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1.
Pharm Res ; 37(4): 74, 2020 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-32215749

RESUMEN

PURPOSE: Zonisamide clinical indications are expanding beyond the classic treatment of epileptic seizures to Parkinson's disease and other neurodegenerative diseases. However, the systemic safety profile of zonisamide may compromise its use as a first-line drug in any clinical condition. Since zonisamide is marketed as oral formulations, the present study aimed at exploring the potential of the intranasal route to centrally administer zonisamide, evaluating the systemic bioavailability of zonisamide and comparing its brain, lung and kidney pharmacokinetics after intranasal, oral and intravenous administrations. METHODS: In vitro cell studies demonstrated that zonisamide and proposed thermoreversible gels did not affect the viability of RPMI 2650 or Calu-3 cells. Thereafter, male CD-1 mice were randomly administered with zonisamide by oral (80 mg/kg), intranasal or intravenous (16.7 mg/kg) route. At predefined time points, animals were sacrificed and plasma and tissues were collected to quantify zonisamide and describe its pharmacokinetics. RESULTS: Intranasal route revealed a low absolute bioavailability (54.95%) but the highest value of the ratio between the area under the curve (AUC) between brain and plasma, suggesting lower systemic adverse events and non-inferior effects in central nervous system comparatively to intravenous and oral routes. Furthermore, drug targeting efficiency and direct transport percentage into the brain were 149.54% and 33.13%, respectively, corroborating that a significant fraction of zonisamide suffers direct nose-to-brain transport. Lung and kidney exposures obtained after intranasal administration were lower than those observed after intravenous injection. CONCLUSIONS: This pre-clinical investigation demonstrates a direct nose-to-brain delivery of zonisamide, which may be a promising strategy for the treatment of central diseases.


Asunto(s)
Administración Intranasal , Encéfalo/metabolismo , Zonisamida/farmacocinética , Administración Intravenosa , Administración Oral , Animales , Disponibilidad Biológica , Línea Celular , Humanos , Riñón/metabolismo , Pulmón/metabolismo , Masculino , Ratones , Mucosa Nasal/metabolismo , Zonisamida/administración & dosificación
2.
Chemosphere ; 244: 125546, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32050342

RESUMEN

Selenium (Se) is the most common micronutrient and that becomes toxic when present at higher concentrations in aquatic environments. Astaxanthin (AST) has been documented to possess antioxidant and anti-inflammatory properties. The aim of this study was to explore the potential of dietary AST and Se exposure on oxidative stress, and inflammatory response in Channa argus. After acclimation, 540 fish were randomly distributed into nine groups housed in twenty-seven glass tanks. The fish were exposed for 8 weeks to waterborne Se at 0, 100 and 200 µg L-1 or dietary AST at 0, 50 and 100 mg kg-1. The results shown that Se accumulation in the kidney, liver, spleen, intestine and gill were significantly increased following Se exposure, dietary 50 and 100 mg kg-1 AST supplementation decreased the accumulation of Se in the kidney, liver, spleen, and intestine. In addition, AST supplementation can decrease oxidative stress and inflammatory response in the liver and spleen following exposure to waterborne Se. These results indicate that AST has the potential to alleviate the effects of Se toxicity in C. argus.


Asunto(s)
Peces/fisiología , Selenio/toxicidad , Contaminantes Químicos del Agua/toxicidad , Animales , Antioxidantes/metabolismo , Bioacumulación , Dieta , Branquias/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Estrés Oxidativo/efectos de los fármacos , Selenio/metabolismo , Bazo , Xantófilas/toxicidad
3.
Life Sci ; 246: 117382, 2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-32004509

RESUMEN

Our preliminary research revealed that metformin, a classic anti-diabetic drug, could rescue Parkin protein expression and mitophagy in high glucose-challenged human renal epithelial cells in vitro, but the molecular mechanism remains to be explored. In the study, Human Renal Cortical Epithelial Cells (HRCEpiC) and Human Renal Proximal Tubular Epithelial Cells (HRPTEpic) were challenged with high glucose with or without metformin pre-treatment to monitor Parkin mRNA and protein expression level change. PRKN gene knockdown was performed by lentiviral-based shRNA delivery. Cell viability, apoptosis and mitophagy were monitored after treatment. Mitochondrial damage was evaluated by analyzing mitochondrial permeability transition pore opening, membrane potential change, mitochondrial superoxide accumulation and cytochrome C release. Protein levels of activating transcription factor 4 (ATF4), p53 phospho-Ser15, IκBα phosphor-Ser32, IKKα phosphor-Ser176/180 in whole cell lysate and nuclear entry of p50/p65 were assessed by western blot. Okadaic acid was used to inhibit protein phosphatase 2A (PP2A). The data suggested high glucose challenge significantly reduced PRKN gene expression, mitophagy, mitochondria integrity and cell viability in vitro, which was rescued by metformin co-treatment. The effects of metformin were crippled by PRKN gene knockdown. Metformin increased PRKN gene transcription while reducednuclear factor kappa B (NF-κB) activation but not that of p53 or ATF4. Inhibiting PP2A weakened NF-κB inhibition and PRKN induction by metformin in high glucose-challenged cells, reducing its mitochondrial protective and cytoprotective effect. So, we concluded thatmetformin protects human renal epithelial cells from high glucose-induced apoptosis by restoring Parkin protein expression and mitophagy via PP2A activation and NF-κB inhibition.


Asunto(s)
Células Epiteliales/efectos de los fármacos , Hipoglucemiantes/farmacología , Riñón/efectos de los fármacos , Metformina/farmacología , FN-kappa B/metabolismo , Proteína Fosfatasa 2/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Western Blotting , Nefropatías Diabéticas/tratamiento farmacológico , Activación Enzimática/efectos de los fármacos , Células Epiteliales/metabolismo , Glucosa/farmacología , Humanos , Riñón/citología , Riñón/metabolismo , Mitocondrias/efectos de los fármacos , Reacción en Cadena en Tiempo Real de la Polimerasa
4.
Life Sci ; 246: 117400, 2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-32032645

RESUMEN

AIMS: Comparative sub-acute toxicity, including tolerance and dependence potential of fentanyl and its three novel and potent analogues was determined in mice. MAIN METHODS: Comparative sub-acute (21 d, intraperitoneal; 1/10 LD50) toxicity of fentanyl and its three novel analogues viz., N-(1-(2-phenoxyethyl)-4-piperidinyl) propionanilide (2), N-isopropyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (5), and N-t-butyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (6) was determined in mice. Animals were observed for additional seven days to assess the recovery. The brain, liver and kidney toxicity was assessed on the basis of various biochemical, oxidative, histological, and neuroadaptive markers. The expression levels of key neuronal markers associated with drug tolerance and dependence were investigated by western blot and immunohistochemistry. KEY FINDINGS: Fentanyl and its analogues caused abnormal levels of liver and kidney specific biomarkers in plasma. Brain malondialdehyde (MDA) levels were raised by all the treatments and kidney MDA level by analogue 6 (21 d). Reduced glutathione levels in brain, liver, and kidney were diminished by all the treatments (21 & 28 d) and a significant change in the levels of antioxidant enzymes was also produced mainly after 21 d. The deleterious effects of fentanyl and its analogues were further substantiated by corresponding histopathological changes in brain, liver and kidney (21 & 28 d). These compounds were also found to produce neuroadaptive changes as evidenced by the increased expression levels of c-Fos, glucocorticoid receptor, N-methyl-d-aspartate receptor1 and µ-opioid receptor (21 & 28 d). SIGNIFICANCE: Three novel analogues of fentanyl were envisaged to have alternative therapeutic potentials. However, their comparative sub-acute toxicity revealed undesirable side effects, thereby masking their therapeutic ability.


Asunto(s)
Fentanilo/toxicidad , Animales , Biomarcadores/análisis , Western Blotting , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Daño del ADN/efectos de los fármacos , Fentanilo/análogos & derivados , Glutatión/análisis , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Malondialdehído/análisis , Ratones , Estrés Oxidativo/efectos de los fármacos
5.
J Agric Food Chem ; 68(9): 2765-2772, 2020 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-32045244

RESUMEN

Fatty acid esters of 3-monochloropropane 1,2-diol (3-MCPD esters) are processing-induced food toxicants, with the kidney as their major target organ. For the first time, this study treated Sprague Dawley (SD) rats with 3-MCPD 1-monooleate at 10 and 100 mg/kg BW/day and 1-monostearate at 15 and 150 mg/kg BW/day for 90 days and examined for their potential semi-long-term nephrotoxicity and the associated molecular mechanisms. No bodyweight difference was observed between groups during the study. Both 3-MCPD 1-monooleate and 1-monostearate resulted in a dose-dependent increase of serum urea creatinine, uric acid and urea nitrogen levels, and histological renal impairment. The proteomic analysis of the kidney samples showed that the 3-MCPD esters deregulated proteins involved in the pathways for ion transportation, apoptosis, the metabolism of xenobiotics, and enzymes related to endogenous biological metabolisms of carbohydrates, amino acids, nitrogen, lipids, fatty acids, and the tricarboxylic acid (TCA) cycle, providing partial explanation for the nephrotoxicity of 3-MCPD esters.


Asunto(s)
Enfermedades Renales/metabolismo , Riñón/efectos de los fármacos , Estearatos/toxicidad , alfa-Clorhidrina/toxicidad , Animales , Creatinina/orina , Ésteres/metabolismo , Ésteres/toxicidad , Humanos , Riñón/metabolismo , Enfermedades Renales/etiología , Enfermedades Renales/genética , Enfermedades Renales/orina , Masculino , Proteómica , Ratas , Ratas Sprague-Dawley , Estearatos/química , Estearatos/metabolismo , Ácido Úrico/orina , alfa-Clorhidrina/metabolismo
6.
Adv Exp Med Biol ; 1227: 81-94, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32072500

RESUMEN

Gremlin is a member of the TGF-ß superfamily that can act as a BMP antagonist, and recently, has been described as a ligand of the vascular endothelial growth factor receptor 2 (VEGFR2). Gremlin shares properties with the Notch signaling pathway. Both participate in embryonic development and are reactivated in pathological conditions. Gremlin is emerging as a potential therapeutic target and biomarker of renal diseases. Here we review the role of the Gremlin-VEGFR2 axis in renal damage and downstream signaling mechanisms, such as Notch pathway.


Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/metabolismo , Receptores Notch/metabolismo , Transducción de Señal , Animales , Humanos , Riñón/metabolismo , Riñón/patología , Factor de Crecimiento Transformador beta/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo
7.
PLoS One ; 15(1): e0221914, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31990917

RESUMEN

Nephronophthisis-related ciliopathies (NPHP-RC) are a group of inherited genetic disorders that share a defect in the formation, maintenance or functioning of the primary cilium complex, causing progressive cystic kidney disease and other clinical manifestations. Mutations in centrosomal protein 164 kDa (CEP164), also known as NPHP15, have been identified as a cause of NPHP-RC. Here we have utilised the MRC-Wellcome Trust Human Developmental Biology Resource (HDBR) to perform immunohistochemistry studies on human embryonic and foetal tissues to determine the expression patterns of CEP164 during development. Notably expression is widespread, yet defined, in multiple organs including the kidney, retina and cerebellum. Murine studies demonstrated an almost identical Cep164 expression pattern. Taken together, these data support a conserved role for CEP164 throughout the development of numerous organs, which, we suggest, accounts for the multi-system disease phenotype of CEP164-mediated NPHP-RC.


Asunto(s)
Cilios/genética , Ciliopatías/genética , Enfermedades Renales Quísticas/genética , Proteínas de Microtúbulos/genética , Animales , Cilios/patología , Ciliopatías/patología , Modelos Animales de Enfermedad , Feto/metabolismo , Regulación del Desarrollo de la Expresión Génica/genética , Humanos , Riñón/metabolismo , Riñón/patología , Enfermedades Renales Quísticas/patología , Ratones , Retina/metabolismo , Retina/patología
8.
Life Sci ; 243: 117272, 2020 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-31926251

RESUMEN

AIM: Despite the great efficacy reported for cisplatin as a widely used chemotherapeutic agent, its clinical use is limited by the challenge of facing its serious side effect; nephrotoxicity. In this study, the effect of the benzbromarone on peroxisome proliferator-activated receptor-alpha (PPAR-α) was investigated against cisplatin nephrotoxicity. MAIN METHODS: Rats were administered benzbromarone (10 mg/kg/day; p.o.) for 14 days, and cisplatin (6.5 mg/kg; i.p.) as a single dose on the 10th day. Blood and kidney tissue samples were collected for determination of kidney function, biochemical and molecular markers, as well as histopathological investigation. KEY FINDINGS: Benzbromarone improved kidney function, that was evidenced by reduced serum creatinine and blood urea nitrogen to nearly the half, compared to the group administered cisplatin alone. The protein expression of PPAR-α was enhanced with benzbromarone treatment, along with a considerable suppression of oxidative stress as benzbromarone reduced mRNA expression of NADPH oxidase, while increased the anti-oxidant HO-1 protein expression associated with enhancing Nrf2. Besides, it displayed a marked anti-inflammatory effect involved suppression of p38 MAPK/NF-κB p65 signaling pathway and its downstream targets. Moreover, benzbromarone retarded apoptosis associated with reducing the pro-apoptotic (Bax) and enhancing the anti-apoptotic (Bcl-2) protein expressions. The protective effects of benzbromarone were also confirmed by histopathological results. SIGNIFICANCE: Our data confirm the relation between PPAR-α, and the deleterious effects induced by cisplatin. It can also be suggested that enhancing PPAR-α expression by benzbromarone is a promising therapeutic approach that overcomes cisplatin nephrotoxicity, involving regulation of different signaling pathways: Nrf2/HO-1, p38 MAPK/NF-κB p65, and Bax/Bcl-2.


Asunto(s)
Benzbromarona/farmacología , Cisplatino/toxicidad , Riñón/efectos de los fármacos , PPAR gamma/metabolismo , Animales , Antioxidantes/farmacología , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Inflamación/inducido químicamente , Riñón/metabolismo , Riñón/patología , Pruebas de Función Renal , Masculino , Estrés Oxidativo/efectos de los fármacos , PPAR gamma/fisiología , ARN Mensajero/genética , Ratas , Ratas Wistar
9.
Life Sci ; 243: 117294, 2020 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-31927047

RESUMEN

Renal fibrosis is a common pathological manifestation of almost all forms of kidney disease irrespective of the etiological cause. Microvascular rarefaction represents itself as an important phenomenon associated with renal fibrosis and shows strong correlation with decline in renal functions. Lysyl oxidase (LOX) catalyzes crosslinking of extracellular matrix (ECM) proteins including collagens, plays an important role in stabilization of degradation resistant matrix. Since, there seems to be a causal link between deposition of excessive ECM and microvascular rarefaction, we investigated the effects of reduction in renal fibrosis on microvascular rarefaction in acute as well as end stage kidney. We used a well-established unilateral ureteral obstruction (UUO)-induced renal fibrosis model to produce renal fibrosis in animals. We treated animals with a LOX inhibitor, ß-aminopropionitrile (BAPN, 100 mg/kg, i.p.) and investigated effects on renal fibrosis and microvascular rarefaction. We observed that LOX inhibition was associated with reduction in collagen deposition in UUO-induced renal fibrosis animal model. Further, ECM normalization by LOX inhibition decreased the loss of peritubular capillaries (PTCs) in fibrotic kidney in acute study while the LOX inhibition failed to inhibit PTCs loss in end stage kidney. The results of present study suggested that inhibition of LOX reduces collagen deposition and renal fibrosis. Further, the reduction in fibrosis fails to protect from PTCs loss in chronic study suggesting the absence of strong link between reduction in fibrosis and improvement in PTCs in an end stage kidney.


Asunto(s)
Capilares/patología , Receptores de Hialuranos/metabolismo , Riñón/patología , Pericitos/patología , Proteína-Lisina 6-Oxidasa/antagonistas & inhibidores , Aminopropionitrilo/farmacología , Animales , Catálisis , Colágeno/metabolismo , Transición Epitelial-Mesenquimal , Fibrosis , Riñón/irrigación sanguínea , Riñón/metabolismo , Masculino , Ratones , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/patología
10.
Clin Sci (Lond) ; 134(2): 239-259, 2020 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-31943002

RESUMEN

Mitochondrial stress has been widely observed in diabetic kidney disease (DKD). Cyclophilin D (CypD) is a functional component of the mitochondrial permeability transition pore (mPTP) which allows the exchange of ions and solutes between the mitochondrial matrix to induce mitochondrial swelling and activation of cell death pathways. CypD has been successfully targeted in other disease contexts to improve mitochondrial function and reduced pathology. Two approaches were used to elucidate the role of CypD and the mPTP in DKD. Firstly, mice with a deletion of the gene encoding CypD (Ppif-/-) were rendered diabetic with streptozotocin (STZ) and followed for 24 weeks. Secondly, Alisporivir, a CypD inhibitor was administered to the db/db mouse model (5 mg/kg/day oral gavage for 16 weeks). Ppif-/- mice were not protected against diabetes-induced albuminuria and had greater glomerulosclerosis than their WT diabetic littermates. Renal hyperfiltration was lower in diabetic Ppif-/- as compared with WT mice. Similarly, Alisporivir did not improve renal function nor pathology in db/db mice as assessed by no change in albuminuria, KIM-1 excretion and glomerulosclerosis. Db/db mice exhibited changes in mitochondrial function, including elevated respiratory control ratio (RCR), reduced mitochondrial H2O2 generation and increased proximal tubular mitochondrial volume, but these were unaffected by Alisporivir treatment. Taken together, these studies indicate that CypD has a complex role in DKD and direct targeting of this component of the mPTP will likely not improve renal outcomes.


Asunto(s)
/metabolismo , Diabetes Mellitus Experimental/metabolismo , Enfermedades Renales/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Albuminuria/genética , Albuminuria/metabolismo , Animales , /genética , Ciclosporina/farmacología , Diabetes Mellitus Experimental/genética , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Peróxido de Hidrógeno/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/genética , ATPasas de Translocación de Protón/metabolismo
11.
Medicine (Baltimore) ; 99(1): e18596, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31895808

RESUMEN

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. Because the molecular mechanisms of DKD are not fully understood, exploration of hub genes and the mechanisms underlying this disease are essential for elucidating the pathogenesis and progression of DKD. Accordingly, in this study, we performed an analysis of gene expression in DKD. The differentially expressed genes (DEGs) included 39 upregulated genes and 113 downregulated genes in the GSE30528 dataset and 127 upregulated genes and 18 downregulated genes in the GSE30529 dataset. Additionally, functional analyses were performed to determine the roles of DEGs using glomeruli samples from patients with DKD and healthy controls from the GSE30528 dataset and using tubule samples from patients with DKD and healthy controls from the GSE30529 dataset. These DEGs were enriched in pathways such as the Wnt signaling pathway, metabolic pathways, and the mammalian target of rapamycin signaling pathway in the GSE30528 dataset and the longevity regulating pathway and Ras signaling pathway in the GSE30529 dataset. Moreover, a protein-protein interaction network was constructed using the identified DEGs, and hub gene analysis was performed. Furthermore, correlation analyses between key genes and pathological characteristics of DKD indicated that CCR4, NTNG1, HGF and ISL1 are related to DKD, and NTNG1 and HGF may server as diagnostic biomarkers in DKD using the receiver-operator characteristic (ROC) curve. Collectively, our findings established 2 reliable biomarkers for DKD.


Asunto(s)
Nefropatías Diabéticas/metabolismo , Factor de Crecimiento de Hepatocito/metabolismo , Riñón/metabolismo , Netrinas/metabolismo , Biomarcadores/metabolismo , Estudios de Casos y Controles , Proteínas Ligadas a GPI/metabolismo , Humanos
12.
Gene ; 731: 144334, 2020 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-31935508

RESUMEN

SOX9 plays a crucial, extensive and conservative role in the process of somatic tissue development and adult regeneration through the positive self-regulation mediated by SOM across all vertebrates. In this study, we have cloned SOX9 from the kidney of hatchling Alligator sinensis. The full-length of SOX9 cDNA is 3878 bp with an open reading frame encoding 494 amino acids. Amino acid alignment analyses indicated that the SOX9 exhibit highly conserved functional domains. Using the droplet digital PCR, the mRNA abundances of SOX9 during nephrogenesis in A. sinensis showed prominent changes in the embryonic development, suggesting that SOX9 might combines a vital role in the regulation of complex renal development. Interestingly, we detected the nucleocytoplasmic shuttling of SOX9 protein using immunofluorescence, implying that nucleocytoplasmic shuttling is critical to the regulation of SOX9 in the renal embryonic development. Collectively, these data provide an important foundation for further studies on renal developmental biology and molecular biology of non-mammalian SOX9. Furthermore, it provides new insights into the phenomenon of SOX9 nucleocytoplasmic shuttling in Alligator sinensis, which is probably of great significance to the development of kidney metanephros embryo.


Asunto(s)
Caimanes y Cocodrilos , Riñón/embriología , Riñón/metabolismo , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Transporte Activo de Núcleo Celular , Caimanes y Cocodrilos/embriología , Caimanes y Cocodrilos/genética , Caimanes y Cocodrilos/metabolismo , Animales , Núcleo Celular/metabolismo , Clonación Molecular , Regulación del Desarrollo de la Expresión Génica , Organogénesis/genética , Transporte de ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo
13.
Toxicol Lett ; 323: 19-24, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-31962156

RESUMEN

Cultured kidney cells maintained in conventional growth media with high glucose levels exhibit increased glycolytic activity compared to the cells in vivo. In contrast, renal proximal tubules utilize substrates such as ketone bodies and rely on mitochondrial oxidative phosphorylation. LLC-PK1 cells maintain many features of the proximal tubule but are exposed to glucose concentrations ranging from 17 to 25 mM. This may impact their reliability in predicting mitochondrial toxicity. This study is designed to test the impact of the ketone body acetoacetate on metabolic characteristics of LLC-PK1 cells. Basal respiration, maximal respiration, spare respiratory capacity and ATP-linked respiration were significantly increased in cells grown in growth medium supplemented with 5 mM acetoacetate. In contrast, glycolytic capacity, as well as glycolytic reserve were significantly reduced in the acetoacetate group. There was an increased expression in biomarkers of mitochondrial biogenesis, and an increase in mitochondrial protein expression. Cells grown in medium complemented with acetoacetate displayed a significantly lower LC50 when treated with clotrimazole and diclofenac. There was a marked increase in uncoupled respiration in the presence of diclofenac, while clotrimazole and ciprofibrate significantly decreased respiration in the acetoacetate. The results indicate that acetoacetate complemented media can alter cellular metabolism and increase sensitization to toxicants.


Asunto(s)
Acetoacetatos/farmacología , Riñón/efectos de los fármacos , Animales , Células Cultivadas , Clotrimazol/toxicidad , Diclofenaco/toxicidad , Ácidos Fíbricos/toxicidad , Glucólisis/efectos de los fármacos , Riñón/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Oxidación-Reducción , Porcinos
14.
J Agric Food Chem ; 68(6): 1563-1570, 2020 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-31927998

RESUMEN

Ethanamizuril(N-{4-[4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-methyl-phenoxy]-phenyl}-acetamide, EZL) is a new anticoccidiosis compound and belongs to the class of triazines. In this study, the metabolism, distribution, and excretion of EZL were evaluated in chickens after administration of EZL at a single dosage. According to the relevant drug biotransformation rules, the exact molecular mass detection, the fragmentation characteristics, and the retention times, a total of five metabolites were identified in vivo in chickens, including two phase I metabolites and three phase II conjugated metabolites. The major metabolic pathways of EZL in chickens were deacetylation, hydroxylation, and glucuronidation. Regarding 14C-tissue residues after administration, kidney was considered to be the target tissue, as 14C-tissue residues could be detected at 240 h postdose. DeacetylEZL (M3) was the main metabolite, accounting for 68.65% and 25.62% of 14C in kidney at 6 and 24 h, respectively. In heart, muscle, skin+fat, and lung tissues, EZL was the main radioactive substance accounting for 94.88%, 97.32%, 96.23%, and 91.3% of 14C, respectively. In the liver, EZL and M3 were 20.76% and 54.65% of 14C, respectively. In chicken tissues the ratio of M5 was too low to be quantitated and it was mainly detected in chicken fecal and bile samples. In chicken excreta, EZL, M3, and glucuronidation of EZL (M5) accounted for 7.02%, 12.33%, and 10.32% of the dose, respectively and were eliminated primarily. This study presents the first detection of EZL metabolites, which is helpful for further understanding of the metabolic mechanism and in vivo intermediate processes of EZL. The results of this study will be good bases for better understanding EZL's anticoccidiosis mechanism and will serve as a helpful reference for assessing the risks to animals and humans.


Asunto(s)
Coccidiostáticos/farmacocinética , Triazinas/farmacocinética , Animales , Biotransformación , Pollos , Coccidiostáticos/administración & dosificación , Coccidiostáticos/metabolismo , Hidroxilación , Riñón/química , Riñón/metabolismo , Hígado/química , Hígado/metabolismo , Pulmón/química , Pulmón/metabolismo , Músculos/química , Músculos/metabolismo , Triazinas/administración & dosificación , Triazinas/metabolismo
15.
Bratisl Lek Listy ; 121(1): 73-78, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31950843

RESUMEN

AIM: The aim of the present study was to investigate the immunohistochemical expression of selected collagen types, namely collagen types I and V and procollagen type III in the renal parenchyma and interstitium and in the myocardium of spontaneously hypertensive rats. MATERIAL AND METHODS: For the present study, we used two age groups of 6- and 12-month-old spontaneously hypertensive rats. An immunohistochemical analysis was conducted with monoclonal antibodies against collagen types I and V and procollagen type III. A semi-quantitative analysis of immunostaining intensity was conducted with the Image J software. RESULTS: In the kidney, all three molecules showed higher expression at the age of 12 months, which was particularly notable for procollagen type III and collagen type V, which stained as highly-positive. In the myocardium, the immunoreactivity of collagen types I and V was stronger in 12-month-old animals, while that of procollagen type III did not change substantially. CONCLUSION: The present study suggests a role of collagen types III and V in hypertensive kidney disease, while also establishing the role of increased expression of collagen types I and V in adverse myocardial remodeling (Tab. 1, Fig. 2, Ref. 48).


Asunto(s)
Hipertensión , Riñón , Miocardio , Animales , Colágeno/metabolismo , Corazón , Hipertensión/metabolismo , Hipertensión/fisiopatología , Riñón/metabolismo , Miocardio/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Remodelación Vascular
16.
J Zoo Wildl Med ; 50(4): 891-896, 2020 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-31926520

RESUMEN

Clinical assessment of renal function in avian species often involves the measurement of plasma uric acid and blood urea nitrogen, relatively insensitive markers of renal dysfunction and dehydration. In mammals, endogenous creatinine is widely used as an indicator of renal glomerular dysfunction. However, avian species produce primarily creatine. Here, renal creatine, 99mTc99-DTPA (diethylenepentaacetic acid, DTPA) and 99mTc-MAG3 (mercaptoacetyl triglycine, MAG3) renal clearances are characterized in the pigeon avian model by infusing DTPA with inulin and creatine with each tracer and examining the slope of their blood disappearance curves. Clearance curves for inulin and DTPA were parallel, suggesting DTPA is cleared by renal filtration. MAG3 clearance (slope: -2.74 × 105, r2 = 0.97) had a slope almost 10-fold steeper than for DTPA (slope: -6.29 × 104, r2 = 0.90), and orders of magnitude steeper than for creatine (slope: -1.4, r2 = 1.0). These results suggest that DTPA is cleared by glomerular filtration like inulin, while MAG3 is filtered and actively excreted in a manner similar to mammals. In contrast, creatine is filtered and resorbed, has a larger volume of distribution (Vd), or exhibits a greater blood protein binding, making it more complex as a renal marker, when compared with creatinine handling in mammals. The two radiotracers can be readily adapted for use in birds, inviting both qualitative and semiquantitative functional evaluation of avian renal function for research and clinical purposes. The elimination of creatine appears to be more complex requiring further study.


Asunto(s)
Columbidae/metabolismo , Creatina/metabolismo , Riñón/metabolismo , Oligopéptidos/metabolismo , Ácido Pentético/farmacocinética , Polietileneimina/análogos & derivados , Animales , Medios de Contraste/farmacocinética , Polietileneimina/farmacocinética
17.
Life Sci ; 244: 117331, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31972209

RESUMEN

AIM: Drug-induced liver and kidney injuries are worldwide problems that cause restrictions in the use of drugs. The injury is highly mediated by oxidative stress and inflammation pathways. So, demonstrating the role of the natural compound (Vit.D) on the prevention of acetaminophen (APAP) overdose toxicity and the molecular mechanism through NrF2/BACH1/HO-1 pathway is promising. EXPERIMENTAL: Male Sprague Dawley rats (40 rats) were divided randomly into 4 groups: Normal, APAP, APAP+Vit.D (500 IU/kg) and APAP+Vit.D (1000 IU/kg). The APAP toxicity caused by 2 g/kg (orally) on day 7. KEY FINDINGS: Vit D decreased significantly liver and kidney functions: serum ALT and AST activities (P < 0.0005); creatinine and urea (P < 0.0005) concentrations; liver and kidney histopathological scores. Furthermore, Vit.D ameliorated APAP-caused oxidative stress through the liver malondialdehyde concentration's decrease and the total antioxidant capacity's increase (P < 0.0005). The molecular mechanism of Vit.D may include the prevention of high deteriorating increase of oxidative stress mediators: hepatic and renal NrF2 and BACH1 tissue expression in addition to serum HO-1 (P < 0.0005); the increase of inflammatory mediators; hepatic and renal NF-κB tissue expression, serum interleukin-10 (P < 0.0005) and TNF-α (P < 0.05). The 500 IU/kg Vit.D administration caused better protection results especially on the histopathological and immunohistochemical results than the 1000 IU/kg Vit.D administration. SIGNIFICANCE: Vit.D ameliorates APAP-induced liver and kidney injury that may be attributed to its ability to moderately increase antioxidant status to counteract the toxicity without the massive destructive increase in the anti-oxidant pathway (NrF2/HO-1/BACH1). So, this work represents a great prophylactic role of Vit.D against drug-induced liver and kidney injury.


Asunto(s)
Acetaminofén/toxicidad , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Hemo Oxigenasa (Desciclizante)/metabolismo , Riñón/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Represoras/metabolismo , Vitamina D/administración & dosificación , Enfermedad Aguda , Analgésicos no Narcóticos/toxicidad , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Regulación de la Expresión Génica/efectos de los fármacos , Hemo Oxigenasa (Desciclizante)/genética , Riñón/metabolismo , Riñón/patología , Masculino , Factor 2 Relacionado con NF-E2/genética , Ratas , Ratas Sprague-Dawley , Proteínas Represoras/genética , Vitaminas/administración & dosificación
18.
Life Sci ; 243: 117226, 2020 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-31904366

RESUMEN

Hypertension is a risk factor for premature death and roughly 50% of hypertensive patients are salt-sensitive. The incidence of salt-sensitive hypertension increases with age. However, the mechanisms of salt-sensitive hypertension are not well understood. We had demonstrated decreased renal sodium­hydrogen exchanger regulatory factor 1 (NHERF1) expression in old salt-resistant F344 rats. Based on those studies we hypothesized that NHERF1 expression is required for the development of some forms of salt-sensitive hypertension. To address this hypothesis, we measured blood pressure in NHERF1 expressing salt-sensitive 4-mo and 24-mo-old male and female Fischer Brown Norway (FBN) rats male and female 18-mo-old NHERF1 knock-out (NHERF1-/-) mice and wild-type (WT) littermates on C57BL/6J background after feeding high salt (8% NaCl) diet for 7 days. Our data demonstrate that 8% salt diet increased blood pressure in both male and female 24-mo-old FBN rats but not in 4-mo-old FBN rats and in 18-mo-old male and female WT mice but not in NHERF1-/- mice. Renal dopamine 1 receptor (D1R) expression was decreased in 24-mo-old rats, compared with 4-mo-old FBN rats. However, sodium chloride cotransporter (NCC) expression increased in 24-mo-old FBN rats. In FBN rats, age had no effect on NaK ATPase α1 and NKCC2 expression. By contrast, high salt diet increased the renal expressions of NKCC2, and NCC in 24-mo-old FBN rats. High salt diet also increased NKCC2 and NCC expression in WT mice but not NHERF1-/- mice. Our data suggest that renal NHERF1 expression confers salt sensitivity with aging, associated with increased expression of sodium transporters.


Asunto(s)
Envejecimiento/metabolismo , Hipertensión/metabolismo , Fosfoproteínas/fisiología , Cloruro de Sodio Dietético/administración & dosificación , Intercambiadores de Sodio-Hidrógeno/fisiología , Animales , Presión Sanguínea , Modelos Animales de Enfermedad , Femenino , Riñón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfoproteínas/genética , Ratas , Ratas Endogámicas F344 , Intercambiadores de Sodio-Hidrógeno/genética
19.
Biomed Chromatogr ; 34(2): e4727, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31657461

RESUMEN

A potent xanthine oxidoreductase inhibitor (LS087) was recently proved to exhibit a similar hypouricemic potency to febuxostat. A hyperuricemia model induced by potassium oxonate and hypoxanthine was proposed in specific pathogen-free male Kunming mice, and the serum urea nitrogen, creatinine and uric acid levels were measured after oral administration of LS087. Furthermore, renal histopathology was conducted by staining with hematoxylin and eosin, periodic acid-Schiff and Masson's trichrome stains, respectively. The results showed that the levels of serum urea nitrogen and uric acid significantly decreased compared with the model group, but the level of creatinine showed no significant changes. The pathological abnormalities in kidney tubules were improved after LS087 administration. Ten metabolites (M1-M10) of LS087 were identified after a single oral dosing of 10 mg/kg in rats. M6 was the primary LS087 metabolite in vivo with a pathway of methylation. The toxicity and potential risks of LS087 and its metabolites were predicted using the ProTox-II software. LS087 and the major metabolites (M2, M3, M5, M6, M7 and M8) were predicted to have no potential hepatotoxicity, but some metabolites with a total rate of <1% (M1, M4, M9, and M10) showed potential hepatotoxicity. M1 and M8 showed potential carcinogenicity. The LS087 biotransformation pathway in rat was well characterized.


Asunto(s)
Inhibidores Enzimáticos , Hiperuricemia/metabolismo , Xantina Deshidrogenasa/antagonistas & inhibidores , Animales , Biotransformación , Creatinina/sangre , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/toxicidad , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Ratones , Ratas , Ratas Sprague-Dawley
20.
Chem Biol Interact ; 315: 108897, 2020 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-31726037

RESUMEN

Type 2 diabetes mellitus (T2DM) is a disease with a drastically growing worldwide prevalence. It is usually associated with numerous complications of which; diabetic nephropathy (DN); is a main complication of microvasculature and more seriously, a common cause of end-stage renal disease (ESRD). Unfortunately, both the lack of a definitive remedy alongside the economic and the social burden on DN patients enforces considerable impetus for developing alternative therapies. IL-33 is a newly discovered member of the IL-1 cytokine family. IL33/ST2 signaling plays a crucial role in acute and chronic kidney diseases. Calycosin is an isoflavone with reported IL33 signaling inhibitory activity. The present study aimed to investigate if calycosin possess renal protective effect in high-fat diet/STZ-induced T2DM model and to clarify the potential underlying mechanisms. HFD-STZ control rats showed functional and structural renal damage confirmed by increased serum creatinine, blood urea nitrogen and albuminuria associated with marked renal glomerulosclerosis and interstitial fibrosis. Initiation of inflammation, oxidative stress, and fibrosis was evident as depicted by elevated renal levels of IL33/ST2 mRNA as well as increased renal NF-κBp65, TNF-α, IL-1ß, MDA, and TGF-ß contents with suppressed Nrf2 and TAC. Calycosin treatment markedly improved the aforementioned makers of renal injury and dysfunction, modulated IL33/ST2 signaling, inflammatory cytokines, oxidative stress and fibrotic processes. This was accompanied by improvement of T2DM-induced renal ultramicroscopic and histopathological alterations.


Asunto(s)
Fibrosis/tratamiento farmacológico , Interleucina-33/metabolismo , Isoflavonas/farmacología , Riñón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Receptores de Interleucina-1/metabolismo , Animales , Citocinas/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/inducido químicamente , Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Dieta Alta en Grasa/efectos adversos , Fibrosis/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Riñón/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Estreptozocina/farmacología
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