Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 99
Filtrar
1.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(5): 538-542, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34816669

RESUMO

Objective: To investigate the effects of calcium-sensing receptor (CaSR) on the c-Jun N-terminal kinase (JNK) in myocardial injury induced by endotoxin. Methods: The endotoxic model of neonatal rats was made by intraperitoneal injection of LPS(5 mg/kg). Neonatal Wistar rats were randomly divided into 6 groups: ①control group (saline group), ②endotoxin (LPS) group, ③LPS + CaSR agonist group, ④LPS + CaSR inhibitor group, ⑤LPS + JNK inhibitor group, ⑥LPS + CaSR inhibitor + JNK inhibitor group. The morphology of myocardium was observed by HE staining. The content of lactate dehydrogenase(LDH) in serum was determined. And the expression of IL-6 mRNA was detected by PCR. The protein expressions of CaSR and JNK were analyzed by Western blot. Results: Compared with the control group, the myocardial injury was aggravated in the LPS group. The content of LDH and the expressions of IL-6 mRNA, CaSR and JNK were increased significantly (P<0.05). Compared with the LPS group,myocardial injury was aggravated in the CaSR agonist group. The content of LDH and the expressions of IL-6 mRNA,CaSR and JNK were increased (P<0.05). In the CaSR inhibitor group,myocardial injury was reduced. The content of LDH and the expressions of CaSR and JNK were decreased (P<0.05). In the JNK inhibitor group,myocardial injury was further alleviated. The content of LDH and the expressions of IL-6 mRNA, CaSR and JNK were decreased (P<0.05). Myocardial injury was significantly reduced in the CaSR inhibitor + JNK inhibitor group. The content of LDH and the expressions of IL-6 mRNA, CaSR and JNK were further reduced (P<0.05). Conclusion: CaSR is involved in myocardial injury induced by LPS in neonatal rats perhaps through the JNK pathway.


Assuntos
Sistema de Sinalização das MAP Quinases , Receptores de Detecção de Cálcio , Animais , Apoptose , Endotoxinas , Ratos , Ratos Wistar , Receptores de Detecção de Cálcio/metabolismo
2.
Front Cell Dev Biol ; 9: 733831, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34805144

RESUMO

Tubular cell senescence is a common biologic process and contributes to the progression of chronic kidney disease (CKD); however, the molecular mechanisms regulating tubular cell senescence are poorly understood. Here, we report that integrin ß3 (ITGB3) expression was increased in tubular cells and positively correlated with fibrosis degree in CKD patients. ITGB3 overexpression could induce p53 pathway activation and the secretion of TGF-ß, which, in turn, resulted in senescent and profibrotic phenotype change in cultured tubular cells. Moreover, according to the CMAP database, we identified isoliquiritigenin (ISL) as an agent to inhibit ITGB3. ISL treatment could suppress Itgb3 expression, attenuate cellular senescence, and prevent renal fibrosis in mice. These results reveal a crucial role for integrin signaling in cellular senescence, potentially identifying a new therapeutic direction for kidney fibrosis.

3.
Aging (Albany NY) ; 13(17): 21778-21790, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34520395

RESUMO

We investigated the influence of signal transducer and activator of transcription-3 (STAT3) on the spinal cord tissue grafts of rat fetuses with spina bifida aperta. In particular, we hoped to identify whether transfection of the STAT3 overexpression plasmid increases the survival of spinal cord transplantation in order to improve therapeutic efficacy. The fetal rat model of spina bifida aperta was established using retinoic acid and treated with a microsurgical injection of bone marrow mesenchymal stem cells (BMSCs). The animals were divided into either the blank control group, negative control group or the experimental group. The optical density (OD) value of BMSCs viability was determined using the Cell Counting Kit-8 (CCK-8). The expression of STAT3, phosphorylated STAT3 (pSTAT3), neural markers and apoptosis-related factors were evaluated using real-time PCR and Western blot. The OD value in the experimental group was highest at eight hours after transplantation using CCK-8. The expression of pSTAT3, glial fibrillary acidic protein, neuron-specific enolase, neurofilament and nestin in the experimental group was significantly higher compared to the blank control group and negative control group (P<0.05). However, STAT3 expression in the experimental group was statistically significantly decreased (P<0.05). The relative expression of caspase-8 and bcl-2 in the experimental group were significantly lower compared to the blank control group and negative control group (P<0.05). Transfection of the recombinant lentivirus-mediated STAT3 overexpression plasmid with BMSCs can help improve the efficiency of transforming into neural cells and provide new seed cells for the treatment of congenital spina bifida aperta.

4.
Ann Med ; 53(1): 1576-1588, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34477472

RESUMO

BACKGROUND: Long noncoding RNAs (LncRNAs) are regulatory molecules that play important roles in various biological and pathological processes. Herein, we aimed to explore whether maternally expressed gene 8 (MEG8) promotes M1 macrophage polarization among Henoch-Schonlein purpura (HSP) rats, and to investigate the underlying mechanism. METHODS: Relative mRNA expression of MEG8, miR-181a-5p and suppressor of SH2 domain-containing tyrosine phosphatase 2 (SHP2) were examined using quantitative reverse transcription polymerase chain reaction. Furthermore, expression of SHP2 and the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway-related proteins was identified using western blot. Luciferase activity assay was conducted to evaluate whether miR-181a-5p could bind to MEG8 or SHP2. The macrophage phenotype was determined using flow cytometry and enzyme-linked immunosorbent assay. RESULTS: We observed macrophage polarization towards the M2 phenotype in the peripheral blood of HSP rats. Furthermore, MEG8 and SHP2 expression were down-regulated, while miR-181a-5p was up-regulated in monocyte-derived macrophages from the HSP rats compared to the control group. Furthermore, MEG8 functioned as a sponge for miR-181a-5p in order to facilitate SHP2 expression. Moreover, miR-181a-5p mimic and SHP2 knockdown significantly reversed the MEG8 overexpression-mediated suppression of JAK2/STAT3 signalling, and promotion of M1 polarization. CONCLUSIONS: The lncRNA MEG8 sponged miR-181a-5p, which contributes to M1 macrophage polarization by regulating SHP2 expression in HSP rats.Key MessagesLncRNA MEG8 downregulation and M2 polarization in Henoch Schonlein purpura rats.MEG8 upregulation enhances M1 polarization and suppresses JAK2/STAT3 pathway.MEG8 sponges miRNA-181a-5p to regulate SHP2 expression.MiRNA-181a-5p upregulation reverses lncRNA MEG8-mediated enhancement of M1 polarization and inhibition of JAK2/STAT3 pathway.SHP2 downregulation reverses lncRNA MEG8-mediated enhancement of M1 polarization and inhibition of JAK2/STAT3 pathway.

5.
Cell Signal ; 86: 110088, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34265414

RESUMO

Retinoblastoma (RB) is the primary neoplasms of the retina that is most common in pediatrics age. Long non-coding RNAs (lncRNAs) has been noticed for strong relation to the occurrence and progress of retinoblastoma. Previously, we have demonstrated that lncRNA colon cancer-associated transcript 1 (CCAT1) in two RB cell lines SO-RB50 and Y79 was obviously overexpressed, and notably, lncRNA CCAT1 attenuated miR-218-5p expressionand induced proliferation, cell migration and invasion. But, how lncRNA CCAT1 acts in RB development and the potential molecular mechanisms remain to be determined. In this study, the expression levels of lncRNA CCAT1 and miR-218-5p were evaluated in RB tissues by Q-PCR, which established the results in the cell lines. Further, lncRNA CCAT1 was shown to promote epithelial-to-mesenchymal transition (EMT), cellular migration and invasion of RB cells by functional analysis of downregulation and overexpression of lncRNA CCAT1 with specific siRNA and pcDNA transfection. By performing bioinformatics and dual luciferase reporter assay, we verified the direct interaction between lncRNA CCAT1 and miR-218-5p. Besides, bioinformatics analysis indicated that metal regulatory transcription factor 2 (MTF2) might be a potent novel target for miR-218-5p, which was further validated with luciferase reporter assay, Q-PCR and also Western blot analysis. Functional analysis and rescue analysis showed that lncRNA CCAT1 via competitive binding to miR-218-5p to modulate MTF2 expression thus accelerate EMT, cell migration and invasion of RB. In conclusion, here we identified the lncRNA CCAT1/miR-218-5p/MTF2 axis in RB cell lines. Our investigations on the function of lncRNA CCAT1 and the roles of the related molecules hint a novel potential target fo RB therapy.

6.
Can J Diabetes ; 2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34266745

RESUMO

BACKGROUND: Our aim in this study was to explore the risk factors for kidney disease in Chinese men and women with type 2 diabetes (T2D) and to clarify the relationship between obesity and the risk of chronic kidney disease (CKD). METHODS: This retrospective study included 3,194 patients with T2D. Among 2,574 T2D patients without CKD at baseline, 753 with follow-up records of at least 12 months were included in the retrospective cohort. Logistic regression and Cox regression were used to evaluate the risk for CKD in men and women. A restricted cubic spline model was used to analyze the association of body mass index (BMI) and waist circumference (WC) with CKD risk. RESULTS: Multivariate logistic regression analysis suggested that obesity was a risk factor for T2D with CKD in men but not in women. After a median follow-up period of 2.8 years, the incidence of CKD in men with obesity was significantly higher than that in men with obesity with T2D (p=0.039), but there was no statistically significant difference between women with obesity and women without obesity with T2D (p=0.825). In the restricted cubic spline model analysis, BMI and WC were associated with CKD risk in a nonlinear fashion in males and females. The risk of CKD was higher in males with a BMI of ≥29.5 kg/m2 or a WC of ≥100 cm, whereas there was no difference observed in females. CONCLUSIONS: Obesity was strongly related to T2D with CKD in men. Male diabetes patients with obesity, especially abdominal obesity, are more likely to develop CKD.

7.
Cell Death Dis ; 12(5): 432, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931588

RESUMO

Renal tubular epithelial cells (TECs) play a key role in renal fibrogenesis. After persistent injuries that are beyond self-healing capacity, TECs will dedifferentiate, undergo growth arrest, convert to profibrogenic phenotypes, and resort to maladaptive plasticity that ultimately results in renal fibrosis. Evidence suggests that glycogen synthase kinase (GSK) 3ß is centrally implicated in kidney injury. However, its role in renal fibrogenesis is obscure. Analysis of publicly available kidney transcriptome database demonstrated that patients with progressive chronic kidney disease (CKD) exhibited GSK3ß overexpression in renal tubulointerstitium, in which the predefined hallmark gene sets implicated in fibrogenesis were remarkably enriched. In vitro, TGF-ß1 treatment augmented GSK3ß expression in TECs, concomitant with dedifferentiation, cell cycle arrest at G2/M phase, excessive accumulation of extracellular matrix, and overproduction of profibrotic cytokines like PAI-1 and CTGF. All these profibrogenic phenotypes were largely abrogated by GSK3ß inhibitors or by ectopic expression of a dominant-negative mutant of GSK3ß but reinforced in cells expressing the constitutively active mutant of GSK3ß. Mechanistically, GSK3ß suppressed, whereas inhibiting GSK3ß facilitated, the activity of cAMP response element-binding protein (CREB), which competes for CREB-binding protein, a transcriptional coactivator essential for TGF-ß1/Smad signaling pathway to drive TECs profibrogenic plasticity. In vivo, in mice with folic acid-induced progressive CKD, targeting of GSK3ß in renal tubules via genetic ablation or by microdose lithium mitigated the profibrogenic plasticity of TEC, concomitant with attenuated interstitial fibrosis and tubular atrophy. Collectively, GSK3ß is likely a pragmatic therapeutic target for averting profibrogenic plasticity of TECs and improving renal fibrosis.


Assuntos
Células Epiteliais/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Túbulos Renais/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Animais , Técnicas de Cultura de Células , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Knockout , Transfecção
8.
Front Pediatr ; 9: 675022, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981656

RESUMO

Background: Accumulating evidence suggests a connection between the gut microbiota and neonatal diseases. Hypoxia may play an important role in the intestinal lesions in neonates. Objective: This study aims to determine whether the gut microbiota differs between intrauterine hypoxic rats and healthy controls and to identify the factors that influence the changes in the gut microbiota. Methods: We constructed an intrauterine hypoxia model in rats and collected the intestinal contents of intrauterine hypoxic newborn rats and normal newborn rats within 4 h and on the seventh day after birth. They were divided them into the intrauterine hypoxia first-day group (INH1), intrauterine hypoxia seventh-day group (INH7), normal first-day group (NOR1), and normal seventh-day group (NOR7). The contents of the intestines were sequenced with 16S rRNA sequencing, the sequencing results were analyzed for biological information, and the differences in the diversity, richness, and individual taxa among the groups were analyzed. Results: The abundance of the gut microbiota of neonatal rats with intrauterine hypoxia was higher than that of the control group rats. Intrauterine hypoxia altered the structural composition of the gut microbiota in neonatal rats. The INH1 group showed increased species richness, phylogenetic diversity, and ß-diversity, and altered relative abundance in several taxa compared to those in the control group. The differences in the microbiota among the four groups were significantly higher than those within the group, and the differences in the abundance and diversity of the INH7 and NOR7 groups decreased after 7 days of suckling. Functional analysis based on the Cluster of Orthologous Groups (COG) suggested that 23 functional COG categories. There was no significant difference in the functional categories between the hypoxia group and the normal group. Conclusion: Intrauterine hypoxia changed the initial colonization of the gut microbiota in neonatal rats. It could increase the species richness and ß-diversity of the gut microbiota, and altered relative abundances of several taxa.

9.
Am J Med Sci ; 361(6): 776-785, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33667434

RESUMO

BACKGROUND: We aimed to investigate the mechanisms of renal fibrosis and explore the effect of CD4+CD25+Foxp3+ regulatory T cells (Treg) on renal fibrosis after the obstruction was removed. METHODS: Fifty-five C57BL/6 mice were randomly divided into three groups: the unilateral ureteral obstruction (UUO) group, the relief for unilateral ureteral obstruction (RUUO) group, and the RUUO+Treg group. Renal fibrosis indexes of RUUO mice were evaluated using hematoxylin and eosin (HE) and, Masson staining and immunohistochemistry after CD4+CD25+Treg cells were injected into the tail vein at the moment of recanalization. We detected the levels of Treg, M1, and M2 markers by flow cytometry, and the levels of transforming growth factor (TGF)-ß1, interleukin (IL)-1ß, IL-6 and IL-10 using ELISA. RESULTS: The tubular necrosis score, AO value of α-SMA (smooth muscle actin), and collagen area on the 3rd and 14th days post RUUO were up-regulated compared with the 7th day post RUUO (P<0.05). After injection of Treg via tail vein, the tubular necrosis score, AO value of α-SMA, TGF-ß1 level, and collagen area in the RUUO+Treg group on the 14th day were down-regulated compared with the RUUO group (P<0.05). Moreover, Treg could transform M1 macrophages into M2 macrophages, manifesting as up-regulated expression of CD206 compared with the RUUO group (P<0.05). Treg could also down-regulate the secretion of IL-6 and IL-1ß while up-regulating the secretion of IL-10 in vitro compared with the M1 group (P<0.05). CONCLUSIONS: The kidney could deteriorate into a state of injury and fibrosis after the obstruction was removed, and Treg could effectively protect the kidney function.


Assuntos
Rim/imunologia , Rim/patologia , Macrófagos/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/transplante , Animais , Células Cultivadas , Técnicas de Cocultura , Fibrose/imunologia , Fibrose/patologia , Fibrose/terapia , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
10.
Neuroreport ; 32(5): 352-358, 2021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33661803

RESUMO

Long noncoding RNA (LncRNA) H19 has been proven to be involved in many kinds of cancers including glioma, and a previous study has shown an autophagy regulation of H19. The mammalian target of rapamycin (mTOR) signaling pathway plays a key role in autophagy and Unc-51 like autophagy activating kinase 1 (ULK1) is also thought to be involved in autophagy signaling. In our study, we investigated the role of mTOR/ULK1 autophagy signaling in the H19-mediated promotion of glioma proliferation. Human glioma cells U87 and U251 and normal human astrocytes HA1800 were used in the study. First, the expression of H19 was determined in U87, U251, and HA1800 cells. Then, the cell proliferation and migration of glioma cells were detected, while the protein levels of main molecules of the mTOR/ULK1 pathway and autophagy-related proteins were also examined. Rapamycin, an inhibitor of mTOR, was used to further study the role of H19 in autophagy. We observed that overexpressed H19 promoted the proliferation and migration in glioma cells. The autophagy of U87 cells was suppressed when H19 was overexpressed and enhanced when H19 was silenced. H19 overexpression inhibited mTOR phosphorylation and promoted ULK1 phosphorylation. H19 promoted proliferation, migration, and autophagy by regulating mTOR signaling. In conclusion, we validate that H19 contributes to the proliferation and autophagy of glioma cells through the mTOR/ULK1 pathway.

11.
Am J Physiol Renal Physiol ; 320(3): F273-F284, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33427062

RESUMO

Peritoneal dialysis (PD)-related peritoneal fibrosis (PF) is characterized by progressive extracellular matrix (ECM) accumulation in peritoneal mesothelial cells (PMCs) during long-term use of high glucose (HG)-based dialysates. Activation of the renin-angiotensin system (RAS) has been shown to be associated with PF. The aim of this study was to explore the underlying mechanism of the RAS in HG-induced PF. We treated C57BL/6 mice and a human PMC line with HG to induce a PF model and to stimulate ECM accumulation, respectively. RAS activity was blocked using valsartan or angiotensin II (ANGII) type 1 receptor siRNA. The major findings were as follows. First, mice in the HG group exhibited increased collagen deposition and expression of ECM proteins, including α-smooth muscle actin (α-SMA) and collagen type I in the peritoneum. Consistent with the in vivo data, HG upregulated α-SMA expression in human peritoneal mesothelial cells (HPMCs) in a time- and dose-dependent manner. Second, HG stimulation led to RAS activation in HPMCs, and inactivation of RAS decreased the expression of ECM proteins in vivo and in vitro, even during HG stimulation. Finally, RAS-mediated ECM production was associated with lipid accumulation in HPMCs and depended on the dysregulation of the low-density lipoprotein receptor (LDLr) pathway. HG-stimulated HPMCs showed increased coexpression of LDLr and α-SMA, whereas blockade of RAS activity reversed the effect. Furthermore, inhibition of LDLr signaling decreased α-SMA and collagen type I expression in HPMCs when treated with HG and ANG II. In conclusion, increased intracellular RAS activity impaired lipid homeostasis and induced ECM accumulation in HPMCs by disrupting the LDLr pathway, which contributed to PF.


Assuntos
Matriz Extracelular/metabolismo , Fibrose Peritoneal/metabolismo , Peritônio/metabolismo , Receptores de LDL/metabolismo , Sistema Renina-Angiotensina , Actinas/metabolismo , Animais , Linhagem Celular , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Matriz Extracelular/patologia , Glucose , Humanos , Masculino , Camundongos Endogâmicos C57BL , Oxirredução , Fibrose Peritoneal/induzido quimicamente , Fibrose Peritoneal/genética , Fibrose Peritoneal/patologia , Peritônio/patologia , Receptores de LDL/genética , Sistema Renina-Angiotensina/genética , Transdução de Sinais
12.
Ther Adv Respir Dis ; 14: 1753466620929225, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32482141

RESUMO

BACKGROUND: Talaromyces marneffei, also named Penicillium marneffei, is an opportunistic pathogen that can cause systemic or limited infection in human beings. This infection is especially common in human immunodeficiency virus (HIV)-infected hosts; however, it has also been recently reported in HIV-negative hosts. Here, we report a very rarely seen case of T. marneffei pulmonary infection in a non-HIV-infected patient with signal transducer and activator of transcription 3 (STAT3) mutation. CASE PRESENTATION: A 34-year-old woman was admitted to our hospital for uncontrollable nonproductive cough and dyspnea with exercise. She had been immunocompromised since infancy. Computerized tomography scan showed multiple ground glass opacities with multiple bullae in both lungs. Next generation sequencing (NGS) of the bronchoalveolar lavage fluid identified T. marneffei nucleotide sequences. Culture of bronchoscopy specimens further verified the results. The patient was HIV negative, and blood gene detection indicated STAT3 mutation. To date, following the application of itraconazole, the patient has recovered satisfactorily. CONCLUSION: In clinical practice, T. marneffei infection among HIV-negative individuals is relatively rare, and we found that patients who are congenitally immunocompromised due to STAT3 mutation may be potential hosts. Early diagnosis and timely treatment are expected to improve the prognosis of T. marneffei infection. NGS is a powerful technique that may play an important role in this progress. The reviews of this paper are available via the supplemental material section.


Assuntos
Análise Mutacional de DNA , Hospedeiro Imunocomprometido/genética , Pneumopatias Fúngicas/diagnóstico , Mutação , Micoses/diagnóstico , Infecções Oportunistas/diagnóstico , Fator de Transcrição STAT3/genética , Talaromyces/patogenicidade , Adulto , Diagnóstico Precoce , Feminino , Teste de HIV , Sequenciamento de Nucleotídeos em Larga Escala , Interações Hospedeiro-Patógeno , Humanos , Pneumopatias Fúngicas/genética , Pneumopatias Fúngicas/imunologia , Pneumopatias Fúngicas/microbiologia , Micoses/genética , Micoses/imunologia , Micoses/microbiologia , Infecções Oportunistas/genética , Infecções Oportunistas/imunologia , Infecções Oportunistas/microbiologia , Valor Preditivo dos Testes , Talaromyces/imunologia
13.
Exp Biol Med (Maywood) ; 245(11): 983-993, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32408765

RESUMO

IMPACT STATEMENT: Our study provided new insight into the mechanism underlying the preservation of the peritoneum by valsartan. The results demonstrated that the mice receiving chronic high glucose (HG) peritoneal dialysis solution infusion showed a typical feature of peritoneal fibrosis (PF), as well as higher expression of α-smooth muscle actin (α-SMA) and collagen I. In vitro, HG increased the protein expression of α-SMA and collagen I in a dose-dependent manner, while valsartan significantly ameliorated these pathological changes. Interestingly, there was a parallel decrease in the activity of mammalian target of rapamycin complex 1 (mTORC1) and the protein expression levels of α-SMA and collagen I upon treatment with valsartan in vivo and in vitro. Moreover, the mTOR agonist MHY1485 reversed the downregulation of α-SMA and collagen I in vitro, even in the presence of valsartan. Altogether, our findings reported for the first time that valsartan exerts a protective effect against HG-induced PF by inhibiting the activity of the mTORC1 pathway.


Assuntos
Soluções para Diálise/toxicidade , Glucose/toxicidade , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fibrose Peritoneal/induzido quimicamente , Fibrose Peritoneal/prevenção & controle , Valsartana/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Soluções para Diálise/química , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Diálise Peritoneal/métodos , Fibrose Peritoneal/metabolismo , Peritônio/efeitos dos fármacos , Peritônio/patologia , Transdução de Sinais/efeitos dos fármacos
14.
Int Urol Nephrol ; 51(11): 2073-2081, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31401712

RESUMO

Obstructive nephropathy is a common cause for chronic kidney disease. Surgery, which is adopted to promptly relieve the obstruction, is the most important method to save damaged kidneys. However, earlier studies have shown that renal function will continue to deteriorate until the terminal stage after the obstruction' relief. The aim of this study is to explore the renal fibrosis and investigate the effect of losartan on renal fibrosis after the obstruction' relief using an improved mouse model of relief for unilateral ureteral obstruction (RUUO). Experiments carried out using C57BL/6 mice (n = 30) were randomly divided into RUUO + Losartan group, RUUO group and sham group. Using an improved mouse RUUO model, this study revealed that the mouse kidney for 3- or 7-day unilateral ureteral obstruction undergoing the RUUO surgery was still in a state of injury and fibrosis, while losartan could effectively ameliorate renal fibrosis by upregulating the expression of CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) in kidney after the surgery of RUUO.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Rim/patologia , Losartan/uso terapêutico , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/fisiologia , Regulação para Cima/efeitos dos fármacos , Animais , Fibrose/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Fatores de Tempo , Resultado do Tratamento , Obstrução Ureteral/complicações , Obstrução Ureteral/cirurgia
15.
Redox Biol ; 26: 101275, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31349118

RESUMO

Transition of acute kidney injury (AKI) to chronic kidney disease (CKD) represents an important cause of kidney failure. However, how AKI is transformed into CKD remains elusive. Following folic acid injury, mice developed AKI with ensuing CKD transition, featured by variable degrees of interstitial fibrosis and tubular cell atrophy and growth arrest. This lingering injury of renal tubules was associated with sustained oxidative stress that was concomitant with an impaired Nrf2 antioxidant defense, marked by mitigated Nrf2 nuclear accumulation and blunted induction of its target antioxidant enzymes, like heme oxygenase (HO)-1. Activation of the canonical Keap1/Nrf2 signaling, nevertheless, seems intact during CKD transition because Nrf2 in injured tubules remained activated and elevated in cytoplasm. Moreover, oxidative thiol modification and activation of Keap1, the cytoplasmic repressor of Nrf2, was barely associated with CKD transition. In contrast, glycogen synthase kinase (GSK)3ß, a key modulator of the Keap1-independent Nrf2 regulation, was persistently overexpressed and hyperactive in injured tubules. Likewise, in patients who developed CKD following AKI due to diverse etiologies, like volume depletion and exposure to radiocontrast agents or aristolochic acid, sustained GSK3ß overexpression was evident in renal tubules and coincided with oxidative damages, impaired Nrf2 nuclear accumulation and mitigated induction of antioxidant gene expression. Mechanistically, the Nrf2 response against oxidative insult was sabotaged in renal tubular cells expressing a constitutively active mutant of GSK3ß, but reinforced by ectopic expression of dominant negative GSK3ß in a Keap1-independent manner. In vivo in folic acid-injured mice, targeting GSK3ß in renal tubules via conditional knockout or by weekly microdose lithium treatment reinstated Nrf2 antioxidant response in the kidney and hindered AKI to CKD transition. Ergo, our findings suggest that GSK3ß-mediated Keap1-independent regulation of Nrf2 may serve as an actionable therapeutic target for modifying the long-term sequelae of AKI.


Assuntos
Injúria Renal Aguda/metabolismo , Antioxidantes/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Animais , Biomarcadores , Biópsia , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças , Ácido Fólico/efeitos adversos , Imuno-Histoquímica , Lítio/administração & dosagem , Lítio/farmacologia , Masculino , Camundongos , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia
16.
Ren Fail ; 41(1): 497-506, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31215300

RESUMO

Objectives: To improve the mouse model of relief for unilateral ureteral obstruction (RUUO) and explore the pathological process of renal fibrosis after the obstruction was relieved. Methods: C57BL/6 mice in model group were randomly divided into RUUO group, improved RUUO group, and UUO group. After leaving Unilateral Ureteral Obstruction (UUO) for 3 days, the obstruction was released by reimplantation way in RUUO group and in reimplantation + catheter way in improved RUUO group. C57BL/6 mice in observation group were randomly divided into 1d RUUO group, 3d RUUO group, 7d RUUO group, and 14d RUUO group. Three days after UUO, the obstruction was released by reimplantation + catheter in four groups. We detected the renal volume, H&E, Masson staining, and immunohistochemistry of kidney pathology on the seventh day after RUUO in model group and on the 1st, 3rd, 7th, and 14th day after RUUO in observation group. Results: Comparing with mice in RUUO group, mice in improved RUUO group had lower renal volume, tubular damage score, and collagen area percentage. After the obstruction was relieved, the renal volume decreased gradually within 2 weeks. The tubular damage score in 7d RUUO group was lower than that in 1d RUUO and 3d RUUO group. However, the tubular damage score in 14d RUUO group was higher than that in 7d RUUO group. The tendency of collagen area percentage and α-SMA IOD value were consistent with the tubular damage score. Conclusions: Using the method of reimplantation + catheter, a reliable mice model of RUUO can be got. After RUUO, the de-obstructed kidneys are still in damage and fibrosis state.


Assuntos
Modelos Animais de Doenças , Rim/patologia , Obstrução Ureteral/complicações , Cateterismo Urinário/métodos , Animais , Fibrose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ureter/cirurgia , Obstrução Ureteral/etiologia , Obstrução Ureteral/cirurgia , Cateterismo Urinário/instrumentação , Cateteres Urinários
17.
Vaccine ; 37(23): 3031-3039, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31036452

RESUMO

INTRODUCTION: Human papillomavirus (HPV) vaccination has been proven to effectively protect against HPV infection and infection-associated cancer. However, there are concerns about the relationship between HPV vaccination and the risk of autoimmune disorders (ADs). Therefore, we performed a systematic review and meta-analysis to comprehensively evaluate the relationship between HPV vaccination and ADs risk. METHODS: To identify relevant studies, we conducted a systematic search in EMBASE and PubMed databases of scientific articles published through June 2018. Fixed or random effects models were adopted to estimate overall relative risk. RESULTS: In total, 20 studies (12 cohort studies, 6 case-control studies, and 2 randomized controlled trials) involving more than 169,000 AD events were included in our meta-analysis. Our results show that HPV vaccination was not associated with an increased risk of subsequent ADs (odds ratio [OR] = 1.003, 95% confidence interval (CI): 0.95-1.06), particularly among those with a prior ADs (OR = 0.82, 95% CI: 0.7-0.96). Most of the subgroup analysis results based on the location or type of ADs were consistent with the overall results. CONCLUSION: No evidence of an association between HPV vaccination and ADs was found. Given the low number of estimates for individual AD, additional and larger observational studies are needed to verify our findings.


Assuntos
Doenças Autoimunes/etiologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/efeitos adversos , Vacinação/efeitos adversos , Estudos de Casos e Controles , Humanos , Razão de Chances , Papillomaviridae , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco
18.
Int Urol Nephrol ; 51(6): 1071-1078, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31089945

RESUMO

PURPOSE: The aim of this study was to investigate the effects and possible mechanism of tea polyphenols (TPs) on the senescence of human glomerular mesangial cells (HGMCs) under high glucose conditions. METHODS: HGMCs were divided into the normal group (NG, 5.5 mmol/L glucose), mannitol group (MNT, 5.5 mmol/L glucose and 24.5 mmol/L mannitol), TP group (TP, 30 mmol/L glucose and 5 µg/mL TP) and high-dose D-glucose group (HG, 30 mmol/L glucose). The effects of TP on the cell morphology of HGMCs; the percentage of cells positive for senescence-associated ß-galactosidase (SA-ß-gal); the ratio of G1 phase of cell cycle; telomere length; and the expression of p-Akt, p53, p21 and Rb proteins of the Akt-p53-p21 signaling pathway and the expression miR-126 were examined. RESULTS: High glucose led to premature senescence of HGMCs, as evident from the increase in the percentage of SA-ß-gal-positive cells, decrease in telomere length, cell cycle arrest at G1 phase,decrease in the expression of miR-126 and p-Akt and increase in the expression of p53, p21 and Rb proteins in the HG group. In contrast, in the TP group, these effects of high glucose treatment were abrogated and this indicates that TP had a protective effect on HGMCs. CONCLUSIONS: High glucose induces the senescence of HGMCs in vitro via the miR-126 and Akt-p53-p21 signaling pathways. TP can delay the high glucose-induced senescence of HGMCs by regulating the activity of these signaling pathways. Thus, the polyphenols present in tea may have potential for the treatment of diabetic nephropathies associated with premature senescence.


Assuntos
Senescência Celular/efeitos dos fármacos , MicroRNAs/fisiologia , Polifenóis/farmacologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Células Cultivadas , Humanos , Hiperglicemia , Células Mesangiais , Transdução de Sinais , Chá
19.
Am J Transl Res ; 11(3): 1473-1485, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30972175

RESUMO

Peritoneal fibrosis (PF) is characterized by progressive accumulation of extracellular matrix (ECM) components in the peritoneum under high glucose conditions. Rapamycin has previously been shown to inhibit ECM accumulation of peritoneal mesothelial cells (PMCs) and prevent PF. Here we explored the undefined mechanisms by which rapamycin inhibits ECM accumulation of PMCs. We used high-glucose peritoneal dialysis solution (PDS) in a mouse peritoneal dialysis model to induce in vivo PF and in human PMCs in vitro to stimulate ECM accumulation. The mice that received chronic PDS infusions showed typical features of PF, including markedly increased peritoneal thickness, excessive matrix deposition, increased peritoneal permeability, and higher expressions of α-smooth muscle actin and collagen I. Rapamycin significantly ameliorated these pathological changes. There was a parallel decrease in lipid accumulation in the peritoneum of rapamycin-treated mice. Rapamycin significantly inhibited high-glucose PDS-induced ECM accumulation and reduced the lipid droplet in human PMCs in the presence of PDS. The effects of rapamycin on intracellular lipid metabolism correlated with a series of steps in lipid homeostasis; namely, a decrease in low density lipoprotein receptor-mediated lipid influx, which was mediated through the downregulation of sterol regulatory element-binding protein-2 (SREBP-2) and SREBP cleavage-activating protein (SCAP), and an increase in adenosine triphosphate-binding cassette transporter A1-mediated lipid efflux, which was mediated through the upregulation of the liver X receptor α and peroxisome proliferator-activated receptor α. We conclude that rapamycin shows a clear protective effect on high-glucose PDS-induced PF by improving the disruption of intracellular lipid homeostasis.

20.
Am J Med Sci ; 357(4): 311-315, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30904046

RESUMO

BACKGROUND: Cell adhesion molecules have been documented to be elevated in numerous immune inflammatory diseases. Minimal change disease (MCD) is an immune disorder. This study aimed to evaluate whether levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble E-selectin (sE-selectin) reflect disease activity in adult-onset MCD. METHODS: A sandwich enzyme-linked immunosorbent assay was used to measure the soluble adhesion molecules in 40 patients with nephrotic-range proteinuria and biopsy-proven MCD, obtained at the time of diagnosis and during remission. Thirty-five age- and sex-matched healthy volunteers served as controls. RESULTS: Patients with MCD during the active stage showed significantly higher levels of sVCAM-1 and sE-selectin when compared to controls. Moreover, sVCAM-1 had significantly positive correlations with both urine protein and serum cholesterol, and was negatively associated with serum albumin. Multiple analyses showed that serum albumin was an independent predictor of sVCAM-1. The correlations between sE-selectin and other clinical parameters were not statistically significant. At follow-up, these markers systematically decreased as the disease went into remission, but the increase in sVCAM-1 persisted even in patients obtaining complete remission for 6 months. CONCLUSIONS: Patients with active MCD had increased levels of sVCAM-1 and sE-selectin. The correlation between sVCAM-1 and proteinuria, serum albumin and cholesterol and its decline during remission indicate that sVCAM-1 is associated with disease activity.


Assuntos
Nefrose Lipoide/genética , Proteinúria/fisiopatologia , Molécula 1 de Adesão de Célula Vascular/genética , Adulto , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Nefrose Lipoide/fisiopatologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...