Motawi, T. M. K., N. A. H. Sadik, D. Sabry, S. A. Fahim, and N. N. Shahin, "rs62139665 Polymorphism in the Promoter Region of EpCAM Is Associated With Hepatitis C Virus-Related Hepatocellular Carcinoma Risk in Egyptians", Frontiers in Oncology, vol. 11, 2022. AbstractWebsite

Hepatocellular carcinoma (HCC) is a universal health problem that is particularly alarming in Egypt. The major risk factor for HCC is hepatitis C virus (HCV) infection which is a main burden in Egypt. The epithelial cell adhesion molecule (EpCAM) is a stem cell marker involved in the tumorigenesis and progression of many malignancies, including HCC. We investigated the association of -935 C/G single nucleotide polymorphism in EpCAM promoter region (rs62139665) with HCC risk, EpCAM expression and overall survival in Egyptians. A total of 266 patients (128 HCV and 138 HCC cases) and 117 age- and sex-matched controls participated in this study. Genotyping, performed using allelic discrimination and confirmed by sequencing, revealed a significant association between EpCAM rs62139665 and HCC susceptibility, with higher GG genotype and G allele distribution in HCC patients than in non-HCC subjects. Such association was not detected in HCV patients compared to controls. EpCAM gene expression levels, determined in blood by RT-qPCR, and its serum protein expression levels, determined by ELISA, were significantly higher in GG relative to GC+CC genotype carriers in HCV and HCC patients in a recessive model. ROC analysis of EpCAM protein levels revealed significant discriminatory power between HCC patients and non-HCC subjects, with improved diagnostic accuracy when combining α-fetoprotein and EpCAM compared to that of α-fetoprotein alone. Altogether, EpCAM rs62139665 polymorphism is significantly associated with HCC and with EpCAM gene and protein expression levels in the Egyptian population. Moreover, serum EpCAM levels may hold promise for HCC diagnosis and for improving the diagnostic accuracy of α-fetoprotein.

Motawi, T. M. K., D. Sabry, N. I. Shehata, M. M. William, and A. T. Fahim, "Impact of FOXP1 rs2687201 genetic variant on the susceptibility to HCV-related hepatocellular carcinoma in Egyptians.", Journal of biochemical and molecular toxicology, pp. e22965, 2021. Abstract

Hepatocellular carcinoma (HCC) constitutes a challenging health problem in Egypt due to the high incidence of hepatitis C virus (HCV) infection. Improved understanding of genetic mechanisms underlying the individual predisposition to HCC will lead to enhancements in the early diagnosis, treatment, and prevention of this disease. Transcription factor forkhead box P1 (FOXP1) is involved in the cellular processes of proliferation, differentiation, metabolism, and longevity. In addition, it has been implicated in hepatic tumorigenesis. The present study explored the association of C/A single-nucleotide polymorphism in the FOXP1 gene (rs2687201) with HCC susceptibility in HCV Egyptian patients. The study included 108 patients with HCV-dependant HCC, 86 HCV patients, and 80- age and gender-matched healthy controls. rs2687201 genotyping was performed by allelic discrimination method using TaqMan real-time PCR assays while FOXP1 gene expression and protein level were determined using qRT-PCR and enzyme-linked immunoassay, respectively. Our results revealed a significant association between FOXP1 rs2687201 and HCC risk where (A) allele was significantly more frequent in patients with HCC compared to controls (odds ratio [OR]: 1.88, 95% confidence interval [CI]: 1.17-3.04, p = 0.01) and to HCV patients (OR: 1.85, 95% CI: 1.62-2.94, p = 0.012). Furthermore, FOXP1 gene and protein expression levels were remarkably higher in (CA + AA) than in CC genotype carriers in a dominant model. The (CA + AA) genotype displayed a significantly shorter overall survival than the CC genotype in HCC patients. In conclusion, FOXP1 gene polymorphism rs2687201 is significantly associated with HCC, but not with HCV infection, in Egyptian patients.

Motawi, T. K., O. G. Shaker, S. O. Hassanin, S. G. Ibrahim, and M. A. Senousy, "Genetic and epigenetic control on clock genes in multiple sclerosis.", Journal of genetics and genomics = Yi chuan xue bao, 2021.
Motawi, T. M. K., M. M. William, M. M. Nooh, and H. M. Abd-Elgawad, "Amelioration of cyclophosphamide toxicity via modulation of metabolizing enzymes by avocado (Persea americana) extract.", The Journal of pharmacy and pharmacology, 2021. Abstract

OBJECTIVES: Cyclophosphamide (CPA) is highly effective in treating several human tumours and autoimmune disorders; but, it triggers deleterious side effects. Avocado, Persea americana (Mill.), is a widely consumed fruit with pronounced nutritional and medicinal value. Though many studies examined the protective mechanisms of natural products against CPA toxicity, almost none investigated the modulation of CPA metabolism as a potential underlying mechanism for protection. Here, we investigated the modulating effect of avocado extract (AE) on certain CPA metabolizing enzymes and its correlation with the extent of CPA-induced pulmonary toxicity and urotoxicity.

METHODS: Rats received oral AE (0.9 g/kg body weight/day) 7 days before a single CPA injection (150 mg/kg body weight) and continued AE intake for 2, 7 or 28 days to study three phases of CPA-induced urotoxicity and pulmonary toxicity.

KEY FINDINGS: CPA acutely elevated then reduced hepatic microsomal cytochrome P450 2B6 (CYP2B6) content and significantly suppressed bladder and lung glutathione-S-transferase activity. Furthermore, CPA elevated lung myeloperoxidase activity, DNA content and hydroxyproline level and bladder blood content. AE ameliorated CPA-induced derangements through suppression of CYP2B6 and myeloperoxidase and augmentation of glutathione-S-transferase activity in CPA-treated rats.

CONCLUSIONS: AE modulation of CPA metabolizing enzymes and potential anti-inflammatory effect may mitigate CPA-induced toxicity.

Motawi, T. K., N. A. H. Sadik, M. A. Hamed, S. A. Ali, W. K. B. Khalil, and Y. R. Ahmed, "Potential therapeutic effects of antagonizing adenosine A receptor, curcumin and niacin in rotenone-induced Parkinson's disease mice model.", Molecular and cellular biochemistry, vol. 465, issue 1-2, pp. 89-102, 2020. Abstract

Parkinson's disease (PD) is the second common age-related neurodegenerative disease. It is characterized by control loss of voluntary movements control, resting tremor, postural instability, bradykinesia, and rigidity. The aim of the present work is to evaluate curcumin, niacin, dopaminergic and non-dopaminergic drugs in mice model of Parkinson's disease through behavioral, biochemical, genetic and histopathological observations. Mice treated with rotenone rerecorded significant increase in adenosine A receptor (AR) gene expression, α synuclein, acetylcholinesterase (AchE), malondialdehyde (MDA), angiotensin-II (Ang-II), c-reactive protein (CRP), interleukin-6 (IL-6), caspase-3 (Cas-3) and DNA fragmentation levels as compared with the control group. While, significant decrease in dopamine (DA), norepinephrine (NE), serotonin (5-HT), superoxide dismutase (SOD), reduced glutathione (GSH), ATP, succinate and lactate dehydrogenases (SDH &LDH) levels were detected. Treatment with curcumin, niacin, adenosine AR antagonist; ZM241385 and their combination enhanced the animals' behavior and restored all the selected parameters with variable degrees of improvement. The brain histopathological features of hippocampal and substantia nigra regions confirmed our results. In conclusion, the combination of curcumin, niacin and ZM241385 recorded the most potent treatment effect in Parkinsonism mice followed by ZM241385, as a single treatment. ZM241385 succeeded to antagonize adenosine A receptor by diminishing its gene expression and ameliorating all biochemical parameters under investigation. The newly investigated agent; ZM241385 has almost the same pattern of improvement as the classical drug; Sinemet®. This could shed the light to the need of detailed studies on ZM241385 for its possible role as a promising treatment against PD. Additionally, food supplements such as curcumin and niacin were effective in Parkinson's disease eradication.

Motawi, T. M. K., N. I. Zakhary, H. A. Darwish, H. Abdullah, and S. A. Tadros, "Significance of Some Non-Invasive Biomarkers in the Early Diagnosis and Staging of Egyptian Breast Cancer Patients.", Asian Pacific journal of cancer prevention : APJCP, vol. 21, issue 11, pp. 3279-3284, 2020. Abstract

INTRODUCTION: Breast cancer is one of the most relevant malignancies among women. Early diagnosis and accurate staging of breast cancer is important for the selection of an appropriate therapeutic strategy and achieving a better outcome.

AIM: This study aimed to explore the significance of some non-invasive biomarkers in the early diagnosis and staging of Egyptian breast cancer patients.

SUBJECTS AND METHODS: A total of 135 female patients with physically and pathologically confirmed breast cancer and 40 unrelated controls as well as 40 patients with benign breast mass were enrolled in this study. The malignant breast cancer group was further divided into four groups according to tumor size. Serum levels of carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1), resistin and visfatin were determined by enzyme immunoassay.

RESULTS: Elevated levels of CEACAM1, resistin and visfatin were observed in breast cancer patients when compared with normal control and benign groups. The cutoff values, sensitivities and specificities of these biomarkers were appropriate for the discrimination of breast cancer from controls. Additionally, the serum levels of visfatin increased positively with tumor size and consequently with breast cancer stages.

CONCLUSION: CEACAM1, resistin and visfatin are valuable in early diagnosis of breast cancer, with visfatin being preferentially used in staging.

Motawi, T. K., N. N. Shahin, K. Awad, A. S. Maghraby, D. N. Abd-Elshafy, and M. M. Bahgat, "Glycolytic and immunological alterations in human U937 monocytes in response to H1N1 infection.", IUBMB life, vol. 72, issue 11, pp. 2481-2498, 2020. Abstract

We monitored changes that took place in glycolytic enzymes, the pyruvate end product of glycolysis, tumor necrosis factor α (TNFα), and toll-like receptors (TLRs) both at the transcriptional and translational levels upon direct interaction between PR8-H1N1 and the human monocytes U937 in vitro system. U937 were first treated with H1N1 infectious viral particles or phorbol-12-myristate-13-acetate (PMA) or left untreated and later infected with the H1N1 virus. Levels of phosphofructokinase 1 (PFK1) and pyruvate were biochemically quantified. In addition, levels of TNFα, TLR3, and TLR7 were measured by ELISA. The transcriptional profiles of PFKs, inflammatory cytokines, TLR3 and TLR7 were relatively quantified by qRT-PCR. The results generally revealed significant changes in both the transcriptional and translational profiles of the studied biochemical and immunological parameters upon influenza infection in a time-dependent manner. In conclusion, H1N1 infection triggers transcriptional and translational changes in immortalized human monocytes, which might serve as markers for infection subject for further validation for their specificities.

Motawi, T. M. K., Z. M. Abdel-Nasser, and N. N. Shahin, "Ameliorative Effect of Necrosulfonamide in a Rat Model of Alzheimer's Disease: Targeting Mixed Lineage Kinase Domain-like Protein-Mediated Necroptosis.", ACS chemical neuroscience, vol. 11, issue 20, pp. 3386-3397, 2020. Abstract

Alzheimer's disease (AD) is a progressively debilitating neurodegenerative disorder that has no effective remedy, so far, with available therapeutic modalities being only symptomatic and of modest efficacy. Necroptosis is a form of controlled cell death with a recently emerging link to the pathogenesis of several neurodegenerative diseases. This study investigated the role of necroptosis in the pathogenesis of AD and evaluated the potential beneficial effect of the necroptosis inhibitor, necrosulfonamide (NSA), in a rat model of AD. AD was induced by oral administration of AlCl (17 mg/kg/day) for 6 consecutive weeks. Administration of NSA (1.65 mg/kg/day) intraperitoneally for 6 weeks significantly amended AlCl-induced spatial learning and memory deficits, as demonstrated by enhanced rat performance in Morris water and Y-mazes. NSA alleviated the abnormally high hippocampal expression of tumor necrosis factor-alpha (TNF-α), β-site amyloid precursor protein cleaving enzyme 1 (BACE1), β-amyloid, glycogen synthase kinase-3β (GSK-3β), phosphorylated tau protein, and acetylcholinesterase with concordant replenishment of acetylcholine. The amendments of AD perturbations achieved by NSA correlated with its inhibitory effect on the phosphorylation of the key necroptotic executioner, mixed lineage kinase domain-like protein (MLKL). Histopathological alterations supported the biochemical findings. In conclusion, NSA treatment represents a promising anti-Alzheimer's approach, mitigating AD neuropathologies via targeting MLKL-dependent necroptosis.

Motawi, T. K., N. N. Shahin, A. S. Maghraby, M. Kirschfink, D. N. Abd-Elshafy, K. Awad, and M. M. Bahgat, "H1N1 Infection Reduces Glucose Level in Human U937 Monocytes Culture.", Viral immunology, vol. 33, issue 5, pp. 384-390, 2020. Abstract

Infection with influenza A (H1N1) virus contributes significantly to the global burden of acute respiratory diseases. Glucose uptake and metabolic changes are reported in different cell types after infections with different virus types, including influenza A virus. Alteration of glucose metabolism specifically in immune cells has major health consequences. The aim of this study was to monitor glucose concentration in unstimulated and stimulated U937 human monocytes with infectious or heat inactivated H1N1 or or in nonpathogenically stimulated monocytes with phorbol-12-myristate-13-acetate. Stimulated or unstimulated U937 human monocytes were subjected to H1N1 infection for different time points and the glucose profile in the growth medium was measured post infection. Results showed that regardless to whether the initial stimuli on U937 cells were of pathogen or nonpathogen origins, challenge infection by H1N1 causes a significant reduction of glucose levels 36 h post infection. In conclusion, H1N1 infection has a direct effect on the glucose uptake of U937 cells . This effect can be related to either H1N1 infection or cell differentiation status that might occur due to the exerted stimuli.

Motawi, T. K., S. A. Ahmed, M. A. Hamed, S. A. EL-Maraghy, and W. M. Aziz, "Melatonin and/or rowatinex attenuate streptozotocin-induced diabetic renal injury in rats.", Journal of biomedical research, vol. 33, issue 2, pp. 113-121, 2019. Abstract

The study aimed to explore the prophylactic effect of melatonin, rowatinex; a naturally occurring renal drug, and its combination on diabetic nephropathy in type 2 diabetic rats. Diabetes was induced by intraperitoneal injection of a single dose of streptozotocin (50 mg/g body weight). Three days before diabetes induction, rats were daily treated with melatonin, rowatinex and their combination continuously for 8 weeks. Evaluation was done through measuring blood urea nitrogen (BUN), serum uric acid, serum creatinine, urine creatinine, creatinine clearance, nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), total antioxidant capacity (TAC), kidney injury molecule-1 (KIM-1), heat shock protein-70 (HSP-70), caspase-3, transforming growth factor β1 (TGFβ1), DNA degradation by the comet assay and total protein contents. Histopathologic study was also done for the kidney and the pancreas. Drastic changes in all measured parameters of the diabetic rats were observed. Treatment with melatonin and rowatinex showed amelioration to variable degrees. In conclusion, melatonin showed the most potent effect on protecting rats from deleterious action of diabetic nephropathy followed by its combination with rowatinex.