C3 glomerulopathy is a disease including both dense deposit disease and C3 glomerulonephritis has an estimated prevalence of 2 to 3 per million. Originally, these pathologies were defined as glomerular pathology chara...C3 glomerulopathy is a disease including both dense deposit disease and C3 glomerulonephritis has an estimated prevalence of 2 to 3 per million. Originally, these pathologies were defined as glomerular pathology characterized by accumulation of C3 with absent or scanty immunoglobulin deposition. The keystone defect in both of these pathologies is the unregulated hyperactivity of alternative complement pathway. Specifically, in C3 glomerulopathy patients, there exists a prolongation of C3 cleavage which causes the uncontrolled alternative pathway activation. Many treatments have been investigated for treating C3 glomerulopathy to little or no avail, including calcineurin inhibitors, plasmapharesis, and anti-CD20 monoclonal antibodies. The next logical step is exploring the efficacy of anti-C5 monoclonal antibody therapy in C3 glomerulopathies to target the specific pathophysiology of this particular disease. Eculizumab is an anti-C5 monoclonal antibody that blocks the terminal step of complement activation. This drug has proven to be an effective treatment in other nephrologic pathologies that are caused by complement dysregulation. Here in this paper we discuss and present various case studies and clinical trials available that experiment with Eculizumab in patients with either dense deposit disease or C3 glomerulonephritis. In most of these patients, treatment with Eculizumab has demonstrated clinical and biochemical improvements in kidney function. These results provide encouraging evidence that suggest Eculizumab as a promising therapy for patients with C3 glomerulopathy and warrant that more extensive clinical trials can be designed as a next step.展开更多
Epilepsy is a brain condition characterized by the recurrence of unprovoked seizures.Recent studies have shown that complement component 3(C3)aggravate the neuronal injury in epilepsy.And our previous studies revealed...Epilepsy is a brain condition characterized by the recurrence of unprovoked seizures.Recent studies have shown that complement component 3(C3)aggravate the neuronal injury in epilepsy.And our previous studies revealed that TRPV1(transient receptor potential vanilloid type 1)is involved in epilepsy.Whether complement C3 regulation of neuronal injury is related to the activation of TRPV1 during epilepsy is not fully understood.We found that in a mouse model of status epilepticus(SE),complement C3 derived from astrocytes was increased and aggravated neuronal injury,and that TRPV 1-knockout rescued neurons from the injury induced by complement C3.Circular RNAs are abundant in the brain,and the reduction of circRad52 caused by complement C3 promoted the expression of TRPV 1 and exacerbated neuronal injury.Mechanistically,disorders of neuron-glia interaction mediated by the C3-TRPV1 signaling pathway may be important for the induction of neuronal injury.This study provides support for the hypothesis that the C3-TRFV1 pathway is involved in the prevention and treatment of neuronal injury and cognitive disorders.展开更多
Objective:Myeloma bone disease(MBD)is the most common complication of multiple myeloma(MM).Our previous study showed that the serum levels of C3/C4 in MM patients were significantly positively correlated with the seve...Objective:Myeloma bone disease(MBD)is the most common complication of multiple myeloma(MM).Our previous study showed that the serum levels of C3/C4 in MM patients were significantly positively correlated with the severity of bone disease.However,the mechanism of C3 a/C4 a in osteoclasts MM patients remains unclear.Methods:The formation and function of osteoclasts were analyzed after adding C3 a/C4 a in vitro.RNA-seq analysis was used to screen the potential pathways affecting osteoclasts,and the results were verified by Western blot,q RT-PCR,and pathway inhibitors.Results:The osteoclast area per view induced by 1μg/m L(mean±SD:50.828±12.984%)and 10μg/m L(53.663±12.685%)of C3 a was significantly increased compared to the control group(0μg/m L)(34.635±8.916%)(P<0.001 and P<0.001,respectively).The relative m RNA expressions of genes,OSCAR/TRAP/RANKL/cathepsin K,induced by 1μg/m L(median:5.041,3.726,1.638,and 4.752,respectively)and 10μg/m L(median:5.140,3.702,2.250,and 5.172,respectively)of C3 a was significantly increased compared to the control group(median:3.137,2.004,0.573,and 2.257,respectively)(1μg/m L P=0.001,P=0.003,P<0.001,and P=0.008,respectively;10μg/m L:P<0.001,P=0.019,P<0.001,and P=0.002,respectively).The absorption areas of the osteoclast resorption pits per view induced by 1μg/m L(mean±SD:51.464±11.983%)and 10μg/m L(50.219±12.067%)of C3 a was also significantly increased(33.845±8.331%)(P<0.001 and P<0.001,respectively)compared to the control.There was no difference between the C4 a and control groups.RNA-seq analysis showed that C3 a promoted the proliferation of osteoclasts using the phosphoinositide 3-kinase(PI3 K)signaling pathway.The relative expressions of PIK3 CA/phosphoinositide dependent kinase-1(PDK1)/serum and glucocorticoid inducible protein kinases(SGK3)genes and PI3 K/PDK1/p-SGK3 protein in the C3 a group were significantly higher than in the control group.The activation role of C3 a in osteoclasts of MM patients was reduced by the SGK inhibitor(EMD638683).Conclusions:C3 a activated osteoclasts by regulating the PI3 K/PDK1/SGK3 pathways in MM patients,which was reduced using a SGK inhibitor.Overall,our results identified potential therapeutic targets and strategies for MBD patients。展开更多
A major portion of the beneficial effect of mesenchymal stem cells (MSC) is due to the production of trophic and angiogenic factors by these cells, and one of the efforts to improve the therapeutic efficacy of these c...A major portion of the beneficial effect of mesenchymal stem cells (MSC) is due to the production of trophic and angiogenic factors by these cells, and one of the efforts to improve the therapeutic efficacy of these cells lies in enhancing this capacity. Since there is complement activation in all areas of tissue injury, and both C3a and C5a activate MSC, it was asked whether stimulation with C3a or C5a would upregulate the production of trophic factors by MSC. C3a caused significant up-regulation of various angiogenic factors, including VEGF, CXCL8/IL-8 and IL-6. In contrast there was no detectable production of the pro-inflammatory cytokines TNF-α and IL-1β in spite of nuclear translocation of NFκB. Although C5a also caused moderate up-regulation of angiogenic factors, the effect was borderline significant. Furthermore the production of angiogenic factors induced by C3a was of physiological relevance: Supernatants of MSCs cultured under serum-free conditions induced minimal tube formation of HUVECs as an in vitro measure of angiogenesis;tube formation was considerably enhanced, when supernatants from C3a-stimulated MSC were used, while C3a itself had no direct angiogenic effect on HUVECs. The signaling cascade responsible for the production of angiogenic factors by C3a or C5a could be defined as activation of the rho cascade which was necessary for nuclear translocation of NFκB p65 and of phospho-ERK1/2. Although rho was only transiently activated, inhibition of the rho or “downstream of it” of the NFκB pathway, prevented C3a-and C5a-induced up-regulation of angiogenic factors.展开更多
The recurrence of renal disease after renal transplantation is becoming one of the main causes of graft loss afterkidney transplantation. This principally concerns some of the original diseases as the atypical hemolyt...The recurrence of renal disease after renal transplantation is becoming one of the main causes of graft loss afterkidney transplantation. This principally concerns some of the original diseases as the atypical hemolytic uremic syndrome(HUS), the membranoproliferative glomerulonephritis(MPGN), in particular the MPGN now called C3 glomerulopathy. Both this groups of renal diseases are characterized by congenital(genetic) or acquired(autoantibodies) modifications of the alternative pathway of complement. These abnormalities often remain after transplantation because they are constitutional and poorly influenced by the immunosuppression. This fact justifies the high recurrence rate of these diseases. Early diagnosis of recurrence is essential for an optimal therapeutically approach, whenever possible. Patients affected by end stage renal disease due to C3 glomerulopathies or to atypical HUS, may be transplanted with extreme caution. Living donor donation from relatives is not recommended because members of the same family may be affected by the same gene mutation. Different therapeutically approaches have been attempted either for recurrence prevention and treatment. The most promising approach is represented by complement inhibitors. Eculizumab, a monoclonal antibody against C5 convertase is the most promising drug, even if to date is not known how long the therapy should be continued and which are the best dosing. These facts face the high costs of the treatment. Eculizumab resistant patients have been described. They could benefit by a C3 convertase inhibitor, but this class of drugs is by now the object of randomized controlled trials.展开更多
The innate immune response is a complex process involving multiple pathogen-recognition receptors, including toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors. Complement is...The innate immune response is a complex process involving multiple pathogen-recognition receptors, including toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors. Complement is also a critical component of innate immunity. While complement is known to interact with TLR-mediated signals, the interactions between NOD-like receptors and complement are not well understood. Here we report a synergistic interaction between C5a and Nod2 signaling in RAW 264.7 marophages. Long-term treatment with muramyl dipeptide (MDP), a NOD2 ligand, enhanced C5a-mediated expression of chemokine mRNAs in RAW 264.7 cells. This response was dependent on NOD2 expression and was associated with a decrease in expression of C5L2, a receptor for C5a which acts as a negative modulator of C5a receptor (C5aR) activity. MDP amplified C5a-mediated phosphorylation of p38 MAPK. Treatment of RAW264.7 cells with an inhibitor of p38 attenuated the synergistic effects of C5aon MDP-primed cells on MIP-2, but not MCP-1, mRNA. In contrast, inhibition of AKT prevented C5a stimulation of MCP-1, but not MIP-2, mRNA, in MDP-primed cells. Taken together, these data demonstrated a synergistic interaction between C5a and NOD2 in the regulation of chemokine expression in macrophages, associated with a down-regulation of C5L2, a negative regulator of C5a receptor activity.展开更多
A plant material consisted by Family Poaceae was fermented by Yeast and Lactobaccilli (U-164). This material was proved by as safe in animal safety experiment for oral administration. In order to prove the effect of U...A plant material consisted by Family Poaceae was fermented by Yeast and Lactobaccilli (U-164). This material was proved by as safe in animal safety experiment for oral administration. In order to prove the effect of U-164 against physiological function, the animal and human trials were set up to look into mainly leukocyte functions. In animal experiment, anti-oxidative effect and antibody response in immune-compromised host and diabetes meritus were made up. For human use, peripheral lymphocyte in number and subset ratio were followed up to one month after administration. In order to understand its effect, human complement component analysis was made by immune-electrophoresis. Our results showed that U-164 augmented the level of lymphocytes, while U-164 down regulated the level of granulocytes. In our clinical study with 19 healthy volunteers, granulocyte and lymphocyte ratio was obtained as neutral in peripheral blood being increased significantly 30 days after the ingestion of U-164. In experimental animal study, the compromised host as well as normal animal was administered with cancer chemotherapeutic agent (Mytomycin-C). Our observations showed against antibody producing cell, this material recovered the antibody production in the host compromising the immure responsiveness. We also proposed an idea that U-164 exhibited tonic effects via activating complement components. Moreover, we tried to access further to the anti-oxidative activities of this U-164. This modification brought to the significant lifted up for anti-oxidative activity for phagocytic cell.展开更多
BACKGROUND C3 glomerulopathies(C3G)are a rare cause of kidney failure resulting from complement dysregulation.Small studies demonstrate a high rate of recurrence and poor outcomes in kidney transplantation.Treatment e...BACKGROUND C3 glomerulopathies(C3G)are a rare cause of kidney failure resulting from complement dysregulation.Small studies demonstrate a high rate of recurrence and poor outcomes in kidney transplantation.Treatment efficacy in this setting with eculizumab,a terminal complement inhibitor,is largely unknown.AIM To determine the outcomes of kidney transplantation in patients with C3G and the potential impact of eculizumab.METHODS We retrospectively studied kidney transplant recipients who underwent a post-transplant biopsy confirming C3G between January 1,1993 and December 31,2023 at a single center.Only the first episode of kidney transplant was reviewed.The electronic medical records were reviewed for post-transplant allograft function,indication for biopsy,time to biopsy from transplant,time to allograft failure from transplantation,post-C3G treatment,complement laboratory testing,and concurrent malignancy/infection.Reports,and when available slides and immunofluorescence/electron microscopic images,were re-reviewed by a renal pathologist.RESULTS A total of fifteen patients were included in this study.Fourteen patients had suspected recurrent disease,with a pre-transplant native kidney report of C3G.One patient developed de novo C3G.Median post kidney transplant clinical follow up time was 91 months.Median time to recurrence was 7 months with median graft survival of 48 months post kidney transplantation.The most common index biopsy pattern of injury was endocapillary prolif-erative glomerulonephritis(often with exudative features)with or without mesangial hypercellularity(56%)followed by membranoproliferative glomerulonephritis(25%).Most patients developed membranoproliferative glomerulonephritis pattern of injury on follow up biopsies(63%).Seven patients with recurrent disease received treatment with eculizumab with a median graft survival of 73 months,with five functioning grafts by the end of the study period.Seven patients with recurrent disease did not receive therapy,and all lost their graft with a median graft survival of 22 months(P=0.003).CONCLUSION C3G following kidney transplantation is mostly a recurrent disorder with a poor prognosis in untreated patients.Untreated recurrence has a poor prognosis with median allograft survival<2 years.Early treatment with eculizumab may improve transplant outcomes in patients with recurrent C3G.展开更多
目的观察针药并用对子宫内膜异位症疼痛大鼠CLEC5A、NLRP3和IL-1β表达的影响,探讨针药并用缓解子宫内膜异位症疼痛的作用机制。方法从48只大鼠随机选取8只进行假手术作为假手术组,剩余40只进行子宫内膜异位症造模,模型建立后根据异位...目的观察针药并用对子宫内膜异位症疼痛大鼠CLEC5A、NLRP3和IL-1β表达的影响,探讨针药并用缓解子宫内膜异位症疼痛的作用机制。方法从48只大鼠随机选取8只进行假手术作为假手术组,剩余40只进行子宫内膜异位症造模,模型建立后根据异位囊肿总体积再区组随机分为模型组、布洛芬组、针灸组、中药组和针药组,每组8只。假手术组、模型组固定并给予等量0.9%生理盐水灌胃,布洛芬组固定并给予布洛芬和0.9%生理盐水混悬液灌胃,针灸组给于固定针灸干预,中药组固定并给予加味没竭片和0.9%生理盐水混悬液灌胃,针药组给予固定针灸和加味没竭片0.9%生理盐水混悬液灌胃。造模后和干预后测量并计算子宫内膜异位症大鼠异位囊肿体积,并测量6组大鼠痛阈。干预后检测6组内膜组织C型凝集素结构域家族5成员A(C-type lectin domain family 5 member A,CLEC5A)、NLR家族Pyrin域蛋白3(NOD-like receptor family pyrin domain containing protein 3,NLRP3)、白细胞介素-1β(interleukin 1β,IL-1β)蛋白和m RNA表达水平。结果针灸组、针药组干预后异位囊肿体积减少值和痛阈增加值均优于模型组(P<0.05)。模型组在位及异位内膜组织中CLEC5A、NLRP3、IL-1β蛋白表达水平高于正常子宫内膜组织(P<0.05)。针灸组、针药组在位及异位内膜组织中CLEC5A和NLRP3蛋白表达水平及异位内膜组织中IL-1β蛋白表达水平低于模型组(P<0.05),针灸组在位内膜IL-1β表达显著低于模型组(P<0.05)。针药组在位内膜组织CLEC5A蛋白表达水平低于布洛芬组和中药组(P<0.05),NLRP3蛋白表达水平低于布洛芬组(P<0.05);异位内膜组织CLEC5A蛋白表达水平低于针灸组、布洛芬组和中药组(P<0.05),NLRP3蛋白表达水平低于布洛芬组和中药组(P<0.05),IL-1β蛋白表达水平显著低于布洛芬组(P<0.05)。模型组在位和异位内膜CLEC5A m RNA水平高于假手术组子宫内膜(P<0.05),模型组在位内膜IL-1βm RNA水平显著高于假手术组子宫内膜(P<0.05)。布洛芬组、针灸组、中药组和针药组异位内膜CLEC5A m RNA水平低于模型组(P<0.05);中药组异位内膜NLRP3、IL-1βm RNA水平低于模型组(P<0.05)。结论针药并用可能通过下调在位及异位内膜组织中CLEC5A m RNA及蛋白表达,调节NLRP3、IL-1β蛋白表达水平,缩小异位囊肿体积,提高痛阈,进而缓解大鼠子宫内膜异位症疼痛。展开更多
Lipid-coated perfluorocarbon nanodroplets(lp-NDs)hold great promise in bio-medicine as vehicles for drug delivery,molecular imaging and vaccine agents.However,their clinical utility is restricted by limited targeted a...Lipid-coated perfluorocarbon nanodroplets(lp-NDs)hold great promise in bio-medicine as vehicles for drug delivery,molecular imaging and vaccine agents.However,their clinical utility is restricted by limited targeted accumulation,attributed to the innate immune system(IIS),which acts as the initial defense mechanism in humans.This study aimed to optimize lp-ND formulations to mini-mize non-specific clearance by the IIS.Ginsenosides(Gs),the principal components of Panax ginseng,possessing complement inhibition ability,structural similarity to cholesterol,and comparable fat solubi-lity to phospholipids,were used as promising candidate IIS inhibitors.Two different types of ginsenoside-based Ip-NDs(Gs Ip-NDs)were created,and their efficacy in reducing IS recognition was examined.The Gs p-NDs were observed to inhibit the adsorption of C3 in the protein corona(PC)and the generation of SC5b-9.Adding Gs to Ip-NDs reduced complement adsorption and phagocytosis,resulting in a longer blood circulation time in vivo compared to lp-NDs that did not contain Gs.These results suggest that Gs can act as anti-complement and anti-phagocytosis adjuvants,potentially reducing non-specific clear-ance by the IS and improving lifespan.展开更多
文摘C3 glomerulopathy is a disease including both dense deposit disease and C3 glomerulonephritis has an estimated prevalence of 2 to 3 per million. Originally, these pathologies were defined as glomerular pathology characterized by accumulation of C3 with absent or scanty immunoglobulin deposition. The keystone defect in both of these pathologies is the unregulated hyperactivity of alternative complement pathway. Specifically, in C3 glomerulopathy patients, there exists a prolongation of C3 cleavage which causes the uncontrolled alternative pathway activation. Many treatments have been investigated for treating C3 glomerulopathy to little or no avail, including calcineurin inhibitors, plasmapharesis, and anti-CD20 monoclonal antibodies. The next logical step is exploring the efficacy of anti-C5 monoclonal antibody therapy in C3 glomerulopathies to target the specific pathophysiology of this particular disease. Eculizumab is an anti-C5 monoclonal antibody that blocks the terminal step of complement activation. This drug has proven to be an effective treatment in other nephrologic pathologies that are caused by complement dysregulation. Here in this paper we discuss and present various case studies and clinical trials available that experiment with Eculizumab in patients with either dense deposit disease or C3 glomerulonephritis. In most of these patients, treatment with Eculizumab has demonstrated clinical and biochemical improvements in kidney function. These results provide encouraging evidence that suggest Eculizumab as a promising therapy for patients with C3 glomerulopathy and warrant that more extensive clinical trials can be designed as a next step.
基金by the National Natural Science Foundation of China(81571481 and 82060588)the Natural Science Foundation of Hubei Province,China(2017CFA017)+1 种基金the Wuhan Science and Technology Project(2019020701011444)the Medical Science Advancement Program of Wuhan University(TFJC2018001 and TFLC2018001).
文摘Epilepsy is a brain condition characterized by the recurrence of unprovoked seizures.Recent studies have shown that complement component 3(C3)aggravate the neuronal injury in epilepsy.And our previous studies revealed that TRPV1(transient receptor potential vanilloid type 1)is involved in epilepsy.Whether complement C3 regulation of neuronal injury is related to the activation of TRPV1 during epilepsy is not fully understood.We found that in a mouse model of status epilepticus(SE),complement C3 derived from astrocytes was increased and aggravated neuronal injury,and that TRPV 1-knockout rescued neurons from the injury induced by complement C3.Circular RNAs are abundant in the brain,and the reduction of circRad52 caused by complement C3 promoted the expression of TRPV 1 and exacerbated neuronal injury.Mechanistically,disorders of neuron-glia interaction mediated by the C3-TRPV1 signaling pathway may be important for the induction of neuronal injury.This study provides support for the hypothesis that the C3-TRFV1 pathway is involved in the prevention and treatment of neuronal injury and cognitive disorders.
基金supported by the National Natural Science Foundation of China(Grant Nos.81770110,81900131,and 82000219)the Anticancer Major Special Project of Tianjin(Grant No.12ZCDZSY18000)+4 种基金the Tianjin Municipal Natural Science Foundation(Grant Nos.18JCYBJC27200 and 18JCQNJC80400)the Tianjin Education Commission Research Project(Grant Nos.2018KJ043 and 2018KJ045)the Tianjin Health and Family Planning Commission(Grant No.15KG150)the Youth Incubation Fund of Tianjin Medical University General Hospital(Grant No.ZYYFY2019020)the Tianjin Science and Technology Planning Project(Grant No.20YFZCSY00060)。
文摘Objective:Myeloma bone disease(MBD)is the most common complication of multiple myeloma(MM).Our previous study showed that the serum levels of C3/C4 in MM patients were significantly positively correlated with the severity of bone disease.However,the mechanism of C3 a/C4 a in osteoclasts MM patients remains unclear.Methods:The formation and function of osteoclasts were analyzed after adding C3 a/C4 a in vitro.RNA-seq analysis was used to screen the potential pathways affecting osteoclasts,and the results were verified by Western blot,q RT-PCR,and pathway inhibitors.Results:The osteoclast area per view induced by 1μg/m L(mean±SD:50.828±12.984%)and 10μg/m L(53.663±12.685%)of C3 a was significantly increased compared to the control group(0μg/m L)(34.635±8.916%)(P<0.001 and P<0.001,respectively).The relative m RNA expressions of genes,OSCAR/TRAP/RANKL/cathepsin K,induced by 1μg/m L(median:5.041,3.726,1.638,and 4.752,respectively)and 10μg/m L(median:5.140,3.702,2.250,and 5.172,respectively)of C3 a was significantly increased compared to the control group(median:3.137,2.004,0.573,and 2.257,respectively)(1μg/m L P=0.001,P=0.003,P<0.001,and P=0.008,respectively;10μg/m L:P<0.001,P=0.019,P<0.001,and P=0.002,respectively).The absorption areas of the osteoclast resorption pits per view induced by 1μg/m L(mean±SD:51.464±11.983%)and 10μg/m L(50.219±12.067%)of C3 a was also significantly increased(33.845±8.331%)(P<0.001 and P<0.001,respectively)compared to the control.There was no difference between the C4 a and control groups.RNA-seq analysis showed that C3 a promoted the proliferation of osteoclasts using the phosphoinositide 3-kinase(PI3 K)signaling pathway.The relative expressions of PIK3 CA/phosphoinositide dependent kinase-1(PDK1)/serum and glucocorticoid inducible protein kinases(SGK3)genes and PI3 K/PDK1/p-SGK3 protein in the C3 a group were significantly higher than in the control group.The activation role of C3 a in osteoclasts of MM patients was reduced by the SGK inhibitor(EMD638683).Conclusions:C3 a activated osteoclasts by regulating the PI3 K/PDK1/SGK3 pathways in MM patients,which was reduced using a SGK inhibitor.Overall,our results identified potential therapeutic targets and strategies for MBD patients。
文摘A major portion of the beneficial effect of mesenchymal stem cells (MSC) is due to the production of trophic and angiogenic factors by these cells, and one of the efforts to improve the therapeutic efficacy of these cells lies in enhancing this capacity. Since there is complement activation in all areas of tissue injury, and both C3a and C5a activate MSC, it was asked whether stimulation with C3a or C5a would upregulate the production of trophic factors by MSC. C3a caused significant up-regulation of various angiogenic factors, including VEGF, CXCL8/IL-8 and IL-6. In contrast there was no detectable production of the pro-inflammatory cytokines TNF-α and IL-1β in spite of nuclear translocation of NFκB. Although C5a also caused moderate up-regulation of angiogenic factors, the effect was borderline significant. Furthermore the production of angiogenic factors induced by C3a was of physiological relevance: Supernatants of MSCs cultured under serum-free conditions induced minimal tube formation of HUVECs as an in vitro measure of angiogenesis;tube formation was considerably enhanced, when supernatants from C3a-stimulated MSC were used, while C3a itself had no direct angiogenic effect on HUVECs. The signaling cascade responsible for the production of angiogenic factors by C3a or C5a could be defined as activation of the rho cascade which was necessary for nuclear translocation of NFκB p65 and of phospho-ERK1/2. Although rho was only transiently activated, inhibition of the rho or “downstream of it” of the NFκB pathway, prevented C3a-and C5a-induced up-regulation of angiogenic factors.
文摘The recurrence of renal disease after renal transplantation is becoming one of the main causes of graft loss afterkidney transplantation. This principally concerns some of the original diseases as the atypical hemolytic uremic syndrome(HUS), the membranoproliferative glomerulonephritis(MPGN), in particular the MPGN now called C3 glomerulopathy. Both this groups of renal diseases are characterized by congenital(genetic) or acquired(autoantibodies) modifications of the alternative pathway of complement. These abnormalities often remain after transplantation because they are constitutional and poorly influenced by the immunosuppression. This fact justifies the high recurrence rate of these diseases. Early diagnosis of recurrence is essential for an optimal therapeutically approach, whenever possible. Patients affected by end stage renal disease due to C3 glomerulopathies or to atypical HUS, may be transplanted with extreme caution. Living donor donation from relatives is not recommended because members of the same family may be affected by the same gene mutation. Different therapeutically approaches have been attempted either for recurrence prevention and treatment. The most promising approach is represented by complement inhibitors. Eculizumab, a monoclonal antibody against C5 convertase is the most promising drug, even if to date is not known how long the therapy should be continued and which are the best dosing. These facts face the high costs of the treatment. Eculizumab resistant patients have been described. They could benefit by a C3 convertase inhibitor, but this class of drugs is by now the object of randomized controlled trials.
文摘The innate immune response is a complex process involving multiple pathogen-recognition receptors, including toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors. Complement is also a critical component of innate immunity. While complement is known to interact with TLR-mediated signals, the interactions between NOD-like receptors and complement are not well understood. Here we report a synergistic interaction between C5a and Nod2 signaling in RAW 264.7 marophages. Long-term treatment with muramyl dipeptide (MDP), a NOD2 ligand, enhanced C5a-mediated expression of chemokine mRNAs in RAW 264.7 cells. This response was dependent on NOD2 expression and was associated with a decrease in expression of C5L2, a receptor for C5a which acts as a negative modulator of C5a receptor (C5aR) activity. MDP amplified C5a-mediated phosphorylation of p38 MAPK. Treatment of RAW264.7 cells with an inhibitor of p38 attenuated the synergistic effects of C5aon MDP-primed cells on MIP-2, but not MCP-1, mRNA. In contrast, inhibition of AKT prevented C5a stimulation of MCP-1, but not MIP-2, mRNA, in MDP-primed cells. Taken together, these data demonstrated a synergistic interaction between C5a and NOD2 in the regulation of chemokine expression in macrophages, associated with a down-regulation of C5L2, a negative regulator of C5a receptor activity.
文摘A plant material consisted by Family Poaceae was fermented by Yeast and Lactobaccilli (U-164). This material was proved by as safe in animal safety experiment for oral administration. In order to prove the effect of U-164 against physiological function, the animal and human trials were set up to look into mainly leukocyte functions. In animal experiment, anti-oxidative effect and antibody response in immune-compromised host and diabetes meritus were made up. For human use, peripheral lymphocyte in number and subset ratio were followed up to one month after administration. In order to understand its effect, human complement component analysis was made by immune-electrophoresis. Our results showed that U-164 augmented the level of lymphocytes, while U-164 down regulated the level of granulocytes. In our clinical study with 19 healthy volunteers, granulocyte and lymphocyte ratio was obtained as neutral in peripheral blood being increased significantly 30 days after the ingestion of U-164. In experimental animal study, the compromised host as well as normal animal was administered with cancer chemotherapeutic agent (Mytomycin-C). Our observations showed against antibody producing cell, this material recovered the antibody production in the host compromising the immure responsiveness. We also proposed an idea that U-164 exhibited tonic effects via activating complement components. Moreover, we tried to access further to the anti-oxidative activities of this U-164. This modification brought to the significant lifted up for anti-oxidative activity for phagocytic cell.
文摘BACKGROUND C3 glomerulopathies(C3G)are a rare cause of kidney failure resulting from complement dysregulation.Small studies demonstrate a high rate of recurrence and poor outcomes in kidney transplantation.Treatment efficacy in this setting with eculizumab,a terminal complement inhibitor,is largely unknown.AIM To determine the outcomes of kidney transplantation in patients with C3G and the potential impact of eculizumab.METHODS We retrospectively studied kidney transplant recipients who underwent a post-transplant biopsy confirming C3G between January 1,1993 and December 31,2023 at a single center.Only the first episode of kidney transplant was reviewed.The electronic medical records were reviewed for post-transplant allograft function,indication for biopsy,time to biopsy from transplant,time to allograft failure from transplantation,post-C3G treatment,complement laboratory testing,and concurrent malignancy/infection.Reports,and when available slides and immunofluorescence/electron microscopic images,were re-reviewed by a renal pathologist.RESULTS A total of fifteen patients were included in this study.Fourteen patients had suspected recurrent disease,with a pre-transplant native kidney report of C3G.One patient developed de novo C3G.Median post kidney transplant clinical follow up time was 91 months.Median time to recurrence was 7 months with median graft survival of 48 months post kidney transplantation.The most common index biopsy pattern of injury was endocapillary prolif-erative glomerulonephritis(often with exudative features)with or without mesangial hypercellularity(56%)followed by membranoproliferative glomerulonephritis(25%).Most patients developed membranoproliferative glomerulonephritis pattern of injury on follow up biopsies(63%).Seven patients with recurrent disease received treatment with eculizumab with a median graft survival of 73 months,with five functioning grafts by the end of the study period.Seven patients with recurrent disease did not receive therapy,and all lost their graft with a median graft survival of 22 months(P=0.003).CONCLUSION C3G following kidney transplantation is mostly a recurrent disorder with a poor prognosis in untreated patients.Untreated recurrence has a poor prognosis with median allograft survival<2 years.Early treatment with eculizumab may improve transplant outcomes in patients with recurrent C3G.
文摘目的观察针药并用对子宫内膜异位症疼痛大鼠CLEC5A、NLRP3和IL-1β表达的影响,探讨针药并用缓解子宫内膜异位症疼痛的作用机制。方法从48只大鼠随机选取8只进行假手术作为假手术组,剩余40只进行子宫内膜异位症造模,模型建立后根据异位囊肿总体积再区组随机分为模型组、布洛芬组、针灸组、中药组和针药组,每组8只。假手术组、模型组固定并给予等量0.9%生理盐水灌胃,布洛芬组固定并给予布洛芬和0.9%生理盐水混悬液灌胃,针灸组给于固定针灸干预,中药组固定并给予加味没竭片和0.9%生理盐水混悬液灌胃,针药组给予固定针灸和加味没竭片0.9%生理盐水混悬液灌胃。造模后和干预后测量并计算子宫内膜异位症大鼠异位囊肿体积,并测量6组大鼠痛阈。干预后检测6组内膜组织C型凝集素结构域家族5成员A(C-type lectin domain family 5 member A,CLEC5A)、NLR家族Pyrin域蛋白3(NOD-like receptor family pyrin domain containing protein 3,NLRP3)、白细胞介素-1β(interleukin 1β,IL-1β)蛋白和m RNA表达水平。结果针灸组、针药组干预后异位囊肿体积减少值和痛阈增加值均优于模型组(P<0.05)。模型组在位及异位内膜组织中CLEC5A、NLRP3、IL-1β蛋白表达水平高于正常子宫内膜组织(P<0.05)。针灸组、针药组在位及异位内膜组织中CLEC5A和NLRP3蛋白表达水平及异位内膜组织中IL-1β蛋白表达水平低于模型组(P<0.05),针灸组在位内膜IL-1β表达显著低于模型组(P<0.05)。针药组在位内膜组织CLEC5A蛋白表达水平低于布洛芬组和中药组(P<0.05),NLRP3蛋白表达水平低于布洛芬组(P<0.05);异位内膜组织CLEC5A蛋白表达水平低于针灸组、布洛芬组和中药组(P<0.05),NLRP3蛋白表达水平低于布洛芬组和中药组(P<0.05),IL-1β蛋白表达水平显著低于布洛芬组(P<0.05)。模型组在位和异位内膜CLEC5A m RNA水平高于假手术组子宫内膜(P<0.05),模型组在位内膜IL-1βm RNA水平显著高于假手术组子宫内膜(P<0.05)。布洛芬组、针灸组、中药组和针药组异位内膜CLEC5A m RNA水平低于模型组(P<0.05);中药组异位内膜NLRP3、IL-1βm RNA水平低于模型组(P<0.05)。结论针药并用可能通过下调在位及异位内膜组织中CLEC5A m RNA及蛋白表达,调节NLRP3、IL-1β蛋白表达水平,缩小异位囊肿体积,提高痛阈,进而缓解大鼠子宫内膜异位症疼痛。
基金This work was supported by the National Natural Science Foundation for Young Scholars of China(82302199)the National Science Foundation of China(82371977,82071940)the Medical Research Project of Chengdu Municipal Health Commission(2021017,2022338,China).
文摘Lipid-coated perfluorocarbon nanodroplets(lp-NDs)hold great promise in bio-medicine as vehicles for drug delivery,molecular imaging and vaccine agents.However,their clinical utility is restricted by limited targeted accumulation,attributed to the innate immune system(IIS),which acts as the initial defense mechanism in humans.This study aimed to optimize lp-ND formulations to mini-mize non-specific clearance by the IIS.Ginsenosides(Gs),the principal components of Panax ginseng,possessing complement inhibition ability,structural similarity to cholesterol,and comparable fat solubi-lity to phospholipids,were used as promising candidate IIS inhibitors.Two different types of ginsenoside-based Ip-NDs(Gs Ip-NDs)were created,and their efficacy in reducing IS recognition was examined.The Gs p-NDs were observed to inhibit the adsorption of C3 in the protein corona(PC)and the generation of SC5b-9.Adding Gs to Ip-NDs reduced complement adsorption and phagocytosis,resulting in a longer blood circulation time in vivo compared to lp-NDs that did not contain Gs.These results suggest that Gs can act as anti-complement and anti-phagocytosis adjuvants,potentially reducing non-specific clear-ance by the IS and improving lifespan.
