BACKGROUND： Certain components of tetramethylpyrazine, a traditional Chinese medicine, exhibit protective effects against brain injury. OBJECTIVE： To investigate the effects of different Naoxintong doses on expressi...BACKGROUND： Certain components of tetramethylpyrazine, a traditional Chinese medicine, exhibit protective effects against brain injury. OBJECTIVE： To investigate the effects of different Naoxintong doses on expression of nuclear factor-kappa B （ kB）, interleukin-6, tumor necrosis factor-α, and complement 3 in rats following focal cerebral ischemia. DESIGN, TIME AND SETTING： The randomized experiment was performed at the Laboratory of Neurology, Second Hospital of Hebei Medical University from June 2004 to June 2006. MATERIALS： A total of 150 adult, healthy, male, Sprague Dawley rats, weighing 280-320g, were selected. Naoxintong powder （mainly comprising szechwan lovage rhizome, milkvetch root, danshen root, and radix angelicae sinensis） was obtained from Buchang Pharmacy Co., Ltd. in Xianyang City of Shanxi Province of China, lot number 040608. METHODS： The rats were randomly assigned into sham operation, saline, high-dose Naoxintong, moderate-dose Naoxintong, and low-dose Naoxintong groups, with 30 rats in each group. Rat models of middle cerebral artery occlusion were established using the suture method, with the exception of the sham operation group. Rats in the high-dose, moderate-dose and low-dose Naoxintong groups received 4, 2, and 1 g/kg Naoxintong respectively, by gavage. Rats in the saline group were treated with 1 mL saline by gavage All rats were administered by gavage at 5 and 23 hours following surgery, and subsequently, once per day. MAIN OUTCOME MEASURES： At 6, 24, 48, 72 hours, and 7 days following model establishment, brain water content was measured. Histopathological changes in brain tissues were detected using hematoxylin-eosin staining. Expression of nuclear factor- kB, interleukin-6, tumor necrosis factor- α, and complement 3 was examined by immunohistochemistry. RESULTS： A total of 150 rats were included in the final analysis with no loss. Brain water content was significantly increased in the ischemic hemisphere of rats from the saline, as well as the high-dose, moderate-dose, and low-dose Naoxintong groups at 24 hours, which reached a peak at 48 hours. At 6, 24, 48, 72 hours, and 7 days, brain water content was greater in the ischemic hemisphere of rats from the saline, as well as the high-dose, moderate-dose, and low-dose Naoxintong groups, compared with the sham operation group （P 〈 0.05）. At 24 and 48 hours, brain water content was reduced in the high-dose and moderate-dose Naoxintong groups, compared to the saline and low-dose Naoxintong groups （P 〈 0.05）. In the saline, as well as high-dose, moderate-dose, and low-dose Naoxintong groups, neuronal edema was observed at 6 hours surrounding the ischemic sites. Inflammatory cells appeared at 24 hours, reached a peak at 48 hours, and gradually diminished. A small amount of glial cell proliferation and neuronal degeneration were observed in the hippocampus at 72 hours following infarction. Microglial proliferation and aggregation were detected at 7 days after infarction. Expression of nuclear factor- kB, interleukin-6, tumor necrosis factor-α, and complement 3 was significantly less in the high-dose, moderate-dose, and low-dose Naoxintong groups, compared to the sham operation group （P 〈 0.05）. Expression of the above-mentioned inflammatory cytokines was lower in rat brain tissues of the high-dose Naoxintong group, compared to the low-dose Naoxintong group （P 〈 0.05）. CONCLUSION： High-dose Naoxintong and moderate-dose Naoxintong significantly alleviated rat brain edema and decreased expression of nuclear factor-kB, interleukin-6, tumor necrosis factor-α, and complement 3 in brain tissues. The protective effect of high-dose Naoxintong was most significant.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
AIM: To help clarifying the possibility of connective-tissue diseases in men with penile or testicular prostheses. METHODS: Eight patients underwent inflatable penile prostheses and 15, testicular prostheses consented...AIM: To help clarifying the possibility of connective-tissue diseases in men with penile or testicular prostheses. METHODS: Eight patients underwent inflatable penile prostheses and 15, testicular prostheses consented to the study. Their medical records were reviewed and a follow-up interview and physical and serological examinations were performed. RESULTS: In patients with penile prostheses, there was no abnormal antinuclear antibody (ANA) or IgM elevation. The serum levels of the rheumatoid factor (RF), C4, IgA and IgG were abnormal in one patient, and the levels of erythrocyte sedimentation rate (ESR) and C3, abnormal in two. Four had elevated IgE. In patients with testicular prostheses, there was no abnormal RF, ANA or IgM. The serum levels of ESR and IgA were abnormal in two, and three had abnormal C4, ten abnormal C3, and eleven decreased IgG. All had increased IgE. Men with penile prostheses had higher serum levels of IgG and IgM than those with testicular prostheses (P=0.001, P=0.016, respectively). The rates of abnormal values of IgE and IgG were higher in men with testicular prostheses than in men with penile prostheses (P=0.008, P=0.009, respectively). Physical examination was normal in all patients and nobody had documented symptoms pertinent to connective-tissue diseases. CONCLUSION: Our findings suggest that the risk of connective-tissue diseases is not higher in patients wearing prostheses as the ANA is negative and there is no apparent manifestation suggestive of connective-tissue diseases.展开更多
BACKGROUND Previous publications indicated that genetic predisposition might play important roles in the onset of osteonecrosis of the femoral head(ONFH)in systemic lupus erythematosus(SLE).Some gene loci such as comp...BACKGROUND Previous publications indicated that genetic predisposition might play important roles in the onset of osteonecrosis of the femoral head(ONFH)in systemic lupus erythematosus(SLE).Some gene loci such as complement C3d receptor 2(CR2),nitric oxide synthase 3(NOS3),collagen type II alpha 1 chain(COL2A1),protein tyrosine phosphatase non-receptor type 22(PTPN22),and transient receptor potential cation channel subfamily V member 4(TRPV4)were reported to be involved in this process.AIM To investigate whether the risk of ONFH in SLE is associated with single nucleotide variations(SNVs)in these five genes.METHODS SNVs in the CR2,NOS3,COL2A1,PTPN22,and TRPV4 genes were examined by using FastTarget and Illumina Miseq sequencing technologies in 49 cases of SLE with ONFH.Burrows–wheeler aligner was used to align the sequencing reads to hg19,and GATK and Varscan programs were used to perform SNV calling.PolyPhen-2,SIFT,and MutationTaster were used to assess the functional effects of non-synonymous SNVs.RESULTS Six of the 49 patients were confirmed to have low frequency SNVs,including one patient with SNVs in NOS3(exon 6:c.814G>A:p.E272K and exon 7:c.814G>A:p.E272K.),four in COL2A1(rs41263847:exon 29:c.1913C>T:p.T638I,exon 28:c.1706C>T:p.T569I,and rs371445823:exon 8:c.580G>A:p.A194T,exon 7:c.373G>A:p.A125T),and one in CR2(rs45573035:exon 2:c.200C>G:p.T67S).CONCLUSION The onset of ONFH in SLE might be associated with the identified SNVs in NOS3,COL2A1,and CR2.展开更多
Combined liver and kidney transplantation(CLKT)is indicated in patients with failure of both organs,or for the treatment of end-stage chronic kidney disease(ESKD)caused by a genetic defect in the liver.The aim of the ...Combined liver and kidney transplantation(CLKT)is indicated in patients with failure of both organs,or for the treatment of end-stage chronic kidney disease(ESKD)caused by a genetic defect in the liver.The aim of the present review is to provide the most up-to-date overview of the rare conditions as indications for CLKT.They are major indications for CLKT in children.However,in some of them(e.g.,atypical hemolytic uremic syndrome or primary hyperoxaluria),CLKT may be required in adults as well.Primary hyperoxaluria is divided into three types,of which type 1 and 2 lead to ESKD.CLKT has been proven effective in renal function replacement,at the same time preventing recurrence of the disease.Nephronophthisis is associated with liver fibrosis in 5%of cases and these patients are candidates for CLKT.In alpha 1-antitrypsin deficiency,hereditary C3 deficiency,lecithin cholesterol acyltransferase deficiency and glycogen storage diseases,glomerular or tubulointerstitial disease can lead to chronic kidney disease.Liver transplantation as a part of CLKT corrects underlying genetic and consequent metabolic abnormality.In atypical hemolytic uremic syndrome caused by mutations in the genes for factor H,successful CLKT has been reported in a small number of patients.However,for this indication,CLKT has been largely replaced by eculizumab,an anti-C5 antibody.CLKT has been well established to provide immune protection of the transplanted kidney against donor-specific antibodies against class I HLA,facilitating transplantation in a highly sensitized recipient.展开更多
Invasive fungal infections are life-threatening,and neutrophils are vital cells of the innate immune system that defend against them.The role of LTA4H-LTB_(4)-BLT1 axis in regulation of neutrophil responses to fungal ...Invasive fungal infections are life-threatening,and neutrophils are vital cells of the innate immune system that defend against them.The role of LTA4H-LTB_(4)-BLT1 axis in regulation of neutrophil responses to fungal infection remains poorly understood.Here,we demonstrated that the LTA4H-LTB_(4)-BLT1 axis protects the host against Candida albicans and Aspergillus fumigatus,but not Cryptococcus neoformans infection,by regulating the antifungal activity of neutrophils.Our results show that deleting Lta4h or Blt1 substantially impairs the fungal-specific phagocytic capacity of neutrophils.Moreover,defective activation of the spleen tyrosine kinase(Syk)and extracellular signal-related kinase(ERK1/2)pathways in neutrophils accompanies this impairment.Mechanistically,BLT1 regulates CR3-mediated,β-1,3-glucan-induced neutrophil phagocytosis,while a physical interaction with CR3 with slight influence on its dynamics is observed.Our findings thus demonstrate that the LTA4H-LTB_(4)-BLT1 axis is essential for the phagocytic function of neutrophils in host antifungal immune response against Candida albicans and Aspergillus fumigatus.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
Background Graves＇ ophthalmopathy/orbitopathy （GO） patients often suffer ocular surface damages and tear fluid proteins play a significant role in maintaining healthy ocular surfaces,while changes in tear protein c...Background Graves＇ ophthalmopathy/orbitopathy （GO） patients often suffer ocular surface damages and tear fluid proteins play a significant role in maintaining healthy ocular surfaces,while changes in tear protein components reflect the changes ocular surface abnormalities.In this study proteomics techniques were used to investigate tear protein compositions in GO patients.Methods We carried out a case-control study by comparing tear fluid contents of GO patients with that of healthy subjects.In the first step the tears were subjected to SDS-PAGE electrophoresis and then single protein bands were analyzed by to in-gel trypsin digestion and nano-flow liquid mass spectrometry （LC-MS/MS） using a MS software.Results In tear samples of GO subjects,the protein fractions of inflammation-related protein immunoglobulin kappa chain C region （IgKC） and serum albumin were essentially reduced,whereas a novel isoform of complement component 3 （C3）,which we detected in control subjects,was completely absent in the GO patients＇ tears.Conclusions Reduced protein concentrations of particularly IgKC and complement C3 as well as albumin in the tears of GO patients may contribute to changes in their ocular surfaces via diminished reactive oxygen species （ROS） depletion and adaptive immune responses.The completely absent of C3 in the GO patients＇ tears,may imply that an important inflammatory signaling pathway is affected,which needs further investigation.展开更多
The present study was designed to evaluate the protective effects of ethanol extracts of Rabdosia japonica var. glaucocalyx(Maxim.) Hara(RJ) on lipopolysaccharide(LPS)-induced acute lung injury(ALI) in mice and the po...The present study was designed to evaluate the protective effects of ethanol extracts of Rabdosia japonica var. glaucocalyx(Maxim.) Hara(RJ) on lipopolysaccharide(LPS)-induced acute lung injury(ALI) in mice and the possible underlying mechanisms of action. The mice were orally administrated with RJ extract(16, 32 or 64 mg?kg–1) daily for consecutive7 days before LPS challenge. The ung specimens and the bronchoalveolar lavage fluid(BALF) were collected for histopathological examinations and biochemical analyses. Pretreatment with RJ significantly enhanced superoxide dismutase(SOD) activity and reduced the wet-to-dry weight(W/D) ratio, the levels of nitric oxide(NO) and protein leakage, and myeloperoxidase(MPO) activity in mice with ALI, in a dose-dependent manner. RJ reduced complement deposition and significantly attenuated LPS-induced ALI by reducing productions of inflammatory mediators, such as tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-1β(IL-1β). The results demonstrated that RJ may attenuate LPS-induced ALI via reducing the production of pro-inflammatory mediators, and reducing complement deposition and radicals.展开更多
Background It is generally accepted that gliomas are the most common primary brain tumors with poor prognosis. We aimed to explore the relationship of the immunity of the central nervous system and the genesis and dev...Background It is generally accepted that gliomas are the most common primary brain tumors with poor prognosis. We aimed to explore the relationship of the immunity of the central nervous system and the genesis and development of glioma. Methods G422 glioma was implanted in the brain of BALB/c mice （immuno-competent mice）, nude mice （T cell related immuno-deficient） and complement C3 knock-out mice （complement C3 related immunodeficient）. The survival time of the host, growth and histopathology of the tumor, and concentrations of tumor necrosis factor-α （TNF-α） and interferon-γ （INF-γ） in tumor tissues were assessed. Results Tumor spheres were formed in all mice after injection, and glial fibrillary acidic protein （GFAP） positive staining of the cells declared their glioma origin. The longest median survival time of （44.3±6.0） days was found in BALB/c mice, followed by （24.8±5.2） days in nude mice and the shortest （18.6±5.8） days in complement C3 knock-out mice. Accordingly, the growth of the tumor was fastest in complement C3 knock-out mice, followed by the nude mice and slowest in the BALB/c mice. Although the proportions of infiltrating CD68^± lymphocytes in tumor tissues showed no significant difference （P 〉0.05）, TNF-α level in the nude and C3 knock-out mice, （28.11±4.86） μmol/L and （22.87±6.36） μmol/L respectively, were significantly lower （P 〈0.01） than that in the BALB/c mice, which was （230.21±39.17） μmol/L. The INF-γ level was highest in the BALB/c mice （（180.76±29.19） μmol/L）, followed by the nude mice （（113.46±23.76） μmol/L） and then the C3 knock-out mice （（16.84±4.45） μmol/L）. Conclusions The G422 glioma implanted in the brains of mice with different immune ability would be a useful model for studying the relationship of the immune system and tumor in the central nervous system. Furthermore, the T cells and complement C3 compartments of the immune response may affect the growth of implanted tumors and inflammatory factors such as TNF-α and INF-γ.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
Traditionally, determination of inhibitory potency of complement inhibitors is performed by the hemolytic assay. However, this assay is not applicable to the lectin pathway, thus impeding the understanding of compleme...Traditionally, determination of inhibitory potency of complement inhibitors is performed by the hemolytic assay. However, this assay is not applicable to the lectin pathway, thus impeding the understanding of complement inhibitors against the overall function of the complement system. The main objective of our study was to develop a specific enzyme-linked immunosorbent assay(ELISA) as an alternative method to assess the anti-complement activity, particularly against the lectin pathway. By using respective coating substrates against different activation pathways, followed by capturing the stable C3c fragments, our ELISA method can be used to screen complement inhibitors against the classical pathway and the lectin pathway. The inhibitory effect of suramin on the classical pathway, as measured by our hemolytic assay is consistent with previous reports. Further assessment of suramin and Bupleurum polysaccharides against the lectin pathway showed a good reproducibility of the method. Comparison of the lectin pathway IC50 between Bupleurum smithii var. parvifolium polysaccharides(1.055 mg/mL) and Bupleurum chinense polysaccharides(0.98 mg/mL) showed that, similar to the classical and alterative pathway, these two Bupleurum polysaccharides had comparable anti-complementary properties against the lectin pathway. The results demonstrate that the described ELISA assay can compensate for the shortcomings of the hemolytic assay in lectin pathway.展开更多
The bimodulus material is a classical model to describe the elastic behavior of materials with tension-compression asymmetry.Due to the inherently nonlinear properties of bimodular materials,traditional iteration meth...The bimodulus material is a classical model to describe the elastic behavior of materials with tension-compression asymmetry.Due to the inherently nonlinear properties of bimodular materials,traditional iteration methods suffer from low convergence efficiency and poor adaptability for large-scale structures in engineering.In this paper,a novel 3D algorithm is established by complementing the three shear moduli of the constitutive equation in principal stress coordinates.In contrast to the existing 3D shear modulus constructed based on experience,in this paper the shear modulus is derived theoretically through a limit process.Then,a theoretically self-consistent complemented algorithm is established and implemented in ABAQUS via UMAT;its good stability and convergence efficiency are verified by using benchmark examples.Numerical analysis shows that the calculation error for bimodulus structures using the traditional linear elastic theory is large,which is not in line with reality.展开更多
This study deals with the data of Tripterygium Wilfordii polyglucoside (1 mg/kg·day)combined with Radix Salviae Miltiorrhizae (6 - 15 g/d) in the treatment of purpuric nephritis, comparedwith a control group usin...This study deals with the data of Tripterygium Wilfordii polyglucoside (1 mg/kg·day)combined with Radix Salviae Miltiorrhizae (6 - 15 g/d) in the treatment of purpuric nephritis, comparedwith a control group using Tripterygium Wilfordii polyglucoside treatment only. The average time of ede-mad-isappearance and blood pressure-resumption to a normal range were 8. 72 ± 3. 07 and 7. 44 ± 5. 17days in the test group, which was much better than in the control group (P<0. 05) . The average time ofhematuria-disappearance in the test group and the control group were 36. 37 ± 11. 50 and 47. 73 ± 14. 03days respectively. The average time for C3 levels in the urine to resume to normal in the test group and thecontrol group were 40. 33±4. 51 and 50. 00±5. 30 days respectively (P<0.01) . The time for microcircu-lation of nail fold to return to normal after treatment in the test group and the control group were 39. 00±11. 03 and 66. 00± 9. 01 days respectively (P<0. 001) . These results indicate the effect on the test groupwas much better than that on the control group.展开更多
基金Supported by: the Scientific Technology Research and Development Plan of Hebei Province, No. 06276103Dthe Natural Science Foundation of Hebei Province, No. C2006000915
文摘BACKGROUND： Certain components of tetramethylpyrazine, a traditional Chinese medicine, exhibit protective effects against brain injury. OBJECTIVE： To investigate the effects of different Naoxintong doses on expression of nuclear factor-kappa B （ kB）, interleukin-6, tumor necrosis factor-α, and complement 3 in rats following focal cerebral ischemia. DESIGN, TIME AND SETTING： The randomized experiment was performed at the Laboratory of Neurology, Second Hospital of Hebei Medical University from June 2004 to June 2006. MATERIALS： A total of 150 adult, healthy, male, Sprague Dawley rats, weighing 280-320g, were selected. Naoxintong powder （mainly comprising szechwan lovage rhizome, milkvetch root, danshen root, and radix angelicae sinensis） was obtained from Buchang Pharmacy Co., Ltd. in Xianyang City of Shanxi Province of China, lot number 040608. METHODS： The rats were randomly assigned into sham operation, saline, high-dose Naoxintong, moderate-dose Naoxintong, and low-dose Naoxintong groups, with 30 rats in each group. Rat models of middle cerebral artery occlusion were established using the suture method, with the exception of the sham operation group. Rats in the high-dose, moderate-dose and low-dose Naoxintong groups received 4, 2, and 1 g/kg Naoxintong respectively, by gavage. Rats in the saline group were treated with 1 mL saline by gavage All rats were administered by gavage at 5 and 23 hours following surgery, and subsequently, once per day. MAIN OUTCOME MEASURES： At 6, 24, 48, 72 hours, and 7 days following model establishment, brain water content was measured. Histopathological changes in brain tissues were detected using hematoxylin-eosin staining. Expression of nuclear factor- kB, interleukin-6, tumor necrosis factor- α, and complement 3 was examined by immunohistochemistry. RESULTS： A total of 150 rats were included in the final analysis with no loss. Brain water content was significantly increased in the ischemic hemisphere of rats from the saline, as well as the high-dose, moderate-dose, and low-dose Naoxintong groups at 24 hours, which reached a peak at 48 hours. At 6, 24, 48, 72 hours, and 7 days, brain water content was greater in the ischemic hemisphere of rats from the saline, as well as the high-dose, moderate-dose, and low-dose Naoxintong groups, compared with the sham operation group （P 〈 0.05）. At 24 and 48 hours, brain water content was reduced in the high-dose and moderate-dose Naoxintong groups, compared to the saline and low-dose Naoxintong groups （P 〈 0.05）. In the saline, as well as high-dose, moderate-dose, and low-dose Naoxintong groups, neuronal edema was observed at 6 hours surrounding the ischemic sites. Inflammatory cells appeared at 24 hours, reached a peak at 48 hours, and gradually diminished. A small amount of glial cell proliferation and neuronal degeneration were observed in the hippocampus at 72 hours following infarction. Microglial proliferation and aggregation were detected at 7 days after infarction. Expression of nuclear factor- kB, interleukin-6, tumor necrosis factor-α, and complement 3 was significantly less in the high-dose, moderate-dose, and low-dose Naoxintong groups, compared to the sham operation group （P 〈 0.05）. Expression of the above-mentioned inflammatory cytokines was lower in rat brain tissues of the high-dose Naoxintong group, compared to the low-dose Naoxintong group （P 〈 0.05）. CONCLUSION： High-dose Naoxintong and moderate-dose Naoxintong significantly alleviated rat brain edema and decreased expression of nuclear factor-kB, interleukin-6, tumor necrosis factor-α, and complement 3 in brain tissues. The protective effect of high-dose Naoxintong was most significant.
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AIM: To help clarifying the possibility of connective-tissue diseases in men with penile or testicular prostheses. METHODS: Eight patients underwent inflatable penile prostheses and 15, testicular prostheses consented to the study. Their medical records were reviewed and a follow-up interview and physical and serological examinations were performed. RESULTS: In patients with penile prostheses, there was no abnormal antinuclear antibody (ANA) or IgM elevation. The serum levels of the rheumatoid factor (RF), C4, IgA and IgG were abnormal in one patient, and the levels of erythrocyte sedimentation rate (ESR) and C3, abnormal in two. Four had elevated IgE. In patients with testicular prostheses, there was no abnormal RF, ANA or IgM. The serum levels of ESR and IgA were abnormal in two, and three had abnormal C4, ten abnormal C3, and eleven decreased IgG. All had increased IgE. Men with penile prostheses had higher serum levels of IgG and IgM than those with testicular prostheses (P=0.001, P=0.016, respectively). The rates of abnormal values of IgE and IgG were higher in men with testicular prostheses than in men with penile prostheses (P=0.008, P=0.009, respectively). Physical examination was normal in all patients and nobody had documented symptoms pertinent to connective-tissue diseases. CONCLUSION: Our findings suggest that the risk of connective-tissue diseases is not higher in patients wearing prostheses as the ANA is negative and there is no apparent manifestation suggestive of connective-tissue diseases.
基金Supported by National Natural Science Foundation of China,No.81671605.
文摘BACKGROUND Previous publications indicated that genetic predisposition might play important roles in the onset of osteonecrosis of the femoral head(ONFH)in systemic lupus erythematosus(SLE).Some gene loci such as complement C3d receptor 2(CR2),nitric oxide synthase 3(NOS3),collagen type II alpha 1 chain(COL2A1),protein tyrosine phosphatase non-receptor type 22(PTPN22),and transient receptor potential cation channel subfamily V member 4(TRPV4)were reported to be involved in this process.AIM To investigate whether the risk of ONFH in SLE is associated with single nucleotide variations(SNVs)in these five genes.METHODS SNVs in the CR2,NOS3,COL2A1,PTPN22,and TRPV4 genes were examined by using FastTarget and Illumina Miseq sequencing technologies in 49 cases of SLE with ONFH.Burrows–wheeler aligner was used to align the sequencing reads to hg19,and GATK and Varscan programs were used to perform SNV calling.PolyPhen-2,SIFT,and MutationTaster were used to assess the functional effects of non-synonymous SNVs.RESULTS Six of the 49 patients were confirmed to have low frequency SNVs,including one patient with SNVs in NOS3(exon 6:c.814G>A:p.E272K and exon 7:c.814G>A:p.E272K.),four in COL2A1(rs41263847:exon 29:c.1913C>T:p.T638I,exon 28:c.1706C>T:p.T569I,and rs371445823:exon 8:c.580G>A:p.A194T,exon 7:c.373G>A:p.A125T),and one in CR2(rs45573035:exon 2:c.200C>G:p.T67S).CONCLUSION The onset of ONFH in SLE might be associated with the identified SNVs in NOS3,COL2A1,and CR2.
文摘Combined liver and kidney transplantation(CLKT)is indicated in patients with failure of both organs,or for the treatment of end-stage chronic kidney disease(ESKD)caused by a genetic defect in the liver.The aim of the present review is to provide the most up-to-date overview of the rare conditions as indications for CLKT.They are major indications for CLKT in children.However,in some of them(e.g.,atypical hemolytic uremic syndrome or primary hyperoxaluria),CLKT may be required in adults as well.Primary hyperoxaluria is divided into three types,of which type 1 and 2 lead to ESKD.CLKT has been proven effective in renal function replacement,at the same time preventing recurrence of the disease.Nephronophthisis is associated with liver fibrosis in 5%of cases and these patients are candidates for CLKT.In alpha 1-antitrypsin deficiency,hereditary C3 deficiency,lecithin cholesterol acyltransferase deficiency and glycogen storage diseases,glomerular or tubulointerstitial disease can lead to chronic kidney disease.Liver transplantation as a part of CLKT corrects underlying genetic and consequent metabolic abnormality.In atypical hemolytic uremic syndrome caused by mutations in the genes for factor H,successful CLKT has been reported in a small number of patients.However,for this indication,CLKT has been largely replaced by eculizumab,an anti-C5 antibody.CLKT has been well established to provide immune protection of the transplanted kidney against donor-specific antibodies against class I HLA,facilitating transplantation in a highly sensitized recipient.
基金supported by the National Key Research and Development Program of China(2019YFA0508502 to XL)National Natural Science Foundation of China(31930039,31821003,91942303 to XL)+1 种基金the General Financial Grant from the China Postdoctoral Science Foundation(2020M670301 to YX)annual funding from Tsinghua University-Peking University Jointed Center for Life Sciences.
文摘Invasive fungal infections are life-threatening,and neutrophils are vital cells of the innate immune system that defend against them.The role of LTA4H-LTB_(4)-BLT1 axis in regulation of neutrophil responses to fungal infection remains poorly understood.Here,we demonstrated that the LTA4H-LTB_(4)-BLT1 axis protects the host against Candida albicans and Aspergillus fumigatus,but not Cryptococcus neoformans infection,by regulating the antifungal activity of neutrophils.Our results show that deleting Lta4h or Blt1 substantially impairs the fungal-specific phagocytic capacity of neutrophils.Moreover,defective activation of the spleen tyrosine kinase(Syk)and extracellular signal-related kinase(ERK1/2)pathways in neutrophils accompanies this impairment.Mechanistically,BLT1 regulates CR3-mediated,β-1,3-glucan-induced neutrophil phagocytosis,while a physical interaction with CR3 with slight influence on its dynamics is observed.Our findings thus demonstrate that the LTA4H-LTB_(4)-BLT1 axis is essential for the phagocytic function of neutrophils in host antifungal immune response against Candida albicans and Aspergillus fumigatus.
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.
文摘Background Graves＇ ophthalmopathy/orbitopathy （GO） patients often suffer ocular surface damages and tear fluid proteins play a significant role in maintaining healthy ocular surfaces,while changes in tear protein components reflect the changes ocular surface abnormalities.In this study proteomics techniques were used to investigate tear protein compositions in GO patients.Methods We carried out a case-control study by comparing tear fluid contents of GO patients with that of healthy subjects.In the first step the tears were subjected to SDS-PAGE electrophoresis and then single protein bands were analyzed by to in-gel trypsin digestion and nano-flow liquid mass spectrometry （LC-MS/MS） using a MS software.Results In tear samples of GO subjects,the protein fractions of inflammation-related protein immunoglobulin kappa chain C region （IgKC） and serum albumin were essentially reduced,whereas a novel isoform of complement component 3 （C3）,which we detected in control subjects,was completely absent in the GO patients＇ tears.Conclusions Reduced protein concentrations of particularly IgKC and complement C3 as well as albumin in the tears of GO patients may contribute to changes in their ocular surfaces via diminished reactive oxygen species （ROS） depletion and adaptive immune responses.The completely absent of C3 in the GO patients＇ tears,may imply that an important inflammatory signaling pathway is affected,which needs further investigation.
基金supported by China Postdoctoral Science Foundation(No.20100471390)Natural Science Foundation of Jiangsu Province(No.BK2011296)+1 种基金Foundation of Suzhou Science and Technology Bureau(No.SYS201206)Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)
文摘The present study was designed to evaluate the protective effects of ethanol extracts of Rabdosia japonica var. glaucocalyx(Maxim.) Hara(RJ) on lipopolysaccharide(LPS)-induced acute lung injury(ALI) in mice and the possible underlying mechanisms of action. The mice were orally administrated with RJ extract(16, 32 or 64 mg?kg–1) daily for consecutive7 days before LPS challenge. The ung specimens and the bronchoalveolar lavage fluid(BALF) were collected for histopathological examinations and biochemical analyses. Pretreatment with RJ significantly enhanced superoxide dismutase(SOD) activity and reduced the wet-to-dry weight(W/D) ratio, the levels of nitric oxide(NO) and protein leakage, and myeloperoxidase(MPO) activity in mice with ALI, in a dose-dependent manner. RJ reduced complement deposition and significantly attenuated LPS-induced ALI by reducing productions of inflammatory mediators, such as tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-1β(IL-1β). The results demonstrated that RJ may attenuate LPS-induced ALI via reducing the production of pro-inflammatory mediators, and reducing complement deposition and radicals.
文摘Background It is generally accepted that gliomas are the most common primary brain tumors with poor prognosis. We aimed to explore the relationship of the immunity of the central nervous system and the genesis and development of glioma. Methods G422 glioma was implanted in the brain of BALB/c mice （immuno-competent mice）, nude mice （T cell related immuno-deficient） and complement C3 knock-out mice （complement C3 related immunodeficient）. The survival time of the host, growth and histopathology of the tumor, and concentrations of tumor necrosis factor-α （TNF-α） and interferon-γ （INF-γ） in tumor tissues were assessed. Results Tumor spheres were formed in all mice after injection, and glial fibrillary acidic protein （GFAP） positive staining of the cells declared their glioma origin. The longest median survival time of （44.3±6.0） days was found in BALB/c mice, followed by （24.8±5.2） days in nude mice and the shortest （18.6±5.8） days in complement C3 knock-out mice. Accordingly, the growth of the tumor was fastest in complement C3 knock-out mice, followed by the nude mice and slowest in the BALB/c mice. Although the proportions of infiltrating CD68^± lymphocytes in tumor tissues showed no significant difference （P 〉0.05）, TNF-α level in the nude and C3 knock-out mice, （28.11±4.86） μmol/L and （22.87±6.36） μmol/L respectively, were significantly lower （P 〈0.01） than that in the BALB/c mice, which was （230.21±39.17） μmol/L. The INF-γ level was highest in the BALB/c mice （（180.76±29.19） μmol/L）, followed by the nude mice （（113.46±23.76） μmol/L） and then the C3 knock-out mice （（16.84±4.45） μmol/L）. Conclusions The G422 glioma implanted in the brains of mice with different immune ability would be a useful model for studying the relationship of the immune system and tumor in the central nervous system. Furthermore, the T cells and complement C3 compartments of the immune response may affect the growth of implanted tumors and inflammatory factors such as TNF-α and INF-γ.
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 grants from the National Natural Science Foundation of China (Nos. 81274165, 81330089 and 30925042)the State Key Program for Innovative Drugs from the Ministry of Science and Technology of the people’s Republic of China (No. 2012ZX09301001-003)+1 种基金the Science and Technology Commission of Shanghai Municipality (Nos. 12JC1400800 and 10XD1405900)Fudan's Undergraduate Research Opportunities Program (Xiyuan, No. 102305)
文摘Traditionally, determination of inhibitory potency of complement inhibitors is performed by the hemolytic assay. However, this assay is not applicable to the lectin pathway, thus impeding the understanding of complement inhibitors against the overall function of the complement system. The main objective of our study was to develop a specific enzyme-linked immunosorbent assay(ELISA) as an alternative method to assess the anti-complement activity, particularly against the lectin pathway. By using respective coating substrates against different activation pathways, followed by capturing the stable C3c fragments, our ELISA method can be used to screen complement inhibitors against the classical pathway and the lectin pathway. The inhibitory effect of suramin on the classical pathway, as measured by our hemolytic assay is consistent with previous reports. Further assessment of suramin and Bupleurum polysaccharides against the lectin pathway showed a good reproducibility of the method. Comparison of the lectin pathway IC50 between Bupleurum smithii var. parvifolium polysaccharides(1.055 mg/mL) and Bupleurum chinense polysaccharides(0.98 mg/mL) showed that, similar to the classical and alterative pathway, these two Bupleurum polysaccharides had comparable anti-complementary properties against the lectin pathway. The results demonstrate that the described ELISA assay can compensate for the shortcomings of the hemolytic assay in lectin pathway.
基金the National Natural Science Foundation of China(Grant 51908071)Scientific Research Project of Education Department of Hunan Province(Grant 18C0194)Open Fund of Key Laboratory of Road Structure and Material of Ministry of Transport,Changsha University of Science&Technology(Grant kfi 170303).
文摘The bimodulus material is a classical model to describe the elastic behavior of materials with tension-compression asymmetry.Due to the inherently nonlinear properties of bimodular materials,traditional iteration methods suffer from low convergence efficiency and poor adaptability for large-scale structures in engineering.In this paper,a novel 3D algorithm is established by complementing the three shear moduli of the constitutive equation in principal stress coordinates.In contrast to the existing 3D shear modulus constructed based on experience,in this paper the shear modulus is derived theoretically through a limit process.Then,a theoretically self-consistent complemented algorithm is established and implemented in ABAQUS via UMAT;its good stability and convergence efficiency are verified by using benchmark examples.Numerical analysis shows that the calculation error for bimodulus structures using the traditional linear elastic theory is large,which is not in line with reality.
文摘This study deals with the data of Tripterygium Wilfordii polyglucoside (1 mg/kg·day)combined with Radix Salviae Miltiorrhizae (6 - 15 g/d) in the treatment of purpuric nephritis, comparedwith a control group using Tripterygium Wilfordii polyglucoside treatment only. The average time of ede-mad-isappearance and blood pressure-resumption to a normal range were 8. 72 ± 3. 07 and 7. 44 ± 5. 17days in the test group, which was much better than in the control group (P<0. 05) . The average time ofhematuria-disappearance in the test group and the control group were 36. 37 ± 11. 50 and 47. 73 ± 14. 03days respectively. The average time for C3 levels in the urine to resume to normal in the test group and thecontrol group were 40. 33±4. 51 and 50. 00±5. 30 days respectively (P<0.01) . The time for microcircu-lation of nail fold to return to normal after treatment in the test group and the control group were 39. 00±11. 03 and 66. 00± 9. 01 days respectively (P<0. 001) . These results indicate the effect on the test groupwas much better than that on the control group.
