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1.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(4): 433-438, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34374266

RESUMO

Objective: To study the effects and mechanisms of astaxanthin combined with aerobic exercise on renal senescence of rat induced by D-galactose. Methods: Sixty 3-month-old SPF SD rats were divided into control group (C group), acute senescence group (S group), astaxanthin+acute senescence group (AS group), aerobic exercise+acute senescence group (ES group), astaxanthin+aerobic exercise+acute senescence group (AES group), by two-factor two-level 2×2 factorial design with 12 rats in each group. Acute senescence model of rat was establshed by intraperitoneal injection with 100 mg/(kg·d) D-galactose, and the intervention was conducted with 20 mg/(kg·d) astaxanthin and/or aerobic exercise with 60% VO2max for 6 weeks. The histopathological/ultrastructural changes of the kidney were observed by light microscope/electron microscope; the levels of SOD, γ-GCS and MDA were detected by ELISA, and LDF in kidney was determined by fluorescence colorimetry; the protein expression of Nrf2 signaling pathway was detected by immunohistochemistry. Results: Compared with AS and ES group, in AES group, the improvement of renal tissue morphology/ultrastructure was more significant; LDF was decreased significantly (P<0.01); SOD activity was significantly increased (P<0.01); γ-GCS was significantly higher than that of AS group, but not significantly different from that of ES group (P>0.05); there was no significant difference in MDA between groups (P>0.05); the levels of Nrf2 and p-Nrf2 were increased significantly (P<0.05, P<0.01); HO-1 was significantly higher than that of ES group(P<0.05), but not significantly different compared with that of AS group(P>0.05). Conclusion: Astaxanthin combined with aerobic exercise can delay aging process of kidney, its mechanism may be that the combination regulate the protein expression in Nrf2 signaling pathway, Ⅱ detoxifying enzymes and antioxidant enzyme activity, and improve oxidative stress in kidney of rat induced by D-galactose.


Assuntos
Galactose , Fator 2 Relacionado a NF-E2 , Envelhecimento , Animais , Rim/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Xantofilas
2.
Ecotoxicol Environ Saf ; 223: 112583, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352574

RESUMO

Nickel (Ni), a widely distributed metal, is an important pollutant in the environment. Although kidney is a crucial target of Ni toxicity, information on autophagy and the potential mechanisms of Ni-induced renal toxicity are still poorly described. As we discovered, NiCl2 could induce renal damage including decrease in renal weight, renal histological alterations, and renal function injury. According to the obtained results, NiCl2 could obviously increase autophagy, which was characterized by increase of LC3 expression and decrease of p62 expression. Meanwhile, the result of ultrastructure observation showed increased autolysosomes numbers in the kidney of NiCl2-treated mice. In addition, NiCl2 increased mRNA and protein levels of autophagy flux proteins including Beclin1, Atg5, Atg12, Atg16L1, Atg7, and Atg3. Furthermore, NiCl2 induced autophagy through AMPK and PI3K/AKT/mTOR pathways which featured down-regulated expression levels of p-PI3K, p-AKT and p-mTOR and up-regulated expression levels of p-AMPK and p-ULK1. In summary, the above results indicate involvement of autophagy in renal injury induced by NiCl2, and NiCl2 induced autophagy via PI3K/AKT/mTOR and AMPK pathways in mouse kidney.


Assuntos
Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Autofagia , Rim/metabolismo , Camundongos , Níquel , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
3.
FASEB J ; 35(9): e21823, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34396581

RESUMO

Exercise training exerts protective effects against diabetic nephropathy. This study aimed to investigate whether exercise training could attenuate diabetic renal injury via regulating endogenous hydrogen sulfide (H2 S) production. First, C57BL/6 mice were allocated into the control, diabetes, exercise, and diabetes + exercise groups. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ). Treadmill exercise continued for four weeks. Second, mice was allocated into the control, diabetes, H2 S and diabetes + H2 S groups. H2 S donor sodium hydrosulfide (NaHS) was intraperitoneally injected once daily for four weeks. STZ-induced diabetic mice exhibited glomerular hypertrophy, tissue fibrosis and increased urine albumin levels, urine protein- and albumin-to-creatinine ratios, which were relieved by exercise training. Diabetic renal injury was associated with apoptotic cell death, as evidenced by the enhanced caspase-3 activity, the increased TdT-mediated dUTP nick-end labeling -positive cells and the reduced expression of anti-apoptotic proteins, all of which were attenuated by exercise training. Exercise training enhanced renal sirtuin 1 (SIRT1) expression in diabetic mice, accompanied by an inhibition of the p53-#ediated pro-apoptotic pathway. Furthermore, exercise training restored the STZ-mediated downregulation of cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE) and the reduced renal H2 S production. NaHS treatment restored SIRT1 expression, inhibited the p53-mediated pro-apoptotic pathway and attenuated diabetes-associated apoptosis and renal injury. In high glucose-treated MPC5 podocytes, NaHS treatment inhibited the p53-mediated pro-apoptotic pathway and podocyte apoptosis in a SIRT1-dependent manner. Collectively, exercise training upregulated CBS/CSE expression and enhanced the endogenous H2 S production in renal tissues, thereby contributing to the modulation of the SIRT1/p53 apoptosis pathway and improvement of diabetic nephropathy.


Assuntos
Nefropatias Diabéticas/metabolismo , Sulfeto de Hidrogênio/metabolismo , Condicionamento Físico Animal/fisiologia , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/fisiologia , Caspase 3/metabolismo , Linhagem Celular , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/fisiopatologia , Rim/metabolismo , Rim/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Podócitos/metabolismo , Transdução de Sinais/fisiologia
4.
Sci Rep ; 11(1): 16843, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413390

RESUMO

Elevated angiotensin-converting enzyme 2 (ACE2) expression in organs that are potential targets of severe acute respiratory syndrome coronavirus 2 may increase the risk of coronavirus disease 2019 (COVID-19) infection. Previous reports show that ACE2 alter its tissue-specific expression patterns under various pathological conditions, including renal diseases. Here, we examined changes in pulmonary ACE2 expression in two mouse chronic kidney disease (CKD) models: adenine-induced (adenine mice) and aristolochic acid-induced (AA mice). We also investigated changes in pulmonary ACE2 expression due to renin-angiotensin system (RAS) blocker (olmesartan) treatment in these mice. Adenine mice showed significant renal functional decline and elevated blood pressure, compared with controls. AA mice also showed significant renal functional decline, compared with vehicles; blood pressure did not differ between groups. Renal ACE2 expression was significantly reduced in adenine mice and AA mice; pulmonary expression was unaffected. Olmesartan attenuated urinary albumin excretion in adenine mice, but did not affect renal or pulmonary ACE2 expression levels. The results suggest that the risk of COVID-19 infection may not be elevated in patients with CKD because of their stable pulmonary ACE2 expression. Moreover, RAS blockers can be used safely in treatment of COVID-19 patients with CKD.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Rim/metabolismo , Insuficiência Renal Crônica/metabolismo , SARS-CoV-2/fisiologia , Adenina , Enzima de Conversão de Angiotensina 2/genética , Animais , Ácidos Aristolóquicos , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Imidazóis/administração & dosagem , Rim/patologia , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Tetrazóis/administração & dosagem
5.
Molecules ; 26(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34361705

RESUMO

In order to seek novel technetium-99m folate receptor-targeting agents, two folate derivatives (CN5FA and CNPFA) were synthesized and radiolabeled to obtain [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA complexes, which exhibited high radiochemical purity (>95%) without purification, hydrophilicity, and good stability in vitro. The KB cell competitive binding experiments indicated that [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA had specificity to folate receptor. Biodistribution studies in KB tumor-bearing mice illustrated that [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA had specific tumor uptake. Compared with [99mTc]Tc-CN5FA, the tumor/muscle ratios of [99mTc]Tc-CNPFA were higher, resulting in a better SPECT/CT imaging background. According to the results, the two 99mTc complexes have potential as tumor imaging agents to target folate receptors.


Assuntos
Diagnóstico por Imagem/métodos , Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/química , Rim/diagnóstico por imagem , Nitrilas/química , Compostos Radiofarmacêuticos/síntese química , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Ligação Competitiva , Estabilidade de Medicamentos , Receptores de Folato com Âncoras de GPI/genética , Ácido Fólico/farmacocinética , Expressão Gênica , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células KB , Rim/metabolismo , Camundongos , Ligação Proteica , Compostos Radiofarmacêuticos/farmacocinética , Tecnécio/química , Distribuição Tecidual
6.
Commun Biol ; 4(1): 959, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381146

RESUMO

The association between kidney stone disease and renal fibrosis has been widely explored in recent years but its underlying mechanisms remain far from complete understanding. Using label-free quantitative proteomics (nanoLC-ESI-LTQ-Orbitrap MS/MS), this study identified 23 significantly altered secreted proteins from calcium oxalate monohydrate (COM)-exposed macrophages (COM-MP) compared with control macrophages (Ctrl-MP) secretome. Functional annotation and protein-protein interactions network analysis revealed that these altered secreted proteins were involved mainly in inflammatory response and fibroblast activation. BHK-21 renal fibroblasts treated with COM-MP secretome had more spindle-shaped morphology with greater spindle index. Immunofluorescence study and gelatin zymography revealed increased levels of fibroblast activation markers (α-smooth muscle actin and F-actin) and fibrotic factors (fibronectin and matrix metalloproteinase-9 and -2) in the COM-MP secretome-treated fibroblasts. Our findings indicate that proteins secreted from macrophages exposed to COM crystals induce renal fibroblast activation and may play important roles in renal fibrogenesis in kidney stone disease.


Assuntos
Oxalato de Cálcio/metabolismo , Fibroblastos/metabolismo , Rim/metabolismo , Macrófagos/metabolismo , Animais , Oxalato de Cálcio/química , Cricetinae , Humanos , Mapas de Interação de Proteínas , Células U937
7.
Molecules ; 26(16)2021 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-34443393

RESUMO

Zizyphus lotus L. (Desf.) (Z. lotus) is a medicinal plant largely distributed all over the Mediterranean basin and is traditionally used by Moroccan people to treat many illnesses, including kidney failure. The nephrotoxicity of gentamicin (GM) has been well documented in humans and animals, although the preventive strategies against it remain to be studied. In this investigation, we explore whether the extract of Zizyphus lotus L. (Desf.) Fruit (ZLF) exhibits a protective effect against renal damage produced by GM. Indeed, twenty-four Wistar rats were separated into four equal groups of six each (♂/♀ = 1). The control group was treated orally with distilled water (10 mL/kg); the GM treated group received distilled water (10 mL/kg) and an intraperitoneal injection of GM (80 mg/kg) 3 h after; and the treated groups received ZLF extract orally at the doses 200 or 400 mg/kg and injected intraperitoneally with the GM. All treatments were given daily for 14 days. At the end of the experiment, the biochemical parameters and the histological observation related the kidney function was explored. ZLF treatment has significantly attenuated the nephrotoxicity induced by the GM. This effect was indicated by its capacity to decrease significantly the serum creatinine, uric acid, urea, alkaline phosphatase, gamma-glutamyl-transpeptidase, albumin, calcium, sodium amounts, water intake, urinary volume, and relative kidney weight. In addition, this effect was also shown by the increase in the creatinine clearance, urinary creatinine, uric acid, and urea levels, weight gain, compared to the rats treated only with the GM. The hemostasis of oxidants/antioxidants has been significantly improved with the treatment of ZLF extract, which was shown by a significant reduction in malondialdehydes levels. Histopathological analysis of renal tissue was correlated with biochemical observation. Chemical analysis by HPLC-DAD showed that the aqueous extract of ZLF is rich in phenolic compounds such as 3-hydroxycinnamic acid, catechin, ferulic acid, gallic acid, hydroxytyrosol, naringenin, p- coumaric Acid, quercetin, rutin, and vanillic acid. In conclusion, ZLF extract improved the nephrotoxicity induced by GM, through the improvement of the biochemical and histological parameters and thus validates its ethnomedicinal use.


Assuntos
Injúria Renal Aguda/patologia , Citoproteção/efeitos dos fármacos , Frutas/química , Gentamicinas/efeitos adversos , Rim/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ziziphus/química , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/prevenção & controle , Animais , Modelos Animais de Doenças , Rim/metabolismo , Rim/patologia , Ratos , Ratos Wistar
8.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360776

RESUMO

Oxidative stress is an imbalance between pro- and antioxidants that adversely influences the organism in various mechanisms and on many levels. Oxidative damage occurring concomitantly in many cellular structures may cause a deterioration of function, including apoptosis and necrosis. The damage leaves a molecular "footprint", which can be detected by specific methodology, using certain oxidative stress biomarkers. There is an intimate relationship between oxidative stress, inflammation, and functional impairment, resulting in various diseases affecting the entire human body. In the current narrative review, we strengthen the connection between oxidative stress mechanisms and their active compounds, emphasizing kidney damage and renal transplantation. An analysis of reactive oxygen species (ROS), antioxidants, products of peroxidation, and finally signaling pathways gives a lot of promising data that potentially will modify cell responses on many levels, including gene expression. Oxidative damage, stress, and ROS are still intensively exploited research subjects. We discuss compounds mentioned earlier as biomarkers of oxidative stress and present their role documented during the last 20 years of research. The following keywords and MeSH terms were used in the search: oxidative stress, kidney, transplantation, ischemia-reperfusion injury, IRI, biomarkers, peroxidation, and treatment.


Assuntos
Injúria Renal Aguda/metabolismo , Transplante de Rim , Rim/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Injúria Renal Aguda/história , Injúria Renal Aguda/patologia , Animais , Biomarcadores/metabolismo , História do Século XXI , Humanos , Rim/patologia , Traumatismo por Reperfusão/história , Traumatismo por Reperfusão/patologia
9.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360801

RESUMO

Senna and rhubarb are often used as routine laxatives, but there are differences in mechanism of action and potential side effects. Here, we studied metabolites of senna anthraquinones (SAQ), rhubarb anthraquinones (RAQ) and their chemical marker, sennoside A (SA), in a rat diarrhea model. In in vitro biotransformation experiments, SAQ, RAQ and SA were incubated with rat fecal flora solution and the metabolites produced were analyzed using HPLC. In in vivo studies, the same compounds were investigated for purgation induction, with measurement of histopathology and Aqps gene expression in six organs. The results indicated that SAQ and RAQ had similar principal constituents but could be degraded into different metabolites. A similar profile of Aqps down-regulation for all compounds was seen in the colon, suggesting a similar mechanism of action for purgation. However, in the kidneys and livers of the diarrhea-rats, down-regulation of Aqps was found in the RAQ-rats whereas up-regulation of Aqps was seen in the SAQ-rats. Furthermore, the RAQ-rats showed lower Aqp2 protein expression in the kidneys, whilst the SA-rats and SAQ-rats had higher Aqp2 protein expression in the kidneys. This may have implications for side effects of SAQ or RAQ in patients with chronic kidney or liver diseases.


Assuntos
Aquaporina 2/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/metabolismo , Fígado/metabolismo , Rheum/química , Senna (Planta)/química , Senosídeos/farmacologia , Animais , Masculino , Especificidade de Órgãos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Senosídeos/química
10.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361023

RESUMO

Aging is an unavoidable part of life. The more aged we become, the more susceptible we become to various complications and damages to the vital organs, including the kidneys. The existing drugs for kidney diseases are mostly of synthetic origins; thus, natural compounds with minimal side-effects have attracted growing interest from the scientific community and pharmaceutical companies. A literature search was carried out to collect published research information on the effects of resveratrol on kidney aging. Recently, resveratrol has emerged as a potential anti-aging agent. This versatile polyphenol exerts its anti-aging effects by intervening in various pathologies and multi-signaling systems, including sirtuin type 1, AMP-activated protein kinase, and nuclear factor-κB. Researchers are trying to figure out the detailed mechanisms and possible resveratrol-mediated interventions in divergent pathways at the molecular level. This review highlights (i) the causative factors implicated in kidney aging and the therapeutic aspects of resveratrol, and (ii) the effectiveness of resveratrol in delaying the aging process of the kidney while minimizing all possible side effects.


Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/farmacologia , Rim/efeitos dos fármacos , Resveratrol/farmacologia , Envelhecimento/metabolismo , Animais , Humanos , Rim/crescimento & desenvolvimento , Rim/metabolismo , Sirtuína 1/metabolismo
11.
Life Sci ; 283: 119870, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352258

RESUMO

OBJECTIVE: Increased renal and hepatic gluconeogenesis are important sources of fasting hyperglycemia in type 2 diabetes (T2D). The inhibitory effect of co-administration of sodium nitrite and sodium hydrosulfide (NaSH) on hepatic but not renal gluconeogenesis has been reported in rats with T2D. The present study aimed to determine the effects of co-administration of sodium nitrite and NaSH on the expression of genes involved in renal gluconeogenesis in rats with T2D. METHODS: T2D was induced by a combination of a high-fat diet and low-dose streptozotocin (30 mg/kg). Male Wistar rats were divided into 5 groups (n = 6/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite+NaSH. Nitrite and NaSH were administered for nine weeks at a dose of 50 mg/L (in drinking water) and 0.28 mg/kg (daily intraperitoneal injection), respectively. Serum levels of urea and creatinine, and mRNA expressions of PEPCK, G6Pase, FBPase, PC, PI3K, AKT, PGC-1α, and FoxO1 in the renal tissue, were measured at the end of the study. RESULTS: Nitrite decreased mRNA expression of PEPCK by 39%, G6Pase by 43%, FBPase by 41%, PC by 63%, PGC-1α by 45%, and FoxO1 by 27% in the renal tissue of rats with T2D; co-administration of nitrite and NaSH further decreases FoxO1, while had no additive effects on the tissue expression of the other genes. In addition, nitrite+NaSH decreased elevated serum urea levels by 58% and creatinine by 37% in rats with T2D. CONCLUSION: The inhibitory effect of nitrite on gluconeogenesis in T2D rats is at least in part due to decreased mRNA expressions of renal gluconeogenic genes. Unlike effects on hepatic gluconeogenesis, co-administration of nitrite and NaSH has no additive effects on genes involved in renal gluconeogenesis in rats with T2D.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Gluconeogênese/efeitos dos fármacos , Rim/metabolismo , Nitrito de Sódio/farmacologia , Sulfetos/farmacologia , Animais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Rim/patologia , Masculino , Ratos , Ratos Wistar
12.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445337

RESUMO

In fibrotic diseases, myofibroblasts derive from a range of cell types including endothelial-to-mesenchymal transition (EndMT). Increasing evidence suggests that miRNAs are key regulators in biological processes but their profile is relatively understudied in EndMT. In human umbilical vein endothelial cells (HUVEC), EndMT was induced by treatment with TGFß2 and IL1ß. A significant decrease in endothelial markers such as VE-cadherin, CD31 and an increase in mesenchymal markers such as fibronectin were observed. In parallel, miRNA profiling showed that miR-126-3p was down-regulated in HUVECs undergoing EndMT and over-expression of miR-126-3p prevented EndMT, maintaining CD31 and repressing fibronectin expression. EndMT was investigated using lineage tracing with transgenic Cdh5-Cre-ERT2; Rosa26R-stop-YFP mice in two established models of fibrosis: cardiac ischaemic injury and kidney ureteric occlusion. In both cardiac and kidney fibrosis, lineage tracing showed a significant subpopulation of endothelial-derived cells expressed mesenchymal markers, indicating they had undergone EndMT. In addition, miR-126-3p was restricted to endothelial cells and down-regulated in murine fibrotic kidney and heart tissue. These findings were confirmed in patient kidney biopsies. MiR-126-3p expression is restricted to endothelial cells and is down-regulated during EndMT. Over-expression of miR-126-3p reduces EndMT, therefore, it could be considered for miRNA-based therapeutics in fibrotic organs.


Assuntos
Transdiferenciação Celular/genética , Rim/patologia , MicroRNAs/fisiologia , Miocárdio/patologia , Animais , Células Cultivadas , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Fibrose/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Rim/metabolismo , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/patologia
14.
Am J Physiol Renal Physiol ; 321(3): F355, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34460353
15.
Chem Biol Interact ; 347: 109605, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34333021

RESUMO

Cell injury is a necessary and critical event during CaOx kidney stone formation. Sirt1 exerts a number of pleiotropic effects, protecting against renal cell injury. This study aims to explore the relationship between Sirt1 and CaOx kidney stone formation and the underlying mechanism. Sirt1 expression in renal tissues or HK-2 cells was detected by Western blot, immunohistochemistry and immunofluorescence. Apoptosis in renal tissues was examined by TUNEL staining. Renal pathological changes and the crystals deposition were detected by hematoxylin-eosin and Von Kossa staining. Crystal-cell adhesion and cell injury in HK-2 cells were assessed by atomic absorption spectrometry and flow cytometry, respectively. Sirt1 expression in nephrolithiasis patients was downregulated and the level of apoptosis was increased. Further study found that Sirt1 expression was decreased in both in vivo and in vitro models. Interestingly, the levels of cell injury were elevated in vivo and in vitro models. Suppressing Sirt1 expression promoted COM-induced crystal-cell adhesion and exacerbated cell injury. In contrast, increasing the expression of Sirt1 by lentivirus transfection in vitro and resveratrol administration in vivo, alleviated crystal deposition and cell damage. Our findings suggest that Sirt1 could inhibit kidney stone formation, at least in part, through attenuating CaOx -induced cell injury.


Assuntos
Oxalato de Cálcio/efeitos adversos , Cálculos Renais/metabolismo , Sirtuína 1/metabolismo , Idoso , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Oxalato de Cálcio/química , Oxalato de Cálcio/farmacologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Linhagem Celular , Cristalização , Feminino , Inativação Gênica , Glioxilatos , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Cálculos Renais/induzido quimicamente , Cálculos Renais/tratamento farmacológico , Cálculos Renais/patologia , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Necrose/induzido quimicamente , Necrose/metabolismo , Resveratrol/uso terapêutico , Sirtuína 1/genética
16.
Chem Biol Interact ; 347: 109619, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34364837

RESUMO

Owing to the ineffectiveness of the currently used therapies against melanoma, there has been a shift in focus toward alternative therapies involving the use of natural compounds. This study assessed the anticancer effects of oleanolic acid (OA) and its ability to induce apoptosis in A375SM and A375P melanoma cells in vivo. Compared to the control group, viability of A375P and A375SM cells decreased following OA treatment. In OA-treated A375SM and A375P cells, 4',6-diamidino-2-phenylindole staining showed an increase in the apoptotic body, and flow cytometry revealed increased number of apoptotic cells compared to that in the control group. OA-treated A375SM cells exhibited an increased expression of the apoptotic proteins, cleaved poly (ADP-ribose) polymerase (PARP) and B-cell lymphoma (Bcl)-2-associated X protein (Bax) as well as decreased expression of the antiapoptotic protein Bcl-2 compared to that in the control group. In OA-treated A375P cells, expression patterns of cleaved PARP and Bcl-2 were similar to those in OA-treated A375SM cells; however, no difference was reported in the expression of Bax compared to that in the control group. Additionally, OA-treated melanoma cells showed decreased expression of phospho-nuclear factor-κB (p-NF-κB), phospho-inhibitor of nuclear factor-κBα (p-IκBα), and phospho-IκB kinase αß than that in the control group. Moreover, immunohistochemistry showed a comparatively decreased level of p-NF-κB in the OA-treated group than that in the control group. Xenograft analysis confirmed the in vivo anticancer effects of OA against A375SM cells. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay revealed an increased number of TUNEL-positive cells in the OA-treated group compared to that in the control group. In conclusion, the study results suggest that OA induces apoptosis of A375SM and A375P cells in vitro and apoptosis of A375SM cells in vivo. Furthermore, the in vitro and in vivo anticancer effects were mediated by the NF-κB pathway.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Ácido Oleanólico/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Rim/citologia , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos BALB C , Subunidade p50 de NF-kappa B/metabolismo , Neoplasias/metabolismo , Ácido Oleanólico/farmacologia , Ácido Oleanólico/toxicidade , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Nat Commun ; 12(1): 4662, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341345

RESUMO

Impaired cellular cholesterol efflux is a key factor in the progression of renal, cardiovascular, and autoimmune diseases. Here we describe a class of 5-arylnicotinamide compounds, identified through phenotypic drug discovery, that upregulate ABCA1-dependent cholesterol efflux by targeting Oxysterol Binding Protein Like 7 (OSBPL7). OSBPL7 was identified as the molecular target of these compounds through a chemical biology approach, employing a photoactivatable 5-arylnicotinamide derivative in a cellular cross-linking/immunoprecipitation assay. Further evaluation of two compounds (Cpd A and Cpd G) showed that they induced ABCA1 and cholesterol efflux from podocytes in vitro and normalized proteinuria and prevented renal function decline in mouse models of proteinuric kidney disease: Adriamycin-induced nephropathy and Alport Syndrome. In conclusion, we show that small molecule drugs targeting OSBPL7 reveal an alternative mechanism to upregulate ABCA1, and may represent a promising new therapeutic strategy for the treatment of renal diseases and other disorders of cellular cholesterol homeostasis.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , Nefropatias Diabéticas/metabolismo , Compostos Orgânicos/farmacologia , Podócitos/metabolismo , Proteinúria/metabolismo , Receptores de Esteroides/antagonistas & inibidores , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Transporte Biológico/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células HEK293 , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Camundongos da Linhagem 129 , Camundongos Knockout , Estrutura Molecular , Niacinamida/química , Niacinamida/farmacologia , Compostos Orgânicos/síntese química , Compostos Orgânicos/química , Podócitos/citologia , Interferência de RNA , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Células THP-1
18.
J Chromatogr A ; 1652: 462350, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34198103

RESUMO

This study aimed to (i) develop a sensitive method for simultaneous detection and quantification of imidacloprid (IMI) and seven of its metabolites in tissue specimens, and to (ii) determine the biodistribution of the IMI compounds in tissues of C57BL/6J male mice; after exposure to 0.6 mg/kg bw/day of IMI (10% of no observable adverse effect level of IMI) through a powdered diet for 24 weeks. We successfully developed a method which was accurate (recoveries were ≥ 70% for most compounds), sensitive (LODs ≤ 0.47 ng/mL and LOQs ≤ 1.43 ng/mL were recorded for all detected compounds, R2 ≥ 0.99) and precise (RSDs ≤ 20%) for routine analysis of IMI and seven of its metabolites in blood and various tissue matrices. After bio-distributional analysis, IMI and five of its metabolites were detected in mice. Brain, testis, lung, kidney, inguinal white adipose tissue and gonadal white adipose tissue mainly accumulated IMI, blood and mesenteric white adipose tissue mainly accumulated IMI-olefin; liver mainly accumulated desnitro-IMI; pancreas predominately accumulated 4-hydroxy-IMI. The desnitro-dehydro-IMI and the desnitro-IMI metabolites recorded tissue-blood concentration ratios ≥ 1.0 for testis, brain, lung and kidney. The cumulative levels of the six detected IMI compounds (Σ6 IMI compounds) were found in the decreasing order: blood > testis > brain > kidney > lung > iWAT > gWAT > mWAT > liver > pancreas. Altogether, this study provided essential data needed for effective mechanistic elucidation of compound-specific adverse outcomes associated with chronic exposures to IMI in mammalian species.


Assuntos
Cromatografia Líquida , Inseticidas/farmacocinética , Neonicotinoides/farmacocinética , Nitrocompostos/farmacocinética , Espectrometria de Massas em Tandem , Tecido Adiposo Branco/metabolismo , Animais , Encéfalo/metabolismo , Inseticidas/administração & dosagem , Inseticidas/análise , Inseticidas/sangue , Rim/metabolismo , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neonicotinoides/administração & dosagem , Neonicotinoides/análise , Neonicotinoides/sangue , Nitrocompostos/administração & dosagem , Nitrocompostos/análise , Nitrocompostos/sangue , Testículo/metabolismo , Distribuição Tecidual
19.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299017

RESUMO

Oxygen deficiency in cells, tissues, and organs can not only prevent the proper development of biological functions but it can also lead to several diseases and disorders. In this sense, the kidney deserves special attention since hypoxia can be considered an important factor in the pathophysiology of both acute kidney injury and chronic kidney disease. To provide better knowledge to unveil the molecular mechanisms involved, new studies are necessary. In this sense, this work aims to study, for the first time, an in vitro model of hypoxia-induced metabolic alterations in human proximal tubular HK-2 cells because renal proximal tubules are particularly susceptible to hypoxia. Different groups of cells, cultivated under control and hypoxia conditions at 0.5, 5, 24, and 48 h, were investigated using untargeted metabolomic approaches based on reversed-phase liquid chromatography-mass spectrometry. Both intracellular and extracellular fluids were studied to obtain a large metabolite coverage. On the other hand, multivariate and univariate analyses were carried out to find the differences among the cell groups and to select the most relevant variables. The molecular features identified as affected metabolites were mainly amino acids and Amadori compounds. Insights about their biological relevance are also provided.


Assuntos
Hipóxia Celular , Cromatografia de Fase Reversa/métodos , Células Epiteliais/metabolismo , Túbulos Renais Proximais/metabolismo , Metabolômica/métodos , Espectrometria de Massas em Tandem/métodos , Ativação Metabólica/genética , Ativação Metabólica/fisiologia , Hipóxia Celular/genética , Linhagem Celular , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Técnicas In Vitro , Rim/citologia , Rim/metabolismo , Rim/patologia , Metaboloma/genética , Análise Multivariada , Análise de Componente Principal
20.
Anal Chem ; 93(28): 9835-9844, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34232631

RESUMO

Insulin resistance (IR) is a typical sign of metabolic dysregulation caused by fine particulate matter (PM2.5), but the underlying signaling has not been clearly determined. Herein, a microfluidic liver-kidney microphysiological system (LK-MPS) is presented to assess the signaling pathways of IR generated by PM2.5 at 200 µg/mL for 24 h. The LK-MPS device consisted of a biomimetic liver-kidney architecture and reconstructed two circulation paths: the liver metabolism-kidney excretion (LM-KE) and kidney excretion-liver metabolism (KE-LM), by which PM2.5 is feasibly distributed in the two organs. Transmission electron microscopy (TEM) analysis revealed that PM2.5 can embed in the cytoplasm and nuclei, undergo transport by vesicles, and lead to the destruction of mitochondria. Further comprehensive immunofluorescence, enzyme-linked immunosorbent assays (ELISAs) and untargeted metabolomic analyses confirmed that PM2.5 disturbed the classic IRS-1/AKT signaling pathway (INSR, IRS-1, PI3K, AKT, GLUT2, GLUT4, and FOXO1 downregulated) and IR-related metabolic pathways: UDP-hexosamine (UDP-GlcNAc), gluconeogenesis (ß-d-glucose 6-phosphate), and lipid biosynthesis (ceramide (Cer) and triacylglycerol (TG)) pathways, leading to the disorder of glucose levels. Collectively, these disorders aggravate hepatic and renal IR. Pearson's correlation coefficient test showed that elemental carbon (EC), polycyclic aromatic hydrocarbons (PAHs), and metals (Ca, Co, and V) were negatively correlated to the dysregulated proteins (INSR, IRS-1, AKT, FOXO1, GLUT2, and GLUT4). These findings may partially explain IR-related signaling pathways triggered by PM2.5.


Assuntos
Resistência à Insulina , Insulina , Humanos , Rim/metabolismo , Fígado/metabolismo , Microfluídica , Material Particulado/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
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