Curcumin protects against lamotrigine-induced chronic ovarian and uterine toxicity in rats by regulating PPAR-γ and ROS production.

Lamotrigine (LTG) is an antiepileptic drug with possible adverse effects on the female reproductive system. Curcumin was declared to improve ovarian performance. Therefore, this study aimed to clarify ovulatory dysfunction (OD) associated with LTG and the role of curcumin in ameliorating this dysfunction. Adult female Wister albino rats were assigned into four groups: negative control (received saline), positive control (received curcumin only), LTG, and LTG with curcumin groups. Drugs were administered for 90 days. The hormonal profile, including testosterone, estrogen, progesterone, luteinizing hormone, and follicle-stimulating hormone, in addition to the lipid profile and glycemic analysis, were tested. Oxidative stress biomarkers analysis in the ovaries and uterus and peroxisome proliferator-activated receptor-γ (PPAR-γ) gene expression were also included. Histopathological examination of ovarian and uterine tissues and immunohistochemical studies were also performed. Curcumin could improve the OD related to chronic LTG intake. That was proved by the normalization of the hormonal profile, glycemic control, lipidemic status, oxidative stress markers, and PPAR-γ gene expression. The histopathological and immunohistochemical examination of ovarian and uterine tissues revealed an improvement after curcumin administration. The results describe an obvious deterioration in ovarian performance with LTG through the effect on lipidemic status, PPAR-γ gene, and creating an oxidative stress condition in the ovaries of chronic users, with a prominent improvement with curcumin addition to the treatment protocol.

Dipeptidyl peptidase-4 inhibitor: Sitagliptin down-regulated toll-like receptor 4 signaling pathway to reduce uterine injury in rats.

Objectives: Uterine ischemia is a common problem with ongoing controversy about its pathogenesis and prevention. The present study aimed to investigate the protective role of sitagliptin against uterine ischemia-reperfusion injury (IRI). Materials and Methods: Rats were allocated into 4 groups: control, sitagliptin (SIT) (5 mg/kg), IR; ischemia was induced followed by reperfusion, and IR+SIT; SIT was administered 1 hr before IRI. Uteri were removed for histopathological and biochemical observations. Malondialdehyde (MDA), total nitrites (NOx), reduced glutathione (GSH), superoxide dismutase (SOD) activity, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and toll-like receptor 4 (TLR4) were all measured. Hematoxylin and eosin (H&E) stain, Periodic acid-Schiff stain (PAS), and caspase-3 immunostaining were applied. Results: In the IR+SIT group; NOx, GSH, and SOD activities increased significantly. Meanwhile, the levels of MDA, TNF-α, IL-6, TLR4, and caspase-3 immunoexpression showed a significant reduction, as compared with the IR group. In the IR+SIT group, an improvement in the histopathological picture was noticed. Conclusion: The results showed that sitagliptin confers protection against uterine IRI through anti-oxidant, anti-inflammatory, and anti-apoptotic effects with a possible role for TLR4.

Xanthine Oxidase Inhibitor, Febuxostat Is Effective against 5-Fluorouracil-Induced Parotid Salivary Gland Injury in Rats Via Inhibition of Oxidative Stress, Inflammation and Targeting TRPC1/CHOP Signalling Pathway.

The current research aimed to examine the ameliorative role of febuxostat (FEB), a highly potent xanthine oxidase inhibitor, against 5-fluorouracil (5-FU)-induced parotid salivary gland damage in rats, as FEB is a pleiotropic drug that has multiple pharmacological effects. A total of 32 Wistar adult male rats were randomly arranged into four groups. Group 1: the control group; given only the vehicle for 14 days, then given a saline i.p. injection from the 10th to the 14th day. Group 2: the FEB group; rats received FEB (10 mg/kg) once daily po for 14 days before receiving a saline i.p. injection from the 10th to the 14th day. Group 3: the 5-FU group; from the 10th to the 14th day, rats received an intraperitoneal injection of 5-FU (35 mg/kg/day). Group 4: the FEB/5-FU group; rats were pre-treated with FEB po for 14 days before receiving 5-FU i.p injections for five consecutive days from the 10th to the 14th day. Parotid gland damage was detected histologically and biochemically by the evaluation of oxidative stress markers (malondialdehyde (MDA) and nitric oxide levels (NOx)), oxidant defences (reduced glutathione (GSH) and superoxide dismutase (SOD)), inflammatory markers (tumour necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß)), and transient receptor potential canonical1 (TRCP1) and C/EBP homologous protein (CHOP). FEB pre-treatment reduced MDA, TNF-, and IL-1 while increasing SOD, GSH, and NOx. FEB also significantly increased TRPC1 and decreased CHOP in parotid gland tissue. In conclusion, FEB pre-treatment reduced 5-FU-induced parotid salivary gland damage not only through its powerful anti-inflammatory and antioxidant effects, but also through its effect on the TRPC1/CHOP signalling pathway.

Role of IL-6/STAT3 pathway in mediating the protective effect of agomelatine against methotrexate-induced lung/intestinal tissues damage in rats.

BACKGROUND: Methotrexate (MTX), an anticancer drug, has been linked to multiple organ toxicity. The drug-induced acute toxic symptoms can negatively affect the patient's commitment to the course of treatment. MATERIALS AND METHODS: This study aimed to investigate the mitigating action of agomelatine (Ago) against MTX-induced lung and intestinal toxicity. Forty eight male Wister rats were randomized into six experimental groups: Group 1: Control; Groups 2 and 3: received Ago L&H (20/40 mg/kg, respectively by gavage); Group 4: received MTX 10 mg/kg/day, i.p. on days 7-9; Group 5: received Ago L (20 mg/kg) + MTX; Group 6: received Ago H (40 mg/kg) +MTX. The duration of the study was 10 days. Lung/intestine oxidative markers were measured. Lung/intestinal tissues IL-6, STAT3, and HO-1 levels were evaluated by ELISA. Besides, lung/intestinal tissues were examined for Histological changes, collagen fibers detection using Massonꞌs trichome stain, and immunohistochemical study using HSP70 antibody. RESULTS: MDA, NOx, IL-6, and STAT3 levels were significantly higher in the MTX group's lungs and intestines, indicating lung and intestinal toxicity. There were substantial decreases in GSH, SOD tissue levels, and HSP 70 immunoexpression, as well as histological changes suggesting significant lung and intestinal injury. All of the above parameters improved significantly by using Ago. CONCLUSION: By reducing oxidative stress, inflammatory processes, and modulating the IL-6/STAT3 pathway, Ago has potent ameliorative effects against MTX-induced lung/intestinal toxicities.

Dapsone Ameliorates Isoproterenol-Induced Myocardial Infarction via Nrf2/ HO-1; TLR4/ TNF-α Signaling Pathways and the Suppression of Oxidative Stress, Inflammation, and Apoptosis in Rats.

Myocardial infarction (MI) is a critical condition that can happen with high doses or rapid termination of beta blockers therapy. The study aimed to evaluate the potential anti-toxic value of DAP against isoproterenol (ISO) - induced MI. Twenty-eight male Wistar rats were used for the study. The rodents were assigned to four groups (n = 7) and the treatments were given for 12 days as follows; Group 1 (control): were administrated normal saline, Group 2 (DAP control): were administrated DAP (10 mg/kg/day IP), Group 3 (ISO group): were administrated ISO (100 mg/kg, IP on the 11th and 12th days of the experiment), and Group 4 (DAP + ISO): co-treated with DAP plus ISO. The measured parameters were cardiac malondialdehyde (MDA), reduced glutathione (GSH), total nitrite/nitrate (NOx), catalase (CAT), serum cardiac biomarkers; CK-MB, ALT, LDH, and ALK-PH. Also, interleukin-1ß (IL-1ß), tumor necrosis factor-alpha (TNF-α), Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1), toll-like receptor 4 (TLR4), caspase-3 activity, and hepatic BAX and Bcl-2 were also assessed. Also, histological examination and vimentin immuno-expressions were studied. ISO group exhibited MI as evidenced by the elevation in serum cardiac biomarkers, MDA, NOx, IL-1ß, TNF-α, and caspase-3 together with the reduction in GSH, Nrf2, HO-1 levels, and a faint vimentin immuno-reaction. Histological alterations revealing distorted cardiomyocytes; vacuolation, edema, pyknosis, and fragmentation were also noticed. DAP significantly ameliorated all the examined toxicity indicators. DAP revealed efficient ameliorative actions against ISO-caused MI by marked reduction in myocardial infarct size and suppressed oxidative stress, inflammation, and apoptosis via the up-regulation of the Nrf2/HO-1; TLR4/TNF-α signaling pathways.

Evaluation of time passed since death by examination of oxidative stress markers, histopathological, and molecular changes of major organs in male albino rats.

Recent biochemical, metabolic, and molecular profiles of various body fluids showed more accurate correlation to the postmortem interval than the traditional physical examination. Our study aimed to evaluate time passed since death in relation to oxidative stress markers, HMGB1 genetic expression, histopathological examination, and BCL2 immunohistochemical analysis in major organs (heart, kidney, and testis). Forty-two adult male rats were included and randomly divided into seven equal groups. After sacrification, the rodents were kept at room temperature and major organs were obtained at 0, 12, 24, 48, 72, 96, and 120 h. Malonaldehyde (MDA), superoxide dismutase (SOD), reduced glutathione (GSH) tissue levels, High mobility group box 1 protein (HMGB1) gene expression, histopathological, and B cell lymphoma 2 (BCL2) immunohistochemical expressions were analyzed. Postmortem interval was correlated to different tissue levels of MDA, SOD, and GSH. HMGB1 showed enhanced postmortem gene expression with a peak at 48 h after death. Obvious time-dependent histopathological changes were observed in all the examined organs. Dilated spaces, extravasation, and fragmentation scores in heart specimens were higher at 96 and 120 h compared with the other groups. Renal changes in the form of shrunken glomeruli, loss of tubular epithelium, and hyalinization and testicular findings in the form of epithelial detachment, vacuolation, and loss of sperms started at 72 h postmortem. BCL2 expression began to decrease 24 h and became negative at 96 h after death. In conclusion, HMGB1 gene expression can be used for estimation of time passed since death as it shows time-dependent changes in the form of a progressive increase with a peak at 48 h then it begins to decline. Oxidants and antioxidants are correlated to PMI until 120 h after death. Histopathological changes in the heart, kidney, and testis are also time-dependent until the 5th day after death. BCL2 immunohistochemical expression begins to decline 24 h until 96 h after death when it becomes negative.

Vitamin E protects against gabapentin-induced chronic hepatic and renal damage associated with the inhibition of apoptosis and tissue injury in rats.

AIMS: This study aimed to investigate the potential protective effects of vitamin E against gabapentin-induced chronic liver and kidney injury associated with the inhibition of biomarkers of apoptosis and tissue injury. MATERIALS AND METHODS: Four groups of adult male rats were included; control, gabapentin (100 mg/kg/day), Vitamin E (80 mg/kg/day), and a combination of gabapentin and Vitamin E for 90 days. Serum levels of AST, ALT, LDH, ALP, urea, and creatinine were measured in addition to malondialdehyde (MDA), and reduced glutathione (GSH) tissue levels. P53 gene expression, histological, and immunohistochemical examinations were performed in liver and kidney tissue samples. KEY FINDINGS: Gabapentin increased AST, ALT, LDH, ALP, urea, creatinine, MDA, and p53 gene expression and it reduced GSH. Moreover, gabapentin administration caused structural changes in the hepatic and renal architecture with a weak Periodic acid-Schiff (PAS) reaction that reflects glycogen deposition in the liver and kidney and a positive immunoreaction for BCL2-associated X protein (BAX) that reflects activated apoptosis. Vitamin E significantly (p<0.05) reversed the biochemical alterations associated with chronic gabapentin administration and improved the histopathological picture of hepatic and renal tissue with a partial inhibition of BAX. SIGNIFICANCE: Chronic administration of gabapentin causes hepatic and renal impairments, which is ameliorated by Vitamin E; possibly due to the inhibition of biomarkers of apoptosis and tissue injury.

Vinpocetine ameliorates L-arginine induced acute pancreatitis via Sirt1/Nrf2/TNF pathway and inhibition of oxidative stress, inflammation, and apoptosis.

OBJECTIVES: Acute pancreatitis (AP) is a common severe critical illness with a high mortality rate. We aimed to study the effect of vinpocetine (Vinpo) in the treatment of AP because of its anti-inflammatory, antioxidant, and antiapoptotic effects. MATERIALS AND METHODS: Thirty two adult male albino Wistar rats were randomized to four groups: control group, Vinpo group (20 mg/kg.P.O.), l-arginine group (two intraperitoneal injections of l-arginine 2.5 g/kg, 1 h apart), and Vinpo + L-arginine group. Vinpo administration was once daily for 7 consecutive days and started 1 h later after l-arginine administration. We measured serum enzyme biomarkers (lipase and amylase), levels of pancreatic malondialdehyde (MDA), total antioxidant capacity (TAC), reduced glutathione (GSH), total sulfhydryl (T-SH), total nitrite/nitrate (NOx), Interluken-6 (IL-6), tumor necrosis factor-alpha (TNF-α), Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Sirtuin type 1 (Sirt1), and caspase-3 activity. Furthermore; histological changes, anti-insulin, and inducible nitric oxide synthase (iNOS) immuno-expressions were examined. RESULTS: l-arginine group displayed AP as manifested by a significant increase in serum lipase and amylase, MDA, NOx, IL-6, TNF-α, caspase-3 with iNOS immuno-expression. Histological changes indicating marked pancreatic injury were observed together with a significant decrease in TAC, GSH, T-SH, Nrf2, Sirt1 levels, and anti-insulin immuno-expression. Vinpo showed a significant amelioration in all parameters. CONCLUSION: Vinpo possesses potent ameliorative effects against AP by decreasing oxidative stress, inflammatory process, and apoptosis through regulation of the Sirt1/Nrf2/TNF-α pathway.

The potential protective effect of modafinil in intestinal ischemic reperfusion-induced in rats.

OBJECTIVE: Intestinal ischemia reperfusion (IR) is a pathophysiologic process that leads to oxidative stress and acute inflammatory responses. Understanding the mechanisms explaining this inflammation is essential to developing therapeutic strategies. Therefore, the purpose of this study was to evaluate the protective outcome of modafinil (Mod) against intestinal damages caused by intestinal IR injury. METHODS/MATERIALS: Fourty adult Male Wistar rats were randomly divided into four groups: sham control group; intestinal IR group; Mod pre-treated IR group and Mod post-treated IR group. Mod in a dose of 10 mg/kg was injected intraperitoneally once daily for 7 days pre or post IR treatment. RESULTS: Mod significantly attenuated the IR induced elevations in intestinal malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor alpha (TNF-α), interleukin 1-ß (IL-1ß) and P-glycoprotein (P-gp) levels, caspase-3 activity. However, a significant increase in TAC was reported as compared with the IR group but its post-treated IR group was highly protective. Mod post-treatment down-regulated the IR induced cyclo-oxygenase-2 (COX-2) over-expression. Distorted mucosa with loss of surface epithelial cells, epithelial separation oedematous lamina propria and inflammatory cellular infiltration detected by histopathological examination of intestinal tissue, were markedly ameliorated by Mod post-treatment. On the other hand, Mod pre-treatment showed less protection against intestinal IR in rats. CONCLUSION: Current study suggests that Mod post-treatment ameliorated intestinal damages, so it can be considered a potential therapeutic agent to protect against the major clinical challenge of intestinal injury resulting from IR.

Protective effects of either C-peptide or l-arginine on pancreatic ß-cell function, proliferation, and oxidative stress in streptozotocin-induced diabetic rats.

Diabetes and cardiometabolic risk factors including hypertension and dyslipidemia are the major threats to human health in the 21st century. Apoptosis in pancreatic tissue is one of the major causes of diabetes type 1 progression. The aim of this study was to investigate the effects of C-peptide or l-arginine on some cardiometabolic risk factors, pancreatic morphology, function and apoptosis, and the mechanisms of their actions. Forty adult male albino rats were divided into four equal groups: 1-control nondiabetic, 2-diabetic (no treatment), 3-diabetic + C-peptide, and 4-diabetic + l-arginine. Diabetes was induced by a single intraperitoneal injection of high dose streptozotocin. At the end of the experiment, sera glucose, insulin levels, total antioxidant capacity (TAC), malondialdehyde (MDA), nitric oxide (NO), and pancreatic MDA, TAC, and B-cell lymphoma 2 were measured. The morphology and proliferating activity of the pancreas were examined by hematoxylin and eosin histological stain, proliferative cell nuclear antigen (PCNA), and insulin antibodies. Our results showed that induction of diabetes caused hyperglycemia, dyslipidemia, and oxidative stress. However, administration of C-peptide or l-arginine significantly improved the pancreatic histopathology with a significant increase in the area % of insulin immunoreactivity, the number of PCNA immunopositive cells, the number of islets, and the diameter of islets compared with the diabetic group. C-peptide treatment of the diabetic rats completely corrected these errors, while l-arginine partially antagonized the above diabetic complications. So the administration of C-peptide as an adjuvant therapy in type 1 diabetes can significantly decrease apoptosis of pancreas and subsequent progression of diabetes complication.

Somatostatin analogue, Octreotide, improves restraint stress-induced liver injury by ameliorating oxidative stress, inflammatory response, and activation of hepatic stellate cells.

The aim of this study is to investigate the effect of somatostatin (SST) analogue, Octreotide, on some features of liver injury induced by immobilization stress (IS) in adult male albino rats. Eighteen adult male albino rats were randomly divided into three equal groups: control, IS, and Octreotide-treated stressed groups. Octreotide (40 µg/kg body weight, subcutaneously) was administrated twice daily for 8 days during the exposure to IS. Octreotide was found to reduce the IS significantly and induce elevations in the plasma level of corticosterone, liver transaminases, and tumor necrosis factor α (TNF-α) as compared with IS group. Furthermore, Octreotide administration has significantly elevated the decline in the total antioxidant capacities (TAC) and lowered the elevated malondialdehyde (MDA) levels observed with IS in the hepatic tissue. Additionally, Octreotide treatment provided protection against the histopathological changes in the stressed liver in the form of significant reduction in the mean number of degenerated hepatocytes, the area % of collagen fibers, and glial fibrillary acid protein (GFAP) immunostaining with a significant increase in the mean number of normal hepatocytes. In conclusion, stressed rats showed disturbed liver functions and its oxidant-antioxidant status with highly expression hepatic stellate cells (HSCs), which were all improved by Octreotide administration, SST analogue.