Rice bran extract mitigates depressive-like behavior in dextran sulfate sodium-induced colitis: Involvement of the gut-brain axis and Sirt1 signaling pathway.

Inflammatory bowel disease (IBD) patients frequently suffer from depressive disorders as well. The present study was carried out to explore whether treatment with a standardized rice bran extract (RBE) could affect depression-like behavior in rats with dextran sulfate sodium (DSS)-induced colitis. Male Wistar rats were treated with RBE (100 mg/kg/day; p.o.) for 2 weeks. During the second week, colitis was induced by feeding the rats with 5 % (w/v) DSS in drinking water. RBE protected against DSS-induced body weight loss as well as against the macro- and microscopic inflammatory changes of the colon. Additionally, RBE mitigated DSS-induced dysregulation in blood-brain barrier tight junctional proteins, preserved the hippocampal histopathological architecture and improved the animal behavior in the forced swimming test. This was associated with modulation of hippocampal oxidative stress marker; GSH as well as hippocampal pro-inflammatory mediators; NF-ĸB and IL-1ß. Treatment with RBE also led to a profound increase in the hippocampal levels of Sirt1, PGC-1α, Nrf2, and HO-1, which were drastically dropped by DSS. In conclusion, the study revealed the protective effect of RBE against DSS-induced depressive-like behavior through modulation of different parameters along the gut-brain axis and up-regulated the Sirt1/PGC-1α/Nrf2/HO-1 signaling pathway.

Innovative challenge for the inhibition of hepatocellular carcinoma progression by combined targeting of HSP90 and STAT3/HIF-1α signaling.

Hepatocellular carcinoma (HCC) is the third foremost cause of cancer-related deaths. HCC has a very bad prognosis because it is asymptomatic in the early stages, resulting in a late diagnosis, and it is highly resistant to conventional chemotherapy. Such chemotherapies have been proven disappointing because they provide extremely low survival benefits. This study discloses that the STAT3/HIF-1α is an auspicious therapeutic attack site for conceivable repression of HCC development. A site that can be targeted by simultaneous administration of a STAT3 inhibitor in the context of HSP90 inhibition. 17-DMAG binds to HSP90 and constrains its function, resulting in the degradation of HSP90 client proteins HIF-1α and STAT3. Hypoxia recruits STAT3/HIF-1α complex within the VEGF promoter. Additionally, it was acknowledged that STAT3 is an essential mediator of VEGF transcription by direct binding to its promoter. Furthermore, it induces HIF-1α stability and enhances its transcriptional activity. Herein, we revealed that the combination therapy using 17-DMAG and nifuroxazide, a STAT3 inhibitor, repressed the diethylnitrosamine-induced alterations in the structure of the liver. This effect was mediated via decreasing the levels of the HSP90 client proteins HIF-1α and pSTAT3 resulting in the suppression of the STAT3/HIF-1α complex transcriptional activity. To conclude, 17-DMAG/NFXZD combination therapy-induced disruption in the STAT3/HIF-1α loop led to a potential antiangiogenic activity and showed apoptotic potential by inhibiting autophagy and inducing ROS/apoptosis signaling. Additionally, this combination therapy exhibited promising survival prolongation in mice with HCC. Consequently, the use of 17-DMAG/NFXZD renders an inspirational perspective in managing HCC. However, further investigations are compulsory.

Neuroprotective Effect of Morin Hydrate against Attention-Deficit/Hyperactivity Disorder (ADHD) Induced by MSG and/or Protein Malnutrition in Rat Pups: Effect on Oxidative/Monoamines/Inflammatory Balance and Apoptosis.

Monosodium glutamate (MSG) is one of the most widely used food additives. However, it has been linked to protein malnutrition (PM) and various forms of toxicities such as metabolic disorders and neurotoxic effects. The current study is the first to explore the association between MSG, PM, and induced brain injury similar to attention-deficit/hyperactivity disorder (ADHD). Moreover, we determined the underlying mechanistic protective pathways of morin hydrate (MH)-a natural flavonoid with reported multiple therapeutic properties. PM was induced by feeding animals with a low protein diet and confirmed by low serum albumin measurement. Subsequently, rat pups were randomized into seven groups of 10 rats each. Group I, III, and VI were normally fed (NF) and groups II, IV, V, and VII were PM fed. Group I served as normal control NF while Group II served as PM control animals. Group III received NF + 0.4 g/kg MSG, Group IV: PM + 0.4 g/kg MSG, Group V: PM + 60 mg/kg MH, Group VI: NF + 0.4 kg/g MSG + 60 mg/kg MH and Group VII: PM + 0.4 kg/kg MSG + 60 mg/kg MH. At the end of the experimental period, animals were subjected to behavioral and biochemical tests. Our results showed that treatment of rats with a combination of MSG + PM-fed exhibited inferior outcomes as evidenced by deteriorated effects on behavioral, neurochemical, and histopathological analyses when compared to rats who had received MSG or PM alone. Interestingly, MH improved animals' behavior, increased brain monoamines, brain-derived neuroprotective factor (BDNF), antioxidant status and protein expression of Nrf2/HO-1. This also was accompanied by a significant decrease in brain MDA, inflammatory markers (NF-kB, TNF-α and IL1ß), and suppression of TLR4/NLRP3/caspase-1 axis. Taken together, MSG and/or PM are associated with neuronal dysfunction. Our findings suggest MH as a potential neuroprotective agent against brain insults via targeting Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome signaling pathways.

Targeting the Oxytocin System to Ameliorate Early Life Depressive-Like Behaviors in Maternally-Separated Rats.

Oxytocin (OXT) -"the love hormone"- has been involved in the anti-depressant activity of some selective serotonin reuptake inhibitors (SSRIs). The exact mechanism underlying the OXT pathway in depression is not fully clear. This study aimed to investigate the effect of OXT analogue, carbetocin (CBT) and the SSRI, escitalopram (ESCIT) on depressive-like behaviors following maternal separation (MS). It is worthy to mention that intranasal CBT has been approved by U.S. Food and Drug Administration (FDA) for Prader-Willi syndrome. Adolescent Wistar albino maternally-separated rats were given CBT, (100 µg/animal/d via inhalation route), and, ESCIT, (20 mg kg-1, per os ( p.o.)) either alone or in combination for 7 d. Repeated 3-h MS demonstrated increased immobility time in forced swim test (FST) and decreased locomotor activity in open field test. MS elevated plasma level of adrenocortico-trophic hormone (ACTH) but notably reduced plasma OXT, with no effect on hippocampal OXT-R expression. Following MS, hippocampal contents of 5-hydroxytryptamine receptors (5HT1A-R), serotonin transporter (SERT) were increased. CBT and ESCIT corrected the behavioral dysfunction in FST and suppressed the high levels of ACTH. Additionally, both treatments boosted OXT level, reduced 5HT1A-R and normalized SERT contents, which reflects increased availability of serotonin. Finally, CBT markedly ameliorated the histopathological damage induced by MS and suppressed the increased glial fibrillary acidic protein. CBT and ESCIT manage depressive-like behavior by positively affecting serotonergic and oxytocinergic systems. Targeting OXT system -using CBT- ameliorated depressive like behaviors induced by maternal separation most probably via enhancing OXT plasma levels, attenuating hormonal ACTH and restoring the expression of hippocampal oxytocin and serotonin mechanisms.

Beneficial effects of benfotiamine, a NADPH oxidase inhibitor, in isoproterenol-induced myocardial infarction in rats.

BACKGROUND: Acute myocardial infarction (AMI) remains the most common cause of morbidity and mortality worldwide. The present study was directed to investigate the beneficial effects of benfotiamine pre- and post-treatments in isoproterenol (ISO)-induced MI in rats. METHODS: Myocardial heart damage was induced by subcutaneous injection of ISO (150 mg/kg) once daily for two consecutive days. Benfotiamine (100 mg/kg/day) was given orally for two weeks before or after ISO treatment. RESULTS: ISO administration revealed significant changes in electrocardiographic recordings, elevation of levels of cardiac enzymes; creatinine kinase (CK-MB) and troponin-I (cTn-I), and perturbation of markers of oxidative stress; nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and glutathione peroxidase (GPx) and markers of inflammation; protein kinase C (PKC), nuclear factor-kappa B (NF-κB) and metalloproteinase-9 (MMP-9). The apoptotic markers (caspase-8 and p53) were also significantly elevated in ISO groups in addition to histological alterations. Groups treated with benfotiamine pre- and post-ISO administration showed significantly decreased cardiac enzymes levels and improved oxidative stress, inflammatory and apoptotic markers compared to the ISO groups. CONCLUSION: The current study highlights the potential role of benfotiamine as a promising agent for prophylactic and therapeutic interventions in myocardial damage in several cardiovascular disorders via NADPH oxidase inhibition.

Tropisetron modulates peripheral and central serotonin/insulin levels via insulin and nuclear factor kappa B/receptor for advanced glycation end products signalling to regulate type-2 diabetes in rats.

Despite its known central effect, 5% of serotonin is found centrally, while around 95% is found peripherally. Serotonin is stored and co-released with insulin upon pancreatic islets stimulation by glucose. This fact raises the curiosity regarding its possible role in diabetes. Hence, in this study, we assessed the possible modulatory effects of tropisetron, a 5-HT3 receptor antagonist, on type 2 diabetes mellitus models in rats. The rats were allocated into two groups: normal and diabetic. The latter group was treated with metformin (500 mg kg-1, p.o.), tropisetron (1 and 2 mg kg-1, i.p.), and a combination of metformin and tropisetron (1 mg kg-1). The different treatment regimens corrected glucose and lipid homeostasis manifested by the decrease in serum levels of glucose, fructosamine, homeostasis model of insulin resistance, triglycerides, total cholesterol, free fatty acid, as well as receptor for advanced glycation end products. Additionally, the treatments elevated levels of insulin, serotonin, and homeostasis model of ß-cell function. On the molecular level, treatments corrected the altered insulin signaling cascade (phosphorylated insulin receptor substrate 1, phosphorylated protein kinase B, and glucose transporter 4), and inhibited ß-catenin and phosphorylated nuclear factor kappa B p65 in the assessed soleus skeletal muscle. A similar pattern was duplicated in the hippocampus. This study provided evidence for the role of tropisetron on type 2 diabetes mellitus via modulating the insulin signaling cascade (insulin, phosphorylated insulin receptor substrate 1, phosphorylated protein kinase B, and glucose transporter 4), improving lipid/glucose profile, decreasing inflammatory markers (receptor for advanced glycation end products, and phosphorylated nuclear factor kappa B p65), as well as increasing 5-HT and reducing ß-catenin.

Impact of ADMA (asymmetric dimethylarginine) on physiology with respect to diabetes mellitus and respiratory system BEAS-2B cells (human bronchial epithelial cells).

OBJECTIVES: Asymmetric dimethylarginine (ADMA) is a non-selective nitric oxide (NO) synthase inhibitor associated with cardiovascular and metabolic disorders. This study aimed to investigate ADMA with respect to both diabetes and respiratory disease. METHODS: Glucose was determined by hexokinase method, insulin by a radioimmunoassay. Griess test was used for NO assay and cytokinines were assayed by ELISA. Ciliary beat frequency was determined by high speed video using a microscope. KEY FINDINGS: ADMA induced an increase in blood glucose and plasma insulin levels in rats; the ratio of these effects indicates the induction of a diabetic situation (insulin resistance). L-arginine increased blood glucose and initially slightly decreased plasma insulin. A pretreatment with ADMA abolished these effects. ADMA shows similar effects in vitro (insulin-secreting cell line, INS-1 cells). L-arginine increased production of NO, which was reversed by ADMA (INS-1 cells). ADMA also reduced NO production positively modulated by various substances, namely metformin, ciglitazone, losartan and nateglinide, but nevertheless inhibited insulin release induced by these compounds. ADMA stimulated the production of cytokines such as interleukin (IL-6) and macrophage inflammatory protein-2 (MIP-2) (rat IL-8 analogue) from INS-1 cells. 5-Aminoimidazole-4-carboxamide-1-ß-4-ribofuranoside (AICAR), a direct adenosine monophosphate protein kinase (AMPK) activator and anti-inflammatory agent, induced NO production and reduced cytokine release. In contrast to diabetes parameters, ADMA had no effect of on the respiratory system (cytokine secretion from BEAS-2B cells (IL-8, regulated on activation, normal T cell expressed and secreted, and tumour necrosis factor-α), ciliary beat frequency and smooth muscle contraction of rat trachea). CONCLUSIONS: ADMA has a pathophysiological impact leading to a diabetic situation but has no impact on the respiratory system.