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Abuohashish, H. M., M. M. Ahmed, D. Sabry, M. M. Khattab, and S. S. Al-Rejaie, "The ACE-2/Ang1-7/Mas cascade enhances bone structure and metabolism following angiotensin-II type 1 receptor blockade.", European journal of pharmacology, vol. 807, pp. 44-55, 2017 Apr 22. Abstract

The renin angiotensin system (RAS) regulates numerous systemic functions and is expressed locally in skeletal tissues. Angiotensin1-7 (Ang1-7) is a beneficial member of the RAS, and the therapeutic effects of a large number of angiotensin receptors blockers (ARBs) are mediated by an Ang1-7-dependent cascade. This study examines whether the reported osteo-preservative effects of losartan are mediated through the angiotensin converting enzyme2 (ACE-2)/Ang1-7/Mas pathway in ovariectomized (OVX) rats. Sham and OVX animals received losartan (10mg/kg/d p.o.) for 6 weeks. A specific Mas receptor blocker (A-779) was delivered via mini-osmotic pumps during the losartan treatment period. Serum and urine bone metabolism biomarker levels were measured. Bone trabecular and cortical morphometry were quantified in distal femurs, whereas mineral contents were estimated in ashed bones, serum and urine. Finally, the expression of RAS components, the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) was determined. Losartan significantly improved the elevated bone metabolism marker levels and altered trabecular and cortical structures in OVX animals, and restored normal urinary and skeletal mineral levels. Mas receptor inhibition significantly abolished all osteo-protective effects of losartan and enhanced the deleterious effects of OVX. Losartan enhanced OVX-induced up-regulation of ACE-1, AngII, angiotensin type 1 (AT1) receptor and RANKL expression, and increased ACE-2, Ang1-7, Mas and OPG expression in OVX animals. However, A-779 significantly eradicated the effects of losartan on RAS components and RANKL/OPG expression. Thus, Ang1-7 are involved in the osteo-preservative effects of losartan via Mas receptor, which may add therapeutic value to this well-known antihypertensive agent.

Abuohashish, H. M., M. M. Ahmed, D. Sabry, M. M. Khattab, and S. S. Al-Rejaie, "Angiotensin (1-7) ameliorates the structural and biochemical alterations of ovariectomy-induced osteoporosis in rats via activation of ACE-2/Mas receptor axis.", Scientific reports, vol. 7, issue 1, pp. 2293, 2017 May 23. Abstract

The local and systemic renin angiotensin system (RAS) influences the skeletal system micro-structure and metabolism. Studies suggested angiotensin 1-7 (Ang(1-7)) as the beneficial RAS molecule via Mas receptor activation. This study examines the function of Ang(1-7) in bone micro-architecture and metabolism in an ovariectomized (OVX) rodent model of osteoporosis. OVX rats showed structural and bone metabolic degeneration in parallel with suppressed expressions of the angiotensin converting enzyme-2 (ACE-2)/Ang(1-7)/Mas components. The infusion of Ang(1-7) markedly alleviated the altered bone metabolism and significantly enhanced both trabecular (metaphyseal) and cortical (metaphyseal-diaphyseal) morphometry. Urinary and bones minerals were also improved in OVX rats by Ang(1-7). The infusion of the heptapeptide enhanced ACE-2/Mas receptor expressions, while down-regulated AngII, ACE, and AngII type-1 receptor (AT1R) in OVX animals. Moreover, Ang(1-7) markedly improved osteoprotegerin (OPG) and lowered receptor activator NF-κB ligand (RANKL) expressions. The defensive properties of Ang(1-7) on bone metabolism, structure and minerals were considerably eradicated after blockage of Mas receptor with A-779. Ang(1-7)-induced up-regulated ACE-2/Ang(1-7)/Mas cascade and OPG expressions were abolished and the expressions of ACE/AngII/AT1R and RANKL were provoked by A-779. These findings shows for the first time the novel valuable therapeutic role of Ang(1-7) on bone health and metabolism through the ACE-2/Mas cascade.

Ahmed G Abdel Salam, Hazem M Ata, T. M. Salman, L. A. Rashed, D. Sabry, and M. F. Schaalan, "Potential therapeutic utility of mesenchymal stem cells in inflammatory bowel disease in mice", International immunopharmacology, vol. 22, issue 2, pp. 515-521, 2014.
Alaa El-Din, Y., D. Sabry, S. H. Ahmed, and A. Mohamed, "FOXD1-mTOR Signaling Pathway on Oral Squamous Cell Carcinoma and Its Inhibition by Rosemary Extract (Invitro-Study).", Asian Pacific journal of cancer prevention : APJCP, vol. 23, issue 9, pp. 3071-3081, 2022. Abstract

BACKGROUND: FOXD1 expression in oral squamous cell carcinoma remains uncovered. The aim was to detect the anticancer effect of Rosemary Extract RE through the evaluation of FOXD1 gene expression in (OSCC) by quantitative PCR.

METHODS: OSCC cell line was served as a control group. Moreover, the OSCC cell line (SCC-15) was treated with RE (OSCC/ RE group) at 24, 48, and 72 hs time intervals. We assessed the antioxidant activity of RE by evaluation of lipid peroxidation (MDA) and superoxide dismutase (SOD) levels. The cytotoxic effects of RE were examined by MTT assay. mTOR and LC3 I/II autophagy protein markers were assessed by western blot. Apoptosis activity was assessed.

RESULTS: The study results were statistically assessed. Intergroup comparisons were analyzed, whereas intragroup comparisons were conducted utilizing one-way repeated measures ANOVA, followed by multiple pairwise paired t-tests with Bonferroni correction revealed a significant increase of FOXD1 gene expression in the control OSCC group in comparison to the OSCC/RE group (p-value <0.001). A significant decrease of mTOR/LC3I/II proteins expression in the OSCC/RE group compared to the control OSCC group (p-value <0.001).

CONCLUSION: FOXD1 can be considred a diagnostic biomarker for OSCC. RE inhibits autophagy of oral human cancer cells via mTOR/LC3I/II-dependent pathways and decrease caspase -3 apoptotic level.

Alaa El-Din, Y., D. Sabry, A. H. Abdelrahman, and S. Fathy, "Potential therapeutic effects of induced pluripotent stem cells on induced salivary gland cancer in experimental rats.", Biotechnic & histochemistry : official publication of the Biological Stain Commission, pp. 1-8, 2018 Oct 19. Abstract

Salivary gland neoplasms exhibit complex histopathology in a variety of tumor types and treatment options depend largely on the stage of the cancer. Induced pluripotent stem cells (iPS) have been investigated for treating induced salivary gland cancer and for restoring salivary gland function. We investigated iPS treatment for salivary gland cancer both in vitro and in vivo. For our study in vitro, we re-programmed human skin fibroblasts to form iPS cells using a plasmid containing Oct4, Sox2, L-MYC and LIN28. For our study in vivo, we used 30 white male albino rats divided into the following groups of 10: group 1 (control): rats were injected with phosphate-buffered saline (PBS), group 2 induced squamous cell carcinoma (SCC): rat submandibular glands were injected with squamous carcinoma cells (SCC), group 3 (induced SCC/iPS): SCC treated rats treated with 5 × 106 iPS cells. Submandibular glands from rats of all groups were examined histologically and real time PCR was performed for amylase, and COX I and COX II gene expression. We confirmed that submandibular gland specimens included tumor tissue before starting treatment with iPS. iPS treated cases exhibited regeneration of salivary glands, although minor degenerative and vascularization changes remained. The acinar cells regained their proper organization, but continued to exhibit abnormal activity including hyperchromatism. iPS cells may be useful for treating salivary gland carcinomas.

Ali, M. M., S. A. Khater, A. A. Fayed, D. Sabry, and S. F. Ibrahim, "Apoptotic endocrinal toxic effects of perchlorate in human placental cells.", Toxicology reports, vol. 8, pp. 863-870, 2021. Abstract

Background: Perchlorate is a strong oxidizing agent and has many adverse health effects. This study investigated the potential oxidative, apoptotic, and endocrinal toxic effects of perchlorate in human placenta-derived mesenchymal stem cells (HP-MSCs).

Methods: HP-MSCs were treated with two doses of perchlorate (5 and 15 μg/L) for three days. The perchlorate's effects were detected by histopathological examination, aromatase/CYP19 A1 activity, reactive oxygen species production (ROS), and Caspase-3 expression.

Results: The highest perchlorate concentration (15 μg/L) caused significant placental histopathological changes. The placental cell viability was significantly affected by a significant increase in ROS generation; caspase-3 expression, and a significant reduction of CYP 19 activity. Despite the slight induction effect of the lowest perchlorate concentration (5 μg/L) on caspase 3 expression, CYP 19 activity, and ROS generation, it did not affect placental cellular viability.

Conclusion: This study suggested that perchlorate could modulate aromatase activity and placental cytotoxicity. The continuous monitoring of the actual perchlorate exposure is needed and could be cost-effective.

Assem, M., S. Kamal, D. Sabry, N. Soliman, and R. M. Aly, "Preclinical Assessment of the Proliferation Capacity of Gingival and Periodontal Ligament Stem Cells from Diabetic Patients", Open Access Macedonian Journal of Medical Sciences, pp. 1-6, 2018. moustafa_paper.pdf
Aziz, M. T. A., M. F. El-Asmar, T. Mostafa, H. Atta, M. A. A. Wassef, H. H. Fouad, N. K. Roshdy, L. A. Rashed, and D. Sabry, "Effects of nitric oxide synthase and heme oxygenase inducers and inhibitors on molecular signaling of erectile function", Journal of Clinical Biochemistry and Nutrition, vol. 37, no. 3: 日本酸化ストレス学会 JCBN 事務局, pp. 103–111, 2005. Abstract
Aziz, M., T. Mostafa, H. Atta, L. Rashed, S. A. Marzouk, E. M. Obaia, D. Sabry, A. A. Hassouna, A. M. El-Shehaby, and A. A. T. Aziz, "The role of PDE5 inhibitors in heme oxygenase–cGMP relationship in rat cavernous tissues", The Journal of Sexual Medicine, vol. 5, no. 7: Wiley Online Library, pp. 1636–1645, 2008. Abstract
Aziz, A. E., M. Talaat, F. M. Al-Asmar, T. Mostafa, H. Atta, L. Rashed, D. Sabry, S. Ashour, and A. T. Abdel Aziz, "Assessment of heme oxygenase-1 (HO-1) activity in the cavernous tissues of sildenafil citrate-treated rats", Asian journal of andrology, vol. 9, no. 3: Wiley Online Library, pp. 377–381, 2007. Abstract
Aziz, A. E., M. Talaat, M. F. El-Asmer, T. Mostafa, S. Mostafa, H. Atta, M. Abdel Aziz Wassef, H. Fouad, L. Rashed, D. Sabry, et al., "ORIGINAL RESEARCH—BASIC SCIENCE: Heme Oxygenase vs. Nitric Oxide Synthase in Signaling Mediating Sildenafil Citrate Action", The journal of sexual medicine, vol. 4, no. 4ii: Wiley Online Library, pp. 1098–1107, 2007. Abstract
Aziz, A. E., M. Talaat, E. Asmer, M. Farid, T. Mostafa, H. Atta, S. Mahfouz, H. Fouad, L. Rashed, D. Sabry, et al., "Effects of Losartan, HO-1 Inducers or HO-1 Inhibitors on Erectile Signaling in Diabetic Rats", The journal of sexual medicine, vol. 6, no. 12: Wiley Online Library, pp. 3254–3264, 2009. Abstract
Aziz, M. T. A., M. F. El-Asmar, A. M. Rezq, M. A. A. Wassef, H. Fouad, N. K. Roshy, H. H. Ahmed, L. A. Rashed, D. Sabry, F. M. Taha, et al., "Effects of a novel curcumin derivative on insulin synthesis and secretion in streptozotocin-treated rat pancreatic islets in vitro", Chinese medicine, vol. 9, issue 1, pp. 1-12, 2014.
Aziza, A. E. M. T., A. E. E. A. Nabia, A. E. M. Hamidc, D. Sabrya, H. M. Attaa, L. A. Raheda, A. Shamaae, and S. Mahfouzf, "Endothelial progenitor cells regenerate infracted myocardium with neovascularisation development.", Journal of Advanced Research, vol. 6, issue 2, pp. 133–144, 2015. Abstract

We achieved possibility of isolation, characterization human umbilical cord blood endothelial progenitor cells (EPCs), examination potency of EPCs to form new blood vessels and differentiation into cardiomyoctes in canines with acute myocardial infarction (AMI). EPCs were separated and cultured from umbilical cord blood. Their phenotypes were confirmed by uptake of double stains dioctadecyl tetramethylindocarbocyanine-labeled acetylated LDL and FITC-labeled Ulex europaeus agglutinin 1 (DILDL-UEA-1). EPCs of cord blood were counted. Human VEGFR-2 and eNOS from the cultured EPCs were assessed by qPCR. Human EPCs was transplanted intramyocardially in canines with AMI. ECG and cardiac enzymes (CK-MB and Troponin I) were measured to assess severity of cellular damage. Histopathology was done to assess neovascularisation. Immunostaining was done to detect EPCs transdifferentiation into cardiomyocytes in peri-infarct cardiac tissue. qPCR for human genes (hVEGFR-2, and eNOS) was done to assess homing and angiogenic function of transplanted EPCs. Cultured human cord blood exhibited an increased number of EPCs and significant high expression of hVEGFR-2 and eNOS genes in the culture cells. Histopathology showed increased neovascularization and immunostaining showed presence of EPCs newly differentiated into cardiomyocyte-like cells. Our findings suggested that hEPCs can mediate angiogenesis and differentiate into cardiomyoctes in canines with AMI.

CTO, chronic total occlusion; CAG, coronary angiography; AMI, acute myocardial infarction; DILDL-FITC labeled UEA-11, 1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine-labeled acetylated LDL (DiLDL,) and FITC-labeled Ulex europaeus agglutinin-1; MVD, multivessel disease; CFU, colony forming unit

Badr, A. M., O. Elkholy, M. Said, S. A. Fahim, M. El-Khatib, D. Sabry, and R. M. Gaber, "Diagnostic significance of hsa_circ_0000146 and hsa_circ_0000072 biomarkers for Diabetic Kidney Disease in patients with type 2 diabetes mellitus.", Journal of medical biochemistry, vol. 42, issue 2, pp. 239-248, 2023. Abstract

BACKGROUND: Diabetic Kidney Disease (DKD) is a significant challenge in healthcare. However, there are currently no reliable biomarkers for renal impairment diagnosis, prognosis, or staging in DKD patients. CircRNAs and microRNAs have emerged as noninvasive and efficient biomarkers.

METHODS: We explored Cannabinoid receptor 1 (CNR1), C reactive protein (CRP), hsa_circ_ 0000146 and 0000072, and hsa-miR-21 and 495 as diagnostic biomarkers in DKD. The serum concentrations of CRP and CNR1 were measured using ELISA. Rt-qPCR was used to evaluate the expression levels of CNR1, circRNAs, and miRNAs in 55 controls, 55 type 2 diabetes mellitus patients, and 55 DKD patients. Their diagnostic value was determined by their ROC curve. KEGG pathway was used to predict the functional mechanism of the circRNA's target genes.

RESULTS: DKD patients exhibited a significant increase in CRP and CNR1 levels and the expression of miR-21 and 495. The expression levels of circ_0000146 and 0000072 decreased in DKD patients. ROC analysis revealed that circRNAs and miRNAs alone or CNR1 and CRP have significant diagnostic potential. The functional prediction results showed the involvement of hsa_circ_0000146 and 0000072 in various pathways that regulate DKD.

CONCLUSIONS: Therefore, the examined circRNAs and miRNAs may represent a novel noninvasive biomarker for diagnosing and staging DKD.

Bahaa Moustafa Zayed, M. Megdy, and D. Sabry, "SP746ASSESSMENT OF HEPATIC FIBROSIS BY FIBROSCAN IN EGYPTIAN CHRONIC HEMODIALYSIS PATIENTS WITH HCV GENOTYPE 4", Nephrology Dialysis Transplantation, vol. 30, issue suppl 3, pp. iii624-iii624, 2015.
Baki, N. A. M., Z. O. Nawito, N. M. S. Abdelsalam, D. Sabry, H. Elashmawy, N. A. Seleem, A. A. A. - A. Taha, and M. E. Ghobashy, "Does Intra-Articular Injection of Platelet-Rich Plasma Have an Effect on Cartilage Thickness in Patients with Primary Knee Osteoarthritis?", Current rheumatology reviews, 2021. Abstract

OBJECTIVES: To determine the effect of intra-articular injection of platelet-rich plasma (PRP) in patients with primary knee osteoarthritis (OA) by clinical evaluation and ultrasonographic (US) assessment of cartilage thickness.

PATIENTS AND METHODS: A total of 100 patients with mild to severe primary knee OA using the Kellgren-Lawrence (K-L) grading scale were included and divided into two groups. Group I included 50 patients who were given two intra-articular knee injections of PRP, 1 week apart; Group II included 50 patients who received non-steroidal anti-inflammatory drugs (NSAIDs) and chondroprotective drugs. Functional assessment of all OA patients done using the basal WOMAC score, at 2 and 6 months.US assessment of femoral condylar cartilage thickness was conducted basally and at 6 months.

RESULTS: Improvement of WOMAC score was observed at 2 and 6 months in Group I following PRP injection compared to Group II (p values < 0.001), The improvement of WOMAC in Group I occurred in all severity degrees of OA (p < 0.001). Moreover, a significant increase in cartilage thickness at the intercondylar area (ICA) at 6 months relative to baseline assessment by US in Group I (p = 0.041) was found.

CONCLUSION: Treatment with PRP injections can reduce pain and improve knee function in patients with various degrees of articular degeneration. Further studies are needed to clarify the anabolic effect of PRP on the articular cartilage.

Bawazeer, S., D. Sabry, R. H. Mahmoud, H. M. Elhanbuli, N. N. Yassen, and M. N. Abdelhafez, "Association of SPARC gene polymorphisms rs3210714 and rs7719521 with VEGF expression and utility of Nottingham Prognostic Index scoring in breast cancer in a sample of Egyptian women.", Molecular biology reports, vol. 45, issue 6, pp. 2313-2324, 2018 Dec. Abstract

Breast cancer is the most common malignancy in women. To our knowledge, there is no single study conducted on the role of secreted protein acidic and rich in cysteine (SPARC) gene polymorphism in breast cancer risk or prognosis. The present study aims to investigate the probable role of SPARC genetic polymorphisms in development of breast cancer; their correlation with immunohistochemical expression of VEGF; and their association with breast cancer prognosis in the Egyptian population. The study sample included 238 Egyptian females who were divided into two groups: breast cancer group (118 patients) and healthy control group (120 subjects). SPARC gene single nucleotide polymorphisms rs3210714 and rs7719521 were genotyped. Allelic and genotypic frequencies were determined in both groups and association with ductal breast carcinoma, clinicopathological and prognostic characters were determined. For SPARC rs3210714, a significant difference was observed in the codominant model and both A and G alleles' frequencies between breast cancer patients and control group (P < 0.001). For rs7719521, a significant difference in codominant and dominant models as well as in both A and C alleles' frequencies between breast cancer and control groups (P < 0.001) was observed. A significant relation was found between SPARC rs3210714 and rs7719521, and immunohistochemical expression of VEGF (P = 0.046 and P = 0.027, respectively). SPARC rs7719521 showed a significant association with Nottingham Prognostic Index (NPI) (P = 0.032). The present study revealed that SPARC rs3210714 and rs7719521 polymorphisms are associated with breast cancer risk and its prognosis. Therefore, these SNPs may be useful in predicting the increased risk of breast cancer.

Behiry, E. G., M. A. Al-Azzouny, D. Sabry, O. G. Behairy, and N. E. Salem, "Association of NKX2-5, GATA4, and TBX5 polymorphisms with congenital heart disease in Egyptian children.", Molecular genetics & genomic medicine, pp. e612, 2019 Mar 04. Abstract

BACKGROUND: Several genes encoding transcription factors are known to be the primary cause of congenital heart disease. NKX2-5 and GATA4 were the first congenital heart disease-causing genes identified by linkage analysis. This study designed to study the association of five single-nucleotide variants of NKX2-5, GATA4, and TBX5 genes with sporadic nonsyndromic cases of a congenital cardiac septal defect in Egyptian children.

METHODS: Venous blood samples from 150 congenital heart disease children (including a ventricular septal defect, atrial septal defect, tetralogy of Fallot, and patent ductus arteriosus) and 90 apparently healthy of matched age and sex were studied by polymerase chain reaction followed by direct sequencing in order to study two single-nucleotide variants of NKX2-5 (rs2277923, rs28936670), two single-nucleotide variants of GATA4 (rs368418329, rs56166237) and one single-nucleotide variant TBX5 (rs6489957). The distribution of genotype and allele frequency in the congenital heart diseases (CHD) group and control group were analyzed.

RESULTS: We found different genotype frequencies of the two variants of NKX2-5, as CT genotype of rs2277923 was present in 58% and 36% in cases and control respectively, and TT genotype present in 6% of the cases. Also regarding missense variant rs28936670, heterozygous AG presented in 82% of the cases. Also, we observed a five prime UTR variant rs368418329, GT (42% of the cases) and GG (46% of the cases) genotypes showed the most frequent presentation in cases. While regarding a synonymous variant rs56166237, GT and GG were the most presented in cases (41.4%, 56% respectively) in contrast to control group (20%, 1.7% respectively). Also, a synonymous variant in TBX5, the distribution of genotype frequency was significantly different between the CHD group and control group. CT genotype of TBX5 -rs6489957 was found in 12 ASD, 24 VSD, six PDA, three aortic coarctation and nine fallot that represent 42% of the cases.

CONCLUSIONS: Significantly higher frequency of different allelle of five variants was observed in cases when compared to the control group, with significant risky effect for the development of septal defect. In addition to two polymorphisms of NKX2-5 (rs2277923, rs28936670) variant in the cardiac septal defect, two variants in GATA4 (rs368418329, rs56166237) and one variant in TBX5 (rs6489957) seem to have a role in the pathogenesis of congenital heart disease.

D, S., A. R, A. S, Fathy W, Eldemery A, and E. A, "Braf, Kras and Helicobacter pylori epigenetic changes-associated chronic gastritis in Egyptian patients with and without gastric cancer.", World journal of microbiology and biotechnology, vol. 32, issue 6, pp. 92, 2016.
Darweesh, S. K., R. A. Abd Alziz, H. Omar, D. Sabry, and W. Fathy, "Secreted protein acidic and rich in cysteine gene variants: Impact on susceptibility and survival of hepatocellular carcinoma patients.", Journal of gastroenterology and hepatology, 2018 Nov 13, 2019. Abstract

BACKGROUND AND AIM: Secreted protein acidic and rich in cysteine (SPARC) is a glycoprotein involved in extracellular matrix remodeling, which regulates cell growth. It could be involved in hepatic fibrogenesis related to chronic inflammations, hepatocellular carcinoma (HCC) angiogenesis, and tumor progression. We aimed to study the expressions of single nucleotide polymorphisms in the SPARC gene and their impact on susceptibility and survival of HCC patients.

METHODS: We conducted a case-control study on 200 HCC patients and 50 matched healthy controls. All patients were subjected to laboratory investigations, ultrasound, and real-time polymerase chain reaction to detect the genetic polymorphisms (rs3210714, rs11950384, and rs7719521) in the SPARC gene in the blood.

RESULTS: One hundred sixty (80%) patients were men with a mean age of 43 years. The SPARC gene showed a significant higher prevalence of rs3210714 mutation (i.e. AA or AG) and a significant lower prevalence of rs11950384 mutation (i.e. AA or AC) among HCC patients in comparison with controls (83% vs 22%, P ≤ 0.001) and (65.5 vs 86%, P = 0.005), respectively, while rs7719521 mutation did not reach significance. On univariate and multivariate analyses, elder age and having at least one copy of the mutant rs3210714 were associated with a significantly increased risk of HCC (P < 0.001 for both), whereas the presence of at least one copy of the mutant rs11950384 carried a significantly reduced risk of having HCC (P < 0.01). Overall survival did not differ significantly between any of the SPARC gene mutation groups.

CONCLUSIONS: The SPARC gene polymorphisms had a diverse impact on the susceptibility of HCC due to its ability to inhibit or promote tumor progression. SPARC gene polymorphisms were not related to survival of our HCC patients, and probably, this needs further analysis of other SPARC gene nucleotides.

Ebrahim, N., H. A. Al Saihati, O. Mostafa, A. Hassouna, S. Abdulsamea, E. A. E. A. M. El Gebaly, N. H. Abo-Rayah, D. Sabry, M. El-Sherbiny, A. G. Madboly, et al., "Prophylactic Evidence of MSCs-Derived Exosomes in Doxorubicin/Trastuzumab-Induced Cardiotoxicity: Beyond Mechanistic Target of NRG-1/Erb Signaling Pathway.", International journal of molecular sciences, vol. 23, issue 11, 2022. Abstract

Trastuzumab (Trz) is a humanized monoclonal antibody targeting epidermal growth factor receptor 2 (HER2; ErbB2). The combined administration of Trz and doxorubicin (DOX) has shown potent anti-cancer efficacy; however, this regimen may be accompanied by severe cardiac toxicity. Mesenchymal stem cells (MSCs)-derived exosomes are nanosized vesicles that play a crucial role in cell-cell communication and have shown efficacy in the treatment of various diseases. In this study, we aim to investigate the cardioprotective effects of MSCs-derived exosomes in a DOX/Trz- mediated cardiotoxicity model, and the possible mechanisms underlying these effects are elucidated. Forty-nine male rats were randomly assigned into four groups: Group I (control); Group II (Dox/Trz); Group III (protective group); and Group IV (curative group). Cardiac hemodynamic parameters, serum markers of cardiac injury, oxidative stress indices, and cardiac histopathology were investigated. Further, transcript profile of specific cardiac tissue injury markers, apoptotic markers, and fibrotic markers were analyzed using qRT-PCR, while the protein expressions of pAkt/Akt, pERK/ERK, pJNK/JNK, pJNK/JNK, and pSTAT3/STAT3 were evaluated by ELISA. Additionally, cardiac mirR-21 and miR-26a were assessed. A combined administration of DOX/Trz disrupted redox and Ca homeostasis in cardiac tissue induced myocardial fibrosis and myofibril loss and triggered cardiac DNA damage and apoptosis. This cardiotoxicity was accompanied by decreased NRG-1 mRNA expression, HER2 protein expression, and suppressed AKT and ERK phosphorylation, while triggering JNK phosphorylation. Histological and ultra-structural examination of cardiac specimens revealed features typical of cardiac tissue injury. Moreover, a significant decline in cardiac function was observed through biochemical testing of serum cardiac markers and echocardiography. In contrast, the intraperitoneal administration of MSCs-derived exosomes alleviated cardiac injury in both protective and curative protocols; however, superior effects were observed in the protective protocol. The results of the current study indicate the ability of MSCs-derived exosomes to protect from and attenuate DOX/Trz-induced cardiotoxicity. The NRG-1/HER2, MAPK, PI3K/AKT, PJNK/JNK, and PSTAT/STAT signaling pathways play roles in mediating these effects.

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., 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., 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.