Agmatine improves renal function in gentamicin-induced nephrotoxicity in rats.

The present study was designed to explore the possible protective effects of agmatine, a known nitric oxide (NO) synthase inhibitor, against gentamicin-induced nephrotoxicity in rats. For this purpose, we quantitatively evaluated gentamicin-induced renal structural and functional alterations using histopathological and biochemical approaches. Furthermore, the effect of agmatine on gentamicin-induced hypersensitivity of urinary bladder rings to acetylcholine (ACh) was evaluated. Twenty-four male Wistar albino rats were randomly divided into 3 groups, namely control, gentamicin (100 mg/kg, i.p.), and gentamicin plus agmatine (40 mg/kg, orally). At the end of the study, all rats were sacrificed and then blood and urine samples and kidneys were taken. Administration of agmatine significantly decreased kidney/body mass ratio, serum creatinine, lactate dehydrogenase (LDH), renal malondialdehyde (MDA), myeloperoxidase (MPO), NO, and tumor necrosis factor-alpha (TNF-α) while it significantly increased creatinine clearance and renal superoxide dismutase (SOD) activity when compared with the gentamicin-treated group. Additionally, agmatine ameliorated tissue morphology as evidenced by histological evaluation and reduced the responses of isolated bladder rings to ACh. Our study indicates that agmatine administration with gentamicin attenuates oxidative-stress associated renal injury by reducing oxygen free radicals and lipid peroxidation, restoring NO level and inhibiting inflammatory mediators such as TNF-α.

Celecoxib, a selective cyclooxygenase-2 inhibitor, attenuates renal injury in a rat model of Cisplatin-induced nephrotoxicity.

BACKGROUND: Cisplatin is an effective chemotherapeutic agent successfully used in the treatment of a wide range of tumors. Nevertheless, nephrotoxicity has restricted its clinical use. Recent studies have strongly suggested that inflammatory mechanisms may play an important role in the pathogenesis of cisplatin nephrotoxicity. Celecoxib, a selective cyclooxygenase-2 inhibitor used as anti-inflammatory, may therefore have a protective effect on cisplatin-induced renal injury. METHODS: In the present study, rats were injected intraperitoneally with a single dose of cisplatin (7 mg/kg) and/or celecoxib (30 mg/kg) for 5 days. RESULTS: Nephrotoxicity manifested biochemically by elevations in serum creatinine, blood urea nitrogen, and proteinuria, and an increase in kidney weight as a percentage of total body weight. In addition, a marked decrease in serum albumin was observed. Lipid peroxidation in the kidney was monitored by measuring the malondialdehyde level and glutathione content, which were increased and depleted, respectively. Administration of celecoxib with cisplatin attenuated cisplatin-induced changes in kidney function parameters and oxidative stress markers. Histopathological examination of the kidney confirmed these results. CONCLUSION: In conclusion, this study indicates that celecoxib may be a promising drug for clinical use as a nephroprotectant against cisplatin-induced nephrotoxicity.

Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy.

Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of antitumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy of immunotherapy. An acidic pH environment blocked T-cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was posttranslational. Acidification did not affect cytoplasmic pH, suggesting that signals transduced by external acidity were likely mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T-cell infiltration. Furthermore, combining bicarbonate therapy with anti-CTLA-4, anti-PD1, or adoptive T-cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation.

Flavocoxid attenuates gentamicin-induced nephrotoxicity in rats.

Gentamicin is a widely used antibiotic against serious and life-threatening infections; however, its usefulness is limited by the development of nephrotoxicity. The present study was designed to determine whether flavocoxid has a protective effect against gentamicin-induced nephrotoxicity in rats. For this purpose, we quantitatively evaluated gentamicin-induced renal structural and functional alterations using histopathological and biochemical approaches. Furthermore, the effect of flavocoxid on gentamicin induced hypersensitivity of urinary bladder rings to acetylcholine (ACh) was determined. Twenty-four male Wistar albino rats were randomly divided into three groups, namely control, gentamicin (100 mg/kg, i.p.) and gentamicin plus flavocoxid (20 mg/kg, orally). At the end of the study, all rats were sacrificed and then blood, urine samples and kidneys were collected for further analysis. Gentamicin administration caused a severe nephrotoxicity which was evidenced by an elevated renal somatic index (RSI), serum creatinine, blood urea nitrogen, serum lactate dehydrogenase, and protein in urine with a concomitant reduction in serum albumin and normalized creatinine clearance value as compared with the controls. Moreover, a significant increase in renal contents of malondialdehyde, myeloperoxidase, and tumor necrosis factor-alpha with a significant decrease in renal reduced glutathione and superoxide dismutase activities was detected upon gentamicin administration together with increasing the sensitivity of isolated urinary bladder rings to ACh. Exposure to gentamicin induced necrosis of renal tubular epithelial cells. Flavocoxid protected kidney tissue against the oxidative damage and the nephrotoxic effect caused by gentamicin treatment. In addition, flavocoxid significantly reduced the responses of isolated bladder rings to ACh. The results from our study indicate that flavocoxid supplement attenuates gentamicin-induced renal injury via the amelioration of oxidative stress and inflammation of renal tubular cells.

Protective effect of allicin against gentamicin-induced nephrotoxicity in rats.

In this study, the modulator effect of allicin on the oxidative nephrotoxicity of gentamicin in the kidneys of rats was investigated by determining indices of lipid peroxidation and the activities of antioxidant enzymes, as well as by histological analyses. Furthermore, the effect of allicin on gentamicin induced hypersensitivity of urinary bladder rings to ACh was estimated. Twenty-four male Wistar albino rats were randomly divided into three groups, control, gentamicin (100mg/kg, i.p.) and gentamicin+allicin (50mg/kg, orally). At the end of the study, all rats were sacrificed and then urine, blood samples and kidneys were taken. Gentamicin administration caused a severe nephrotoxicity as evidenced by an elevated kidney/body weight ratio, serum creatinine, blood urea nitrogen (BUN), serum lactate dehydrogenase (LDH) and proteinuria with a reduction in serum albumin and creatinine clearance as compared with control group. In addition, a significant increase in renal contents of malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NOx) and tumor necrosis factor-alpha (TNF-α) concomitantly with a significant decrease in renal reduced glutathione (GSH) and superoxide dismutase (SOD) activities was detected upon gentamicin injection. Exposure to gentamicin increased the sensitivity of isolated urinary bladder rings to ACh and induced acute renal tubular epithelial cells necrosis. Administration of allicin significantly decreased kidney/body weight ratio, serum creatinine, LDH, renal MDA, MPO, NOx and TNF-α while it significantly increased creatinine clearance, renal GSH content and renal SOD activity when compared to gentamicin-treated group. Additionally, allicin significantly reduced the responses of isolated bladder rings to ACh and ameliorated tissue morphology as evidenced by histological evaluation. Our study indicates that allicin exerted protection against structural and functional damage induced by gentamicin possibly due to its antioxidant, anti-inflammatory and immunomodulatory properties in addition to its ability to retaining nitric oxide level.

Angiogenesis inhibitors in cancer therapy: mechanistic perspective on classification and treatment rationales.

Angiogenesis, a process of new blood vessel formation, is a prerequisite for tumour growth to supply the proliferating tumour with oxygen and nutrients. The angiogenic process may contribute to tumour progression, invasion and metastasis, and is generally accepted as an indicator of tumour prognosis. Therefore, targeting tumour angiogenesis has become of high clinical relevance. The current review aimed to highlight mechanistic details of anti-angiogenic therapies and how they relate to classification and treatment rationales. Angiogenesis inhibitors are classified into either direct inhibitors that target endothelial cells in the growing vasculature or indirect inhibitors that prevent the expression or block the activity of angiogenesis inducers. The latter class extends to include targeted therapy against oncogenes, conventional chemotherapeutic agents and drugs targeting other cells of the tumour micro-environment. Angiogenesis inhibitors may be used as either monotherapy or in combination with other anticancer drugs. In this context, many preclinical and clinical studies revealed higher therapeutic effectiveness of the combined treatments compared with individual treatments. The proper understanding of synergistic treatment modalities of angiogenesis inhibitors as well as their wide range of cellular targets could provide effective tools for future therapies of many types of cancer.