•Nephrotoxicity is a serious effect of Doxorubicin, a widely used anticancer drug.•Thymoquinone (TQ) is a major constituent of Nigella sativa oil.•TQ was reported to have potent anti-oxidative and ...anti-inflammatory effects.•This study suggested a potential role for TQ in Doxorubicin-induced nephrotoxicity.•TQ attenuated renal oxidative stress, inflammation and reversed redox imbalance.
Doxorubicin (DOX) is a chemotherapeutic drug widely used for the treatment of various neoplastic conditions. However, its application is limited because of its toxic effects in many organs. Nephrotoxicity is a serious effect of DOX. The aim of this study was to determine the protective effect of thymoquinone (TQ), a predominant bioactive constituent of Nigella sativa oil, with well documented potent anti-oxidative and anti-inflammatory effects. Male Sprague Dawley rats received DOX (3.5mg/kg twice weekly) with or without TQ (50mg/kg/day, oral supplementation) for 3weeks. Elevated levels of serum urea, creatinine and urinary albumin excretion were observed in DOX-treated animals, indicating DOX-induced nephrotoxicity. Moreover, enhanced lipid peroxidation (LPO), as equivalents of malondialdehyde (MDA), in the renal tissue was accompanied by a significant decrease in the activities of superoxide dismutase (SOD) and glutathione-S-transferase (GST) in DOX-treated group. In addition, DOX treatment induced significant increase in renal levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and NADPH oxidase 4 (NOX-4), and marked decrease in interleukin-10 (IL-10) levels, nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA levels and nuclear binding activity. Histopathological analysis showed severe damage in the renal tissue of DOX treated animals. Animals treated with TQ were found to have markedly reduced renal damage with restoration of all mentioned markers toward normal values. In conclusion, DOX-induced renal damage involved a redox imbalance in renal tissue, which could be reversed by TQ, suggesting a possible potential role for TQ in DOX-induced nephrotoxicity.
Type 2 diabetes mellitus (T2DM) is a disease with a drastically growing worldwide prevalence. It is usually associated with numerous complications of which; diabetic nephropathy (DN); is a main ...complication of microvasculature and more seriously, a common cause of end-stage renal disease (ESRD). Unfortunately, both the lack of a definitive remedy alongside the economic and the social burden on DN patients enforces considerable impetus for developing alternative therapies. IL-33 is a newly discovered member of the IL-1 cytokine family. IL33/ST2 signaling plays a crucial role in acute and chronic kidney diseases. Calycosin is an isoflavone with reported IL33 signaling inhibitory activity. The present study aimed to investigate if calycosin possess renal protective effect in high-fat diet/STZ-induced T2DM model and to clarify the potential underlying mechanisms. HFD-STZ control rats showed functional and structural renal damage confirmed by increased serum creatinine, blood urea nitrogen and albuminuria associated with marked renal glomerulosclerosis and interstitial fibrosis. Initiation of inflammation, oxidative stress, and fibrosis was evident as depicted by elevated renal levels of IL33/ST2 mRNA as well as increased renal NF-κBp65, TNF–α, IL-1β, MDA, and TGF-β contents with suppressed Nrf2 and TAC. Calycosin treatment markedly improved the aforementioned makers of renal injury and dysfunction, modulated IL33/ST2 signaling, inflammatory cytokines, oxidative stress and fibrotic processes. This was accompanied by improvement of T2DM-induced renal ultramicroscopic and histopathological alterations.
•IL33/ST2 signaling is activated in T2DM induced renal injury.•IL33/ST2 axis is associated with inflammation and fibrosis in diabetic kidney.•Calycosin treatment preserved renal structure and function in diabetic rats.
Diabetic nephropathy (DN) is a serious complication of diabetes mellitus. Moreover,it is amongst the most common causes of end-stage renal failure. Inflammation is a crucial player in both ...development and progression of DN. JAK2/STA3 is a pleotropic cascade reported to regulate diverse inflammatory events. Previous studies reported involvement of JAK2/STA3 signal transduction pathway in diabetes-associated renal injury. In the current study, the inhibitory effect of nifuroxazide (25 mg/kg/day, orally) against inflammatory condition associating diabetic kidney progression in rats was evaluated. The underlying hypothesis is mainly via the inhibitory effect of nifuroxazide on STAT3 signaling. Results revealed that nifuroxazide effectively inhibited STAT3 activation in diabetic male rats, improved glomerular filtration function, protected against diabetes-induced histopathological and ultramicroscopic structural alterations. Further, nifuroxazide treatment significantly reduced renal macrophage infiltration and fibrosis and decreased mRNA and protein levels of TNF-α and IL-18 in diabetic renal tissue. The current findings shed the light on nifuroxazide's efficacy as an alternative anti-inflammatory therapy to hinder the development and progression of DN in diabetic patients mainly via STAT3 inhibition.
•Inflammation plays crucial role in development of Diabetic nephropathy (DN).•JAK2/STA3 cascade regulates diverse inflammatory events.•Nifuroxazide is an oral antibiotic with inhibitory effect on STA3 activation.•Nifuroxazide inhibited STAT3 activation in diabetic rats.•Nifuroxazide protected against diabetes-induced renal injury.
Abstract
Objectives
To investigate the protective effect of vanillin in cisplatin (CP)-induced nephrotoxicity in rats and elucidate the role of nrf-2 and its downstream antioxidant molecules.
Methods
...Rats received vanillin (100 mg/kg orally) for 10 constitutive days and CP (7.5 mg/kg, once, ip) on day 6 of vanillin administration.
Key findings
Cisplatin suppressed body weight gain, increased serum urea and creatinine and renal malondialdehyde and nitric oxide while decreased renal total antioxidant capacity. Up-regulation of NADPH oxidase-4 (NOX-4) was marked in renal tissue of CP-treated rats along with down-regulation of the antioxidant genes (nuclear factor erythroid 2-related factor2 (NRF2) and haem oxygenase-1(HO-1)). Increased tumour necrosis factor-α and decreased interleukin-10 with increased myeloperoxidase activity were apparent in renal tissue of CP-treated rats along with marked tubular injury, neutrophil infiltration and increased apoptosis (caspase-3) and some degree of interstitial fibrosis. Vanillin prophylactic administration prevented the deterioration of kidney function, oxidative and nitrosative stress. It also suppressed NOX-4 and up-regulated NRF2 and HO-1 expression in renal tissue. Inflammation, apoptosis and tubular injury were also inhibited by vanillin.
Conclusions
The antioxidant mechanism by which vanillin protected against CP-induced nephrotoxicity involved the inhibition of NOX-4 along with the stimulation of Nrf2/HO-1 signalling pathway. These in turn inhibited inflammation and apoptosis.
Hyperhomocysteinemia (HHcy) is remarkably common among the aging population. The relation between HHcy and the development of neurodegenerative diseases, such as Alzheimer’s disease (AD) and eye ...diseases, and age-related macular degeneration (AMD) and diabetic retinopathy (DR) in elderly people, has been established. Disruption of the blood barrier function of the brain and retina is one of the most important underlying mechanisms associated with HHcy-induced neurodegenerative and retinal disorders. Impairment of the barrier function triggers inflammatory events that worsen disease pathology. Studies have shown that AD patients also suffer from visual impairments. As an extension of the central nervous system, the retina has been suggested as a prominent site of AD pathology. This review highlights inflammation as a possible underlying mechanism of HHcy-induced barrier dysfunction and neurovascular injury in aging diseases accompanied by HHcy, focusing on AD.
Sodium nitrite is a widely used color fixative and preservative. However, it has been reported to exert deleterious toxic effects on various body organs. Moreover, thymoquinone (TQ), the active ...constituent of Nigella sativa oil is known to possess beneficial antioxidant and anti-inflammatory effects. The present study was conducted to evaluate the potential protective effects of TQ against sodium nitrite-induced renal toxicity.
Male Sprague-Dawley rats were treated with sodium nitrite (80mg/kg, po, daily) in presence or absence of TQ (25 and 50mg/kg, po, daily). Morphological changes in renal sections were assessed by staining with Hematoxylin/Eosin and Periodic acid–Schiff. Renal homogenate was used for measurement of oxidative stress markers (MDA and GSH), inflammatory markers (CRP, TNF-α, IL-6, IL-1β), anti-inflammatory cytokines (IL-10 and IL-4) and apoptotic markers (caspase-3/caspase-8/caspase-9).
Treatment with sodium nitrite significantly increased markers of renal dysfunction, oxidative stress, inflammation and apoptosis. These effects were markedly attenuated by TQ in dose dependent manner.
TQ has a potential protective effect against sodium nitrite-induced renal toxicity. This can be attributed to its ability to dampen oxidative stress, restore the normal balance between pro- and anti-inflammatory cytokines and protect renal tissue form extrinsic and intrinsic apoptosis.
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Diabetic nephropathy (DN) is a diabetic complication characterized by disruption of renal microvasculature, reactive oxygen species accumulation and increased inflammation, all of which contribute to ...renal injury. Phenethyl isothiocyanate (PEITC) is a naturally occurring isothiocyanate well known for its antioxidant and anti-inflammatory effects, yet its reno-preventive effects against DN has not been investigated. The current study looked into the in vivo reno-protective effects of PEITC in STZ-induced DN in rats. PEITC (3, 10 and 30 mg/kg) was administered orally for 8 weeks post DM establishment. PEITC treatment significantly improved kidney and liver functions, renal histopathological features, tissue fibrosis, macrophage infiltration and blood glucose levels compared to DN control. Mechanistically, PEITC treatment alleviated DN-induced renal damage via modulating glycation and oxidative stresses and inflammatory response. As such, PEITC activated glyoxalase 1 (GLO1) that induced a retraction in renal tissue expression of advanced glycation end products (AGEs) and its receptor (RAGE). PEITC activated nuclear erythroid 2-related factor 2 (Nrf2) and increased expression of its downstream targets, hemeoxygenase-1 (HO-1) and gamma glutamate-cysteine (γ-GCS). Additionally, PEITC treatment decreased the expression of Nrf2 repressor protein, keap1. The anti-inflammatory effect of PEITC was driven, at least in part, via reducing the NLRP3 inflammasome activation as indicated by down regulation of NLRP3, TXNIP, capsase-1 and IL-1β, TNF-alpha and IL-6. In conclusion; PEITC attenuated DN progression in a dose dependent manner mainly via interruption of AGE/RAGE and NLPR3/TXNIP/NrF2 crosstalk.
Caffeic acid phenethyl ester is found in honey bee propolis. It has immunomodulatory, anti-inflammatory and anti-cancer properties. Rotenone is a pesticide commonly used for inducing experimental ...Parkinson's disease (PD) due to complex I inhibition and microglia activating properties. The current study examined neuroprotective effect of caffeic acid against rotenone-induced neurodegeneration in groups of seven mice.
Mice received protective doses of caffeic acid (2.5, 5 or 10 mg/kg) daily and nine injections of rotenone (1 mg kg, subcutaneously) - every 48 h. Behavioral evaluation of motor function was done by a battery of tests including open-field test, cylinder test, pole test and rotarod test; all these tests showed motor impairment.
Assay of striatal dopamine highlighted a significant decrease and increases in inflammatory markers. In addition, histopathological assessment of substantia nigra neurons demonstrated low immunostaining for tyrosine hydroxylase (TH) in rotenone treated mice. PCR analysis highlighted upregulation for genes encoding CD
b (a microglia surface antigen), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and nuclear factor-κB (NFκB). Treatment with caffeic acid (5 or 10 mg/kg) amended most of rotenone-induced motor deficits, lessened microglia expression and inflammatory mediators and improved the nigral TH immunostaining.
These results confirmed the anti-inflammatory activity of caffeic acid and highlighted its neuroprotective activity against rotenone-induced neurodegeneration in mice.
•Crocin has chemo-preventive effect against experimentally-induced hepatocarcinogenesis.•Crocin modulated both intrinsic/extrinsic apoptotic pathways.•Crocin increased Nrf2 signaling pathway and HO-1 ...expression.•Crocin suppressed Keap-1 expression and hepatic content of c-JNK.
The results of the current study investigated the chemo-preventive effect of crocin against hepatocarcinogenesis in rats with particular focus on the evaluation of the modulatory impact of crocin on apoptotic and nuclear factor erythroid 2–related factor 2 (Nrf2) signaling pathways. Thioacetamide (TAA) (200 mg/kg, I.P.) was used for experimental induction of hepatocarcinogenesis in rats. Crocin administration significantly attenuated TAA-induced cancerous lesions with concomitant attenuation of impaired liver functions. This was associated with significant enhancement in hepatic Nrf2 and heme oxygenase-1 (HO-1) expression with parallel suppression in Keap-1 expression. Inline, crocin induced a significant improvement in hepatic oxidative status with enhanced antioxidant batteries. Crocin administration significantly suppressed the hepatic content of c-Jun N-terminal kinase (c-JNK) with significant upregulation in TNF-related apoptosis-inducing ligand (TRAIL) and caspase-8 protein expression as well as p53 gene expression; biomarkers of apoptosis. Moreover, hepatic expression of the apoptotic BAX significantly increased and the anti-apoptotic Bcl-2 significantly decreased in the liver specimen; biomarkers of intrinsic apoptosis. In conclusion; crocin attenuates experimentally induced hepato-carcinogenesis via modulation of oxidative/apoptotic signaling. Namely, crocin induced hepatic expression of Nrf2 with downstream modulation of endogenous HO-1 and Keap-1 signaling with modulation of various key players of apoptosis including; c-JNK, p53, TRAIL, caspase-8, BAX, and Bcl-2.
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