Mirabegron alleviates acetic acid-induced colitis in rats: Role of adiponectin and GSTM1/GSH detoxification pathway.

The prevalence of the debilitating chronic disease ulcerative colitis (UC) is increasing significantly. Mirabegron is a selective beta-3 adrenergic receptor (ß-3 AR) agonist used to treat an overactive bladder. Previous reports have demonstrated the antidiarrheal effect of ß-3AR agonists. Therefore, the current study aims to investigate the potential symptomatic effects of mirabegron on an experimental colitis model. The effects of oral administration of mirabegron (10 mg/kg) for seven days on rats receiving intra-rectal acetic acid instillation on the sixth day were examined using adult male Wistar rats. Sulfasalazine was utilized as a reference medication. Gross, microscopic, and biochemical observations of the experimental colitis were performed. The quantity and mucin content of goblet cells were found to have significantly decreased in the colitis group. In the colons of rats administered mirabegron, the number of goblet cells and the optical density of its mucin content increased. Mirabegron's ability to increase adiponectin in serum and decrease glutathione, GSTM1, and catalase in the colon may account for its protective effects. In addition, mirabegron decreased the expression of the proteins caspase-3 and NF-κB p65. It also prevented the activation of their upstream signaling receptors TLR4 and p-AKT by acetic acid administration. In conclusion, mirabegron prevented acetic acid-induced colitis in rats, possibly due to its antioxidant, anti-inflammatory, and antiapoptotic properties.

Pregnenolone Inhibits Doxorubicin-Induced Cardiac Oxidative Stress, Inflammation, and Apoptosis-Role of Matrix Metalloproteinase 2 and NADPH Oxidase 1.

The clinical usefulness of doxorubicin (DOX) is limited by its serious adverse effects, such as cardiotoxicity. Pregnenolone demonstrated both anti-inflammatory and antioxidant activity in animal models. The current study aimed to investigate the cardioprotective potential of pregnenolone against DOX-induced cardiotoxicity. After acclimatization, male Wistar rats were randomly grouped into four groups: control (vehicle-treated), pregnenolone (35 mg/kg/d, p.o.), DOX (15 mg/kg, i.p, once), and pregnenolone + DOX. All treatments continued for seven consecutive days except DOX, which was administered once on day 5. The heart and serum samples were harvested one day after the last treatment for further assays. Pregnenolone ameliorated the DOX-induced increase in markers of cardiotoxicity, namely, histopathological changes and elevated serum levels of creatine kinase-MB and lactate dehydrogenase. Moreover, pregnenolone prevented DOX-induced oxidative changes (significantly lowered cardiac malondialdehyde, total nitrite/nitrate, and NADPH oxidase 1, and elevated reduced glutathione), tissue remodeling (significantly decreased matrix metalloproteinase 2), inflammation (significantly decreased tumor necrosis factor-α and interleukin 6), and proapoptotic changes (significantly lowered cleaved caspase-3). In conclusion, these findings show the cardioprotective effects of pregnenolone in DOX-treated rats. The cardioprotection achieved by pregnenolone treatment can be attributed to its antioxidant, anti-inflammatory, and antiapoptotic actions.

Stem cells therapeutic effect in a reserpine-induced fibromyalgia rat model: A possible NLRP3 inflammasome modulation with neurogenesis promotion in the cerebral cortex.

Fibromyalgia is a chronic pain syndrome with a multifactorial pathophysiology affecting 2-8 % of the population. AIMS: To investigate the therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) against fibromyalgia-related cerebral cortex damage and the possible underlying mechanisms of action. MATERIALS AND METHODS: Rats were randomly allocated into three groups; control, fibromyalgia and fibromyalgia treated with BMSCs groups. Physical and behavioural assessments were performed. Cerebral cortices were collected for biochemical and histological assessment. KEY FINDINGS: Fibromyalgia group showed behavioural changes indicating presence of pain, fatigue, depression, and sleep disturbances. Moreover, biochemical biomarkers alterations were demonstrated by a significant decrease in brain monoamines and GSH levels, but MDA, NO, TNF-alpha, HMGB-1, NLRP3, and caspase-1 levels significantly increased. Furthermore, histological assessment revealed structural and ultrastructural alterations indicating neuronal and neuroglial degeneration with microglia activation, an increase in mast cell number and IL-1ß immune-expression. Additionally, a significant decrease in Beclin-1 immune-expression, and blood brain barrier disruption were noticed. Interestingly, BMSCs administration significantly improved behavioural alterations, restored the reduced brain monoamines and oxidative stress markers, and reduced TNF-alpha, HMGB-1, NLRP3, and caspase-1 levels. Profoundly, cerebral cortices demonstrated improved histological structure, significant decrease in mast cell number and IL-1ß immune-expression, besides a significant increase in Beclin-1 and DCX immune-expression. SIGNIFICANCE: For the best of our knowledge, this is the first study showing ameliorative effects for BMSCs treatment in fibromyalgia-related cerebral cortical damage. The neurotherapeutic effects of BMSCs could be attributed to NLRP3 inflammasome signaling pathway inhibition, mast cell deactivation, and stimulation of neurogenesis and autophagy.

Testicular cytoprotective effect of glucagon like peptide-1 in diabetic rats involves inhibition of apoptosis, endoplasmic reticulum stress and activation of autophagy.

This study aimed to explore the possible cytoprotective effects of exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in the testicles of diabetic rats. Exenatide has numerous advantageous properties in addition to its hypoglycemic effect. However, its impact on testicular tissue in diabetes needs more clarification. Therefore, rats were divided into control, exenatide-treated, diabetic and exenatide-treated diabetic groups. Blood glucose and serum levels of insulin, testosterone, pituitary gonadotropins and kisspeptin-1 were measured. Real-time PCR for beclin-1, p62, mammalian target of rapamycin (mTOR), and AMP-activated protein kinase (AMPK), were estimated in testicular tissue in addition to markers of oxidative stress, inflammation, and endoplasmic reticulum stress. Also, immuno-expression of protein P53, nuclear erythroid factor2 (Nrf2) and vimentin was conducted. Exenatide was able to attenuate diabetic toxic changes and enhance autophagy in testicular tissue. These results indicate the protective effect of exenatide against diabetic testicular dysfunction.

Administration of hemin ameliorates ovarian ischemia reperfusion injury via modulation of heme oxygenase-1 and p-JNK/p-NF-κBp65/iNOS signaling pathway.

AIMS: Ovarian torsion is the fifth common gynecological emergency that can affect females of all ages particularly during reproductive age and its management by detorsion leads to ovarian ischemia reperfusion (IR) injury. Therefore, prophylactic measures are required to protect the ovarian function after detorsion. So that, our study aimed to assess the effect and underlying mechanisms of heme oxygenase-1 (HO-1) inducer; hemin against ovarian damage induced by IR injury in rats. MAIN METHODS: Female rats were divided into: sham group, hemin group, ovarian IR (OIR) groups with and without hemin treatment. Serum levels of reduced glutathione (GSH) and interleukin 1 ß (IL-1ß) were measured in addition to ovarian levels of malondialdehyde (MDA), nitric oxide (NO) and superoxide dismutase (SOD). Ovarian phospho-Janus kinase (p-JNK) levels and gene expressions of HO-1 and inducible nitric oxide synthase (iNOS) were determined. Moreover, histopathological changes and expressions of phospho-nuclear factor kappa B p65 (p-NF-κB p65) and cleaved caspase-3 were done. KEY FINDINGS: Treatment of OIR rats with hemin led to significant attenuation of ovarian damage through histological examination which was associated with significant increase in ovarian expression of HO-1, ovarian SOD and serum GSH levels with significant decrease in ovarian p-JNK levels, expressions of p-NF-κB p65, iNOS and cleaved caspase-3 in addition to serum IL-1ß levels. SIGNIFICANCE: The protective effect of hemin can be attributed to the increased expression of HO-1 which showed antioxidant, anti-inflammatory and anti-apoptotic effects. Therefore, hemin can be administered to prevent ovarian IR injury which occurs after detorsion.