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.

Association Between Vitamin D Level and Z-Score Changes of Bone Density in College-Age Saudi Girls: A Cross-Sectional Study.

Objective: Vitamin D (VD) deficiency is a worldwide health problem. VD plays a crucial role in calcium homeostasis, phosphorus metabolism and bone health. Still much remain to understand the effect of VD deficiency on bone mass. This study aimed to evaluate the relationship between VD levels and bone mass density (BMD) among college-age Saudi females. Methods: In a cross-sectional study, 460 females with a median age of 21 years, were enrolled, completed a comprehensive, structured questionnaire which was validated by experienced endocrinologist, a dietician, and a statistician. Body mass indexes (BMI) were calculated, and BMD was estimated through quantitative ultrasound to ankle. Serum VD, calcium, phosphate, parathyroid hormone, and alkaline phosphatase were measured using chemiluminescent immunoassay technique. Results: VD deficiency reached up to 83.3% (66.9% insufficiency and 16.4% deficiency). Lower than normal BMD was detected in 18.3% of subjects, with only 1.1% having a non-age-matched high risk for osteoporosis. The significant independent predictors of Z-score were age of menarche, menstrual irregularities, dairy products consumption, physical activity, BMI, alkaline phosphatase, and history of previous VD supplementation. Conclusion: VD deficiency and low BMD are highly prevalent among college-age Saudi females. Low BMD is not linked to serum level of VD but to its previous use as a supplementation. Early lifestyle changes, attention to gynecological problems, and prevention of VD deficiency are all needed to support BMD among these girls.

Liraglutide ameliorates diabetic-induced testicular dysfunction in male rats: role of GLP-1/Kiss1/GnRH and TGF-ß/Smad signaling pathways.

Introduction: Glucagon-like peptide -1 (GLP-1) is released by intestinal cells to stimulate glucose-dependent insulin release from the pancreas. GLP-1 has been linked to ameliorating obesity and/or diabetic complications as well as controlling reproductive function. Liraglutide is a GLP-1 receptor agonist (GLP-1RA) with 97% homology with GLP-1. The main objective of this study was to investigate the ameliorative role of liraglutide in diabetic-induced reproductive dysfunction in male rats. Methods: Rats were randomly allocated into 3 groups; a control group, a diabetic group, and a liraglutide-treated diabetic group. Results: In the diabetic group, a significant increase in BMI, FBG, HbA1c, HOMA-IR, TC, TAG, LDL, IL6, TNFα, and MDA, as well as decreased serum insulin, HDL, GSH, total testosterone, LH, and FSH, were shown compared to the control group. Furthermore, A significant downregulation in relative hypothalamic gene expression of GLP-1R, PPAR-α, PGC-1α, kiss, kiss1R, leptin, leptin R, GnRH GLP-1R, testicular PGC-1α, PPARα, kiss1, kiss1R, STAR, CYP17A1, HSD17B3, CYP19A, CYP11A1, and Smad7, as well as upregulation in hypothalamic GnIH and testicular TGF- ß and Smad2 expression, were noticed compared to the control group. Liraglutide treatment significantly improved such functional and structural reproductive disturbance in diabetic rats. Conclusion: GLP-1RAs ameliorated the deleterious effects of diabetes on reproductive function by targeting GLP-1/leptin/kiss1/GnRH, steroidogenesis, and TGF- ß/Smad pathways.

Aleppo galls alleviate paracetamol-induced hepatotoxicity and tissue damage: an experimental study.

BACKGROUND: Acute paracetamol toxicity is a common and potentially life-threatening emergency causing liver failure that may necessitate liver transplantation. Unfortunately, current therapies are still defective. OBJECTIVES: To investigate the protective effects exerted by Aleppo galls (Quercus infectoria Olivier) extract against acute paracetamol toxicity in mice. METHODOLOGY: Eighteen mice were divided into three experimental groups, each included six mice in each group. The groups included: negative control group, paracetamol toxicity group that received an acute toxic intraperitoneal dose of paracetamol (250 mg/kg) for four consecutive days, and treatment group (received 250 mg/kg paracetamol followed few hours later by Aleppo galls extract for the same duration). Animals were anaesthetized using ether anaesthesia. Animals were sacrificed by decapitation and blood samples were drawn. Paracetamol toxicity effects versus Aleppo galls protection were evaluated on liver function tests, liver histology, serum cholesterol and serum triglycerides. RESULTS: Acute paracetamol toxicity caused significantly elevated serum transaminases (ALT and AST), decreased serum albumin, and increased serum cholesterol and triglycerides. Aleppo galls extract exerted significant protective effects and restored near normal serum levels of the previously-mentioned parameters. Upon histopathological evaluation, mice in the control group showed normal hepatic architecture with preserved hepatic cords and sinuses. Acute paracetamol toxicity induced peripheral zonal degeneration with focal necrosis of the hepatic tissue. The hepatocytes showed cytoplasmic vacuolation with indistinct cell borders. Central hepatic venules were congested. Administration of Aleppo galls extract reduced the tissue damaging effects induced by paracetamol toxicity with only minimal residual degenerative changes that were observed with absent necrosis. CONCLUSION: Quercus infectoria Olivier (Aleppo galls) is a promising source of phytochemicals and future therapeutics.

Effect of voluntary running on expression of myokines in brains of rats with depression.

This study aimed to demonstrate the histopathology and immunoexpression of exercise-derived myokines in dentate gyrus (DG), medial prefrontal cortex (mPFC) and cerebellum of depressed Wistar rats during depression and after practising voluntary running. Depression was developed by forced swimming for 2 weeks. Voluntary running was performed by voluntary running for 3 weeks. Brain sections were processed and immunostained to detect brain-derived neurotrophic factor (BDNF), macrophage migration inhibitory factor (MIF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). ImageJ software was used to measure the optical density (OD). BDNF was expressed in neurons in DG, mPFC and granular and Purkinje cells in cerebellum. MIF was expressed in neurons of sub-granular zone in DG, mPFC and Purkinje cells. VEGF was expressed in many neurons in DG, mPFC and Purkinje cells. IL-6 was expressed in some neurons in DG, in neuropil of mPFC and in Purkinje cells. In depression, the OD of studied myokines significantly decreased in all examined areas. After voluntary running, the OD of myokines significantly increased in all areas. This study defines the immunohistochemical expression of myokines in brain areas in depression and after voluntary running and reveals the involvement of the mPFC and cerebellum in the pathophysiology of depression.

Voluntary running improves depressive behaviours and the structure of the hippocampus in rats: A possible impact of myokines.

This study investigated the impact of voluntary exercise on depressive behaviours, serum and hippocampal levels of myokines, and histopathological features of hippocampal formation in rats. Depressed rats were allowed to voluntarily run on a wheel for 3weeks. Locomotor activity was assessed by a forced swimming test and the myokine levels in sera and hippocampal homogenates were measured using Enzyme-linked Immunosorbent Assay. Brain sections were analysed for hippocampal structure and neuronal counts. Voluntary running produced significant increase in the distance moved by rats and significant decrease in immobility duration. After voluntary running, there were significant increases in serum and hippocampal brain-derived neurotrophic factor (BDNF) and macrophage migration inhibitory factor (MIF), significant increase in hippocampal vascular endothelial growth factor (VEGF), and significant decrease in serum interleukin-6 (IL-6). Significant correlation was detected between the serum levels of BDNF and MIF (r=0.276) as well as IL-6 (r=-0.340). In addition, significant correlation was observed between hippocampal BDNF levels and MIF (r=0.500) and VEGF levels (r=0.279). After voluntary running, there was significant decrease in number degenerated neurons in hippocampal areas and significant increase in number of healthy neurons in the upper limb of the dentate gyrus, but not in its lower limb, compared to depression group. This study showed the relation of myokines to the development and/or relief of depression, as well as the correlation between serum and hippocampal myokine levels. Attention should be paid to studying the biological effects of myokines on different hippocampal areas that could respond differently to treatments.