Psoriasis is a chronic autoimmune disease featured by patches on the skin.It is caused by malfunction of immune cells and keratinocytes with inflammation as one of its key features.Apigenin(API)is a natural flavonoid ...Psoriasis is a chronic autoimmune disease featured by patches on the skin.It is caused by malfunction of immune cells and keratinocytes with inflammation as one of its key features.Apigenin(API)is a natural flavonoid with anti-inflammatory and immunoregulatory properties.Therefore,we speculated that API can ameliorate psoriasis,and determined its effect on the development of psoriasis by using imiquimod(IMQ)-induced psoriasis mouse model.Our results showed that API attenuated IMQ-induced phenotypic changes,such as erythema,scaling and epidermal thickening,and improved splenic hyperplasia.Abnormal differentiation of immune cells was restored in API-treated mice.Mechanistically,we revealed that API is a key regulator of signal transducer activator of transcription 3(STAT3).API regulated immune responses by reducing interleukin-23(IL-23)/STAT3/IL-17A axis.Moreover,it suppressed IMQ-caused cell hyperproliferation by inactivating STAT3 through regulation of extracellular signal-regulated kinase 1/2 and nuclear factor-κB(NF-κB)pathway.Furthermore,API reduced expression of inflammatory cytokines through inactivation of NF-κB.Taken together,our study demonstrates that API can ameliorate psoriasis and may be considered as a strategy for psoriasis treatment.展开更多
Inflammation plays an important role in the development of several cancers.Inflammatory cytokines,including tumor necrosis factor-α(TNF-α),are associated with the induction of inflammation.Chronic inflammation contr...Inflammation plays an important role in the development of several cancers.Inflammatory cytokines,including tumor necrosis factor-α(TNF-α),are associated with the induction of inflammation.Chronic inflammation contributes to the progression of cancer through several mechanisms,including increased cytokine production and activation of transcription factors,such as nuclear factor-κB(NF-κB).Zerumbone(ZER),a component of subtropical ginger(Zingiber zerumbet Smith),seems to have anti-inflammatory,anti-cancer,and antioxidant activities.In this study,we aimed to explore the protective function and mechanisms of ZER against TNF-α-induced cancer-promoting cytokines.We found that the viability of stimulated human fibroblast cell lines was reduced after treatment with ZER(IC50=18µmol/L),compared to un-stimulated fibroblasts(IC50=40µmol/L).Besides,ZER inhibited mRNA expression and protein secretion of transforming growth factor-β(TGF-β),interleukin-33(IL-33),monocyte chemoattractant protein-1(MCP-1),and stromal cell-derived factor 1(SDF-1),which were produced by TNF-α-induced fibroblasts,as measured by quantitative real time-PCR(qRT-PCR)and ELISA assays.The mRNA expression levels of TGF-β,IL-33,SDF-1,and MCP-1 showed 8,5,2.5,and 4-fold reductions,respectively.Moreover,secretion of TGF-β,IL-33,SDF-1,and MCP-1 was reduced to 3.65±0.34 ng/mL,6.3±0.26,1703.6±295.2,and 5.02±0.18 pg/mL,respectively,compared to the untreated group.In addition,the conditioned media(CM)of TNF-α-stimulated fibroblasts increased the NF-κB expression in colorectal cancer cell lines(HCT-116 and Sw48),while in the vicinity of ZER,the expression of NF-κB was reversed.Considering the significant effects of ZER,this component can be used as an appropriate alternative herbal treatment for cancer-related chronic inflammation.展开更多
The relationship between intracelluar trypsinogen activation and NF-κB activation in rat pancreatic acinar cells induced by M3 cholinergic receptor agonist (carbachol) hyperstimulation was studied. Rat pancreatic a...The relationship between intracelluar trypsinogen activation and NF-κB activation in rat pancreatic acinar cells induced by M3 cholinergic receptor agonist (carbachol) hyperstimulation was studied. Rat pancreatic acinar cells were isolated, cultured and treated with carbachol, the active protease inhibitor (pefabloc) and NF-κB inhibitor (PDTC) in vitro. Intracelluar trypsin activity was measured by using a fluorogenic substrate. The activity of NF-κB was monitored by using electrophoretic mobility shift assay. The results showed that after pretreatment with 2 mmol/L pefabloc, the activities of trypsin and NF-κB in pancreatic acinar cells treated with high concertrations of carbachol (10^-3 mol/L) in vitro was significantly decreased as compared with control group (P〈0.01 ). The addition of 10^-2 mol/L PDTC resulted in a significant decrease of NF-κB activities in pancreatic acinar cells after treated with high concertrations of carbachol (10^-3 mol/L) in vitro, but the intracelluar trypsinogen activity was not obviously inhibited (P〉0.05). It was concluded that intracelluar trypsinogen activation is likely involved in the regulation of high concertrations of carbachol-induced NF-κB activation in pancreatic acinar cells in vitro. NF-κB activation is likely not necessary for high concertrations of carbachol-induced trypsinogen activation in pancreatic acinar cells in vitro.展开更多
The relationship between M3 cholinergic receptor agonist (carbachol) hyperstimulationinduced pancreatic acinar cellular injury and trypsinogen activation or NF-κB activation in rats was studied in vitro. Rat pancre...The relationship between M3 cholinergic receptor agonist (carbachol) hyperstimulationinduced pancreatic acinar cellular injury and trypsinogen activation or NF-κB activation in rats was studied in vitro. Rat pancreatic acinar ceils were isolated, cultured and treated with carbachol, the active protease inhibitor (pefabloc), and NF-κB inhibitor (PDTC) in vitro. Intracellular trypsin activity was measured by using a fluorogenic substrate. The cellular injury was evaluated by measuring the leakage of LDH from pancreatic acinar ceils. The results showed that as compared with control group, 10-3 mol/L carbachol induced a significant increase of the intracellular trypsin activity and the leakage of LDH from pancreatic acinar cells. Pretreatment with 2 mmol/L pefabloc could significantly decrease the activity of trypsin and the leakage of LDH from pancreatic acinar cells (P〈0. 01) following the treatment with a high concentration of carbachol (10^-3 mol/L) in vitro. The addition of 10^-2mol/L PDTC didn't result in a significant decrease in the activity of trypsin and the leakage of LDH from pancreatic acinar cells treated with a high concentration of carbachol (10^-3 mol/L) in vitro (P〉0. 05). It was concluded that intracellular trypsinogen activation is likely involved in pancreatic acinar cellular injury induced by carbachol hyperstimulation in vitro. NF-κB activation may not be involved in pancreatic acinar cellular injury induced by carbachol hyperstimulation in vitro.展开更多
Tetrandrine (1 μM), a bis-benzylisoquinoline alkaloid isolated from Stephania tetrandra S Moore, signifi-cantly decreased tumor necrosis factor alpha (TNFα;10 ng/ml)-induced increase in the number of micro vessels t...Tetrandrine (1 μM), a bis-benzylisoquinoline alkaloid isolated from Stephania tetrandra S Moore, signifi-cantly decreased tumor necrosis factor alpha (TNFα;10 ng/ml)-induced increase in the number of micro vessels that budded from cultured rat choroidal explants. Tetrandrine also decreased the TNFα-induced in-crease in the number of cells composing the microvessels. Ammonium pyrrolidine dithiocarbamate (APDC;0.1-0.3 μM), an inhibitor of nuclear factor-κB (NF-κB), decreased the TNFα-induced increase in the number of microvessels in a concentration-dependent manner. TNFα increased the phosphorylation and degradation of inhibitor of NF-κB (IκBα), as well as increasing the DNA-binding activity of NF-κB in choroidal explants. TNF? induced an increase of vascular endothelial growth factor (VEGF)-A mRNA, but not VEGF-C mRNA or VEGF-D mRNA. TNFα-induced angiogenic action was inhibited by treatment of VEGF-A antibody in cultured choroidal capillaries. Tetrandrine inhibited the TNFα-induced increases of phosphorylation and degradation of IκBα, and reduced the TNFα-induced increase of DNA-binding activity of NF-κB in chor-oidal explants. In conclusion, tetrandrine inhibits TNFα-induced activation of NF-κB in the choroidal capil-laries via inhibition of TNFα-induced phosphorylation of IκBα.展开更多
宫颈癌是女性第二好发的恶性肿瘤,对于晚期患者,放疗联合化疗是主要的治疗方法。但放化疗诱导的炎症使肿瘤产生了治疗抵抗并引起正常组织的损伤。其中激活的转录因子核因子-κB(nuclear factor-κB,NF-κB)和信号转导及转录激活因子3...宫颈癌是女性第二好发的恶性肿瘤,对于晚期患者,放疗联合化疗是主要的治疗方法。但放化疗诱导的炎症使肿瘤产生了治疗抵抗并引起正常组织的损伤。其中激活的转录因子核因子-κB(nuclear factor-κB,NF-κB)和信号转导及转录激活因子3(signal transducer and activator of transduction 3,STAT3),是炎症反应的中心环节。展开更多
Persistent generalized low bone mineral density (BMD) has been reported in patients with adolescent idiopathic scoliosis (AIS).However,the exact mechanisms and causes of the low BMD in AIS patients are largely unknown...Persistent generalized low bone mineral density (BMD) has been reported in patients with adolescent idiopathic scoliosis (AIS).However,the exact mechanisms and causes of the low BMD in AIS patients are largely unknown.The purpose of this study was to examine the relationship between the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) levels in osteoblasts (OBs) from AIS patients with low BMD and with comparison made between the patients and controls.Twenty AIS patients and eight age-matched controls were included in the present study.The BMD of lumbar spine and proximal femur was measured in all subjects.OBs from the cancellous bone of each subject was harvested and primarily cultured.The mRNA and protein expression of RANKL and OPG in OBs was detected by RT-PCR and Western blotting.The results showed BMD was lower in AIS patients than in controls.A significantly higher mRNA and protein expression of RANKL was observed in OBs from AIS patients,while no significant difference was found in the expression of OPG between AIS patients and controls.As a result,RANKL/OPG ratio in patients with AIS was remarkably higher than controls.Our study preliminarily demonstrated expression of RANKL was higher in OBs from AIS patients with low BMD as compared with controls,suggesting the unbalanced RANKL/OPG ratio caused by an over-expression of RANKL in OBs may be responsible for the low BMD in AIS patients.展开更多
Objective Antimony(Sb)has recently been identified as a novel nerve poison,although the cellular and molecular mechanisms underlying its neurotoxicity remain unclear.This study aimed to assess the effects of the nucle...Objective Antimony(Sb)has recently been identified as a novel nerve poison,although the cellular and molecular mechanisms underlying its neurotoxicity remain unclear.This study aimed to assess the effects of the nuclear factor kappa B(NF-κB)signaling pathway on antimony-induced astrocyte activation.Methods Protein expression levels were detected by Western blotting.Immunofluorescence,cytoplasmic and nuclear fractions separation were used to assess the distribution of p65.The expression of protein in brain tissue sections was detected by immunohistochemistry.The levels of mRNAs were detected by Quantitative real-time polymerase chain reaction(qRT-PCR)and reverse transcriptionpolymerase chain reaction(RT-PCR).Results Antimony exposure triggered astrocyte proliferation and increased the expression of two critical protein markers of reactive astrogliosis,inducible nitric oxide synthase(iNOS)and glial fibrillary acidic protein(GFAP),indicating that antimony induced astrocyte activation in vivo and in vitro.Antimony exposure consistently upregulated the expression of inflammatory factors.Moreover,it induced the NF-κB signaling,indicated by increased p65 phosphorylation and translocation to the nucleus.NF-κB inhibition effectively attenuated antimony-induced astrocyte activation.Furthermore,antimony phosphorylated TGF-β-activated kinase 1(TAK1),while TAK1 inhibition alleviated antimonyinduced p65 phosphorylation and subsequent astrocyte activation.Conclusion Antimony activated astrocytes by activating the NF-κB signaling pathway.展开更多
The mesencephalic astrocyte-derived neurotrophic factor(MANF)has been recently identified as a neurotrophic factor,but its role in hepatic fibrosis is unknown.Here,we found that MANF was upregulated in the fibrotic li...The mesencephalic astrocyte-derived neurotrophic factor(MANF)has been recently identified as a neurotrophic factor,but its role in hepatic fibrosis is unknown.Here,we found that MANF was upregulated in the fibrotic liver tissues of the patients with chronic liver diseases and of mice treated with CCl4.MANF deficiency in either hepatocytes or hepatic mono-macrophages,particularly in hepatic mono-macrophages,clearly exacerbated hepatic fibrosis.Myeloid-specific MANF knockout increased the population of hepatic Ly6C^(high)macrophages and promoted HSCs activation.Furthermore,MANF-sufficient macrophages(from WT mice)transfusion ameliorated CCl4-induced hepatic fibrosis in myeloid cells-specific MANF knockout(MKO)mice.Mechanistically,MANF interacted with S100A8 to competitively block S100A8/A9 heterodimer formation and inhibited S100A8/A9-mediated TLR4-NF-κB signal activation.Pharmacologically,systemic administration of recombinant human MANF significantly alleviated CCl_(4)-induced hepatic fibrosis in both WT and hepatocytes-specific MANF knockout(HKO)mice.This study reveals a mechanism by which MANF targets S100A8/A9-TLR4 as a“brake”on the upstream of NF-κB pathway,which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment.展开更多
Osteoclasts are the bone resorbing cells essential for bone remodeling.Osteoclasts are formed from hematopoietic progenitors in the monocyte/macrophage lineage.Osteoclastogenesis is composed of several steps including...Osteoclasts are the bone resorbing cells essential for bone remodeling.Osteoclasts are formed from hematopoietic progenitors in the monocyte/macrophage lineage.Osteoclastogenesis is composed of several steps including progenitor survival,differentiation to mononuclear pre-osteoclasts,fusion to multi-nuclear mature osteoclasts,and activation to bone resorbing osteoclasts.The regulation of osteoclastogenesis has been extensively studied,in which the receptor activator of NF-κB ligand(RANKL)-mediated signaling pathway and downstream transcription factors play essential roles.However,less is known about osteoclast fusion,which is a property of mature osteoclasts and is required for osteoclasts to resorb bone.Several proteins that affect cell fusion have been identified.Among them,dritic cell-specific transmembrane protein(DC-STAMP)is directly associated to osteoclast fusion in vivo.Cytokines and factors influence osteoclast fusion through regula-tion of DC-STAMP.Here we review the recently discovered new factors that regulate osteoclast fusion with specific focus on DC-STAMP.A better understanding of the mechanistic basis of osteoclast fusion will lead to the development of a new therapeutic strategy for bone disorders due to elevated osteoclast bone resorption.Cell-cell fusion is essential for a variety of cellular biological processes.In mammals,there is a limited number of cell types that fuse to form multinucleated cells,such as the fusion of myoblasts for the formation of skeletal muscle and the fusion of cells of the monocyte/macrophage lineage for the formation of multinucleated osteoclasts and giant cells.In most cases,cellcell fusion is beneficial for cells by enhancing function.Myoblast fusion increases myofiber size and diameter and thereby increases contractile strength.Multinucleated osteoclasts have far more bone resorbing activity than their mono-nuclear counterparts.Multinucleated giant cells are much more efficient in the removal of implanted materials and bacteria due to chronic infection than macrophages.Therefore,they are also called foreign-body giant cells.Cell fusion is a complicated process involving cell migration,chemotaxis,cell-cell recognition and attachment,as well as changes into a fusion-competent status.All of these steps are regulated by multiple factors.In this review,we will discuss osteoclast fusion and regulation.展开更多
Objective:To investigate the immunomodulatory activity of polysaccharides from the roots of Brassica rapa.Methods:The crude polysaccharide from roots of B.rapa(BRP)was extracted and purified to further investigate the...Objective:To investigate the immunomodulatory activity of polysaccharides from the roots of Brassica rapa.Methods:The crude polysaccharide from roots of B.rapa(BRP)was extracted and purified to further investigate the active fraction of BRT for inducing macrophage phagocytosis.Results:Effects on RAW264.7 cells demonstrated that BRP behaved better phagocytic capacity and had potent immunomodulatory activity,including increasing production of nitric oxide(NO),tumor necrosis factor a(TNFa)and upregulating mRNA levels of inducible NO synthase(iNOS)and TNFa.Furthermore,modulation of macrophage by BRP was indicated to be mediated via the activation of Akt and nuclear factor-kappa B(NF-κB).Conclusion:The beneficial effects of BRP could be used as an immunotherapeutic adjuvant in treatment of inflammatory diseases.展开更多
基金supported by the National Natural Science Foundation of China(NSFC)(81973316,82173807)the China Postdoctoral Science Foundation(2020M681914)+1 种基金the Fund from Tianjin Municipal Health Commission(ZC200093)the Open Fund of Tianjin Central Hospital of Obstetrics and Gynecology/Tianjin Key Laboratory of human development and reproductive regulation(2021XHY01)。
文摘Psoriasis is a chronic autoimmune disease featured by patches on the skin.It is caused by malfunction of immune cells and keratinocytes with inflammation as one of its key features.Apigenin(API)is a natural flavonoid with anti-inflammatory and immunoregulatory properties.Therefore,we speculated that API can ameliorate psoriasis,and determined its effect on the development of psoriasis by using imiquimod(IMQ)-induced psoriasis mouse model.Our results showed that API attenuated IMQ-induced phenotypic changes,such as erythema,scaling and epidermal thickening,and improved splenic hyperplasia.Abnormal differentiation of immune cells was restored in API-treated mice.Mechanistically,we revealed that API is a key regulator of signal transducer activator of transcription 3(STAT3).API regulated immune responses by reducing interleukin-23(IL-23)/STAT3/IL-17A axis.Moreover,it suppressed IMQ-caused cell hyperproliferation by inactivating STAT3 through regulation of extracellular signal-regulated kinase 1/2 and nuclear factor-κB(NF-κB)pathway.Furthermore,API reduced expression of inflammatory cytokines through inactivation of NF-κB.Taken together,our study demonstrates that API can ameliorate psoriasis and may be considered as a strategy for psoriasis treatment.
基金This study was supported by a grant from Hamadan University of Medical Sciences(No.9511267103).
文摘Inflammation plays an important role in the development of several cancers.Inflammatory cytokines,including tumor necrosis factor-α(TNF-α),are associated with the induction of inflammation.Chronic inflammation contributes to the progression of cancer through several mechanisms,including increased cytokine production and activation of transcription factors,such as nuclear factor-κB(NF-κB).Zerumbone(ZER),a component of subtropical ginger(Zingiber zerumbet Smith),seems to have anti-inflammatory,anti-cancer,and antioxidant activities.In this study,we aimed to explore the protective function and mechanisms of ZER against TNF-α-induced cancer-promoting cytokines.We found that the viability of stimulated human fibroblast cell lines was reduced after treatment with ZER(IC50=18µmol/L),compared to un-stimulated fibroblasts(IC50=40µmol/L).Besides,ZER inhibited mRNA expression and protein secretion of transforming growth factor-β(TGF-β),interleukin-33(IL-33),monocyte chemoattractant protein-1(MCP-1),and stromal cell-derived factor 1(SDF-1),which were produced by TNF-α-induced fibroblasts,as measured by quantitative real time-PCR(qRT-PCR)and ELISA assays.The mRNA expression levels of TGF-β,IL-33,SDF-1,and MCP-1 showed 8,5,2.5,and 4-fold reductions,respectively.Moreover,secretion of TGF-β,IL-33,SDF-1,and MCP-1 was reduced to 3.65±0.34 ng/mL,6.3±0.26,1703.6±295.2,and 5.02±0.18 pg/mL,respectively,compared to the untreated group.In addition,the conditioned media(CM)of TNF-α-stimulated fibroblasts increased the NF-κB expression in colorectal cancer cell lines(HCT-116 and Sw48),while in the vicinity of ZER,the expression of NF-κB was reversed.Considering the significant effects of ZER,this component can be used as an appropriate alternative herbal treatment for cancer-related chronic inflammation.
文摘The relationship between intracelluar trypsinogen activation and NF-κB activation in rat pancreatic acinar cells induced by M3 cholinergic receptor agonist (carbachol) hyperstimulation was studied. Rat pancreatic acinar cells were isolated, cultured and treated with carbachol, the active protease inhibitor (pefabloc) and NF-κB inhibitor (PDTC) in vitro. Intracelluar trypsin activity was measured by using a fluorogenic substrate. The activity of NF-κB was monitored by using electrophoretic mobility shift assay. The results showed that after pretreatment with 2 mmol/L pefabloc, the activities of trypsin and NF-κB in pancreatic acinar cells treated with high concertrations of carbachol (10^-3 mol/L) in vitro was significantly decreased as compared with control group (P〈0.01 ). The addition of 10^-2 mol/L PDTC resulted in a significant decrease of NF-κB activities in pancreatic acinar cells after treated with high concertrations of carbachol (10^-3 mol/L) in vitro, but the intracelluar trypsinogen activity was not obviously inhibited (P〉0.05). It was concluded that intracelluar trypsinogen activation is likely involved in the regulation of high concertrations of carbachol-induced NF-κB activation in pancreatic acinar cells in vitro. NF-κB activation is likely not necessary for high concertrations of carbachol-induced trypsinogen activation in pancreatic acinar cells in vitro.
文摘The relationship between M3 cholinergic receptor agonist (carbachol) hyperstimulationinduced pancreatic acinar cellular injury and trypsinogen activation or NF-κB activation in rats was studied in vitro. Rat pancreatic acinar ceils were isolated, cultured and treated with carbachol, the active protease inhibitor (pefabloc), and NF-κB inhibitor (PDTC) in vitro. Intracellular trypsin activity was measured by using a fluorogenic substrate. The cellular injury was evaluated by measuring the leakage of LDH from pancreatic acinar ceils. The results showed that as compared with control group, 10-3 mol/L carbachol induced a significant increase of the intracellular trypsin activity and the leakage of LDH from pancreatic acinar cells. Pretreatment with 2 mmol/L pefabloc could significantly decrease the activity of trypsin and the leakage of LDH from pancreatic acinar cells (P〈0. 01) following the treatment with a high concentration of carbachol (10^-3 mol/L) in vitro. The addition of 10^-2mol/L PDTC didn't result in a significant decrease in the activity of trypsin and the leakage of LDH from pancreatic acinar cells treated with a high concentration of carbachol (10^-3 mol/L) in vitro (P〉0. 05). It was concluded that intracellular trypsinogen activation is likely involved in pancreatic acinar cellular injury induced by carbachol hyperstimulation in vitro. NF-κB activation may not be involved in pancreatic acinar cellular injury induced by carbachol hyperstimulation in vitro.
文摘Tetrandrine (1 μM), a bis-benzylisoquinoline alkaloid isolated from Stephania tetrandra S Moore, signifi-cantly decreased tumor necrosis factor alpha (TNFα;10 ng/ml)-induced increase in the number of micro vessels that budded from cultured rat choroidal explants. Tetrandrine also decreased the TNFα-induced in-crease in the number of cells composing the microvessels. Ammonium pyrrolidine dithiocarbamate (APDC;0.1-0.3 μM), an inhibitor of nuclear factor-κB (NF-κB), decreased the TNFα-induced increase in the number of microvessels in a concentration-dependent manner. TNFα increased the phosphorylation and degradation of inhibitor of NF-κB (IκBα), as well as increasing the DNA-binding activity of NF-κB in choroidal explants. TNF? induced an increase of vascular endothelial growth factor (VEGF)-A mRNA, but not VEGF-C mRNA or VEGF-D mRNA. TNFα-induced angiogenic action was inhibited by treatment of VEGF-A antibody in cultured choroidal capillaries. Tetrandrine inhibited the TNFα-induced increases of phosphorylation and degradation of IκBα, and reduced the TNFα-induced increase of DNA-binding activity of NF-κB in chor-oidal explants. In conclusion, tetrandrine inhibits TNFα-induced activation of NF-κB in the choroidal capil-laries via inhibition of TNFα-induced phosphorylation of IκBα.
文摘宫颈癌是女性第二好发的恶性肿瘤,对于晚期患者,放疗联合化疗是主要的治疗方法。但放化疗诱导的炎症使肿瘤产生了治疗抵抗并引起正常组织的损伤。其中激活的转录因子核因子-κB(nuclear factor-κB,NF-κB)和信号转导及转录激活因子3(signal transducer and activator of transduction 3,STAT3),是炎症反应的中心环节。
基金supported by the National Natural ScienceFoundation of China (No.81101335)
文摘Persistent generalized low bone mineral density (BMD) has been reported in patients with adolescent idiopathic scoliosis (AIS).However,the exact mechanisms and causes of the low BMD in AIS patients are largely unknown.The purpose of this study was to examine the relationship between the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) levels in osteoblasts (OBs) from AIS patients with low BMD and with comparison made between the patients and controls.Twenty AIS patients and eight age-matched controls were included in the present study.The BMD of lumbar spine and proximal femur was measured in all subjects.OBs from the cancellous bone of each subject was harvested and primarily cultured.The mRNA and protein expression of RANKL and OPG in OBs was detected by RT-PCR and Western blotting.The results showed BMD was lower in AIS patients than in controls.A significantly higher mRNA and protein expression of RANKL was observed in OBs from AIS patients,while no significant difference was found in the expression of OPG between AIS patients and controls.As a result,RANKL/OPG ratio in patients with AIS was remarkably higher than controls.Our study preliminarily demonstrated expression of RANKL was higher in OBs from AIS patients with low BMD as compared with controls,suggesting the unbalanced RANKL/OPG ratio caused by an over-expression of RANKL in OBs may be responsible for the low BMD in AIS patients.
基金supported by the National Natural Science Foundation of China[21477058,81703255]Scientific Research Project of Nantong of Jiangsu[JC2019027,JC2019137]+2 种基金the Qing Lan Project for Excellent Young Key Teachers of Colleges and Universities of Jiangsu Province(2020)the Postgraduate Research&Practice Innovation Program of Jiangsu Province[KYCX20_2854]Large Instruments Open Foundation of Nantong University[KFJN2054]。
文摘Objective Antimony(Sb)has recently been identified as a novel nerve poison,although the cellular and molecular mechanisms underlying its neurotoxicity remain unclear.This study aimed to assess the effects of the nuclear factor kappa B(NF-κB)signaling pathway on antimony-induced astrocyte activation.Methods Protein expression levels were detected by Western blotting.Immunofluorescence,cytoplasmic and nuclear fractions separation were used to assess the distribution of p65.The expression of protein in brain tissue sections was detected by immunohistochemistry.The levels of mRNAs were detected by Quantitative real-time polymerase chain reaction(qRT-PCR)and reverse transcriptionpolymerase chain reaction(RT-PCR).Results Antimony exposure triggered astrocyte proliferation and increased the expression of two critical protein markers of reactive astrogliosis,inducible nitric oxide synthase(iNOS)and glial fibrillary acidic protein(GFAP),indicating that antimony induced astrocyte activation in vivo and in vitro.Antimony exposure consistently upregulated the expression of inflammatory factors.Moreover,it induced the NF-κB signaling,indicated by increased p65 phosphorylation and translocation to the nucleus.NF-κB inhibition effectively attenuated antimony-induced astrocyte activation.Furthermore,antimony phosphorylated TGF-β-activated kinase 1(TAK1),while TAK1 inhibition alleviated antimonyinduced p65 phosphorylation and subsequent astrocyte activation.Conclusion Antimony activated astrocytes by activating the NF-κB signaling pathway.
基金supported by the National Natural Science Foundation of China(81973336)the Joint Fund of the National Natural Science Foundation of China(U21A20345)。
文摘The mesencephalic astrocyte-derived neurotrophic factor(MANF)has been recently identified as a neurotrophic factor,but its role in hepatic fibrosis is unknown.Here,we found that MANF was upregulated in the fibrotic liver tissues of the patients with chronic liver diseases and of mice treated with CCl4.MANF deficiency in either hepatocytes or hepatic mono-macrophages,particularly in hepatic mono-macrophages,clearly exacerbated hepatic fibrosis.Myeloid-specific MANF knockout increased the population of hepatic Ly6C^(high)macrophages and promoted HSCs activation.Furthermore,MANF-sufficient macrophages(from WT mice)transfusion ameliorated CCl4-induced hepatic fibrosis in myeloid cells-specific MANF knockout(MKO)mice.Mechanistically,MANF interacted with S100A8 to competitively block S100A8/A9 heterodimer formation and inhibited S100A8/A9-mediated TLR4-NF-κB signal activation.Pharmacologically,systemic administration of recombinant human MANF significantly alleviated CCl_(4)-induced hepatic fibrosis in both WT and hepatocytes-specific MANF knockout(HKO)mice.This study reveals a mechanism by which MANF targets S100A8/A9-TLR4 as a“brake”on the upstream of NF-κB pathway,which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment.
基金Supported by(in part)Grants R01-AR43510 to Boyce BF and R01-AR48697 to Xing L from the National Institute of Arthritis and Musculoskeletal and Skin Diseases,United States
文摘Osteoclasts are the bone resorbing cells essential for bone remodeling.Osteoclasts are formed from hematopoietic progenitors in the monocyte/macrophage lineage.Osteoclastogenesis is composed of several steps including progenitor survival,differentiation to mononuclear pre-osteoclasts,fusion to multi-nuclear mature osteoclasts,and activation to bone resorbing osteoclasts.The regulation of osteoclastogenesis has been extensively studied,in which the receptor activator of NF-κB ligand(RANKL)-mediated signaling pathway and downstream transcription factors play essential roles.However,less is known about osteoclast fusion,which is a property of mature osteoclasts and is required for osteoclasts to resorb bone.Several proteins that affect cell fusion have been identified.Among them,dritic cell-specific transmembrane protein(DC-STAMP)is directly associated to osteoclast fusion in vivo.Cytokines and factors influence osteoclast fusion through regula-tion of DC-STAMP.Here we review the recently discovered new factors that regulate osteoclast fusion with specific focus on DC-STAMP.A better understanding of the mechanistic basis of osteoclast fusion will lead to the development of a new therapeutic strategy for bone disorders due to elevated osteoclast bone resorption.Cell-cell fusion is essential for a variety of cellular biological processes.In mammals,there is a limited number of cell types that fuse to form multinucleated cells,such as the fusion of myoblasts for the formation of skeletal muscle and the fusion of cells of the monocyte/macrophage lineage for the formation of multinucleated osteoclasts and giant cells.In most cases,cellcell fusion is beneficial for cells by enhancing function.Myoblast fusion increases myofiber size and diameter and thereby increases contractile strength.Multinucleated osteoclasts have far more bone resorbing activity than their mono-nuclear counterparts.Multinucleated giant cells are much more efficient in the removal of implanted materials and bacteria due to chronic infection than macrophages.Therefore,they are also called foreign-body giant cells.Cell fusion is a complicated process involving cell migration,chemotaxis,cell-cell recognition and attachment,as well as changes into a fusion-competent status.All of these steps are regulated by multiple factors.In this review,we will discuss osteoclast fusion and regulation.
基金supported by grants from the Natural Science Foundation of China (81760778)the Fundamental Research Funds for Public-interest Scientific Institution in Xinjiang Uygur Autonomous Region (KYGY2016169)CAMS Innovation Fund for Medical Sciences (2017-I2M-1-012)
文摘Objective:To investigate the immunomodulatory activity of polysaccharides from the roots of Brassica rapa.Methods:The crude polysaccharide from roots of B.rapa(BRP)was extracted and purified to further investigate the active fraction of BRT for inducing macrophage phagocytosis.Results:Effects on RAW264.7 cells demonstrated that BRP behaved better phagocytic capacity and had potent immunomodulatory activity,including increasing production of nitric oxide(NO),tumor necrosis factor a(TNFa)and upregulating mRNA levels of inducible NO synthase(iNOS)and TNFa.Furthermore,modulation of macrophage by BRP was indicated to be mediated via the activation of Akt and nuclear factor-kappa B(NF-κB).Conclusion:The beneficial effects of BRP could be used as an immunotherapeutic adjuvant in treatment of inflammatory diseases.