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1.
Am J Nephrol ; 55(3): 334-344, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38228096

RESUMO

INTRODUCTION: Renal fibrosis (RF), being the most important pathological change in the progression of CKD, is currently assessed by the evaluation of a biopsy. This present study aimed to apply a novel functional MRI (fMRI) protocol named amide proton transfer (APT) weighting to evaluate RF noninvasively. METHODS: Male Sprague-Dawley (SD) rats were initially subjected to bilateral kidney ischemia/reperfusion injury (IRI), unilateral ureteral obstruction, and sham operation, respectively. All rats underwent APT mapping on the 7th and 14th days after operation. Besides, 26 patients underwent renal biopsy at the Nephrology Department of Shanghai Tongji Hospital between July 2022 and May 2023. Patients underwent APT and apparent diffusion coefficient (ADC) mappings within 1 week before biopsy. MRI results of both patients and rats were calculated by comparing with gold standard histology for fibrosis assessment. RESULTS: In animal models, the cortical APT (cAPT) and medullary APT (mAPT) values were positively correlated with the degree of RF. Compared to the sham group, IRI group showed significantly increased cAPT and mAPT values on the 7th and 14th days after surgery, but no group differences were found in ADC values. Similar results were found in human patients. Cortical/medullary APT values were significantly increased in patients with moderate-to-severe fibrosis than in patients with mild fibrosis. ROC curve analysis indicated that APT value displayed a better diagnostic value for RF. Furthermore, combination of cADC and cAPT improved fibrosis detection by imaging variables alone (p < 0.1). CONCLUSION: APT values had better diagnostic capability at early stage of RF compared to ADC values, and the addition of APT imaging to conventional ADC will significantly improve the diagnostic performance for predicting kidney fibrosis.


Assuntos
Fibrose , Rim , Imageamento por Ressonância Magnética , Ratos Sprague-Dawley , Masculino , Animais , Fibrose/diagnóstico por imagem , Humanos , Ratos , Pessoa de Meia-Idade , Rim/diagnóstico por imagem , Rim/patologia , Imageamento por Ressonância Magnética/métodos , Traumatismo por Reperfusão/diagnóstico por imagem , Feminino , Adulto , Amidas , Prótons , Nefropatias/diagnóstico por imagem , Nefropatias/patologia , Nefropatias/diagnóstico , Idoso , Insuficiência Renal Crônica/diagnóstico por imagem , Insuficiência Renal Crônica/patologia , Obstrução Ureteral/diagnóstico por imagem , Modelos Animais de Doenças
2.
Acta Pharmacol Sin ; 44(10): 2091-2102, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37217601

RESUMO

Renal fibrosis relies on multiple proteins and cofactors in its gradual development. Copper is a cofactor of many enzymes involved in renal microenvironment homeostasis. We previously reported that intracellular copper imbalance occurred during renal fibrosis development and was correlated with fibrosis intensity. In this study, we investigated the molecular mechanisms of how copper affected renal fibrosis development. Unilateral ureteral obstruction (UUO) mice were used for in vivo study; rat renal tubular epithelial cells (NRK-52E) treated with TGF-ß1 were adapted as an in vitro fibrotic model. We revealed that the accumulation of copper in mitochondria, rather than cytosol, was responsible for mitochondrial dysfunction, cell apoptosis and renal fibrosis in both in vivo and in vitro fibrotic models. Furthermore, we showed that mitochondrial copper overload directly disrupted the activity of respiratory chain complex IV (cytochrome c oxidase), but not complex I, II and III, which hampered respiratory chain and disrupted mitochondrial functions, eventually leading to fibrosis development. Meanwhile, we showed that COX17, the copper chaperone protein, was significantly upregulated in the mitochondria of fibrotic kidneys and NRK-52E cells. Knockdown of COX17 aggravated mitochondrial copper accumulation, inhibited complex IV activity, augmented mitochondrial dysfunction and led to cell apoptosis and renal fibrosis, whereas overexpression of COX17 could discharge copper from mitochondria and protect mitochondrial function, alleviating renal fibrosis. In conclusion, copper accumulation in mitochondria blocks complex IV activity and induces mitochondrial dysfunction. COX17 plays a pivotal role in maintaining mitochondrial copper homeostasis, restoring complex IV activity, and ameliorating renal fibrosis.


Assuntos
Cobre , Nefropatias , Obstrução Ureteral , Animais , Camundongos , Ratos , Linhagem Celular , Cobre/metabolismo , Fibrose , Nefropatias/metabolismo , Mitocôndrias/metabolismo , Obstrução Ureteral/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo
3.
Am J Physiol Renal Physiol ; 321(4): F517-F526, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34486400

RESUMO

Increasing evidence shows that long noncoding RNAs (lncRNAs) play an important role in kidney disease. In this study, we investigated the role of the lncRNA growth arrest-specific 5 (GAS5) in the pathogenesis of renal fibrosis. We found that GAS5 was markedly decreased in the fibrotic kidney of a unilateral ureteral obstructive nephropathy mouse model. In addition, GAS5 was expressed in mouse tubular epithelial cells (mTECs) and interstitial fibroblasts in normal renal tissue and was especially highly expressed in the cytoplasm. In vitro experiments showed that GAS5 was downregulated by transforming growth factor-ß1 (TGF-ß1) in a dose- and time-dependent manner. Overexpression of GAS5 blocked TGF-ß1-induced collagen type I and fibronectin expression and vice versa. Mechanistic experiments revealed that Smad3 but not Smad2 drove the regulation of GAS5. More importantly, GAS5 interacted with miR-142-5p and was involved in the renoprotective effect by participating in the competing endogenous RNA network. Finally, we also found that knockdown of GAS5 promoted TGF-ß1-induced mouse tubular epithelial cell apoptosis via the Smad3 pathway. Taken together, our results uncovered a lncRNA/miRNA competing endogenous RNA network-based mechanism that modulates extracellular matrix formation and cell apoptosis via the Smad3 pathway.NEW & NOTEWORTHY In this work, we mainly discuss long noncoding RNA growth arrest-specific 5 (GAS5), acting in a renoprotective role via the Smad3/miRNA-142-5p axis, that modulates extracellular matrix formation and cell apoptosis. Overexpression of GAS5 effectively blocked renal fibrosis in vitro. This study reveals that GAS5 may represent as a novel and precision therapeutic target for alleviating renal fibrosis.


Assuntos
Células Epiteliais/efeitos dos fármacos , Nefropatias/prevenção & controle , Túbulos Renais/efeitos dos fármacos , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibrose , Humanos , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Camundongos Endogâmicos C57BL , MicroRNAs/genética , RNA Longo não Codificante/genética , Transdução de Sinais , Proteína Smad3/genética , Obstrução Ureteral/complicações
4.
Ying Yong Sheng Tai Xue Bao ; 31(7): 2323-2331, 2020 Jul.
Artigo em Zh | MEDLINE | ID: mdl-32715698

RESUMO

The value evaluation of endangered species can provide important supports for policy-making in biodiversity conservation. We evaluated the stakeholders' preference and willingness to pay (WTP) from the perspective of stakeholders by the choice experiment method (CEM) and discussed the ecological compensation mechanism, with Elaeagnus mollis, a national secondary key protected plant as an example. Based on the interest demands analysis of three stakeholders, the management departments, enterprises and farmers, we measured five species attributes of E. mollis, including planting area, product classification, seedling varieties, protection investment, and far-mers' income. Furthermore, the preference of stakeholders and WTP for different attribute variables were analyzed using random parameter model (RPL). The results showed that the preference of respondents for the variable of "increase investment in protection" was the strongest and WTP was the highest (331.00 yuan·a-1·household-1). The stakeholders had stronger preference for the variables of "simultaneous development of high and low-end products" and "development of high-end products", with WTP being 242.71 and 227.57 yuan·a-1·household-1, respectively. For the variables of "farmers' income", "unchanged investment in protection", "seedling varieties" and "planting area", stakeholders showed certain preference and WTP from strong to weak. The prefe-rence for "no investment in protection" and "development of low-end products" was weaker and the WTP was negative. Through direct and indirect approaches of compensation, ecological compensation could be implemented for the objects of ecological compensation (E. mollis and associated habitat). The value of compensating surplus (CS) calculated was 285.62 yuan·a-1·household-1.


Assuntos
Elaeagnaceae , Espécies em Perigo de Extinção , Animais , Compensação e Reparação , Ecossistema , Fazendeiros , Humanos
5.
Cell Death Dis ; 11(3): 211, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32235836

RESUMO

Copper ions play various roles in mammalian cells, presumably due to their involvement in different enzymatic reactions. Some studies indicated that serum copper correlates with fibrosis in organs, such as liver and lung. However, the mechanism is unknown. Here, we explored the role of copper in kidney fibrosis development and possible underlying mechanisms. We found that copper transporter 1 (CTR1) expression was increased in the kidney tissues in two fibrosis models and in patients with kidney fibrosis. Similar results were also found in renal tubular epithelial cells and fibroblast cells treated with transforming growth factor beta (TGF-ß). Mechanistically, the upregulation of CTR1 required Smads-dependent TGF-ß signaling pathway and Smad3 directly binded to the promoter of CTR1 in renal fibroblast cells using chromatin immunoprecipitation. Elevated CTR1 induced increase of copper intracellular influx. The elevated intracellular copper ions activated lysyl oxidase (LOX) to enhance the crosslinking of collagen and elastin, which then promoted kidney fibrosis. Reducing intracellular copper accumulation by knocking down CTR1 ameliorated kidney fibrosis in unilateral ureteral obstruction induced renal fibrosis model and renal fibroblast cells stimulated by TGF-ß. Treatment with copper chelator tetrathiomolybdate (TM) also alleviated renal fibrosis in vivo and in vitro. In conclusion, intracellular copper accumulation plays a unique role to kidney fibrosis by activating LOX mediated collagen and elastin crosslinking. Inhibition of intracellular copper overload may be a potential portal to alleviate kidney fibrosis.


Assuntos
Cobre/efeitos adversos , Fibrose/genética , Nefropatias/genética , Proteína-Lisina 6-Oxidase/metabolismo , Animais , Cobre/metabolismo , Humanos , Ratos , Transdução de Sinais
6.
Oncotarget ; 8(16): 27007-27021, 2017 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-28212580

RESUMO

Chinese Herbal Medicine (CHM) plays a significant role in breast cancer treatment. We conduct the study to ascertain the relative molecular targets of effective Chinese herbs in treating stage IV breast cancer.Survival benefit of CHM was verified by Kaplan-Meier method and Cox regression analysis. A bivariate correlation analysis was used to find and establish the effect of herbs in complex CHM formulas. A network pharmacological approach was adopted to explore the potential mechanisms of CHM.Patients in the CHM group had a median survival time of 55 months, which was longer than the 23 months of patients in the non-CHM group. Cox regression analysis indicated that CHM was an independent protective factor. Correlation analysis showed that 10 herbs were strongly correlated with favorable survival outcomes (P<0.01). Bioinformatics analyses suggested that the 10 herbs might achieve anti-breast cancer activity primarily through inhibiting HSP90, ERα and TOP-II related pathways.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Adulto , Idoso , Biomarcadores Tumorais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Terapia Combinada , Composição de Medicamentos , Medicamentos de Ervas Chinesas/química , Feminino , Humanos , Estimativa de Kaplan-Meier , Medicina Tradicional Chinesa , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Transdução de Sinais/efeitos dos fármacos
7.
Medicine (Baltimore) ; 95(35): e4389, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27583849

RESUMO

Increasing evidence has shown that Chinese Herbal Medicine (CHM) has efficient therapeutic effects for advanced gastric adenocarcinoma, while the therapeutic mechanisms underlying this treatment remain unclear.In this study, the Kaplan-Meier method and Cox regression analysis were used to evaluate the survival benefit of CHM treatment, and correlation analysis was applied to identify the most effective components in the formulas. A network pharmacological approach was developed to decipher the potential therapeutic mechanisms of CHM.CHM treatment was an independent protective factor. The hazard ratio was 0.364 (95% CI 0.245-0.540; P < 0.001). The median survival time was 18 months for patients who received CHM treatment, while for patients without CHM treatment was decreased to 9 months (P < 0.001). Thirteen out of the total 204 herbs were significantly correlated with favorable survival outcomes (P < 0.05), likely representing the most effective components in these formulas. Bioinformatics analyses suggested that the simultaneous manipulation of multiple targets in proliferation pathways (such as epidermal growth factor receptor, fibroblast growth factor receptor 2, human epidermal growth factor receptor 2, proliferating cell nuclear antigen, and insulin like growth factor 2) and the process of cancer metastasis (collagen families, fibronectin 1 and matrix metalloproteinases families) might largely account for the mechanisms of the 13 herbs against gastric adenocarcinoma.A network pharmacology method was introduced to decipher the underlying mechanisms of CHM, which provides a good foundation for herbal research based on clinical data.


Assuntos
Adenocarcinoma/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Carcinogênese/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Biologia Computacional , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Taxa de Sobrevida
8.
Sci Rep ; 6: 24944, 2016 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-27143508

RESUMO

Traditional Chinese medicine (TCM) has been used to treat tumors for years and has been demonstrated to be effective. However, the underlying molecular mechanisms of herbs remain unclear. This study aims to ascertain molecular targets of herbs prolonging survival time of patients with advanced hepatocellular carcinoma (HCC) based on network pharmacology, and to establish a research method for accurate treatment of TCM. The survival benefit of TCM treatment with Chinese herbal medicine (CHM) was proved by Kaplan-Meier method and Cox regression analysis among 288 patients. The correlation between herbs and survival time was performed by bivariate correlation analysis. Network pharmacology method was utilized to construct the active ingredient-target networks of herbs that were responsible for the beneficial effects against HCC. Cox regression analysis showed CHM was an independent favorable prognostic factor. The median survival time was 13 months and the 5-year overall survival rates were 2.61% in the TCM group, while there were 6 months, 0 in the non-TCM group. Correlation analysis demonstrated that 8 herbs closely associated with prognosis. Network pharmacology analysis revealed that the 8 herbs regulated multiple HCC relative genes, among which the genes affected proliferation (KRAS, AKT2, MAPK), metastasis (SRC, MMP), angiogenesis (PTGS2) and apoptosis (CASP3) etc.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Plantas Medicinais , Perfilação da Expressão Gênica , Humanos , Testes Farmacogenômicos , Análise de Sobrevida , Resultado do Tratamento
9.
Medicine (Baltimore) ; 94(26): e1008, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26131801

RESUMO

Traditional Chinese medicine (TCM) is one of the most common complementary and alternative medicines used in the treatment of patients with cancer worldwide. However, the clinical effect of TCM on patients with pancreatic cancer remains unclear. This study was aimed to explore the efficacy of TCM on selected patients with pancreatic cancer and to study the usefulness of multimodality treatment, including TCM and western medicine (WM), in pancreatic cancer.From January 2009 to October 2013, 107 patients with pancreatic cancer were included in this study. Kaplan-Meier curves were used to assess the differences in survival time. Cox regression analysis was performed to determine survival trends adjusted for clinical and demographic factors.Cox regression analysis suggested that elevated CA19-9 levels (P = 0.048), number of cycles of chemotherapy (P = 0.014), and TCM were independent prognostic factors (P < 0.001). The survival hazards ratio of TCM was 0.419 (95% confidence interval [CI], 0.261-0.671). The median overall survival (OS) was 19 months for patients with TCM treatment, while the median OS was 8 months for those without TCM treatment (P < 0.001). Patients who received multimodality treatment using TCM and WM had the best prognosis with a median OS of 19 months (P < 0.001). Patients with heat-clearing, diuresis-promoting and detoxification TCM treatment had a longer survival time (32.4 months) than those with blood-activating and stasis-dissolving (9.8 months) and tonifying qi and yang treatment (6.1 months; P = 0.008).These results indicate that TCM has an important potential value for improving the prognosis of patients with pancreatic cancer, and multimodality treatment, including TCM and WM, leads to the best prognosis. More importantly, we suggest that heat-clearing, diuresis-promoting, and detoxification TCM treatment may improve the efficacy of TCM in pancreatic cancer.


Assuntos
Adenocarcinoma/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Neoplasias Pancreáticas/terapia , Fitoterapia , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Estudos Retrospectivos
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