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1.
Kidney Int ; 104(2): 305-323, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37164261

RESUMO

Damage-associated molecular patterns (DAMPs) are a cause of acute kidney injury (AKI). Our knowledge of these DAMPs remains incomplete. Here, we report serum peroxiredoxin 1 (Prdx1) as a novel DAMP for AKI. Lipopolysaccharide (LPS) and kidney ischemia/reperfusion injury instigated AKI with concurrent increases in serum Prdx1 and reductions of Prdx1 expression in kidney tubular epithelial cells. Genetic knockout of Prdx1 or use of a Prdx1-neutralizing antibody protected mice from AKI and this protection was impaired by introduction of recombinant Prdx1 (rPrdx1). Mechanistically, lipopolysaccharide increased serum and kidney proinflammatory cytokines, macrophage infiltration, and the content of M1 macrophages. All these events were suppressed in Prdx1-/- mice and renewed upon introduction of rPrdx1. In primary peritoneal macrophages, rPrdx1 induced M1 polarization, activated macrophage-inducible C-type lectin (Mincle) signaling, and enhanced proinflammatory cytokine production. Prdx1 interacted with Mincle to initiate acute kidney inflammation. Of note, rPrdx1 upregulated Mincle and the spleen tyrosine kinase Syk system in the primary peritoneal macrophages, while knockdown of Mincle abolished the increase in activated Syk. Additionally, rPrdx1 treatment enhanced the downstream events of Syk, including transcription factor NF-κB signaling pathways. Furthermore, serum Prdx1 was found to be increased in patients with AKI; the increase of which was associated with kidney function decline and inflammatory biomarkers in patient serum. Thus, kidney-derived serum Prdx1 contributes to AKI at least in part by activating Mincle signaling and downstream pathways.


Assuntos
Injúria Renal Aguda , NF-kappa B , Camundongos , Animais , NF-kappa B/metabolismo , Lipopolissacarídeos , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Inflamação/metabolismo , Injúria Renal Aguda/genética , Injúria Renal Aguda/metabolismo , Alarminas , Camundongos Endogâmicos C57BL
2.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 45(6): 987-996, 2023 Dec 30.
Artigo em Zh | MEDLINE | ID: mdl-38173112

RESUMO

As the incidence of diabetes mellitus is rapidly increasing worldwide,that of related complications,such as diabetic kidney disease(DKD),also increases,conferring a heavy economic burden on the patients,families,society,and government.Diabetes mellitus complicated with chronic kidney disease(CKD)includes DKD and the CKD caused by other reasons.Because of the insufficient knowledge about CKD,the assessment of diabetes mellitus complicated with CKD remains to be improved.The therapies for diabetes mellitus complicated with CKD focus on reducing the risk factors.In clinical practice,DKD may not be the CKD caused by diabetes.According to clinical criteria,some non-diabetic kidney disease may be misdiagnosed as DKD and not be treated accurately.This review summarizes the status quo and research progress in the assessment,diagnosis,and treatment of diabetes mellitus complicated with CKD and predicts the directions of future research in this field.


Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Nefropatias Diabéticas , Insuficiência Renal Crônica , Humanos , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/terapia , Nefropatias Diabéticas/etiologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/terapia , Fatores de Risco , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/terapia
3.
Biochem Biophys Res Commun ; 534: 694-701, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33220928

RESUMO

Fluorofenidone (AKF-PD) is a novel pyridone agent that reduces the deposition of extracellular matrix (ECM) in various models of renal fibrosis. However, there are no reports on the effect of AKF-PD in preventing fibrosis in the folic acid nephropathy model. Besides, the mechanisms of action of AKF-PD in preventing renal fibrosis are not fully understood. In the study, we observed that AKF-PD reduced folate-induced kidney injury, ameliorated the deterioration of renal function, and suppressed the deposition of ECM by decreasing the expression of collagen I, collagen III, transforming growth factor-ß (TGF-ß), fibronectin (FN), and alpha smooth muscle actin (α-SMA) in the folic acid nephropathy model. Additionally, AKF-PD suppressed the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome to reduce the production of caspase-1 and IL-1ß, and alleviated mitochondrial oxidative damage by promoting mitochondrial energy metabolism and reducing the expression of NADPH oxidase 4 (NOX4). The results of in vitro experiments demonstrated that AKF-PD suppressed NLRP3 inflammasome activation in activated peritoneal-derived macrophages (PDMs) and renal tubular epithelial cells (RTECs). AKF-PD increased the intracellular ATP content and decreased the expression of NOX4, while preventing the excessive production of mitochondrial reactive oxygen species (mtROS) in activated PDMs. In conclusion, this study demonstrated that AKF-PD inhibited renal fibrosis by suppressing the mtROS-NLRP3 pathway in the folic acid nephropathy model. These findings provide new evidence in support of the clinical use of AKF-PD in the treatment of diseases related to renal fibrosis.


Assuntos
Nefropatias/tratamento farmacológico , Rim/patologia , Piridonas/farmacologia , Animais , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibrose , Ácido Fólico/toxicidade , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/patologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/patologia , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo
4.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(12): 1403-1408, 2021 Dec 28.
Artigo em Inglês, Zh | MEDLINE | ID: mdl-35232911

RESUMO

Diabetic kidney disease (DKD) is one of the serious microvascular complications of diabetes mellitus (DM), and it is also the leading cause for the end-stage kidney disease (ESKD), but the clinical treatment for it is limited at present. The pathogenesis of DKD is complex. Many studies have shown that podocyte injury is the core event of DKD, and oxidative stress is closely related to podocyte injury in DKD. Oxidative stress mediates podocyte apoptosis and slit diaphragm damage in DKD through various pathways. The antioxidant drugs can slow down the progression of DKD through reducing podocyte injury and are expected to enter clinical trials. The research status of antioxidant drugs is very important, which will provide new strategies for the clinical treatment of DKD.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Falência Renal Crônica , Podócitos , Apoptose , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Humanos , Falência Renal Crônica/metabolismo , Falência Renal Crônica/patologia , Estresse Oxidativo , Podócitos/metabolismo , Podócitos/patologia
5.
FASEB J ; 33(12): 14325-14336, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31661638

RESUMO

Cisplatin (CP) is one of the most effective chemotherapeutics in the treatment of human cancers. However, the beneficial effects of CP are limited by the toxic effects, especially nephrotoxicity. Fluorofenidone (AKFPD) is a promising multifunctional antifibrosis pyridinone drug discovered by our group. But there is no evidence of its protective effects against acute kidney injury (AKI). Therefore, we investigated the protective effects of AKFPD on CP-induced AKI in vivo and in vitro. Compared with the model group, treatment with AKFPD effectively ameliorated kidney damages. In order to elucidate the mechanisms, we discovered that AKFPD treatment notably alleviated generation of reactive oxygen species, reduced the phosphorylation levels of MAPKs (ERK1 and 2, JNKs, and p38), suppressed inflammatory response, inhibited apoptosis, and abated the expression of CP transporters (organic cation transporter 2 and copper transport protein 1) compared with the model group. Moreover, because renal ischemia reperfusion injury (IRI)-induced AKI and LPS-induced AKI are the major models representative of renal transplantation-correlated AKI and sepsis-related AKI, which are also the main causes of AKI, we have also proved the effectiveness of AKFPD on these models. In conclusion, these findings suggest that AKFPD is a potent drug for CP-, IRI-, and LPS-caused AKI and elucidate the underlying mechanism.-Jiang, Y., Quan, J., Chen, Y., Liao, X., Dai, Q., Lu, R., Yu, Y., Hu, G., Li, Q., Meng, J., Xie, Y., Peng, Z., Tao, L. Fluorofenidone protects against acute kidney injury.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Cisplatino/toxicidade , Piridonas/farmacologia , Animais , Antineoplásicos/toxicidade , Linhagem Celular , Transportador de Cobre 1/genética , Transportador de Cobre 1/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Rim/citologia , Rim/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Transportador 2 de Cátion Orgânico/genética , Transportador 2 de Cátion Orgânico/metabolismo , Peroxidase/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Traumatismo por Reperfusão
6.
Int J Med Sci ; 17(7): 970-984, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308551

RESUMO

Artificial intelligence (AI), as an advanced science technology, has been widely used in medical fields to promote medical development, mainly applied to early detections, disease diagnoses, and management. Owing to the huge number of patients, kidney disease remains a global health problem. Challenges remain in its diagnosis and treatment. AI could take individual conditions into account, produce suitable decisions and promise to make great strides in kidney disease management. Here, we review the current studies of AI applications in kidney disease in alerting systems, diagnostic assistance, guiding treatment and evaluating prognosis. Although the number of studies related to AI applications in kidney disease is small, the potential of AI in the management of kidney disease is well recognized by clinicians; AI will greatly enhance clinicians' capacity in their clinical practice in the future.


Assuntos
Inteligência Artificial , Diagnóstico por Computador , Nefropatias/diagnóstico , Nefropatias/terapia , Anemia/terapia , Pressão Sanguínea , Humanos , Processamento de Imagem Assistida por Computador , Nefropatias/patologia , Transplante de Rim , Prognóstico
7.
Clin Exp Nephrol ; 24(10): 865-875, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32740698

RESUMO

BACKGROUND: Chronic kidney disease (CKD) stage 3 was divided into two subgroups by eGFR (45 mL/ min 1.73 m2). There is difference in prevalence of CKD, racial differences, economic development, genetic, and environmental backgrounds between China and Western countries. METHODS: We used a computational intelligence model (CKD stage 3 Modeling, CSM) to distinguish CKD stage 3 with CKD stage 3a/3b by data distribution rules, pearson correlation coefficient (PCC), spearman correlation (SCC) analysis, logistic regression (LR), random forest (RF), support vector machine (SVM), and neural network (Nnet) to develop Prognostic Model for patients with CKD stage 3a/3b in South Central China. Furthermore, we used RF to discover risk factors of progression of CKD stage 3a and 3b to CKD stage 5. 1090 cases of CKD stage 3 patients in Xiangya Hospital were collected. Among them, 455 patients progressed to CKD stage 5 in a median follow-up of 4 years (IQR 4.295, 4.489). RESULTS: We found that the common risk factors for progression of CKD stage 3a/3b to CKD stage 5 included albumin, creatinine, total protein, etc. Proteinuria, direct bilirubin, hemoglobin, etc. accounted for the progression from stage CKD stage 3a to stage 5. The risk factors for CKD stage 3b progression to stage 5 included low-density lipoprotein cholesterol, diabetes, eosinophil percentage, etc. CONCLUSIONS: CSM could be used as a point-of-care test to screen patients at high risk for disease progression, might allowing individualized therapeutic management.


Assuntos
Modelos Estatísticos , Redes Neurais de Computação , Insuficiência Renal Crônica/fisiopatologia , Máquina de Vetores de Suporte , Adulto , China , Progressão da Doença , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco
8.
Med Sci Monit ; 26: e922839, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32822333

RESUMO

BACKGROUND Recent guidelines recommend that patients with immunoglobulin A nephropathy (IgAN) and proteinuria 0.5-1 g/d and >1 g/d be treated with long-term renin-angiotensin system blockade (RASB). This study investigated whether patients with IgAN and persistent hematuria, but without proteinuria, can benefit from RASB. MATERIAL AND METHODS IgAN patients with persistent hematuria at four centers were recruited from January 2013 to December 2018. Patients were divided into those who did and did not receive long-term RASB. The primary outcome was the appearance of proteinuria, and the secondary outcomes were the decreased percentage of hematuria, rate of decline in estimated glomerular filtration rate (eGFR) and final blood pressure. The effects of RASB on these outcomes were assessed by multivariate Cox regression models and propensity score matching. RESULTS Of the 110 eligible patients, 44 (40.0%) received RASB and 66 (60.0%) did not. Treated patients had higher diastolic pressure. The unadjusted primary outcome, the appearance of proteinuria, was significantly less frequent in individuals who were than who were not treated with RASB. Multivariate Cox regression showed that RASB reduced the risk of the primary outcome and the levels of hematuria. The rate of eGFR decline and final blood pressure did not differ in the two groups. CONCLUSIONS RASB reduced the risk of proteinuria development and increased the remission of hematuria in patients with IgAN who presented with persistent hematuria alone. RASB, however, did not affect blood pressure in patients without hypertension and did not affect the rate of eGFR decline.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/tratamento farmacológico , Hematúria/complicações , Hematúria/tratamento farmacológico , Hipertensão/complicações , Sistema Renina-Angiotensina/efeitos dos fármacos , Adulto , Pressão Sanguínea/efeitos dos fármacos , Feminino , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Modelos de Riscos Proporcionais , Proteinúria/prevenção & controle , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
9.
J Transl Med ; 17(1): 86, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30876475

RESUMO

BACKGROUND: Chronic kidney disease (CKD) leads to end-stage renal failure and cardiovascular events. An attribute to these progressions is abnormalities in inflammation, which can be evaluated using the neutrophil-to-lymphocyte ratio (NLR). We aimed to investigate the association of NLR with the progression of end stage of renal disease (ESRD), cardiovascular disease (CVD) and all-cause mortality in Chinese patients with stages 1-4 CKD. METHODS: Patients with stages 1-4 CKD (18-74 years of age) were recruited at 39 centers in 28 cities across 22 provinces in China since 2011. A total of 938 patients with complete NLR and other relevant clinical variables were included in the current analysis. Cox regression analysis was used to estimate the association between NLR and the outcomes including ESRD, CVD events or all-cause mortality. RESULTS: Baseline NLR was related to age, hypertension, serum triglycerides, total serum cholesterol, CVD history, urine albumin to creatinine ratio (ACR), chronic kidney disease-mineral and bone disorder (CKD-MBD), hyperlipidemia rate, diabetes, and estimated glomerular filtration rate (eGFR). The study duration was 4.55 years (IQR 3.52-5.28). Cox regression analysis revealed an association of NLR and the risk of ESRD only in patients with stage 4 CKD. We did not observe any significant associations between abnormal NLR and the risk of either CVD or all-cause mortality in CKD patients in general and CKD patients grouped according to the disease stages in particular. CONCLUSION: Our results suggest that NLR is associated with the risk of ESRD in Chinese patients with stage 4 CKD. NLR can be used in risk assessment for ESRD among patients with advanced CKD; this application is appealing considering NLR being a routine test. Trial registration ClinicalTrials.gov Identifier NCT03041987. Registered January 1, 2012. (retrospectively registered) ( https://www.clinicaltrials.gov/ct2/show/NCT03041987?term=Chinese+Cohort+Study+of+Chronic+Kidney+Disease+%28C-STRIDE%29&rank=1 ).


Assuntos
Povo Asiático , Falência Renal Crônica/sangue , Falência Renal Crônica/etiologia , Linfócitos/patologia , Neutrófilos/patologia , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/mortalidade , Estudos de Coortes , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Falência Renal Crônica/mortalidade , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/mortalidade
10.
Kidney Blood Press Res ; 44(4): 656-668, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31387101

RESUMO

BACKGROUND/AIMS: Cyclosporine A (CsA) is an immunosuppressant drug that is used during organ transplants. However, its utility is limited by its nephrotoxic potential. This study aimed to investigate whether fluorofenidone (AKF-PD) could provide protection against CsA-induced nephrotoxicity. METHODS: Eighty-five male Sprague-Dawley rats were divided into 5 groups: drug solvent, CsA, CsA with AKF-PD (250, 500 mg/kg/day), and CsA with pirfenidone (PFD, 250 mg/kg/day). Tubulointerstitial injury index, extracellular matrix (ECM) deposition, expression of type I and IV collagen, transforming growth factor (TGF)-ß1, platelet-derived growth factor (PDGF), Fas ligand (FASL), cleaved-caspase-3, cleaved-poly(ADP-ribose) polymerase (PARP)-1, and the number of transferase-mediated nick end-labeling (TUNEL)-positive renal tubule cells were determined. In addition, levels of TGF-ß1, FASL, cleaved-caspase-3, cleaved-PARP-1, and number of annexin V-positive cells were determined in rat proximal tubular epithelial cells (NRK-52E) treated with CsA (20 µmol/L), AKF-PD (400 µg/mL), PFD (400 µg/mL), and GW788388 (5 µmol/L). RESULTS: AKF-PD (250, 500 mg/kg/day) significantly reduced tubulointerstitial injury, ECM deposition, expression of type I and IV collagen, TGF-ß1, PDGF, FASL, cleaved-caspase-3, cleaved-PARP-1, and number of TUNEL-positive renal tubule cells in the CsA-treated kidneys. In addition, AKF-PD (400 µg/mL) significantly decreased TGF-ß1, FASL, cleaved-caspase-3, and PARP-1 expression in NRK-52E cells and further reduced the number of annexin V-positive cells. CONCLUSION: AKF-PD protect kidney from fibrosis and apoptosis in CsA-induced kidney injury.


Assuntos
Ciclosporina/toxicidade , Fibrose/prevenção & controle , Rim/lesões , Piridonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Rim/patologia , Masculino , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley
11.
Nephrology (Carlton) ; 23(6): 573-584, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28437591

RESUMO

AIM: We explored whether Fluorofenidone reduced interleukin-1ß (IL-1ß) production by interacting with NLRP3 inflammasome in unilateral ureteral obstruction (UUO). METHODS: Ureteral obstruction rats were treated with Fluorofenidone (500 mg/kg per day) for 3, 7 days. Morphologic analysis and leukocytes infiltration were assessed in ligated kidneys. Furthermore, plasmids of NLRP3, ASC, pro-Caspase-1, pro-IL-1ß were co-transfected into 293 T cells, and then treated with Fluorofenidone (2 mM). The expression of NLRP3, ASC, pro-caspase-1, cleavage caspase-1, pro-IL-1ß and cleavage IL-1ß were measured by Western blot or real-time PCR in vivo and in vitro. Moreover the interaction of NLRP3 inflammasome-assembly was detected by co-immunoprecipitation and confocal immunofluorescence. RESULTS: Fluorofenidone treatment significantly attenuated renal fibrosis and leukocytes infiltration in UUO model. Fluorofenidone had no effect on the expression of pro-IL-1ß. Interestingly, Fluorofenidone inhibited the activation of NLRP3 inflammasome, downregulated Caspase-1 levels and thereby decreased the cleavage of pro-IL-1ß into IL-1ß in vivo and in vitro. Fluorofenidone treatment distinctively weakened the interaction between NLRP3 and ASC, as well as ASC and pro-Caspase-1 in vivo. However, Fluorofenidone treatment only significantly weakened the interaction between ASC and pro-Caspase-1 in co-transfected 293 T cells. CONCLUSION: Fluorofenidone serves as a novel anti-inflammatory agent that attenuates IL-1ß production in UUO model by interacting with NLRP3 inflammasome.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamassomos/efeitos dos fármacos , Interleucina-1beta/metabolismo , Rim/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nefrite/prevenção & controle , Piridonas/farmacologia , Obstrução Ureteral/tratamento farmacológico , Animais , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspase 1/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo , Fibrose , Células HEK293 , Humanos , Inflamassomos/genética , Inflamassomos/imunologia , Inflamassomos/metabolismo , Interleucina-1beta/genética , Rim/imunologia , Rim/metabolismo , Rim/patologia , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Nefrite/imunologia , Nefrite/metabolismo , Nefrite/patologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Obstrução Ureteral/imunologia , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
12.
Biochim Biophys Acta ; 1862(4): 556-565, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26692170

RESUMO

Cervical cancer is caused by infections with human papillomaviruses (HPV) and genetic alternations in the cervical epithelium. While the former is well studied, the latter remains unclear. We report here that CYB5D2/Neuferricin possesses tumor suppressing activity towards cervical tumorigenesis. Ectopic expression of CYB5D2 did not affect HeLa cell proliferation and the cell's ability to form xenograft tumors, but significantly inhibited HeLa cell invasion in vitro and the cell-produced lung metastasis in NOD/SCID mice. Knockdown of CYB5D2 enhanced HeLa cell invasion. Two mutations in CYB5D2, the substitutions of arginine (R) 7 with either proline (P) or glycine (G), were reported in colon cancer. Both CYB5D2(R7P) and CYB5D2(R7G) were incapable of inhibiting HeLa cell invasion. CYB5D2 binds heme, in which aspartate (D) 86 is required. While CYB5D2(D86G) is heme-binding defective, it inhibited HeLa cell invasion. On the other hand, CYB5D2(R7P) and CYB5D2(R7G) bound heme but did not inhibit HeLa cell invasion. Collectively, CYB5D2 inhibits HeLa cell invasion independently of its heme binding. Furthermore, immunohistochemistry examination of CYB5D2 expression in 20 normal cervical tissues and 40 cervical squamous cell carcinomas (SCC) revealed a CYB5D2 reduction in 87.5% (35/40) of SCC. Analysis of CYB5D2 gene expression and genomic alteration data available from Oncomeine™ detected significant reductions of CYB5D2 mRNA in 40 SCCs and CYB5D2 gene copy number in 107 SCCs. Collectively, we provide evidence that CYB5D2 is a candidate tumor suppressor of cervical tumorigenesis.


Assuntos
Citocromos b5/biossíntese , Regulação Neoplásica da Expressão Gênica , Proteínas Supressoras de Tumor/biossíntese , Neoplasias do Colo do Útero/enzimologia , Animais , Citocromos b5/genética , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Invasividade Neoplásica , Proteínas Supressoras de Tumor/genética , Neoplasias do Colo do Útero/genética
13.
BMC Nephrol ; 18(1): 311, 2017 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-29029600

RESUMO

BACKGROUND: This study aimed to compare clinical features and health-related quality of life (HRQoL) in the Chinese chronic kidney disease (CKD) 3 population and determined the necessity of the subdivision of CKD3 in Chinese patients with CKD. METHODS: Participants with stage 3 CKD (18-74 years of age) were recruited at 39 clinical centers located at 28 cities in 22 provinces of China. The sociodemographic status, medical history, anthropometric measurements, and lifestyle behaviors were documented at entry, and blood and urine samples were collected. The estimated glomerular filtration rate was calculated using the CKD-EPI creatinine equation. The HRQoL was evaluated using the kidney disease quality-of-life instrument. A linear regression model was used to estimate the association between HRQoL and CKD stages (G3b vs G3a). RESULTS: The levels of intact parathyroid hormone, systolic blood pressure, uric acid, and high-density lipoprotein cholesterol were statistically significantly higher, whereas the levels of serum bicarbonate and hemoglobin were statistically significantly lower in the G3b group compared with the G3a group. Compared with CKD G3a group, the proportions of subjects with hyperuricemia and anemia were significantly higher in CKD G3b group (61.4% vs. 52.0% and 26.4% vs. 17.9%, respectively, P< 0.01). The HRQoL scores in "physical functioning (PCS)", "symptoms and problems", "effects of the kidney disease" and "burden of the kidney disease" were statistically significantly lower in the CKD G3b group compared with the CKD G3a group (90.88 ± 11.05 vs. 89.30 ± 11.52, 88.29 ± 11.94 vs. 86.49 ± 13.45, 55.86 ± 26.40 vs. 52.10 ± 27.64, 46.56 ± 8.16 vs. 44.51 ± 9.22, respectively, P< 0.01). Further, CKD G3b was associated with a lower score of physical functioning compared with G3a (regression coefficient =-1.12 [95%CI: -2.23, -0.16]). CONCLUSIONS: The preliminary results of this study suggested that modest differences existed in many important clinical features and KDQoL between patients with G3a and G3b CKD in a Chinese population. Also, a significant association between CKD3 subdivision of the disease and PCS was detected. Although further work is needed, we can speculate based on these results the CKD3 subdivision may be clinically meaningful for Chinese patients with CKD.


Assuntos
Efeitos Psicossociais da Doença , Qualidade de Vida , Insuficiência Renal Crônica/classificação , Insuficiência Renal Crônica/fisiopatologia , Adulto , Anemia/sangue , Anemia/etiologia , Bicarbonatos/sangue , Pressão Sanguínea , China , HDL-Colesterol/sangue , Feminino , Taxa de Filtração Glomerular , Hemoglobinas/metabolismo , Humanos , Hiperuricemia/sangue , Hiperuricemia/etiologia , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Insuficiência Renal Crônica/complicações , Ácido Úrico/sangue
14.
Mol Cell Biochem ; 407(1-2): 77-87, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26033204

RESUMO

Signaling through the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, especially JAK2/STAT3, is involved in renal fibrosis. Fluorofenidone (FD), a novel pyridone agent, exerts anti-fibrotic effects in vitro and in vivo. Herein, we sought to investigate whether FD demonstrates its inhibitory function through preventing JAK2/STAT3 pathway. In this study, we examined the effect of FD on activation of rat renal interstitial fibroblasts, glomerular mesangial cells (GMC), and expression of JAK2/STAT3. Moreover, we explored the histological protection effects of FD in UUO rats, db/db mice, and phosphorylation of JAK2/STAT3 cascade. Our studies found that pretreatment with FD resulted in blockade of activation of fibroblast and GMC manifested by fibronectin (FN) and α-smooth muscle actin (α-SMA) protein expression and decline of STAT3 tyrosine phosphorylation induced by IL-6 or high glucose. In unilateral ureteral obstruction rats and a murine model of spontaneous type 2 diabetes (db/db mice), treatment with FD blocked the expression of FN and α-SMA, prevented renal fibrosis progression, and attenuated STAT3 activation. However, FD administration did not interfere with JAK2 activation both in vivo and in vitro. In summary, the molecular mechanism by which FD exhibits renoprotective effects appears to involve the inhibition of STAT3 phosphorylation.


Assuntos
Nefropatias/enzimologia , Nefropatias/prevenção & controle , Piridonas/administração & dosagem , Fator de Transcrição STAT3/metabolismo , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Nefropatias/genética , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos , Piridonas/farmacologia , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/genética
15.
Kidney Blood Press Res ; 40(1): 89-99, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26029782

RESUMO

BACKGROUND/AIMS: We evaluated the therapeutic effects of fluorofenidone (AKF-PD), a novel pyridone agent, targeting oxidative stress and fibrosis in obstructive nephropathy. METHODS: AKF-PD was used to treat renal interstitial fibrosis in unilateral ureteral obstruction (UUO) obstructive nephropathy in rats. The expression of NOX2 (gp91phox), fibronectin and extracellular signal regulated kinase (ERK) were detected by western blot. A level of Malondialdehyde (MDA), an oxidative stress marker, was measured by ELISA. In addition, ROS and the expressions of NOX2, collagen I (a1), fibronectin and p-ERK were measured in angiotensin (Ang) II-stimulated rat proximal tubular epithelial cells (NRK-52E) in culture. RESULTS: In NRK-52E cells, AKF-PD reduced AngII induced expressions of ROS, NOX2, fibronectin, collagen I (a1) and p-ERK. In UUO kidney cortex, AKF-PD attenuated the degree of renal interstitial fibrosis, which was associated with reduced the expressions of collagen I (a1) and fibronectin. Furthermore, AKF-PD downregulated the expressions of NOX2, MDA and p-ERK. CONCLUSION: AKF-PD treatment inhibits the progression of renal interstitial fibrosis by suppressing oxidative stress and ERK/MAPK signaling pathway.


Assuntos
Nefropatias/tratamento farmacológico , Nefropatias/enzimologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Glicoproteínas de Membrana/antagonistas & inibidores , NADPH Oxidases/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Piridonas/uso terapêutico , Animais , Fibrose , Regulação Enzimológica da Expressão Gênica , Nefropatias/patologia , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Glicoproteínas de Membrana/biossíntese , NADPH Oxidase 2 , NADPH Oxidases/biossíntese , Estresse Oxidativo/fisiologia , Piridonas/farmacologia , Ratos , Ratos Sprague-Dawley
16.
Biochim Biophys Acta ; 1833(1): 90-100, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23098854

RESUMO

Non-homologous end joining (NHEJ) is one of the major pathways that repairs double-stranded DNA breaks (DSBs). Activation of DNA-PK is required for NHEJ. However, the mechanism leading to DNA-PKcs activation remains incompletely understood. We provide evidence here that the MEK-ERK pathway plays a role in DNA-PKcs-mediated NHEJ. In comparison to the vehicle control (DMSO), etoposide (ETOP)-induced DSBs in MCF7 cells were more rapidly repaired in the presence of U0126, a specific MEK inhibitor, based on the reduction of γH2AX and tail moments. Additionally, U0126 increased reactivation of luciferase activity, which resulted from the repair of restriction enzyme-cleaved DSBs. Furthermore, while inhibition of ERK activation using the dominant-negative MEK1K97M accelerated the repair of DSBs, enforcing ERK activation with the constitutively active MEK1Q56P reduced DSB repair. In line with MEK activating ERK1 and ERK2 kinases, knockdown of either ERK1 or ERK2 increased DSB repair. Consistent with the activation of DNA-PKcs being required for NHEJ, we demonstrated that inhibition of ERK activation using U0126, MEK1K97M, and knockdown of ERK1 or ERK2 enhanced ETOP-induced activation of DNA-PKcs. Conversely, enforcing ERK activation by MEK1Q56P reduced ETOP-initiated DNA-PKcs activation. Taken together, we demonstrate that ERK reduces NHEJ-mediated repair of DSBs via attenuation of DNA-PKcs activation.


Assuntos
Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Proteínas Nucleares/agonistas , RNA Interferente Pequeno/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Proteína Quinase Ativada por DNA/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Etoposídeo/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Nucleares/metabolismo , Células Tumorais Cultivadas , Regulação para Cima/efeitos dos fármacos
17.
Biochim Biophys Acta ; 1822(6): 875-84, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22406297

RESUMO

Loss of IQGAP2 contributes to the tumorigenesis of hepatocellular carcinoma and gastric cancer. However, whether IQGAP2 also suppresses prostate tumorigenesis remains unclear. We report here that IQGAP2 is a candidate tumour suppressor of prostate cancer (PC). Elevated IQGAP2 was detected in prostatic intraepithelial neoplasia (PIN), early stages of PCs (Gleason score ≤3), and androgen-dependent LNCaP PC cells. However, IQGAP2 was expressed at substantially reduced levels not only in prostate glands and non-tumorigenic BPH-1 prostate epithelial cells but also in advanced (Gleason score 4 or 5) and androgen-independent PCs. Furthermore, xenograft tumours that were derived from stem-like DU145 cells displayed advanced features and lower levels of IQGAP2 in comparison to xenograft tumours that were produced from non stem-like DU145 cells. Collectively, these results suggest that IQGAP2 functions in the surveillance of prostate tumorigenesis. Consistent with this concept, ectopic IQGAP2 reduced the proliferation of DU145, PC3, and 293T cells as well as the invasion ability of DU145 cells. While ectopic IQGAP2 up-regulated E-cadherin in DU145 and PC3 cells, knockdown of IQGAP2 reduced E-cadherin expression. In primary PC and DU145 cells-derived xenograft tumours, the majority of tumours with high levels of IQGAP2 were strongly-positive for E-cadherin. Therefore, IQGAP2 may suppress PC tumorigenesis, at least in part, by up-regulation of E-cadherin. Mechanistically, overexpression of IQGAP2 significantly reduced AKT activation in DU145 cells and inhibition of AKT activation upregulated E-cadherin, suggesting that IQGAP2 increases E-cadherin expression by inhibiting AKT activation. Taken together, we demonstrate here that IQGAP2 is a candidate tumour suppressor of PC.


Assuntos
Transformação Celular Neoplásica , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Supressoras de Tumor/metabolismo , Proteínas Ativadoras de ras GTPase/genética , Proteínas Ativadoras de ras GTPase/metabolismo , Animais , Caderinas/biossíntese , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Próstata/metabolismo , Próstata/patologia , Neoplasia Prostática Intraepitelial/metabolismo , Neoplasia Prostática Intraepitelial/patologia , Proteínas Proto-Oncogênicas c-akt/biossíntese , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Transplante Heterólogo , Proteínas Supressoras de Tumor/genética
18.
Nephrology (Carlton) ; 18(10): 690-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23841831

RESUMO

AIM: Oxidative stress plays an important role in the progression of renal interstitial fibrosis. The nicotinamide adeninedinucleotide phosphate (NADPH) oxidase (Nox) family is considered one of the major sources of reactive oxygen species (ROS). In the present study, we investigated the inhibitory effects of a novel anti-fibrotic agent, Fluorofenidone (AKF-PD), upon Nox-mediated oxidative stress and deposition of extracellular matrix (ECM) in the development of renalinterstitial fibrosis. METHODS: AKF-PD was used to treat renal fibrosis in unilateral ureteral obstruction (UUO) obstructive nephropathy in rats. The expression of Nox homologues, p-Akt, collagen I and III were detected by immunoblotting or immunohistochemistry. Levels of 8-iso prostaglandin F2alpha (8-Iso PGF2a) was measured by enzyme linked immunosorbent assay. In addition, ROS and the expression of collagen I (1a), Nox subunits and p-Akt was measured in angiotensin (Ang) II-stimulated rat proximal tubular epithelial (NRK-52E) cells in culture. RESULTS: AKF-PD treatment significantly attenuated tubulo-interstitial injury, ECM deposition and oxidative stress in fibrotic rat kidneys. In addition, AKF-PD inhibited the expression of ROS, Collagen I (1a), Nox2, p-Akt in Ang II-stimulated NRK-52E cells. CONCLUSION: AKF-PD attenuates the progression of renal interstitial fibrosis partly by suppressing NADPH oxidase and ECM deposition via the PI3K/Akt signalling pathway, suggesting AKF-PD is a potential novel therapeutic agent against renal fibrosis.


Assuntos
Antioxidantes/farmacologia , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Inibidores Enzimáticos/farmacologia , Nefropatias/prevenção & controle , Túbulos Renais/efeitos dos fármacos , NADPH Oxidases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Angiotensina II/farmacologia , Animais , Linhagem Celular , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Colágeno Tipo I/metabolismo , Dinoprosta/análogos & derivados , Dinoprosta/metabolismo , Modelos Animais de Doenças , Fibrose , Nefropatias/enzimologia , Nefropatias/etiologia , Nefropatias/patologia , Túbulos Renais/enzimologia , Túbulos Renais/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Losartan/farmacologia , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , NADPH Oxidase 2 , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Ratos , Ratos Sprague-Dawley , Transfecção , Obstrução Ureteral/complicações
19.
Biomed Pharmacother ; 164: 114844, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37224750

RESUMO

AIMS: Acute liver failure (ALF) is a life-threatening disease characterized by abrupt and extensive hepatic necrosis and apoptosis, resulting in high mortality. The approved drug, N-acetylcysteine (NAC), is only effective for acetaminophen (APAP)-associated ALF at the early stage. Thus, we investigate whether fluorofenidone (AKF-PD), a novel antifibrosis pyridone agent, protects against ALF in mice and explore its underlying mechanisms. METHODS: ALF mouse models were established using APAP or lipopolysaccharide/D-galactosamine (LPS/D-Gal). Anisomycin and SP600125 were used as JNK activator and inhibitor, respectively, and NAC served as a positive control. Mouse hepatic cell line AML12 and primary mouse hepatocytes were used for in vitro studies. RESULTS: AKF-PD pretreatment alleviated APAP-induced ALF with decreased necrosis, apoptosis, reactive oxygen species (ROS) markers, and mitochondrial permeability transition in liver. Additionally, AKF-PD alleviated mitochondrial ROS stimulated by APAP in AML12 cells. RNA-sequencing in the liver and subsequent gene set enrichment analysis showed that AKF-PD significantly impacted MAPK and IL-17 pathway. In vitro and in vivo studies demonstrated that AKF-PD inhibited APAP-induced phosphorylation of MKK4/JNK, while SP600125 only inhibited JNK phosphorylation. The protective effect of AKF-PD was abolished by anisomycin. Similarly, AKF-PD pretreatment abolished hepatotoxicity caused by LPS/D-Gal, decreased ROS levels, and diminished inflammation. Furthermore, unlike NAC, AKF-PD, inhibited the phosphorylation of MKK4 and JNK upon pretreatment, and improved survival in cases of LPS/D-Gal-induced mortality with delayed dosing. CONCLUSIONS: In summary, AKF-PD can protect against ALF caused by APAP or LPS/D-Gal, in part, via regulating MKK4/JNK pathway. AKF-PD might be a novel candidate drug for ALF.


Assuntos
Falência Hepática Aguda , Sistema de Sinalização das MAP Quinases , Camundongos , Animais , Espécies Reativas de Oxigênio/metabolismo , Acetaminofen/metabolismo , Lipopolissacarídeos/farmacologia , Anisomicina/metabolismo , Anisomicina/farmacologia , Fígado , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/prevenção & controle , Piridonas/farmacologia , Necrose/metabolismo , Camundongos Endogâmicos C57BL , Hepatócitos
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