Osteoporosis has become a serious health problem throughout the world which is associated with an increased risk of bone fractures and mortality among the people of middle to old ages.Diabetes is also a major health p...Osteoporosis has become a serious health problem throughout the world which is associated with an increased risk of bone fractures and mortality among the people of middle to old ages.Diabetes is also a major health problem among the people of all age ranges and the sufferers due to this abnormality increasing day by day.The aim of this review is to summarize the possible mechanisms through which diabetes may induce osteoporosis.Diabetes mellitus generally exerts its effect on different parts of the body including bone cells specially the osteoblast and osteoclast,muscles,retina of the eyes,adipose tissue,endocrine system specially parathyroid hormone(PTH) and estrogen,cytokines,nervous system and digestive system.Diabetes negatively regulates osteoblast differentiation and function while positively regulates osteoclast differentiation and function through the regulation of different intermediate factors and thereby decreases bone formation while increases bone resorption.Some factors such as diabetic neuropathy,reactive oxygen species,Vitamin D,PTH have their effects on muscle cells.Diabetes decreases the muscle strength through regulating these factors in various ways and ultimately increases the risk of fall that may cause bone fractures.展开更多
晚期糖基化终末产物受体(receptor for advanced glycation end products,RAGE)是一种多配体的膜受体,与配体结合后可启动多条信号通路,引起细胞内氧化应激和炎症反应等,导致细胞功能紊乱。RAGE在糖尿病并发症、炎症、阿尔采末病和肿瘤...晚期糖基化终末产物受体(receptor for advanced glycation end products,RAGE)是一种多配体的膜受体,与配体结合后可启动多条信号通路,引起细胞内氧化应激和炎症反应等,导致细胞功能紊乱。RAGE在糖尿病并发症、炎症、阿尔采末病和肿瘤等疾病的发生和发展中起重要作用。应用可溶性RAGE(sRAGE)、抗RAGE抗体或干扰RAGE与配体结合的抑制剂阻断RAGE的活化,是防治上述疾病的新策略。该文对RAGE配体与疾病的关系和RAGE-配体激活的信号通路进行阐述,并对近年来关于RAGE抑制剂的研究进展进行总结。展开更多
Many health benefits have been ascribed to allicin, including vasorelaxant activities. However, the molecular mechanisms underlying these effects remain unknown. To apply allicin in clinical anti-HCC treatment, differ...Many health benefits have been ascribed to allicin, including vasorelaxant activities. However, the molecular mechanisms underlying these effects remain unknown. To apply allicin in clinical anti-HCC treatment, different doses of allicin and Adriamycin （ADM） were led into transplanted tumor model established by injecting HCC BEL7402 cells into subcutaneous tissue of nude mice. Treatment with allicin and ADM resulted in tumor regression with inducing of Bax and Fas ligand （FasL） mRNA.展开更多
TGF-β 1–3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix(ECM). The biological functions of TGF-β in adu...TGF-β 1–3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix(ECM). The biological functions of TGF-β in adults can only be delivered after ligand activation, mostly in response to environmental perturbations. Although involved in multiple biological and pathological processes of the human body, the exact roles of TGF-β in maintaining stem cells and tissue homeostasis have not been well-documented until recent advances, which delineate their functions in a given context. Our recent findings, along with data reported by others, have clearly shown that temporal and spatial activation of TGF-β is involved in the recruitment of stem/progenitor cell participation in tissue regeneration/remodeling process, whereas sustained abnormalities in TGF-β ligand activation, regardless of genetic or environmental origin, will inevitably disrupt the normal physiology and lead to pathobiology of major diseases. Modulation of TGF-β signaling with different approaches has proven effective pre-clinically in the treatment of multiple pathologies such as sclerosis/fibrosis, tumor metastasis, osteoarthritis, and immune disorders. Thus, further elucidation of the mechanisms by which TGF-β is activated in different tissues/organs and how targeted cells respond in a context-dependent way can likely be translated with clinical benefits in the management of a broad range of diseases with the involvement of TGF-β.展开更多
Bone metastasis is the leading cause of death in prostate cancer patients,for which there is currently no effective treatment.Since the bone microenvironment plays an important role in this process,attentions have bee...Bone metastasis is the leading cause of death in prostate cancer patients,for which there is currently no effective treatment.Since the bone microenvironment plays an important role in this process,attentions have been directed to the interactions between cancer cells and the bone microenvironment,including osteoclasts,osteoblasts,and bone stromal cells.Here,we explained the mechanism of interactions between prostate cancer cells and metastasis-associated cells within the bone microenvironment and further discussed the recent advances in targeted therapy of prostate cancer bone metastasis.This review also summarized the effects of bone microenvironment on prostate cancer metastasis and the related mechanisms,and provides insights for future prostate cancer metastasis studies.展开更多
Capsaicin in chili peppers bestows the sensation of spiciness. Since the discovery of its receptor, transient receptor potential vanilloid 1 （TRPV1） ion channel, how capsaicin activates this channel has been under e...Capsaicin in chili peppers bestows the sensation of spiciness. Since the discovery of its receptor, transient receptor potential vanilloid 1 （TRPV1） ion channel, how capsaicin activates this channel has been under extensive investigation using a variety of experimental techniques including mutagenesis, patch-clamp recording, crystallography, cryo-electron microscopy, computational docking and molecular dynamic simu- lation. A framework of how capsaicin binds and acti- vates TRPV1 has started to merge： capsaicin binds to a pocket formed by the channel＇s transmembrane seg- ments, where it takes a ＂tail-up, head-down＂ configu- ration. Binding is mediated by both hydrogen bonds and van der Waals interactions. Upon binding, cap- saicin stabilizes the open state of TRPV1 by ＂pull-and- contact＂ with the $4-$5 linker. Understanding the ligand-host interaction will greatly facilitate pharma- ceutical efforts to develop novel analgesics targeting TRPV1.展开更多
Osteoporosis is a common bone disease characterized by reduced bone and increased risk of fracture. In postmenopausal women, osteoporosis results from bone loss attributable to estrogen deficiency. Osteoclast differen...Osteoporosis is a common bone disease characterized by reduced bone and increased risk of fracture. In postmenopausal women, osteoporosis results from bone loss attributable to estrogen deficiency. Osteoclast differentiation and activation is mediated by receptor activator of nuclear factor-κB ligand(RANKL), its receptor receptor activator of nuclear factor-κB(RANK), and a decoy receptor for RANKL, osteoprotegerin(OPG). The OPG/RANKL/RANK system plays a pivotal role in osteoclast biology. Currently, a fully human antiRANKL monoclonal antibody named denosumab is being clinically used for the treatment of osteoporosis and cancer-related bone disorders. This review describes recent advances in RANKL-related research, a story from bench to bedside. First, the discovery of the key factors, OPG/RANKL/RANK, revealed the molecular mechanism of osteoclastogenesis. Second, we established three animal models:(1) a novel and rapid bone loss model by administration of glutathione-S transferase-RANKL fusion protein to mice;(2) a novel mouse model of hypercalcemia with anorexia by overexpression of soluble RANKL using an adenovirus vector; and(3) a novel mouse model of osteopetrosis by administration of a denosumab-like anti-mouse RANKL neutralizing monoclonal antibody. Lastly, anti-human RANKL monoclonal antibody has been successfully applied to the treatment of osteoporosis and cancer-related bone disorders in many countries. This is a real example of applying basic science to clinical practice.展开更多
Accumulating evidence has demonstrated that regulatory T(Treg) cells play an important role in the maintenance of immunologic self-tolerance and in down-regulating various immune responses.Thus,there has recently been...Accumulating evidence has demonstrated that regulatory T(Treg) cells play an important role in the maintenance of immunologic self-tolerance and in down-regulating various immune responses.Thus,there has recently been an increasing interest in studying the biology of Treg cells as well as their potential application in treating immune diseases.Many types of Treg cell subsets have been reported in a variety of disease models. Among these subsets,αβTCR^+CD3^+CD4^-CD8^- double negative(DN) Treg cells are defined by their capability of inhibiting immune responses via directly killing effector T cells in an antigen specific fashion.Furthermore,DN Treg cells have been shown to develop regulatory activity after encountering specific antigens,partially mediated by the acquisition of MHC-peptide complexes from antigen presenting cells(APCs).The presentation of acquired alloantigens on DN T cells allows for the specific interaction between DN Treg cells and alloantigen reactive effector T cells.Once the DN Treg and target cells have come into contact,killing is then mediated by Fas/Fas-ligand interactions,and perhaps through other unidentified pathways.Further characterization of the functions,molecular expression and mechanisms of activation of DN Treg cells will help in the development of novel therapies to induce antigen specific tolerance to self and foreign antigens.Cellular & Molecular Immunology.2004;1(5):328-335.展开更多
After it was suggested 30 years ago that the osteoblast lineage controlled the formation of osteoclasts, methods were developed that established this to be the case, but the molecular controls were elusive. Over more ...After it was suggested 30 years ago that the osteoblast lineage controlled the formation of osteoclasts, methods were developed that established this to be the case, but the molecular controls were elusive. Over more than a decade much evidence was obtained for signaling mechanisms that regulated the production of a membrane- bound regulator of osteoclastogenesis, in the course of which intercellular communication in bone was revealed in its complexity. The discovery of regulation by tumor necrosis factor ligand and receptor families was made in the last few years of the twentieth century, leading since then to a new physiology of bone, and to exciting drug development.展开更多
AIM： To determine the effect of pioglitazone, a specific peroxisome proliferator-activated receptor-γ, （PPARγ） ligand, on development of severe acute pancreatitis （SAP） and expression of nuclear factor-kappa B ...AIM： To determine the effect of pioglitazone, a specific peroxisome proliferator-activated receptor-γ, （PPARγ） ligand, on development of severe acute pancreatitis （SAP） and expression of nuclear factor-kappa B （NF-κB） and intercellular adhesion molecule-1 （ICAM-1） in the pancreas. METHODS： Male Sprague-Dawley （SD） rats （160-200 g） were randomly allocated into three groups （n = 18 in each group）： severe acute pancreatitis group, pioglitazone group, sham group. SAP was induced by retrograde infusion of 1 mL/kg body weight 5% sodium taurocholate （STC） into the biliopancreatic duct of male SD rats. Pioglitazone was injected intraperitoneally two hours piror to STC infusion. Blood and ascites were obtained for detecting amylase and ascitic capacity. Pancreatic wet/dry weight ratio, expression of NF-κB and ICAM-1 in pancreatic tissues were detected by immunohistochemical staining. Pancreatic tissue samples were stained with hematoxylin and eosin （HE） for routine optic microscopy. RESULTS： Sham group displayed normal pancreatic structure. SAP group showed diffuse hemorrhage, necrosis and severe edema in focal areas of pancreas. There was obvious adipo-saponification in abdominal cavity. Characteristics such as pancreatic hemorrhage, necrosis, severe edema and adipo-saponification were found in pioglitazone group, but the levels of those injuries were lower in pioglitazone group than those in SAP group. The wet/dry pancreatic weight ratio, ascetic capacity, serum and ascitic activities of anylase in the SAP group were significantly higher than those in the sham group and pioglitazone group respectively （6969.50 ± 1368.99 vs 2104.67 ± 377.16, 3.99 ± 1.22 vs 2.48 ± 0.74, P 〈 0.01 or P 〈 0.05）. According to Kusske criteria, the pancreatic histologic score showed that interstitial edema, inflammatory infiltration, parenchyma necrosis and parenchyma hommorrhage in SAP group significantly differed from those in the sham group and pioglitazone group （7.17 ± 1.83 vs 展开更多
(1,4-Bis-（4-bromobenzoyl）benzene) as the monomer has been synthesized and characterized by Friedel-Crafts benzoylation reaction.Novel poly（imino ketone）s（PIKs） as high performance polymers have been obtained by ...(1,4-Bis-（4-bromobenzoyl）benzene) as the monomer has been synthesized and characterized by Friedel-Crafts benzoylation reaction.Novel poly（imino ketone）s（PIKs） as high performance polymers have been obtained by the condensation polymerization of（1,4-bis-（4-bromobenzoyl）benzene） and aromatic diamines via palladium-catalyzed aryl amination reaction.The strcture of PIKs is characterized by means of FT-IR and（）1H-NMR spectroscopy,and the results show an agreement with the proposed structure.DSC and TG measurements show that PIKs possess high glass transition temperature（Tg>230℃） and good thermal stability with high decomposition temperatures（TD>500℃）.PIKs also exhibit the excellent solubility,PIK-3 can be dissolved in common organic solvent CHCl3 at room temperature（20℃）.展开更多
文摘Osteoporosis has become a serious health problem throughout the world which is associated with an increased risk of bone fractures and mortality among the people of middle to old ages.Diabetes is also a major health problem among the people of all age ranges and the sufferers due to this abnormality increasing day by day.The aim of this review is to summarize the possible mechanisms through which diabetes may induce osteoporosis.Diabetes mellitus generally exerts its effect on different parts of the body including bone cells specially the osteoblast and osteoclast,muscles,retina of the eyes,adipose tissue,endocrine system specially parathyroid hormone(PTH) and estrogen,cytokines,nervous system and digestive system.Diabetes negatively regulates osteoblast differentiation and function while positively regulates osteoclast differentiation and function through the regulation of different intermediate factors and thereby decreases bone formation while increases bone resorption.Some factors such as diabetic neuropathy,reactive oxygen species,Vitamin D,PTH have their effects on muscle cells.Diabetes decreases the muscle strength through regulating these factors in various ways and ultimately increases the risk of fall that may cause bone fractures.
文摘晚期糖基化终末产物受体(receptor for advanced glycation end products,RAGE)是一种多配体的膜受体,与配体结合后可启动多条信号通路,引起细胞内氧化应激和炎症反应等,导致细胞功能紊乱。RAGE在糖尿病并发症、炎症、阿尔采末病和肿瘤等疾病的发生和发展中起重要作用。应用可溶性RAGE(sRAGE)、抗RAGE抗体或干扰RAGE与配体结合的抑制剂阻断RAGE的活化,是防治上述疾病的新策略。该文对RAGE配体与疾病的关系和RAGE-配体激活的信号通路进行阐述,并对近年来关于RAGE抑制剂的研究进展进行总结。
基金This study was supported by a grant from Nature ScienceFoundation of Shandong Province, China (No. Y2004C34) .
文摘Many health benefits have been ascribed to allicin, including vasorelaxant activities. However, the molecular mechanisms underlying these effects remain unknown. To apply allicin in clinical anti-HCC treatment, different doses of allicin and Adriamycin （ADM） were led into transplanted tumor model established by injecting HCC BEL7402 cells into subcutaneous tissue of nude mice. Treatment with allicin and ADM resulted in tumor regression with inducing of Bax and Fas ligand （FasL） mRNA.
基金supported by U.S. National Institutes of Health grants (AR063943 and DK057501 to X.C. AR064833 to J.L.C.)+3 种基金the National Natural Science Foundation of China (81771099 to X.X.)the Key Project for Frontier Research of Science and Technology Department of Sichuan Province (2016JY0006 to X.Z.)Sichuan Province Science and Technology Innovation Team Program (2017TD0016 to Q.Y.).X.X.supported by the visiting scholar fellowship from West China Hospital of Stomatology, Sichuan University
文摘TGF-β 1–3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix(ECM). The biological functions of TGF-β in adults can only be delivered after ligand activation, mostly in response to environmental perturbations. Although involved in multiple biological and pathological processes of the human body, the exact roles of TGF-β in maintaining stem cells and tissue homeostasis have not been well-documented until recent advances, which delineate their functions in a given context. Our recent findings, along with data reported by others, have clearly shown that temporal and spatial activation of TGF-β is involved in the recruitment of stem/progenitor cell participation in tissue regeneration/remodeling process, whereas sustained abnormalities in TGF-β ligand activation, regardless of genetic or environmental origin, will inevitably disrupt the normal physiology and lead to pathobiology of major diseases. Modulation of TGF-β signaling with different approaches has proven effective pre-clinically in the treatment of multiple pathologies such as sclerosis/fibrosis, tumor metastasis, osteoarthritis, and immune disorders. Thus, further elucidation of the mechanisms by which TGF-β is activated in different tissues/organs and how targeted cells respond in a context-dependent way can likely be translated with clinical benefits in the management of a broad range of diseases with the involvement of TGF-β.
基金This work was supported the National Natural Science Foundation of China(Nos.81803097 and 81602727)the Natural Science Foundation of Shandong Province(No.ZR2017QH005).
文摘Bone metastasis is the leading cause of death in prostate cancer patients,for which there is currently no effective treatment.Since the bone microenvironment plays an important role in this process,attentions have been directed to the interactions between cancer cells and the bone microenvironment,including osteoclasts,osteoblasts,and bone stromal cells.Here,we explained the mechanism of interactions between prostate cancer cells and metastasis-associated cells within the bone microenvironment and further discussed the recent advances in targeted therapy of prostate cancer bone metastasis.This review also summarized the effects of bone microenvironment on prostate cancer metastasis and the related mechanisms,and provides insights for future prostate cancer metastasis studies.
文摘Capsaicin in chili peppers bestows the sensation of spiciness. Since the discovery of its receptor, transient receptor potential vanilloid 1 （TRPV1） ion channel, how capsaicin activates this channel has been under extensive investigation using a variety of experimental techniques including mutagenesis, patch-clamp recording, crystallography, cryo-electron microscopy, computational docking and molecular dynamic simu- lation. A framework of how capsaicin binds and acti- vates TRPV1 has started to merge： capsaicin binds to a pocket formed by the channel＇s transmembrane seg- ments, where it takes a ＂tail-up, head-down＂ configu- ration. Binding is mediated by both hydrogen bonds and van der Waals interactions. Upon binding, cap- saicin stabilizes the open state of TRPV1 by ＂pull-and- contact＂ with the $4-$5 linker. Understanding the ligand-host interaction will greatly facilitate pharma- ceutical efforts to develop novel analgesics targeting TRPV1.
文摘Osteoporosis is a common bone disease characterized by reduced bone and increased risk of fracture. In postmenopausal women, osteoporosis results from bone loss attributable to estrogen deficiency. Osteoclast differentiation and activation is mediated by receptor activator of nuclear factor-κB ligand(RANKL), its receptor receptor activator of nuclear factor-κB(RANK), and a decoy receptor for RANKL, osteoprotegerin(OPG). The OPG/RANKL/RANK system plays a pivotal role in osteoclast biology. Currently, a fully human antiRANKL monoclonal antibody named denosumab is being clinically used for the treatment of osteoporosis and cancer-related bone disorders. This review describes recent advances in RANKL-related research, a story from bench to bedside. First, the discovery of the key factors, OPG/RANKL/RANK, revealed the molecular mechanism of osteoclastogenesis. Second, we established three animal models:(1) a novel and rapid bone loss model by administration of glutathione-S transferase-RANKL fusion protein to mice;(2) a novel mouse model of hypercalcemia with anorexia by overexpression of soluble RANKL using an adenovirus vector; and(3) a novel mouse model of osteopetrosis by administration of a denosumab-like anti-mouse RANKL neutralizing monoclonal antibody. Lastly, anti-human RANKL monoclonal antibody has been successfully applied to the treatment of osteoporosis and cancer-related bone disorders in many countries. This is a real example of applying basic science to clinical practice.
文摘Accumulating evidence has demonstrated that regulatory T(Treg) cells play an important role in the maintenance of immunologic self-tolerance and in down-regulating various immune responses.Thus,there has recently been an increasing interest in studying the biology of Treg cells as well as their potential application in treating immune diseases.Many types of Treg cell subsets have been reported in a variety of disease models. Among these subsets,αβTCR^+CD3^+CD4^-CD8^- double negative(DN) Treg cells are defined by their capability of inhibiting immune responses via directly killing effector T cells in an antigen specific fashion.Furthermore,DN Treg cells have been shown to develop regulatory activity after encountering specific antigens,partially mediated by the acquisition of MHC-peptide complexes from antigen presenting cells(APCs).The presentation of acquired alloantigens on DN T cells allows for the specific interaction between DN Treg cells and alloantigen reactive effector T cells.Once the DN Treg and target cells have come into contact,killing is then mediated by Fas/Fas-ligand interactions,and perhaps through other unidentified pathways.Further characterization of the functions,molecular expression and mechanisms of activation of DN Treg cells will help in the development of novel therapies to induce antigen specific tolerance to self and foreign antigens.Cellular & Molecular Immunology.2004;1(5):328-335.
基金Supported by The National Health and Medical Research Council(Australia)the Victorian Government OIS Program
文摘After it was suggested 30 years ago that the osteoblast lineage controlled the formation of osteoclasts, methods were developed that established this to be the case, but the molecular controls were elusive. Over more than a decade much evidence was obtained for signaling mechanisms that regulated the production of a membrane- bound regulator of osteoclastogenesis, in the course of which intercellular communication in bone was revealed in its complexity. The discovery of regulation by tumor necrosis factor ligand and receptor families was made in the last few years of the twentieth century, leading since then to a new physiology of bone, and to exciting drug development.
基金Supported by Health Bureau Foundation of Jiangxi Province, No.20045019Natural Science Foundation of Jiangxi Province, No.0640069
文摘AIM： To determine the effect of pioglitazone, a specific peroxisome proliferator-activated receptor-γ, （PPARγ） ligand, on development of severe acute pancreatitis （SAP） and expression of nuclear factor-kappa B （NF-κB） and intercellular adhesion molecule-1 （ICAM-1） in the pancreas. METHODS： Male Sprague-Dawley （SD） rats （160-200 g） were randomly allocated into three groups （n = 18 in each group）： severe acute pancreatitis group, pioglitazone group, sham group. SAP was induced by retrograde infusion of 1 mL/kg body weight 5% sodium taurocholate （STC） into the biliopancreatic duct of male SD rats. Pioglitazone was injected intraperitoneally two hours piror to STC infusion. Blood and ascites were obtained for detecting amylase and ascitic capacity. Pancreatic wet/dry weight ratio, expression of NF-κB and ICAM-1 in pancreatic tissues were detected by immunohistochemical staining. Pancreatic tissue samples were stained with hematoxylin and eosin （HE） for routine optic microscopy. RESULTS： Sham group displayed normal pancreatic structure. SAP group showed diffuse hemorrhage, necrosis and severe edema in focal areas of pancreas. There was obvious adipo-saponification in abdominal cavity. Characteristics such as pancreatic hemorrhage, necrosis, severe edema and adipo-saponification were found in pioglitazone group, but the levels of those injuries were lower in pioglitazone group than those in SAP group. The wet/dry pancreatic weight ratio, ascetic capacity, serum and ascitic activities of anylase in the SAP group were significantly higher than those in the sham group and pioglitazone group respectively （6969.50 ± 1368.99 vs 2104.67 ± 377.16, 3.99 ± 1.22 vs 2.48 ± 0.74, P 〈 0.01 or P 〈 0.05）. According to Kusske criteria, the pancreatic histologic score showed that interstitial edema, inflammatory infiltration, parenchyma necrosis and parenchyma hommorrhage in SAP group significantly differed from those in the sham group and pioglitazone group （7.17 ± 1.83 vs
文摘(1,4-Bis-（4-bromobenzoyl）benzene) as the monomer has been synthesized and characterized by Friedel-Crafts benzoylation reaction.Novel poly（imino ketone）s（PIKs） as high performance polymers have been obtained by the condensation polymerization of（1,4-bis-（4-bromobenzoyl）benzene） and aromatic diamines via palladium-catalyzed aryl amination reaction.The strcture of PIKs is characterized by means of FT-IR and（）1H-NMR spectroscopy,and the results show an agreement with the proposed structure.DSC and TG measurements show that PIKs possess high glass transition temperature（Tg>230℃） and good thermal stability with high decomposition temperatures（TD>500℃）.PIKs also exhibit the excellent solubility,PIK-3 can be dissolved in common organic solvent CHCl3 at room temperature（20℃）.
