l-carnitine modulates autophagy, oxidative stress and inflammation in trazodone induced testicular toxicity.

BACKGROUND: Trazadone is an antidepressant and may affect reproductive hormones and spermatogenesis. l-carnitine is an amino acid that exhibits antioxidant actions. This study was designed to investigate the potential protective effects of l-carnitine against trazadone-induced testicular toxicity in male rats and the possible underlying mechanisms such as oxidative stress, inflammation and autophagy. METHODS: thirty-two male Wistar rats were divided randomly into four equal groups (n = 8). Testicular damage was induced by oral administration of Trazadone (TRZ, 20 mg/kg/day, p.o.) for four weeks (TRZ group). l-carnitine (LC, 200 mg/kg/day, p.o.) was applied for four weeks (LC group). LC + TRZ group administered the same doses of LC and TRZ concomitantly. The control group received distilled water (as vehicle). RESULTS: the protective treatment with LC attenuated the decline of sperm count and motility resulted from trazadone administration. Moreover, LC ameliorated trazadone increased lipid peroxidation (MDA) and reduction of total thiol and catalase activity. LC modulated the elevation in tumor necrosis factor- α (TNF-α), and increased the expression of autophagy related genes Becline-1, ATG 5 and ATG-12 in rat testes. Serum level of FSH, LH and total testosterone were increased significantly (p < 0.001) in LC + TRZ group. Histopathological findings further supported the protective effects of LC against trazadone -induced testicular injury by increasing free sperms within the lumen of spermatogenic cells and improving testicular degeneration. CONCLUSION: These findings supported the protective effects of l-carnitine on rat testes due to suppression of oxidative stress, inflammation and enhancing autophagy. l-carnitine may be recommended as adjuvant therapy to trazadone treatment.

New insights into weight management by orlistat in comparison with cinnamon as a natural lipase inhibitor.

BACKGROUND AND OBJECTIVES: Orlistat which is taken by obese patients may present some therapeutic assistance through its inhibition of lipase activity. Otherwise, a natural lipase inhibitor as cinnamon is widely used traditional medicine to decrease cholesterol and body weight. The current study aimed to investigate the weight management of orlistat in comparison with cinnamon through different obesity related targets. METHODS: Subjects were divided into: Group 1: subjects received cinnamon capsules for 60 days. Group 2: subjects were received orlistat twice daily for 30 days, then once daily for another 30 days. Blood samples were collected at baseline and after 2 months. RESULTS: Both orlistat and cinnamon groups showed a significant reduction in BMI, lipid profile, and lipase activity compared with baseline. Orlistat group showed significant elevation (p < 0.001) in glucagon, insulin-degrading enzyme (IDE) and dopamine level concomitant with the decrease of serum glutamate compared with baseline level of the same group and cinnamon group. However, cinnamon reduced serum insulin level and insulin resistance (IR) compared with baseline level of the same group and orlistat group. CONCLUSIONS: Orlistat can be used in weight management not only for its pancreatic lipase inhibition but also, due to its indirect appetite reduction effect through elevated glucagon, IDE and dopamine levels and its inhibitory effect on glutamate neurotransmitter, whereas, cinnamon improves BMI and glycaemic targets.

Ginger extract adjuvant to doxorubicin in mammary carcinoma: study of some molecular mechanisms.

PURPOSE: The present study aimed to investigate the molecular mechanisms underlying the anticancer properties of ginger extract (GE) in mice bearing solid Ehrlich carcinoma (SEC) and to evaluate the use of GE in combination with doxorubicin (DOX) as a complementary therapy against SEC. METHODS: SEC was induced in 60 female mice. Mice were divided into four equal groups: SEC, GE, DOX and GE + DOX. GE (100 mg/kg orally day after day) and DOX (4 mg/kg i.p. for 4 cycles every 5 days) were given to mice starting on day 12 of inoculation. On the 28th day, blood samples were collected, mice were scarified, tumor volume was measured, and tumor tissues were excised. RESULTS: The anti-cancer effect of GE was mediated by activation of adenosine monophosphate protein kinase (AMPK) and down-regulation of cyclin D1 gene expression. GE also showed pro-apoptotic properties as evidenced by elevation of the P53 and suppression of nuclear factor-kappa B (NF-κB) content in tumor tissue. Co-administration of GE alongside DOX markedly increased survival rate, decreased tumor volume, and increased the level of phosphorylated AMPK (PAMPK) and improved related pathways compared to DOX group. In addition, the histopathological results demonstrated enhanced apoptosis and absence of multinucleated cells in tumor tissue of GE + DOX group. CONCLUSION: AMPK pathway and cyclin D1 gene expression could be a molecular therapeutic target for the anticancer effect of GE in mice bearing SEC. Combining GE and DOX revealed a greater efficacy as anticancer therapeutic regimen.

Branched chain amino acids supplementation modulates TGF-ß1/Smad signaling pathway and interleukins in CCl4 -induced liver fibrosis.

The alterations and low levels of circulating branched chain amino acids (BCAAs), leucine, isoleucine, and valine, are associated with liver diseases. The study was designed to evaluate hepatoprotective effect of BCAAs on CCl4 -induced liver fibrosis and to investigate the molecular mechanisms underlying these effects in rats. In all, 30 male rats were divided into three groups. Control group (n = 10) and CCl4 group (n = 10), where rats were injected with CCl4 (1 mL/kg of 0.5 : 1 v/v injected i.p. twice weekly for 12 weeks). In CCl4 + BCAAs group (n = 10), rats were injected with similar doses of CCl4 and supplemented with a mixture of 600 mg/kg BCAAs (2 : 1 : 1.2 leucine : isoleucine : valine) by oral gavage, three times/week for 12 weeks. Liver fibrosis was assessed by measuring total bilirubin, total protein, alanine aminotransferase, and aspartate aminotransferase, hydroxyproline content, and serum IL-6 and IL-10. Histopathologic studies and α-smooth muscle actin (α-SMA) were detected immunohistochemically in liver. Serum insulin level, blood glucose, liver malodialdehyde concentration (MDA), glutathione peroxidase, and superoxide dismutase (SOD) activities were quantified. TGF-ß1, Smad3, and Smad7 gene expressions were estimated by qRT-PCR. BCAAs suppressed liver fibrosis induced by CCl4 treatment. BCAAs modulated liver indices and downregulated TGF-ß1, Smad3, and Smad7 expressions in hepatocytes. BCAAs enhanced liver antioxidant enzyme activities (P < 0.001), reduced serum levels of TGF-ß1, IL-6, and IL-10 compared to CCL4 group and ameliorated histopathologic changes in rat liver. BCAAs may have a protective role against liver fibrosis via antioxidant and anti-inflammatory mechanisms.

Fish oil and wheat-germ oil supplementation restores ovarian function in streptozotocin-diabetic rats.

Diabetes is a chronic metabolic disorder and has a profound impact on women's reproductive health. This study aimed to investigate the protective effect of a mixture of fish oil (FO) and wheat-germ oil (WGO) on ovarian dysfunction in diabetic rats. Female Albino rats were divided into control, diabetic and FO-WGO-diabetic groups. Diabetes was induced by intraperitoneal injection of 65mgkg-1 streptozotocin (STZ). Three weeks later, rats were given oral supplement of 0.4gkg-1 oil mix (1000mg FO+100mg WGO) daily for 3 weeks. Antioxidant activity was assessed by measuring malondialdehyde (MDA) and reduced glutathione (GSH) levels, the GSH:oxidised glutathione (GSSG) ratio and superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) activities. Ovary function was indicated by serum concentrations of FSH, oestradiol (E2), LH, anti-Müllerian hormone (AMH), ovary histopathology and follicle counts. Anti-inflammatory properties were detected by measuring nuclear factor (NF)-κB in follicular cells by immunohistochemistry. FO-WGO supplementation enhanced CAT, SOD and GPx activities and raised GSH levels and the GSH:GSSG ratio. Supplementation also increased FSH, E2, LH and AMH levels and follicle counts. Moreover, NF-kB expression and MDA were reduced. These findings indicate that FO-WGO supplementation preserved ovarian function in STZ-induced diabetic rats.

Fish oil and wheat germ oil supplementation modulates brain injury in streptozotocin-induced diabetic rats.

BACKGROUND: Uncontrolled diabetes mellitus causes neuronal damage because of increased intracellular glucose. Natural products as complementary therapy may reduce neuronal complications. This study investigated whether fish oil (FO) and wheat germ oil (WGO) supplementation protects the brain in streptozotocin (STZ)-induced diabetic rats by estimating lipid peroxidation and the inflammatory and anti-oxidant status of the brain. METHODS: Diabetes was induced in male Wistar rats by a single i.p. injection of STZ (60 mg/kg). Four weeks after diabetes induction, rats were divided into an untreated group and a group supplemented with 0.4 g/kg per day FO +WGO mix, p.o., for 4 weeks. Brain oxidant status was assessed by measuring nitric oxide (NO), malondialdehyde (MDA), reduced glutathione (GSH), the GSH/oxidized glutathione (GSSG) ratio, and superoxide dismutase (SOD) and catalase (CAT) activity. Inflammatory biomarkers (tumor necrosis factor [TNF]-α levels and nuclear factor (NF)-κß immunoreaction) were measured in brains, combined with histological studies. Cholinergic function was assessed on the basis of acetylcholine (ACh) levels and acetylcholinesterase (AChE) activity. RESULTS: Supplementation with FO + WGO reduced MDA and NO ( P < 0.001) in diabetic rat brains and enhanced brain antioxidant capacity, as evidenced by increased GSH, GSH/GSSG ratio ( P < 0.01), and SOD and CAT activity ( P < 0.01). In addition, FO + WGO supplementation suppressed NF-κB immunoreaction and TNF-α levels ( P < 0.001). Cholinergic function was improved by FO + WGO as a result of increased ACh levels and reduced AChE activity ( P < 0.001). CONCLUSIONS: Supplementation of the diet with the FO + WGO mix modulated diabetic brain injury and this mix could potentially be used for preventing diabetic neurodegenerative sequelae.

Renoprotective effects of montelukast, a cysteinyl leukotriene receptor antagonist, against methotrexate-induced kidney damage in rats.

Methotrexate (MTX) is a cytotoxic chemotherapeutic agent used for treatment of several cancers. Nephrotoxicity, an adverse side effect of high-dose MTX, is attributed to abnormal production of reactive oxygen species (ROS), inflammatory mediators, and neutrophil infiltration. Montelukast (MON) is a cysteinyl leukotriene receptor antagonist. Recently, it has gained a considerable interest as a ROS scavenger and inflammatory modulator. In this study, we investigated the effect of MON against MTX-induced nephrotoxicity. Rats were divided into four groups: control group, MON group (10 mg/kg, orally), MTX group (20 mg/kg, i.p., single injection), and MON + MTX group (MON was administered 5 days before and 5 days after MTX administration). At the end of the experiment, serum was collected for analysis of blood urea nitrogen (BUN) and creatinine. Glutathione (GSH), lipid peroxides (malondialdehyde), tumor necrosis factor alpha (TNF-α) levels, superoxide dismutase, myeloperoxidase activities, and nuclear factor kappa beta (NF-κB) protein expression were determined in renal tissues. In addition, kidney tissues were examined histopathologically and immunohistochemically for NF-κB. MTX administration produced acute renal damage as indicated from severe elevation in BUN and serum creatinine. The role of oxidative stress and inflammatory mechanisms in MTX-induced nephrotoxicity was evidenced from the unbalance in tissue oxidative parameters, increased TNF-α levels, and NF-κB expression in renal tissues. On the other hand, MON significantly reduced the toxic effects of MTX as indicted from normalization of kidney-specific parameters, oxidative stress, and inflammatory mediators. This data was further supported by histopathological studies. Thus, co-administration of MON may be promising in alleviating the systemic side effects of MTX.