Liraglutide and Naringenin relieve depressive symptoms in mice by enhancing Neurogenesis and reducing inflammation.

Depression is a debilitating mental disease that negatively impacts individuals' lives and society. Novel hypotheses have been recently proposed to improve our understanding of depression pathogenesis. Impaired neuroplasticity and upregulated neuro-inflammation add-on to the disturbance in monoamine neurotransmitters and therefore require novel anti-depressants to target them simultaneously. Recent reports demonstrate the antidepressant effect of the anti-diabetic drug liraglutide. Similarly, the natural flavonoid naringenin has shown both anti-diabetic and anti-depressant effects. However, the neuro-pharmacological mechanisms underlying their actions remain understudied. The study aims to evaluate the antidepressant effects and neuroprotective mechanisms of liraglutide, naringenin or a combination of both. Depression was induced in mice by administering dexamethasone (32 mcg/kg) for seven consecutive days. Liraglutide (200 mcg/kg), naringenin (50 mg/kg) and a combination of both were administered either simultaneously or after induction of depression for twenty-eight days. Behavioral and molecular assays were used to assess the progression of depressive symptoms and biomarkers. Liraglutide and naringenin alone or in combination alleviated the depressive behavior in mice, manifested by decrease in anxiety, anhedonia, and despair. Mechanistically, liraglutide and naringenin improved neurogenesis, decreased neuroinflammation and comparably restored the monoamines levels to that of the reference drug escitalopram. The drugs protected mice from developing depression when given simultaneously with dexamethasone. Collectively, the results highlight the usability of liraglutide and naringenin in the treatment of depression in mice and emphasize the different pathways that contribute to the pathogenesis of depression.

Portulaca oleracea L. (purslane) improves the anti-inflammatory, antioxidant and autophagic actions of metformin in the hippocampus of diabetic demented rats.

Great body of evidence links cognitive decline to diabetes/insulin resistance. In this study the effect of Portulaca oleracea (PUR) (100 mg/kg), Metformin (MET) (200 mg/kg), a first line diabetes mellitus type 2 therapy, and their combination on cognitive function and hippocampal markers in diabetic rats were assessed. Male rats were injected with streptozotocin (30 mg/kg on two successive weeks) followed by 4 weeks of treatment. Possible antioxidant, anti-inflammatory, and autophagy enhancing mechanisms of these drugs were investigated in the hippocampal tissue using spectrophotometry, ELISA, and western blotting. Diabetic rats suffered significant cognitive impairment in Morris's water maze, hippocampal TBARS elevation, GSH depletion, and SOD upregulation. In addition, diabetes promoted the secretion of hippocampal inflammatory cytokines, TNF-α and IL-1ß, and depleted anti-inflammatory cytokines as IL-10. Such detrimental changes were reversed by MET and/or PUR. Notably, AMPK was upregulated by diabetes, then restored to normal by MET and/or PUR. The pattern of change in AMPK expression was concomitant with changes in oxidative and inflammatory burden. Hence, AMPK is believed to be a key mediator in most of the measured pre-AD markers in this study. However, from our results, PUR is believed to have non-AMPK dependent actions as well. In conclusion, antidiabetic agents as metformin and purslane extract proved to be invaluable in addressing the cognitive decline and hippocampal changes that arise as a complication of diabetes. They mainly acted through AMPK pathway; however, their usefulness was not limited to AMPK pathways since their combination was suggested to have a different mechanism.

Inclusion of Nitrofurantoin into the Realm of Cancer Chemotherapy via Biology-Oriented Synthesis and Drug Repurposing.

Structural modifications of the antibacterial drug nitrofurantoin were envisioned, employing drug repurposing and biology-oriented drug synthesis, to serve as possible anticancer agents. Eleven compounds showed superior safety in non-cancerous human cells. Their antitumor efficacy was assessed on colorectal, breast, cervical, and liver cancer cells. Three compounds induced oxidative DNA damage in cancer cells with subsequent cellular apoptosis. They also upregulated the expression of Bax while downregulated that of Bcl-2 along with activating caspase 3/7. The DNA damage induced by these compounds, demonstrated by pATM nuclear shuttling, was comparable in both MCF7 and MDA-MB-231 (p53 mutant) cell lines. Mechanistic studies confirmed the dependence of these compounds on p53-mediated pathways as they suppressed the p53-MDM2 interaction. Indeed, exposure of radiosensitive prostatic cancer cells to low non-cytotoxic concentrations of compound 1 enhanced the cytotoxic response to radiation indicating a possible synergistic effect. In vivo antitumor activity was verified in an MCF7-xenograft animal model.

Synthesis, anti-inflammatory screening, molecular docking, and COX-1,2/-5-LOX inhibition profile of some novel quinoline derivatives.

New quinoline compounds comprising pyrazole scaffold through different amide linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory activity. Eight compounds (5c, 11b,c, 12c, 14a,b, 20a and 21a) were found to exhibit promising anti-inflammatory profiles in acute and sub-acute inflammatory models. They were screened for their ulcerogenic activity and none of them showed significant ulcerogenic activity comparable to the reference drug celecoxib and are well tolerated by experimental animals with high safety margin (ALD50 > 0.3 g/kg). Compounds 5c, 11b,c, 12c, 14a,b, 20a and 21a showed significant in vitro LOX inhibitory activity higher than that of zileuton. In vitro COX-1/COX-2 inhibition study revealed that compounds 12c, 14a,b and 20a showed higher selectivity towards COX-2 than COX-1. Among the tested compounds, 12c, 14a and 14b showed the highest inhibitory activity against COX-2 with an IC50 values of 0.1, 0.11 and 0.11 µM respectively. The docking experiments attempted to postulate the binding mode for the most active compounds in the binding site of COX-2 enzymes and confirmed the high selectivity binding towards COX-2 enzyme over COX-1.