Exploring the molecular mechanisms of MSC-derived exosomes in Alzheimer's disease : Autophagy, insulin and the PI3K/Akt/mTOR signaling pathway

The authors thank you for acknowledging technical and financial support from the Ministry of Education and the University of Hafr Al Batin, Saudi Arabia. The authors gratefully acknowledge all mothers’ volunteers in the community around the Faculty of Agriculture, Benha University, for their cooperationPeer reviewe

Human mesenchymal stem cell-derived extracellular vesicles/estrogen combined therapy safely ameliorates experimentally induced intrauterine adhesions in a female rat model

Abstract Background Mesenchymal stem cells (MSCs) have diverse functions in regulating injury and inflammation through the secretion of extracellular vesicles (EVs). Methods In this study, we investigated the systemic administration of extracellular vesicles derived from human umbilical cord mesenchymal stem cells (UCMSCs-EVs) as a therapeutic agent for intrauterine adhesions (IUAs) caused by endometrial injury. Additionally, we investigated the therapeutic impact of both UCMSCs-EVs and estrogen either separately or in combination in a rat model. The inflammation, vascularization, proliferation, and extent of fibrosis were assessed by a histopathological and immunohistochemical assessment using transforming growth factor (TGF)-β as a fibrotic marker and vascular endothelial growth factor (VEGF) as a vascular marker. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6 (inflammatory cytokines), CD140b (a marker of endometrial stem cells), and RUNX2 (an antifibrotic factor). Finally, Western blotting was used to evaluate collagen I and β-actin expression. Results The therapeutic groups treated with either UCMSCs-EVs alone or combined with estrogen exhibited a significant decrease in inflammation and fibrosis (TNF-α, TGF-β, IL-1, IL-6, RUNX2, and collagen-I) as well as a significant decrease in vascularization (VEGF) compared with the untreated rats with IUAs. The most significant results were obtained in animals with IUAs that received a combined therapy of UCMSCs-EVs and estrogen. Conclusions We conclude that the synergistic action of human UCMSCs-EVs combined with estrogen provides a highly effective alternative regenerative agent in IUA treatment

Therapeutic Potential of Bone Marrow Derived Mesenchymal Stem Cells in Modulating Astroglyosis of Surgical Induced Experimental Spinal Cord Injury

Background: Spinal cord injury (SCI) unsuccessful regeneration was due to glial scar development. It was a major obstacle to axonal restoration. Safe therapeutic intervention by the use of bone marrow derived stem cells (BMMSCs) transplantation applied in the present study could reduce spinal disability. Material and methods: Forty male albino rats were divided into four groups: GI: negative control (n = 10 rats); GII: positive control after SCI (n = 10 rats); GIII: SCI + BM − MSCs intravenous injected and GIV: SCI + BM − MSCs intra lesion injected (n = 10 rats in each group). The samples were taken from spinal cord tissues around the region of injury and were subjected to histological, immunohistochemical assessment. RNA extraction and real time PCR for detection of nerve regeneration and astrocyte response to the injury were also performed. Results: Clinical improvement occurred by the enhancement in the Basso, Beattie and Bresnahan (BBB) score after SCI. Histological examinations showed positive regenerative responses in GIV compared to GIII. Conclusion: BM-MSCs transplantation has a promising role in enhancing the microenvironment for nerve regeneration through stumbling the glial scaring formation and inflammatory response af- ter chronic spinal cord injury especially by using intra-lesion route injection

Oral Administration of Thymoquinone Attenuates Diazinon-induced Renal Injury in Rat: The Involvement of Keap1/Nrf2/HO1/NQO Signaling Pathway

The most prevalent component of the volatile oil found in Nigella sativa seeds is thymoquinone (TQ). As well as being used as food supplements, the seeds and oil are also utilized in traditional medicine to treat a variety of ailments. The purpose of this investigation was to determine whether TQ could protect rats from acute nephrotoxicity caused by diazinon (DZN). Six equal groups of thirty six adult’s male Wistar rats were created at random. Group 1 (G1) was maintained in typical control circumstances and given saline daily intragastric (IG) for 4 weeks; G2 was administered 0.1 mL olive oil IG for 4 weeks; G3 was administered 0.1 mL DMSO IG for 4 weeks; G4 was administered IG TQ at a dose of 10 mg/kg B.W. daily for 4 weeks; G5 was administered IG DZN at a dose of 15 mg/kg B.W. daily for 4 weeks; G6 was administered IG TQ daily one hour before DZN at the same dose in G4 and G5 for 4 weeks. The findings shown that TQ reduces the renal dysfunctions brought on by DZN by restoring urea and creatinine levels as well as oxidative indicators. Although the expression of Keap-1 was also elevated, overexpression of Nrf2 also enhanced the expression of heme oxygenase-1 (HO-1), and NFκB in renal tissue. Also, TQ increased antiapoptotic (BCL2) factors and decrease proapoptotic (BAX) factors. As a result, it is hypothesized that TQ may be helpful in the prevention and management of acute nephrotoxicity brought on by DZN

Nephroprotective Effect of N-Acetyl-L-Cysteine against Diazinon-induced Nephrotoxicity in Rats via IKβ, NFκB, NLRP3 Signaling Pathway

The present study analyzes the efficacy of N-acetyl cysteine (NAC) against diazinon (DZN)-induced nephrotoxicity in male Wistar rats. Rats were divided into five groups with six animals in each group: Group 1 (G1) was maintained in typical control circumstances and given saline once daily intragastric (IG) for 4 weeks; G2 was administered 0.1 mL olive oil IG for 4 weeks; G3 was administered IG NAC 150 mg/kg daily as an aqueous solution for 4 weeks; G4 was administered IG diazinon at a dose of 15 mg/kg daily for 4 weeks; and G5 was administered IG NAC daily one hour before diazinon at the same dose in G3 and G4 for 4 weeks. Sub-chronic exposure to DZN impairs the kidney structure and function, as evidenced by the histopathology, immunohistochemistry, and gene expression of NLRP3, NFκB, IKB, BCL2, BAX mRNA. Our findings showed that NAC reduces the renal dysfunctions induced by DZN by restoring urea and creatinine levels as well as oxidative indicators. Moreover, serum inflammatory markers (IL-1β and TNF-α) concentrations were ameliorated by NAC treatment. However, NAC has shown to play a beneficial role against nephrotoxicity by reversing the cytoarchitecture and downregulation of inflammatory (NLRP3, NFκB, IKB) and apoptotic (BAX) as well as upregulated BCL2 genes and proteins in kidney tissues, bringing them to near-normal levels. Moreover, IHC examination of renal tissue revealed the attenuation of expression of TNF-α. Therefore, NAC could be potentially used to protect the kidneys from pathological changes induced by DZN

Mesenchymal Stem Cell-Derived Exosomes Ameliorated Diabetic Nephropathy by Autophagy Induction through the mTOR Signaling Pathway

Background: Diabetic nephropathy (DN) is a serious complication of diabetes mellitus and a common cause of end-stage renal disease. Autophagy has a defensive role against kidney damage caused by hyperglycemia. Mesenchymal stem cell (MSC)-derived exosomes are currently considered as a new promising therapy for chronic renal injury. However, the renal-protective mechanism of exosomes on DN is not completely understood. We examined the potential role of MSC-derived exosomes for enhancement of autophagy activity and their effect on DN. In our study, we used five groups of rats: control; DN; DN treated with exosomes; DN treated with 3-methyladenine (3-MA) and chloroquine (inhibitors of autophagy); and DN treated with 3-methyladenine (3-MA), chloroquine, and exosome groups. We assessed renal function, morphology, and fibrosis. Moreover, ratios of the autophagy markers mechanistic target of rapamycin (mTOR), Beclin-1, light chain-3 (LC3-II), and LC3-II/LC3-I were detected. Additionally, electron microscopy was used for detection of autophagosomes. Results: Exosomes markedly improved renal function and showed histological restoration of renal tissues, with significant increase of LC3 and Beclin-1, and significant decrease of mTOR and fibrotic marker expression in renal tissue. All previous effects were partially abolished by the autophagy inhibitors chloroquine and 3-MA. Conclusion: We conclude that autophagy induction by exosomes could attenuate DN in a rat model of streptozotocin-induced diabetes mellitus

Adipose Tissue-Derived Mesenchymal Stem Cell Modulates the Immune Response of Allergic Rhinitis in a Rat Model

This study was designed to investigate the potential effects and underlying mechanism of adipose tissue-derived mesenchymal stem cells (MSCs) on allergic inflammation compared to Montelukast as an antileukotriene drug in a rat model of allergic rhinitis (AR). The effect of MSCs was evaluated in albino rats that were randomly divided into four (control, AR, AR + Montelukast, and AR + MSCs) groups. Rats of AR group were sensitized by ovalbumin (OVA) and then challenged with daily nasal drops of OVA diluted in sterile physiological saline (50 μL/nostril, 100 mg/mL, 10% OVA) from day 15 to day 21 of treatment with/without Montelukast (1 h before each challenge) or MSCs I/P injection (1 × 106 MCSs; weekly for three constitutive weeks). Both Montelukast and MSCs treatment started from day 15 of the experiment. At the end of the 5th week, blood samples were collected from all rats for immunological assays, histological, and molecular biology examinations. Both oral Montelukast and intraperitoneal injection of MSCs significantly reduced allergic symptoms and OVA-specific immunoglobulin E (IgE), IgG1, IgG2a and histamine as well as increasing prostaglandin E2 (PGE2). Further analysis revealed that induction of nasal innate cytokines, such as interleukin (IL)-4 and TNF-α; and chemokines, such as CCL11 and vascular cell adhesion molecule-1 (VCAM-1), were suppressed; and transforming growth factor-β (TGF-β) was up-regulated in Montelukast and MSCs-treated groups with superior effect to MSCs, which explained their underlying mechanism. In addition, the adipose tissue-derived MSCs-treated group had more restoring effects on nasal mucosa structure demonstrated by electron microscopical examination

Bioprospecting for Novel Probiotic Strains from Human Milk and Infants: Molecular, Biochemical, and Ultrastructural Evidence

Human milk comprises a diverse array of microbial communities with health-promoting effects, including colonization and development of the infant’s gut. In this study, we characterized the bacterial communities in the Egyptian mother–infant pairs during the first year of life under normal breastfeeding conditions. Out of one hundred isolates, forty-one were chosen for their potential probiotic properties. The selected isolates were profiled in terms of morphological and biochemical properties. The taxonomic evidence of these isolates was investigated based on 16S rRNA gene sequence and phylogenetic trees between the isolates’ sequence and the nearest sequences in the database. The taxonomic and biochemical evidence displayed that the isolates were encompassed in three genera: Lactobacillus, Enterococcus, and Lactococcus. The Lactobacillus was the most common genus in human milk and feces samples with a high incidence of its different species (Lacticaseibacillus paracasei, Lactobacillus delbrueckii, Lactiplantibacillus plantarum, Lactobacillus gasseri, and Lacticaseibacillus casei). Interestingly, BlastN and Jalview alignment results evidenced a low identity ratio of six isolates (less than 95%) with database sequences. This divergence was supported by the unique physiological, biochemical, and probiotic features of these isolates. The isolate L. delbrueckii, ASO 100 exhibited the lowest identity ratio with brilliant probiotic and antibacterial features suggesting the high probability of being a new species. Nine isolates were chosen and subjected to probiotic tests and ultrastructural analysis; these isolates exhibited antibiotic resistance and antibacterial activity with high probiotic characteristics, and high potentiality to be used as prophylactic and therapeutic agents in controlling intestinal pathogens