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The present study was conducted to investigate the role of vitamin C versus platelet-rich plasma (PRP) against sodium fluoride (NaF)-induced cardiotoxicity and cell death in rats' myocardium. Previous studies suggest that NaF decreased cellular viability and intracellular antioxidant power.The present study revealed that NaF administration caused histological alterations in the cardiac muscle and increased the accumulation of intracellular reactive oxygen species, the expression of inducible nitric oxide synthases and proliferating cell nuclear antigen as well as collagen deposition in cardiac tissue. As supported by colorimetric analysis, an elevation in malondialdehyde level and a decrease in both superoxide dismutase (SOD) and thioredoxin-1 oxidoreductase (TrX) levels were seen, whereas molecular analysis revealed a decrease in Keap1 and an increase in Nrf2 and HO-1 gene expression. Pretreatment with vitamin C and PRP prior to NaF administration significantly improved the altered parameters and enhanced the cellular antioxidant capability of myocardium resulting in protection of cardiac muscle from NaF-induced cytotoxicity and apoptotic cell death.The cyto-protective activity of PRP was found to be comparable to that of the known antioxidant, vitamin C.

Depression is still one of challenging, and widely encountered disorders with complex etiology. The role of healthy diet and olive oil in ameliorating depression has been claimed. This study was designed to explore the effects of oleuropein; the main constituent of olive oil; on depression-like behaviors that are induced by repeated administration of corticosterone (40 mg/kg, i.p.), once a day for 21 days, in mice. Oleuropein (8, 16, and 32 mg/kg, i.p.) or fluoxetine (20 mg/kg, positive control, i.p.1) was administered 30 minutes prior to corticosterone injection. Sucrose consumption test, open-field test (OFT), tail suspension test (TST), and forced swimming test (FST) were performed. Reduced Glutathione (GSH), lipid peroxidation, and biogenic amines; serotonin, dopamine, and nor-epinephrine; levels were also analyzed in brain homogenates. Corticosterone treatment induced depression-like behaviors, it increased immobility time in the TST, OFT, and FST, decreased the number of movements in OFT, and decreased sucrose consumption. Corticosterone effect was associated with depletion of reduced glutathione and increase of lipid peroxidation, in addition to modification of biogenic amines; decreased serotonin and dopamine. Oleuropein or fluoxetine administration counteracted corticosterone-induced changes. In conclusion, oleuropein showed a promising antidepressant activity, that is evident by improving corticosterone-induced depression-like behaviors, and normalizing levels of biogenic amines.

5-Fluorouracil (5-FU) is a front-line cytotoxic therapy. However, intestinal mucositis is a well-known adverse event of 5-FU, which limits its therapeutic use. Indeed, thymol, which is a monoterpene component of the essential oil derived from thymus, has a potential anti-inflammatory and immunomodulatory activity. Therefore, this study aimed to investigate the potential chemoprotective effect of thymol against 5-FU-induced intestinal mucositis. Rats were either exposed to two doses of 5-FU (150 mg/kg, ip) and/or treated with thymol (60 or 120 mg/kg). Oxidative stress and inflammatory markers, as well as pathological changes, were assessed. 5-FU-induced severe intestinal damages as were evidenced by histopathological changes as well as oxidative and inflammatory responses. Thymol pretreatment inhibited 5-FU-induced oxidative stress by reducing lipid peroxidation and increasing intestinal levels of antioxidant systems. Moreover, inflammatory response markers, such as interleukin-6, prostaglandin E2, and COX-2 were also improved. The immunoblotting analysis also showed that thymol significantly inhibited the 5-FU-induced expression of nuclear factor-κB, tumor necrosis factor-α, and transforming growth factor β-1 (TGF-β1), in addition to the suppression of p38 and phosphorylated c-Jun N-terminal kinases (p-JNK) mitogen-activated protein kinase proteins' expressions. Our study is the first to demonstrate the promising protective effect of thymol against 5-FU-induced intestinal mucositis through inhibition of oxidative, inflammatory pathways, and suppression of TGF-β/p38/p-JNK signaling.

Liver fibrosis is a common chronic hepatic disease. This study was done to examine the effect of pyridoxamine against thioacetamide-induced hepatic fibrosis. Animals were divided into four groups (1) control group; (2) Thioacetamide group (200 mg/kg, i.p.) twice a week for eight weeks; (3) Pyridoxamine-treated group treated with pyridoxamine (100 mg/kg/day, i.p.) for eight weeks; (4) Thioacetamide and pyridoxamine group, in which pyridoxamine was given (100 mg/kg/day, i.p.) during thioacetamide injections. Thioacetamide treatment resulted in hepatic dysfunction manifested by increased serum levels of bilirubin, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Oxidative stress was noted by increased hepatic lipid peroxidation and decreased glutathione (GSH). Increased concentrations of total nitrite/nitrate, advanced glycation end products (AGEs), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), matrix metalloproteinases (MMP-29) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were noticed in hepatic tissues. Immunostaining sections also revealed overexpression of MMP-2, MMP-9 and collagen IV. Liver fibrosis was confirmed by severe histopathological changes. Pyridoxamine improved the assessed parameters. Moreover, histopathological and immunohistological studies supported the ability of pyridoxamine to reduce liver fibrosis. The findings of the present study provide evidence that pyridoxamine is a novel target for the treatment of liver fibrosis.

Radiotherapy represents a critical component in cancer treatment. However, premature ovarian failure (POF) is a major hurdle of deleterious off-target effects in young females, which, therefore, call for an effective radioprotective agent. The present study aimed to explore the molecular mechanism underlying the protective effects of N-acetyl-L-cysteine (NAC) against γ-radiation-provoked POF. Immature female Sprague-Dawley rats were orally-administered NAC (50 mg/kg) and were exposed to a single whole-body dose of 3.2 Gy ϒ-radiation. NAC administration remarkably reversed abnormal serum estradiol and anti-Mullerian hormone levels by 73% and 40%, respectively while ameliorating the histopathological and ultrastructural alterations-triggered by γ-radiation. Mechanistically, NAC alleviated radiation-induced oxidative damage through significantly increased glutathione peroxidase activity by 102% alongside with decreasing NADPH oxidase subunits (p22 and NOX4) gene expressions by 48% and 38%, respectively compared to the irradiated untreated group. Moreover, NAC administration achieved its therapeutic effect by inhibiting ovarian apoptosis-induced by radiation through downregulating p53 and Bax levels by 33% and 16%, respectively while increasing the Bcl-2 mRNA expression by 135%. Hence, the Bax/Bcl2 ratio and cytochrome c expression were subsequently reduced leading to decreased caspase 3 activity by 43%. Importantly, the anti-apoptotic property of NAC could be attributed to inactivation of MAPK signaling molecules; p38 and JNK, and enhancement of the ovarian vascular endothelial growth factor (VEGF) expression. Taken together, our results suggest that NAC can inhibit radiotherapy-induced POF while preserving ovarian function and structure through upregulating VEGF expression and suppressing NOX4/MAPK/p53 apoptotic signaling.

Cisplatin (CP) nephrotoxicity is associated with the induction of oxidative stress, inflammation, and apoptosis. Several studies demonstrated the antioxidant, anti-inflammatory, and antiapoptotic effects of dandelion leaf extract (DLE); therefore, this research aimed to investigate the protective effects of DLE against CP-induced nephrotoxicity. Thirty-two male Wistar rats were divided into 4 groups: normal control, DLE control received 500 mg/kg daily for 11 days, intoxicated group received vehicle daily for 11 days and a single dose of CP (7 mg/kg, intraperitonealp) on day 5, and DLE + CP group received DLE (500 mg/kg) daily for 11 days plus a single dose of CP (7 mg/kg) on day 5. The dose of DLE is selected based on a dose–effect study using different doses. Dandelion leaf extract pretreatment ameliorated CP-induced nephrotoxicity as evident by histopathological examination, alleviating CP-induced elevation in serum creatinine, blood urea nitrogen, oxidative stress marker (thiobarbituric acid reactive substances), tumor necrosis factor-α (as inflammatory cytokine), and caspase-9 and caspase-3 (as apoptotic markers). In addition, DLE reduced nuclear factor-κB and cytochrome c expression, and DNA fragmentation. It also maintained levels of reduced glutathione, superoxide dismutase, and serum albumin. Thus, the present study shows that DLE is a promising nephroprotective agent for CP-induced nephrotoxicity through antioxidant, anti-inflammatory, and antiapoptotic activities.

Premature ovarian failure (POF) is a common cause of infertility in premenopausal women who are unavoidably exposed to cytotoxic therapy. Radiotherapy is one of the most effective cytotoxic treatments. However, the radiosensitivity of ovarian tissues limits its therapeutic outcome and results in the depletion of the primordial follicle and loss of fertility. Therefore, the need for an effective radioprotective therapy is evident especially when none of the current clinically used modalities for radioprotection succeeds efficiently. The present study investigated the potential radioprotective effect of carvacrol (CAR) (80 mg) or thymol (80 mg) on gamma- (γ-) irradiation-induced ovarian damage as well as their role in the cross-talk between IGF-1 and TNF-α signaling and antioxidative activity. In immature female Wister rats, a single dose of whole-body irradiation (3.2 Gy, L D 20 ) produced considerable ovarian damage, which was evident by histopathological findings and hormonal changes. Interestingly, pretreatment with CAR or thymol significantly enhanced the follicular development and restored the anti-Mullerian hormone (AMH), E2, and FSH levels. Both essential oils improved the irradiation-mediated oxidative stress and reduction in proliferating cell nuclear antigen (PCNA) expression. Moreover, irradiated rats exhibited an inverse relationship between IGF-1 and TNF-α levels two days post irradiation, which was further inverted by the pretreatment with CAR and thymol and ought to contribute in their radioprotective mechanisms. In conclusion, CAR and thymol showed a radioprotective effect and rescued the ovarian reserve mainly through counteracting oxidative stress and the dysregulated cross-talk between IGF-1 and TNF-α.

Ethnopharmacological relevance Sesame (Sesamum indicum, L., Family: Pedaliaceae) is a notable folk medicine in Middle East, Asia and Africa. Many traditional and pharmacological studies have documented the unique nature of sesame oil (SO). SO has been reported to have many pharmacological effects related to the anti-inflammatory and antioxidant capacity of its components. Neuroinflammation and oxidative stress have been the predominant pathogenic events in Alzheimer's disease (AD) which is one of the most common neurodegenerative diseases. Aim of study we aimed to explore the neuroprotective effect and the probable mechanisms of SO against aluminium chloride (AlCl3)-induced AD symptoms. Materials and methods Rats were treated daily with AlCl3 (100 mg/kg/i.p.) either alone or with SO (two different doses) for six weeks. Behavioral (Open-field and Morris water maze tests), histopathological, and biochemical examinations were used to evaluate the neuroprotective effect and the underlying mechanisms of SO against AlCl3-induced AD symptoms. Results Our results indicated that SO significantly improved learning and memory impairments induced by AlCl3. Indeed, SO treatment significantly restored the elevated level of acetylcholinesterase (AChE) and amyloid beta (Aβ) overexpression. Moreover, AlCl3 treatment afforded histopathological changes, increase the expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) in addition to mitigation of oxidative stress status in the brain. SO abolished all these abnormalities. Meanwhile, AlCl3 induced activation of p38 mitogen-activated protein kinase (p38MAPK) and decreased brain-derived neurotrophic factor (BDNF) which were inhibited by SO. Furthermore, SO administration modulated the expression of the peroxisome proliferator-activated receptor gamma (PPAR-γ) and nuclear factor kappa B (NF-κB). Conclusions In conclusion, the neuroprotective effect of SO involved the modulation of different mechanisms targeting oxidative stress, neuroinflammation, and cognitive functions. SO may modulate different molecular targets involved in AD pathogenesis by alterations of NF-κB/p38MAPK/BDNF/PPAR-γ signalling and this may be attributed to the synergistic effect of their active components.

Doxorubicin (DOX) is one of the most effective chemotherapeutic drugs; however, its incidence of cardiotoxicity compromises its therapeutic index. Chrysin, a natural flavone, possesses multiple biological activities, such as antioxidant, anti-inflammatory and anti-cancer. The present study was designed to investigate whether chrysin could protect against DOX-induced acute cardiotoxicity; and if so, unravel the molecular mechanisms of this protective effect. Chrysin was administered to male albino rats once daily for 12 consecutive days at doses of 25 and 50mg/kg orally. DOX (15 mg/kg; i.p.) was administered on day 12. Chrysin pretreatment significantly protected against DOX-induced myocardial damage which was characterized by conduction abnormalities, increased serum creatine kinase isoenzyme-MB (CK-MB), and lactate dehydrogenase (LDH) and myofibrillar disarrangement. As indicators of oxidative stress, DOX caused significant glutathione depletion, lipid peroxidation and reduction in activities of antioxidant enzymes; catalase (CAT) and superoxide dismutase (SOD). Chrysin pretreatment significantly attenuated DOX-induced oxidative injury. Additionally, DOX provoked inflammatory responses by increasing the expressions of nuclear factor kappa-B (NF-κB), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and the levels of tumor necrosis factor-alpha (TNF-α) and nitric oxide while chrysin pretreatment significantly inhibited these inflammatory responses. Furthermore, DOX induced apoptotic tissue damage by increasing Bax and cytochrome c expressions and caspase-3 activity while decreasing the expression of Bcl-2. Chrysin pretreatment significantly ameliorated these apoptotic actions of DOX. Collectively, these findings indicate that chrysin possesses a potent protective effect against DOX-induced acute cardiotoxicity via suppressing oxidative stress, inflammation and apoptotic tissue damage.

Arctium lappa L (A. lappa) is a popular medicinal plant with promising hepatoprotective activity. This study investigated the protective effect of A. lappa root extract (ALRE) on lead (Pb) hepatotoxicity, pointing to its ability to modulate oxidative stress, inflammation, and protein kinase B/Akt/glycogen synthase kinase (GSK)-3&beta, signaling. Rats received 50 mg/kg lead acetate (Pb(Ac)2) and 200 mg/kg ALRE or vitamin C (Vit. C) for 7 days, and blood and liver samples were collected. Pb(Ac)2 provoked hepatotoxicity manifested by elevated serum transaminases and lactate dehydrogenase, and decreased total protein. Histopathological alterations, including distorted lobular hepatic architecture, microsteatotic changes, congestion, and massive necrosis were observed in Pb(II)-induced rats. ALRE ameliorated liver function and prevented all histological alterations. Pb(II) increased hepatic lipid peroxidation (LPO), nitric oxide (NO), caspase-3, and DNA fragmentation, and serum C-reactive protein, tumor necrosis factor-&alpha, and interleukin-1&beta, Cellular antioxidants, and Akt and GSK-3&beta, phosphorylation levels were decreased in the liver of Pb(II)-induced rats. ALRE ameliorated LPO, NO, caspase-3, DNA fragmentation and inflammatory mediators, and boosted antioxidant defenses in Pb(II)-induced rats. In addition, ALRE activated Akt and inhibited GSK-3&beta, in the liver of Pb(II)-induced rats. In conclusion, ALRE inhibits liver injury in Pb(II)-intoxicated rats by attenuating oxidative injury and inflammation, and activation of Akt/GSK-3&beta, signaling pathway.

Ethanol consumption is one of the common causative agents implicated in gastric ulcer development. Oxidative stress plays a major role in the induction and development of gastric ulceration. NADPH oxidases (NOXs) and Nuclear factor erythroid 2-related factor 2 (Nrf2) are key players in ethanol-induced ulcers. High-mobility group box 1 (HMGB1), a ubiquitous nuclear protein, mediates various inflammation functions. However, the role of HMGB1 in ethanol-induced gastric ulcer is not yet elucidated. Raspberry Ketone (RK) is a natural phenolic compound with antioxidant and anti-inflammatory properties. In the present study, absolute ethanol (7.5 ml/kg) was used to induce gastric ulceration in rats. Raspberry Ketone (RK) (50 mg/kg) was given orally one hour before the administration of absolute ethanol. Interestingly, ethanol-induced gastric ulcer was associated with Nrf2 downregulation, which was correlated with NOX-1, 2 NOX-4, and HMGB1 upregulation, and was significantly reversed by RK pre-treatment. RK pre-treatment provided 80% gastroprotection. Gastroprotective properties of RK were mediated via antioxidant, anti-inflammatory (suppression of NF-kB and tumor necrosis factor-α), and antiapoptotic activities (reduction of Bax/Bcl2 ratio). Gastroprotective properties of RK were confirmed by histopathological examination. In conclusion, this study is the first to provide evidence to the role of HMGB1 in ethanol-induced gastric ulcer, and the crosstalk of Nrf2, NOXs and HMGB1. It also demonstrates that RK represents a promising gastroprotective activity comparable to omeprazole.

The deleterious damage of reproductive function following radiotherapy is of increasing importance. In the present study, we investigated the impact of long-term sodium selenite (SS) treatment on radiotherapy-induced ovarian injury in a rat model. Two-week after radiation exposure vaginal cyclicity was arrested, and serum FSH level was elevated in irradiated female rats. SS significantly ameliorated ovarian and uterine oxidative stress induced by irradiation through decreasing the lipid peroxide level and increasing the glutathione level, and glutathione peroxidase activity. In the presence of SS, ovarian cytochrome c and caspase 3 expressions triggered by radiotherapy were decreased. SS significantly counteracted radiation-induced a widespread loss of ovarian follicles and caused further stimulation of follicular proliferation through enhancing PCNA expression. Despite such alteration in ovarian function, serum estradiol level did not change after irradiation, whereas SS significantly increased it. In conclusion, long-term SS treatment improved reproductive development, which was impaired by radiotherapy.