Bone marrow mesenchymal stem cells expressing Neat-1, Hotair-1, miR-21, miR-644, and miR-144 subsided cyclophosphamide-induced ovarian insufficiency by remodeling the IGF-1-kisspeptin system, ovarian apoptosis, and angiogenesis.

Ovarian insufficiency is one of the common reproductive disorders affecting women with limited therapeutic aids. Mesenchymal stem cells have been investigated in such disorders before yet, the exact mechanism of MSCs in ovarian regeneration regarding their epigenetic regulation remains elusive. The current study is to investigate the role of the bone marrow-derived mesenchymal stem cells (BM-MSCs) lncRNA (Neat-1 and Hotair1) and miRNA (mir-21-5p, mir-144-5p, and mir-664-5p) in mitigating ovarian granulosa cell apoptosis as well as searching BM-MSCs in altering the expression of ovarian and hypothalamic IGF-1 - kisspeptin system in connection to HPG axis in a cyclophosphamide-induced ovarian failure rat model. Sixty mature female Sprague Dawley rats were divided into 3 equal groups; control group, premature ovarian insufficiency (POI) group, and POI + BM-MSCs. POI female rat model was established with cyclophosphamide. The result revealed that BM-MSCs and their conditioned media displayed a significant expression level of Neat-1, Hotair-1, mir-21-5p, mir-144-5p, and mir-664-5p. Moreover, BM-MSCs transplantation in POI rats improves; the ovarian and hypothalamic IGF-1 - kisspeptin, HPG axis, ovarian granulosa cell apoptosis, steroidogenesis, angiogenesis, energy balance, and oxidative stress. BM-MSCs expressed higher levels of antiapoptotic lncRNAs and microRNAs that mitigate ovarian insufficiency.

The corrective role of superparamagnetic iron oxide nanoparticles for the genes controlling hypothalamus-pituitary-testis-axis in male obesity-associated secondary hypogonadism.

Background: Obesity is one of the most prevalent and perilous health affairs. Male obesity-associated secondary hypogonadism (MOSH) is one of many of its complexities, which is mounting in parallel with the aggravation of obesity. Magnetic nanoparticles seem to be an advanced favorable trend in multiple biomedical fields. Aim: In this study, we explore the therapeutic effects of superparamagnetic iron oxide nanoparticles (SPIONs) coated with carboxymethyl cellulose (CMC) on an obese male rat model with MOSH syndrome, comparing their impacts with a well-known anti-obesity medication (Orlistat). Methods: 42 male albino rats split into 7 equal groups: 1-negative control: nonobese, untreated; 35 rats fed the high fat-high fructose (HFHF) diet for a period of 12 weeks. Obese rats splitted into 6 equal groups; 2-positive control: obese untreated; 3-obese given Orlistat (30 mg/kg); 4-obese given CMC-SPIONs (25 mgFe/kg); 5-obese given CMC-SPIONs (50 mgFe/kg); 6-obese given CMC-SPIONs(25 mgFe/kg) + Orlistat (30 mg/kg), 7-obese given CMC-SPIONs (50 mgFe/kg) + Orlistat (30 mg/kg); all treatments given orally for 4 weeks. During sacrifice, blood serum and sectioned hypothalamic, pituitary, testicular, and adipose tissues were collected for biochemical and biomolecular assessments. Results: The HFHF diet for 12 weeks resulted in a significant upsurge in body weight, body mass index, serum fasting glucose, insulin resistance, TAG, total cholesterol, and LDL-c; HDL-c was dropped. Serum FSH, LH, and testosterone values declined. A significant disorder in expression levels of genes regulating the hypothalamic-pituitary-testicular-axis pathway. Hypothalamic GnRH, Kisspeptin-1, Kisspeptin-r1, and Adipo-R1 values declined. GnIH and Leptin-R1 values raised up. Pituitary GnRH-R values declined. Testicular tissue STAR, HSD17B3, and CYP19A1 values declined. Adipose tissue adiponectin declined, while leptin raised up. CMC-SPIONs 25-50 mg could modulate the deranged biochemical parameters and correct the deranged expression levels of all previous genes. Co-treatments revealed highly synergistic effects on all parameters. Overall, CMC-SPIONs have significant efficiency whether alone or with Orlisat in limiting obesity and consequence subfertility. Conclusion: CMC-SPIONs act as an incoming promising contender for obesity and MOSH disorders management, and need more studies on their mechanisms.

Lipid nanoparticles of quercetin (QU-Lip) alleviated pancreatic microenvironment in diabetic male rats: The interplay between oxidative stress - unfolded protein response (UPR) - autophagy, and their regulatory miRNA.

BACKGROUND: Autophagy is a well-preserved mechanism essential in minimizing endoplasmic reticulum stress (ER)-related cell death. Defects in ß-cell autophagy have been linked to type 1 diabetes, particularly deficits in the secretion of insulin, boosting ER stress sensitivity and possibly promoting pancreatic ß-cell death. Quercetin (QU) is a potent antioxidant and anti-diabetic flavonoid with low bioavailability, and the precise mechanism of its anti-diabetic activity is still unknown. Aim This study aimed to design an improved bioavailable form of QU (liposomes) and examine the impact of its treatment on the alleviation of type 1 diabetes induced by STZ in rats. METHODS: Seventy SD rats were allocated into seven equal groups 10 rats of each: control, STZ, STZ + 3-MA, STZ + QU-Lip, and STZ + 3-MA + QU-Lip. Fasting blood glucose, insulin, c-peptide, serum IL-6, TNF-α, pancreatic oxidative stress, TRAF-6, autophagy, endoplasmic reticulum stress (ER stress) markers expression and their regulatory microRNA (miRNA) were performed. As well as, docking analysis for the quercetin, ER stress, and autophagy were done. Finally, the histopathological and immunohistochemical analysis were conducted. SIGNIFICANCE: QU-Lip significantly decreased glucose levels, oxidative, and inflammatory markers in the pancreas. It also significantly downregulated the expression of ER stress and upregulated autophagic-related markers. Furthermore, QU-Lip significantly ameliorated the expression of several MicroRNAs, which both control autophagy and ER stress signaling pathways. However, the improvement of STZ-diabetic rats was abolished upon combination with an autophagy inhibitor (3-MA). The findings suggest that QU-Lip has therapeutic promise in treating type 1 diabetes by modulating ER stress and autophagy via an epigenetic mechanism.

Effect of Selenium Nanoparticles and/or Bee Venom against STZ-Induced Diabetic Cardiomyopathy and Nephropathy.

The main purpose of our study was to examine the role of selenium nanoparticles (SeNPs) and/or bee venom (BV) in ameliorating diabetic cardiomyopathy (DCM) and nephropathy (DN) at the biochemical, histopathological and molecular levels. Fifty male albino rats were used in this experiment, divided into five groups: control, Streptozocin (STZ) diabetic, STZ-diabetic treated with SeNPs, STZ-diabetic treated with BV, and STZ-diabetic treated with SeNPs and BV. Biochemically, STZ injection resulted in a significant increase in serum glucose, BUN, creatinine, CRP, CK-MB, AST, LDH and cardiac troponins with a significant decrease in the serum insulin and albumin concentrations. Histopathologically, STZ injection resulted in diabetes, as revealed by glomerulonephritis, perivascular hemorrhage, inflammatory cell infiltrations and fibrosis, with widening of interstitial spaces of cardiomyocytes, loss of muscle cells continuity and some hyaline degeneration. At the molecular levels, the expression levels of miRNA 328, miRNA-21, TGFß1, TGFß1R, JAK1, STST-3, SMAD-1 and NFκß genes were significantly up-regulated, whereas the expression levels of SMAD-7 were significantly down-regulated. It is concluded that SeNPs and/or BV administration ameliorates the deleterious effects resulting from STZ administration through improving the biochemical, histopathological and molecular effects, suggesting their protective role against the long-term diabetic complications of DCM and DN.

ß-Cell Autophagy Pathway and Endoplasmic Reticulum Stress Regulating-Role of Liposomal Curcumin in Experimental Diabetes Mellitus: A Molecular and Morphometric Study.

Background: Autophagy can confer protection to pancreatic ß-cells from the harmful effects of metabolic stress by delaying apoptosis. Curcumin (CUR) alleviates oxidative and endoplasmic reticulum (ER) stress, activates autophagy, reduces inflammation, and decreases ß-cell damage in type I diabetes. Liposomal CUR (LPs-CUR) has a higher therapeutic value and better pharmacokinetics than CUR. Objectives: We determined LPs-CUR's ability to alleviate stress, reduce ß-cell damage and unraveled the mechanism underlying its protective effect using a streptozotocin (STZ)-induced type I diabetic rat model. Methods: Sprague−Dawley rats were grouped into vehicle control, STZ-diabetic (STZ 65 mg/kg), STZ-diabetic-3-MA (3-methyladenine [3-MA] 10 mg/kg b.wt), STZ. diabetic-LPs-CUR (LPs-CUR 10 mg/kg b.wt), and STZ diabetic-LPs-CUR-3-MA (LPs-CUR 10 mg/kg b.wt; 3-MA 10 mg/kg b.wt). Results: LPs-CUR significantly reduced blood glucose, oxidative stress, and cellular inflammation in the pancreatic tissue (p < 0.001). ER stress-dependent genes included ATF-6, eIF-2, CHOP, JNK, BiP, and XBP LPs-CUR significantly suppressed fold changes, while it upregulated the autophagic markers Beclin-1 and LC3-II. Conclusions: LP-CUR ameliorates ß-cell damage by targeting the autophagy pathway with the regulatory miRNAs miR-137 and miR-29b, which functionally abrogates ER stress in ß-cells. This study presents a new therapeutic target for managing type I diabetes using miR-137 and miR-29b.

Transplantation of adipose-derived mesenchymal stem cells ameliorates acute hepatic injury caused by nonsteroidal anti-inflammatory drug diclofenac sodium in female rats.

BACKGROUND: Although the beneficial role of adipose-derived mesenchymal stem cells (AD-MSCs) in acute liver injury has been addressed by numerous studies employing different liver injury inducers, the role of rat AD-MSCs (rAD-MSCs) in diclofenac sodium (DIC) - induced acute liver injury has not yet been clarified. OBJECTIVE: This study aimed to investigate whether rat adipose- rAD-MSCs injected intraperitoneal could restore the DIC-induced hepatoxicity. METHODS: Hepatotoxicity was induced by DIC in a dose-based manner, after which intraperitoneal injection of rAD-MSCs was performed. RESULTS: Here, the transplanted cells migrated to the injured liver, and this was evidenced by detecting the specific SRY in the liver samples. After administering DIC, a significant decrease in body weight, survival rate, serum proteins, antioxidants, anti-apoptotic gene expression, and certain growth factors, whereas hepatic-specific markers, pro-inflammatory mediators, and oxidative, pro-apoptotic, and ER-stress markers were elevated. These adverse effects were significantly recovered after engraftment with rAD-MSCs. This was evidenced by enhanced survival and body weight, improved globulin and albumin values, increased expression of SOD, GPx, BCL-2, VEGF, and FGF-basic expression, and decreased serum ALT, AST, ALP, and total bilirubin. rAD-MSCs also reduced liver cell damage by suppressing the expression of MDA, IL-1B, IL-6, BAX, JNK, GRP78/BiP, CHOP, XBP-1, and cleaved caspase 3/7. Degenerative hepatic changes and multifocal areas of fatty change within liver cells were observed in DIC-received groups. These changes were improved with the transplantation of rAD-MSCs. CONCLUSIONS: We could conclude that targeted AD-MSCs could be applied to reduce hepatic toxicity caused by NSAIDs (DIC).