RESUMO
Early apoptosis of grafted islets is one of the main factors affecting the efficacy of islet transplantation. The combined transplantation of islet cells and bone marrow mesenchymal stem cells (BMSCs) can significantly improve the survival rate of grafted islets. Transcription factor insulin gene enhancer binding protein 1 (ISL1) is shown to promote the angiogenesis of grafted islets and the paracrine function of mesenchymal stem cells during the co-transplantation, yet the regulatory mechanism remains unclear. By using ISL1-overexpressing BMSCs and the subtherapeutic doses of islets for co-transplantation, we managed to reduce the apoptosis and improve the survival rate of the grafts. Our metabolomics and proteomics data suggested that ISL1 upregulates aniline (ANLN) and Inhibin beta A chain (INHBA), and stimulated the release of caffeine in the BMSCs. We then demonstrated that the upregulation of ANLN and INHBA was achieved by the binding of ISL1 to the promoter regions of the two genes. In addition, ISL1 could also promote BMSCs to release exosomes with high expression of ANLN, secrete INHBA and caffeine, and reduce streptozocin (STZ)-induced islets apoptosis. Thus, our study provides mechanical insight into the islet/BMSCs co-transplantation and paves the foundation for using conditioned medium to mimic the ISL1-overexpressing BMSCs co-transplantation.
Assuntos
Exossomos , Insulinas , Ilhotas Pancreáticas , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Compostos de Anilina/metabolismo , Apoptose/genética , Cafeína/metabolismo , Cafeína/farmacologia , Meios de Cultivo Condicionados , Subunidades beta de Inibinas , Insulinas/metabolismo , Ilhotas Pancreáticas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Estreptozocina/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Revascularization of the islet transplant is a crucial step that defines the success rate of patient recovery. Bone marrow-derived mesenchymal stem cells (BMSCs) have been reported to promote revascularization; however, the underlying cellular mechanism remains unclear. Moreover, our liquid chromatography-tandem mass spectrometry results showed that BMSCs could promote the expression of insulin gene enhancer binding protein-1 (ISL1) in islets. ISL1 is involved in islets proliferation and plays a potential regulatory role in the revascularization of islets. This study identifies the ISL1 protein as a potential modulator in BMSCs-mediated revascularization of islet grafts. We demonstrated that the survival rate and insulin secretion of islets were increased in the presence of BMSCs, indicating that BMSCs promote islet revascularization in a coculture system and rat diabetes model. Interestingly, we also observed that the presence of BMSCs led to an increase in ISL1 and vascular endothelial growth factor A (VEGFA) expression in both islets and the INS-1 rat insulinoma cell line. In silico protein structure modeling indicated that ISL1 is a transcription factor that has four binding sites with VEGFA mRNA. Further results showed that overexpression of ISL1 increased both the abundance of VEGFA transcripts and protein accumulation, while inhibition of ISL1 decreased the abundance of VEGFA. Using a ChIP-qPCR assay, we demonstrated that direct molecular interactions between ISL1 and VEGFA occur in INS-1 cells. Together, these findings reveal that BMSCs promote the expression of ISL1 in islets and lead to an increase in VEGFA in islet grafts. Hence, ISL1 is a potential target to induce early revascularization in islet transplantation.
Assuntos
Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas , Células-Tronco Mesenquimais , Animais , Medula Óssea/metabolismo , Humanos , Ilhotas Pancreáticas/metabolismo , Transplante das Ilhotas Pancreáticas/métodos , Células-Tronco Mesenquimais/metabolismo , Ratos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The families of copper-containing membrane-bound monooxygenases (CuMMOs) and soluble di-iron monooxygenases (SDIMOs) are involved not only in methane oxidation but also in short-chain alkane oxidation. Here, we describe Rhodococcus sp. strain ZPP, a bacterium able to grow with ethane or propane as the sole carbon and energy source, and report on the horizontal gene transfer (HGT) of actinobacterial hydrocarbon monooxygenases (HMOs) of the CuMMO family and the sMMO (soluble methane monooxygenase)-like SDIMO in the genus Rhodococcus. The key function of HMO in strain ZPP for propane oxidation was verified by allylthiourea inhibition. The HMO genes (designated hmoCAB) and those encoding sMMO-like SDIMO (designated smoXYB1C1Z) are located on a linear megaplasmid (pRZP1) of strain ZPP. Comparative genomic analysis of similar plasmids indicated the mobility of these plasmids within the genus Rhodococcus. The plasmid pRZP1 in strain ZPP could be conjugatively transferred to a recipient Rhodococcus erythropolis strain in a mating experiment and showed similar ethane- and propane-consuming activities. Finally, our findings demonstrate that the horizontal transfer of plasmid-based CuMMO and SDIMO genes confers the ability to use ethane and propane on the recipient. IMPORTANCE CuMMOs and SDIMOs initiate the aerobic oxidation of alkanes in bacteria. Here, the supposition that horizontally transferred plasmid-based CuMMO and SDIMO genes confer on the recipient similar abilities to use ethane and propane was proposed and confirmed in Rhodococcus. This study is a living example of HGT of CuMMOs and SDIMOs and outlines the plasmid-borne properties responsible for gaseous alkane degradation. Our results indicate that plasmids can support the rapid evolution of enzyme-mediated biogeochemical processes.
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Proteínas de Bactérias/genética , Oxigenases de Função Mista/genética , Rhodococcus/genética , Etano/metabolismo , Transferência Genética Horizontal , Genes Bacterianos , Oxirredução , Plasmídeos , Propano/metabolismo , Rhodococcus/metabolismoRESUMO
OBJECTIVE: To investigate the effects of morinda officinalis how (MOH) on SPAG11T and microRNA-210 (miR-210) in the testis tissue of SD rats with varicocele (VC). METHODS: Forty SD rats were randomly divided into four groups of an equal number: blank control, VC model control, low-dose MOH and high-dose MOH. The rats in the former two groups were treated intragastrically with normal saline and those in the latter two with MOH extract at 200 and 400 mg/kg/d, respectively, all for 30 days. Then, the testis tissues of the rats were harvested for measurement of the levels of SOD, MDA and AI and determination of the expressions of vimentin, sperm-associated antigen 11T (SPAG11T) protein and RNA, and miR-210. RESULTS: There were no statistically significant differences in the testicular and epididymal weights among the four groups of rats (P > 0.05). Compared with the rats in the VC model control group, those in the MOH groups showed a remarkably increased SOD content (P < 0.05) but a decreased MDA level and AI in the testis tissue (P < 0.05). The expression of vimentin mRNA in the testis tissue was significantly reduced in the VC model control in comparison with that in the blank control group (0.18 ± 0.03 vs 1.00 ± 0.02), but dramatically up-regulated after treated with low-dose MOH (0.68 ± 0.07) and high-dose MOH (0.92 ± 0.08) (F = 432.901, P< 0.01). The level of SPAG11T mRNA was also remarkably decreased in the VC model control group compared with the blank controls (0.32 ± 0.04 vs 1.00 ± 0.05), but markedly elevated after treated with low-dose MOH (0.61 ± 0.09) and high-dose MOH (0.82 ± 0.13) (F = 117.423, P< 0.01). The level of testicular miR-210, however, was significantly increased in the VC model controls compared with the blank controls (1.39 ± 0.12 vs 1.00 ± 0.06), but decreased in both the low-dose MOH (1.17 ± 0.08) and high-dose MOH groups (1.09 ± 0.08) (F = 36.136, P< 0.01). CONCLUSIONS: MOH extract can up-regulate the expressions of vimentin and SPAG11T and inhibit that of miR-210 in the testis tissue of varicocele rats.
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MicroRNAs , Morinda , Extratos Vegetais , Varicocele , beta-Defensinas/genética , Animais , Masculino , MicroRNAs/genética , Morinda/química , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , TestículoRESUMO
BACKGROUND: Delayed graft function (DGF) is an important complication of kidney transplantation and can be diagnosed according to different definitions. DGF has been suggested to be associated with the long-term outcome of kidney transplantation surgery. However, the best DGF definition for predicting renal transplant outcomes in Chinese donations after cardiac death (DCDs) remains to be determined. METHOD: A total of 372 DCD kidney transplant recipients from June 2013 to July 2017 in the First Affiliated Hospital of Xi'an Jiaotong University were included in this retrospective study to compare 6 different DGF definitions. The relationships of the DGF definitions with transplant outcome were analyzed, including graft loss (GL) and death-censored graft loss (death-censored GL). Renal function indicators, including one-year estimated glomerular filtration rate (eGFR) and three-year eGFR, and were compared between different DGF groups. RESULTS: The incidence of DGF varied from 4.19 to 35.22% according to the different DGF diagnoses. All DGF definitions were significantly associated with three-year GL as well as death-censored GL. DGF based on requirement of hemodialysis within the first week had the best predictive value for GL (AUC 0.77), and DGF based on sCr variation during the first 3 days post-transplant had the best predictive value for three-year death-censored GL (AUC 0.79). Combination of the 48-h sCr reduction ratio and classical DGF can improve the AUC for GL (AUC 0.85) as well as the predictive accuracy for death-censored GL (83.3%). CONCLUSION: DGF was an independent risk factor for poor transplant outcome. The combination of need for hemodialysis within the first week and the 48-h serum creatinine reduction rate has a better predictive value for patient and poor graft outcome.
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Função Retardada do Enxerto/diagnóstico , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias/diagnóstico , Doadores de Tecidos , Adulto , Área Sob a Curva , China , Creatinina/sangue , Função Retardada do Enxerto/epidemiologia , Feminino , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Parada Cardíaca , Humanos , Terapia de Imunossupressão/métodos , Imunossupressores/uso terapêutico , Incidência , Estimativa de Kaplan-Meier , Rim/fisiologia , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Sensibilidade e Especificidade , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Natural killer cells play important roles in tumor immune surveillance, and cancer cells must resist this surveillance in order to progress and metastasise. INTRODUCTION: The study aimed to explore the mechanism of how breast cancer cells become resistant to the cytotoxicity of NK cells. METHODS: We established NK-resistant breast cancer cells by exposing MDA-MB-231 cells and MCF-7 cells to NK92 cells. Profiles of lncRNA were compared between the NK-resistant and parental cell lines. Primary NK cells were isolated by MACS, and the NK attacking effect was tested by non-radioactive cytotoxicity. The change in lncRNAs was analyzed by Gene-chip. The interaction between lncRNA and miRNA was displayed by Luciferase assay. The regulation of the gene was verified by QRT-PCR and WB. The clinical indicators were detected by ISH, IH, and ELISA, respectively. RESULTS: UCA1 was found to be significantly up-regulated in both NK-resistant cell lines, and we confirmed such up-regulation on its own to be sufficient to render parental cell lines resistant to NK92 cells. We found that UCA1 up-regulated ULBP2 via the transcription factor CREB1, while it up-regulated ADAM17 by "sponging" the miR-26b-5p. ADAM17 facilitated the shedding of soluble ULBP2 from the surface of breast cancer cells, rendering them resistant to killing by NK cells. UCA1, ADAM17, and ULBP2 were found to be expressed at higher levels in bone metastases of breast cancer than in primary tumors. CONCLUSION: Our data strongly suggest that UCA1 up-regulates ULBP2 expression and shedding, rendering breast cancer cells resistant to killing by NK cells.
Assuntos
Neoplasias da Mama , MicroRNAs , RNA Longo não Codificante , Feminino , Humanos , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células , Células Matadoras Naturais , MicroRNAs/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
The microbiome in a specific human organ has been well-studied, but few reports have investigated the multi-organ microbiome as a whole. Here, we aim to analyse the intra-individual inter-organ and intra-organ microbiome in deceased humans. We collected 1608 samples from 53 sites of 7 surface organs (oral cavity, esophagus, stomach, small intestine, appendix, large intestine and skin; n = 33 subjects) and performed microbiome profiling, including 16S full-length sequencing. Microbial diversity varied dramatically among organs, and core microbial species co-existed in different intra-individual organs. We deciphered microbial changes across distinct intra-organ sites, and identified signature microbes, their functional traits, and interactions specific to each site. We revealed significant microbial heterogeneity between paired mucosa-lumen samples of stomach, small intestine, and large intestine. Finally, we established the landscape of inter-organ relationships of microbes along the digestive tract. Therefore, we generate a catalogue of bacterial composition, diversity, interaction, functional traits, and bacterial translocation in human at inter-organ and intra-organ levels.
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Apêndice , Microbiota , Humanos , Translocação Bacteriana , Estômago , Microbiota/genética , BocaRESUMO
BACKGROUND: If chronic allograft nephropathy can be detected early and treated, the long-term survival rate of the transplanted kidney may be effectively improved. PURPOSE: To compare the application value of real-time sound touch elastography (STE), strain elastography, and color Doppler flow imaging in evaluating chronic kidney disease of transplanted kidneys. MATERIALS AND METHODS: A total of 101 patients with renal transplantation were divided into a normal group (serum creatinine <134 mol/L, 58 patients) and a chronic allograft nephropathy group after renal transplantation over 6 months (serum creatinine >134 mol/L, 43 patients). The maximum elastic modulus (Emax) was determined, and receiver operator characteristics were used to compare the diagnostic efficacy of STE ultrasound. RESULTS: Emean, Emax, B/A (the strain rate of the internal oblique muscle tissue/ the strain rate of the central renal cortex) of cortical standard strain ratio in strain elastography, and resistance index (RI) between normal and chronic allograft nephropathy groups have statistical significance (P < .05). Emax is superior to B/A and arcuate artery RI in the chronic cortex in the diagnosis of renal dysfunction, and the area under the receiver operator characteristics curve is 0.88. The estimated glomerular filtration rate was negatively correlated with renal cortex Emax, B/A, and arcuate artery RI, among which Emax was the strongest (r = - 0.713, P < .001). The renal cortical Emax cut-off was 30.95 kPa, the sensitivity was 92%, the specificity was 88%, and the accuracy was 88%. CONCLUSION: The STE technique to evaluate chronic renal dysfunction after renal transplantation is more sensitive than traditional strain-type elastography and hemodynamic parameters, with renal function decline, renal cortex Emax, renal cortical B/A, and arcuate artery RI gradually increased, and renal cortex Emax was particularly obvious.
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Técnicas de Imagem por Elasticidade , Glomerulosclerose Segmentar e Focal , Insuficiência Renal Crônica , Humanos , Tato , Técnicas de Imagem por Elasticidade/métodos , Creatinina , Rim/diagnóstico por imagem , Rim/fisiologia , Insuficiência Renal Crônica/diagnóstico por imagem , Insuficiência Renal Crônica/cirurgia , Complicações Pós-OperatóriasRESUMO
Activation of NF-κB pathway and co-stimulatory system CD40/CD40L promotes the inflammation, which plays a key role in the failure of islet graft. Therefore, the purpose of this study was to determine if simultaneous blockade of CD40/CD40L and IκB/NF-κB pathways could protect islet graft. Streptozocin-induced diabetic Wistar rats were transplanted intraportally with 2000 IEQ islets isolated from Sprague-Dawley rats. The rats were divided into five groups: nontreatment group, AdGFP-treated group, Ad-IκBα-treated group, Ad-sCD40LIg-treated group, and Ad-IκBα-IRES(2) -sCD40L-treated group. The islet graft mean survival time (MST), insulin expression of islet grafts, and the levels of cytokines in peripheral blood, were measured for the animals in each group. Our study confirmed that islet cells transfected with low doses of adenovirus could achieve high transfection efficiency, and would not affect the function of islet cells (P > 0.05). Splenocytes cultured with Ad-IκBα-IRES2-CD40L-transfected islets resulted in homospecific hyporesponsiveness. The islet graft MST (>100 d) in the Ad-IκBα-IRES2-sCD40L-treated group was dramatically prolonged compared with that in the nontreatment group (7.1 ± 1.16 d). In addition, TNF-α, IL-1ß, and IFN-γ were diminished in the Ad-IκBα-IRES2-sCD40L-treated group, which was commensurate with the reduced cellular infiltration (P < 0.01). Simultaneous blockade of the CD40/CD40L and IκB/NF-κB pathways could effectively extend the survival of islet grafts.
Assuntos
Antígenos CD40/biossíntese , Ligante de CD40/biossíntese , Transplante das Ilhotas Pancreáticas/métodos , Ilhotas Pancreáticas/citologia , NF-kappa B/metabolismo , Animais , Linhagem Celular , Citocinas/biossíntese , Diabetes Mellitus Experimental , Sobrevivência de Enxerto , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Baço/citologia , Estreptozocina/farmacologia , Fatores de TempoRESUMO
BACKGROUND: The complement system plays an important role in the immune response to transplantation, and the diagnostic significance of peritubular capillary (PTC) C4d deposition (C4d+) in grafts is controversial. The study aimed to fully investigate the risk factors for PTC C4d+ and analyze its significance in biopsy pathology of kidney transplantation. METHODS: This retrospective study included 124 cases of kidney transplant with graft biopsy and donor-specific antibody (DSA) testing from January 2017 to December 2019 in a single center. The effects of recipient pathological indicators, eplet mismatch (MM), and DSAs on PTC C4d+ were examined using univariate and multivariate logistic regression analyses. RESULTS: In total, 35/124 (28%) were PTC C4d+, including 21 with antibody-mediated rejection (AMR), eight with renal tubular injury, three with T cell-mediated rejection, one with glomerular disease, and two others. Univariate analysis revealed that DSAs (Pâ<â0.001), glomerulitis (Pâ<â0.001), peritubular capillaritis (Pâ<â0.001), and human leukocyte antigen (HLA) B eplet MM (Pâ=â0.010) were the influencing factors of PTC C4d+. According to multivariate analysis, DSAs (odds ratio [OR]: 9.608, 95% confidence interval [CI]: 2.742-33.668, Pâ<â0.001), glomerulitis (OR: 3.581, 95%CI: 1.246-10.289, Pâ=â0.018), and HLA B eplet MM (OR: 1.166, 95%CI: 1.005-1.353, Pâ=â0.042) were the independent risk factors for PTC C4d+. In receiver operating characteristic curve analysis, the area under the curve was increased to 0.831 for predicting PTC C4d+ when considering glomerulitis, DSAs, and HLA B eplet MM. The proportions of HLA I DSAs and PTC C4d+ in active antibody-mediated rejection were 12/17 and 15/17, respectively; the proportions of HLA class II DSAs and PTC C4d+ in chronic AMR were 8/12 and 7/12, respectively. Furthermore, the higher the PTC C4d+ score was, the more serious the urinary occult blood and proteinuria of recipients at the time of biopsy. CONCLUSIONS: PTC C4d+ was mainly observed in AMR cases. DSAs, glomerulitis, and HLA B eplet MM are the independent risk factors for PTC C4d+.
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Transplante de Rim , Aloenxertos , Biópsia , Complemento C4b , Rejeição de Enxerto , Antígenos HLA , Antígenos HLA-B , Humanos , Transplante de Rim/efeitos adversos , Fragmentos de Peptídeos , Estudos Retrospectivos , Fatores de RiscoRESUMO
OBJECTIVE: to study the relationship between the expression of serum human leucocyte antigen-G5 (HLA-G5)/soluble CD30 (sCD30) and the function of renal graft in kidney transplant recipients and investigate the immune status of recipients with combined HLA-G5 and sCD30. METHODS: from January 2002 to November 2008, a total of 66 kidney transplant recipients in our centre were selected as subjects and divided into three groups: stable function of renal graft (n = 38), acute rejection (n = 15) and chronic rejection (n = 13). The expressions of serum HLA-G5 and sCD30 were detected. There were two different immune conditions with acute/chronic allograft rejection and normal renal graft in kidney transplant recipients as evaluated by combined HLA-G5 and sCD30. The sensitivity, specificity and critical value of the method were analyzed by the curve of receiver operating characteristic. RESULTS: the levels of HLA-G5 and sCD30 were significantly correlated with serum creatinine (r = -0.493, 0.691, both P < 0.01). Within the first year post-transplantation, the sensitivity was 78.6% and the specificity 85.7% when HLA-G5 critical value 82 microg/L and sCD30 critical value 12.2 microg/L. After one year post-transplantation: the sensitivity was 92.3% and the specificity 84.6% when HLA-G5 critical value 141 microg/L and sCD30 critical value 10.3 microg/L. CONCLUSION: the immune state of recipients are evaluated by combine HLA-G5 and sCD30 which may be a simple and valid method.
Assuntos
Rejeição de Enxerto/imunologia , Antígenos HLA/sangue , Antígenos de Histocompatibilidade Classe I/sangue , Antígeno Ki-1/sangue , Transplante de Rim/imunologia , Adulto , Idoso , Feminino , Antígenos HLA/imunologia , Antígenos HLA-G , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Antígeno Ki-1/imunologia , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Adulto JovemRESUMO
Proteasome inhibitor bortezomib offers one more option for acute or chronic antibody-mediated rejection after kidney transplantation, but aggravated acute kidney injury (AKI) in some cases early after surgery using bortezomib bring new problem. Here, we evaluated the effects of bortezomib and ONX-0914 on renal tubule injury in a mouse model of ischemia-reperfusion injury. After treated with bortezomib, serum creatinine, usea nitrogen and tubular necrosis significantly increased compared with vehicle-treated mice, but decreased in ONX-0914 group mildly. Infiltration of neutrophil and macrophage were less in bortezomib and ONX-0914-treated mice than vehicle-treated group, and the same was observed on oxidative stress in the kidneys. Furthermore, the apoptosis of renal tubular epithelial cells increased in bortezomib-treated mice' kidneys compared with ONX-0914 and vehicle-treated controls. In vitro HK2 cell experiments also demonstrated the proapoptotic effect of bortezomib. The mRNA expression of several proapoptotic factors increased in kidneys of bortezomib-treated mice. In brief, bortezomib, as a proteasome inhibitor, shows a certain cytotoxicity to renal tubular epithelial cell during ischemia/reperfusion injury (IRI) through increased apoptosis. ONX-0914, as an immunoproteasome inhibitor, showed equal potency on anti-inflammation and oxidative stress relieving compared with bortezomib, while less cytotoxicity. The results render the immunoproteasome is a better target for anti-rejection and protecting kidney function in the field of organ transplantation.
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OBJECTIVE: To evaluate the efficacy of kushenin in treating patients with chronic hepatitis C after renal transplantation. METHODS: Fifty-five patients were randomly assigned by lottery to the treatment group (29 cases) and control group (26 cases). The same immunosuppression therapy was given to all patients in both groups. Patients in the treatment group were treated with kushenin 0.6 g once a day, while those in the control group were treated with conventional liver protective agents such as vitamins. The treatment duration of both groups was 3 months. The incidences of serious hepatitis and acute rejection reaction, serum biochemistry parameters including indicators of liver and kidney functions, hepatic fibrosis index, and serum HCV-RNA were compared between the two groups. RESULTS: (1) The incidence of serious hepatitis in the treatment group and the control group was 3.45% (1/29 cases) and 11.54% (3/26 cases), respectively, which was insignificantly different between the two groups (P=0.335). (2) The incidence of acute rejection in the treatment group was 6.90% (2/29 cases) and that in the control group was 7.69% (2/26 cases), showing insignificant difference (P=0.335). (3) The differences in serum alanine aminotransferase (ALT), direct bilirubin (DBIL), hyaluronic acid (HA), propeptide collagen type III (PC III), laminin (LN), collagen type IV (Col IV) levels between the two groups were insignificant before transplantation (P>0.05), while the above-mentioned parameters in the treatment group were significantly lower than those in the control group after transplantation (P<0.05). The difference in serum creatinine (SCr) and endogenous creatinine clearance rate (CCr) between the two groups was insignificant before and after transplantation (P>0.05). (4) The negative conversion rate of HCV-RNA in the treatment group was 31.03% (9/29 cases), significantly higher than the value of 11.54% (3/26 cases) in the control group after transplantation (P<0.05). (5) The levels of serum ALT and DBIL in patients with HCV-RNA converted to negative were significantly lower than those with still-positive HCV-RNA (P<0.05). CONCLUSIONS: Kushenin has a certain effect on inhibiting the proliferation of HCV, protecting liver cells, and anti-liver fibrosis. On the other hand, it has no obvious influence on renal allograft function. Thus, the drug is clinically safe and effective for use in treating patients with chronic hepatitis C after renal transplantation.
Assuntos
Antivirais/administração & dosagem , Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/etiologia , Transplante de Rim/efeitos adversos , Pterocarpanos/administração & dosagem , Pterocarpanos/uso terapêutico , Adolescente , Adulto , Antivirais/efeitos adversos , China/epidemiologia , Feminino , Rejeição de Enxerto , Hepacivirus/genética , Hepatite C Crônica/epidemiologia , Hepatite C Crônica/fisiopatologia , Humanos , Incidência , Testes de Função Renal , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Testes de Função Hepática , Masculino , Pterocarpanos/efeitos adversos , RNA Viral/sangueRESUMO
The mol-ecule of the title compound, C(13)H(18)N(2)O(5), adopts a trans configuration with respect to the C=N bond. The dihedral angle between the benzene ring and the hydrazinecarboxylic acid plane is 49.75â (5)° and an intra-molecular C-Hâ¯O inter-action occurs. In the crystal structure, the mol-ecules are linked into a chain along [010] by N-Hâ¯O hydrogen bonds, and a C-Hâ¯π contact further stabilizes the structure.
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Arctigenin (ATG) is one of the main active substances in fruit derived from Arctium lappa L. Previous studies have reported that ATG have antitumor, neuroprotective, antioxidant, antifibrosis and anti-inflammatory functions. However, the actions of ATG in kidney with acute injury following ischemia/ reperfusion (I/R) is still uncertain. In our study, mice were subjected to kidney I/R by having the kidney pedicles clamped and administered with vehicle or ATG (1, 3 or 9â¯mg/kg/d) via oral gavage for 7 consecutive days prior to I/R. Notably, ATG aggravated kidney I/R injury with the concentration increases. Multiple biochemical assays and histological examination showed ATG significantly alleviated the inflammatory response as reflected by a decreased expression of proinflammatory cytokine, TLR4/MyD88, and NF-κB, along with the infiltration of CD68+ macrophage and CD11b+Gr1+ neutrophil in the kidneys. Meanwhile, ATG alleviated I/R-induced oxidative stress proved by increasing kidney manganese superoxide dismutase and glutathione peroxidase activity but reducing levels of malonaldehyde and inducible nitric oxide synthase. On the contrary, apoptosis was significantly increased in kidneys of ATG-treated mice compared with vehicle-treated controls, especially in tubular cells. There were increased numbers of TUNEL positive cells and increased Bcl-2, Bax, cleaved-caspase-3, and cleaved-caspase-9 expression. The current study demonstrates that pretreatment of ATG aggravates I/R induced acute kidney injury by increasing apoptosis of tubular cells despite reducing infiltrating inflammatory cells and proinflammatory cytokine.
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Injúria Renal Aguda/prevenção & controle , Anti-Inflamatórios/uso terapêutico , Apoptose/efeitos dos fármacos , Furanos/uso terapêutico , Rim/efeitos dos fármacos , Lignanas/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Furanos/administração & dosagem , Furanos/efeitos adversos , Inflamação , Rim/imunologia , Rim/metabolismo , Rim/patologia , Lignanas/administração & dosagem , Lignanas/efeitos adversos , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologiaRESUMO
NLRC5, as the largest member of nucleotide-binding domain and leucine-rich repeat (NLR) family, was involved in various physiological processes, such as inflammation, fibrosis, innate immunity and diabetic nephropathy. However, the role of NLRC5 in acute kidney injury remains unclear. The aim of this study was to investigate the role of NLRC5 in human renal proximal tubular epithelial cells (HK-2) exposed to hypoxia/reoxygenation (H/R). Our results demonstrated that the expression of NLRC5 was significantly up-regulated in HK-2 cells exposed to H/R. Knockdown of NLRC5 significantly improved the viability of HK-2 cells exposed to H/R. In addition, knockdown of NLRC5 efficiently inhibited H/R-induced oxidative stress and apoptosis in HK-2 cells. Mechanistically, knockdown of NLRC5 markedly enhanced the activation of PIK3/Akt signaling pathway in H/R-stimulated HK-2 cells. In summary, our findings indicate that knockdown of NLRC5 attenuates renal I/R injury in vitro through the activation of PI3K/Akt signaling pathway.
Assuntos
Técnicas de Silenciamento de Genes , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Rim/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Apoptose/genética , Linhagem Celular , Sobrevivência Celular/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Estresse Oxidativo , Traumatismo por Reperfusão/genética , Regulação para Cima/genéticaRESUMO
BACKGROUND: Immunosuppressive agents are still inefficient in preventing biopsy-proven acute rejection (BPAR) after expanded criteria donor (ECD) kidney transplantation. The aim of this study was to investigate the relationships between early immunosuppressive exposure and the development of BPAR. METHODS: We performed a retrospective study of 58 recipients of ECD kidney transplantation treated with enteric-coated-mycophenolate sodium, tacrolimus (Tac), and prednisone. The levels of mycophenolic acid-area under the curve (MPA-AUC)0-12h and Tac C0were measured at the 1st week and the 1st month posttransplant, respectively. The correlation was assessed by multivariate logistic regression. RESULTS: The occurrence rates of BPAR and antibody-mediated rejection were 24.1% and 10.3%, respectively. A low level of MPA-AUC0-12h at the 1st week posttransplant was found in BPAR recipients (38.42 ± 8.37 vs. 50.64 ± 13.22, P < 0.01). In addition, the incidence of BPAR was significantly high (P < 0.05) when the MPA-AUC0-12hlevel was <30 mg·h-1·L-1 at the 1st week (15.0% vs. 44.4%) or the Tac C0was <4 ng/ml at the 1st month posttransplant (33.3% vs. 21.6%). Multivariable logistic regression analysis showed that the MPA-AUC0-12h at the 1st week (OR: 0.842, 95% CI: 0.784-0.903) and the Tac C0at the 1st month (OR: 0.904, 95% CI: 0.822-0.986) had significant inverse correlation with BPAR (P < 0.05). CONCLUSIONS: Low-level exposure of MPA and Tac C0in the early weeks posttransplant reflects an increased acute rejection risk, which suggested that MPA-AUC0-12h <30 mg·h-1·L-1 and Tac C0 <4 ng/ml should be avoided in the first few weeks after transplantation.
Assuntos
Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Ácido Micofenólico/uso terapêutico , Tacrolimo/uso terapêutico , Adulto , Feminino , Humanos , Imunossupressores/química , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/química , Estudos Retrospectivos , Tacrolimo/química , Fatores de TempoRESUMO
BACKGROUND: Hypothermic machine perfusion (HMP) is being used more often in cardiac death kidney transplantation; however, the significance of assessing organ quality and predicting delayed graft function (DGF) by HMP parameters is still controversial. Therefore, we used a readily available HMP variable to design a scoring model that can identify the highest risk of DGF and provide the guidance and advice for organ allocation and DCD kidney assessment. METHODS: From September 1, 2012 to August 31, 2016, 366 qualified kidneys were randomly assigned to the development and validation cohorts in a 2:1 distribution. The HMP variables of the development cohort served as candidate univariate predictors for DGF. The independent predictors of DGF were identified by multivariate logistic regression analysis with a P < 0.05. According to the odds ratios (ORs) value, each HMP variable was assigned a weighted integer, and the sum of the integers indicated the total risk score for each kidney. The validation cohort was used to verify the accuracy and reliability of the scoring model. RESULTS: HMP duration (OR = 1.165, 95% confidence interval [CI]: 1.008-1.360, P = 0.043), resistance (OR = 2.190, 95% CI: 1.032-10.20, P < 0.001), and flow rate (OR = 0.931, 95% CI: 0.894-0.967, P = 0.011) were the independent predictors of identified DGF. The HMP predictive score ranged from 0 to 14, and there was a clear increase in the incidence of DGF, from the low predictive score group to the very high predictive score group. We formed four increasingly serious risk categories (scores 0-3, 4-7, 8-11, and 12-14) according to the frequency associated with the different risk scores of DGF. The HMP predictive score indicates good discriminative power with a c-statistic of 0.706 in the validation cohort, and it had significantly better prediction value for DGF compared to both terminal flow (P = 0.012) and resistance (P = 0.006). CONCLUSION: The HMP predictive score is a good noninvasive tool for assessing the quality of DCD kidneys, and it is potentially useful for physicians in making optimal decisions about the organs donated.
Assuntos
Função Retardada do Enxerto , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Adulto , Feminino , Humanos , Imunossupressores/uso terapêutico , Modelos Logísticos , Masculino , Análise Multivariada , Razão de Chances , Preservação de ÓrgãosRESUMO
BACKGROUND: Vascular resistance and flow rate during hypothermic machine perfusion (HMP) of kidneys is correlated with graft function. We aimed to determine the effects of increasing HMP pressure versus maintaining the initial pressure on kidney transplantation outcomes. METHODS: We retrospectively reviewed the data of 76 primary transplantation patients who received HMP-preserved kidneys from 48 donors after cardiac death between September 1, 2013, and August 31, 2015. HMP pressure was increased from 30 to 40 mmHg (1 mmHg = 0.133 kPa) in kidneys with poor flow and/or vascular resistance (increased pressure [IP] group; 36 patients); otherwise, the initial pressure was maintained (constant pressure group; 40 patients). Finally, the clinical characteristics and transplantation outcomes in both groups were assessed. RESULTS: Delayed graft function (DGF) incidence, 1-year allograft, patient survival, kidney function recovery time, and serum creatinine level on day 30 were similar in both groups, with improved flow and resistance in the IP group. Among patients with DGF, kidney function recovery time and DGF duration were ameliorated in the IP group. Multivariate logistic regression analysis revealed that donor hypertension (odds ratio [OR]: 1.43, 95% confidence interval [CI]: 1.02-2.06, P = 0.035), donor terminal serum creatinine (OR: 1.27, 95% CI: 1.06-1.62, P = 0.023), warm ischemic time (OR: 3.45, 95% CI: 1.97-6.37, P = 0.002), and terminal resistance (OR: 3.12, 95% CI: 1.76-6.09, P = 0.012) were independent predictors of DGF. Cox proportional hazards analysis showed that terminal resistance (hazard ratio: 2.06, 95% CI: 1.32-5.16, P = 0.032) significantly affected graft survival. CONCLUSION: Increased HMP pressure improves graft perfusion but does not affect DGF incidence or 1-year graft survival.