Anti-ischemic drug trimetazidine blocks mercury nephrotoxicity by suppressing renal redox imbalance, inflammatory stress and caspase-dependent apoptosis in rats.

Trimetazidine (TMZ) is a promising emerging therapeutic piperazine derivative for renal pathologies. However, the nephroprotective mechanism of TMZ against heavy metal-induced toxicity is unknown. This study, therefore, aimed to explore whether TMZ could mitigate mercury-induced nephrotoxicity in rats. Rats were injected TMZ (3 mg/kg bw) and/or mercury chloride (HgCl2) (4 mg/kg bw) for 4 days (n = 6 rats per group). The blood analysis revealed marked increases in creatinine, urea and uric acid levels in HgCl2 group compared to the control. HgCl2 induced prominent decreases in renal superoxide dismutase (SOD), catalase (CAT), glutathione peroxide (GPx) activities compared to the control followed by marked increases in the levels of malondialdehyde (MDA), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), caspase-3 and caspase-9. Whereas the renal levels of anti-inflammatory cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10) reduced considerably compared to the control. Contrarily, it was found that in the rats administered TMZ + HgCl2, levels of renal markers, MDA, TNF-α, IL-6 and caspases-3/-9 were prominently reduced compared to the HgCl2 group. The renal SOD, CAT, GPx, IL-4, and IL-10 were markedly elevated along with ameliorated histopathological lesions. On the whole, therefore, TMZ could be repurposed for blocking HgCl2 nephrotoxicity via inhibition of oxidative inflammation and apoptosis in rats.

Cytotoxic Activity of Herbal Medicines as Assessed in Vitro: A Review.

Since time immemorial, human beings have sought natural medications for treatment of various diseases. Weighty evidence demonstrates the use of chemical methodologies for sensitive evaluation of cytotoxic potentials of herbal agents. However, due to the ubiquitous use of cytotoxicity methods, there is a need for providing updated guidance for the design and development of in vitro assessment. The aim of this review is to provide practical guidance on common cell-based assays for suitable assessment of cytotoxicity potential of herbal medicines and discussing their advantages and disadvantages Relevant articles in authentic databases, including PubMed, Web of Science, Science Direct, Scopus, Google Scholar and SID, from 1950 to 2022 were collected according to selection criteria of in vitro cytotoxicity assays and protocols. In addition, the link between cytotoxicity assay selection and different factors such as the drug solvent, concentration and exposure duration were discussed.

Naringenin blocks hepatic cadmium accumulation and suppresses cadmium-induced hepatotoxicity via amelioration of oxidative inflammatory signaling and apoptosis in rats.

Liver is one of the targets of cadmium (Cd) bioaccumulation for hepatic damage and pathologies via oxidative inflammation and apoptosis. The current study explored whether the citrus flavonoid naringenin (NAR) could prevent hepatic accumulation of Cd and Cd hepatotoxicity in a rat model. Rats in group 1 received normal saline; group 2 received NAR (50 mg/kg body weight); group 3 received CdCl2 (5 mg/kg body weight); group 4 received NAR + CdCl2, for four consecutive weeks. Assays related to markers of oxidative stress, inflammation, and apoptosis were carried out using liver homogenate. Blood and liver sample analyses revealed significant elevation of blood and hepatic Cd levels coupled with prominent increases in alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activities, whereas the albumin and total protein levels were decreased considerably. Hepatic superoxide dismutase (SOD), catalase (CAT), glutathione peroxide (GPx) activities diminished significantly compared to control followed by marked increases in malondialdehyde (MDA) levels, and dysregulation in caspase and cytokine (TNF-α, IL-6, IL-4, IL-10) levels. However, it was found that in the rats administered NAR + Cd, the levels of Cd, hepatic enzymes, MDA, TNF-α, IL-6, and caspases-3/-9 were prominently reduced compared to the Cd group. The hepatic SOD, CAT, GPx, IL-4, IL-10, albumin, and total protein were markedly elevated along with alleviated hepatic histopathological abrasions. Taken together therefore, NAR is a potential flavonoid for blocking hepatic Cd bioaccumulation and consequent inhibition of Cd-induced oxidative inflammation and apoptotic effects on the liver of rats.

Hyperoside attenuates neuroinflammation, cognitive impairment and oxidative stress via suppressing TNF-α/NF-κB/caspase-3 signaling in type 2 diabetes rats.

OBJECTIVES: Literature findings have instituted the role of hyperglycemia-induced oxidative stress and inflammation in the pathogenesis of cognitive derangement in diabetes mellitus (DM). Hyperoside (HYP) is a flavanone glycoside reported to possess diverse pharmacological benefits such as antioxidant and anti-inflammatory properties. The study explored whether HYP could mitigate DM-induced cognitive dysfunction and further elucidate on potential molecular mechanism in rats. METHODS: Streptozotocin/high-fat diet-induced diabetic rats were treated orally with HYP (50, 200 and 400 mg/kg/day) for six consecutive weeks. The blood glucose and serum insulin levels, Morris water maze test, intraperitoneal glucose tolerance test, and brain acetylcholinesterase (AChE) activity were determined. The brain expression of inflammatory nuclear factor-kappa B (NF-κB), tumour necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6), as well as superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), total antioxidant capacity (TAC), malondialdehyde (MDA), lipid profile and caspase-3 activity were estimated. RESULTS: DM evoked hyperlipidemia, hypoinsulinemia, cognitive dysfunction by markedly increased AChE and reduction in learning and memory capacity. Brain activities of SOD and CAT, and levels of TAC and GSH were considerably depressed, whereas levels of IL-1ß, IL-6, TNF-α, NF-κB, caspase-3 and MDA were prominently increased. Interestingly, the HYP treatment dose-dependently abrogated the altered cognitive and biochemical parameters. DISCUSSION: The results suggested that hyperoside prevents DM-induced cognitive dysfunction, neuroinflammation and oxidative stress via antioxidant, anti-inflammatory and antiapoptotic mechanisms in rats.

Antimicrobial and Larvicidal Activities of Different Ocimum Essential Oils Extracted by Ultrasound-Assisted Hydrodistillation.

Infectious diseases and their vectors have remained a concern for human population from their historical origin. Microbial pathogens have also emerged as a potent threat to the healthcare systems even in developed countries. Essential oils remain a less explored method for infectious disease control; besides, the ultrasound-assisted extraction (UAE) of essential oil production has emerged as promising source of bioactive volatiles over conventional methods. This study analyzed the possible use of UAE- Essential oils (EOs) from different species of Ocimum plants (Ocimum basilicum (OB), O. gratissimum (OG), O. tenuiflorum (OT), and O. canum (OC)) in the management of microbial pathogens and mosquito larval control. The antibacterial activity was estimated in terms of a disc diffusion assay and minimum inhibitory concentrations against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Salmonella enteritidis. The larvicidal property was found using three important mosquito vectors and the LC50 value was determined. Furthermore, antioxidant and anti-inflammatory properties were estimated in terms of radical scavenging activities and the inhibition of lipoxygenase enzyme activity. The EOs exhibited significant DPPH radical scavenging (high in OG), hydrogen-peroxide scavenging (OB) and lipoxygenase inhibition (OB). The antibacterial activity was high in OB and OG (p < 0.05) and the larvicidal activity was of higher sensitivity against Aedis and Culex, whereas Armigeres was more resistant. However, no sign of toxicity in the Allium cepa model or non-targeted organism Guppy fishes was observed. Overall, the UAE extracted Ocimum essential oils were found to be effective against various human pathogenic microbial organisms, with OB and OG being highly active. Likewise, the EOs was also able to induce mortality in the larval forms of various mosquito vectors.

Hepatoprotective effect of polyphenols isolated from virgin coconut oil against sub-chronic cadmium hepatotoxicity in rats is associated with improvement in antioxidant defense system.

Cadmium (Cd) is a ubiquitous non-essential environmental and industrial toxicant that affects various organs in humans and experimental animals. Robust evidence confirms the contribution of oxidative stress to the pathogenesis of Cd-induced hepatic damage. Potent polyphenols found in virgin coconut oil (VCO) are free radical scavengers that may be beneficial against Cd hepatotoxicity. Thus, we aimed to evaluate the possible protective effect of polyphenols isolated from VCO on Cd-induced hepatotoxicity and oxidative stress in rats. Rats were pretreated with polyphenols isolated from VCO (10, 20, and 50 mg/kg, orally) 2 weeks prior to concurrent Cd administration (5 mg/kg, orally) for 5 weeks. Subsequently, liver damage, hepatic oxidative stress, and histopathological alterations were evaluated. In vitro antioxidant assays (DPPH and FRAP) were carried out on VCO polyphenols. Cadmium induced liver damage demonstrated by significant alterations in serum markers of liver damage, as well as pronounced decrease in albumin and total protein compared to control. Further, Cd remarkably depressed hepatic activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) content. Hepatic lipid peroxidation was markedly increased as highlighted by malondialdehyde (MDA) content. Sub-chronic administration of VCO polyphenols to Cd-treated rats produced a significant hepatoprotective effect and restored hepatic oxidative stress markers comparable to control. The prominent improvement in histopathology of rat liver confirmed the biochemical findings. The findings suggest potential beneficial effect of VCO polyphenols on Cd-induced hepatotoxicity and oxidative stress in rats; the mechanism underlying this action is associated with improvement in antioxidant defense system.

Tiliacora triandra extract and its major constituent attenuates diabetic kidney and testicular impairment by modulating redox imbalance and pro-inflammatory responses in rats.

BACKGROUND: Literature has demonstrated that diabetes is associated with renal complication and testicular dysfunctions. The current study explored the potential of Tiliacora triandra extract and its major component against diabetic kidney and testicular damages in rats. METHODS: Diabetes was induced by high fat diet/streptozotocin (HFD/STZ) and treated orally with Tiliacora triandra extract (TTE, 100 and 400 mg kg-1 body weight) and its major component, 5,7-dihydroxy-6-oxoheptadecanoic acid (DHA, 25 mg kg-1 body weight) for 30 consecutive days. Testicular activities of testicular enzymes, serum levels of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), sperm parameters and urinalysis for protein and albumin levels were evaluated. Renal and testicular biomarkers of oxidative stress and pro-inflammation were analysed along with histology. RESULTS: The experimental diabetes induced significant alterations in the levels and activities of indices evaluated compared to non-diabetic normal rats. The 28-day treatment of diabetic rats with TTE and DHA markedly improved activities of testicular enzymes, restored levels of testosterone, LH and FSH and sperm parameters compared to untreated diabetic rats. TTE and DHA abrogated proteinuria and reversed urine albumin level. Testicular and renal oxidative stress and pro-inflammation were attenuated in diabetic rats treated with TTE and DHA. The diabetes-mediated histopathological damage was alleviated in the kidney and testis. CONCLUSION: The protective effect of TTE and DHA against diabetes induced kidney and testicular damages may be related to its antioxidant and anti-inflammatory activities. © 2020 Society of Chemical Industry.

Nephroprotective Effect of Moringa Oleifera Seed Oil on Gentamicin-Induced Nephrotoxicity in Rats: Biochemical Evaluation of Antioxidant, Anti-inflammatory, and Antiapoptotic Pathways.

Objective: Gentamicin is an efficacious aminoglycoside antibiotic widely used to treat life-threatening Gram-negative bacteria infections. However, its specific non-targeted induction of nephrotoxicity is a worrying clinical challenge. The study explored the nephroprotective effect of Moringa oleifera seed oil (MOO) against gentamicin-induced oxidative nephrotoxicity, pro-inflammation, and apoptosis in male Wistar rats.Method: Twenty-four rats divided into 4 groups (n = 6) were administered MOO (5 ml/kg) for 16 days and/or gentamicin (100 mg/kg bw/d, ip) injected from day 11 to day 16. The renal antioxidant enzyme activities reduced glutathione, lipid peroxidation, and serum renal markers. Urea and creatinine levels were estimated. The renal expression of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and nitric oxide (NO) were determined. Renal levels of inducible nitric oxide synthase (iNOS), nuclear factor-ĸB (NF-ĸB), and caspase-3 were determined to detect possible mechanism of inflammation and apoptosis with histology.Results: MOO prominently reduced serum creatinine and urea levels with amelioration of histopathological abrasions induced by gentamicin (GM). It significantly depressed oxidative stress through lowering of renal malondialdehyde (MDA) and elevation of renal superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities, and reduced glutathione (GSH) level. MOO restored renal content of IL-1ß, IL-6, TNF-α, and NO, coupled with the mechanistic downregulation of NF-ĸB, iNOS, and caspase-3 activities. The histopathological alterations were ameliorated by MOO.Conclusions: MOO possesses marked nephroprotective effect against GM-induced renal damage via modulating oxidative stress, inflammation, and apoptosis in Wistar rats.

Ginger juice prevents cisplatin-induced oxidative stress, endocrine imbalance and NO/iNOS/NF-κB signalling via modulating testicular redox-inflammatory mechanism in rats.

The off-target testicular toxicity of the anticancer drug, cisplatin, is a current clinical concern and worrisome to male cancer patients. Growing evidence has implicated oxidative stress and inflammation in cisplatin toxicity. We have explored whether fresh ginger juice could mitigate testicular toxicity induced by anticancer drug cisplatin in rats. Rats were subjected to oral administration of fresh ginger juice (5 ml/kg body weight/day) for 5 days against testicular damage induced by single ip injection of cisplatin (CIS) (10 mg/kg body weight) on day 2 only. Testicular activities of antioxidant enzymes, malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), inflammatory cytokines, inducible nitric oxide synthase (iNOS) and nuclear factor-ĸB (NF-ĸB) and serum hormone levels were estimated. CIS-induced prominent decreases in antioxidant enzyme activities, GSH and serum hormone levels, whereas levels of MDA, cytokines, NO, iNOS and NF-ĸB increased remarkably (p < .05) compared to control. Interestingly, the CIS-induced testicular alterations were considerably mitigated by the fresh ginger juice via abrogation of oxidative stress and anti-inflammatory mechanism. The study suggests, for the first time, antioxidant and anti-inflammatory effects of ginger juice against CIS testicular damage. Fresh ginger juice may have beneficial health impact on testicular side effect of CIS chemotherapy.

Protective Effects of Nucleosides-Rich Extract from Cordyceps cicadae against Cisplatin Induced Testicular Damage.

Cisplatin (CISP) is an efficacious anticancer agent used in chemotherapy, however, the constraint to its clinical utility is the stray organ toxicity including testicular damage linked to oxidative and inflammatory cascades. This study aimed to explore the protective effect of nucleosides-rich extract from Cordyceps cicadae (NRCE) against CISP-induced testicular damage in rats. Rats were subjected to prophylactic oral administration of NRCE (50, 100 and 400 mg/kg body weight/day) for 7 days prior to testicular toxicity induced by CISP (10 mg/kg, ip) and were sacrificed after 72 h post-CISP injection. Cisplatin caused significant deficits in sperm count, viability and motility, testosterone and follicle stimulating hormone (FSH) compared to normal control. It depressed testicular activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), total antioxidant content (TAC), whereas malondialdehyde (MDA) increased remarkably. CISP considerably increased tumor necrosis factor-alpha (TNF-α) and interleukin-one beta (IL-1ß) with alterations in testis histology compared to normal control. Interestingly, NRCE pretreatment inhibited the CISP-induced alterations in reproductive indices, restored the antioxidant activities in testes as well as inflammatory mediators and histology comparable to control. Our findings demonstrate that NRCE could prevent CISP testicular damage via inhibition of oxidative stress and pro-inflammation in rats.

Zinc abrogates anticancer drug tamoxifen-induced hepatotoxicity by suppressing redox imbalance, NO/iNOS/NF-ĸB signaling, and caspase-3-dependent apoptosis in female rats.

Tamoxifen (TAM) is used in breast cancer chemotherapy since its approval by the Food and Drug Administration in 1977. However, TAM therapy is accompanied with hepatotoxicity - a source of worry to clinicians. Oxidative stress and inflammation are the major implicated mechanisms contributing to TAM hepatotoxicity. In this study, we explored whether zinc (Zn) supplementation could prevent TAM-induced hepatotoxicity in female Wistar rats. Rats were subjected to oral pretreatment of Zn (100 mg/kg body weight (b.w.)/day) for 14 days against hepatic toxicity induced by single intraperitoneal administration of TAM (50 mg/kg b.w.) on day 13. TAM markedly elevated serum liver enzymes, whereas total protein and albumin considerably reduced. TAM caused prominent depletion of hepatic-reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activity. Also, TAM significantly increased malondialdehyde (MDA) level. Further, it raised liver levels of tumor necrosis factor-α (TNF-α), interleukin-1ß, (IL-1ß), interleukin-6 (IL-6), and nitric oxide (NO) confirmed by the liver histopathological alterations. The mechanistic inflammatory expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-ĸB), and expression of caspase-3 protein prominently increased. Zinc supplementation significantly modulated serum liver function markers, antioxidant enzymes, and GSH and MDA levels. Zinc downregulated the expression of cytokines, NO, iNOS, NF-ĸB and caspase-3, and ameliorated histopathological changes. Zinc protects against TAM-induced hepatotoxicity; it may serve as an adjuvant supplement for female patients undergoing TAM chemotherapy.

Geraniol prevents CCl4-induced hepatotoxicity via suppression of hepatic oxidative stress, pro-inflammation and apoptosis in rats.

Carbon tetrachloride (CCl4) is a classic chemical hepatotoxicant that triggers liver damage through hepatic exacerbation of oxidative stress. Geraniol (GRL) is a natural bioactive acyclic monoterpene with several pharmacological effects. We thus explored whether GRL could prevent CCl4-triggered hepatic toxicity. Rats were divided and administered GRL (100 mg/kg) and/or CCl4 (1 ml/kg of 1:1 v/v CCl4: olive oil) in Control group, GRL group, CCl4 group, GRL + CCl4 groups 2 times per week for 4 consecutive weeks. CCl4 caused significantly (p < 0.05) elevated serum activities of alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TB), whereas the albumin (ALB) and total protein (TP) levels were significantly (p < 0.05) reduced relative to the control group. The liver activities of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) decreased significantly (p < 0.05), while malondialdehyde (MDA) level evidently elevated in comparison to the control group. The CCl4 exposure caused significant increases in proinflammatory interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), apoptotic caspase-3 and caspase-9 levels, whereas the anti-inflammatory interleukin-4 (IL-4) and interleukin-10 (IL-10) were reduced in consistent with histopathological changes compared to the control. On the contrary, the GRL administration prevented the hepatic toxicity and lesions through restoration of liver status markers, antioxidant enzyme activities, MDA, cytokines and apoptosis in comparison to the CCl4 group. Altogether, the findings reveal that GRL could abrogate CCl4-provoked hepatic toxicity via inhibition of hepatic oxidative stress, inflammation and apoptosis in rats.

Molecular mechanisms underpinning the protection against antiretroviral drug-induced sperm-endocrine aberrations and testicular toxicity: A review.

The introduction of highly active antiretroviral therapy (HAART) has revolutionized the treatment of HIV/AIDS worldwide. The HAART approach is the combination of two or more antiretroviral drugs of different classes and are responsible for patient's survival and declining death rates from HIV/AIDS and AIDS-related events. However, the severe and persistent reproductive side effect toxicity of HAART regimens is of great concern to patients within the reproductive age. Till date, the underlying pathophysiology of the HAART-induced reproductive toxicity remains unraveled. Nevertheless, preclinical studies show that oxidative stress and inflammation may be involved in HAART-induced sperm-endocrine deficit and reproductive aberrations. Studies are emerging demonstrating the efficacy of plant-based and non-plant products against the molecular alterations and testicular toxicity of HAART. The testicular mechanisms of mitigation by these products are associated with enhancement of testicular steroidogenesis, spermatogenesis, inhibition of oxidative stress and inflammation. This review presents the toxic effects of HAART on spermatogenesis, reproductive hormones and testis integrity. It also provides insights on the molecular mechanisms underlying the mitigation of HAART testicular toxicity by plant-based and non-plant agents. However, effect of repurposing clinical drugs to combat HAART toxicity is unknown, and more mechanistic studies are evidently needed. Altogether, plant-based and non-plant products are potential agents for prevention of rampant endocrine dysfunction and testicular toxicity of HAART.

Epigenetic Alterations in Alzheimer's Disease: Impact on Insulin Signaling and Advanced Drug Delivery Systems.

Alzheimer's disease (AD) is a neurodegenerative condition that predominantly affects the hippocampus and the entorhinal complex, leading to memory lapse and cognitive impairment. This can have a negative impact on an individual's behavior, speech, and ability to navigate their surroundings. AD is one of the principal causes of dementia. One of the most accepted theories in AD, the amyloid ß (Aß) hypothesis, assumes that the buildup of the peptide Aß is the root cause of AD. Impaired insulin signaling in the periphery and central nervous system has been considered to have an effect on the pathophysiology of AD. Further, researchers have shifted their focus to epigenetic mechanisms that are responsible for dysregulating major biochemical pathways and intracellular signaling processes responsible for directly or indirectly causing AD. The prime epigenetic mechanisms encompass DNA methylation, histone modifications, and non-coding RNA, and are majorly responsible for impairing insulin signaling both centrally and peripherally, thus leading to AD. In this review, we provide insights into the major epigenetic mechanisms involved in causing AD, such as DNA methylation and histone deacetylation. We decipher how the mechanisms alter peripheral insulin signaling and brain insulin signaling, leading to AD pathophysiology. In addition, this review also discusses the need for newer drug delivery systems for the targeted delivery of epigenetic drugs and explores targeted drug delivery systems such as nanoparticles, vesicular systems, networks, and other nano formulations in AD. Further, this review also sheds light on the future approaches used for epigenetic drug delivery.

Oxyresveratrol-ß-cyclodextrin mitigates streptozotocin-induced Alzheimer's model cognitive impairment, histone deacetylase activity in rats: in silico & in vivo studies.

Alzheimer's disease (AD) is associated with cognitive deficits and epigenetic deacetylation that can be modulated by natural products. The role of natural oxyresveratrol-ß-cyclodextrin (ORV) on cognition and histone deacetylase activity in AD is unclear. Herein, in-silico docking and molecular dynamics simulation analysis determined that oxyresveratrol potentially targets histone deacetylase-2 (HDAC2). We therefore evaluated the in vivo ameliorative effect of ORV against cognitive deficit, cerebral and hippocampal expression of HDAC in experimental AD rats. Intracerebroventricular injection of STZ (3 mg/kg) induced experimental AD and the rats were treated with low dose (200 mg/kg), high dose (400 mg/kg) of ORV and donepezil (10 mg/kg) for 21 days. The STZ-induced AD caused cognitive and behavioural deficits demonstrated by considerable increases in acetylcholinesterase activity and escape latency compared to sham control. The levels of malondialdehyde (MDA) and HDAC activity were significantly increased in AD disease group comparison to the sham. Interestingly, the ORV reversed the cognitive-behavioural deficit and prominently reduced the MDA and HDAC levels comparable to the effect of the standard drug, donepezil. The findings suggest anti-AD role of ORV via antioxidant effect and inhibition of HDAC in the hippocampal and frontal cortical area of rats for AD.

Naringin ameliorates 5-fluorouracil induced cardiotoxicity: An insight into its modulatory impact on oxidative stress, inflammatory and apoptotic parameters.

5-fluorouracil (5-FU) is an efficacious fluoropyrimidine antimetabolite anticancer drug, however, its clinical utility is constrained due to side effect toxicity on delicate organs, including the heart. This study thus aimed at exploring the cardioprotective potentials of naringin (NRG) against 5-FU-induced cardiotoxicity in rats. We divided Wistar rats into four experimental groups (n = 6) for the administration of NRG (100 mg/kg bw, orally) and/or 5-FU (150 mg/kg bw, intraperitoneal). NRG was administered for 10 days, while 5-FU was injected on the 8th day only. Serum troponin-I (cTn-I) and creatine kinase (CK) were estimated. Cardiac activities/level of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), reduced glutathione (GSH), malondialdehyde (MDA), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) and nuclear factor-ĸB (NF-κB) and caspase-3 were determined. 5-FU markedly increased cTn-I, CK, cardiac inflammatory mediators and caspase-3 expressions, whereas antioxidant mediators decreased appreciably when compared to the control groups. Interestingly, the prophylactic administration of NRG prominently inhibited the 5-FU-provoked oxidative stress, pro-inflammation and apoptosis in the heart of rats. Histopathology confirmed the biochemical results of the heart. Therefore, NRG is a potential natural flavonoid for mitigation of 5-FU cardiotoxicity in rats.

Antidiabetic drug sitagliptin blocks cyclophosphamide cerebral neurotoxicity by activating Nrf2 and suppressing redox cycle imbalance, inflammatory iNOS/NO/NF-κB response and caspase-3/Bax activation in rats.

Cyclophosphamide (CYP) is a classic DNA-interacting anticancer agent with broad application in chemotherapy. However, CYP cerebral neurotoxicity is a worrisome side effect for clinicians and patients. Strategies to mitigate the underlying oxidative inflammatory cascades and neuroapoptosis induced by CYP are urgently needed. Herein, we have repurposed an antidiabetic drug, sitagliptin (STG), for a possible abrogation of CYP-induced cerebral neurotoxicity in rats. Healthy rats were administered STG (20 mg/kg body weight) for 5 days prior to neurotoxicity induced by CYP (200 mg/kg body weight, ip) on day 5 only, and rats were sacrificed after 24 h post-CYP injection. CYP caused profound increases in the cerebral levels of nitric oxide (NO), acetylcholinesterase (AChE), malondialdehyde (MDA), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), nuclear factor-kappaB (NF-κB), inducible nitric oxide synthase (iNOS), caspase-3 and Bax protein compared to the control. Furthermore, CYP markedly depressed the activities of glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD), along with levels of reduced glutathione (GSH) and nuclear factor erythroid 2-related factor2 (Nrf2) compared to the control (p < 0.05). Interestingly, STG pretreatment inhibited the CYP-induced alterations in caspase-3, Bax, pro-inflammatory cytokines, NO, iNOS, AChE, NF-κB, and restored the cerebral antioxidant apparatus, including the Nrf2 and histopathological abrasions. Therefore, these findings show that STG could be repurposed to prevent CYP-induced cerebral toxicity in the brain.

Morin hydrate downregulates inflammation-mediated nitric oxide overproduction and potentiates antioxidant mechanism against anticancer drug doxorubicin oxidative hepatorenal toxicity in rats.

Objective: Doxorubicin (DOX) is a frontline antineoplastic drug that kills cancer cells through genotoxic mechanism; however, it induces organ toxicities. This study assayed whether morin hydrate (MOH) could abrogate DOX hepatorenal toxicity in rats. Materials and Methods: There were 4 groups of rats: Control, MOH, DOX and MOH + DOX. Rats were administered MOH (orally, 100 mg/kg bw) for 7 consecutive days, while DOX was injected (40 mg/kg, ip) on the 5th day only. Hepatorenal function markers, and glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) activities were estimated in both organs. Hepatorenal glutathione (GSH), malondialdehyde (MDA), and nitric oxide (NO) levels were estimated with histopathology. Results: DOX significantly (p<0.05) reduced antioxidant enzyme activities and GSH level, while NO and MDA levels increased (p<0.05) compared to the control. DOX prominently altered hepatorenal indices and induced histopathological alterations. MOH abrogated the DOX hepatorenal toxicity and alleviated the histological lesions in the liver and kidney. Conclusion: MOH restored the indices via antioxidant mechanism and downregulation of NO overproduction in rats.

Synergistic Action of Virgin Coconut Oil and Clomiphene in Reversing Endocrine Dysregulation in Letrozole-Model of Polycystic Ovarian Syndrome in Rats: Role of Nrf2/HMOX-1 Pathway.

Polycystic ovarian syndrome (PCOS) is an endocrine disorder in women's reproductive age. Currently, the pathophysiology of PCOS is unclear, and the limited treatment options are unsatisfactory. Virgin coconut oil (VCO) is functional food oil associated with pharmacological effects in reproductive disorders. Therefore, we aimed to evaluate whether VCO could enhance clomiphene (CLO) therapy against PCOS in female rats. Rats were randomly divided: (1) Control, (2) PCOS model, (3) PCOS + CLO, (4) PCOS + VCO, and (5) PCOS + CLO + VCO. The PCOS was induced via daily letrozole (1 mg/kg, orally) administration for 21 days. After the PCOS induction, CLO, VCO, and CLO + VCO were administered from days 22 to 36. Serum levels of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, estrogen, progesterone, and prolactin were estimated. Polymerase chain reaction gene expression for nuclear factor-erythroid-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), catalase (CAT), glutathione reductase (GSR), LH receptor (LHr), androgen receptor (AR), tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and caspase-3 were analyzed. The letrozole-induced PCOS caused considerable increases in GnRH, LH, prolactin, estrogen, and testosterone, whereas FSH decreased significantly compared to the control. The gene expression of Nrf2, HO-1, CAT, and GSR were markedly diminished, while IL-1ß, TNF-α, caspase-3, AR, and LHr prominently increased compared to control. Interestingly, the CLO and VCO separately exerted anti-inflammatory and endocrine balance effects. However, VCO-enhanced CLO effect in LH, prolactin and testosterone, Nrf2, HO-1, CAT, GSR, and AR. VCO may synergize with CLO to depress hyperandrogenism and oxidative inflammation in PCOS.

Nephroprotective effects of Datura stramonium leaves against methotrexate nephrotoxicity via attenuation of oxidative stress-mediated inflammation and apoptosis in rats.

Objective: Methotrexate (MTX) is a frontline antimetabolite anticancer drug which is used in different cancer treatments but its nephrotoxicity is a notable drawback that limits its clinical use. The present study was undertaken to examine whether Datura stramonium leaf extract (DSLE) could block MTX nephrotoxic side effect in rats. Materials and Methods: Animals were divided randomly into Control, Ethanol extract, MTX, and Extract + MTX groups. DSLE (200 mg/kg bw) was orally administered for 21 days, while MTX was injected intraperitoneally (ip) on the 18th day. Serum levels of urea, creatinine and uric acid were determined. Kidney samples were used to determine glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) activities, and renal levels of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and caspase-3. Results: Injection of MTX resulted in considerable increases (p<0.05) in creatinine, urea, and uric acid levels as well as renal MDA, NO, IL-6, TNF-α and caspase-3 compared to the controls. SOD and GPx increased significantly, while GSH was significantly depleted. Interestingly, DSLE markedly reduced (p<0.05) levels of creatinine, urea, uric acid, TNF-α, NO, MDA and caspase-3, whereas renal GSH increased markedly compared to the MTX group. Conclusion: DSLE has nephroprotective activity against MTX toxicity. However, further mechanistic studies are needed.