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Acute kidney injury (AKI) is one of the most serious complications of cisplatin anticancer therapies. Cilastatin is a highly promising nephroprotective agent to eventually enter ...clinical use, but its biochemical mechanism is still not fully understood. We have employed an untargeted metabolomics approach based on capillary electrophoresis mass spectrometry (CE-MS) analysis of serum and urine from an in vivo rat model, to explore the metabolic pathways involved in cisplatin-induced AKI and cilastatin nephroprotection. A total of 155 and 76 identified metabolites were found to be significantly altered during cisplatin treatment in urine and serum, respectively. Most of these altered metabolites were either partially or totally recovered by cilastatin and cisplatin co-treatment. The main metabolic pathways disturbed by cisplatin during AKI involved diverse amino acids metabolism and biosynthesis, tricarboxylic acids (TCA) cycle, nicotinate and nicotinamide metabolism, among others. Cilastatin was proved to protect diverse cisplatin-altered pathways involving metabolites related to immunomodulation, inflammation, oxidative stress and amino acid metabolism in proximal tubules. However, cisplatin-altered mitochondrial metabolism (especially, the energy-producing TCA cycle) remained largely unprotected by cilastatin, suggesting an unresolved mitochondrial direct damage. Multivariate analysis allowed effective discrimination of cisplatin-induced AKI and cilastatin renoprotection based on metabolic features. A number of potential serum and urine biomarkers could also be foreseen for cisplatin-induced AKI detection and cilastatin nephroprotection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Nephrotoxicity is one of the most serious health consequences of cadmium (Cd) toxic exposure. Cd was associated with nephrotoxicity through different mechanisms including apoptosis, inflammation, and ...oxidative stress. This study investigated the effects of glimepiride on renal inflammatory reactions and oxidative stress in response to Cd in mice animal model, pointing to the possible role of JNK/NF-кB and PI3K/AKT signaling.
Four groups of animals were created; the control group, the glimepiride group (4 mg/kg; i.p.), CdCl2 nephrotoxic group (6.5 mg/kg; i.p.), and the CdCl2/glimepiride group. On the other hand, molecular docking studies were used to investigate the affinity of glimepiride towards JNK, AKT, and PI3K targets.
The CdCl2 group's serum creatinine and urea levels were found to have a significant increase when compared to the normal group. High expression of 8-OHDG, JNK, AKT, and NGAL was also detected in the CdCl2 group. In addition, coagulative necrosis of the renal tubules and increased immunostaining of NF-κB and PI3K. Furthermore, glimepiride significantly decreased the serum creatinine and urea level and alleviated the degenerative and necrotic changes within the renal tubules. Moreover, the renal NGAL and JNK were suppressed, and oxidants/antioxidants hemostasis was observed.
The available data show that glimepiride is an attractive strategy for improving the nephrotoxicity associated with CdCl2 through inhibition of JNK/NF-κB, PI3K/AKT inflammatory pathways. From the abovementioned results, glimepiride treatment might be a potential therapeutic approach to treat renal tissue against severe acute renal damage induced by the toxic effects of CdCl2.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The major side effect of tacrolimus (Tac) is nephrotoxicity. We studied whether supplementation of coenzyme Q10, (CoQ10) a potent antioxidant, can reduce Tac‐induced nephrotoxicity via improving ...mitochondrial function. In an in vitro study, CoQ10 reduced the production of Tac‐induced mitochondrial reactive oxygen species and abolished the loss of mitochondrial membrane potential in proximal tubular cell line. Assessment of mitochondrial function revealed that CoQ10 decreased oxygen consumption and mitochondrial respiration rate increased by Tac, suggesting improvement of mitochondrial function to synthesize ATP with CoQ10 treatment. The effect of the CoQ10 in vitro study was observed in an experimental model of chronic Tac‐induced nephropathy. CoQ10 attenuated Tac‐induced oxidative stress and was accompanied by function and histologic improvement. On electron microscopy, addition of CoQ10 increased not only the number but also the volume of mitochondria compared with Tac treatment only. Our data indicate that CoQ10 improves Tac‐induced mitochondrial dysfunction in kidney. Supplementary CoQ10 treatment may be a promising approach to reduce Tac‐induced nephrotoxicity.—Yu, J. H., Lim, S. W., Luo, K., Cui, S., Quan, Y., Shin, Y. J., Lee, K. E., Kim, H. L., Ko, E. J., Chung, B. H., Kim, J. H., Chung, S. J., Yang, C. W. Coenzyme Q10 alleviates tacrolimus‐induced mitochondrial dysfunction in kidney. FASEB J. 33, 12288‐12298 (2019). www.fasebj.org
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Nanotechnology is one of the frontier areas of research involving nanoscale manipulation of atoms and molecules. Its development is one of the most innovative advancement of biomedical field in the ...past decade. Nowadays this emerging field focuses on developing new generation nanomaterials like Quantum dots for multitasking purposes such as medical diagnostics, drug delivery, gene therapy etc. ‘Quantum dots’ also known as semiconductor nanocrystals are rapidly becoming a critical tool for a variety of biomedical applications owing to their exceptional photo physical properties. Most probably, liver and kidney are the organs prone to Quantum dots (QDs) as part of their metabolism and excretion during their applications. Toxicity is a major obstacle when considering QDs for various biomedical applications. Significant challenges still exist and need to be validated before their clinical applications. This review focus on to the science behind quantum dots, various biomedical applications and their interaction with liver and kidney. Safety concerns being the major downside of its application are also briefly discussed followed by factors affecting their toxicity. Also, strategies towards modification of quantum dots for reducing cytotoxicity are illustrated and concluded with a glance at the future direction of quantum dots.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Environmental accumulation of nano- and microplastics pose serious risks to human health. Polystyrene (PS) is a polymer commonly used in the production of plastics. However, PS can adsorb cadmium ...(Cd), thereby influencing bioavailability and toxicity in vivo. Moreover, PS and Cd can accumulate in the mammalian kidney. Therefore, the aim of the present study was to assess the effects of combined exposure to PS and Cd in the kidney. Kidney damage was evaluated in male mice gavaged with PS (diameter, 100 nm and/or 1 μm) and Cd for 25 days.The results showed that PS at 100 nm caused more severe oxidative damage and cell apoptosis than PS at 1 μm. Combined exposure to PS at both 100 nm and 1 μm caused more severe kidney damage than the single administration groups. The extent of kidney toxicity caused by Cd differed with the combination of PS particles at 100 nm vs. 1 μm. The degree of damage to kidney function, pathological changes, and cell apoptosis induced by Cd+100 nm PS+1μm PS was the most severe. An increase in the Bax/Bcl2 ratio and overexpression of p53 and caspase-3 revealed that renal cell apoptosis might be induced via the mitochondrial pathway. Collectively, these findings demonstrate that the size of PS particles dictates the combined effects of PS and Cd in kidney tissues. Kidney damage caused by the combination of different sizes of PS particle and Cd is more complicated under actual environmental conditions.
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•The kidney damage induced by 100 nm PS was more severe than that induced by 1 μm PS.•The 100 nm PS+1 μm PS group caused more severe kidney damage than the single group.•The kidney toxicity differed between group at Cd + 100 nm PS and Cd + 1 μm PS.•The combined effects of Cd + 100 nm PS + 1 μm PS on mouse kidney were the strongest.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cisplatin is a highly effective chemotherapeutic agent commonly used in the treatment of a wide variety of malignancies. However, its clinical usage is severely limited by its serious side effects, ...especially nephrotoxicity. Anemoside B4, is a major saponins, rich in root of Pulsatilla chinensis (Bunge), has anti-inflammation in vitro. However, the antioxidant or anti-inflammatory effects of anemoside B4 in cisplatin-induced nephrotoxicity have not been clearly demonstrated.
In this study, we investigated whether anemoside B4 exhibits protective effects against cisplatin-induced nephrotoxicity involving antioxidant or anti-apoptosis effects.
To clarify it, the effects of anemoside B4 on HEK 293 cell viability was measured by CCK8 kits, intracellular antioxidant capacity including glutathione reduced (GSH), catalase (CAT) were estimated using chemical kits, apoptosis rate and intracellular reactive oxygen species (ROS) was analyzed by flow cytometry, apoptosis protein was measured by western blotting. In vivo model of cisplatin-induced mice acute renal failure was performed to evaluate the properties of anemoside B4. Besides, to evaluate the effect of anemoside B4 on the anti-tumor activity of cisplatin, S180 xenograft models were used.
Anemoside B4 potently increased cisplatin-treated HEK 293T cells viability on the concentration and time manners and inhibited cells apoptosis, as demonstrated by the decreased cleaved PARP protein expressions. Anemoside B4 decreased reactive oxygen species (ROS) content and improved superoxide dismutase (SOD) activity. In vivo experiment showed that pretreatment with anemoside B4 effectively adjusted body weight and kidney index, and reduced cisplatin-elevated blood urea nitrogen (BUN) and creatinine (CREA) levels, as well as ameliorated the histopathological damage. Further studies showed that anemoside B4 did not reduce antitumor activity of cisplatin in murine S180 cancer xenograft tumor models. In addition, anemoside B4 per set showed low toxicity in mice.
The strong antioxidant and anti-apoptosis effects of anemoside B4 may provide therapeutic potential for cisplatin-induced nephrotoxicity without compromising its therapeutic efficiency.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Nephrotoxic medication (NTMx) exposure is a common cause of acute kidney injury (AKI) in hospitalized children. The Nephrotoxic Injury Negated by Just-in time Action (NINJA) program decreased NTMx ...associated AKI (NTMx-AKI) by 62% at one center. To further test the program, we incorporated NINJA across nine centers with the goal of reducing NTMx exposure and, consequently, AKI rates across these centers. NINJA screens all non-critically ill hospitalized patients for high NTMx exposure (over three medications on the same day or an intravenous aminoglycoside over three consecutive days), and then recommends obtaining a daily serum creatinine level in exposed patients for the duration of, and two days after, exposure ending. Additionally, substitution of equally efficacious but less nephrotoxic medications for exposed patients starting the day of exposure was recommended when possible. The main outcome was AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) serum creatinine criteria (increase of 50% or 0.3 mg/dl over baseline). The primary outcome measure was AKI episodes per 1000 patient-days. Improvement was defined by statistical process control methodology and confirmed by Autoregressive Integrated Moving Average (ARIMA) modeling. Eight consecutive bi-weekly measure rates in the same direction from the established baseline qualified as special cause change for special process control. We observed a significant and sustained 23.8% decrease in NTMx-AKI rates by statistical process control analysis and by ARIMA modeling; similar to those of the pilot single center. Thus, we have successfully applied the NINJA program to multiple pediatric institutions yielding decreased AKI rates.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP