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.

Arbutin abrogates cisplatin-induced hepatotoxicity via upregulating Nrf2/HO-1 and suppressing genotoxicity, NF-κB/iNOS/TNF-α and caspase-3/Bax/Bcl2 signaling pathways in rats.

BACKGROUND: Cisplatin is a potent anticancer agent widely employed in chemotherapy. However, cisplatin leads to toxicity on non-targeted healthy organs, including the liver. We investigated the hepatoprotective mechanism of arbutin (ARB), a glycosylated hydroquinone, against cisplatin-induced hepatotoxicity. METHODS: Rats were orally administered with ARB (ARB1 = 50 mg/kg; ARB2 = 100 mg/kg) for 14 consecutive days against hepatotoxicity induced by a single dose of cisplatin (10 mg/kg) on day 15. Three days after the intraperitoneal cisplatin injection, serum and liver tissue were collected for subsequent analyses. RESULTS: Cisplatin triggered marked increases in serum AST, ALT, and ALP activities, hepatic malondialdehyde (MDA) and reactive oxygen species (ROS) coupled with a considerable diminution in hepatic activities of superoxide dismutase (SOD), catalase (CAT) and the concentration of reduced glutathione (GSH). The gene expressions of interleukin-1ß (IL-1ß), tumor necrosis factor (TNF-α), and IL-6 were notably increased. The pre-administration of ARB1 and ARB2 reduced AST, ALT and ALP in serum and restored SOD, CAT, GSH, ROS, MDA and cytokine levels which was also evidenced by alleviated hepatic lesions. Further, cisplatin-induced prominent alterations in the gene expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), iNOS, NF-κB, Bax, Bcl-2, caspase-3 and 8-OHdG in the liver. Interestingly, ARB protected the liver and mitigated the cisplatin-induced alterations in serum AST, ALT, ALP, and reduced hepatic redox markers, 8-OdG, inflammatory markers and gene expressions. CONCLUSION: The findings demonstrate that ARB is a potential protective adjuvant against cisplatin-induced hepatotoxicity via inhibition of hepatic oxidative stress, inflammation, and apoptosis.

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.

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.

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.

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.

Role of Chitosan-Loaded Solanine Glycoalkaloid from Solanum scabrum Mill. Leaf Extract as Anti-Inflammatory and In Vitro Anticancer Agents.

Objectives: Solanum scabrum Mill. commonly "African nightshade" or "huckleberry" is a plant, whose leaves are used by tribes in Nigeria and Cameroon for making the popular "Kombi" and "Njama Njama" soups, respectively. This study aimed to evaluate the anti-inflammatory and anticancer activities of the leaf crude methanol extract from S. scabrum. Materials and Methods: Fractions of the plant were tested for anti-inflammatory potential and in vitro anticancer activity on MCF-7 and HMVII cell lines by carrageenan-induced oedema in mice, and cytotoxicity assays such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide, transwell migration and invasion assays, and apoptosis study by flow cytometry, respectively. Results: Bioguided isolation yielded a white crystalline compound 3-nitro dibenzofuran (C12H7NO3, m/z; 213.19 g/mol, m.p.; 181.49 °C). 1H-NMR showed seven signals at δ (ppm) 2.8-4.3 consisting of two doublets and five singlets, while 13C-NMR revealed twelve carbons, which are majorly methyl carbons at δ (ppm) between 120 and 195. All tested samples demonstrated dose-dependent anti-inflammatory activity in carrageenan-induced mice. The isolated compound, i.e. solanine, and chitosan-loaded drugs showed significant inhibitory activity on the cell lines with inhibitory concentration 50 (IC50) values of 8.52, 0.82, and 22.1 µg/mL, respectively on MCF-7 cell line and 4.54, 0.08, and 12.1 µg/mL, respectively, on HMVII cell line, while doxorubicin (adriamycin) positive control, had IC50 values of 0.02 and 0.06 µg/mL, respectively, on MCF-7 and HMVII cancer cells. Selectivity index of solanine was the lowest in the study, hence, it lacks the ability to differentiate between cancerous and normal cell Vero E6 cell lines. Chitosan-loaded drugs quicken early apoptosis and sustained late apoptosis in cells with much improved selective indices. Conclusion: The results obtained from this study further affirmed the use of chitosan nanoparticles as carriers for anticancer drugs.

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.

Pharmacognostic profiles, evaluation of analgesic, anti-inflammatory and anticonvulsant activities of Newbouldia laevis (P. Beauv.) Seem. ex Bureau leaf and root extracts in Wistar rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Newbouldia laevis is a popular medicinal plant whose leaves and roots are used in Nigeria as ethnomedicinal prescriptions for pain, inflammation, convulsion, and epilepsy. These claims have not been scientifically verified prior to this study. AIM OF THE STUDY: To determine pharmacognostic profiles of the leaves and roots and evaluate the analgesic, anti-inflammatory, and anticonvulsant activities of methanol leaf and root extracts in Wistar rats. MATERIAL AND METHODS: The pharmacognostic profiles of the leaves and roots were determined using standard procedures to serve as fingerprints for the plant. The methanol leaf and root extracts of Newbouldia laevis were tested for acute toxicity using the OECD's up and down method at the maximum dose of 2000 mg/kg (orally) in Wistar rats. Analgesic studies were carried out in acetic acid-induced writhing in rats and tail immersion. The anti-inflammatory activity of the extracts was evaluated using carrageenan-induced rat paw-oedema and formalin-induced inflammation in rats' mode. The anticonvulsant activity was determined using strychnine-induced, pentylenetetrazol-induced, and maximal electroshock-induced rat convulsion models. For each of these studies, the extracts doses of 100, 200 and 400 mg/kg were administered to the rats following the oral route. RESULTS: The pharmacognostic profiles showed that the leaves possessed deep-sunken paracytic stomata (5-8-16 mm2; adaxial, 8-11-24 mm2; abaxial epidermis), vein islets (2-4-10 mm2; adaxial), vein terminations (10-14-18 mm2; adaxial), palisade ratio (8.3-12.5-16.4 mm2; adaxial, 2.5-6.8-12.2 mm2; adaxial), covering unicellular trichome (8-14; adaxial), spheroidal calcium oxalate crystals (3-5 µm), and oval-shaped striated starch grain with no hilum (0.5-4.3 µm). The transverse section of the leaf showed the presence of spongy and palisade parenchyma as well as a closed vascular bundle. The root powder showed the presence of brachy sclereid, fibers without lumen, and lignin. All physicochemical parameters fall within the acceptable limits, phytochemical contents showed mainly glycosides, alkaloids, and steroids while acute oral toxicity (LD50) of the parts for 14 days did not produce any toxicity signs or mortality in the rats. The extracts produced dose-dependent (100-400 mg/kg) analgesic involving opioid receptors, anti-inflammatory, and anticonvulsant activities in the rats which were significant (p ≤ 0.05) when compared to the standard drugs. The leaf extract possessed the most potent analgesic and anti-inflammatory effects in the rats, while the most anticonvulsant effects were observed in rats treated with the leaf extract. Both extracts showed elevated levels of protection against strychnine-induced, pentylenetetrazol-induced, and maximal electroshock-induced seizure in rats. CONCLUSION: Our study revealed some pharmacognostic profiles of Newbouldia laevis leaves and roots that are vital for its identification from closely related species often used for adulteration in traditional medicine. The study further showed that the leaf and root extracts of the plant possessed dose-dependent analgesics, anti-inflammatory and anti-convulsant activities in rats, thus, justifying its use for the treatment of these diseases in Nigerian traditional medicine. There is a need to further study its mechanisms of action towards drug discovery.

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.

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.

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.

Chemical Composition and Biological Activities of the Leaf Essential Oils of Curcuma longa, Curcuma aromatica and Curcuma angustifolia.

Curcuma species are widely used as a food additive and also in various medicinal purposes. The plant is a rich source of essential oil and is predominantly extracted from the rhizomes. On the other hand, the leaves of the plants are usually considered as an agrowaste. The valorization of these Curcuma leaf wastes into essential oils is becoming accepted globally. In the present study, we aim to extract essential oils from the leaves of Curcuma longa (LEO), C. aromatica (REO), and C. anguistifolia (NEO). The chemical composition of these essential oils was analyzed by GC-MS. Free radical scavenging properties were evaluated against the radical sources, including DPPH, ABTS, and hydrogen peroxide. The antibacterial activity was assessed by the disc diffusion method and Minimum inhibitory concentration analysis against Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli, Pseudomonas aeruginosa and Salmonella enterica) bacteria. Results identified the compounds α-phellandrene, 2-carene, and eucalyptol as predominant in LEO. The REO was predominated by camphor, 2-bornanone, and curdione. The main components detected in NEO were eucalyptol, curzerenone, α-lemenone, longiverbenone, and α-curcumene. Antioxidant properties were higher in the LEO with IC50 values of 8.62 ± 0.18, 9.21 ± 0.29, and 4.35 ± 0.16 µg/mL, against DPPH, ABTS, and hydrogen peroxide radicals. The cytotoxic activity was also evident against breast cancer cell lines MCF-7 and MDA-MB-231 cells; the LEO was found to be the most active against these two cell lines (IC50 values of 40.74 ± 2.19 and 45.17 ± 2.36 µg/mL). Likewise, the results indicated a higher antibacterial activity for Curcuma longa essential oil with respective IC50 values (20.6 ± 0.3, 22.2 ± 0.3, 20.4 ± 0.2, and 17.6 ± 0.2 mm). Hence, the present study confirms the possible utility of leaf agrowastes of different Curcuma spp. as a possible source of essential oils with pharmacological potential.

Hesperidin and hesperetin against heavy metal toxicity: Insight on the molecular mechanism of mitigation.

Toxic heavy metals (THMs) are non-essential hazardous environmental pollutants with intractable health challenges in humans and animals. Exposure to lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As), nickel (Ni), and chromium (Cr) are ubiquitous and unavoidable due to food contamination, mining, and industrial mobilization. They are triggers of tissue impairment and aberrant signaling pathways that cascade into several toxicities and pathologies. Each of Pb, Cd, Hg, As, Ni, and Cr aggravate oxidative inflammation, protein dysregulation, apoptotic induction, DNA damage, endocrine deficits, and mitochondrial dysfunction contributing to the pathophysiology of diseases. Hesperidin (HSD) and hesperetin (HST) are flavonoids from citrus fruits, and systematic investigations suggest their potential to combat the molecular alterations and toxicities induced by THMs. They mitigate heavy metal toxicity via antioxidant, anti-inflammatory, and anti-apoptotic effects via scavenging free radicals and modulation of ATPases, cell cycle proteins, and various cellular signaling pathways, including Nrf2/HO-1/ARE, PI3K/mTOR/Akt, MAPK/caspase-3/Bax/Bcl-2, iNOS/NF-κB/TNF-α/COX-2. This review summarized the mechanistic effects of heavy metal toxicity and the insights on molecular mechanisms underlying mitigation of heavy metal toxicity by HSD and HST. Hesperidin and hesperetin are potential flavonoids for the modulation of pathological signaling networks associated with THMs. Therefore, HSD and HST can be suggested as natural dietary agents and blockers of harmful effects of THMs.

Repurposing FDA-approved drugs against the toxicity of platinum-based anticancer drugs.

Platinum-based anticancer drugs (PADs), mainly cisplatin, carboplatin, and oxaliplatin, are widely used efficacious long-standing anticancer agents for treating several cancer types. However, clinicians worry about PAD chemotherapy and its induction of severe non-targeted organ toxicity. Compelling evidence has shown that toxicity of PAD on delicate body organs is associated with free radical generation, DNA impairment, endocrine and mitochondrial dysfunctions, oxidative inflammation, apoptosis, endoplasmic reticulum stress, and activation of regulator signaling proteins, cell cycle arrest, apoptosis, and pathways. The emerging trend is the repurposing of FDA-approved non-anticancer drugs (FNDs) for combating the side effects toxicity of PADs. Thus, this review chronicled the mechanistic preventive and therapeutic effects of FNDs against PAD organ toxicity in preclinical studies. FNDs are potential clinical drugs for the modulation of toxicity complications associated with PAD chemotherapy. Therefore, FNDs may be suggested as non-natural agent inhibitors of unpalatable side effects of PADs.

Silymarin abrogates acrylamide-induced oxidative stress-mediated testicular toxicity via modulation of antioxidant mechanism, DNA damage, endocrine deficit and sperm quality in rats.

Acrylamide (ACR) is a toxic chemical formed in foods processed at high temperature; it is a food-borne toxicant with increasing public health attention due to its carcinogenic, neurotoxic and reproductive toxicities. However, till date, it is unknown whether silymarin (SIL) could attenuate ACR testicular toxicity. Therefore, the present study investigated the effect of SIL on ACR testiculotoxicity in rats. Rats were randomly divided and administered respective agents in Control group, ACR group, SIL group and ACR + SIL group for consecutive 14 days. Rat exposure to ACR resulted in significant reduction in the level of serum testosterone, whereas FSH and LH levels prominently increased compared to control. Acrylamide induced marked decreases in sperm count and sperm motility followed by a considerable increase in sperm abnormality percentage in the ACR-exposed rats in comparison to control. The testicular activities of glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) were significantly diminished, whereas malondialdehyde (MDA) level considerably increased. Additionally, ACR induced marked DNA fragmentation and histopathological lesions compared to control. Interestingly, the co-treatment of SIL with ACR attenuated the altered reproductive indices and restored antioxidant balance and DNA integrity. Overall, SIL prevents ACR-induced testicular reproductive deficits via modulation of antioxidant mechanism in rats.

Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Exhibits Antioxidant Mechanism for Abrogation of Cyclophosphamide-Induced Cardiac Damage and Oxidative Hepatorenal Toxicity in Rats.

Cyclophosphamide (CYP) is a potent DNA-interactive anticancer drug; however, its clinical drawbacks are chiefly associated with induction of oxidative multi-organ toxicity. Sitagliptin (STG) is an antidiabetic dipeptidyl peptidase-4 inhibitor drug with antioxidant efficacy. Herein, we have explored whether STG could abrogate the CYP-induced oxidative stress-mediated cardiac and hepatorenal toxicities in male rats. Sitagliptin (20 mg/kg, o.p) was administered to rats for 5 consecutive days against organ toxicities induced by CYP (200 mg/kg, i.p) on day 5 only. CYP induced marked injuries in the liver, kidney and heart underscored by prominent increases in serum activities of ALT, AST, LDH, creatine kinase and levels of urea, uric acid and creatinine, while albumin level significantly decreased compared to normal control rats. Further, CYP considerably reduced the activities of SOD, CAT, GPx, and levels of GSH, whereas MDA level increased significantly in comparison to control rats. These biochemical alterations were confirmed by multiple histopathological lesions in the tissues. Interestingly, the STG pretreatment abrogated the biochemical and histopathological changes induced by CYP. These results provide first evidence that repurposing STG may protect the liver, kidney and heart from the oxidative deterioration associated with CYP chemotherapy.