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Ebrahim, N., A. A. Dessouky, O. Mostafa, A. Hassouna, M. M. Yousef, Y. Seleem, E. A. E. A. M. El Gebaly, M. M. Allam, A. S. Farid, B. A. Saffaf, et al., "Adipose mesenchymal stem cells combined with platelet-rich plasma accelerate diabetic wound healing by modulating the Notch pathway.", Stem cell research & therapy, vol. 12, issue 1, pp. 392, 2021. Abstract

BACKGROUND: Diabetic foot ulceration is a serious chronic complication of diabetes mellitus characterized by high disability, mortality, and morbidity. Platelet-rich plasma (PRP) has been widely used for diabetic wound healing due to its high content of growth factors. However, its application is limited due to the rapid degradation of growth factors. The present study aimed to evaluate the efficacy of combined adipose-derived mesenchymal stem cells (ADSCs) and PRP therapy in promoting diabetic wound healing in relation to the Notch signaling pathway.

METHODS: Albino rats were allocated into 6 groups [control (unwounded), sham (wounded but non-diabetic), diabetic, PRP-treated, ADSC-treated, and PRP+ADSCs-treated groups]. The effect of individual and combined therapy was evaluated by assessing wound closure rate, epidermal thickness, dermal collagen, and angiogenesis. Moreover, gene and protein expression of key elements of the Notch signaling pathway (Notch1, Delta-like canonical Notch ligand 4 (DLL4), Hairy Enhancer of Split-1 (Hes1), Hey1, Jagged-1), gene expression of angiogenic marker (vascular endothelial growth factor and stromal cell-derived factor 1) and epidermal stem cells (EPSCs) related gene (ß1 Integrin) were assessed.

RESULTS: Our data showed better wound healing of PRP+ADSCs compared to their individual use after 7 and 14 days as the combined therapy caused reepithelialization and granulation tissue formation with a marked increase in area percentage of collagen, epidermal thickness, and angiogenesis. Moreover, Notch signaling was significantly downregulated, and EPSC proliferation and recruitment were enhanced compared to other treated groups and diabetic groups.

CONCLUSIONS: These data demonstrated that PRP and ADSCs combined therapy significantly accelerated healing of diabetic wounds induced experimentally in rats via modulating the Notch pathway, promoting angiogenesis and EPSC proliferation.

Ebrahim, N., Y. M. H. Mandour, A. S. Farid, E. Nafie, A. Z. Mohamed, M. Safwat, R. Taha, D. Sabry, S. M. Sorour, and A. Refae, "Adipose Tissue-Derived Mesenchymal Stem Cell Modulates the Immune Response of Allergic Rhinitis in a Rat Model.", International journal of molecular sciences, vol. 20, issue 4, 2019 Feb 18. Abstract

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.

Ebrahim, N., O. Mostafa, R. E. El Dosoky, I. A. Ahmed, A. S. Saad, A. Mostafa, D. Sabry, K. A. Ibrahim, and A. S. Farid, "Human mesenchymal stem cell-derived extracellular vesicles/estrogen combined therapy safely ameliorates experimentally induced intrauterine adhesions in a female rat model.", Stem cell research & therapy, vol. 9, issue 1, pp. 175, 2018 Jun 28. 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.

Ebrahim, N., E. Ehsan, E. A. Ghany, D. Sabry, and A. Shamaa, "Mesenchymal stem cells transplantation attenuates experimentally induced brain injury after neonatal hypoxia by different two routes of administrations ", Biocell, vol. 43, issue 1, pp. 21-28, 2019.
Ebrahim, N., I. A. Ahmed, N. I. Hussien, A. A. Dessouky, A. S. Farid, A. M. Elshazly, O. Mostafa, W. B. E. Gazzar, S. M. Sorour, Y. Seleem, et al., "Mesenchymal Stem Cell-Derived Exosomes Ameliorated Diabetic Nephropathy by Autophagy Induction through the mTOR Signaling Pathway.", Cells, vol. 7, issue 12, 2018 Nov 22. Abstract

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.

El-Menoufy, H., L. A. A. Aly, M. T. A. Aziz, H. M. Atta, N. K. Roshdy, L. A. Rashed, and D. Sabry, "The role of bone marrow-derived mesenchymal stem cells in treating formocresol induced oral ulcers in dogs", Journal of oral pathology & medicine, vol. 39, no. 4: Wiley Online Library, pp. 281–289, 2010. Abstract
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El-Rifaie, A. - A. A., D. Sabry, R. W. Doss, M. A. Kamal, and D. M. Abd El Hassib, "Heme oxygenase and iron status in exosomes of psoriasis patients.", Archives of dermatological research, 2018 Aug 13. Abstract

Psoriasis is an autoimmune skin disease characterized by hyperproliferation of keratinocytes due to interplay between keratinocytes and immune cells. Iron status plays an important role in modifying the function of the immune system. Heme oxygenase (HO), heme-degrading enzyme, plays important role in protective response to oxidative cellular stress. We aimed in this study to map the iron status and HO levels and declare the role HO enzyme in iron homeostasis and immune-modulation in psoriasis. Fifty-one patients with psoriasis and 50 age- and sex-matched healthy controls were enrolled in this study. 5 mL blood sample was withdrawn from each subject. Hepcidin, iron soluble transferring receptor (sTfR), and total iron binding capacity (TIBC) were estimated using ELISA technique and, HO-1 gene level was detected using RT-PCR (reverse transcription-polymerase chain reaction). Iron levels, TIBC, and hepcidin were significantly lower in cases compared to controls. On the contrary, sTfR and HO-1 were significantly over-expressed in cases compared to controls (p < 0.05 in all). HO-1 expression negatively correlated with PASI score and disease extent (%) (r = - 0.614-, p = 0.001; r = - 0.807-, p = 0.001 respectively). There were no significant associations between HO-1 expression and iron, TIBC, hepcidin, sTfR levels (p > 0.05 in all). Iron supplements for the patients with psoriasis are important to maintain haematopoiesis. The induction of HO-1 might have be a promising approach for the treatment of psoriasis through antioxidant ability, immunomodulatory role as well as its role in heme synthesis.

El-Tantawy, W. H., D. Sabry, and E. N. Abd Al Haleem, "Comparative study of antifibrotic activity of some magnesium-containing supplements on experimental liver toxicity. Molecular study.", Drug and chemical toxicology, vol. 40, issue 1, pp. 47-56, 2017 Jan. Abstract

INTRODUCTION: Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) proteins including collagen that occurs in most types of chronic liver diseases. This study aimed to investigate and compare the therapeutic efficacy of different magnesium (Mg)-containing supplements (formulations A, B, and C) on carbon tetrachloride (CCl4)-induced liver fibrosis in rats.

METHODS: Liver fibrosis was induced by intraperitoneal injection of rats with CCl4 (1:1 in olive oil, 2 mL/kg, three times/week) for 4 weeks, and then rats were orally treated with different Mg-containing supplements (formulations A, B, and C) once daily for another one month. Liver fibrosis was quantified by evaluation of expressions of Collagen I, transforming growth factor β-1 (TGFβ1), platelet-derived growth factor-C (PDGF-C), nuclear factor kappa-β (NF-κβ), and measurement of hepatic collagen (hydroxyproline) level. Also, malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH) level, superoxide dismutase (SOD), and glutathione-S-transferase (GST) activities were estimated.

RESULTS: CCl4 administration significantly elevated expressions of the studied genes, hepatic hydroxyproline, MDA, and NO levels and caused depletion of GSH level, decreased SOD, and GST activities when compared with those of their corresponding control, p < 0.05. All magnesium supplements significantly inhibited expressions of the studied genes and attenuated the hepatic hydroxyproline level as compared with those of CCl4-treated group; p < 0.05; for NF-κβ, the highest inhibition was by formulations B and C. Regarding Collagen I, TGFβ1, and hepatic hydroxyproline content, the highest inhibition was by Formulation C, and Formulation A revealed highest inhibition for PDGF-C. All magnesium supplements revealed normalization of oxidant and antioxidants parameters. Histopathological examination supports the biochemical and molecular findings.

CONCLUSION: Mg supplements were effective in the treatment of hepatic CCl4-induced fibrosis-rat model.

El-Tantawy, W. H., D. Sabry, and E. N. Abd Al Haleem, "Comparative study of antifibrotic activity of some magnesium-containing supplements on experimental liver toxicity. Molecular study.", Drug and chemical toxicology, pp. 1-10, 2016 May 5. Abstract

INTRODUCTION: Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) proteins including collagen that occurs in most types of chronic liver diseases. This study aimed to investigate and compare the therapeutic efficacy of different magnesium (Mg)-containing supplements (formulations A, B, and C) on carbon tetrachloride (CCl4)-induced liver fibrosis in rats.

METHODS: Liver fibrosis was induced by intraperitoneal injection of rats with CCl4 (1:1 in olive oil, 2 mL/kg, three times/week) for 4 weeks, and then rats were orally treated with different Mg-containing supplements (formulations A, B, and C) once daily for another one month. Liver fibrosis was quantified by evaluation of expressions of Collagen I, transforming growth factor β-1 (TGFβ1), platelet-derived growth factor-C (PDGF-C), nuclear factor kappa-β (NF-κβ), and measurement of hepatic collagen (hydroxyproline) level. Also, malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH) level, superoxide dismutase (SOD), and glutathione-S-transferase (GST) activities were estimated.

RESULTS: CCl4 administration significantly elevated expressions of the studied genes, hepatic hydroxyproline, MDA, and NO levels and caused depletion of GSH level, decreased SOD, and GST activities when compared with those of their corresponding control, p < 0.05. All magnesium supplements significantly inhibited expressions of the studied genes and attenuated the hepatic hydroxyproline level as compared with those of CCl4-treated group; p < 0.05; for NF-κβ, the highest inhibition was by formulations B and C. Regarding Collagen I, TGFβ1, and hepatic hydroxyproline content, the highest inhibition was by Formulation C, and Formulation A revealed highest inhibition for PDGF-C. All magnesium supplements revealed normalization of oxidant and antioxidants parameters. Histopathological examination supports the biochemical and molecular findings.

CONCLUSION: Mg supplements were effective in the treatment of hepatic CCl4-induced fibrosis-rat model.

Eldin, S. A., D. Sabry, M. Abdelgwad, and M. A. Ramadan, "Some health effects of work-related stress among nurses working in critical care units.", Toxicology and industrial health, vol. 37, issue 3, pp. 142-151, 2021. Abstract

Occupational stress is a major health problem among nurses. Critical care nurses appear to experience more stress at work compared to others. Stress is associated with multiple system disorders, hormonal, and immunological disturbances, and genetic effects. The aim of our study was the detection of health effects of work-related stress and to investigate the link between stress and immune response, alterations of hormones, and expression of micro-RNA (miRNA) among critical care nurses. An exposed 80 critical care nurses matched to 80 controls were involved in our study. Full history, psychological assessment using the General Health Questionnaire (GHQ12) and a complete clinical examination were done for both groups. Serum interleukin (IL)-6, IL-10, luteinizing hormone (LH), follicle-stimulating hormone, thyroid-stimulating hormone (TSH), free triiodothyronine, and free thyroxine (FT4) were measured by enzyme-linked immunosorbent assay, micro-RNA26, and 142 extractions. The exposed group had a mean age of 41 ± 10 years old and mean work duration of 22 ± 9.7 years, matched to 80 controls. The exposed group (32.5%) was associated with severe psychological distress (GHQ scores > 20) compared to only 5% among controls. In addition, the exposed group had a significantly higher level of miRNA 26, miRNA 142, TSH, LH, and IL-6 when compared to the control group. However, there a significantly lower level of FT4 among the exposed group compared to the control group, there were no statistically significant differences between the studied participants regarging FT3,FSH and IL-10 levels. Stress is prevalent among critical care nurses and is reflected on their psychological health with an increase in inflammatory cytokines and disturbances in endocrine functions.

Elsetohy, K. A., M. A. S. Al-Ghussein, D. Sabry, A. M. Nada, A. A. Eldaly, and A. H. Wahba, "ARE RENALASE RS2576178 AND RS10887800 POLYMORPHISMS ASSOCIATED WITH PREGNANCY INDUCED HYPERTENSION?", WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, vol. 3, issue 8, pp. 177-192, 2014.
Esmat, G. E., W. A. Akel, R. A. A. Aziz, A. Al Sayed Taha, D. Sabry, L. A. Rashed, A. Mostafa, A. Y. El Kazaz, and S. H. Ahmed, "Hepatitis C Viral Kinetic Changes in a Retrospective Cohort Study of Chronic Hepatitis C Virus Egyptian Patients on Pegylated Interferon and Ribavirin Therapy.", Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, vol. 36, issue 3, pp. 149-58, 2016 Mar. Abstract

The aim of this study was to determine the relative importance of the kinetics of antiviral response compared to baseline host and virological factors for predicting treatment outcome. A retrospective analysis of 285 chronic hepatitis C virus (HCV) patients, encompassing genotypes 4 treated with peginterferon alpha-2a and ribavirin, was performed. Baseline characteristics were compared across HCV genotypes and pretreatment factors associated with rapid virological response (RVR) were identified. The relative significance of RVR compared to other baseline factors for predicting sustained virological response was analyzed by multiple logistic regression analysis. Ninety-seven percent of the patients harbored HCV genotype 4a patients. The positive predictive value (PPV) of RVR for end-of-treatment response (ETR) was 88% and of early virological response (EVR) was 85%, which means that achievement of both RVR and EVR is a good positive predictive factor of response. The negative predictive value (NPV) of RVR for ETR was low and equals 26.77%, which means that approximately two-thirds of patients were able to achieve ETR despite not experiencing RVR, which means RVR is a bad negative predictive factor of response. The NPV of EVR for ETR was high and equals 90%, which means that only 10% of patients were able to achieve an ETR despite not experiencing EVR, which explains that EVR is a very good negative predictive factor of response. In univariate logistic regression analysis, which included the following: female gender, alanine aminotransferase, aspartate transaminase, α-fetoprotein, baseline HCV-RNA levels, grade of activity, stage of fibrosis, and positive HCV-RNA, by polymerase chain reaction at week 4, none of the previous factors was a significant independent factor of failure of response to treatment. The current study demonstrated that a viremia at week 4 has a good PPV, but it has a very low NPV. The NPV of EVR was more robust for ETR (90%). EVR is regarded as a robust indicator of treatment outcome, and a 12-week stopping rule for patients is strongly evident.

Esmat, G., M. E. Raziky, A. Elsharkawy, D. Sabry, A. Mohamed Hassany, A. Ahmed, N. Assem, M. El Kassas, and W. D, "Impact of vitamin D supplementation on sustained virological response in chronic hepatitis C genotype 4 patients treated by pegylated interferon/ribavirin", Journal of Interferon & Cytokine Research, vol. 35, issue 1, pp. 49-54, 2015.
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