qingre Zaoshi Jiedu Recipe effectively bind to TLR4.Conclusion Qingre Zaoshi Jiedu Recipe can interfere with HR-HPV-related cervicitis–cancer transformation by acting on TLR4 through the Toll-like receptor pathway.
基金supported by a grant from the Scientific Re-search Program of Furong Laboratory(No.2023SK2108).
文摘Background:In recent years,the rising prevalence of obesity and metabolic syndrome has led to an increased number of individuals developing metabolic dysfunction-associated steatotic liver disease(MASLD).Furthermore,given the substantial global prevalence of chronic hepatitis B(CHB),instances of MASLD coexisting with CHB are becoming increasingly commonplace in clinical scenarios.Both conditions can lead to liver fibrosis,cirrhosis,and potentially hepatocellular carcinoma(HCC).However,the intrica-cies of the dual etiology,consequential outcomes,and associated risks of CHB concurrent with MASLD are still not fully understood.Data sources:A literature search was conducted on PubMed for articles published up to March 2024.The search keywords included nonalcoholic fatty liver disease,nonalcoholic steatohepatitis,chronic hepatitis B,liver fibrosis,hepatocellular carcinoma,nuclear factor erythroid 2-related factor 2,and oxidative stress.Results:This review examined recent studies on the interplay between MASLD and CHB.The coexis-tence of these conditions may facilitate the clearance of hepatitis B surface antigen from the serum and impede hepatitis B virus(HBV)replication.Conversely,individuals with coexisting CHB tend to exhibit a lower rate of hypertriglyceridemia and reduced serum triglyceride levels compared with those only having NAFLD.Nevertheless,these observations do not necessarily indicate universally positive outcomes.Indeed,MASLD and CHB may synergistically act as“co-conspirators”to exacerbate clinical manifestations,particularly liver fibrosis and HCC.Conclusions:As our understanding of the interaction between steatosis and HBV infection becomes clearer,we can better assess the risk of advanced liver disease in patients with concurrent CHB and MASLD.These insights will support the exploration of potential underlying mechanisms and may provide recommendations for improving patient outcomes.
基金Supported by the Excellent Youth Project of Anhui Universities,No.2022AH030065National Natural Science Foundation of China,No.82474224 and No.82405244+3 种基金Anhui Provincial Natural Science Foundation,No.2408085MH223Open Projects of Anhui Province Key Laboratory of Meridian Viscera Correlationship,No.2024AHMVC04Research Project of Xin’an Medical and Chinese Medicine Modernization Research Institute,No.2023CXMMTCM016the Anhui Province Scientific Research Planning Project,No.2022AH050438.
文摘BACKGROUND Visceral hypersensitivity is the core pathogenesis of irritable bowel syndrome(IBS)and is often accompanied by negative emotions such as anxiety or depression.Paraventricular hypothalamic nucleus(PVN)corticotropin-releasing factor(CRF)is involved in the stress-related gastrointestinal dysfunction.Electroacupuncture(EA)has unique advantages for the treatment of visceral hypersensitivity and negative emotions in IBS patients.However,the underlying mechanisms remain unclear.AIM To investigate the pathological mechanisms visceral hypersensitivity and negative emotions in IBS,as well as the effect mechanism of EA.METHODS A model of diarrhoeal IBS(IBS-D)with negative emotions was prepared by chronic restraint combined with glacial acetic acid enema.The effect of EA was verified by abdominal withdrawal reflex and open-field test.PVN CRFcolonic mast cell(MC)/transient potential receptor vanilloid type 1(TRPV1)pathway was detected by immunofluorescence,Western blot,ELISA,and toluidine blue staining.Moreover,PVN CRFergic neurons were activated or inhibited by chemogenetical technique to observe the changes of effect indicator.RESULTS In the model group,IBS-D symptoms and negative emotions were successfully induced.Notably,the combination of Baihui(GV20)with Tianshu(ST25)and Dachangshu(BL25)acupoints showed the greatest efficacy in improving the negative emotions and visceral hypersensitivity in model mice.Furthermore,we found that EA inhibited overactivated PVN CRFergic neurons and the overexpression of serum CRF,colonic CRF,CRF-receptor 1(CRFR1),mast cell tryptase(MCT),protease-activated receptor 2 and TRPV1 in model mice.Moreover,we found that activating PVN CRFergic neurons induced negative emotions and visceral hypersensitivity in normal mice;however,inhibiting PVN CRFergic neurons alleviated negative emotions and intestinal symptoms in model mice and decreased the expression of colonic CRF-R1,MCT,and TRPV1.CONCLUSION This research highlights the key role of PVN CRF-MC CRF-R1 and the downstream MC/TRPV1 pathway in the pathological process of IBS-D and the mechanism of the effect of EA.
基金supported by grants from National Transgenic Creature Breeding Grand Project(2014ZX08008-005)Chinese Universities Scientific Fund(2014BH032)Natural Science Foundation of China(31501953, 31471352, 31471400 and 31171380)
文摘Background： Mastitis, an infection caused by Gram-positive bacteria, produces udder inflammation and oxidative injury in milk-producing mammals. Toll-like receptor 2（TLR2） is important for host recognition of invading Grampositive microbes. Over-expression of TLR2 in transgenic dairy goats is a useful model for studying various aspects of infection with Gram-positive bacteria, in vivo.Methods： We over-expressed TLR2 in transgenic dairy goats. Pam3CSK4, a component of Gram-positive bacteria,triggered the TLR2 signal pathway by stimulating the monocytes-macrophages from the TLR2-positive transgenic goats, and induced over-expression of activator protein-1（AP-1）, phosphatidylinositol 3-kinase（PI3K） and transcription factor nuclear factor kappa B（NF-κB） and inflammation factors downstream of the signal pathway.Results： Compared with wild-type controls, measurements of various oxidative stress-related molecules showed that TLR2, when over-expressed in transgenic goat monocytes-macrophages, resulted in weak lipid damage, high level expression of anti-oxidative stress proteins, and significantly increased m RNA levels of transcription factor NF-E2-related factor-2（Nrf2） and the downstream gene, heme oxygenase-1（HO-1）. When Pam3CSK4 was used to stimulate ear tissue in vivo the HO-1 protein of the transgenic goats had a relatively high expression level.Conclusions： The results indicate that the oxidative injury in goats over-expressing TLR2 was reduced following Pam3CSK4 stimulation. The underlying mechanism for this reduction was increased expression of the anti-oxidation gene HO-1 by activation of the Nrf2 signal pathway.
基金supported by the National Natural Science Foundation of China(No.81373872)
文摘Berberine（BBR） is an isoquinoline alkaloid extracted from Rhizoma coptidis and has been used for treating type 2 diabetes mellitus（T2DM） in China. The development of T2 DM is often associated with insulin resistance and impaired glucose uptake in peripheral tissues. In this study, we examined whether BBR attenuated glucose uptake dysfunction through the cholinergic anti-inflammatory pathway in Hep G2 cells. Cellular glucose uptake, quantified by the 2-[N-（7-Nitrobenz-2-oxa-1,3-diazol-4-yl）-amino]-2-deoxy-D-glucose（2-NBDG）, was inhibited by 21% after Hep G2 cells were incubated with insulin（10-6 mol/L） for 36 h. Meanwhile, the expression of alpha7 nicotinic acetylcholine receptor（α7n ACh R） protein was reduced without the change of acetylcholinesterase（ACh E） activity. The level of interleukin-6（IL-6） in the culture supernatant, the ratio of phosphorylated I-kappa-B kinase-β（IKKβ） Ser181/IKKβ and the expression of nuclear factor-kappa B（NF-κB） p65 protein were also increased. However, the treatment with BBR enhanced the glucose uptake, increased the expression of α7n ACh R protein and inhibited ACh E activity. These changes were also accompanied with the decrease of the ratio of p IKKβ Ser181/IKKβ, NF-κB p65 expression and IL-6 level. Taken together, these results suggest that BBR could enhance glucose uptake, and relieve insulin resistance and inflammation in Hep G2 cells. The mechanism may be related to the cholinergic anti-inflammatory pathway and the inhibition of ACh E activity.
基金Supported by the NSFC-Zhejiang Joint Fund for the Integration of Industrialization and Informatization(No.U1809212)the Scientific and Technical Project of Zhejiang Province(No.2021C02069-1-2)+2 种基金the Science and Technology Innovation 2025 Major Special Project of Ningbo City(No.2021Z002)the Collaborative Innovation Center for Zhejiang Marine High-efficiency and Healthy Aquaculturethe K.C.Wong Magna Fund in Ningbo University。
文摘Hypoxia has become an unfavorable factor affecting the sustainable development of the large yellow croaker Larimichthys crocea,an economically important mariculture fish in China.Apoptosis is a consequence of hypoxia on fish.However,the effects of hypoxia stress on apoptosis in L.crocea remain largely unknown.We investigated the effect of environmental hypoxia on apoptosis in L.crocea.Results show that hypoxia induced apoptosis in L.crocea both in vivo and in vitro.The mitochondrial membrane potential was significantly reduced in large yellow croaker fry(LYCF)cells.The expression levels of Bcell lymphoma/leukemia-2(Bcl-2)m RNA and protein were also significantly decreased in the liver and LYCF cells during 96 h and 48 h of hypoxia stress,respectively,whereas the expression level of Bcl-2 associated X(Bax)mRNA,Casp3 mRNA,and activity of caspase-3/7/9 were significantly increased,indicating that hypoxia induced caspase-dependent intrinsic apoptosis in L.crocea.The expression level of the apoptosis-inducing factor(AIF)protein was significantly increased in the liver and LYCF cells.The level of AIF protein was significantly decreased in the cytoplasm but increased in the nuclei of L.crocea,demonstrating that hypoxia induced the AIF-mediated caspase-independent intrinsic apoptosis.In addition,the activity of caspase-8 was significantly increased,indicating that hypoxia stress induced extrinsic apoptosis in L.crocea.Therefore,hypoxia induced apoptosis in L.crocea through both the intrinsic and extrinsic pathways.The present study accumulated basic biological information to help elucidate the mechanism of hypoxia response in marine fish.
基金supported by the National Natural Science Foundation of China,No.81170577
文摘Regenerative capacity is weak after central nervous system injury because of the absence of an enhancing microenvironment and presence of an inhibitory microenvironment for neuronal and axonal repair. In addition to the Nogo receptor（Ng R）, the paired immunoglobulin-like receptor B（Pir B） is a recently discovered coreceptor of Nogo, myelin-associated glycoprotein, and myelin oligodendrocyte glycoprotein. Concurrent blocking of Ng R and Pir B almost completely eliminates the inhibitory effect of myelin-associated inhibitory molecules on axonal regeneration. Pir B participates in a key pathological process of the nervous system, specifically axonal regeneration inhibition. Pir B is an inhibitory receptor similar to Ng R, but their effects are not identical. This study summarizes the structure, distribution, relationship with common nervous system diseases, and known mechanisms of Pir B, and concludes that Pir B is also distributed in cells of the immune and hematopoietic systems. Further investigations are needed to determine if immunomodulation and blood cell migration involve inhibition of axonal regeneration.
