BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese med...BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese medicines.It is known for its suppression of inflammation and mitigation of oxidative stress.Its therapeutic efficacy and mechanistic underpinnings in UC remain uncharacterized.AIM To investigate the therapeutic potential and mechanisms of CE in UC.METHODS The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a dextran sulfate sodium-induced murine colitis model.Network pharmacology was employed to predict potential targets and pathways.Then molecular docking and dynamics simulations were utilized to confirm a stable interaction between CE and the toll-like receptor 4(TLR4)/myeloid differentiation factor 2(MD2)complex.The anti-inflammatory mechanisms were further verified using in vitro assays.Additionally,the gut microbiota composition was analyzed via 16S rRNA gene sequencing.RESULTS CE significantly alleviated colitis symptoms,mitigated histopathological damage,and suppressed inflammation.Moreover,CE restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins(zonula occludens 1,occludin,claudin-1).Mechanistically,CE stably bound to MD2,inhibiting lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells.This led to suppression of the downstream mitogen-activated protein kinase and nuclear factor kappa B signaling pathways,downregulating the expression of tumor necrosis factor-alpha,interleukin-1β,and interleukin-6.Gut microbiota analysis revealed that CE reversed dextran sulfate sodium-induced dysbiosis with significant enrichment of butyrogenic Christensenella minuta.CONCLUSION CE acted on MD2 to suppress proinflammatory cascades,promoting mucosal barrier reconstitution and microbiota remodeling and supporting its therapeutic use in UC.展开更多
BACKGROUND Inflammatory bowel disease(IBD)is a group of chronic,inflammatory disorders that include Crohn’s disease and ulcerative colitis.IBD arises from the interaction of various environmental and genetic factors....BACKGROUND Inflammatory bowel disease(IBD)is a group of chronic,inflammatory disorders that include Crohn’s disease and ulcerative colitis.IBD arises from the interaction of various environmental and genetic factors.Altered gut permeability and mitochondrial stress in the colonic mucosa are two mechanisms previously implicated in IBD pathogenesis.We have previously demonstrated activation of the mitochondrial unfolded protein response(UPRmt)in the colonic mucosa of IBD patients and linked this activation to pro-inflammatory signaling.Growth differentiation factor 15(GDF15)is an important downstream mediator of the UPRmt.AIM To investigate whether GDF15 has a role in IBD and how GDF15 impacts colonic epithelium.METHODS Circulating levels of GDF15 were assessed in plasma samples from IBD patients and healthy controls using an enzyme-linked immunosorbent assay.To study the effects of GDF15 on the colonic mucosa,we employed two different in vitro culture models:Colonic organoids and T84 cells.RESULTS We found that circulating GDF15 Levels were elevated in IBD patients and correlated with markers of inflammation(C-reactive protein)and intestinal permeability[haptoglobin and lipopolysaccharide-binding protein(LBP)].Additionally,we demonstrated that GDF15 alters the intestinal barrier and increases permeability by decreasing the levels of zonula occludens 1 and claudin 1,critical components of tight junctions.Thus,our findings confirm previous reports of increased circulating GDF15 levels in IBD patients and the activation of UPR^(mt).CONCLUSION In the present study,we describe a novel mechanism in IBD pathophysiology,linking mitochondrial stress to the disruption of the intestinal barrier and increased intestinal permeability.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is one of the most aggressive tumors worldwide.Chronic inflammation contributes to tumor evolution,and the infiltration of tumor-associated macrophages(TAMs),also known as M2-li...BACKGROUND Hepatocellular carcinoma(HCC)is one of the most aggressive tumors worldwide.Chronic inflammation contributes to tumor evolution,and the infiltration of tumor-associated macrophages(TAMs),also known as M2-like macrophages,is associated with the most aggressive behavior.Therefore,these macrophages provide the primary growth and migratory factors to the tumor cells,including those of HCC.Current therapies are not well optimized for eliminating trans-formed cells or neutralizing the tumor immune microenvironment leukocytes,such as TAMs.Growth differentiation factor 11(GDF11)may represent a promi-sing dual therapeutic target due to its reported anti-tumorigenic and immuno-modulatory properties.AIM To characterize the effects of GDF11 in M2-like macrophages and the HCC cell interaction using a functional in vitro model.METHODS This research used THP-1 and Huh7 cell lines.We applied recombinant GDF11(50 ng/mL)every 24 hours on THP-1 differentiated macrophages with M2-like polarization using interleukin-4 and interleukin-13.Firstly,the GDF11 effects on signaling,viability,proliferation,metabolism,and redox state in macrophages were charac-terized.Subsequently,we extracted conditioned media(CM)from macrophages and performed indirect co-cultures with Huh7 cells.The functional parameters were proliferation and migration assays.Finally,we charac-terized secretion in the CM using the cytokine array membrane assay.RESULTS The present study demonstrated that GDF11 activates the canonical pathway Smad2/3 without cytotoxic or prolif-erative effects.We provide evidence that GDF11 also diminishes the pro-tumoral properties of M2-like macrophages.GDF11 promoted the reduction of the M2-like macrophage marker,cluster of differentiation 206,indicating a loss of pro-tumoral properties in these leukocytes.Furthermore,this molecule induced changes in metabolism and an increase in reactive oxygen species.Using CM derived from GDF11-treated M2-like macrophages,we observed a reduction in the proliferation and migratory capacity of liver cancer cells.Moreover,the cytokine profile was affected by GDF11 stimulus,demonstrating that this molecule alters the pro-tumoral properties of TAMs,which in turn impact the behavior of HCC-derived cells.CONCLUSION This in vitro study suggests that mitigating tumor-promoting or M2-like macrophages with GDF11 may be an effective strategy for controlling the aggressiveness of HCC.展开更多
OBJECTIVE: To evaluate the effect of compound Gaoziban tablet(复方高滋斑片, CGZBT) on depression, and to investigate the underlying mechanism. METHODS: The components of CGZBT were analysed by high-performance liquid ...OBJECTIVE: To evaluate the effect of compound Gaoziban tablet(复方高滋斑片, CGZBT) on depression, and to investigate the underlying mechanism. METHODS: The components of CGZBT were analysed by high-performance liquid chromatography. Then, we assessed the effects of varying doses of CGZBT on an established chronic unpredictable mild stress(CUMS) model in rats. Whether animals were depressed was evaluated by sucrose preference test, open field test and forced swimming test. Neurotransmitters of hippocampus were detected by liquid chromatography-mass spectrometry. Serum levels of tumor necrosis factor-alpha(TNF-α), interleukin(IL)-1β, IL-6, IL-4, and IL-10 were measured by enzyme-linked immunosorbent assay. Expressions of toll-like receptor 4(TLR4), myeloid differentiation factor 88(My D88), phospho-nuclear factorkappa B(p-NF-κB), cyclooxygenase-2(COX-2), ionized calcium binding adapter molecule-1(IBA-1) were assessed by immunohistochemical staining and western blotting. RESULTS: Eight compounds were identified from CGZBT, moreover, our results showed that CGZBT effectively reversed the CUMS-induced decrease in sucrose preference, shortened the movement distance and prolonged immobility time. CGZBT significantly increased levels of 5-hydroxytryptamine, dopamine, norepinephrine, 5-hydroxyindoleacetic acid levels, and reduced the expression of TNF-α, IL-1β, IL-6, yet increased IL-4 and IL-10. Furthermore, the expressions of TLR4, My D88, COX-2, p-NF-κB and IBA-1 in hippocampus were effectively reversed after treatment with CGZBT. CONCLUSIONS: These results indicated that CGZBT could, at least in part, alleviate depression induced by CUMS via the TLR4/My D88/NF-κB pathway, suggesting its potential as an antidepressant drug.展开更多
Growth differentiation factor 9 （GDF9） is expressed in oocytes and is thought to be required for ovarian folliculogenesis. Given this function, GDF9 may be considered as a candidate gene controlling pig ovulate rate...Growth differentiation factor 9 （GDF9） is expressed in oocytes and is thought to be required for ovarian folliculogenesis. Given this function, GDF9 may be considered as a candidate gene controlling pig ovulate rate. In this study, the complete coding sequence was cloned （encoding a 444 amino acid）, intron sequence and partial 5＇-UTR of pig GDF9. RT-PCR results showed that GDF9 mRNA is expressed in a wide range of tissues of the ruttish Erhualian pig. The expression levels of GDF9 mRNA in pituitary, ovary, uterus and oviduct are higher in the Erhualian pigs than those in Duroc pigs, especially in pituitary with a significant difference （P 〈 0.05）. Comparative sequencing revealed 12 polymorphisms, including 8 single nucleotide polymorphisms （SNPs） and one 314 bp indel in noncoding regions, and the other 3 SNPs in coding regions. Four polymorphisms, G359C, C1801T, T1806C and 314 bp indel, were developed as markers for further use in population variation and association studies. The G359C polymorphism segregates only in Chinese native pigs, Erhualian and Dahuabai, on the contrary, 314 bp indel segregates only in Duroc and Landrace. C1801T and T1806C sites seem to be completely linked and segregate in Erhualian, Dahuabai and Landrace. In a word, GDF9 may be not associated with pig litter size in extensive populations as per the studies of allele distributions of the four polymorphisms and pilot association in four breeds.展开更多
Neuroprotection and neuroregeneration are two of the most promising disease-modifying ther- apies for the incurable and widespread Parkinson＇s disease. In Parkinson＇s disease, progressive degeneration of nigrostriat...Neuroprotection and neuroregeneration are two of the most promising disease-modifying ther- apies for the incurable and widespread Parkinson＇s disease. In Parkinson＇s disease, progressive degeneration of nigrostriatal dopaminergic neurons causes debilitating motor symptoms. Neurotrophic factors play important regulatory roles in the development, survival and maintenance of specific neuronal populations. These factors have the potential to slow down, halt or reverse the loss of nigrostriatal dopaminergic neurons in Parkinsoffs disease. Several neurotrophic fac- tors have been investigated in this regard. This review article discusses the neurodevelopmental roles and therapeutic potential of three dopaminergic neurotrophic factors： glial cell line-derived neurotrophic factor, neurturin and growth/differentiation factor 5.展开更多
OBJECTIVE: To explore whether moxibustion exerts therapeutic effects on rheumatoid arthritis(RA) by regulating the expression of T-cell immunoglobulin and mucin-containing protein-3(TIM-3) and subsequently modulating ...OBJECTIVE: To explore whether moxibustion exerts therapeutic effects on rheumatoid arthritis(RA) by regulating the expression of T-cell immunoglobulin and mucin-containing protein-3(TIM-3) and subsequently modulating the macrophage M1 polarization toll-like receptor 4(TLR4)-myeloid differentiation factor 88(My D88)-nuclear factor kappa B(NF-κB) signaling pathway. METHODS: We utilized moxibustion treatment in RA rat models using the Zusanli(ST36) and Shenshu(BL23) acupoints. Hematoxylin and eosin(HE) staining was used to observe the pathological changes of the synovial tissue under a section light microscope, and pathological scoring was performed according to the grading standard of the degree of synovial tissue disease. Enzyme-linked immunosorbent assay(ELISA) was applied to verify the efficacy of moxibustion in reducing inflammation. Quantitative real-time polymerase chain reaction(q RTPCR) was used to detect the expression of the TIM-3/TLR4-My D88-NF-κB signaling pathway-related molecules, and Western blot was used to detect the contents of synovial NF-κB. RESULTS: We established the Freund's complete adjuvant(FCA)-induced RA model in rats. The expression level of M1 polarization signaling pathway TLR4-My D88-NF-κB and the inflammatory factors interleukin-12(IL-12), tumor necrosis factor alpha(TNF-α), and tumor necrosis factor beta(TNF-β) were significantly increased in the RA model. After moxibustion treatment, the expression level of TLR4-My D88-NF-κB was significantly decreased, and the inflammatory factors IL-12, TNF-α, and TNF-β were decreased, but the expression level was significantly increased in the RA model. When TIM-3 expression was inhibited, the expression level of TLR4-My D88-NF-κB, and the inflammatory factors IL-12, TNF-α, and TNF-β were not suppressed, even after moxibustion treatment. CONCLUSIONS: Moxibustion regulates the key target TIM-3 by acting on the Zusanli(ST36) and Shenshu(BL23) points, thereby inhibiting the M1 polarization of macrophages;that is, it inhibits the TLR4-My D88-NF-κB signaling pathway, and finally achieves alleviation of pathological changes and anti-inflammatory effects.展开更多
OBJECTIVE:To evaluate the efficacy of Liangxue Guyuan decoction(凉血固元汤,LGD)on radiation-induced intestinal injury in rats,and the possible underlying mechanism of action.METHODS:A total of 255 male Sprague-Dawley ...OBJECTIVE:To evaluate the efficacy of Liangxue Guyuan decoction(凉血固元汤,LGD)on radiation-induced intestinal injury in rats,and the possible underlying mechanism of action.METHODS:A total of 255 male Sprague-Dawley rats were used.15 rats were assigned to the control group and the remaining 240 rats were exposed to a^(60)Co source at a dose of 11 Gy.Irradiated rats were randomly divided into model,dexamethasone(DXM),low-dose LGD(LGDl),and high-dose LGD(LGDh)groups and treated for 11 d.The survival rate,weight of body,intestinal pathology and the expression of toll-like receptor 4(TLR4),myeloid differentiation primary response 88(MyD88),and nuclear`factor-kappa B(NF-κB)were recorded.RESULTS:Radiation reduced the survival rate and weight of rats,destroyed the intestinal structure,induced an inflammatory reaction,and increased both protein and mRNA expression of TLR4,MyD88,and NF-κB in ileum.However,LGDh increased the survival rate,inhibited weight loss,alleviated inflammation and improve the expression of TLR4 pathway.CONCLUSIONS:LGD increased the survival rate and inhibit weight loss of irradiated rats,and reduced inflammation and intestinal injury.The underlying mechanism may involve regulation of the TLR4/MyD88/NF-κB pathway.展开更多
OBJECTIVE:To examine the nephroprotective mechanism of modified Huangqi Chifeng decoction(加味黄芪赤风汤,MHCD)in immunoglobulin A nephropathy(IgAN)rats.METHODS:To establish the IgAN rat model,the bovine serum albumin,...OBJECTIVE:To examine the nephroprotective mechanism of modified Huangqi Chifeng decoction(加味黄芪赤风汤,MHCD)in immunoglobulin A nephropathy(IgAN)rats.METHODS:To establish the IgAN rat model,the bovine serum albumin,lipopolysaccharide,and carbon tetrachloride 4 method was employed.The rats were then randomly assigned to the control,model,telmisartan,and high-,medium-,and low-dose MHCD groups,and were administered the respective treatments via intragastric administration for 8 weeks.The levels of 24-h urinary protein,serum creatinine(CRE),and blood urea nitrogen(BUN)were measured in each group.Pathological alterations were detected.IgA deposition was visualized through the use of immunofluorescence staining.The ultrastructure of the kidney was observed using a transmission electron microscope.The expression levels of interleukin-6(IL-6),monocyte chemoattractant protein-1(MCP-1),and transforming growth factor-β1(TGF-β1)were examined by immunohistochemistry and quantitative polymerase chain reaction.Levels of toll-like receptor 4(TLR4),myeloid differentiation factor 88(MyD88),and nuclear factor-kappa B(NF-κB)P65,were examined by immunohistochemistry,Western blotting,and quantitative polymerase chain reaction.RESULTS:The 24-h urine protein level in each group increased significantly at week 6,and worsen from then on.But this process can be reversed by treatments of telmisartan,and high-,medium-,and low-dose of MHCD,and these treatments did not affect renal function.Telmisartan,and high-,and medium-dose of MHCD reduced IgA deposition.Renal histopathology demonstrated the protective effect of high-,medium-,and low-dose of MHCD against kidney injury.The expression levels of MCP-1,IL-6,and TGF-β1 in kidney tissues were downregulated by low,medium and high doses of MHCD treatment.Additionally,treatment of low,medium and high doses of MHCD decreased the protein and mRNA levels of TLR4,MyD88,and NF-κB.CONCLUSIONS:MHCD exerted nephroprotective effects on IgAN rats,and MHCD regulated the expressions of key targets in TLR4/MyD88/NF-κB signaling pathway,thereby alleviating renal inflammation by inhibiting MCP-1,IL-6 expressions,and ameliorating renal fibrosis by inhibiting TGF-β1 expression.展开更多
OBJECTIVE:To investigate the effect of Taohong Siwu decoction(桃红四物汤,TSD)on atherosclerosis in rats as well as investigate the underlying mechanism based on molecular docking.METHODS:Sixty healthy male Sprague-Daw...OBJECTIVE:To investigate the effect of Taohong Siwu decoction(桃红四物汤,TSD)on atherosclerosis in rats as well as investigate the underlying mechanism based on molecular docking.METHODS:Sixty healthy male Sprague-Dawley rats were randomly divided into 6 groups with 10 rats in each group:control group,model group,atorvastatin group(AT,2.0 mg/kg),and TSD groups(20,10,5 g/kg)after 7 d of acclimation.The model of atherosclerosis was successfully established except the control group by high fat diet(HFD)and vitamin D2.Biochemical analyzers were used to detect the levels of triglyceride(TG),total cholestero(TC),low density lipoprotein-cholesterol(LDLC)and high density lipid-cholesterol(HDL-C)in blood lipid.The levels of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6)and interleukin-1β(IL-1β)were determined by enzyme-linked immunosorbent assay.Sudan IV staining and Hematoxylin and eosin staining(HE staining)were performed to observe the pathological changes in aortic tissue.Molecular docking technology was used to predict the best matching between the main components of TSD and the target proteins.The expression of target proteins was further detected by quantitative real time polymerase chain reaction(q RTPCR)and Western blot analysis.RESULTS:The results showed that TSD restricted atherosclerosis development and decreased the inflammatory cytokines in plasma.Molecular docking results predicted that the main components of TSD showed a strong binding ability with toll-like receptor(TLR4),myeloid differentiation primary response protein 88(My D88),and nuclear factor kappa-B(NF-κB).The results of q RT-PCR and Western blot analysis showed that the m RNA and protein expressions of TLR4,My D88 and NF-κB p65 in the aorta were reduced in atorvastatin group and TSD group.CONCLUSIONS:TSD can ameliorate atherosclerosis in rats,and the underlying mechanism is supposed be related to the suppression of inflammatory response by regulating TLR4/My D88/NF-κB signal pathway.展开更多
OBJECTIVE:To investigate the effect of Soothing liver therapy on infertile women undergoing in vitro fertilization and embryo transfer(IVF-ET)and to explore its mechanism.METHODS:Fifty-eight women with tubal infertili...OBJECTIVE:To investigate the effect of Soothing liver therapy on infertile women undergoing in vitro fertilization and embryo transfer(IVF-ET)and to explore its mechanism.METHODS:Fifty-eight women with tubal infertility were randomized into two groups:30 in an experimental group treated with Xiaoyao powder(Shugan)plus gonadotropin-releasing hormone analog(GnRHa)/follicle-stimulating hormone(FSH)/human chorionic gonadotropin(hCG)and 28 in the control group who were treated with GnRHa/FSH/hCG only.The total gonadotropin(Gn)doses required,endometrial thickness,oocyte numbers,high quality embryo production rate and pregnancy rate of the two groups were compared.The concentration of growth differentiation factor-9(GDF-9)in follicular fluid was detected by western blotting and the expression of GDF-9 mRNA in granulosa cells was measured using reverse tran-scription-polymerase chain reaction amplification.RESULTS:In the experimental group,the Gn dose was significantly lower than that in the control group;the endometrial thickness,high quality embryo production and pregnancy rates were significantly higher and the expression of GDF-9 mRNA was also significantly higher than in the control group(all P<0.05).CONCLUSION:Shugan treatment can improve the pregnancy rate of women with tubal infertility;its mechanism is possibly related to the increased expression of GDF-9 in granulosa cells.展开更多
BACKGROUND Multiple system atrophy(MSA) is a serious progressive neurodegenerative disease. Early diagnosis of MSA is very difficult, and diagnostic biomarkers are limited. Growth differentiation factor 15(GDF15) is i...BACKGROUND Multiple system atrophy(MSA) is a serious progressive neurodegenerative disease. Early diagnosis of MSA is very difficult, and diagnostic biomarkers are limited. Growth differentiation factor 15(GDF15) is involved in the differentiation and progression of the central nervous system, and is widely distributed in peripheral blood, which may be a novel biomarker for MSA.AIM To determine serum GDF15 levels, related factors and their potential diagnostic value in MSA patients, compared with Parkinson’s disease(PD) patients and healthy controls.METHODS A case-control study was conducted, including 49 MSA patients, 50 PD patients and 50 healthy controls. Serum GDF15 levels were measured by human enzymelinked immunosorbent assay, and the differences between the MSA, PD and control groups were analyzed. Further investigations were performed in different MSA subgroups according to age of onset, sex, clinical subtypes, diagnostic criteria, and disease duration. Receiver-operating characteristic curve analysiswas used to evaluate the diagnostic value of GDF15, especially for the differential diagnosis between MSA and PD.RESULTS Serum GDF15 levels were significantly higher in MSA patients than in PD patients and healthy controls(P = 0.000). Males and those with a disease duration of more than three years showed higher serum GDF15 levels(P = 0.043 and 0.000;respectively). Serum GDF15 levels may be a potential diagnostic biomarker for MSA patients compared with healthy controls and PD patients(cutoff: 470.42 pg/m L, sensitivity: 85.7%, specificity: 88.0%;cutoff: 1075.91 pg/m L, sensitivity:51.0%, specificity: 96.0%;respectively).CONCLUSION Serum GDF15 levels are significantly higher in MSA patients and provide suggestions on the etiology of MSA.展开更多
BACKGROUND Oral cancer(OC)is the most common malignant tumor in the oral cavity,and is mainly seen in middle-aged and elderly men.At present,OC is mainly treated clinically by surgery or combined with radiotherapy and...BACKGROUND Oral cancer(OC)is the most common malignant tumor in the oral cavity,and is mainly seen in middle-aged and elderly men.At present,OC is mainly treated clinically by surgery or combined with radiotherapy and chemotherapy;but recently,more and more studies have shown that the stress trauma caused by surgery and the side effects of radiotherapy and chemotherapy seriously affect the prognosis of patients.AIM To determine the significance of 125I radioactive seed implantation on growth differentiation factor 11(GDF11)and programmed death receptor-1(PD-1)during treatment of OC.METHODS A total of 184 OC patients admitted to The Second Affiliated Hospital of Jiamusi University from May 2015 to May 2017 were selected as the research subjects for prospective analysis.Of these patients,89 who received 125I radioactive seed implantation therapy were regarded as the research group(RG)and 95 patients who received surgical treatment were regarded as the control group(CG).The clinical efficacy,incidence of adverse reactions and changes in GDF11 and PD-1 before treatment(T0),2 wk after treatment(T1),4 wk after treatment(T2)and 6 wk after treatment(T3)were compared between the two groups.RESULTS The efficacy and recurrence rate in the RG were better than those in the CG(P<0.05),while the incidence of adverse reactions and survival rate were not different.There was no difference in GDF11 and PD-1 between the two groups at T0 and T1,but these factors were lower in the RG than in the CG at T2 and T3(P<0.05).Using receiver operating characteristic(ROC)curve analysis,GDF11 and PD-1 had good predictive value for efficacy and recurrence(P<0.001).CONCLUSION 125I radioactive seed implantation has clinical efficacy and can reduce the recurrence rate in patients with OC.This therapy has marked potential in clinical application.The detection of GDF11 and PD-1 in patients during treatment showed good predictive value for treatment efficacy and recurrence in OC patients,and may be potential targets for future OC treatment.展开更多
Parkinson’s disease is the most common movement disorder worldwide,affecting over 6 million people.It is an age-related disease,occurring in 1%of people over the age of 60,and 3%of the population over 80 years.The di...Parkinson’s disease is the most common movement disorder worldwide,affecting over 6 million people.It is an age-related disease,occurring in 1%of people over the age of 60,and 3%of the population over 80 years.The disease is characterized by the progressive loss of midbrain dopaminergic neurons from the substantia nigra,and their axons,which innervate the striatum,resulting in the characteristic motor and non-motor symptoms of Parkinson’s disease.This is paralleled by the intracellular accumulation ofα-synuclein in several regions of the nervous system.Current therapies are solely symptomatic and do not stop or slow disease progression.One promising disease-modifying strategy to arrest the loss of dopaminergic neurons is the targeted delivery of neurotrophic factors to the substantia nigra or striatum,to protect the remaining dopaminergic neurons of the nigrostriatal pathway.However,clinical trials of two well-established neurotrophic factors,glial cell line-derived neurotrophic factor and neurturin,have failed to meet their primary end-points.This failure is thought to be at least partly due to the downregulation byα-synuclein of Ret,the common co-receptor of glial cell line-derived neurorophic factor and neurturin.Growth/differentiation factor 5 is a member of the bone morphogenetic protein family of neurotrophic factors,that signals through the Ret-independent canonical Smad signaling pathway.Here,we review the evidence for the neurotrophic potential of growth/differentiation factor 5 in in vitro and in vivo models of Parkinson’s disease.We discuss new work on growth/differentiation factor 5’s mechanisms of action,as well as data showing that viral delivery of growth/differentiation factor 5 to the substantia nigra is neuroprotective in theα-synuclein rat model of Parkinson’s disease.These data highlight the potential for growth/differentiation factor 5 as a disease-modifying therapy for Parkinson’s disease.展开更多
Under China's innovation-driven development strategy, venture capital has become an important driving force in urban agglomeration integration and collaborative innovation. This paper uses social network analysis ...Under China's innovation-driven development strategy, venture capital has become an important driving force in urban agglomeration integration and collaborative innovation. This paper uses social network analysis to analyze spatiotemporal differences of venture capital in the Beijing-Tianjin-Hebei urban agglomeration for the period 2005–2015. A gravity model and panel data regression model are used to reveal the influencing factors on spatiotemporal differences in venture capital in the region. This study finds that there is a certain cyclical fluctuation and uneven differentiation in the venture capital network in the Beijing-Tianjin-Hebei urban agglomeration in terms of total investment, and that the three centers of venture capital(Beijing, Shijiazhuang and Tangshan) have a stimulatory effect on surrounding cities; flows of venture capital between cities display certain networking rules, but they are slow to develop and strongly centripetal; there is a strong positive correlation between levels of information infrastructure development and economic development and venture capital investment; and places with relatively underdeveloped financial environments and service industries are less able to apply the fruits of innovation and entrepreneurship and to attract funds. This study can act as a reference for the Beijing-Tianjin-Hebei urban agglomeration in building a world-class super urban agglomeration with the best innovation capabilities in China.展开更多
Background:Myocardial infarctions(MI)is a major threat to human health especially in people exposed to cold environment.The polarization of macrophages towards different functional phenotypes(M1 macrophages and M2 mac...Background:Myocardial infarctions(MI)is a major threat to human health especially in people exposed to cold environment.The polarization of macrophages towards different functional phenotypes(M1 macrophages and M2 macrophages)is closely related to MI repairment.The growth differentiation factor 11(GDF11)has been reported to play a momentous role in inflammatory associated diseases.In this study,we examined the regulatory role of GDF11 in macrophage polarization and elucidated the underlying mechanisms in MI.Methods:In vivo,the mice model of MI was induced by permanent ligation of the left anterior descending coronary artery(LAD),and mice were randomly divided into the sham group,MI group,and MI+GDF11 group.The protective effect of GDF11 on myocardial infarction and its effect on macrophage polarization were verified by echocardiography,triphenyl tetrazolium chloride staining and immunofluorescence staining of heart tissue.In vitro,based on the RAW264.7 cell line,the effect of GDF11 in promoting macrophage polarization toward the M2 type by inhibiting the Notch1 Signaling pathway was validated by qRT-PCR,Western blot,and flow cytometry.Results:We found that GDF11 was significantly downregulated in the cardiac tissue of MI mice.And GDF11 supplementation can improve the cardiac function.Moreover,GDF11 could reduce the proportion of M1 macrophages and increase the accumulation of M2 macrophages in the heart tissue of MI mice.Furthermore,the cardioprotective effect of GDF11 on MI mice was weakened after macrophage clearance.At the cellular level,application of GDF11 could inhibit the expression of M1 macrophage(classically activated macrophage)markers iNOS,interleukin(IL)-1β,and IL-6 in a dose-dependent manner.In contrast,GDF11 significantly increased the level of M2 macrophage markers including IL-10,CD206,arginase 1(Arg1),and vascular endothelial growth factor(VEGF).Interestingly,GDF11 could promote M1 macrophages polarizing to M2 macrophages.At the molecular level,GDF11 significantly down-regulated the Notch1 signaling pathway,the activation of which has been demonstrated to promote M1 polarization in macrophages.Conclusions:GDF11 promoted macrophage polarization towards M2 to attenuate myocardial infarction via inhibiting Notch1 signaling pathway.展开更多
BACKGROUND Growth differentiation factor(GDF)-15 is a member of a transforming growth factor-βcytokine superfamily that regulates metabolism and is released in response to inflammation,hypoxia and tissue injury.It ha...BACKGROUND Growth differentiation factor(GDF)-15 is a member of a transforming growth factor-βcytokine superfamily that regulates metabolism and is released in response to inflammation,hypoxia and tissue injury.It has evolved as one of the most potent cytokines for predicting the severity of infections and inflammatory conditions,such as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.AIM To investigate the utility of GDF-15 in predicting the severity of SARS-CoV-2 infection.METHODS PubMed,Reference Citation Analysis,CNKI,and Goggle Scholar were explored by using related MeSH keywords and data such as the first author’s name,study duration,type and place of study,sample size and subgroups of participants if any,serum/plasma GDF-15 level in pg/mL,area under the curve and cut-off value in receiver operating characteristic analysis,method of measurement of GDF-15,and the main conclusion were extracted.RESULTS In all studies,the baseline GDF-15 level was elevated in SARS-CoV-2-infected patients,and it was significantly associated with severity,hypoxemia,viral load,and worse clinical consequences.In addition,GDF-15 levels were correlated with C-reactive protein,D-dimer,ferritin and procalcitonin,and it had superior discriminatory ability to detect severity and in-hospital mortality of SARS-CoV-2 infection.Hence,GDF-15 might be used to predict the severity and prognosis of hospitalized patients with SARS-CoV-2.CONCLUSION Serial estimation of GDF-15 levels in hospitalized patients with SARS-CoV-2 infection appeared to have useful prognostic value and GDF-15 can be considered a clinically prominent sepsis biomarker for SARS-CoV-2 infection.展开更多
OBJECTIVE:To investigate the role of toll-like receptor 4(TLR4)/mutant myeloid differentiation primary response 88(MyD88)/nuclear factor kappa-B(NF-κB)signaling pathway-mediated inflammation in diabetes mellitus with...OBJECTIVE:To investigate the role of toll-like receptor 4(TLR4)/mutant myeloid differentiation primary response 88(MyD88)/nuclear factor kappa-B(NF-κB)signaling pathway-mediated inflammation in diabetes mellitus with Northwest dryness syndrome.METHODS:Rats were randomly divided into the normal control,type 2 diabetes(T2DM)model,Northwest dryness syndrome+T2DM(Northwest dryness),and simple internal dampness+T2DM(internal dampness)groups.Enzyme-linked immunosorbent assay was used to detect biochemical indexes and inflammatory factors.The histopathological observation was performed.Quantitative real-time polymerase chain reaction and Western blot analysis were used to detect the mRNA and protein expression levels,respectively.RESULTS:Compared with the T2DM group,the glycosylated hemoglobin A1c,insulin,glucose tolerance,the homeostasis model assessment of insulin resistance,tumor necrosis factor-α,interleukin 1β,interleukin 16,malondialdehyde,blood lipid,alanine aminotransferase,and aspartate aminotransferase were significantly elevated in the internal dampness group.Their levels were significantly elevated in the Northwest dryness group than in the T2DM and internal dampness groups.The superoxide dismutase,glutathione peroxidase,liver glycogen,and organ-to-weight ratio were significantly declined in the internal dampness group and the Northwest dryness group than in the T2DM group.However,these levels were elevated in the Northwest dryness group than in the internal dampness group.Moreover,the mRNA expression levels of interferon regulatory factor 5 and NF-κB p65,and the protein expression levels of TLR4,MyD88,and NF-κB were significantly higher in the internal dampness and the Northwest dryness groups than the T2DM group.Additionally,the mRNA and protein levels were significantly higher in the Northwest dryness group than in the internal dampness group.CONCLUSION:Northwest dryness syndrome-mediated TLR4/MyD88/NF-κB pathway and chronic inflammation might be associated with the occurrence and development of T2DM.展开更多
Objective. To investigate the roles of mouse erythroid differentiation and denucleation factor (MKI)DF), a novel factor cloned in our laboratory recently, in erylhroid terminal differentiation.Method. Mouse erythroleu...Objective. To investigate the roles of mouse erythroid differentiation and denucleation factor (MKI)DF), a novel factor cloned in our laboratory recently, in erylhroid terminal differentiation.Method. Mouse erythroleukemia (MEL) cells were transfected with eukaryotie expression plasinid pcl)-NA-MEDDF. Then we investigated the changes on characteristics of cell growth by analyzing cells growth rate, mitotie index and colony-forming rate in semi-solid medium. The expressions of c-mye and p-globin genes were analysed by semi-quantitative RT-PCR.Results. MEL cells transfected with pcDNA-MEDDF showed significant lower growth rate, mitolic index,and colony-forming rate in semi-solid medium ( P<0. 01). The percentage of benzidine-positive cells was 32. 8%after transfection. The expression of β-globin in cells trarisfected with pcDNA-MEDDF was 3. 43 times higherthan that of control (MEL transfected with blank vector, pcDNA3. 1), and the expression of c-rnyc decreased by66. 3% .Conclusions. MEDDF can induce differentiation of MEL cell and suppress its malignancy.展开更多
Objective To explore the feasibility and effectiveness of the self-assembly cartilage tissue engineered with chondrogenically differentiated human bone mesenchymal stem cells (hBMCs) induced by growth differentiation ...Objective To explore the feasibility and effectiveness of the self-assembly cartilage tissue engineered with chondrogenically differentiated human bone mesenchymal stem cells (hBMCs) induced by growth differentiation factor-5 (GDF-5)展开更多
基金Supported by the Provincial Key Cultivation Laboratory for Digestive Disease Research,No.2021SYS13Shanxi Province’s“Si Ge Yi Pi”Science and Technology Driven Medical Innovation Project,No.2021MX03Shanxi Provincial Basic Research Program,No.202403021222423.
文摘BACKGROUND Ulcerative colitis(UC)is a chronic and treatment-resistant disorder requiring potent therapeutics that are effective and safe.Cedrol(CE)is a bioactive natural product present in many traditional Chinese medicines.It is known for its suppression of inflammation and mitigation of oxidative stress.Its therapeutic efficacy and mechanistic underpinnings in UC remain uncharacterized.AIM To investigate the therapeutic potential and mechanisms of CE in UC.METHODS The anti-inflammatory activity and intestinal barrier-repairing effects of CE were assessed in a dextran sulfate sodium-induced murine colitis model.Network pharmacology was employed to predict potential targets and pathways.Then molecular docking and dynamics simulations were utilized to confirm a stable interaction between CE and the toll-like receptor 4(TLR4)/myeloid differentiation factor 2(MD2)complex.The anti-inflammatory mechanisms were further verified using in vitro assays.Additionally,the gut microbiota composition was analyzed via 16S rRNA gene sequencing.RESULTS CE significantly alleviated colitis symptoms,mitigated histopathological damage,and suppressed inflammation.Moreover,CE restored intestinal barrier integrity by enhancing mucus secretion and upregulating tight junction proteins(zonula occludens 1,occludin,claudin-1).Mechanistically,CE stably bound to MD2,inhibiting lipopolysaccharide-induced TLR4 signaling in RAW264.7 cells.This led to suppression of the downstream mitogen-activated protein kinase and nuclear factor kappa B signaling pathways,downregulating the expression of tumor necrosis factor-alpha,interleukin-1β,and interleukin-6.Gut microbiota analysis revealed that CE reversed dextran sulfate sodium-induced dysbiosis with significant enrichment of butyrogenic Christensenella minuta.CONCLUSION CE acted on MD2 to suppress proinflammatory cascades,promoting mucosal barrier reconstitution and microbiota remodeling and supporting its therapeutic use in UC.
基金Supported by the Ministerio de Ciencia,Innovación y Universidades(Spain),No.IJCI-2017-31466the Consejería de Salud y Familia de la Junta de Andalucía,Spain,No.PI-0244-2021+12 种基金No.PI-0245-2021No.PI-0131-2020FEDER funds/Consejería de Economía y Conocimiento,Empresas y Universidad,de la Junta de Andalucía(“A way to make Europe”)(“Andalucía se mueve con Europa”,University of Málaga,No.UMA20-FEDERJA-081No.UMA20-FEDERJA-074the Consejería de Empleo,Empresa y Trabajo Autónomo de la Junta de Andalucía(Investigo program),No.MA-INV-0031-2022-04Sara Borrell grant from the Instituto de Salud Carlos III(ISCIII),No.CD23/00117PFIS contract from the ISCIII,No.FI23-00016Juan Rodés contract from the ISCIII,No.JR22/00067the Miguel Servet program from the ISCIII,No.CP23/00088the Nicolas Monardes Program from the Consejería de Salud de la Junta de Andalucía(Spain),No.RC-0005-2020the Consejería Salud y Familias-Junta de Andalucía,No.RH-0078-2021the University of Málaga(Incorporación de Doctores del II Plan Propio de Investigación,Transferencia y Divulgación Científica de la Universidad de Málaga en 2023)the Miguel Servet program from ISCIII,Spain,No.CP22/00050.
文摘BACKGROUND Inflammatory bowel disease(IBD)is a group of chronic,inflammatory disorders that include Crohn’s disease and ulcerative colitis.IBD arises from the interaction of various environmental and genetic factors.Altered gut permeability and mitochondrial stress in the colonic mucosa are two mechanisms previously implicated in IBD pathogenesis.We have previously demonstrated activation of the mitochondrial unfolded protein response(UPRmt)in the colonic mucosa of IBD patients and linked this activation to pro-inflammatory signaling.Growth differentiation factor 15(GDF15)is an important downstream mediator of the UPRmt.AIM To investigate whether GDF15 has a role in IBD and how GDF15 impacts colonic epithelium.METHODS Circulating levels of GDF15 were assessed in plasma samples from IBD patients and healthy controls using an enzyme-linked immunosorbent assay.To study the effects of GDF15 on the colonic mucosa,we employed two different in vitro culture models:Colonic organoids and T84 cells.RESULTS We found that circulating GDF15 Levels were elevated in IBD patients and correlated with markers of inflammation(C-reactive protein)and intestinal permeability[haptoglobin and lipopolysaccharide-binding protein(LBP)].Additionally,we demonstrated that GDF15 alters the intestinal barrier and increases permeability by decreasing the levels of zonula occludens 1 and claudin 1,critical components of tight junctions.Thus,our findings confirm previous reports of increased circulating GDF15 levels in IBD patients and the activation of UPR^(mt).CONCLUSION In the present study,we describe a novel mechanism in IBD pathophysiology,linking mitochondrial stress to the disruption of the intestinal barrier and increased intestinal permeability.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is one of the most aggressive tumors worldwide.Chronic inflammation contributes to tumor evolution,and the infiltration of tumor-associated macrophages(TAMs),also known as M2-like macrophages,is associated with the most aggressive behavior.Therefore,these macrophages provide the primary growth and migratory factors to the tumor cells,including those of HCC.Current therapies are not well optimized for eliminating trans-formed cells or neutralizing the tumor immune microenvironment leukocytes,such as TAMs.Growth differentiation factor 11(GDF11)may represent a promi-sing dual therapeutic target due to its reported anti-tumorigenic and immuno-modulatory properties.AIM To characterize the effects of GDF11 in M2-like macrophages and the HCC cell interaction using a functional in vitro model.METHODS This research used THP-1 and Huh7 cell lines.We applied recombinant GDF11(50 ng/mL)every 24 hours on THP-1 differentiated macrophages with M2-like polarization using interleukin-4 and interleukin-13.Firstly,the GDF11 effects on signaling,viability,proliferation,metabolism,and redox state in macrophages were charac-terized.Subsequently,we extracted conditioned media(CM)from macrophages and performed indirect co-cultures with Huh7 cells.The functional parameters were proliferation and migration assays.Finally,we charac-terized secretion in the CM using the cytokine array membrane assay.RESULTS The present study demonstrated that GDF11 activates the canonical pathway Smad2/3 without cytotoxic or prolif-erative effects.We provide evidence that GDF11 also diminishes the pro-tumoral properties of M2-like macrophages.GDF11 promoted the reduction of the M2-like macrophage marker,cluster of differentiation 206,indicating a loss of pro-tumoral properties in these leukocytes.Furthermore,this molecule induced changes in metabolism and an increase in reactive oxygen species.Using CM derived from GDF11-treated M2-like macrophages,we observed a reduction in the proliferation and migratory capacity of liver cancer cells.Moreover,the cytokine profile was affected by GDF11 stimulus,demonstrating that this molecule alters the pro-tumoral properties of TAMs,which in turn impact the behavior of HCC-derived cells.CONCLUSION This in vitro study suggests that mitigating tumor-promoting or M2-like macrophages with GDF11 may be an effective strategy for controlling the aggressiveness of HCC.
基金Supported by the Scientific Research Project of Education Department of Hubei Province (D20192003):Synthesis and Anti-hepatocellular Carcinoma Effect of Novel NMT1 Inhibitors。
文摘OBJECTIVE: To evaluate the effect of compound Gaoziban tablet(复方高滋斑片, CGZBT) on depression, and to investigate the underlying mechanism. METHODS: The components of CGZBT were analysed by high-performance liquid chromatography. Then, we assessed the effects of varying doses of CGZBT on an established chronic unpredictable mild stress(CUMS) model in rats. Whether animals were depressed was evaluated by sucrose preference test, open field test and forced swimming test. Neurotransmitters of hippocampus were detected by liquid chromatography-mass spectrometry. Serum levels of tumor necrosis factor-alpha(TNF-α), interleukin(IL)-1β, IL-6, IL-4, and IL-10 were measured by enzyme-linked immunosorbent assay. Expressions of toll-like receptor 4(TLR4), myeloid differentiation factor 88(My D88), phospho-nuclear factorkappa B(p-NF-κB), cyclooxygenase-2(COX-2), ionized calcium binding adapter molecule-1(IBA-1) were assessed by immunohistochemical staining and western blotting. RESULTS: Eight compounds were identified from CGZBT, moreover, our results showed that CGZBT effectively reversed the CUMS-induced decrease in sucrose preference, shortened the movement distance and prolonged immobility time. CGZBT significantly increased levels of 5-hydroxytryptamine, dopamine, norepinephrine, 5-hydroxyindoleacetic acid levels, and reduced the expression of TNF-α, IL-1β, IL-6, yet increased IL-4 and IL-10. Furthermore, the expressions of TLR4, My D88, COX-2, p-NF-κB and IBA-1 in hippocampus were effectively reversed after treatment with CGZBT. CONCLUSIONS: These results indicated that CGZBT could, at least in part, alleviate depression induced by CUMS via the TLR4/My D88/NF-κB pathway, suggesting its potential as an antidepressant drug.
文摘Growth differentiation factor 9 （GDF9） is expressed in oocytes and is thought to be required for ovarian folliculogenesis. Given this function, GDF9 may be considered as a candidate gene controlling pig ovulate rate. In this study, the complete coding sequence was cloned （encoding a 444 amino acid）, intron sequence and partial 5＇-UTR of pig GDF9. RT-PCR results showed that GDF9 mRNA is expressed in a wide range of tissues of the ruttish Erhualian pig. The expression levels of GDF9 mRNA in pituitary, ovary, uterus and oviduct are higher in the Erhualian pigs than those in Duroc pigs, especially in pituitary with a significant difference （P 〈 0.05）. Comparative sequencing revealed 12 polymorphisms, including 8 single nucleotide polymorphisms （SNPs） and one 314 bp indel in noncoding regions, and the other 3 SNPs in coding regions. Four polymorphisms, G359C, C1801T, T1806C and 314 bp indel, were developed as markers for further use in population variation and association studies. The G359C polymorphism segregates only in Chinese native pigs, Erhualian and Dahuabai, on the contrary, 314 bp indel segregates only in Duroc and Landrace. C1801T and T1806C sites seem to be completely linked and segregate in Erhualian, Dahuabai and Landrace. In a word, GDF9 may be not associated with pig litter size in extensive populations as per the studies of allele distributions of the four polymorphisms and pilot association in four breeds.
基金supported by grants from the Irish Research Council(R13702 and R15897SVH/AS/G’OK)+3 种基金the Health Research Board of Ireland(HRA/2009/127GO’K/AS)Science Foundation Ireland(10/RFP/NES2786GO’K)
文摘Neuroprotection and neuroregeneration are two of the most promising disease-modifying ther- apies for the incurable and widespread Parkinson＇s disease. In Parkinson＇s disease, progressive degeneration of nigrostriatal dopaminergic neurons causes debilitating motor symptoms. Neurotrophic factors play important regulatory roles in the development, survival and maintenance of specific neuronal populations. These factors have the potential to slow down, halt or reverse the loss of nigrostriatal dopaminergic neurons in Parkinsoffs disease. Several neurotrophic fac- tors have been investigated in this regard. This review article discusses the neurodevelopmental roles and therapeutic potential of three dopaminergic neurotrophic factors： glial cell line-derived neurotrophic factor, neurturin and growth/differentiation factor 5.
基金the National Natural Science Foundation of China:Study on Immunoregulatory Mechanism of Moxibustion"Regulating Weiqi"to Regulate the Intrasynovial Environment Steady State in Rheumatoid Arthritis Model Rats based on the Skin-resident Memory T cells-Growth Arrest-specific 6/Mer Tyrosine Kinase (No. 82374587)the National Natural Science Foundation of China:Study on the Immune Mechanisms of Macrophage M1/M2 Polarization in the Treatment of Rheumatoid Arthritis by Moxibustion"Strengthening Body Resistance and Eliminating Evil"(No. 81973959)+1 种基金the National Key R&D Program of China:Research on the Functional Characteristics of"Special Effects"and"Common Effects"of Acupoints (No. 2019YFC1709001)Science and Technology Innovation Seedling Project of Sichuan Province:based on Macrophage M1 Polarization Signaling Pathway Toll-like receptor 4/Myeloid differentiation factor 88/Nuclear factor kappa B and its Regulatory Molecule T-cell Immunoglobulin and Mucin-containing Protein-3 Exploring the Effect Mechanism of Moxibustion on Experimental Rheumatoid Arthritis Model (No. 2022037)。
文摘OBJECTIVE: To explore whether moxibustion exerts therapeutic effects on rheumatoid arthritis(RA) by regulating the expression of T-cell immunoglobulin and mucin-containing protein-3(TIM-3) and subsequently modulating the macrophage M1 polarization toll-like receptor 4(TLR4)-myeloid differentiation factor 88(My D88)-nuclear factor kappa B(NF-κB) signaling pathway. METHODS: We utilized moxibustion treatment in RA rat models using the Zusanli(ST36) and Shenshu(BL23) acupoints. Hematoxylin and eosin(HE) staining was used to observe the pathological changes of the synovial tissue under a section light microscope, and pathological scoring was performed according to the grading standard of the degree of synovial tissue disease. Enzyme-linked immunosorbent assay(ELISA) was applied to verify the efficacy of moxibustion in reducing inflammation. Quantitative real-time polymerase chain reaction(q RTPCR) was used to detect the expression of the TIM-3/TLR4-My D88-NF-κB signaling pathway-related molecules, and Western blot was used to detect the contents of synovial NF-κB. RESULTS: We established the Freund's complete adjuvant(FCA)-induced RA model in rats. The expression level of M1 polarization signaling pathway TLR4-My D88-NF-κB and the inflammatory factors interleukin-12(IL-12), tumor necrosis factor alpha(TNF-α), and tumor necrosis factor beta(TNF-β) were significantly increased in the RA model. After moxibustion treatment, the expression level of TLR4-My D88-NF-κB was significantly decreased, and the inflammatory factors IL-12, TNF-α, and TNF-β were decreased, but the expression level was significantly increased in the RA model. When TIM-3 expression was inhibited, the expression level of TLR4-My D88-NF-κB, and the inflammatory factors IL-12, TNF-α, and TNF-β were not suppressed, even after moxibustion treatment. CONCLUSIONS: Moxibustion regulates the key target TIM-3 by acting on the Zusanli(ST36) and Shenshu(BL23) points, thereby inhibiting the M1 polarization of macrophages;that is, it inhibits the TLR4-My D88-NF-κB signaling pathway, and finally achieves alleviation of pathological changes and anti-inflammatory effects.
基金Supported by Logistics Research Projects:Prevention and treatment of acute radiation injury of gastrointestinal tract with Traditional Chinese Medicine(No.AWS14C014)。
文摘OBJECTIVE:To evaluate the efficacy of Liangxue Guyuan decoction(凉血固元汤,LGD)on radiation-induced intestinal injury in rats,and the possible underlying mechanism of action.METHODS:A total of 255 male Sprague-Dawley rats were used.15 rats were assigned to the control group and the remaining 240 rats were exposed to a^(60)Co source at a dose of 11 Gy.Irradiated rats were randomly divided into model,dexamethasone(DXM),low-dose LGD(LGDl),and high-dose LGD(LGDh)groups and treated for 11 d.The survival rate,weight of body,intestinal pathology and the expression of toll-like receptor 4(TLR4),myeloid differentiation primary response 88(MyD88),and nuclear`factor-kappa B(NF-κB)were recorded.RESULTS:Radiation reduced the survival rate and weight of rats,destroyed the intestinal structure,induced an inflammatory reaction,and increased both protein and mRNA expression of TLR4,MyD88,and NF-κB in ileum.However,LGDh increased the survival rate,inhibited weight loss,alleviated inflammation and improve the expression of TLR4 pathway.CONCLUSIONS:LGD increased the survival rate and inhibit weight loss of irradiated rats,and reduced inflammation and intestinal injury.The underlying mechanism may involve regulation of the TLR4/MyD88/NF-κB pathway.
基金Joint Innovation Fundation of JIICM:Health Management of Chronic Kidney Disease Based on Integrated Traditional Chinese And Western Medicine(No.2021IR009)Natural Science Foundation-funded Project:the Mechanism of Modified Huangqi Chifeng Decoction Protect Damaged Podocyte via Cross-Talking of PI3K/AKT/mTOR and AMPK/mTOR/ULK1 Signaling Pathway Regulate Autophapy(No.81873300)+1 种基金the Central Publicinterest Scientific Institution Basal Research Fund of the China Academy of Chinese Medical Sciences:Comprehensive Evaluation of Clinical efficacy of Modified Huangqi Chifeng Decoction on IgA Nephropathy(No.ZZ11-023)the Beijing Municipal of Science and Technology Major Project:Evaluation of Clinical Efficacy of Modified Huangqi Chifeng Decoction in Treating Proteinuria in IgA Nephropathy Based on"Deficiency-Wind-Blood-Stasis-Toxicity"Mechanism in Chinese Medicine(No.Z191100006619063)。
文摘OBJECTIVE:To examine the nephroprotective mechanism of modified Huangqi Chifeng decoction(加味黄芪赤风汤,MHCD)in immunoglobulin A nephropathy(IgAN)rats.METHODS:To establish the IgAN rat model,the bovine serum albumin,lipopolysaccharide,and carbon tetrachloride 4 method was employed.The rats were then randomly assigned to the control,model,telmisartan,and high-,medium-,and low-dose MHCD groups,and were administered the respective treatments via intragastric administration for 8 weeks.The levels of 24-h urinary protein,serum creatinine(CRE),and blood urea nitrogen(BUN)were measured in each group.Pathological alterations were detected.IgA deposition was visualized through the use of immunofluorescence staining.The ultrastructure of the kidney was observed using a transmission electron microscope.The expression levels of interleukin-6(IL-6),monocyte chemoattractant protein-1(MCP-1),and transforming growth factor-β1(TGF-β1)were examined by immunohistochemistry and quantitative polymerase chain reaction.Levels of toll-like receptor 4(TLR4),myeloid differentiation factor 88(MyD88),and nuclear factor-kappa B(NF-κB)P65,were examined by immunohistochemistry,Western blotting,and quantitative polymerase chain reaction.RESULTS:The 24-h urine protein level in each group increased significantly at week 6,and worsen from then on.But this process can be reversed by treatments of telmisartan,and high-,medium-,and low-dose of MHCD,and these treatments did not affect renal function.Telmisartan,and high-,and medium-dose of MHCD reduced IgA deposition.Renal histopathology demonstrated the protective effect of high-,medium-,and low-dose of MHCD against kidney injury.The expression levels of MCP-1,IL-6,and TGF-β1 in kidney tissues were downregulated by low,medium and high doses of MHCD treatment.Additionally,treatment of low,medium and high doses of MHCD decreased the protein and mRNA levels of TLR4,MyD88,and NF-κB.CONCLUSIONS:MHCD exerted nephroprotective effects on IgAN rats,and MHCD regulated the expressions of key targets in TLR4/MyD88/NF-κB signaling pathway,thereby alleviating renal inflammation by inhibiting MCP-1,IL-6 expressions,and ameliorating renal fibrosis by inhibiting TGF-β1 expression.
基金Supported by the National Natural Science Foundation of China:Investigating the Mechanism of Total Saponins in Treating Gouty Arthritis Based on Toll-like Receptor/Myeloid Differentiation Factor 88/Nuclear Factor-Kappa B Signal Pathway and Nacht Leucine-Rich Repeat Protein 3-Inflammasome(No.81573670)Study on the Material Basis and Pathway of Taohong Siwu Decoction in Regulating the Release of Platelet Alpha Granules in Postpartum Blood Stasis(No.81473387)+2 种基金Study on the Regulatory Mechanism of Taohong Siwu Decoction on Experimental Cerebral Ischemia Angiogenesis Based on the Messenger Effect of Platelet Microparticles(No.81503291)Investigating the Material Basis and Molecular Mechanism of Taohong Siwu Decoction Against Vascular Dementia Based on Microdialysis Technology and NOD-Like Receptor Protein 3 Inflammasome Vascular Endothelial Cell Interaction(No.81903953)the Anhui Province Key Research and Development Program:Research on the Development and Preparation of Taohong Siwu Granules(No.1704a0802141)。
文摘OBJECTIVE:To investigate the effect of Taohong Siwu decoction(桃红四物汤,TSD)on atherosclerosis in rats as well as investigate the underlying mechanism based on molecular docking.METHODS:Sixty healthy male Sprague-Dawley rats were randomly divided into 6 groups with 10 rats in each group:control group,model group,atorvastatin group(AT,2.0 mg/kg),and TSD groups(20,10,5 g/kg)after 7 d of acclimation.The model of atherosclerosis was successfully established except the control group by high fat diet(HFD)and vitamin D2.Biochemical analyzers were used to detect the levels of triglyceride(TG),total cholestero(TC),low density lipoprotein-cholesterol(LDLC)and high density lipid-cholesterol(HDL-C)in blood lipid.The levels of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6)and interleukin-1β(IL-1β)were determined by enzyme-linked immunosorbent assay.Sudan IV staining and Hematoxylin and eosin staining(HE staining)were performed to observe the pathological changes in aortic tissue.Molecular docking technology was used to predict the best matching between the main components of TSD and the target proteins.The expression of target proteins was further detected by quantitative real time polymerase chain reaction(q RTPCR)and Western blot analysis.RESULTS:The results showed that TSD restricted atherosclerosis development and decreased the inflammatory cytokines in plasma.Molecular docking results predicted that the main components of TSD showed a strong binding ability with toll-like receptor(TLR4),myeloid differentiation primary response protein 88(My D88),and nuclear factor kappa-B(NF-κB).The results of q RT-PCR and Western blot analysis showed that the m RNA and protein expressions of TLR4,My D88 and NF-κB p65 in the aorta were reduced in atorvastatin group and TSD group.CONCLUSIONS:TSD can ameliorate atherosclerosis in rats,and the underlying mechanism is supposed be related to the suppression of inflammatory response by regulating TLR4/My D88/NF-κB signal pathway.
基金Supported by the National Natural Science Foundation of China(No.81173294)
文摘OBJECTIVE:To investigate the effect of Soothing liver therapy on infertile women undergoing in vitro fertilization and embryo transfer(IVF-ET)and to explore its mechanism.METHODS:Fifty-eight women with tubal infertility were randomized into two groups:30 in an experimental group treated with Xiaoyao powder(Shugan)plus gonadotropin-releasing hormone analog(GnRHa)/follicle-stimulating hormone(FSH)/human chorionic gonadotropin(hCG)and 28 in the control group who were treated with GnRHa/FSH/hCG only.The total gonadotropin(Gn)doses required,endometrial thickness,oocyte numbers,high quality embryo production rate and pregnancy rate of the two groups were compared.The concentration of growth differentiation factor-9(GDF-9)in follicular fluid was detected by western blotting and the expression of GDF-9 mRNA in granulosa cells was measured using reverse tran-scription-polymerase chain reaction amplification.RESULTS:In the experimental group,the Gn dose was significantly lower than that in the control group;the endometrial thickness,high quality embryo production and pregnancy rates were significantly higher and the expression of GDF-9 mRNA was also significantly higher than in the control group(all P<0.05).CONCLUSION:Shugan treatment can improve the pregnancy rate of women with tubal infertility;its mechanism is possibly related to the increased expression of GDF-9 in granulosa cells.
基金Supported by National Natural Science Foundation of China,No.81771373Key Research and Development Plan of Zibo City,No.2019ZC010169 and No.2019ZC010166.
文摘BACKGROUND Multiple system atrophy(MSA) is a serious progressive neurodegenerative disease. Early diagnosis of MSA is very difficult, and diagnostic biomarkers are limited. Growth differentiation factor 15(GDF15) is involved in the differentiation and progression of the central nervous system, and is widely distributed in peripheral blood, which may be a novel biomarker for MSA.AIM To determine serum GDF15 levels, related factors and their potential diagnostic value in MSA patients, compared with Parkinson’s disease(PD) patients and healthy controls.METHODS A case-control study was conducted, including 49 MSA patients, 50 PD patients and 50 healthy controls. Serum GDF15 levels were measured by human enzymelinked immunosorbent assay, and the differences between the MSA, PD and control groups were analyzed. Further investigations were performed in different MSA subgroups according to age of onset, sex, clinical subtypes, diagnostic criteria, and disease duration. Receiver-operating characteristic curve analysiswas used to evaluate the diagnostic value of GDF15, especially for the differential diagnosis between MSA and PD.RESULTS Serum GDF15 levels were significantly higher in MSA patients than in PD patients and healthy controls(P = 0.000). Males and those with a disease duration of more than three years showed higher serum GDF15 levels(P = 0.043 and 0.000;respectively). Serum GDF15 levels may be a potential diagnostic biomarker for MSA patients compared with healthy controls and PD patients(cutoff: 470.42 pg/m L, sensitivity: 85.7%, specificity: 88.0%;cutoff: 1075.91 pg/m L, sensitivity:51.0%, specificity: 96.0%;respectively).CONCLUSION Serum GDF15 levels are significantly higher in MSA patients and provide suggestions on the etiology of MSA.
基金Supported by Heilongjiang Provincial Health and Family Planning Commission Research Project,No.2017-413
文摘BACKGROUND Oral cancer(OC)is the most common malignant tumor in the oral cavity,and is mainly seen in middle-aged and elderly men.At present,OC is mainly treated clinically by surgery or combined with radiotherapy and chemotherapy;but recently,more and more studies have shown that the stress trauma caused by surgery and the side effects of radiotherapy and chemotherapy seriously affect the prognosis of patients.AIM To determine the significance of 125I radioactive seed implantation on growth differentiation factor 11(GDF11)and programmed death receptor-1(PD-1)during treatment of OC.METHODS A total of 184 OC patients admitted to The Second Affiliated Hospital of Jiamusi University from May 2015 to May 2017 were selected as the research subjects for prospective analysis.Of these patients,89 who received 125I radioactive seed implantation therapy were regarded as the research group(RG)and 95 patients who received surgical treatment were regarded as the control group(CG).The clinical efficacy,incidence of adverse reactions and changes in GDF11 and PD-1 before treatment(T0),2 wk after treatment(T1),4 wk after treatment(T2)and 6 wk after treatment(T3)were compared between the two groups.RESULTS The efficacy and recurrence rate in the RG were better than those in the CG(P<0.05),while the incidence of adverse reactions and survival rate were not different.There was no difference in GDF11 and PD-1 between the two groups at T0 and T1,but these factors were lower in the RG than in the CG at T2 and T3(P<0.05).Using receiver operating characteristic(ROC)curve analysis,GDF11 and PD-1 had good predictive value for efficacy and recurrence(P<0.001).CONCLUSION 125I radioactive seed implantation has clinical efficacy and can reduce the recurrence rate in patients with OC.This therapy has marked potential in clinical application.The detection of GDF11 and PD-1 in patients during treatment showed good predictive value for treatment efficacy and recurrence in OC patients,and may be potential targets for future OC treatment.
文摘Parkinson’s disease is the most common movement disorder worldwide,affecting over 6 million people.It is an age-related disease,occurring in 1%of people over the age of 60,and 3%of the population over 80 years.The disease is characterized by the progressive loss of midbrain dopaminergic neurons from the substantia nigra,and their axons,which innervate the striatum,resulting in the characteristic motor and non-motor symptoms of Parkinson’s disease.This is paralleled by the intracellular accumulation ofα-synuclein in several regions of the nervous system.Current therapies are solely symptomatic and do not stop or slow disease progression.One promising disease-modifying strategy to arrest the loss of dopaminergic neurons is the targeted delivery of neurotrophic factors to the substantia nigra or striatum,to protect the remaining dopaminergic neurons of the nigrostriatal pathway.However,clinical trials of two well-established neurotrophic factors,glial cell line-derived neurotrophic factor and neurturin,have failed to meet their primary end-points.This failure is thought to be at least partly due to the downregulation byα-synuclein of Ret,the common co-receptor of glial cell line-derived neurorophic factor and neurturin.Growth/differentiation factor 5 is a member of the bone morphogenetic protein family of neurotrophic factors,that signals through the Ret-independent canonical Smad signaling pathway.Here,we review the evidence for the neurotrophic potential of growth/differentiation factor 5 in in vitro and in vivo models of Parkinson’s disease.We discuss new work on growth/differentiation factor 5’s mechanisms of action,as well as data showing that viral delivery of growth/differentiation factor 5 to the substantia nigra is neuroprotective in theα-synuclein rat model of Parkinson’s disease.These data highlight the potential for growth/differentiation factor 5 as a disease-modifying therapy for Parkinson’s disease.
基金Major Program of the National Natural Science Foundation of China,No.41590842
文摘Under China's innovation-driven development strategy, venture capital has become an important driving force in urban agglomeration integration and collaborative innovation. This paper uses social network analysis to analyze spatiotemporal differences of venture capital in the Beijing-Tianjin-Hebei urban agglomeration for the period 2005–2015. A gravity model and panel data regression model are used to reveal the influencing factors on spatiotemporal differences in venture capital in the region. This study finds that there is a certain cyclical fluctuation and uneven differentiation in the venture capital network in the Beijing-Tianjin-Hebei urban agglomeration in terms of total investment, and that the three centers of venture capital(Beijing, Shijiazhuang and Tangshan) have a stimulatory effect on surrounding cities; flows of venture capital between cities display certain networking rules, but they are slow to develop and strongly centripetal; there is a strong positive correlation between levels of information infrastructure development and economic development and venture capital investment; and places with relatively underdeveloped financial environments and service industries are less able to apply the fruits of innovation and entrepreneurship and to attract funds. This study can act as a reference for the Beijing-Tianjin-Hebei urban agglomeration in building a world-class super urban agglomeration with the best innovation capabilities in China.
基金This work was supported by the National Natural Science Foundation of China(81970320 and 82003749).
文摘Background:Myocardial infarctions(MI)is a major threat to human health especially in people exposed to cold environment.The polarization of macrophages towards different functional phenotypes(M1 macrophages and M2 macrophages)is closely related to MI repairment.The growth differentiation factor 11(GDF11)has been reported to play a momentous role in inflammatory associated diseases.In this study,we examined the regulatory role of GDF11 in macrophage polarization and elucidated the underlying mechanisms in MI.Methods:In vivo,the mice model of MI was induced by permanent ligation of the left anterior descending coronary artery(LAD),and mice were randomly divided into the sham group,MI group,and MI+GDF11 group.The protective effect of GDF11 on myocardial infarction and its effect on macrophage polarization were verified by echocardiography,triphenyl tetrazolium chloride staining and immunofluorescence staining of heart tissue.In vitro,based on the RAW264.7 cell line,the effect of GDF11 in promoting macrophage polarization toward the M2 type by inhibiting the Notch1 Signaling pathway was validated by qRT-PCR,Western blot,and flow cytometry.Results:We found that GDF11 was significantly downregulated in the cardiac tissue of MI mice.And GDF11 supplementation can improve the cardiac function.Moreover,GDF11 could reduce the proportion of M1 macrophages and increase the accumulation of M2 macrophages in the heart tissue of MI mice.Furthermore,the cardioprotective effect of GDF11 on MI mice was weakened after macrophage clearance.At the cellular level,application of GDF11 could inhibit the expression of M1 macrophage(classically activated macrophage)markers iNOS,interleukin(IL)-1β,and IL-6 in a dose-dependent manner.In contrast,GDF11 significantly increased the level of M2 macrophage markers including IL-10,CD206,arginase 1(Arg1),and vascular endothelial growth factor(VEGF).Interestingly,GDF11 could promote M1 macrophages polarizing to M2 macrophages.At the molecular level,GDF11 significantly down-regulated the Notch1 signaling pathway,the activation of which has been demonstrated to promote M1 polarization in macrophages.Conclusions:GDF11 promoted macrophage polarization towards M2 to attenuate myocardial infarction via inhibiting Notch1 signaling pathway.
文摘BACKGROUND Growth differentiation factor(GDF)-15 is a member of a transforming growth factor-βcytokine superfamily that regulates metabolism and is released in response to inflammation,hypoxia and tissue injury.It has evolved as one of the most potent cytokines for predicting the severity of infections and inflammatory conditions,such as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.AIM To investigate the utility of GDF-15 in predicting the severity of SARS-CoV-2 infection.METHODS PubMed,Reference Citation Analysis,CNKI,and Goggle Scholar were explored by using related MeSH keywords and data such as the first author’s name,study duration,type and place of study,sample size and subgroups of participants if any,serum/plasma GDF-15 level in pg/mL,area under the curve and cut-off value in receiver operating characteristic analysis,method of measurement of GDF-15,and the main conclusion were extracted.RESULTS In all studies,the baseline GDF-15 level was elevated in SARS-CoV-2-infected patients,and it was significantly associated with severity,hypoxemia,viral load,and worse clinical consequences.In addition,GDF-15 levels were correlated with C-reactive protein,D-dimer,ferritin and procalcitonin,and it had superior discriminatory ability to detect severity and in-hospital mortality of SARS-CoV-2 infection.Hence,GDF-15 might be used to predict the severity and prognosis of hospitalized patients with SARS-CoV-2.CONCLUSION Serial estimation of GDF-15 levels in hospitalized patients with SARS-CoV-2 infection appeared to have useful prognostic value and GDF-15 can be considered a clinically prominent sepsis biomarker for SARS-CoV-2 infection.
基金the State Key Laboratory of Pathogenesis,Prevention and Treatment of High Incidence Diseases in Central Asia-funded Project:Correlation Study on Chronic Inflammation Mediated by Tolllike Receptor 4/Mutant Myeloid Differentiation Primary Response 88/Nuclear Factor Kappa-B Signaling Pathway(No.SKL-HIDCA-2021-ZY5)。
文摘OBJECTIVE:To investigate the role of toll-like receptor 4(TLR4)/mutant myeloid differentiation primary response 88(MyD88)/nuclear factor kappa-B(NF-κB)signaling pathway-mediated inflammation in diabetes mellitus with Northwest dryness syndrome.METHODS:Rats were randomly divided into the normal control,type 2 diabetes(T2DM)model,Northwest dryness syndrome+T2DM(Northwest dryness),and simple internal dampness+T2DM(internal dampness)groups.Enzyme-linked immunosorbent assay was used to detect biochemical indexes and inflammatory factors.The histopathological observation was performed.Quantitative real-time polymerase chain reaction and Western blot analysis were used to detect the mRNA and protein expression levels,respectively.RESULTS:Compared with the T2DM group,the glycosylated hemoglobin A1c,insulin,glucose tolerance,the homeostasis model assessment of insulin resistance,tumor necrosis factor-α,interleukin 1β,interleukin 16,malondialdehyde,blood lipid,alanine aminotransferase,and aspartate aminotransferase were significantly elevated in the internal dampness group.Their levels were significantly elevated in the Northwest dryness group than in the T2DM and internal dampness groups.The superoxide dismutase,glutathione peroxidase,liver glycogen,and organ-to-weight ratio were significantly declined in the internal dampness group and the Northwest dryness group than in the T2DM group.However,these levels were elevated in the Northwest dryness group than in the internal dampness group.Moreover,the mRNA expression levels of interferon regulatory factor 5 and NF-κB p65,and the protein expression levels of TLR4,MyD88,and NF-κB were significantly higher in the internal dampness and the Northwest dryness groups than the T2DM group.Additionally,the mRNA and protein levels were significantly higher in the Northwest dryness group than in the internal dampness group.CONCLUSION:Northwest dryness syndrome-mediated TLR4/MyD88/NF-κB pathway and chronic inflammation might be associated with the occurrence and development of T2DM.
基金This work supported by the National Natural Sciences Foundation of China(39670364)This work was originally published in Acta Academiae Medicinae Sinicae(200123: 32-35)in Chinese.
文摘Objective. To investigate the roles of mouse erythroid differentiation and denucleation factor (MKI)DF), a novel factor cloned in our laboratory recently, in erylhroid terminal differentiation.Method. Mouse erythroleukemia (MEL) cells were transfected with eukaryotie expression plasinid pcl)-NA-MEDDF. Then we investigated the changes on characteristics of cell growth by analyzing cells growth rate, mitotie index and colony-forming rate in semi-solid medium. The expressions of c-mye and p-globin genes were analysed by semi-quantitative RT-PCR.Results. MEL cells transfected with pcDNA-MEDDF showed significant lower growth rate, mitolic index,and colony-forming rate in semi-solid medium ( P<0. 01). The percentage of benzidine-positive cells was 32. 8%after transfection. The expression of β-globin in cells trarisfected with pcDNA-MEDDF was 3. 43 times higherthan that of control (MEL transfected with blank vector, pcDNA3. 1), and the expression of c-rnyc decreased by66. 3% .Conclusions. MEDDF can induce differentiation of MEL cell and suppress its malignancy.
文摘Objective To explore the feasibility and effectiveness of the self-assembly cartilage tissue engineered with chondrogenically differentiated human bone mesenchymal stem cells (hBMCs) induced by growth differentiation factor-5 (GDF-5)
