Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand...Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.展开更多
Background:Liver cirrhosis results from many forms of chronic damage,characterized by accumulation of extracellular matrix.The present study aimed to explore a potential non-invasive biomarker and its mechanism in the...Background:Liver cirrhosis results from many forms of chronic damage,characterized by accumulation of extracellular matrix.The present study aimed to explore a potential non-invasive biomarker and its mechanism in the progression of liver cirrhosis.Methods:Gene Expression Omnibus(GEO)dataset(GSE15654,n=216)was analyzed to screen genes associated with progression of liver cirrhosis.A total of 181 plasma samples,including healthy control(HC,n=20),chronic hepatitis B(CHB,n=77)and HBV-related liver cirrhosis(LC,n=84),were enrolled for validation.In vitro and in vivo experiments were employed for the mechanistic investigation.Results:GEO dataset analysis showed that relatively low mRNA-expression of C–C motif chemokine ligand 16(CCL16)was associated with elevated Child-Pugh score(P=0.034)and worse prognosis(P=0.025).Plasma CCL16 level decreased in a stepwise pattern,with a median concentration of 10.29,6.57 and 4.47 ng/mL in the HC,CHB and LC groups,respectively(P<0.001).Low plasma CCL16 was significantly related to hepatic dysfunction both in the CHB and LC groups(P<0.05).Combination of CCL16 and ALT showed improved distinguishing capability for LC compared to either alone.In vitro,CCL16 expression was downregulated by lipopolysaccharide and hypoxia.Overexpression of CCL16 from human normal liver cell line(LO2)reduced the extracellular matrix associated proteins(Col1 and Col4)in human hepatic stellate cell line(LX-2).In vivo,the pathological feature of cirrhosis was alleviated by the hepatocytespecific expression of CCL16.Conclusions:CCL16 could be a feasible plasma marker to predict the occurrence and progression of liver cirrhosis.CCL16 might impact liver cirrhosis through inactivating hepatic stellate cells.展开更多
Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation.Overproduced chemokines are responsible for the migratory process of the leukoc...Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation.Overproduced chemokines are responsible for the migratory process of the leukocytes,but the regulatory mechanism underlying the production of chemokines from resident cells of the spinal cord has not been fully elucidated.We examined the protein levels of macrophage migration inhibitory factor and chemokine C-C motif chemokine ligand 2 in a spinal cord contusion model at different time points following spinal cord injury.The elevation of macrophage migration inhibitory factor at the lesion site coincided with the increase of chemokine C-C motif chemokine ligand 2 abundance in astrocytes.Stimulation of primary cultured astrocytes with different concentrations of macrophage migration inhibitory factor recombinant protein induced chemokine C-C motif chemokine ligand 2 production from the cells,and the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine attenuated the stimulatory effect.Further investigation into the underlying mechanism on macrophage migration inhibitory factor-mediated astrocytic production of chemokine C-C motif chemokine ligand 2 revealed that macrophage migration inhibitory factor activated intracellular JNK signaling through binding with CD74 receptor.Administration of the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine following spinal cord injury resulted in the reduction of chemokine C-C motif chemokine ligand 2-recruited microglia/macrophages at the lesion site and remarkably improved the hindlimb locomotor function of rats.Our results have provided insights into the functions of astrocyte-activated chemokines in the recruitment of leukocytes and may be beneficial to develop interventions targeting chemokine C-C motif chemokine ligand 2 for neuroinflammation after spinal cord injury.展开更多
Background:We previously found that the intestinal epithelial chemokine(C-C motif)ligand 7(CCL7)plays an important role in the development of toxin-induced acute liver damage.The detailed effects of intestinal epithel...Background:We previously found that the intestinal epithelial chemokine(C-C motif)ligand 7(CCL7)plays an important role in the development of toxin-induced acute liver damage.The detailed effects of intestinal epithelial CCL7 on chronic diseases;however,are still unclear.Here,we aimed to investigate the impact of intestinal epithelial CCL7 overexpression on high-fat diet(HFD)-induced obesity and steatohepatitis in mice.Methods:Intestinal epithelial CCL7 overexpression(CCL7tgIEC)mice and their wild-type(WT)littermates were fed with normal chow or HFD for 16 weeks to induce obesity and non-alcoholic fatty liver disease.Body weight gain,as well as adipose tissue index were assessed.Liver injury was monitored by histological analysis and real time polymerase chain reaction.Gut microbial composition was analyzed by 16S rRNA gene sequencing.Results:We found that the CCL7tgIEC mice on a HFD had markedly decreased weight gain(8.9 vs.17.0 g,P<0.05)and a lower adipose tissue index that include mesenteric fat(1.0%vs.1.76%,P<0.05),gonadal fat(2.1%vs.6.1%,P<0.05),subcutaneous fat(1.0%vs.2.8%,P<0.05)compared to WT animals.HFD-induced glucose intolerance and insulin resistance were also significantly improved in CCL7tgIEC mice compared to WT.Furthermore,HFD-fed CCL7tgIEC mice displayed less hepatic lipid accumulation and lower expression of inflammatory factors than WT mice.16S rRNA gene sequencing demonstrated that CCL7 overexpression in intestinal epithelial cells improved HFD-induced gut microbial dysbiosis.Conclusions:Our study revealed that CCL7 overexpression in the intestinal epithelium protects mice against the progression of diet-induced obesity,hepatic steatosis,and enteric dysbiosis.展开更多
Severe acute respiratory syndrome coronavirus 2(SARSCoV-2)infection has been extensively shown to cause many neurological sequelae,and cognitive deficits(known as“brain fog”)may particularly and widely occur even in...Severe acute respiratory syndrome coronavirus 2(SARSCoV-2)infection has been extensively shown to cause many neurological sequelae,and cognitive deficits(known as“brain fog”)may particularly and widely occur even in individuals with mild symptoms[1].Peripheral hyperinflammation as well as central nervous system(CNS)local immune responses may synergistically contribute to brain autoimmune injury.In addition to the direct neuroinvasion of SARS-CoV-2 and nonimmune effects such as severe systemic hypoxemia and vascular thrombosis,the central mechanism by which SARSCoV-2 accelerates cognitive-related symptoms may be related to immune effects[2].However,the precise neuroinflammatory mechanisms of SARS-CoV-2 infection have not been fully established.Fernández-Casta-da et al.[3]provided direct evidence and unique insights into the potential mechanism of cognitive impairment in mild respiratory coronavirus disease 2019(COVID-19)cases.展开更多
AIM:To investigate the role of genetic polymorphisms in the progression of hepatic fibrosis in hereditary haemochromatosis.METHODS:A cohort of 245 well-characterised C282Y homozygous patients with haemochromatosis was...AIM:To investigate the role of genetic polymorphisms in the progression of hepatic fibrosis in hereditary haemochromatosis.METHODS:A cohort of 245 well-characterised C282Y homozygous patients with haemochromatosis was studied,with all subjects having liver biopsy data and DNA available for testing.This study assessed the association of eight single nucleotide polymorphisms(SNPs)in a total of six genes including toll-like receptor 4(TLR4),transforming growth factor-beta(TGF-β),oxoguanine DNA glycosylase,monocyte chemoattractant protein 1,chemokine C-C motif receptor 2 and interleukin-10 with liver disease severity.Genotyping was performed using high resolution melt analysis and sequencing.The results were analysed in relation to the stage of hepatic fibrosis in multivariate analysis incorporating other cofactors including alcohol consumption and hepatic iron concentration.RESULTS:There were significant associations between the cofactors of male gender(P=0.0001),increasing age(P=0.006),alcohol consumption(P=0.0001),steatosis(P=0.03),hepatic iron concentration(P<0.0001)and the presence of hepatic fibrosis.Of the candidate gene polymorphisms studied,none showed a significant association with hepatic fibrosis in univariate or multivariate analysis incorporating cofactors.We also specifically studied patients with hepatic iron loading above threshold levels for cirrhosis and compared the genetic polymorphisms between those with no fibrosis vs cirrhosis however there was no significant effect from any of the candidate genes studied.Importantly,in this large,well characterised cohort of patients there was no association between SNPs for TGF-βor TLR4and the presence of fibrosis,cirrhosis or increasing fibrosis stage in multivariate analysis.CONCLUSION:In our large,well characterised group of haemochromatosis subjects we did not demonstrate any relationship between candidate gene polymorphisms and hepatic fibrosis or cirrhosis.展开更多
Objective:This study was performed to explore the possible changes of the serum levels of the cytokines including interleukin 1α(IL-1α),chemokine monocyte chemotactic protein 1(also known as chemokine[C-C motif]liga...Objective:This study was performed to explore the possible changes of the serum levels of the cytokines including interleukin 1α(IL-1α),chemokine monocyte chemotactic protein 1(also known as chemokine[C-C motif]ligand 2[CCL2]),and C-X-C motif chemokine ligand 2(CXCL2)in patients with pemphigus.Methods:The expression levels of IL-1α,CCL2,and CXCL2 in the serum of 57 patients with pemphigus PV(including 42 patients in progressive stage and 15 patients in remission stage)and 31 healthy controls were examined by enzyme-linked immunosorbent assay.The indepent-samples t-test was used to compare the two groups.Oneway analysis of variance was used for multiple-group comparisons,and the post-hoc least significant difference test was used to detect differences among multiple groups.Results:The serum expression levels of CCL2 and IL-1a were all significantly higher in the patients in progressive stage than in the controls([2.69±0.23]ng/mL vs.[2.55±0.28]ng/mL,P=0.043;[0.62±0.27]ng/mL vs.[0.48±0.23]ng/mL,P=0.038,respectively).In addition,the serum expression level of CXCL2 was significantly higher in patients in progressive stage than in in the remission stage([61.70±46.38]ng/mL vs.[24.97±18.46]ng/mL,P=0.037).Sex,disease classification,disease severity,treatment,and mucosal involvement had no significant influence on the expression of IL-1α,CCL2,or CXCL2 in the serum of patients groups and controls(all P>0.05).Conclusion:IL-1α,CCL2,and CXCL2 are heavily involved in the occurrence and development of pemphigus and may be related to the activity of the disease.展开更多
Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 （C-C motif chemokine ligand 2） has been shown ...Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 （C-C motif chemokine ligand 2） has been shown to enhance N-methyl-D-aspartate （NMDA）-induced currents in spinal outer lamina II （Iio） neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expres- sion in excitatory vesicular glutamate transporter subtype 2-positive （VGLUT2＋） neurons. CCL2 increased NMDA- induced currents in CCR2＋/VGLUT2＋ neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin- expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2- expressing excitatory neurons in spinal lamina Iio, and this underlies the generation of central sensitization in patho- logical pain.展开更多
Previous studies have shown that CCL2(C-C motif chemokine ligand 2)induces chronic pain,but the exact mechanisms are still unknown.Here,we established models to explore the potential mechanisms.Behavioral experiments ...Previous studies have shown that CCL2(C-C motif chemokine ligand 2)induces chronic pain,but the exact mechanisms are still unknown.Here,we established models to explore the potential mechanisms.Behavioral experiments revealed that an antagonist of extracellular signal-regulated kinase(ERK)inhibited not only CCL2-induced inflammatory pain,but also pain responses induced by complete Freund’s adjuvant.We posed the question of the intracellular signaling cascade involved.Subsequent experiments showed that CCL2 up-regulated the expression of phosphorylated ERK(pERK)and N-methyl D-aspartate receptor[NMDAR]subtype 2B(GluN2B);meanwhile,antagonists of CCR2 and ERK effectively reversed these phenomena.Whole-cell patchclamp recordings revealed that CCL2 enhanced the NMDAR-induced currents via activating the pERK pathway,which was blocked by antagonists of GluN2B and ERK.In summary,we demonstrate that CCL2 directly interacts with CCR2 to enhance NMDAR-induced currents,eventually leading to inflammatory pain mainly through the CCL2-CCR2-pERK-GluN2B pathway.展开更多
Inflammation,which is mediated by leukocyte trafficking and activation,plays a prominent role in the pathogenesis of acute and chronic liver injury.Chemokines are critical mediators involved in the migration of leukoc...Inflammation,which is mediated by leukocyte trafficking and activation,plays a prominent role in the pathogenesis of acute and chronic liver injury.Chemokines are critical mediators involved in the migration of leukocytes into the diseased liver via binding to their G protein-coupled receptors.CeC motif ligand 5(CCL5)belongs to the CC-chemokine family and is secreted by several hepatic cell pop-ulations including hepatocytes,macrophages,hepatic stellate cells,and endothelial cells upon activation.CCL5 regulates the recruitment and migration of T cells(via CCR5)and NK cells(via CCR1).Moreover,CCL5 activates and stimulates T cell proliferation and cytokine production,sequentially regulating in-flammatory responses.Accumulating studies have identified crucial effects of CCL5 both in liver-disease patients and in experimental models,in which CCL5 is elevated and displays distinct effects according to pathological conditions.In this review,we discussed the crucial functions of CCL5 in liver diseases,including acute liver failure,hepatic ischemia-reperfusion injury,acute liver failure,acute and viral hepatitis,alcoholic liver disease,non-alcoholic fatty liver disease,fibrosis,and hepatocellular carcinoma.Continued understanding the roles of CCL5 in liver disease and their mechanisms of activation are indispensable for the development of effective clinical therapeutics.展开更多
基金supported by the National Natural Science Foundation of China(Key Program),No.11932013the National Natural Science Foundation of China(General Program),No.82272255+2 种基金Armed Police Force High-Level Science and Technology Personnel ProjectThe Armed Police Force Focuses on Supporting Scientific and Technological Innovation TeamsKey Project of Tianjin Science and Technology Plan,No.20JCZDJC00570(all to XC)。
文摘Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.
基金This work was supported by grants from the National Science and Technology Major Project of China[2017ZX10203205]the National Natural Science Funds for Distinguished Young Scholar of China[81625003]+2 种基金Projects of Medical and Health Technology Program in Zhejiang Province[WKJ-ZJ-1514]China Postdoctoral Science Foundation[2017M612014]Zhejiang Medical and Technological Program[2018263185].
文摘Background:Liver cirrhosis results from many forms of chronic damage,characterized by accumulation of extracellular matrix.The present study aimed to explore a potential non-invasive biomarker and its mechanism in the progression of liver cirrhosis.Methods:Gene Expression Omnibus(GEO)dataset(GSE15654,n=216)was analyzed to screen genes associated with progression of liver cirrhosis.A total of 181 plasma samples,including healthy control(HC,n=20),chronic hepatitis B(CHB,n=77)and HBV-related liver cirrhosis(LC,n=84),were enrolled for validation.In vitro and in vivo experiments were employed for the mechanistic investigation.Results:GEO dataset analysis showed that relatively low mRNA-expression of C–C motif chemokine ligand 16(CCL16)was associated with elevated Child-Pugh score(P=0.034)and worse prognosis(P=0.025).Plasma CCL16 level decreased in a stepwise pattern,with a median concentration of 10.29,6.57 and 4.47 ng/mL in the HC,CHB and LC groups,respectively(P<0.001).Low plasma CCL16 was significantly related to hepatic dysfunction both in the CHB and LC groups(P<0.05).Combination of CCL16 and ALT showed improved distinguishing capability for LC compared to either alone.In vitro,CCL16 expression was downregulated by lipopolysaccharide and hypoxia.Overexpression of CCL16 from human normal liver cell line(LO2)reduced the extracellular matrix associated proteins(Col1 and Col4)in human hepatic stellate cell line(LX-2).In vivo,the pathological feature of cirrhosis was alleviated by the hepatocytespecific expression of CCL16.Conclusions:CCL16 could be a feasible plasma marker to predict the occurrence and progression of liver cirrhosis.CCL16 might impact liver cirrhosis through inactivating hepatic stellate cells.
基金supported by the China Postdoctoral Science Foundation,No.2020M681689(to YMH)the Basic Scientific Research Projects of Nantong,Nos.JC2020015(to HX)and JC2020041(to YMH)。
文摘Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation.Overproduced chemokines are responsible for the migratory process of the leukocytes,but the regulatory mechanism underlying the production of chemokines from resident cells of the spinal cord has not been fully elucidated.We examined the protein levels of macrophage migration inhibitory factor and chemokine C-C motif chemokine ligand 2 in a spinal cord contusion model at different time points following spinal cord injury.The elevation of macrophage migration inhibitory factor at the lesion site coincided with the increase of chemokine C-C motif chemokine ligand 2 abundance in astrocytes.Stimulation of primary cultured astrocytes with different concentrations of macrophage migration inhibitory factor recombinant protein induced chemokine C-C motif chemokine ligand 2 production from the cells,and the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine attenuated the stimulatory effect.Further investigation into the underlying mechanism on macrophage migration inhibitory factor-mediated astrocytic production of chemokine C-C motif chemokine ligand 2 revealed that macrophage migration inhibitory factor activated intracellular JNK signaling through binding with CD74 receptor.Administration of the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine following spinal cord injury resulted in the reduction of chemokine C-C motif chemokine ligand 2-recruited microglia/macrophages at the lesion site and remarkably improved the hindlimb locomotor function of rats.Our results have provided insights into the functions of astrocyte-activated chemokines in the recruitment of leukocytes and may be beneficial to develop interventions targeting chemokine C-C motif chemokine ligand 2 for neuroinflammation after spinal cord injury.
基金a grant from the Natural Science Funds for Distinguished Young Scholar of Guangdong Province(No.2016A030306043).
文摘Background:We previously found that the intestinal epithelial chemokine(C-C motif)ligand 7(CCL7)plays an important role in the development of toxin-induced acute liver damage.The detailed effects of intestinal epithelial CCL7 on chronic diseases;however,are still unclear.Here,we aimed to investigate the impact of intestinal epithelial CCL7 overexpression on high-fat diet(HFD)-induced obesity and steatohepatitis in mice.Methods:Intestinal epithelial CCL7 overexpression(CCL7tgIEC)mice and their wild-type(WT)littermates were fed with normal chow or HFD for 16 weeks to induce obesity and non-alcoholic fatty liver disease.Body weight gain,as well as adipose tissue index were assessed.Liver injury was monitored by histological analysis and real time polymerase chain reaction.Gut microbial composition was analyzed by 16S rRNA gene sequencing.Results:We found that the CCL7tgIEC mice on a HFD had markedly decreased weight gain(8.9 vs.17.0 g,P<0.05)and a lower adipose tissue index that include mesenteric fat(1.0%vs.1.76%,P<0.05),gonadal fat(2.1%vs.6.1%,P<0.05),subcutaneous fat(1.0%vs.2.8%,P<0.05)compared to WT animals.HFD-induced glucose intolerance and insulin resistance were also significantly improved in CCL7tgIEC mice compared to WT.Furthermore,HFD-fed CCL7tgIEC mice displayed less hepatic lipid accumulation and lower expression of inflammatory factors than WT mice.16S rRNA gene sequencing demonstrated that CCL7 overexpression in intestinal epithelial cells improved HFD-induced gut microbial dysbiosis.Conclusions:Our study revealed that CCL7 overexpression in the intestinal epithelium protects mice against the progression of diet-induced obesity,hepatic steatosis,and enteric dysbiosis.
基金supported by grants from the National Natural Science Foundation of China(82001240)Natural Science Foundation of Heilongjiang Province(YQ2021H011)+1 种基金China Postdoctoral Science Foundation(2020M670925,2022T150172)Postdoctoral Foundation of Heilongjiang Province(LBHZ19027,LBH-TZ2019).
文摘Severe acute respiratory syndrome coronavirus 2(SARSCoV-2)infection has been extensively shown to cause many neurological sequelae,and cognitive deficits(known as“brain fog”)may particularly and widely occur even in individuals with mild symptoms[1].Peripheral hyperinflammation as well as central nervous system(CNS)local immune responses may synergistically contribute to brain autoimmune injury.In addition to the direct neuroinvasion of SARS-CoV-2 and nonimmune effects such as severe systemic hypoxemia and vascular thrombosis,the central mechanism by which SARSCoV-2 accelerates cognitive-related symptoms may be related to immune effects[2].However,the precise neuroinflammatory mechanisms of SARS-CoV-2 infection have not been fully established.Fernández-Casta-da et al.[3]provided direct evidence and unique insights into the potential mechanism of cognitive impairment in mild respiratory coronavirus disease 2019(COVID-19)cases.
基金Supported by NHMRC Medical Postgraduate Scholarship and the Royal Brisbane and Women’s Hospital Research Foundation to Wood MJthe National Health and Medical Research Council(NHMRC)to Ramm GA and Powell LW+1 种基金the recipient of an NHMRC Senior Research Fellowship,1024672 to Subramaniam VNan NHMRC Senior Research Fellowship,No.552409 to Ramm GA
文摘AIM:To investigate the role of genetic polymorphisms in the progression of hepatic fibrosis in hereditary haemochromatosis.METHODS:A cohort of 245 well-characterised C282Y homozygous patients with haemochromatosis was studied,with all subjects having liver biopsy data and DNA available for testing.This study assessed the association of eight single nucleotide polymorphisms(SNPs)in a total of six genes including toll-like receptor 4(TLR4),transforming growth factor-beta(TGF-β),oxoguanine DNA glycosylase,monocyte chemoattractant protein 1,chemokine C-C motif receptor 2 and interleukin-10 with liver disease severity.Genotyping was performed using high resolution melt analysis and sequencing.The results were analysed in relation to the stage of hepatic fibrosis in multivariate analysis incorporating other cofactors including alcohol consumption and hepatic iron concentration.RESULTS:There were significant associations between the cofactors of male gender(P=0.0001),increasing age(P=0.006),alcohol consumption(P=0.0001),steatosis(P=0.03),hepatic iron concentration(P<0.0001)and the presence of hepatic fibrosis.Of the candidate gene polymorphisms studied,none showed a significant association with hepatic fibrosis in univariate or multivariate analysis incorporating cofactors.We also specifically studied patients with hepatic iron loading above threshold levels for cirrhosis and compared the genetic polymorphisms between those with no fibrosis vs cirrhosis however there was no significant effect from any of the candidate genes studied.Importantly,in this large,well characterised cohort of patients there was no association between SNPs for TGF-βor TLR4and the presence of fibrosis,cirrhosis or increasing fibrosis stage in multivariate analysis.CONCLUSION:In our large,well characterised group of haemochromatosis subjects we did not demonstrate any relationship between candidate gene polymorphisms and hepatic fibrosis or cirrhosis.
文摘Objective:This study was performed to explore the possible changes of the serum levels of the cytokines including interleukin 1α(IL-1α),chemokine monocyte chemotactic protein 1(also known as chemokine[C-C motif]ligand 2[CCL2]),and C-X-C motif chemokine ligand 2(CXCL2)in patients with pemphigus.Methods:The expression levels of IL-1α,CCL2,and CXCL2 in the serum of 57 patients with pemphigus PV(including 42 patients in progressive stage and 15 patients in remission stage)and 31 healthy controls were examined by enzyme-linked immunosorbent assay.The indepent-samples t-test was used to compare the two groups.Oneway analysis of variance was used for multiple-group comparisons,and the post-hoc least significant difference test was used to detect differences among multiple groups.Results:The serum expression levels of CCL2 and IL-1a were all significantly higher in the patients in progressive stage than in the controls([2.69±0.23]ng/mL vs.[2.55±0.28]ng/mL,P=0.043;[0.62±0.27]ng/mL vs.[0.48±0.23]ng/mL,P=0.038,respectively).In addition,the serum expression level of CXCL2 was significantly higher in patients in progressive stage than in in the remission stage([61.70±46.38]ng/mL vs.[24.97±18.46]ng/mL,P=0.037).Sex,disease classification,disease severity,treatment,and mucosal involvement had no significant influence on the expression of IL-1α,CCL2,or CXCL2 in the serum of patients groups and controls(all P>0.05).Conclusion:IL-1α,CCL2,and CXCL2 are heavily involved in the occurrence and development of pemphigus and may be related to the activity of the disease.
基金supported by grants from the National Natural Science Foundation of China(31400949,81502102,31471059,81371498,and 31371121)NIH R01,USA Grants(DE17794,DE22743,and NS87988)
文摘Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 （C-C motif chemokine ligand 2） has been shown to enhance N-methyl-D-aspartate （NMDA）-induced currents in spinal outer lamina II （Iio） neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expres- sion in excitatory vesicular glutamate transporter subtype 2-positive （VGLUT2＋） neurons. CCL2 increased NMDA- induced currents in CCR2＋/VGLUT2＋ neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin- expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2- expressing excitatory neurons in spinal lamina Iio, and this underlies the generation of central sensitization in patho- logical pain.
基金grants from the National Natural Science Foundation of China(81870867,31671088,31471059,and 81502102)the Natural Science Foundation of Shaanxi Province,China(2019SF-071 and 2017ZDJC-01)。
文摘Previous studies have shown that CCL2(C-C motif chemokine ligand 2)induces chronic pain,but the exact mechanisms are still unknown.Here,we established models to explore the potential mechanisms.Behavioral experiments revealed that an antagonist of extracellular signal-regulated kinase(ERK)inhibited not only CCL2-induced inflammatory pain,but also pain responses induced by complete Freund’s adjuvant.We posed the question of the intracellular signaling cascade involved.Subsequent experiments showed that CCL2 up-regulated the expression of phosphorylated ERK(pERK)and N-methyl D-aspartate receptor[NMDAR]subtype 2B(GluN2B);meanwhile,antagonists of CCR2 and ERK effectively reversed these phenomena.Whole-cell patchclamp recordings revealed that CCL2 enhanced the NMDAR-induced currents via activating the pERK pathway,which was blocked by antagonists of GluN2B and ERK.In summary,we demonstrate that CCL2 directly interacts with CCR2 to enhance NMDAR-induced currents,eventually leading to inflammatory pain mainly through the CCL2-CCR2-pERK-GluN2B pathway.
基金This work was supported by the National Natural Science Foundation of China(81873582 and 81670562 to X.Kong).
文摘Inflammation,which is mediated by leukocyte trafficking and activation,plays a prominent role in the pathogenesis of acute and chronic liver injury.Chemokines are critical mediators involved in the migration of leukocytes into the diseased liver via binding to their G protein-coupled receptors.CeC motif ligand 5(CCL5)belongs to the CC-chemokine family and is secreted by several hepatic cell pop-ulations including hepatocytes,macrophages,hepatic stellate cells,and endothelial cells upon activation.CCL5 regulates the recruitment and migration of T cells(via CCR5)and NK cells(via CCR1).Moreover,CCL5 activates and stimulates T cell proliferation and cytokine production,sequentially regulating in-flammatory responses.Accumulating studies have identified crucial effects of CCL5 both in liver-disease patients and in experimental models,in which CCL5 is elevated and displays distinct effects according to pathological conditions.In this review,we discussed the crucial functions of CCL5 in liver diseases,including acute liver failure,hepatic ischemia-reperfusion injury,acute liver failure,acute and viral hepatitis,alcoholic liver disease,non-alcoholic fatty liver disease,fibrosis,and hepatocellular carcinoma.Continued understanding the roles of CCL5 in liver disease and their mechanisms of activation are indispensable for the development of effective clinical therapeutics.
