BACKGROUND:The genetic diversity of chemokines and chemokine receptors has been associated with the outcome of hepatitis B virus infection.The aim of this study was to evaluate whether the copy number variation in the...BACKGROUND:The genetic diversity of chemokines and chemokine receptors has been associated with the outcome of hepatitis B virus infection.The aim of this study was to evaluate whether the copy number variation in the CCL3L1 gene and the polymorphisms of CCR5Δ32 and CCR5-2459A→G (rs1799987) are associated with recurrent hepatitis B in liver transplantation for hepatitis B virus infection-related end stage liver disease.METHODS:A total of 185 transplant recipients were enrolled in this study.The genomic DNA was extracted from whole blood,the copy number of the CCL3L1 gene was determined by a quantitative real-time PCR based assay,CCR5Δ32 was detected by a sizing PCR method,and a single-nucleotide polymorphism in CCR5-2459 was detected by restriction fragment length polymorphism PCR.RESULTS:No CCR5Δ32 mutation was detected in any of the individuals from China.Neither copy number variation nor polymorphism in CCR5-2459 was associated with post-transplant reinfection with hepatitis B virus.However,patients with fewer copies (<4) of the CCL3L1 gene compared with the population median in combination with the CCR5G allele had a significantly higher risk for recurrent hepatitis B (odds ratio=1.93,95% CI:1.00-3.69;P=0.047).CONCLUSION:Patients possessing the compound decreased functional genotype of both CCL3L1 and CCR5 genes might be more likely to have recurrence of hepatitis B after transplantation.展开更多
Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a ...Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a C-C chemokine receptor type 5 antagonist,has been viewed as a new therapeutic strategy for many neuroinflammatory diseases.We studied the effect of maraviroc on TBI-induced neuroinflammation.A moderate-TBI mouse model was subjected to a controlled cortical impact device.Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days.Western blot,immunohistochemistry,and TUNEL(terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI.Our results suggest that maraviroc administration reduced NACHT,LRR,and PYD domains-containing protein 3 inflammasome activation,modulated microglial polarization from M1 to M2,decreased neutrophil and macrophage infiltration,and inhibited the release of inflammatory factors after TBI.Moreover,maraviroc treatment decreased the activation of neurotoxic reactive astrocytes,which,in turn,exacerbated neuronal cell death.Additionally,we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score,rotarod test,Morris water maze test,and lesion volume measurements.In summary,our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI,and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.展开更多
The role of the transcription factor NF-κB in shaping the cancer microenvironment is becoming increasingly clear. Inflammation alters the activity of enzymes that modulate NF-κB function, and causes extensive change...The role of the transcription factor NF-κB in shaping the cancer microenvironment is becoming increasingly clear. Inflammation alters the activity of enzymes that modulate NF-κB function, and causes extensive changes in genomic chromatin that ultimately drastically alter cell-specific gene expression. NF-κB regulates the expression of cytokines and adhesion factors that control interactions among adjacent cells. As such, NF-κB fine tunes tissue cellular composition, as well as tissues' interactions with the immune system. Therefore, NF-κB changes the cell response to hormones and to contact with neighboring cells. Activating NF-κB confers transcriptional and phenotypic plasticity to a cell and thereby enables profound local changes in tissue function and composition. Research suggests that the regulation of NF-κB target genes is specifically altered in cancer. Such alterations occur not only due to mutations of NF-κB regulatory proteins, but also because of changes in the activity of specific proteostatic modules and metabolic pathways. This article describes the molecular mode of NF-κB regulation with a few characteristic examples of target genes.展开更多
Objective：To investigate the effects of curcumin on pain threshold and the expressions of nuclear factorκB（NF-κB）and CX3C chemokine receptor 1（CX3CR1）in spinal cord and dorsal root ganglion（DRG）of the rats wi...Objective：To investigate the effects of curcumin on pain threshold and the expressions of nuclear factorκB（NF-κB）and CX3C chemokine receptor 1（CX3CR1）in spinal cord and dorsal root ganglion（DRG）of the rats with sciatic nerve chronic constrictive injury.Methods：One hundred and twenty male Sprague Dawley rats,weighing 220-250 g,were randomly divided into 4 groups.Sham surgery（sham）group：the sciatic nerves of rats were only made apart but not ligated;chronic constrictive injury（CCI）group：the sciatic nerves of rats were only ligated without any drug treatment;curcumin treated injury（Cur）model group：the rats were administrated with curcumin 100 mg/（kg·d）by intraperitoneal injection for 14 days after CCI;solvent control（SC）group：the rats were administrated with the solvent at the same dose for 14 days after CCI.Thermal withdrawal latency（TWL）and mechanical withdrawal threshold（MWT）of rats were respectively measured on pre-operative day 2 and postoperative day 1,3,5,7,10 and 14.The lumbar segment L4-5 of the spinal cord and the L4,L5 DRG was removed at post-operative day 3,7 and 14.The change of nuclear factorκB（NF-κB）p65 expression was detected by Western blotting while the expression of CX3CR1 was determined by immunohistochemical staining.Results：Compared with the sham group,the TWL and MWT of rats in the CCI group were significantly decreased on each post-operative day（P〈0.01）,which reached a nadir on the 3rd day after CCI,and the expressions of NF-κB p65and CX3CR1 were markedly increased in spinal cord dorsal horn and DRG.In the Cur group,the TWL of rats were significantly increased than those in the CCI group on post-operative day 7,10 and 14（P〈0.05）and MWT increased than those in the CCI group on post-operative day 10 and 14（P〈0.05）.In addition,the administration of curcumin significantly decreased the positive expressions of NF-κB p65 and CX3CR1 in spinal cord and DRG（P〈0.05）.Conclusion：Our study suggests that curcumin could ameliorate the CCI-induced neuropathic pain,probably through inhibiting CX3CR1 expression by the activation of NF-k B p65 in spinal cord and DRG.展开更多
基金supported by grants from the National Basic Research Program of China (973 Program) (2009CB522403)the National S&T Major Project (2008ZX10002-026)
文摘BACKGROUND:The genetic diversity of chemokines and chemokine receptors has been associated with the outcome of hepatitis B virus infection.The aim of this study was to evaluate whether the copy number variation in the CCL3L1 gene and the polymorphisms of CCR5Δ32 and CCR5-2459A→G (rs1799987) are associated with recurrent hepatitis B in liver transplantation for hepatitis B virus infection-related end stage liver disease.METHODS:A total of 185 transplant recipients were enrolled in this study.The genomic DNA was extracted from whole blood,the copy number of the CCL3L1 gene was determined by a quantitative real-time PCR based assay,CCR5Δ32 was detected by a sizing PCR method,and a single-nucleotide polymorphism in CCR5-2459 was detected by restriction fragment length polymorphism PCR.RESULTS:No CCR5Δ32 mutation was detected in any of the individuals from China.Neither copy number variation nor polymorphism in CCR5-2459 was associated with post-transplant reinfection with hepatitis B virus.However,patients with fewer copies (<4) of the CCL3L1 gene compared with the population median in combination with the CCR5G allele had a significantly higher risk for recurrent hepatitis B (odds ratio=1.93,95% CI:1.00-3.69;P=0.047).CONCLUSION:Patients possessing the compound decreased functional genotype of both CCL3L1 and CCR5 genes might be more likely to have recurrence of hepatitis B after transplantation.
基金supported by grants from the National Natural Science Foundation of China, Nos. 81930031 (to JNZ), 81720108015 (to JNZ), 81901525 (to SZ), 82101440 (to DDS), 81801234 (to YZ) and 82071389 (to GLY)the Natural Science Foundation of Tianjin, Nos. 20JCQNJC01270 (to JWW), 20JCQNJC00460 (to GLY), 18JCQNJC81000 (to HTR)+4 种基金Scientific Research Project of Tianjin Education Commission (Natural Science), No. 2018KJ052 (to ZWZ)Tianjin Health and Health Committee Science and Technology Project, No. QN20015 (to JWW)the Science & Technology Development Fund of Tianjin Education Commission for Higher Education, No. 2016YD02 (to YW)Tianjin Key Science and Technology Projects of Innovative Drugs and Medical Devices, No. 19ZXYXSY00070 (to YW)the Clinical Research Fundation of Tianjin Medical University, No. 2018kylc002 (to YW)
文摘Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a C-C chemokine receptor type 5 antagonist,has been viewed as a new therapeutic strategy for many neuroinflammatory diseases.We studied the effect of maraviroc on TBI-induced neuroinflammation.A moderate-TBI mouse model was subjected to a controlled cortical impact device.Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days.Western blot,immunohistochemistry,and TUNEL(terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI.Our results suggest that maraviroc administration reduced NACHT,LRR,and PYD domains-containing protein 3 inflammasome activation,modulated microglial polarization from M1 to M2,decreased neutrophil and macrophage infiltration,and inhibited the release of inflammatory factors after TBI.Moreover,maraviroc treatment decreased the activation of neurotoxic reactive astrocytes,which,in turn,exacerbated neuronal cell death.Additionally,we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score,rotarod test,Morris water maze test,and lesion volume measurements.In summary,our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI,and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.
文摘The role of the transcription factor NF-κB in shaping the cancer microenvironment is becoming increasingly clear. Inflammation alters the activity of enzymes that modulate NF-κB function, and causes extensive changes in genomic chromatin that ultimately drastically alter cell-specific gene expression. NF-κB regulates the expression of cytokines and adhesion factors that control interactions among adjacent cells. As such, NF-κB fine tunes tissue cellular composition, as well as tissues' interactions with the immune system. Therefore, NF-κB changes the cell response to hormones and to contact with neighboring cells. Activating NF-κB confers transcriptional and phenotypic plasticity to a cell and thereby enables profound local changes in tissue function and composition. Research suggests that the regulation of NF-κB target genes is specifically altered in cancer. Such alterations occur not only due to mutations of NF-κB regulatory proteins, but also because of changes in the activity of specific proteostatic modules and metabolic pathways. This article describes the molecular mode of NF-κB regulation with a few characteristic examples of target genes.
基金Supported by National Natural Science Foundation of China(No.81073125)Natural Science Foundation of Zhejiang Province(No.Y2090252)International Cooperation Project of Wenzhou Science and Technology Bureau(No.H20070035)
文摘Objective：To investigate the effects of curcumin on pain threshold and the expressions of nuclear factorκB（NF-κB）and CX3C chemokine receptor 1（CX3CR1）in spinal cord and dorsal root ganglion（DRG）of the rats with sciatic nerve chronic constrictive injury.Methods：One hundred and twenty male Sprague Dawley rats,weighing 220-250 g,were randomly divided into 4 groups.Sham surgery（sham）group：the sciatic nerves of rats were only made apart but not ligated;chronic constrictive injury（CCI）group：the sciatic nerves of rats were only ligated without any drug treatment;curcumin treated injury（Cur）model group：the rats were administrated with curcumin 100 mg/（kg·d）by intraperitoneal injection for 14 days after CCI;solvent control（SC）group：the rats were administrated with the solvent at the same dose for 14 days after CCI.Thermal withdrawal latency（TWL）and mechanical withdrawal threshold（MWT）of rats were respectively measured on pre-operative day 2 and postoperative day 1,3,5,7,10 and 14.The lumbar segment L4-5 of the spinal cord and the L4,L5 DRG was removed at post-operative day 3,7 and 14.The change of nuclear factorκB（NF-κB）p65 expression was detected by Western blotting while the expression of CX3CR1 was determined by immunohistochemical staining.Results：Compared with the sham group,the TWL and MWT of rats in the CCI group were significantly decreased on each post-operative day（P〈0.01）,which reached a nadir on the 3rd day after CCI,and the expressions of NF-κB p65and CX3CR1 were markedly increased in spinal cord dorsal horn and DRG.In the Cur group,the TWL of rats were significantly increased than those in the CCI group on post-operative day 7,10 and 14（P〈0.05）and MWT increased than those in the CCI group on post-operative day 10 and 14（P〈0.05）.In addition,the administration of curcumin significantly decreased the positive expressions of NF-κB p65 and CX3CR1 in spinal cord and DRG（P〈0.05）.Conclusion：Our study suggests that curcumin could ameliorate the CCI-induced neuropathic pain,probably through inhibiting CX3CR1 expression by the activation of NF-k B p65 in spinal cord and DRG.
