RESUMEN
Gentamicin is an aminoglycoside antibiotic with a rapid bactericidal effect on the treatment of many infections. However, its use at high concentrations for more than 7 days causes nephrotoxic side effects. This study investigated the potential of Resatorvid and alpha lipoic acid (ALA) in mitigating gentamicin-induced nephrotoxicity in rats, considering biochemical, histopathological, and molecular parameters. This study randomly distributed 34 Wistar albino rats into four groups: healthy control (n = 6), Gentamicin (80 mg/kg, n = 7), Gentamicin + Sham (%10 hydroalcoholic solution, n = 7), Gentamicin + Resatorvid (5 mg/kg, n = 7), and Gentamicin + ALA (100 mg/kg, n = 7). Resatorvid treatment led to a statistically significant decrease in urinary IL-18, KIM-1, and NGAL levels, whereas ALA treatment significantly reduced KIM-1 levels compared to the gentamicin-only group. Both Resatorvid and ALA showed partial reductions in urine creatinine levels. Moreover, treatments with Resatorvid and ALA resulted in statistically significant decreases in NRF-2, CAS-3, and NR4A2 expressions. However, only Resatorvid demonstrated a statistically significant decrease in NF-B expression. These findings highlight the potential of Resatorvid in ameliorating gentamicin-induced nephrotoxicity, thereby expanding the therapeutic utility of gentamicin and enhancing its efficacy against infections.
Asunto(s)
Antibacterianos , Gentamicinas , Ratas Wistar , Ácido Tióctico , Gentamicinas/toxicidad , Gentamicinas/efectos adversos , Animales , Ácido Tióctico/farmacología , Ácido Tióctico/uso terapéutico , Ratas , Antibacterianos/efectos adversos , Antibacterianos/farmacología , Masculino , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Creatinina/sangre , Creatinina/orina , Enfermedades Renales/inducido químicamente , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/patología , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Moléculas de Adhesión CelularRESUMEN
BACKGROUND: Gentamicin is a commonly used aminoglycoside antibiotic, with ototoxicity as a significant side effect. Ferroptosis, an iron-dependent form of cell death, has been implicated in a variety of disorders. Whether ferroptosis impacts gentamicin ototoxicity is not yet known. The current work used an in-vitro model to examine the influence of gentamicin-induced ferroptosis on cochlear hair cell damage and probable molecular biological pathways. METHODS: House Ear Institute-Organ of Corti 1 (HEI-OC1) cells were treated with different concentrations of gentamicin for 24 hours, with or without ferrostatin-1 pretreatment, to observe gentamicin-induced ferroptosis. The role of p53/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling in gentamicin-induced ferroptosis was explored by pretreating cells with the p53 inhibitor pifithrin-α (PFT-α). We investigated the effect of gentamicin on cells by assessing cell viability. Cellular proteins were isolated and Western blots were performed to detect changes in the expression of p53, SLC7A11, and GPX4. Fluorescence staining was used to assess levels of reactive oxygen species. An enzymatic detection kit was used to detect glutathione, Fe, and malondialdehyde markers. RESULTS: Gentamicin reduced cell viability, glutathione content, and SLC7A11 and GPX4 protein levels, and increased levels of p53 protein, reactive oxygen species, malondialdehyde, and Fe. These effects were largely blocked by pretreatment with ferrostatin-1. Pretreatment with the p53 inhibitor PFT-α prevented the gentamicin-induced reduction in SLC7A11 and GPX4, which alleviated several features of ferroptosis including glutathione depletion, iron overload, and lipid peroxidation build-up. CONCLUSION: Gentamicin induces ferroptosis in the HEI-OC1 cell line, and the mechanism may be related to the p53/SLC7A11/GPX4 signaling pathway.
Asunto(s)
Sistema de Transporte de Aminoácidos y+ , Antibacterianos , Ferroptosis , Gentamicinas , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Transducción de Señal , Proteína p53 Supresora de Tumor , Ferroptosis/efectos de los fármacos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Gentamicinas/toxicidad , Gentamicinas/farmacología , Proteína p53 Supresora de Tumor/metabolismo , Animales , Sistema de Transporte de Aminoácidos y+/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/toxicidad , Línea Celular , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/metabolismo , Órgano Espiral/efectos de los fármacos , Órgano Espiral/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ciclohexilaminas/farmacología , Glutatión Peroxidasa/metabolismo , FenilendiaminasRESUMEN
Containing information molecules from their parent cells and inclining to fuse with targeted cells, bone marrow mesenchymal stromal cells-derived extracellular vesicles (MSCs- EV) are valuable in nanomedicine. BACKGROUND: The effects of aging on the paracrine mechanism and in the production and action of MSCs-EV and their cargos of miR-26a and siRNA-26a for the treatment of tubular renal cells under nephrotoxicity injury remain unelucidated. OBJECTIVE: The purpose of this study was to evaluate MSCs-EV of different ages and their ability to deliver the cargos of miR-26a and siRNA-26a to target renal tubular cells affected by nephrotoxicity injury. METHODS: In a model of gentamicin-induced nephrotoxicity, renal tubular cells treated with MSCs-EV expressing or not expressing microRNA-26a were analyzed. Western blotting was utilized to evaluate cell cycle markers, and MTT assay was utilized to evaluate auto-renovation capacity. RESULTS: Tubular cells under nephrotoxicity injury showed decreased proliferative capacity, but the treatment in the tubular renal cells under nephrotoxicity injury with MSCs-EV expressing microRNA-26a showed nephroprotective effects, regardless of EV age. While the treatment with EV-mediated siRNA-26a failed to preserve the nephroprotective effects equally, regardless of age. CONCLUSION: Mesenchymal stromal cell nanovesicles carry microRNA with nephroprotective proprieties regardless of aging.
Asunto(s)
Proliferación Celular , Túbulos Renales , Células Madre Mesenquimatosas , MicroARNs , Células Madre Mesenquimatosas/metabolismo , MicroARNs/metabolismo , MicroARNs/genética , Animales , Túbulos Renales/patología , Túbulos Renales/metabolismo , Envejecimiento/metabolismo , Envejecimiento/patología , Envejecimiento/genética , Gentamicinas/toxicidad , Gentamicinas/efectos adversos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Factores de Edad , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/genética , Línea Celular , Células Cultivadas , Comunicación Paracrina , Modelos Animales de Enfermedad , HumanosRESUMEN
To reveal the protective effect on the nephrotoxicity of Quercus salicina Blume(QS), a traditional medicine for the treatment of urolithiasis, the 50 % ethanol extract from the branches and leaves of QS was chemically studied by systematic solvent extraction and HPLC chromatography. Two phenolic acids and three flavonoids were identified by nuclear magnetic resonance spectroscopy, namely Ferulic acid (1), p-Hydroxycinnamic acid (2), Hesperidin (3), Formononetin (4), and Quercetin (5). At the same time, the gentamicin-induced nephrotoxicity of zebrafish was used as a model for the first time. The antioxidant activity of these derivatives with good antioxidant activity screened from free radical scavenging experiments in vitro (DPPH and ABTS) was evaluated in vivo, including protein levels (LPO, NO, GSH, and SOD), kidney injury factor (KIM-1), zebrafish kidney pathology and real-time PCR. The results showed that metabolites 1, 3, and 5 had strong antioxidant activity, and oxidative stress in renal tissue was significantly reduced; KIM-1, TNF-α, and IL-6 mRNA expression in a dose-dependent manner, which preliminarily revealed the protective effect of the secondary metabolites of QS on nephrotoxicity, and preliminarily discussed the structure-activity relationship. This study provides an experimental basis for further exploring the mechanism of QS in the kidney.
Asunto(s)
Antioxidantes , Gentamicinas , Enfermedades Renales , Riñón , Estrés Oxidativo , Extractos Vegetales , Quercus , Pez Cebra , Animales , Gentamicinas/toxicidad , Extractos Vegetales/farmacología , Extractos Vegetales/química , Quercus/química , Antioxidantes/farmacología , Antioxidantes/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Estrés Oxidativo/efectos de los fármacos , Metabolismo Secundario , Modelos Animales de EnfermedadRESUMEN
Acute kidney injury (AKI) is characterized by a sudden decline in renal function. Traditional Chinese medicine has employed Fuzi for kidney diseases; however, concerns about neurotoxicity and cardiotoxicity have constrained its clinical use. This study explored mesaconine, derived from processed Fuzi, as a promising low-toxicity alternative for AKI treatment. In this study, we assessed the protective effects of mesaconine in gentamicin (GM)-induced NRK-52E cells and AKI rat models in vitro and in vivo, respectively. Mesaconine promotes the proliferation of damaged NRK-52E cells and down-regulates intracellular transforming growth factor ß1 (TGF-ß1) and kidney injury molecule 1 (KIM-1) to promote renal cell repair. Concurrently, mesaconine restored mitochondrial morphology and permeability transition pores, reversed the decrease in mitochondrial membrane potential, mitigated mitochondrial dysfunction, decreased ATP production, inhibited inflammatory factor release, and reduced early apoptosis rates. In vivo, GM-induced AKI rat models exhibited elevated AKI biomarkers, in which mesaconine was effectively reduced, indicating improved renal function. Mesaconine enhanced superoxide dismutase activity, reduced malondialdehyde content, alleviated inflammatory infiltrate, mitigated tubular and glomerular lesions, and downregulated NF-κB (nuclear factor-κb) p65 expression, leading to decreased tumor necrosis factor-α (TNF-α) and IL-1ß (interleukin-1ß) levels in GM-induced AKI animals. Furthermore, mesaconine inhibited the expression of renal pro-apoptotic proteins (Bax, cytochrome c, cleaved-caspase 9, and cleaved-caspase 3) and induced the release of the anti-apoptotic protein bcl-2, further suppressing apoptosis. This study highlighted the therapeutic potential of mesaconine in GM-induced AKI. Its multifaceted mechanisms, including the restoration of mitochondrial dysfunction, anti-inflammatory and antioxidant effects, and apoptosis mitigation, make mesaconine a promising candidate for further exploration in AKI management.
Asunto(s)
Aconitum , Lesión Renal Aguda , Apoptosis , Riñón , Mitocondrias , Ratas Sprague-Dawley , Animales , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Apoptosis/efectos de los fármacos , Aconitum/química , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Masculino , Ratas , Línea Celular , Riñón/efectos de los fármacos , Riñón/patología , Gentamicinas/toxicidad , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/farmacología , Aconitina/análogos & derivados , Aconitina/farmacología , Aconitina/uso terapéutico , Modelos Animales de Enfermedad , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Humanos , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , DiterpenosRESUMEN
Aminoglycosides are commonly used antibiotics for treatment of gram-negative bacterial infections, however, they might act on inner ear, leading to hair-cell death and hearing loss. Currently, there is no targeted therapy for aminoglycoside ototoxicity, since the underlying mechanisms of aminoglycoside-induced hearing impairments are not fully defined. This study aimed to investigate whether the calcium channel blocker verapamil and changes in intracellular & extracellular calcium could ameliorate aminoglycoside-induced ototoxicity in zebrafish. The present findings showed that a significant decreased number of neuromasts in the lateral lines of zebrafish larvae at 5 days' post fertilization after neomycin (20 µM) and gentamicin (20 mg/mL) exposure, which was prevented by verapamil. Moreover, verapamil (10-100 µM) attenuated aminoglycoside-induced toxic response in different external calcium concentrations (33-3300 µM). The increasing extracellular calcium reduced hair cell loss from aminoglycoside exposure, while lower calcium facilitated hair cell death. In contrast, calcium channel activator Bay K8644 (20 µM) enhanced aminoglycoside-induced ototoxicity and reversed the protective action of higher external calcium on hair cell loss. However, neomycin-elicited hair cell death was not altered by caffeine, ryanodine receptor (RyR) agonist, and RyR antagonists, including thapsigargin, ryanodine, and ruthenium red. The uptake of neomycin into hair cells was attenuated by verapamil and under high external calcium concentration. Consistently, the production of reactive oxygen species (ROS) in neuromasts exposed to neomycin was also reduced by verapamil and high external calcium. Significantly, zebrafish larvae when exposed to neomycin exhibited decreased swimming distances in reaction to droplet stimulus when compared to the control group. Verapamil and elevated external calcium effectively protected the impaired swimming ability of zebrafish larvae induced by neomycin. These data imply that prevention of hair cell damage correlated with swimming behavior against aminoglycoside ototoxicity by verapamil and higher external calcium might be associated with inhibition of excessive ROS production and aminoglycoside uptake through cation channels. These findings indicate that calcium channel blocker and higher external calcium could be applied to protect aminoglycoside-induced listening impairments.
Asunto(s)
Antibacterianos , Bloqueadores de los Canales de Calcio , Calcio , Gentamicinas , Células Ciliadas Auditivas , Neomicina , Verapamilo , Pez Cebra , Animales , Bloqueadores de los Canales de Calcio/farmacología , Calcio/metabolismo , Verapamilo/farmacología , Neomicina/toxicidad , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/metabolismo , Gentamicinas/toxicidad , Antibacterianos/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Ototoxicidad/prevención & control , Aminoglicósidos/toxicidad , Sistema de la Línea Lateral/efectos de los fármacos , Larva/efectos de los fármacos , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/prevención & controlRESUMEN
OBJECTIVES: Gentamicin is one of the most common ototoxic drugs that can lower patients' quality of life. Oxidative stress is a key factors inducing sensory hair cell death during gentamicin administration. So far, there are no effective drugs to prevent or treat gentamicin- induced hearing loss. A recent study found cystic fibrosis transmembrane conductance regulator (CFTR) as a new target to modulate cellular oxidative balance. The objective of this study was to estimate the effect of the CFTR activator ivacaftor on gentamicin-induced ototoxicity and determine its mechanism. METHODS: The hair cell count was analyzed by Myosin 7a staining. Apoptosis was analyzed by TUNEL Apoptosis Kit. Cellular reactive oxygen species (ROS) level was detected by DCFH-DA probes. The Nrf2 related proteins expression levels were analyzed by western blot. RESULTS: An in vitro cochlear explant model showed that gentamicin caused ROS accumulation in sensory hair cells and induced apoptosis, and this effect was alleviated by pretreatment with ivacaftor. Western blotting showed that ivacaftor administration markedly increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO1), and NAD(P)H:quinone oxidoreductase 1 (NQO1). The protective effect of ivacaftor was abolished by the Nrf2 inhibitor ML385. DISCUSSION: Our results indicate the protective role of the CFTR-Nrf2-HO1/NQO1 pathway in gentamicin-induced ototoxicity. Ivacaftor may be repositioned or repurposed towards aminoglycosides-induced hearing loss.
Asunto(s)
Aminofenoles , Pérdida Auditiva , Ototoxicidad , Quinolonas , Humanos , Gentamicinas/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/farmacología , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/farmacología , Calidad de Vida , Estrés Oxidativo , Apoptosis , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/farmacologíaRESUMEN
BACKGROUND: Gentamicin leads to nephrotoxicity with increasing oxidative stress. In the present research the role of citronellol on oxidative damage induced by gentamicin in nephrotoxic rats was evaluated. METHODS AND RESULTS: Forty-twomale Wistar rats were randomly divided into seven equal groups; healthy control, gentamicin, DMSO, citronellol 50, citronellol 100, citronellol 200 and vitamin E. The animals were anesthetized after 12 days of treatment. Kidney and serum samples were received for biochemical, histological changes, and gene expression assessments. The levels of serum glutathione (GSH), serum and kidney glutathione peroxidase (GPX) and the expression of GPX gene against gentamicin group were increased in citronellol treatment groups. The levels of serum and kidney malondialdehyde (MDA), urine protein, serum creatinine and the gene expression of inflammatory factors including tumor necrosis factor-alpha (TNF-α) and Interleukin 6 (IL-6) against gentamicin group were decreased in these groups. Moreover, recuperation in histological alterations was shown in three groups receiving citronellol compared to the gentamicin group. CONCLUSIONS: Citronellol with its antioxidant and anti-inflammatory properties can decrease kidney damage caused by nephrotoxicity induced by gentamicin.
Asunto(s)
Monoterpenos Acíclicos , Antioxidantes , Insuficiencia Renal , Ratas , Animales , Antioxidantes/metabolismo , Gentamicinas/toxicidad , Ratas Wistar , Estrés Oxidativo , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismoRESUMEN
Salidroside (SAL) is a phenol glycoside compound found in plants of the Rhodiola genus which has natural antioxidant and free radical scavenging properties. SAL are able to protect against manganese-induced ototoxicity. However, the molecular mechanism by which SAL reduces levels of reactive oxygen species (ROS) is unclear. Here, we established an in vitro gentamicin (GM) ototoxicity model to observe the protective effect of SAL on GM-induced hair cells (HC) damage. Cochlear explants of postnatal day 4 rats were obtained and randomly divided into six groups: two model groups (treatment with 0.2 mM or 0.4 mM GM for 24 h); two 400 µmol/L SAL-pretreated groups pretreatment with SAL for 3 h followed by GM treatment (0.2 mM or 0.4 mM) for 24 h; 400 µmol/L SAL group (treatment with SAL for 24 h); control group (normal cultured cochlear explants). The protective effects of SAL on GM-induced HC damage, and on mRNA and protein levels of antioxidant enzymes were observed. HC loss occurred after 24 h of GM treatment. Pretreatment with SAL significantly reduced GM-induced OHC loss. In cochlear tissues, mRNA and protein levels of NRF2 and HO-1 were enhanced in the GM alone group compared with the SAL pretreatment GM treatment group. SAL may protect against GM-induced ototoxicity by regulating the antioxidant defense system of cochlear tissues; SAL can activate NRF2/HO-1 signaling, inhibit NF-κB activation, activate AKT, and increase inhibitory phosphorylation of GSK3ß to decrease GSK3 activity, all of which exert antioxidant effects.
Asunto(s)
Gentamicinas , Glucósidos , Ototoxicidad , Ratas , Animales , Gentamicinas/toxicidad , Gentamicinas/metabolismo , FN-kappa B/metabolismo , Antioxidantes/farmacología , Antioxidantes/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Células Ciliadas Auditivas , Cóclea/metabolismo , Fenoles/farmacología , Fenoles/metabolismo , ARN Mensajero/metabolismoRESUMEN
Drug nephrotoxicity has high fatality rates and complications. To study this conditional, traditionally, Gentamicin (GM) is used to induce acute injury and establish a nephrotic syndrome model. Baicalin, a flavonoid derived from baicalin with potent anti-inflammatory and antioxidant activity, has been used to treat various inflammatory diseases. This study aims to investigate the process of baicalin-2-ethoxyethyl ester (BAE) synthesis and its therapeutic effect on GM-induced acute kidney injury (AKI). Briefly, baicalin was processed by various reactions to yield BAE. A GM-induced AKI model was established for in vivo evaluation of the protective effect and mechanism of BAE. The results indicated that BAE reduced serum creatinine and urea nitrogen levels and improved pathological alterations, inflammatory responses, and oxidative stress in renal tissues. Furthermore, it was revealed that BAE might exert anti-inflammatory and anti-oxidative responses during AKI via the NF-κB signaling pathway regulation. The findings imply that BAE has a protective impact on the kidneys and might serve as a potent medicine for treating renal damage.
Asunto(s)
Lesión Renal Aguda , Flavonoides , Transducción de Señal , Humanos , Lesión Renal Aguda/tratamiento farmacológico , Antiinflamatorios/efectos adversos , Flavonoides/farmacología , Flavonoides/uso terapéutico , Gentamicinas/toxicidad , FN-kappa B/metabolismoRESUMEN
The clinical use of gentamicin (GM) is restricted by its nephrotoxic effects. This study aimed for the first time to elucidate the ameliorative effects of the monoterpene linalool (Lin) against GM-mediated acute kidney injury in rats. A total of thirty-two rats were subdivided into four equal groups: control (saline), Lin (100 mg/kg/day), GM (100 mg/kg/day), and GM + Lin (100 and 100 mg/kg/day). Lin and GM were intraperitoneally administered for 12 days. Our results illustrated that Lin ameliorated GM-mediated renal histopathological abnormalities and reduced serum urea and creatinine levels in rats exposed to GM. Lin treatment mitigated oxidative stress in nephrotoxic animals as manifested by reducing serum and renal levels of malondialdehyde and increasing the activities of serum and renal glutathione peroxidase and renal catalase. Moreover, Lin markedly inhibited GM-triggered inflammation by downregulating NF-κB, iNOS, TNF-α, and IL-1ß and reducing renal myeloperoxidase activity and nitric oxide levels. Interestingly, Lin repressed GM-induced apoptosis, as reflected by a marked downregulation of Bax and caspase-3 expression, concurrent with the upregulation of Bcl2 expression. Finally, Lin administration led to a significant downregulation of TGF-ß expression in nephrotoxic animals. In summary, Lin ameliorated GM-mediated nephrotoxicity in rats, at least through its antioxidant, anti-inflammatory, and anti-apoptotic activities and by modulating TGF-ß.
Asunto(s)
Lesión Renal Aguda , Monoterpenos Acíclicos , Apoptosis , Gentamicinas , Interleucina-1beta , FN-kappa B , Óxido Nítrico Sintasa de Tipo II , Estrés Oxidativo , Factor de Crecimiento Transformador beta , Factor de Necrosis Tumoral alfa , Animales , Gentamicinas/toxicidad , Monoterpenos Acíclicos/farmacología , Monoterpenos Acíclicos/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Lesión Renal Aguda/prevención & control , Apoptosis/efectos de los fármacos , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Masculino , Factor de Crecimiento Transformador beta/metabolismo , Ratas , Interleucina-1beta/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Transducción de Señal/efectos de los fármacos , Ratas Wistar , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Monoterpenos/farmacología , Monoterpenos/uso terapéutico , Antioxidantes/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéuticoRESUMEN
The present study aimed to identify the possible effect of gentamicin (GEN) in Rats' Cervi. Estradiol Valerate (EV) was used to induce cervical hyperkeratosis. GEN was administered in absence of EV. Serum and cervical GEN concentration were determined. Levels of malondialdehyde (MDA), total nitrites/nitrate (NOx), reduced glutathione (GSH), tumor necrosis factor-α (TNF-α), sirtuin type 1 (Sirt1) and nuclear factor (erythroid-derived 2)-like-2 factors (Nrf2) were measured in cervix tissue. Expression of BAX and Bcl2 were determined. Cervical histopathological examination was done. EV and GEN significantly increased MDA, NOx, TNF-α and BAX/Bcl2 ratio with decrease in GSH, Nrf2 and Sirt1 levels in cervical tissue. Histopathological picture of diffuse and marked hyperkeratosis was detected in EV and GEN groups. In conclusion, GEN-induced cervical hyperkeratosis via induction of oxidative stress, inflammation and apoptosis.
Asunto(s)
Gentamicinas , Sirtuina 1 , Femenino , Ratas , Animales , Gentamicinas/toxicidad , Sirtuina 1/metabolismo , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Inflamación/inducido químicamente , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Apoptosis , Antioxidantes/farmacologíaRESUMEN
The primary limitation of gentamicin (Gm) treatment is its potential to induce nephrotoxicity, which can restrict both its duration and efficacy. This study aims to investigate the protective effects of Crocin (Cr) against Gm-induced nephrotoxicity and its underlying mechanisms, including inflammation, apoptosis, TLR-4, Nrf-2/HO-1 pathways. 36 Sprague Dawley rats were divided into 6 groups for the study. Group I received only saline. Groups II and III were administered 25 and 50 mg/kg of crocin, respectively. Group IV was treated with 80 mg/kg of Gm. Groups V and VI received 25 and 50 mg/kg of crocin, respectively, in addition to Gm administration. Crocin demonstrated protective effects on kidney tissue. It down-regulated the genes NF-κB, COX-2, TLR-4, Bax, and Caspase-3, while up-regulating Bcl-2, Nrf-2, and HO-1. In conclusion, these findings hold promise for the prevention of Gm-induced nephrotoxicity through the modulation of the Nrf-2/HO-1 pathway.
Asunto(s)
Lesión Renal Aguda , Carotenoides , Gentamicinas , Riñón , FN-kappa B , Animales , Ratas , Apoptosis , Carotenoides/farmacología , Carotenoides/uso terapéutico , Gentamicinas/toxicidad , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Riñón/efectos de los fármacos , FN-kappa B/metabolismo , Estrés Oxidativo , Ratas Sprague-Dawley , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & controlRESUMEN
AIM: Gentamicin-induced nephrotoxicity limits its widespread use as an effective antibacterial agent. Oxidative stress, inflammatory cytokines and apoptotic cell death are major participants in gentamicin-induced nephrotoxicity. We therefore, investigated whether dihydromyricetin (DHM), the antioxidant and anti-inflammatory flavonoid, could protect against the nephrotoxic effects of gentamicin. METHODS: Male Wistar rats administrated gentamicin (100 mg/kg/day, i.p.) for 8 days. DHM (400 mg/kg, p.o.) was concurrently given with gentamicin for 8 days. Control group received the vehicle of DHM and gentamicin. Histopathological examinations, biochemical measurements and immunohistochemical analyses were done at the end of the study. KEY FINDINGS: Treatment with DHM improved the gentamicin induced deterioration of renal functions; serum levels of urea, creatinine and cystatin-C as well as urinary levels of Kim-1 and NGAL, the sensitive indicators for early renal damage, were declined. Additionally, DHM abrogated gentamicin-induced changes in kidney morphology. These nephroprotective effects were possibly mediated via decreasing renal gentamicin buildup, activating the antioxidant enzymes GSH, SOD and CAT and decreasing lipid peroxidation and nitric oxide levels. Further, DHM suppressed renal inflammation and apoptotic cell death by decreasing the expression of nuclear factor-kappa B (NF-κB), TNF-alpha and caspase-3. These effects were correlated to the upregulation of renal SIRT3 expression. Also, DHM activated the regeneration and replacement of injured tubular cells with new ones via enhancing PAX2 expression. SIGNIFICANCE: DHM is a promising therapeutic target that could prevent acute renal injury induced by gentamicin and help renal tubular cells to recover through its antioxidant, anti-inflammatory and antiapoptotic properties.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Sirtuina 3 , Ratas , Animales , Masculino , Humanos , Gentamicinas/toxicidad , Sirtuina 3/metabolismo , Antioxidantes/farmacología , Antioxidantes/metabolismo , Regulación hacia Arriba , Ratas Wistar , Riñón/metabolismo , Estrés Oxidativo , Antiinflamatorios/farmacología , Antiinflamatorios/metabolismo , Factor de Transcripción PAX2/metabolismoRESUMEN
During the drug development process, organ toxicity leads to an estimated failure of one-third of novel chemical entities. Drug-induced toxicity is increasingly associated with mitochondrial dysfunction, but identifying the underlying molecular mechanisms remains a challenge. Computational modeling techniques have proven to be a good tool in searching for drug off-targets. Here, we aimed to identify mitochondrial off-targets of the nephrotoxic drugs tenofovir and gentamicin using different in silico approaches (KRIPO, ProBis and PDID). Dihydroorotate dehydrogenase (DHODH) and pyruvate dehydrogenase (PDH) were predicted as potential novel off-target sites for tenofovir and gentamicin, respectively. The predicted targets were evaluated in vitro, using (colorimetric) enzymatic activity measurements. Tenofovir did not inhibit DHODH activity, while gentamicin potently reduced PDH activity. In conclusion, the use of in silico methods appeared a valuable approach in predicting PDH as a mitochondrial off-target of gentamicin. Further research is required to investigate the contribution of PDH inhibition to overall renal toxicity of gentamicin.
Asunto(s)
Dihidroorotato Deshidrogenasa , Gentamicinas , Gentamicinas/toxicidad , Mitocondrias , Piruvatos , Tenofovir/toxicidadRESUMEN
Gentamicin (GEN) is an aminoglycoside antibiotic used to treat gram-negative bacterial infections. Our study aimed to explore curcumin's (CMN) protective role against GEN-induced renal and cardiac toxicity. Rats were randomly classified into 4 equal groups; Control (cont), GEN (100 mg/kg b.wt, i.p.) for seven days, CMN (200 mg/kg b.wt, orally) for 21 days, and CMN + GEN groups. GEN caused renal and cardiac dysfunctions; increased urea, creatinine, uric acid, cystatin C, CK-MB, LDH, and troponin I serum levels. MDA level was elevated significantly while activities of SOD, CAT, and GSH level were reduced significantly in renal and cardiac tissues. GEN-intoxicated rats showed up-regulation of NF-κB, IL-1ß, Keap1, HMOX1, and BAX with down-regulation of Nrf2, and Bcl-2 mRNA expression in renal and cardiac tissues. Also, GEN-induced up-regulation of renal mRNA expression of KIM-1, NGAL, and intermediate filament proteins [desmin, nestin, and vimentin] as well cardiac gene expression of cMyBP-C and H-FABP. GEN-induced toxicity was significantly attenuated by CMN co-treatment as CMN improved renal and cardiac biomarkers, reduced oxidative stress and inflammatory response, and reversed alterations in mRNA expression of all tested renal and cardiac genes. These outcomes indicated that CMN could protect renal and cardiac tissues against GEN-induced oxidative stress, inflammation, and apoptosis.
Asunto(s)
Curcumina , Gentamicinas , Ratas , Animales , Gentamicinas/toxicidad , FN-kappa B/genética , FN-kappa B/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo , Curcumina/farmacología , Curcumina/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Cardiotoxicidad/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Riñón/metabolismo , Estrés Oxidativo , ARN Mensajero/metabolismo , Apoptosis , Antioxidantes/farmacología , Antioxidantes/metabolismoRESUMEN
Investigation the protective effect of transient receptor potential channel modulator 2-Aminoethoxydiphenyl Borate (2-APB) on aminoglycoside nephrotoxicity caused by reactive oxygen species, calcium-induced apoptosis and inflammation was aimed. Forty Wistar rats were divided (n=8) as follows: Control group; DMSO group; 2-APB group; Gentamicin group (injected 100 mg/kg gentamicin intramuscularly for 10 days); Gentamicin+ 2-APB group (injected 2 mg/kg 2-APB intraperitoneally, then after 30 minutes 100 mg/kg gentamicin was injected intramuscularly for 10 days). Blood samples were collected for biochemical analyses, kidney tissue samples were collected for light, electron microscopic and immunohistochemical investigations. In gentamicin group glomerular degeneration, tubular dilatation, vacuolization, desquamation of tubular cells and hyaline cast formation in luminal space and leukocyte infiltration were seen. Disorganization of microvilli of tubular cells, apical cytoplasmic blebbing, lipid accumulation, myelin figure like structure formation, increased lysosomes, mitochondrial swelling and disorganization of cristae structures, apoptotic changes and widening of intercellular space were found. TNF-α, IL-6 and caspase 3 expressions were increased. BUN and creatinine concentrations were increased. Increase in MDA levels and decrease in SOD activities were determined. Even though degeneration still continues in gentamicin+2-APB treatment group, severity and the area it occupied were decreased and the glomerular and tubule structures were generally preserved. TNF-α, IL-6, caspase 3 immunoreactivities and BUN, creatinine, MDA concentrations were reduced and SOD activities were increased markedly compared to gentamicin group. In conclusion, it has been considered that 2-APB can prevent gentamicin mediated nephrotoxicity with its anti-oxidant, anti-apoptotic and anti-inflammatory effects.
Asunto(s)
Enfermedades Renales , Riñón , Ratas , Animales , Caspasa 3/metabolismo , Caspasa 3/farmacología , Aminoglicósidos/efectos adversos , Aminoglicósidos/metabolismo , Ratas Wistar , Creatinina/metabolismo , Creatinina/farmacología , Factor de Necrosis Tumoral alfa , Interleucina-6 , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Antibacterianos/efectos adversos , Antioxidantes/farmacología , Gentamicinas/toxicidad , Gentamicinas/metabolismo , Superóxido Dismutasa/metabolismo , Estrés OxidativoRESUMEN
Gentamicin (GM) is an aminoglycoside antibiotic used to treat bacterial infections. Nephrotoxicity refers to the impairments of the kidneys caused by the use of GM and can result in decreased kidney function and in severe cases, kidney failure. Aronia melanocarpa extract (AME), also known as the black chokeberry, has been used for its protective effects on the kidneys. AME concentration of 3.38 mg/kg (max antioxidant activity in vitro) was used to determine its effectiveness against induced nephropathy during 30 days. GM treatment caused significant hypoalbuminemia and high values of globulins, creatinine, and urea compared to the control group. GM application lead to hemolysis occurrence, echinocytosis, and platelets aggregation. Significantly high values of segmented neutrophils and low values of non-segmented neutrophils were recorded in the blood of rats treated with chokeberry extract (AME). In the pre-treatment (AME + GM), severe hypochromic anemia and a significant improvement in hematological parameters, as well as a reduction of anemia in the post-treatment (GM + AME), were noted. Post-treatment AME also significantly regulates urea and creatinine values. Statistically significantly low hemoglobin values were found in all groups treated with AME. Current study suggests that compounds in the AME have a moderate beneficial effect against renal injury and anti-inflammatory properties that may help protect the kidneys from injury caused by GM.
Asunto(s)
Enfermedades Renales , Photinia , Ratas , Animales , Ratas Wistar , Gentamicinas/toxicidad , Photinia/química , Creatinina , Enfermedades Renales/inducido químicamente , Enfermedades Renales/tratamiento farmacológico , Riñón , Antioxidantes/farmacología , UreaRESUMEN
Gentamicin, an aminoglycoside antibiotic, is nowadays widely used in the treatment of gram-negative microorganisms. The antimicrobial, anti-inflammatory, and antioxidant activities of eucalyptol, a type of saturated monoterpene, have been reported in many studies. The aim of this study was to examine the possible effects of eucalyptol on gentamicin-induced renal toxicity. A total of 32 rats were divided into 4 groups; Control (C), Eucalyptol (EUC), Gentamicin (GEN), and Gentamicin + Eucalyptol (GEN + EUC). In order to induce renal toxicity, 100 mg/kg gentamicin was administered intraperitoneally (i.p.) for 10 consecutive days in the GEN and GEN + EUC groups. EUC and GEN + EUC groups were given 100 mg/kg orally of eucalyptol for 10 consecutive days. Afterwards, rats were euthanized and samples were taken and subjected to histopathological, biochemical, immunohistochemical, and real-time PCR examinations. The blood urea nitrogen (BUN) and creatinine (CRE) levels were significantly decreased in the GEN + EUC group (0.76 and 0.69-fold, respectively) compared to the GEN group. The glutathione peroxidase (GPx) and catalase (CAT) activities were significantly increased in the GEN + EUC group (1.35 and 2.67-fold, respectively) compared to the GEN group. In GEN group, Nuclear factor kappa B (NF-kB), Interleukin 1-beta (IL-1ß), Inducible nitric oxide synthase (iNOS), Tumor necrosis factor-α (TNF-α), Caspase-3, 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and Nuclear factor erythroid 2-related factor (Nrf2) expression levels were found to be quite irregular. GEN + EUC group decreased the expressions of NF-kB, IL-1ß, iNOS, TNF-α, Caspase-3, and 8-OHdG (0.55, 0.67, 0.54, 0.54, 0.63 and 0.67-fold, respectively), while it caused increased expression of Nrf2 (3.1 fold). In addition, eucalyptol treatment ameliorated the histopathological changes that occurred with gentamicin. The results of our study show that eucalyptol has anti-inflammatory, antioxidative, antiapoptotic, nephroprotective, and curative effects on gentamicin-induced nephrotoxicity.
Asunto(s)
Gentamicinas , FN-kappa B , Ratas , Animales , FN-kappa B/metabolismo , Gentamicinas/toxicidad , Eucaliptol/metabolismo , Eucaliptol/farmacología , Eucaliptol/uso terapéutico , Caspasa 3/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Riñón , Estrés Oxidativo , Antioxidantes/metabolismo , Inflamación/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , ApoptosisRESUMEN
Ototoxicity is a major side effect of aminoglycosides, which can cause irreversible hearing loss. Previous studies on aminoglycoside-induced ototoxicity have primarily focused on the loss of sensory hair cells. Recent investigations have revealed that aminoglycosides can also lead to the loss of ribbon synapses in inner hair cells (IHCs). However, the functional implications of ribbon synapse loss and the underlying mechanisms remain unclear. In this study, we intraperitoneally injected C57BL/6 J mice with 300 mg/kg gentamicin once daily for 3, 10, and 20 days. Then, we performed immunofluorescence staining, patch-clamp recording, proteomics analysis and western blotting to characterize the changes in ribbon synapses in IHCs and the associated mechanisms. After gentamicin treatment, the auditory brainstem response (ABR) threshold was elevated, and the ABR wave I amplitude was decreased. We also observed loss of ribbon synapses in IHCs. Interestingly, ribbon synapse loss occurred on both the modiolar and pillar sides of IHCs. Whole-cell patch-clamp recordings in IHCs revealed a reduction in the calcium current amplitude, along with a shifted half-activation voltage and altered calcium voltage dependency. Moreover, exocytosis of IHCs was reduced, consistent with the reduction in the ABR wave I amplitude. Through proteomic analysis, western blotting, and immunofluorescence staining, we found that gentamicin treatment resulted in downregulation of myosin VI, a protein crucial for synaptic vesicle recycling and replenishment in IHCs. Furthermore, we evaluated the kinetics of endocytosis and found a significant reduction in IHC exocytosis, possibly reflecting the impact of myosin VI downregulation on synaptic vesicle recycling. In summary, our findings demonstrate that gentamicin treatment leads to synaptic dysfunction in IHCs, highlighting the important role of myosin VI downregulation in gentamicin-induced synaptic damage.