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1.
Adv Exp Med Biol ; 1131: 1031-1063, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646544

RESUMO

The calcium-sensing receptor (CaSR) is a G protein-coupled receptor that plays a key role in calcium homeostasis, by sensing free calcium levels in blood and regulating parathyroid hormone secretion in response. The CaSR is highly expressed in parathyroid gland and kidney where its role is well characterised, but also in other tissues where its function remains to be determined. The CaSR can be activated by a variety of endogenous ligands, as well as by synthetic modulators such as Cinacalcet, used in the clinic to treat secondary hyperparathyroidism in patients with chronic kidney disease. The CaSR couples to multiple G proteins, in a tissue-specific manner, activating several signalling pathways and thus regulating diverse intracellular events. The multifaceted nature of this receptor makes it a valuable therapeutic target for calciotropic and non-calciotropic diseases. It is therefore essential to understand the complexity behind the pharmacology, trafficking, and signalling characteristics of this receptor. This review provides an overview of the latest knowledge about the CaSR and discusses future hot topics in this field.


Assuntos
Cálcio , Hiperparatireoidismo Secundário , Receptores de Detecção de Cálcio , Cálcio/metabolismo , Cinacalcete/uso terapêutico , Humanos , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperparatireoidismo Secundário/etiologia , Rim/metabolismo , Glândulas Paratireoides/metabolismo , Receptores de Detecção de Cálcio/química , Receptores de Detecção de Cálcio/metabolismo , Insuficiência Renal Crônica/complicações
2.
Anticancer Res ; 39(10): 5369-5374, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570431

RESUMO

BACKGROUND/AIM: Cytokine-induced killer (CIK) cells are ex vivo expanded major histocompatibility complex (MHC)-unrestricted cytotoxic cells with promising effects against a variety of cancer types. Regulatory T-cells (T-reg) have been shown to reduce the effectiveness of CIK cells against tumor cells. Peptide P60 has been shown to inhibit the immunosuppressive functions of T-regs. This study aimed at examining the effect of p60 on CIK cells efficacy against renal and pancreatic cancer cells. MATERIALS AND METHODS: The effect of P60 on CIK cytotoxicity was examined using flow cytometry, WST-8-based cell viability assay and interferon γ (IFNγ) ELISA. RESULTS: P60 treatment resulted in a significant decrease in the viability of renal and pancreatic cancer cell lines co-cultured with CIK cells. No increase in IFNγ secretion from CIK cells was detected following treatment with P60. P60 caused no changes in the distribution of major effector cell populations in CIK cell cultures. CONCLUSION: P60 may potentiate CIK cell cytotoxicity against tumor cells.


Assuntos
Células Matadoras Induzidas por Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Fatores de Transcrição Forkhead/antagonistas & inibidores , Neoplasias Renais/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Peptídeos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura/métodos , Células Matadoras Induzidas por Citocinas/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Humanos , Interferon gama/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Neoplasias Renais/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo
3.
Anticancer Res ; 39(10): 5515-5524, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570445

RESUMO

BACKGROUND/AIM: Administration of cisplatin in cancer patients is limited by the kidney-related adverse effects; however, a protective strategy is absent. We hypothesized that fucoidan protects the proximal tubule epithelial (TH-1) cells against the effects of cisplatin. MATERIALS AND METHODS: To assess the effect of fucoidan, its effect on reactive oxygen species (ROS) formation, endoplasmic reticulum (ER) stress response, DNA damage response (DDR), apoptosis, and cell-cycle arrest in TH-1 cells was investigated. RESULTS: Cisplatin increased the accumulation of ROS, leading to excessive ER stress. In presence of cisplatin, treatment of TH-1 cells with fucoidan significantly reduced the ER stress by maintaining the complex of GRP78 with PERK and IRE1α. In particular, fucoidan enhanced the antioxidative capacity through up-regulation of PrPC Furthermore, fucoidan suppressed cisplatin-induced apoptosis and cell-cycle arrest, whereas silencing of PRNP blocked these effects of fucoidan. CONCLUSION: Fucoidan may be a potential adjuvant therapy for cancer patients treated with cisplatin as it preserves renal functionality.


Assuntos
Cisplatino/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Túbulos Renais Proximais/efeitos dos fármacos , Polissacarídeos/farmacologia , Substâncias Protetoras/farmacologia , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Células Epiteliais/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Túbulos Renais Proximais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Regulação para Cima/efeitos dos fármacos , eIF-2 Quinase/metabolismo
4.
Ann R Coll Surg Engl ; 101(8): 609-616, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31508984

RESUMO

INTRODUCTION: Hypothermic machine perfusion, an organ preservation modality, involves flow of chilled preservation fluid through an allograft's vasculature. This study describes a simple, reproducible, human model that allows for interrogation of flow effects during ex vivo organ perfusion. MATERIALS AND METHODS: Gonadal veins from deceased human renal allografts were subjected to either static cold storage or hypothermic machine perfusion for up to 24 hours. Caspase-3, Krüppel-like factor 2 expression and electron microscopic analysis were compared between 'flow' and 'no-flow' conditions, with living donor gonadal vein sections serving as negative controls. RESULTS: The increase in caspase-3 expression was less pronounced for hypothermic machine-perfused veins compared with static cold storage (median-fold increase 1.2 vs 2.3; P < 0.05). Transmission electron microscopy provided ultrastructural corroboration of endothelial cell apoptosis in static cold storage conditions. For static cold storage preserved veins, Krüppel-like factor 2 expression diminished in a time-dependent manner between baseline and 12 hours (P < 0.05) but was abrogated and reversed by hypothermic machine perfusion (P < 0.05). CONCLUSIONS: Our methodology is a simple, reproducible and successful model of ex vivo perfusion in the context of human organ preservation. To demonstrate the model's utility, we establish that two widely used markers of endothelial health (caspase-3 and Krüppel-like factor 2) differ between the flow and no-flow conditions of the two predominant kidney preservation modalities. These findings suggest that ex vivo perfusion may mediate the induction of a biochemically favourable endothelial niche which may contribute tohypothermic machine perfusion's association with improved renal transplantation outcomes.


Assuntos
Transplante de Rim/métodos , Rim/irrigação sanguínea , Modelos Biológicos , Soluções para Preservação de Órgãos/farmacocinética , Preservação de Órgãos/métodos , Apoptose , Biomarcadores/metabolismo , Cadáver , Caspase 3/metabolismo , Temperatura Baixa , Endotélio Vascular/metabolismo , Humanos , Rim/metabolismo , Rim/ultraestrutura , Fatores de Transcrição Kruppel-Like/metabolismo , Microscopia Eletrônica , Perfusão/métodos , Veias/metabolismo , Veias/ultraestrutura
5.
Toxicol Lett ; 316: 136-146, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520701

RESUMO

Prenatal dexamethasone exposure (PDE) induces developmental toxicities of multiple organs in offspring, but its serum metabolic profile changes before and after birth are unclear. Here, we employed a LC-MS-based metabolomic approach to detect serum metabolites of PDE offspring rats in utero and adulthood, and explore its change characteristics and toxicological significances. Meanwhile, the bodyweight, serum index related to hepatic and renal function were detected. As compared to healthy control rats, PDE reduced offspring birthweight but caused postnatal catch-up growth accompanied by adult liver and kidney function injury. In utero, the differential metabolites in response to PDE were mainly manifested as enhanced glycolysis, increased protein breakdown and disordered lipid metabolism, and multiple metabolic pathways were changed, which displayed gender differences. In adulthood, PDE offspring showed fewer and inconsistent types of differential metabolites compared to those in utero, which exhibited significant gender differences. The main differential metabolites induced by PDE included lactic acid, carnitine, cortexolone, bile acid, phosphatidylcholine, uric acid and platelet activating factor, which may participate in dexamethasone multi-organ toxicities and multi-disease susceptibility. In conclusion, PDE could induce a gender-difference and sustainable multi-organ damage in the offspring rats via serum metabolic profile analysis, which will enhance offspring susceptibility to multiple adult diseases.


Assuntos
Dexametasona/toxicidade , Metabolismo Energético/efeitos dos fármacos , Glucocorticoides/toxicidade , Metabolômica/métodos , Efeitos Tardios da Exposição Pré-Natal , Fatores Etários , Animais , Animais Recém-Nascidos , Biomarcadores/sangue , Peso ao Nascer/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Dexametasona/administração & dosagem , Feminino , Glucocorticoides/administração & dosagem , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Gravidez , Ratos Wistar , Medição de Risco , Fatores Sexuais , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Fatores de Tempo
6.
BMC Bioinformatics ; 20(1): 441, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455218

RESUMO

BACKGROUND: Although a few comparison methods based on the biological meaning of gene lists have been developed, the goProfiles approach is one of the few that are being used for that purpose. It consists of projecting lists of genes into predefined levels of the Gene Ontology, in such a way that a multinomial model can be used for estimation and testing. Of particular interest is the fact that it may be used for proving equivalence (in the sense of "enough similarity") between two lists, instead of proving differences between them, which seems conceptually better suited to the end goal of establishing similarity among gene lists. An equivalence method has been derived that uses a distance-based approach and the confidence interval inclusion principle. Equivalence is declared if the upper limit of a one-sided confidence interval for the distance between two profiles is below a pre-established equivalence limit. RESULTS: In this work, this method is extended to establish the equivalence of any number of gene lists. Additionally, an algorithm to obtain the smallest equivalence limit that would allow equivalence between two or more lists to be declared is presented. This algorithm is at the base of an iterative method of graphic visualization to represent the most to least equivalent gene lists. These methods deal adequately with the problem of adjusting for multiple testing. The applicability of these techniques is illustrated in two typical situations: (i) a collection of cancer-related gene lists, suggesting which of them are more reasonable to combine -as claimed by the authors- and (ii) a collection of pathogenesis-based transcript sets, showing which of these are more closely related. The methods developed are available in the goProfiles Bioconductor package. CONCLUSIONS: The method provides a simple yet powerful and statistically well-grounded way to classify a set of genes or other feature lists by establishing their equivalence at a given equivalence threshold. The classification results can be viewed using standard visualization methods. This may be applied to a variety of problems, from deciding whether a series of datasets generating the lists can be combined to the simplification of groups of lists.


Assuntos
Algoritmos , Genes , Simulação por Computador , Ontologia Genética , Humanos , Rim/metabolismo , Neoplasias/genética , Estatística como Assunto
7.
Chem Biol Interact ; 311: 108777, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31376360

RESUMO

Nicorandil ameliorated doxorubicin-induced nephrotoxicity; this study aimed to show and explain the mechanism of this protection. A precise method was elucidated to study the effect of nicorandil on doxorubicin-induced nephrotoxicity in rats depending on the critical inflammation pathway TLR4/MAPK P38/NFκ-B. Adult male rats were subdivided into four groups. The 1st group was normal control, the 2nd group received nicorandil (3 mg/kg; p.o., for 4 weeks), the 3rd group received doxorubicin (2.6 mg/kg, i.p., twice per week for 4 weeks), and the fourth group was combination of doxorubicin and nicorandil for 4 weeks. Nephrotoxicity was assessed by biochemical tests through measuring Kidney function biomarkers such as [serum levels of urea, creatinine, albumin and total protein] besides renal kidney injury molecule-1 (KIM-1) and cystatin C], oxidative stress parameters such as [renal tissue malondialdehyde (MDA), reduced glutathione (GSH), SOD, catalase and nrf-2], mediators of inflammation such as [Toll like receptor 4 (TLR-4), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), p38 MAPK, Interleukin 1 beta (IL-1 ß), and Tumor necrosis factor alpha (TNF-α)] and markers of apoptosis [BAX and Bcl-2 in renal tissue]. Finally, our data were supported by histopathology examination. Nicorandil pretreatment resulted in a significant decrease in nephrotoxicity biomarkers, oxidative stress markers, inflammatory mediators and prevented apoptosis through decreasing BAX and increasing Bcl-2 in renal tissues. Nicorandil prevented all the histological alterations caused by doxorubicin. Nicorandil is a promising antidote against doxorubicin-induced nephrotoxicity by neutralizing all toxicity mechanisms caused by doxorubicin through normalizing inflammatory cascade of TLR4/MAPK P38/NFκ-B.


Assuntos
Doxorrubicina/toxicidade , Rim/efeitos dos fármacos , Nicorandil/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Nitrogênio da Ureia Sanguínea , Moléculas de Adesão Celular/sangue , Creatinina/sangue , Glutationa/metabolismo , Interleucina-1beta/metabolismo , Rim/metabolismo , Rim/patologia , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Adv Clin Exp Med ; 28(9): 1161-1170, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31430074

RESUMO

BACKGROUND: The protective effects of brain-derived neurotrophic factor (BDNF) against endoplasmic reticulum (ER) stress in neuronal tissue and endometrial cells have been reported. OBJECTIVES: The aim of this study was to determine whether endogenously produced BDNF protects the kidneys against tunicamycin-induced (Tm) ER stress. MATERIAL AND METHODS: Brain-derived neurotrophic factor heterozygous knockout mice (BDNF(+/-)) and their wild-type (WT) littermates were used. The animals were divided into 4 groups: WT, BDNF(+/-), WT+Tm, and BDNF(+/-)+Tm (n = 7 in each group). After 3 days of saline or Tm injection (0.5 mg/kg; intraperitoneally (i.p.)), renal BDNF, glucose-regulated protein 78 (GRP78), and caspase-12 levels as well as serum BDNF concentration were measured with enzyme-linked immunosorbent assay (ELISA). In the kidney sections, hematoxylin & eosin (H&E) staining, GADD153 immunostaining and TUNEL staining were performed. Serum creatinine levels were measured as an indicator of renal function. RESULTS: Circulating and tissue BDNF levels were significantly lower in the BDNF(+/-) and BDNF(+/-)+Tm groups. Renal levels of GRP78 and caspase-12, apoptotic index, and GADD153 staining were significantly higher in the WT+Tm and BDNF(+/-)+Tm groups. However, apoptosis was more pronounced in the BDNF(+/-)+Tm group than in the WT+Tm group (p < 0.01). Similarly, GADD153 staining was more pronounced in the BDNF(+/-)+Tm group than in the WT+Tm group (p < 0.05). Tm caused a mild deterioration in the kidney tissue of the WT+Tm group, while general deterioration, pyknotic nuclei and swollen cells were observed in the BDNF(+/-)+Tm group. Serum creatinine concentrations were significantly higher in the WT+Tm (p < 0.05) and BDNF(+/-)+Tm (p < 0.05) groups. CONCLUSIONS: This study showed that endogenous BDNF may play a protective role in kidneys against ER stress-induced apoptosis via the suppression of GADD153. As a result, BDNF and related signaling pathways could be considered for therapeutic/protective approaches in kidney disorders.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Estresse do Retículo Endoplasmático , Rim/citologia , Rim/metabolismo , Animais , Apoptose , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Caspase 12 , Camundongos , Fator de Transcrição CHOP , Tunicamicina/farmacologia
9.
Nat Methods ; 16(9): 925-931, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31451764

RESUMO

Matrix-assisted laser desorption-ionization mass spectrometry imaging in transmission-mode geometry (t-MALDI-MSI) can provide molecular information with a pixel size of 1 µm and smaller, which makes this label-free method highly interesting for characterizing the chemical composition of tissues and cells on a (sub)cellular level. However, a major hindrance for wider use of the technology is the reduced ion abundance at small pixel sizes. Here we mitigate this problem by use of laser-induced post-ionization (MALDI-2) and by adapting a t-MALDI-2 ion source to an Orbitrap mass analyzer. We demonstrate the crucial sensitivity and accuracy boosts that are achieved with this combination by visualizing the distribution of numerous phospho- and glycolipids in mouse cerebellum and kidney slices, and in cultured Vero B4 cells. With brain tissue, a pixel size of 600 nm was achieved. Our method could constitute a valuable new tool for research in cell biology and biomedicine.


Assuntos
Encéfalo/metabolismo , Células Epiteliais/metabolismo , Processamento de Imagem Assistida por Computador/métodos , Rim/metabolismo , Imagem Molecular/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Animais , Cercopithecus aethiops , Feminino , Lasers , Camundongos , Camundongos Endogâmicos C57BL , Células Vero
10.
Pestic Biochem Physiol ; 159: 163-172, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400778

RESUMO

Edifenphos (EDF) (O-ethyl-S, S-diphenyldithiophosphate) is an organophosphate pesticide that is extensively used as a fungicide in agricultural rice fields. However, EDF accumulated in various agricultural products and caused potential health hazards to human and other living organisms. Therefore, the present study was investigated to evaluate the ameliorative role of apigenin (APG); a natural antioxidant against EDF-induced hepato-renal toxicity in rats. Six groups with five male Wistar rats each, were used for this purpose; these groups included the control group (A) that received corn oil; (B) 10 mg/kg APG; (C) 10 mg/kg EDF; (D) 25 mg/kg EDF; (E) 10 mg/kg APG pretreatment for 1 h then 10 mg/kg EDF; (F) 10 mg/kg APG pretreatment for 1 h then 25 mg/kg EDF for 14 consecutive days. Oral administration of EDF led to disruption of the intracellular antioxidant machinery which cause the generation of intracellular reactive oxygen species (ROS). However, EDF promotes deleterious effects like oxidative stress, DNA damage, reduced mitochondrial membrane potential, generation of ROS production, activation of caspase 3/9 activities and causing hepato-renal histopathological changes. However, the pretreatment of APG ameliorated the EDF-induced oxidative damage and apoptosis, through their antioxidant activity or by directly scavenging free radical property. Overall, these results suggest that EDF exerts oxidative stress, and APG could be a potent dietary anti-oxidant regimen against EDF-induced toxicity.


Assuntos
Apigenina/farmacologia , Rim/metabolismo , Fígado/metabolismo , Compostos Organotiofosforados/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
11.
Zhonghua Nei Ke Za Zhi ; 58(8): 572-576, 2019 Aug 01.
Artigo em Chinês | MEDLINE | ID: mdl-31365978

RESUMO

Objective: To assess the rate achieving the target vancomycin trough level (VTL) and its influencing factors in critically ill patients. Methods: The retrospective observational study recruited adult patients treated with intravenous vancomycin in the intensive care unit (ICU) at Zhongda Hospital from January 2015 to December 2017. Serum VTL was tested at steady state. Patients' demographics, the sites of infection, microbial culture results, the severity of illness, laboratory data and vancomycin regimen were obtained at the baseline. The rate achieving target VTL (15-20 mg/L) was analyzed based on renal function. Linear regression was performed to determine the influencing factors of VTL. Results: A total of 85 patients were enrolled, among whom only 23.5% (20/85) achieved the target VTL. In patients with normal renal function, the achieving rate was only 11.4% (4/35), and 80.0% (28/35) was lower than the target trough level multiple linear regression analysis showed that procalcitonin (PCT), estimated glomerular filtration rate (eGFR) and acute physiology and chronic health disease classification system Ⅱ (APACHE Ⅱ) score were independent factors associated with VTL. Conclusion: Achieving target VTL in critically ill patients is not satisfactory. Further study to optimize the administration is needed to facilitate prompt attainment of target VTL.


Assuntos
Antibacterianos/farmacocinética , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/metabolismo , Vancomicina/farmacocinética , Administração Intravenosa , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Estado Terminal , Humanos , Pró-Calcitonina/sangue , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Vancomicina/administração & dosagem , Vancomicina/sangue
12.
Life Sci ; 232: 116604, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260684

RESUMO

Chronic kidney disease (CKD) patients present L-arginine (L-arg) deficiency and L-arg supplementation has been used as a treatment. In addition, sarcopenia is another common problem in CKD population, resistance training (RT) is one of the conservative strategies developed to prevent CKD progression, and however there are no evidences of a combination of these two strategies to treat CKD outcomes. The aim of this study was to evaluate the effects of oral L-arg supplementation combined with RT in an experimental model of CKD. Twenty-five Munich-Wistar male rats, 8-week-old were divided in 5 groups: Sham (sedentary control), Nx (CKD sedentary), Nx L-arg (CKD sedentary supplemented with 2% of L-arg), Nx RT (CKD exercised) Nx RT + L-arg (CKD exercised and supplemented with 2% of L-arg). CKD model was obtained by a subtotal 5/6 nephrectomy. RT was performed on a ladder climbing, three weekly sessions on non-consecutive days, with an intensity of 70% maximum carrying capacity. They were submitted to RT and/or L-arg supplementation for 10 weeks. There was a significant improvement in muscle strength, renal function, anti-inflammatory cytokines, arginase metabolism and renal fibrosis after RT. However, the combination of RT and L-arg impaired all the improvements promoted by RT alone. The L-arg supplementation alone did not impair renal fibrosis and renal function. In conclusion, RT improved inflammatory balance, muscle strength, renal function and consequently decreased renal fibrosis. Nevertheless, the association with L-arg supplementation prevented all these effects promoted by RT.


Assuntos
Arginina/farmacologia , Condicionamento Físico Animal/fisiologia , Insuficiência Renal Crônica/dietoterapia , Animais , Arginina/metabolismo , Citocinas/metabolismo , Suplementos Nutricionais , Progressão da Doença , Fibrose/metabolismo , Rim/metabolismo , Masculino , Força Muscular/efeitos dos fármacos , Músculo Esquelético/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Condicionamento Físico Animal/métodos , Ratos , Ratos Wistar , Insuficiência Renal Crônica/metabolismo , Treinamento de Resistência/métodos
13.
Chem Commun (Camb) ; 55(59): 8583-8586, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31274135

RESUMO

We present a near-infrared (NIR) fluorescent probe, NR-HNO, which was successfully applied to visualizing H2S/NO "crosstalk" by the fluorescence detection of nitroxyl with a fast response time (5 min) and a large Stokes shift (131 nm) in living cells and tissue; it was also used to image nitroxyl in live mice.


Assuntos
Compostos de Benzilideno/química , Corantes Fluorescentes/química , Sulfeto de Hidrogênio/metabolismo , Óxido Nítrico/metabolismo , Óxidos de Nitrogênio/análise , Animais , Compostos de Benzilideno/efeitos da radiação , Linhagem Celular Tumoral , Corantes Fluorescentes/efeitos da radiação , Humanos , Rim/metabolismo , Luz , Limite de Detecção , Fígado/metabolismo , Camundongos , Microscopia de Fluorescência/métodos , Nitritos/química , Óxidos de Nitrogênio/metabolismo , Espectrometria de Fluorescência/métodos
14.
Toxicol Lett ; 313: 169-177, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31284021

RESUMO

Acute kidney injury (AKI) is a heterogeneous clinical syndrome with diverse outcomes. The recovery from AKI has prognostic importance. Little research has been done in order to find biomarkers that can predict recovery from AKI. Cav-2 is one of the main constituents of caveolae and is expressed in kidney. This study analyzed the time course of Cav-2 urinary excretion and renal expression in rats treated with cisplatin. Male Wistar rats were injected with cisplatin (5 mg/kg b.w., i.p.), and the studies were performed after 2, 4 and 14 days. Cav-2 abundance was evaluated in urine, in renal homogenates and in apical membranes by Western blotting. Cav-2 in urine was increased only 14 days after treatment, in the recovery phase of cisplatin-induced AKI. These results show that Cav-2 in urine could be useful as a biomarker of renal recovery, but not as an early biomarker of cisplatin-induced AKI. Cav-2 expression in total renal homogenates was not modified with treatment, but a down-regulation of Cav-2 in apical membranes was observed in treated animals. We hypothesize that Cav-2 internalizes into renal cells from their apical membrane in response to cisplatin, and regulates in this manner different signaling proteins involved in the physiopathology of renal damage.


Assuntos
Lesão Renal Aguda/urina , Caveolina 2/urina , Cisplatino , Rim/metabolismo , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/fisiopatologia , Animais , Biomarcadores/urina , Modelos Animais de Doenças , Rim/fisiopatologia , Masculino , Ratos Wistar , Recuperação de Função Fisiológica , Eliminação Renal , Fatores de Tempo
15.
Ecotoxicol Environ Saf ; 182: 109416, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31301596

RESUMO

The main objectives of this study were to purify the glutathione S-transfereses (GSTs) and assess the effect of high doses of acrylamide (ACR) on male albino Wistar rat liver, kidney, testis and bran GST activities, and expression analysis of GST. ACR (50 mg/300 ml) was ingested for 40 days (20 doses) in drinking water on alternative days, on 40 day post ingestion the control and treated tissues were collected for GST purification by affinity column and biochemical characterization of GSTs by substrate specificities, and GST expression by immuno dot blots. In the analysis of the purified GSTs, we observed that liver GSTs were resolved in to three bands known as Yc, Yb and Ya; kidney GSTs were resolved in to two bands known as Yc and Ya; testis and brain GSTs were resolved as four bands known as Yc, Yb, Yß and Yδ on 12.5% sodium dodecyl sulfate polyacrylamide gel (SDS PAGE). In the analysis of biochemical characterization, we observed a significant decrease (p < 0.05) in the specific activities of liver GST isoforms with the substrates 1-chloro 2,4-dinitrobenzene (CDNB), bromosulfophthalein (BSP), p-nitrophenyl acetate (pNPA), p-nitrobenzyl chloride (pNBC) and cumene hydroperoxide (CHP), but showed no activity with ethacrynic acid (ECA) and significant decrease (p < 0.05) in the specific activities of kidney GST isoforms with the substrates CDNB, pNPA, pNBC and CHP, but showed no activity with BSP and ECA, and a significant decrease (p < 0.05) in the specific activities of testis and brain GST isoforms with the substrates CDNB, BSP, pNPA, pNBC, ECA and CHP. In the analysis of immuno dot blots, we observed a decreased expression of liver, kidney, testis and brain GSTs. Through the affinity purification and biochemical characterization, we observed a tissue specific distribution of GSTs that is liver GSTs possess Yc, Yb and Ya sub units known as alpha (α) and mu (µ) class GSTs; kidney GSTs possess Yc and Ya sub units known as (α) alpha class GST; testis and brain GSTs possess Yc, Yb, Yß and Yδ sub units known as alpha (α), mu (µ) and pi (π) class GSTs. Purification studies, biochemical characterization and immuno dot blot analysis were revealed the GSTs were sensitive to high doses of ACR and the high level exposure to ACR cause the damage of detoxification function of GST due to decreased expression and hence lead to cellular dysfunction of vital organs.


Assuntos
Acrilamida/toxicidade , Glutationa Transferase/metabolismo , Animais , Eletroforese em Gel de Poliacrilamida , Glutationa/metabolismo , Isoenzimas , Rim/metabolismo , Fígado/metabolismo , Masculino , Nitrobenzenos , Nitrofenóis , Ratos , Ratos Wistar , Especificidade por Substrato , Testículo/metabolismo , Distribuição Tecidual
16.
DNA Cell Biol ; 38(9): 895-904, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31347925

RESUMO

Ischemia-reperfusion injury is a major reason for acute kidney injury and various kidney diseases. Autophagy plays an important role during renal ischemia-reperfusion injury (RIRI), but it remains controversial whether autophagy contributes to cell survival or ischemia-reperfusion-induced cell death. In the review, we summarized the function of autophagy in the progression of acute ischemic kidney injury, as well as its related molecular mechanisms. While analyzing the opposite roles of autophagy in RIRI, it was concluded that the protective or detrimental function of autophagy was depending on the timing and amount of the activation of cell autophagy. We also summarized the regulatory agents, including active compounds, proteins, or microRNAs (miRNAs), which regulated the cell autophagy during renal acute ischemic kidney injury process. This explained why the opposite conclusion occurred when cell autophagy was studied in the RIRI models from different researchers. Therefore, the article provided a hypothesis to control cell autophagy at the appropriate timing and intensity so as to alleviate renal injury and sustain cell survival of the renal cell.


Assuntos
Autofagia , Rim/irrigação sanguínea , Traumatismo por Reperfusão/metabolismo , Animais , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Humanos , Rim/metabolismo
17.
Life Sci ; 232: 116634, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279782

RESUMO

AIM: Here, we evaluated the possible protective effects of oleuropein, the major phenolic constituent in virgin olive oil against glycerol-induced acute kidney injury (AKI) in rats. MAIN METHODS: Twenty-eight Sprague Dawley rats were allocated equally into four groups as follows: control group, oleuropein group (50 mg/kg body weight), AKI group and the oleuropein + AKI group. AKI was induced by injecting 50% glycerol (10 ml/kg body weight) intramuscularly. KEY FINDINGS: Glycerol injection increased the kidney relative weight as well as rhabdomyolysis (RM)- and AKI-related index levels, including the levels of creatine kinase, lactate dehydrogenase, creatinine, urea, and Kim-1 expression. Additionally, alteration in oxidative conditions in renal tissue was recorded, as confirmed by the elevated malondialdehyde and nitric oxide levels and the decreased glutathione content. Concomitantly, the protein and mRNA expression levels of antioxidant enzymes were suppressed. Moreover, Nfe2l2 and Hmox1 mRNA expression was also downregulated. Glycerol triggered inflammatory reactions in renal tissue, as evidenced by the increased pro-inflammatory cytokines and Ccl2 protein and mRNA expression, whereas myeloperoxidase activity was increased. Furthermore, glycerol injection enhanced apoptotic events in renal tissue by increasing the expression of the pro-apoptotic proteins and decreasing that of anti-apoptotic. However, oleuropein administration reversed the molecular, biochemical, and histological alterations resulting from glycerol injection. SIGNIFICANCE: Our data suggest that oleuropein has potential as an alternative therapy to prevent or minimize RM incidence and subsequent development of AKI, possibly due to its potent anti-stress, anti-inflammatory, and anti-apoptotic effects.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Iridoides/farmacologia , Lesão Renal Aguda/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Moléculas de Adesão Celular/metabolismo , Creatina Quinase/metabolismo , Creatinina/metabolismo , Glutationa/metabolismo , Glicerol/efeitos adversos , Glicerol/farmacologia , Inflamação/metabolismo , Iridoides/metabolismo , Rim/metabolismo , Masculino , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Ratos , Ratos Sprague-Dawley , Rabdomiólise/complicações
18.
Mol Immunol ; 112: 247-255, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31202101

RESUMO

Chronic kidney disease (CKD) involves interstitial fibrosis as an underlying pathological process associated with compromised renal function irrespective of etiological cause of the injury. The transforming growth factor-ß (TGF-ß) plays a pivotal role in progression of renal fibrosis. TGF-ß transduces its downstream signalling by phosphorylation of smad2/3 and also regulates epithelial-mesenchymal-transition (EMT), a program centrally involved in activation of fibroblasts. Renal fibrosis was induced in Swiss albino mice by unilateral ureteral obstruction of animals. Kidney tissues were evaluated for fibrotic protein expression by western blot and immunohistochemistry. The administration of nimbolide (NB) to UUO animals reduced the oxidative stress, expression of ECM proteins, TGF-ß, p-smad and EMT program. Further, NB administration also improved histoarchitecture of obstructed kidney and reduced the collagen deposition in kidney. Our results provided compelling evidence to support antifibrotic activity of NB by reduction in oxidative stress, TGF-ß, and EMT program in fibrotic kidney. The administration of NB in animals blunted the UUO-induced renal injury, inflammation and reduced fibrogenesis in obstructed kidney.


Assuntos
Fibrose/tratamento farmacológico , Limoninas/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Obstrução Ureteral/fisiopatologia , Animais , Transição Epitelial-Mesenquimal , Fibrose/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Obstrução Ureteral/metabolismo
19.
Gen Physiol Biophys ; 38(3): 259-264, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31184312

RESUMO

The peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor and nutrition factor which takes part in the cellular signaling by several agonists such as pioglitazone. PPARγ can serve as potential target in treatments of metabolic syndrome diseases and/or hypertension. In the present study we investigated the effects of pioglitazone, a PPARγ agonist, on hypertension development in young and adult borderline hypertensive rats (BHR). In renal signaling we observed connections between PPARγ and Nrf2, antioxidant in adult animals and differences between young and adult BHR in Nrf2-activated detoxificant outputs (NQO1, HO-1) and NO-synthases. Blood pressure in animals had been detected by cuff plethysmography, cell signaling in the kidney was studied by gene expression determination using qPCR, and nitric oxide synthase (NOS) activity was measured by radioactive detection. Pioglitazone treatment in adult BHR caused no detectable changes in antioxidant and detoxificant responses. The main effects were observed in blood pressure improvement, endothelial NOS expression and NOS activities in both young and adult BHR.


Assuntos
Envelhecimento/fisiologia , Hipertensão , Rim/efeitos dos fármacos , Rim/metabolismo , PPAR gama/agonistas , Pioglitazona/farmacologia , Envelhecimento/efeitos dos fármacos , Animais , Hipertensão/fisiopatologia , Ratos
20.
J Toxicol Sci ; 44(6): 373-391, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31168026

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used therapeutic class in clinical medicine. These are sub-divided based on their selectivity for inhibition of cyclooxygenase (COX) isoforms (COX-1 and COX-2) into: (1) non-selective (ns-NSAIDs), and (2) selective NSAIDs (s-NSAIDs) with preferential inhibition of COX-2 isozyme. The safety and pathophysiology of NSAIDs on the renal and cardiovascular systems have continued to evolve over the years following short- and long-term treatment in both preclinical models and humans. This review summarizes major learnings on cardiac and renal complications associated with pharmaceutical inhibition of COX-1 and COX-2 with focus on preclinical to clinical translatability of cardio-renal data.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Humanos , Rim/metabolismo , Miocárdio/metabolismo
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