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OBJECTIVES: ß-LAPachone (B-LAP) is a natural product with established anti-inflammatory properties. In this study, we investigated the protective potential of B-LAP against diabetic nephropathy in streptozotocin (STZ) induced diabetic mice. MATERIALS AND METHODS: Diabetes induction in mice was carried out by a single intraperitoneal injection of STZ. 2.5 mg/kg/day and 5 mg/kg/day doses of B-LAP were administered orally for twelve weeks and renal histoarchitecture, caspase-3, tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), glutathione peroxidase (GPX), as well as urinary nephrin and neutrophil gelatinase-associated lipocalin (NGAL) were evaluated. Additionally, kidney levels of PI3K, phosphorylated (p)-Akt, p-mTOR, p-CREB, and SIRT1 were assessed in the present investigation. RESULTS: 5 mg/kg B-LAP significantly decreased urinary excretions of nephrin and NGAL. It also mitigated renal TNF-α and MDA levels and simultaneously improved GPX activities. 5 mg/kg B-LAP improved renal function in diabetic mice as indicated by elevated values of creatinine clearance. While B-LAP elevated renal levels of SIRT1, it alleviated PI3K, p-Akt, p-mTOR, and p-CREB levels in the kidneys of diabetic mice. CONCLUSION: Collectively, these findings suggest B-LAP as a potential renoprotective agent in STZ-induced diabetic mice probably via modulating the PI3K/Akt/mTOR pathway.
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OBJECTIVES: Hypercholesterolemia is a common metabolic disorder in developing and developed countries and is associated with the increased rates of chronic kidney disease (CKD). Statin therapy could reduce cholesterol synthesis as well as progression of CKD. Diversity between statins causes variety in pharmacokinetics and pharmacodynamics and also their pleiotropic effects. In the present investigation we aimed to evaluate the protective potentials of both atorvastatin (Ator) (as lipid-soluble statin) and rosuvastatin (Ros) (as water-soluble statin) against renal histopathological damages in the high cholesterol diet induced hypercholesterolemic rats (HCDIHR). MATERIALS AND METHODS: Serum lipid profile, oxidized low density lipoprotein (OX-LDL), malondialdehyde (MDA), urea and creatinine levels, as well as renal histopathology were evaluated. RESULTS: While Ros acted better than Ator to reduce serum low density lipoprotein cholesterol (LDL-C) (P<0.01), atherogenic index (AI) (P<0.01), MDA (P<0.01), and OX-LDL (P<0.01); no significant differences were noted in their cholesterol (P=0.72), triglyceride (TG) (P=0.79), and very low density lipoprotein cholesterol lowering (VLDL-C) (P=0.79) and high density lipoprotein cholesterol elevating effects (HDL-C) (P=0.72). Ator was more effective to reduce renal histopathologic indices compared to Ros, including accumulation of lipid droplet, glomerular foam cells, mesangial cell proliferation, renal hemorrhage, and tubulointerstitial damages in the kidneys of diet induced hypercholesterolemic rats. CONCLUSION: The findings underline that the lipophilic Ator may performs better than Ros in attenuating renal damages in HCDIHR.
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Empagliflozin, a SGLT-2 inhibitor, improves diabetic nephropathy through its pleiotropic anti-inflammatory effects. The present study aims to evaluate empagliflozin effects on renal and urinary levels of tubular epithelial cell injury markers in streptozotocin-induced diabetic rats. Empagliflozin at 10 mg/kg (p.o.) was administered for 4 weeks, beginning 8 weeks after induction of diabetes. Renal function as well as markers of renal tubular epithelial cell injury were assessed in kidney tissue homogenates and urine. Empagliflozin was able to ameliorate diabetes induced elevations in serum cystatin C levels. It also alleviated renal KIM-1/NGAL levels and urinary albumin, α-GST, and RBP excretions. In addition to decreasing urinary levels of cell cycle arrest indices i.e. TIMP-2 and IGFBP7, empagliflozin mitigated acetylated NF-κB levels in renal tissues of diabetic rats. As a whole, these findings reveal empagliflozin capability in improving diabetic nephropathy via ameliorating indices of renal inflammation, injury, and cell cycle arrest on streptozotocin-induced diabetic rats.
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Stem cells are undifferentiated cells and have a great potential in multilineage differentiation. These cells are classified into adult stem cells like Mesenchymal Stem Cells (MSCs) and Embryonic Stem Cells (ESCs). Stem cells also have potential therapeutic utility due to their pluripotency, self-renewal, and differentiation ability. These properties make them a suitable choice for regenerative medicine. Stem cells differentiation toward functional cells is governed by different signaling pathways and transcription factors. Recent studies have demonstrated the key role of microRNAs in the pathogenesis of various diseases, cell cycle regulation, apoptosis, aging, cell fate decisions. Several types of stem cells have different and unique miRNA expression profiles. Our review summarizes novel regulatory roles of miRNAs in the process of stem cell differentiation especially adult stem cells into a variety of functional cells through signaling pathways and transcription factors modulation. Understanding the mechanistic roles of miRNAs might be helpful in elaborating clinical therapies using stem cells and developing novel biomarkers for the early and effective diagnosis of pathologic conditions.
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Diferenciación Celular/genética , Células Madre Embrionarias/citología , Células Madre Mesenquimatosas/citología , MicroARNs/genética , Animales , Apoptosis/genética , Células Madre Embrionarias/metabolismo , Humanos , Células Madre Mesenquimatosas/metabolismo , Medicina Regenerativa , Transducción de Señal , Factores de Transcripción/metabolismoRESUMEN
The incidence of diabetes mellitus (DM) has increased alarmingly over the last decades. Despite taking measures aimed at controlling hyperglycaemia and blood pressure, the rate of end-stage renal disease (ESRD) is continually growing. Upon increased amounts of advanced glycation end products (AGEs) and their correspondent receptors (RAGEs), AGE-RAGE axis is over-activated in DM, being the first step in the initiation and propagation of inflammatory cascades. Meanwhile, HMGB1, released from damaged cells in the diabetic kidneys, is the most notable ligand for the highly expressed toll-like receptors (TLRs) and RAGEs. TLRs play an indispensable role in the pathogenesis of diabetic nephropathy. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are hypoglycaemic agents acting on the renal proximal tubules to prevent glucose reabsorption and therefore increase urinary glucose excretion. Besides improving glycaemic control, these hypoglycaemic agents possess direct renoprotective properties. Here, therefore, we review the most recent findings regarding interrelationship between SGLT2 inhibitors and HMGB1-TLR4 axis.
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Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Proteína HMGB1/metabolismo , Túbulos Renales Proximales/efectos de los fármacos , Reabsorción Renal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Animales , Biomarcadores/sangre , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Humanos , Túbulos Renales Proximales/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Transducción de SeñalRESUMEN
ß-LAPachone (B-LAP) is a naphthoquinone that possesses antioxidant properties. In the present investigation, the protective effect of B-LAP against doxorubicin (DOX)-induced cardiotoxicity was examined in mice. Thirty-five mice were divided into 5 groups: control group, B-LAP (5 mg/kg) group, DOX (15 mg/kg) group, DOX+B-LAP (2.5 mg/kg) group and DOX+B-LAP (5 mg/kg) group. B-LAP was administered orally for 14 days of experimental period. A single dose of DOX (15 mg/kg) was injected intraperitoneally on day 3. Cardiac function, histoarchitecture, indices of oxidative stress and circulating markers of cardiac injury were examined. B-LAP (5 mg/kg) decreased serum levels of lactate dehydrogenase (LDH), creatine kinase MB (CK-MB) and cardiac troponin I (cTnI), and ameliorated cardiac histopathological alterations. In addition to increasing cellular NAD+ /NADH ratio, B-LAP up-regulated the cardiac levels of SIRT1, beclin-1, p-LKB1 and p-AMPK, and reduced the cardiac levels of p-mTOR, interleukin (IL)-1ß, TNF (tumour necrosis factor)-α and caspase-3. B-LAP also elevated the nuclear accumulation of Nrf2 and simultaneously up-regulated the protein levels of haem oxygenase (HO-1) and glutathione S-transferase (GST) in the hearts of DOX mice. While B-LAP reduced malondialdehyde concentrations in heart of DOX-treated mice, it further promoted the activities of cardiac superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT).In accordance with increased cell survival, B-LAP significantly improved the cardiac function of DOX mice. Collectively, these findings underline the protective potential of B-LAP against DOX-induced cardiotoxicity by regulating autophagy and AMPK/Nrf2 signalling pathway in mice.
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Antibióticos Antineoplásicos/toxicidad , Cardiotoxicidad/prevención & control , Doxorrubicina/toxicidad , Naftoquinonas/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Antioxidantes/farmacología , Autofagia/efectos de los fármacos , Cardiotoxicidad/etiología , Supervivencia Celular/efectos de los fármacos , Malondialdehído/metabolismo , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Purpose: This study was aimed to evaluate the site-specific drug delivery of 5-FU with chitosan (CS) as a carrier and quercetin (Qu) against induced colon cancer in Wistar rats. Methods: Cross-linked CS-Qu nanoparticles (NPs) were prepared by ionotropic gelation method. Physicochemical characterization of NPs was performed by Fourier-transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), in vitro drug release, and drug loading efficiency (LE). 1, 2-Dimethylhydrazine (DMH) and dextran sulfate sodium (DSS) were applied to induce adenocarcinoma tumors on inbred male Wistar rats' colon. The treatment group of rats was administered through enema with NPs dispersion. Hematoxylin and eosin staining were performed to the histopathological examination of tumors. Results: Zeta potential and particle size for NPs were +53.5 ± 5 mV and 179 ± 28 nm, respectively. About 96% Qu LE was obtained with a maximum release of 5.63 ±1.59% and 4.62 ± 1.33% after 24 hours in PB solution with pH values of 6 and 7.4, respectively. The numbers of 8 to 21 tumors were observed in all rats administered with DMH and DSS. Significantly decreasing of microvascular density and mitosis count was detected in the treatment group in comparison with cancerous group (P = 0.032 for the former compared to P = 0.016 for the later), respectively. Furthermore, the treatment group showed a high apoptosis rate (P = 0.038). Conclusion: The developed Qu-loaded CS NPs were good candidates for site-specific and sustained drug release in enema treatment. Decreasing of microvascular density and mitosis count, along with increasing the apoptosis percent in the treatment group proved that the NPs could have promising results in site-specific and sustained drug delivery against colorectal cancer.
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Hyperlipidemia and oxidative stress are indispensable features of chronic kidney disease (CKD) that favor the development of atherogenic plaques and cardiovascular disease (CVD). A number of vasoactive mediators including proprotein convertase subtilisin-kexin type 9 (PCSK9), endothelin-1, nitric oxide, and angiotensin II have fundamental roles in the pathophysiology of atherosclerotic events; moreover, their levels are affected by dyslipidemia and oxidative stress due to renal dysfunction. Therefore, therapeutic measures aimed at correcting dyslipidemia and alleviating oxidative stress could potentially protect against CVD in CKD patients. In this review, we discuss the relation between dyslipidemia, oxidative stress, and vasoactive mediators as well as the available treatment options against these disturbances in CKD patients.
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Angiotensina II/fisiología , Dislipidemias/complicaciones , Dislipidemias/metabolismo , Endotelina-1/fisiología , Óxido Nítrico/fisiología , Estrés Oxidativo , Proproteína Convertasa 9/fisiología , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/metabolismo , HumanosRESUMEN
BACKGROUND: One of the important factors in the occurrence of acute kidney injury (AKI) among renal transplant patients (RTPs) is ischemia reperfusion injury (IRI). The current study aimed at determining the anti-inflammatory and anti-oxidative effects of melatonin on the complications of IRI and the level of Klotho expression in these patients. METHODS: A total of 40 renal transplant candidates were randomly assigned into placebo or melatonin group receiving the same dose of 3â¯mg/day. In order to measure serum melatonin levels, inflammatory and oxidative stress factors, renal function biomarkers, and Klotho gene/protein expression, venous blood samples were taken from patients over two different time points, i e, 24â¯h before the transplantation and at discharge from hospital. RESULTS: Melatonin was associated with improvement in renal transplantation, since the serum level of neutrophil gelatinase-associated lipocalin, as a renal functional marker, significantly decreased (Pâ¯<â¯.001). The effect of melatonin as a suppressor of inflammation and oxidative stress was also evident in the melatonin group due to a significant reduction in the serum levels of MDA, CP, 8-OHdG, and TNF-α markers (Pâ¯<â¯.001). CONCLUSIONS: Reduction in serum levels of renal function and oxidative stress/inflammatory markers in the melatonin group indicates that melatonin can inhibit IRI outcomes in RTPs through its anti-oxidant and anti-inflammatory properties. However, these properties do not appear as a result of influence on the level of Klotho gene/protein expression.
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Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Glucuronidasa/metabolismo , Trasplante de Riñón , Melatonina/uso terapéutico , Daño por Reperfusión/prevención & control , 8-Hidroxi-2'-Desoxicoguanosina/sangre , Adulto , Método Doble Ciego , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Glucuronidasa/genética , Humanos , Proteínas Klotho , Lipocalina 2/sangre , Masculino , Malondialdehído/sangre , Persona de Mediana Edad , Carbonilación Proteica , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Despite the major progresses in comprehending the mechanisms of tumor immunosurveillance and the role of innate and adaptive immune systems in recent years, there are still a number of obstacles hindering successful and effective immunotherapy of cancer. Such obstacles have been mainly attributed to the ability of tumors in creating a tolerant microenvironment and exploiting a plethora of immunosuppressive factors that counter effective immune responses against tumor cells. Here we represent a new insight into probable links between immune system disability with metabolism and chronic psychological stress which is beyond the other strategies recruited by tumors to thwart tumor immunosurveillance. In addition, we underscore the prominent role of improper innate immune responses as one of the underlying causes of either pro-tumorigenic capability or tumor immunosurveillance failure. However the insufficiency of stimulatory factors in immune responses is a major fact leading to tumor survival, metabolic suppression of immune cells in tumor microenvironment, as well as the negative influences of chronic stress and depression in cancer patients are important parameters amplifying disability of immune responses which have mostly been underestimated in cancer immunotherapy. Stress-related catecholamines are suggested as immunosuppressive factors. In addition, tumor cells have distinct metabolic pathways and secrete various metabolites in the tumor microenvironment which may inhibit T cells activity. We believe that simultaneous control of metabolic and psychological negative influences on the tumor immunosurveillance, along with addressing the weak aspects of innate and adaptive immune responses in cancer immunotherapy may result in more successful treatment of tumors.
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Inmunidad Innata , Inmunoterapia/métodos , Neoplasias/inmunología , Neurotransmisores/inmunología , Estrés Psicológico/inmunología , Animales , Carcinogénesis/inmunología , Modelos Animales de Enfermedad , Humanos , Vigilancia Inmunológica , Neoplasias/metabolismo , Neoplasias/psicología , Neoplasias/terapia , Neurotransmisores/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/psicología , Escape del Tumor , Microambiente Tumoral/inmunologíaRESUMEN
OBJECTIVES: Empagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, possesses verified anti-inflammatory and anti-oxidative stress effects against diabetic nephropathy. The present investigation aims to examine empagliflozin effects on the renal levels of high mobility group box-1 (HMGB1), a potent inflammatory cytokine, and its respective receptor toll-like receptor-4 (TLR-4) in STZ-induced diabetic rats. MATERIALS AND METHODS: Empagliflozin at 10 mg/kg per os (p.o.) was administered for 4 weeks, starting 8 weeks after the induction of diabetes. Renal function, kidney inflammation, oxidative stress, and apoptosis markers as well as renal HMGB1, receptor for advanced glycation end products (RAGE), and TLR-4 levels were assessed. RESULTS: In addition to down-regulating NF-κB activity in renal cortices, empagliflozin reduced renal levels of HMGB1, RAGE, and TLR-4. It alleviated renal inflammation as indicated by diminished renal expressions of inflammatory cytokines and chemokines like tumor necrosis factor-alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) and also decreased urinary levels of interleukin-6 (IL-6) and alpha-1 acid glycoprotein (AGP). Moreover, empagliflozin ameliorated renal oxidative stress as demonstrated by decreased renal malondialdehyde (MDA) and elevated renal activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX). It also suppressed renal caspase-3, the marker of apoptosis; and furthermore, enhanced renal function noticed by the declined levels of serum urea and creatinine. CONCLUSION: These findings underline that empagliflozin is able to attenuate diabetes-related elevations in renal HMGB1 levels, an influential inflammatory cytokine released from the necrotic and activated cells, and its correspondent receptors, i.e., RAGE and TLR-4.
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OBJECTIVES: Cisplatin is an effective antineoplastic agent; its clinical utility, however, is limited by a few salient toxic side effects like nephrotoxicity. This study aimed to determine the potential protective effects of tangeretin, a citrus-derived flavonoid, against renal tubular cell injury in cisplatin-induced renal toxicity of rats. MATERIALS AND METHODS: Tangeretin was injected intraperitoneally at 2.5 and 5 mg/kg doses for 10 days, and a single dose of cisplatin (8 mg/kg) was injected on the 7th day. Tests of kidney function and tubular injury in renal tissues and urine together with oxidative stress and inflammation markers were examined. RESULTS: Tangeretin ameliorated cisplatin-induced elevations in serum creatinine, BUN, and histopathologic changes. It also attenuated kidney oxidative stress elicited by cisplatin as demonstrated by reduced MDA and increased GSH, CAT, and SOD activities, elevated Nrf2 expression and protein levels of its downstream effectors, HO-1 and NQO-1. Tangeretin further alleviated inflammation evoked by cisplatin as indicated by reduced NF-κB p65 subunit phosphorylation with a simultaneous decrement in its downstream effectors IL-1ß and TNF-α expression and protein levels. Moreover, it declined caspase-3 protein levels and TUNEL positive cells in the kidneys, the markers of apoptosis and DNA fragmentation, thus improving renal endurance. Additionally, tangeretin mitigated renal levels of KIM-1 and NGAL, as well as urinary cystatin C and ß2-microglobulin concentrations, the markers of renal tubular injury. CONCLUSION: Collectively, these data signify the binary profit of tangeretin: enhancement of renal protective mechanisms against cisplatin and attenuation of renal tubular cell injuries induced by the agent.
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Micheliolide (MCL) is a naturally derived anti-inflammatory agent. In the present investigation, we examined the protective potential of MCL against doxorubicin (DOX)-induced cardiotoxicity in mice. Mice were injected with a single 15-mg/kg intraperitoneal dose of DOX at day 1 and the study groups received daily 12.5, 25, and 50 mg/kg doses of MCL for 7 days. Cardiac histopathology, cardiac function, serum markers of cardiac injury, and tissue markers of inflammation, and oxidative stress were examined. MCL decreased serum levels of creatinine kinase MB (CK-MB) and cardiac troponin I (cTnI) levels, ameliorated cardiac tissue architecture, and improved cardiac stroke volume. Apart from reducing the activities of NF-kB p65 subunit, MCL attenuated the cardiac levels of PI3K, phosphorylated (p)-Akt, p-Bad, and caspase-3 levels and simultaneously elevated p-PTEN levels. While the gene expressions of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß) were decreased, the tissue activities of superoxide dismutase (SOD) as well as gene expressions of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase-1 (NQO1) were increased after treatment with MCL. Furthermore, tissue levels of malondialdehyde (MDA) were also decreased. Collectively, these findings point to the protective effects of MCL against DOX-induced cardiotoxicity by regulating PI3K/Akt/NF-kB signaling pathway in mice.
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Antiinflamatorios/farmacología , Doxorrubicina , Cardiopatías/prevención & control , Miocitos Cardíacos/efectos de los fármacos , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sesquiterpenos de Guayano/farmacología , Animales , Cardiotoxicidad , Modelos Animales de Enfermedad , Cardiopatías/inducido químicamente , Cardiopatías/enzimología , Cardiopatías/patología , Mediadores de Inflamación/metabolismo , Masculino , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Estrés Oxidativo/efectos de los fármacos , Fosforilación , Transducción de SeñalRESUMEN
Cisplatin is a broadly prescribed anti-tumor agent for the treatment of diverse cancers. Therapy with cisplatin, however, is associated with various adverse effects including nephrotoxicity and ototoxicity. AMP kinase (AMPK), an evolutionarily conserved enzyme, functions as the fundamental regulator of energy homeostasis. While AMPK activation protects normal tissues against cisplatin-induced toxicities, its impact in cancer is context-dependent and there is no single, uniform role for AMPK. On one hand, some report that AMPK activation augments cisplatin-induced apoptosis in cancer, while on the other hand, few reports indicate that AMPK activation rescues cancer cells from the cytotoxicity induced by cisplatin. Here we review the most salient signaling pathways regulated by AMPK with an emphasis on their relation to cisplatin toxicity and yet discuss context-dependent functions of AMPK in cancer.
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Antineoplásicos/toxicidad , Cisplatino/toxicidad , Sistemas de Liberación de Medicamentos/métodos , Neoplasias/enzimología , Proteínas Quinasas/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/tendencias , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Humanos , Neoplasias/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
ß-Lapachone (B-LAP) is a natural naphtaquinone with established anti-oxidative stress and anti-cancer activities. We aimed to investigate B-LAP protective potential against doxorubicin (DOX)-induced nephrotoxicity in mice. The mice received an oral dose of B-LAP followed by a single intraperitoneal injection of 20 mg/kg DOX a day later. They were then treated for 4 days with 1.25 mg/kg, 2.5 mg/kg, and 5 mg/kg doses of B-LAP. Renal levels of NAD+/NADH ratios, p-AMPKα, p-NF-κB p65, inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) along with renal expressions of TNF-α, IL-1ß, and IL-6 were examined. Serum levels of kidney function markers as well as renal histopathology were also investigated. In addition to increasing the activities of p-AMPKα, B-LAP elevated NAD+/NADH ratios in the kidneys and decreased the renal levels of nuclear p-NF-κB and its correspondent downstream effectors TNF-α, IL-1ß, IL-6, and iNOS in the kidneys. Also, B-LAP effectively ameliorated renal architectural changes and attenuated serum levels of urea, creatinine, and cystatin C. Collectively, these findings suggest the protective actions of B-LAP against DOX-induced nephrotoxicity in mice.
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Antibióticos Antineoplásicos/efectos adversos , Doxorrubicina/efectos adversos , Enfermedades Renales/inducido químicamente , Enfermedades Renales/tratamiento farmacológico , Naftoquinonas/uso terapéutico , Sustancias Protectoras/uso terapéutico , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Citocinas/genética , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Ratones Endogámicos C57BL , NAD/metabolismo , FN-kappa B/metabolismo , Naftoquinonas/farmacología , Sustancias Protectoras/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Osteoblasts are terminally differentiated cells with mesenchymal origins, known to possess pivotal roles in sustaining bone microstructure and homeostasis. These cells are implicated in the pathophysiology of various bone disorders, especially osteoporosis. Over the last few decades, strategies to impede bone resorption, principally by bisphosphonates, have been mainstay of treatment of osteoporosis; however, in recent years more attention has been drawn on bone-forming approaches for managing osteoporosis. MicroRNAs (miRNAs) are a broad category of noncoding short sequence RNA fragments that posttranscriptionally regulate the expression of diverse functional and structural genes in a negative manner. An accumulating body of evidence signifies that miRNAs direct mesenchymal stem cells toward osteoblast differentiation and bone formation through bone morphogenic protein, transforming growth factor-ß, and Wnt signaling pathways. MiRNAs are regarded as excellent future therapeutic candidates because of their small size and ease of delivery into the cells. Considering their novel therapeutic significance, this review discusses the main miRNAs contributing to the anabolic aspects of bone formation and illustrates their interactions with corresponding signaling pathways involved in osteoblastic differentiation.
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Diferenciación Celular/genética , Células Madre Mesenquimatosas/metabolismo , Osteogénesis/genética , Osteoporosis/terapia , Proteínas Morfogenéticas Óseas/genética , Humanos , MicroARNs/genética , Osteoblastos/metabolismo , Osteoblastos/trasplante , Osteoporosis/genética , Transducción de Señal/genética , Factor de Crecimiento Transformador beta/genética , Proteínas Wnt/genéticaRESUMEN
Receptor for advanced glycation end-products (RAGE) is involved in the pathogenesis of diabetic nephropathy. FPS-ZM1, a selective RAGE inhibitor, in combination with valsartan were investigated for their protective potentials on the renal markers of tubular injury in streptozotocin-induced diabetic rats. Rats were assigned into groups of receiving FPS-ZM1 (1â¯mg/kg/day), valsartan (100â¯mg/kg/day), and FPS-ZM1 plus valsartan (1â¯mg/kg/day and 100â¯mg/kg/day, respectively) for one month. Kidney histology, renal inflammation and oxidative stress, and renal and urinary markers of tubular injury were investigated. FPS-ZM1 and valsartan in combination more significantly attenuated renal expressions of tumor necrosis factor-alpha and interleukin-6 genes and reduced urinary levels of interleukin-6. Moreover, the combination elevated renal NAD+/NADH ratios and Sirt1 activities, and mitigated nuclear acetylated NF-κB p65 levels. In addition to alleviating indices of oxidative stress i.e. malondialdehyde, superoxide dismutase and glutathione peroxidase, the combination of FPS-ZM1 and valsartan more effectively upregulated the renal levels of master antioxidant proteins Nrf2, heme oxygenase-1, and NAD(P)H:quinone oxidoreductase-1. Additionally, this dual therapy ameliorated more efficiently the indices of renal tubular injuries as indicated by decreased renal kidney injury molecule-1 levels as well as reduced urinary levels of cystatin C, retinol binding protein, and beta-2-microglobulin. While FPS-ZM1 alone had no appreciable effects on the renal fibrosis, the combination treatment ameliorated fibrosis better than valsartan in the kidneys. Collectively, these findings underline the extra benefits of FPS-ZM1 and valsartan dual administrations in obviating the renal tubular cell injury in streptozotocin-induced diabetic rats partly by suppressing renal inflammation and oxidative stress.
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Benzamidas/farmacología , Diabetes Mellitus Experimental/patología , Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Túbulos Renales/efectos de los fármacos , Túbulos Renales/lesiones , Valsartán/farmacología , Animales , Colágeno/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Interacciones Farmacológicas , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Fibrosis , Productos Finales de Glicación Avanzada/metabolismo , Túbulos Renales/metabolismo , Túbulos Renales/patología , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
INTRODUCTION: Nontraditional risk factors for cardiovascular disease (CVD), including mineral disorder, high fibroblast growth factor 23 (FGF23), low klotho, and low soluble TWEAK could predict the incipient risk of CVD in chronic kidney disease (CKD). The present study evaluates the effect of sevelamer on soluble tumor necrosis factor-like weak inducer of apoptosis (TWEAK), and klotho levels in adenine-induced CKD rats. METHODS AND MATERIALS: Normal control rats without sevelamer were compared with 3 groups of adenine-induced CKD rats, including CKD rats without sevelamer, CKD rats treated with 3% sevelamer, and rats receiving adenine and 3% sevelamer concurrently. After 4 weeks of sevelamer treatment, serum levels of klotho and soluble TWEAK were measured, along with biochemical parameters related to kidney function. RESULTS: Sevelamer significantly reduced serum levels of phosphate and increased serum levels of klotho and soluble TWEAK. Decreased levels of phosphate were negatively correlated with elevated levels of klotho and soluble TWEAK (r = -0.70, P = .003; r = -0.58, P = .02; respectively) in serum. CONCLUSIONS: Sevelamer successfully reduced serum levels of phosphate, and meanwhile, it led to an elevation in serum levels of klotho and soluble TWEAK in rat models of CKD.
Asunto(s)
Apoptosis/efectos de los fármacos , Citocina TWEAK/sangre , Glucuronidasa/sangre , Insuficiencia Renal Crónica/sangre , Sevelamer/farmacología , Adenina , Animales , Proteínas Klotho , Masculino , Fosfatos/sangre , Ratas , Ratas Wistar , Insuficiencia Renal Crónica/inducido químicamenteRESUMEN
BACKGROUND: High serum phosphate and fibroblast growth factor-23 (FGF-23) levels are well-recognized independent risk factors of mortality and morbidity in patients with chronic kidney diseases (CKDs). Sevelamer, as a phosphate chelating agent, reduces serum phosphate and FGF-23 levels produced by bone osteocytes. This study aimed to determine the best dose at which sevelamer could successfully reduce serum phosphate and FGF-23 levels in rat models of adenine-induced CKD. METHODS: CKD was induced using adenine. Healthy and CKD-induced rats were divided into 6 groups as follows: healthy controls; CKD controls; rats treated with 1%, 2%, and 3% sevelamer for CKDs; and healthy rats administered 3% sevelamer. Biochemical factors and serum FGF-23 levels were measured using spectrophotometry and enzyme-linked immunosorbent assay methods. RESULTS: Serum phosphate levels were best decreased in rats receiving 3% sevelamer in their diet (5.91±1.48 mg/dL vs. 8.09±1.70 mg/dL, P<0.05) compared with the CKD control rats. A dose-dependent decrease in serum FGF-23 levels was observed, and the most significant results were obtained in rats receiving 3% sevelamer compared with the CKD control rats (142.60±83.95 pg/mL vs. 297.15±131.10 pg/mL, P<0.01). CONCLUSIONS: Higher sevelamer doses significantly reduced serum phosphate and FGF-23 levels in adenine-induced CKD rats.