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2020
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, 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. 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, N. A. El-Boghdady, N. S. Metwally, and N. N. Nasr, "Impact of betanin against paracetamol and diclofenac induced hepato-renal damage in rats.", Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals, vol. 25, issue 1, pp. 86-93, 2020. Abstract

Paracetamol (PAR) and diclofenac (DF) are the most popular consumed analgesics and anti-inflammatory medications. This study aimed to explore the protective effect of betanin (Bet) against PAR or DF induced hepato-renal damage in rats. Rats were randomly divided into five groups: Normal control (NC) group rats were given saline only. PAR group rats received PAR (400 mg/kg). PAR/Bet treated group rats administered PAR (400 mg/kg) plus Bet (25 mg/kg). DF group rats received DF (10 mg/kg). DF/Bet treated group rats administered DF (10 mg/kg) plus Bet (25 mg/kg). All drugs were given by gavage for 28 consecutive days. PAR and DF administration in high dose and long-time induced liver and kidney injury, disrupted serum lipid profile, enhanced serum levels of inflammatory and oxidative stress markers, triggered DNA fragmentation and caused drastic changes in the histopathological pictures of the two organs. Bet supplementation succeeded to ameliorate most of the biochemical changes and protected DNA from damage as obtained from comet assay. Histological features in H&E taken to different groups also mirrors this findings. Bet exerted a potential anti-inflammatory and antioxidant effect against hepato-renal damage induced by PAR or DF overconsumption.

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.

2019
Motawi, T. K., S. A. EL-Maraghy, S. A. Sharaf, and S. E. Said, "Association of CARD10 rs6000782 and rs1799724 variants with paediatric-onset autoimmune hepatitis.", Journal of advanced research, vol. 15, pp. 103-110, 2019 Jan. Abstract

Although the pathogenesis of paediatric-onset autoimmune hepatitis (pAIH) remains incompletely understood, genetic variants and environmental factors are known to be involved. Caspase recruitment domain family member 10 (CARD10) is a scaffold protein that participates in a complex pathway activating nuclear factor kappa-B (NFκB) and tumour necrosis factor alpha (TNF-α). This study aimed to investigate the association of rs6000782 (g.37928186A > C) and gene promoter rs1799724 (c.-1037C > T) variants with pAIH susceptibility in a cohort of Egyptian children. The research was also extended to assess the relationship of these variants with levels of NFκB-p65 and TNF-α. Fifty-six pAIH patients and 44 age- and sex-matched healthy controls were included. Variant genotyping was performed by polymerase chain reaction (PCR). Serum NFκB-p65 and TNF-α levels were measured using enzyme-linked immunosorbent assays (ELISAs). rs6000782 C and rs1799724 T alleles, separate or in combination, were significantly increased in pAIH patients compared to controls. Serum levels of NFκB-p65 and TNF-α were higher in pAIH differentiating both groups. Moreover, the recessive model of rs6000782 revealed a significant association with the levels of both NFκB-p65 and TNF-α. In conclusion, rs6000782 and rs1799724 variants are potential genetic risk factors for pAIH predisposition, with the former affecting NFκB-p65 and TNF-α levels. Overall, the inflammatory cascade was associated with the degree of liver cell destruction. Clinically, screening and genetic counselling are recommended for relatives of pAIH patients.

Motawi, T. M. K., S. A. EL-Maraghy, D. Sabry, and N. A. Mehana, "The expression of long non coding RNA genes is associated with expression with polymorphisms of HULC rs7763881 and MALAT1 rs619586 in hepatocellular carcinoma and HBV Egyptian patients.", Journal of cellular biochemistry, vol. 120, issue 9, pp. 14645-14656, 2019. Abstract

Long noncoding RNAs (lncRNAs), highly upregulated liver cancer (HULC), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), lncRNA-AF085935, and lncRNA-uc003wbd have been implicated in hepatocellular carcinoma (HCC). Single-nucleotide polymorphism (SNP) in HULC and MALAT1 are associated with HCC susceptibility. However, association between these SNPs and lncRNA-AF085935 and lncRNA-uc003wbd expression and their potential clinical value in differentiating HCC from both hepatitis B virus (HBV)-infected Egyptian patients and the healthy specimens have not been explored yet. In the present study, SNPs rs7763881 in HULC and rs619586 in MALAT1 were genotyped in 70 HBV-positive HCC, 70 HBV patients, and 70 healthy controls in Egyptian population and the level of serum lncRNA-AF085935 and lncRNA-uc003wbd of all the subjects was assayed by quantitative real-time polymerase chain reaction. HULC rs7763881 AC/CC genotype was significantly associated with decreased HCC risk. Similarly, AG/GG of MALAT1 rs619586 was associated with decreased HCC risk with a borderline significance. Serum lncRNA-AF085935 and lncRNA-uc003wbd levels were upregulated in HBV-positive HCC and HBV patients vs controls and discriminated these groups by receiver operating characteristic analysis. Patients carrying AC/CC genotype of rs7763881 and AG/GG of rs619586 had lower serum lncRNA-AF085935 and lncRNA-uc003wbd levels compared with AA genotype. In conclusion, genetic variants of lncRNA HULC and lncRNA MALAT1 are associated with the decreased susceptibility to HCC in HBV-persistent carriers and are correlated with serum lncRNA-AF085935 and lncRNAuc003wbd levels, two potential noninvasive diagnostic biomarkers for HCC.

Motawi, T. K., A. E. Mady, S. Shaheen, S. Z. Elshenawy, R. M. Talaat, and S. M. Rizk, "Genetic variation in microRNA-100 (miR-100) rs1834306 T/C associated with Hepatitis B virus (HBV) infection: Correlation with expression level.", Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, vol. 73, pp. 444-449, 2019. Abstract

Circulating microRNAs (miRNAs) have a vital role in Hepatitis B virus (HBV) diagnosis and therapeutics. miR-100 was reported to be associated with various aspects of HBV biology. This study focused on a miR-100 Single Nucleotide Polymorphism (SNP) (rs1834306 T/C) and its contribution to an individual's susceptibility and prognosis of HBV infection. The effect of SNP on miR-100 expression will be also evaluated. Two hundred subjects: 100 HBV infected patients and 100 age-and-sex-matched healthy individuals served as a control group. SNP detection was performed using polymerase chain reaction technique with sequence-specific primers (PCR-SSP) method and miR-100 expression through quantitative real-time PCR (qRT-PCR). Our result showed a significant up-regulation of miR-100 expression in HBV patients versus the control group (P < .01). A positive correlation was found between viral load and elevation in miR-100 expression (r = 0.508; P < .01). Concerning miR-100 expression in different genotypes/alleles, TC genotype and T allele in coincides with a significantly elevated expression level of miR-100 (P < .001) in HBV patients than in controls. Best of our knowledge, it is the first observational prospective case-control study concerned with miR-100 (rs1834306 T/C) SNP in the Egyptian population. However, the small size of this preliminary work required more prospective investigations to confirm our data.

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.

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, 2019. 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. K., S. A. Ahmed, N. A. El-Boghdady, N. S. Metwally, and N. N. Nasr, "Protective effects of betanin against paracetamol and diclofenac induced neurotoxicity and endocrine disruption in rats.", Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals, pp. 1-22, 2019. Abstract

Overconsumption of Paracetamol (PAR) and diclofenac (DF) have been reported to induce neurotoxicity and endocrine disruption. The current study was designed to explore the protective potential of betanin against paracetamol and diclofenac inducing neurotoxicity and endocrine disruption in a rat model. 40 rats were equally divided into five groups: group I served as control, group II received PAR (400 mg/kg), group III received PAR plus betanin (25mg/kg), group IV received DF (10mg/kg) and group V received DF plus betanin orally for 28 consecutive days. Thyroid axis hormones, sex hormone, neurotransmitters, paraoxonase-1, hemoxygenase-1 and nuclear factor-2 were measured by ELISA. While, the oxidative stress markers were calorimetrically estimated. Moreover, DNA damage and histopathological picture of the brains were investigated. A marked reduction in thyroid axis hormones, brain neurotransmitters and serum testosterone as well as enhanced oxidative stress and brain DNA damage accompanied by drastic changes in the brain histopathological picture were recorded in the challenged PAR and DF groups. Betanin supplementation ameliorated most of the biochemical and histopathological changes induced by PAR or DF. : The study suggests betanin of potential protective effects against neurotoxicity and endocrine disruption induced by PAR and DF overconsumption.

Motawi, T. M. K., N. A. H. Sadik, D. Sabry, N. N. Shahin, and S. A. Fahim, "rs2267531, a promoter SNP within glypican-3 gene in the X chromosome, is associated with hepatocellular carcinoma in Egyptians.", Scientific reports, vol. 9, issue 1, pp. 6868, 2019. Abstract

Hepatocellular carcinoma (HCC) is a major health concern in Egypt owing to the high prevalence of hepatitis C virus (HCV) infection. HCC incidence is characterized by obvious male predominance, yet the molecular mechanisms behind this gender bias are still unidentified. Functional variations in X-linked genes have more impact on males than females. Glypican-3 (GPC3) gene, located in the Xq26 region, has lately emerged as being potentially implicated in hepatocellular carcinogenesis. The current study was designed to examine the association of -784 G/C single nucleotide polymorphism (SNP) in GPC3 promoter region (rs2267531) with HCC susceptibility in male and female Egyptian HCV patients. Our results revealed a significant association between GPC3 and HCC risk in both males and females, evidenced by higher C allele and CC/C genotype frequencies in HCC patients when compared to controls. However, no such association was found when comparing HCV patients to controls. Moreover, GPC3 gene and protein expression levels were significantly higher in CC/C than in GG/G genotype carriers in males and females. The CC/C genotype exhibited a significant shorter overall survival than GG/G genotype in HCC patients. In conclusion, GPC3 rs2267531 on the X chromosome is significantly associated with HCC, but not with HCV infection, in the Egyptian population.

Motawi, T. M. K., N. I. Zakhary, H. A. Darwish, H. A. S. S. A. N. M. ABDALLA, and S. A. Tadros, "Significance of Serum Survivin and -31G/C Gene Polymorphism in the Early Diagnosis of Breast Cancer in Egypt.", Clinical breast cancer, vol. 19, issue 2, pp. e276-e282, 2019. Abstract

BACKGROUND: Breast cancer is one of the most relevant malignancies among women. Molecular abnormalities in promotor region of survivin gene may account for overexpression of survivin and increased breast cancer risk. This study aimed to explore the potential association between survivin promotor gene -31G/C single nucleotide polymorphism (rs9904341) and its serum level alteration on one hand, and the risk of breast cancer in Egyptian patients on the other hand. It also aimed to assess the usefulness of survivin as an early noninvasive diagnostic biomarker and in breast cancer staging.

PATIENTS AND METHODS: A total of 135 patients with physically and pathologically confirmed breast cancer and 40 unrelated control subjects as well as 40 patients with benign breast mass were recruited from the early detection unit at National Cancer Institute, Cairo University. Genotyping was performed using allelic discrimination probes by real-time quantitative PCR and serum survivin by enzyme-linked immunosorbent assay.

RESULTS: The minor allele C of -31G/C survivin single nucleotide polymorphism was more frequent in breast cancer patients (19.3%) compared to the control group (7.5%). Furthermore, subjects with the GC + CC genotype were at increased risk of breast cancer compared to the GG genotype of the control group and also the benign group. Moreover, those patients exhibited higher serum levels of survivin compared to GG genotype. There was also significant elevation of serum survivin in different breast cancer stages.

CONCLUSION: Genetic variation in -31G/C of the survivin gene may contribute to the disposition of breast cancer in the Egyptian population. Serum survivin alteration played a pivotal role in the pathogenesis of breast cancer.

2018
Motawi, T. K., M. R. Mohamed, N. N. Shahin, M. A. M. Ali, and M. A. Azzam, "Time-course expression profile and diagnostic potential of a miRNA panel in exosomes and total serum in acute liver injury.", The international journal of biochemistry & cell biology, vol. 100, pp. 11-21, 2018 May 05. Abstract

Circulating miRNAs have recently emerged as attractive candidates for biomarker discovery. However, they have a variant distribution in circulation, and the diagnostic significance of their compartmentalization is yet to be elucidated. This study explored the time-course expression profile and the diagnostic potential of miRNAs-122a-5p, 192-5p, 193a-3p and 194-5p in exosomal and total serum compartments in two rat models of acute liver injury (ALI). Exosomes were isolated and characterized in terms of morphology, size and CD-63 surface marker expression. Exosomal, serum and hepatic miRNAs were quantified using q-RT-PCR. An inverse expression pattern of hepatic and total serum miRNAs was observed following acetaminophen or thioacetamide-induced liver injury. Conversely, exosomal miRNAs expression pattern varied according to the type of injury. Overall, ROC analysis revealed superior discriminatory ability of exosomal miRNA-122a-5p following either acetaminophen or thioacetamide injury with earlier diagnostic potential and a wider diagnostic window compared to the corresponding total serum counterpart. Moreover, exosomal miRNAs showed higher correlation with ALT activity in both models. In conclusion, exosomal miRNA-122a-5p shows higher diagnostic performance with a broader diagnostic time window and an earlier diagnostic potential than its serum counterpart in ALI. Furthermore, exosomal miRNAs-122a-5p, 192-5p and 193a-3p exhibit an injury-specific signature in ALI and can be used not only as diagnostic tools in liver injury but also to differentiate between different etiologies of injury.

Motawi, T. M. K., S. G. Mahdy, M. M. El-Sawalhi, E. N. Ali, and R. F. A. El-Telbany, "Serum levels of chemerin, apelin, vaspin, and omentin-1 in obese type 2 diabetic Egyptian patients with coronary artery stenosis.", Canadian journal of physiology and pharmacology, vol. 96, issue 1, pp. 38-44, 2018 Jan. Abstract

Cardiovascular diseases (CVD) are the leading cause of death in the diabetic population. Obesity is a serious problem that has been linked with CVD and diabetes via a variety of adipokines. The aims of this study were to evaluate and correlate circulating chemerin, apelin, vaspin, and omentin-1 levels in obese type 2 diabetic Egyptian patients with coronary artery stenosis (CAS), and to assess their usefulness as noninvasive diagnostic biomarkers. Chemerin, apelin, vaspin, and omentin-1 levels were determined by enzyme immunoassay in coronary artery disease (CAD) I patients (45 non-obese, nondiabetic with CAS), CAD II patients (45 obese, diabetic with CAS), and 30 controls. Patients in CAD I and CAD II groups exhibited higher levels of chemerin and apelin together with lower levels of vaspin and omentin-1 than in controls. These alterations were more significant in CAD II than in CAD I patients. Additionally, adipokine levels were individually correlated with each other and with certain biochemical variables. Moreover, chemerin and vaspin levels could differentiate CAD II patients from CAD I and controls. Alterations of these adipokines may play a crucial role in the pathogenesis of CAS in obese type 2 diabetic Egyptian patients. Chemerin and vaspin could be used as markers to support diagnosis of CAS.

Motawi, T. M. K., S. G. Mahdy, M. M. El-Sawalhi, E. N. Ali, and R. F. A. El-Telbany, "Serum levels of chemerin, apelin, vaspin, and omentin-1 in obese type 2 diabetic Egyptian patients with coronary artery stenosis.", Canadian journal of physiology and pharmacology, vol. 96, issue 1, pp. 38-44, 2018 Jan. Abstract

Cardiovascular diseases (CVD) are the leading cause of death in the diabetic population. Obesity is a serious problem that has been linked with CVD and diabetes via a variety of adipokines. The aims of this study were to evaluate and correlate circulating chemerin, apelin, vaspin, and omentin-1 levels in obese type 2 diabetic Egyptian patients with coronary artery stenosis (CAS), and to assess their usefulness as noninvasive diagnostic biomarkers. Chemerin, apelin, vaspin, and omentin-1 levels were determined by enzyme immunoassay in coronary artery disease (CAD) I patients (45 non-obese, nondiabetic with CAS), CAD II patients (45 obese, diabetic with CAS), and 30 controls. Patients in CAD I and CAD II groups exhibited higher levels of chemerin and apelin together with lower levels of vaspin and omentin-1 than in controls. These alterations were more significant in CAD II than in CAD I patients. Additionally, adipokine levels were individually correlated with each other and with certain biochemical variables. Moreover, chemerin and vaspin levels could differentiate CAD II patients from CAD I and controls. Alterations of these adipokines may play a crucial role in the pathogenesis of CAS in obese type 2 diabetic Egyptian patients. Chemerin and vaspin could be used as markers to support diagnosis of CAS.

Motawi, T. K., N. I. Shehata, M. M. ElNokeety, and Y. F. El-Emady, "Potential serum biomarkers for early detection of diabetic nephropathy.", Diabetes research and clinical practice, vol. 136, pp. 150-158, 2018 Feb. Abstract

AIM: Diabetic nephropathy (DN) is considered as one of the diabetic complications affecting up to 40% of patients with type 1 or type 2 diabetes. In clinical practice, the frequently used markers of renal disease and progression are serum creatinine, estimated glomerular filtration rate (eGFR) and albuminuria. The aim of this study is to determine new biomarkers in human serum which are promising for early detection of DN.

METHODS: This study included 50 patients with type 2 diabetes mellitus (T2DM) and 25 clinically healthy individuals. The patients were divided into two groups; group I included 25 T2DM patients with normoalbuminuria, and group II consisted of 25 T2DM patients with microalbuminuria. In all groups, neutrophil gelatinase-associated lipocalin (NGAL), β-trace protein (βTP) and microRNA- 130b (miR-130b) were estimated.

RESULTS: The serum levels of NGAL and βTP were significantly elevated in T2DM patients with microalbuminuria (group II) compared with T2DM patients with normoalbuminuria (group I) and control subjects but there was no significant difference between group I and control subjects. Serum miR-130b level was significantly decreased in patients with T2DM (groups I and II) compared with healthy control subjects, with a higher decrease in their levels in group II compared with group I.

CONCLUSION: Our results suggest that serum NGAL and βTP as tubular and glomerular markers respectively, together with serum miR-130b may be independent and reliable biomarkers for early detection of DN in patients with T2DM.

Motawi, T. M. K., D. Sabry, N. W. Maurice, and S. M. Rizk, "Role of mesenchymal stem cells exosomes derived microRNAs; miR-136, miR-494 and miR-495 in pre-eclampsia diagnosis and evaluation.", Archives of biochemistry and biophysics, vol. 659, pp. 13-21, 2018 Dec 01. Abstract

BACKGROUND: Pre-eclampsia (PE) is one of the most threatening pregnancy complications. So far neither a secure, competent therapy for PE nor effective biomarkers for a premature discovery has been achieved. However, currently, the use of released microRNAs (miRNAs) as potential biomarkers and therapy targets for various diseases is the dominating area of research. The aim of our study was to identify miRNAs 136, 494 and 495 genes expression in exosomes of peripheral blood compared to umbilical cord mesenchymal stem cells (UCMSCs) conditioned media released exososomes in patients with PE, as valuable markers for PE early prediction.

METHODS: Blood samples were collected from 100 patients with PE and 100 control with normal pregnancies. Thirty fresh umbilical cord samples of women with healthy pregnancies (n = 15) and PE patients (n = 15) were retrieved during caesarean deliveries and UCMSCs were isolated from Wharton jelly. The expression of miRNAs 136, 494 and 495 in exosomes of peripheral blood and UCMSCs conditioned media was measured using quantitative real-time PCR method. Unpaired t-test, Pearson correlation test and Receiver operator characteristic (ROC) analysis were used for data analysis.

RESULTS: Our study revealed a significantly higher expression levels of miRNAs 136, 494 and 495 in exosomes of peripheral blood and matched with UCMSCs released exosomes from patients with PE compared to normal pregnancies (p = 0.000). In peripheral blood of PE, they were 6.4, 3.9 and 2.1 folds higher, respectively. ROC analysis revealed that the sensitivity and specificity values of miRNA-136 were 95% and 100%, respectively, with a cut-off value of 2.55. The sensitivity and specificity values of miRNA-494 were 86% and 95%, respectively, with a cut-off value of 0.47. The sensitivity and specificity values of miRNA-495 were 90% and 83%, respectively, with a cut-off value of 1.287.

CONCLUSION: Our findings suggest that exosomes derived miRNA-136, miRNA-494 and miRNA-495 could be promising circulating biomarkers in early detection of PE. Furthermore, UCMSCs released exosomes miRNA-136, miRNA-494 and miRNA-495 genes expression confirmed peripheral blood results analysis.

Motawi, T. K., H. A. Darwish, I. Diab, M. W. Helmy, and M. H. Noureldin, "Combinatorial strategy of epigenetic and hormonal therapies: A novel promising approach for treating advanced prostate cancer.", Life sciences, vol. 198, pp. 71-78, 2018 Apr 01. Abstract

AIMS: Estrogens act as key factors in prostate biology, cellular proliferation and differentiation as well as cancer development and progression. The expression of estrogen receptor (ER)-β appears to be lost during prostate cancer progression through hypermethylation mechanism. Epigenetic drugs such as 5-aza-2'-deoxycytidine (5-AZAC) and Trichostatin A (TSA) showed efficacy in restoring ERβ expression in prostate cancer cells. This study was designed to explore the potential anti-carcinogenic effects resulting from re-expressing ERβ1 using 5-AZAC and/or TSA, followed by its stimulation with Diarylpropionitrile (DPN), a selective ERβ1 agonist, in prostate cancer cell line PC-3.

MAIN METHODS: Cells were treated with 5-AZAC, TSA, DPN and their combination. Subsequently, they were subjected to proliferation assays, determinations of ERβ1 expression, protein levels of active caspase-3, cyclin D1, β-catenin and VEGF.

KEY FINDINGS: Treatment with these drugs exhibited an increase in ERβ1 expression to different extents as well as active caspase-3 levels. Meanwhile, a significant reduction in cyclin D1, VEGF and β-catenin levels was achieved as compared to the vehicle control group (p < 0.05). Interestingly, the triple combination regimen led to the most prominent anti-tumor responses in terms of increased apoptosis, reduced proliferation as well as angiogenesis.

SIGNIFICANCE: The results support the notion that ERβ1 acts as a tumor suppressor protein and suggest that sequential ERβ1 expression and activation can offer significant anti-tumor responses. The study highlights that the strategy of merging epigenetic and hormonal therapies may be beneficial in treating advanced prostate cancer.

2017
Motawi, T. K., S. A. EL-Maraghy, A. N. ElMeshad, O. M. Nady, and O. A. Hammam, "Cromolyn chitosan nanoparticles as a novel protective approach for colorectal cancer.", Chemico-biological interactions, vol. 275, pp. 1-12, 2017 Sep 25. Abstract

Colorectal cancer is the third most common cancer in the world. Cromolyn is a mast cell stabilizer and was proposed as an anticancer agent; however its high polarity limits its bioavailability by rapid washing from the body. We formulated 10 cromolyn chitosan nanoparticles (CCSNPs)(1) following ionic gelation technique to improve its bioavailability and investigated the protective anticancer effect of the optimum formula against colorectal cancer in dimethylhydrazine-induced model in rats. Rats were divided into seven groups, group-1: normal control, group-2: cromolyn control, group-3: CCSNPs control, groups-4 to 7 received dimethylhydrazine for 16 weeks to induce colorectal cancer. Groups-5 to 7 received cromolyn solution, non-medicated chitosan nanoparticles and CCSNPs, respectively as protective treatments. Optimum CCSNPs (size 112.4 nm, charge +39.9 mV, enclosed 93.6% cromolyn and showed a sustained drug release pattern over 48 h) significantly reduced tumor-signaling molecules and the number of aberrant crypt foci compared to dimethylhydrazine. Histopathological examination of colon samples revealed that CCSNPs exerted an augmented protective anticancer effect by ameliorating tumor pathology compared to cromolyn solution. In conclusion, CCSNPs ameliorated tumor pathology and malignant oncogenic signaling molecules in colorectal cancer tissue. Thus, CCSNPs may provide a novel protective approach in colorectal cancer treatment. Moreover, encapsulating cromolyn in chitosan nanoparticles augmented the protective anticancer effect of the drug.

Motawi, T. K., O. G. Shaker, M. F. Ismail, and N. H. Sayed, "Peroxisome Proliferator-Activated Receptor Gamma in Obesity and Colorectal Cancer: the Role of Epigenetics.", Scientific reports, vol. 7, issue 1, pp. 10714, 2017 Sep 06. Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that is deregulated in obesity. PPARγ exerts diverse antineoplastic effects. Attempting to determine the clinical relevance of the epigenetic mechanisms controlling the expression PPARγ and susceptibility to colorectal cancer (CRC) in obese subjects, this study investigated the role of some microRNAs and DNA methylation on the deregulation of PPARγ. Seventy CRC patients (34 obese and 36 lean), 22 obese and 24 lean healthy controls were included. MicroRNA levels were measured in serum. PPARγ promoter methylation was evaluated in peripheral blood mononuclear cells (PBMC). PPARγ level was evaluated by measuring mRNA level in PBMC and protein level in serum. The tested microRNAs (miR-27b, 130b and 138) were significantly upregulated in obese and CRC patients. Obese and CRC patients had significantly low levels of PPARγ. A significant negative correlation was found between PPARγ levels and the studied microRNAs. There was a significant PPARγ promoter hypermethylation in CRC patients that correlated to low PPARγ levels. Our results suggest that upregulation of microRNAs 27b, 130b and 138 is associated with susceptibility to CRC in obese subjects through PPARγ downregulation. Hypermethylation of PPARγ gene promoter is associated with CRC through suppression of PPARγ regardless of BMI.

Motawi, T. K., H. A. Darwish, M. A. Hamed, N. S. El-Rigal, and A. F. Aboul Naser, "Coenzyme Q10 and niacin mitigate streptozotocin- induced diabetic encephalopathy in a rat model.", Metabolic brain disease, vol. 32, issue 5, pp. 1519-1527, 2017 Oct. Abstract

Diabetic encephalopathy is an important complication of diabetes characterized by cognitive impairment, neurochemical and structural abnormalities. This study aimed to investigate the effect of coenzyme Q10 (CoQ10) and niacin as well as their combination in the treatment of encephalopathy associated with streptozotocin (STZ)- induced diabetes in rats. Glibenclamide (reference diabetic drug) and donepezil hydrochloride (acetylcholinesterase inhibitor) were also evaluated. Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg). One month after STZ injection, diabetic rats were treated with the aforementioned drugs for two weeks. The evaluation was done through measuring glucose level, total antioxidant capacity (TAC), interleukin 6 (IL6), DNA degradation as well as serotonin and noradrenaline as neurotransmitters. The present data illustrated that combining CoQ10 and niacin exhibiting the most potent effect in improving the measured parameters and ameliorating some of diabetes complications.

Motawi, T. M. K., S. M. Rizk, N. W. Maurice, A. M. Maged, A. N. Raslan, and A. H. Sawaf, "The role of gene polymorphisms and AMH level in prediction of poor ovarian response in Egyptian women undergoing IVF procedure.", Journal of assisted reproduction and genetics, vol. 34, issue 12, pp. 1659-1666, 2017 Dec. Abstract

OBJECTIVE: The aim of this study is to assess the role of AMH in prediction of poor ovarian response as well as the relation between ESR 2 (+ 1730G>A) (rs4986938) and FSHR p.Thr307Ala (c.919A>G, rs6165) SNPs and the poor ovarian response in Egyptian women undergoing IVF procedure. Discovering the genetic variants associated with ovarian response is an important step towards individualized pharmacogenetic protocols of ovarian stimulation.

METHODS: We performed a prospective study on 216 young women with unexplained infertility. Ovarian stimulation was performed according to the GnRH antagonist protocol with a fixed daily morning dose of human menopausal gonadotrophin (HMG). The estrogen receptor (ESR2) (+ 1730G>A) (rs4986938) and FSH receptor p.Thr307Ala (c.919A>G, rs6165) single nucleotide polymorphisms (SNPs) were detected by real-time polymerase chain reaction. Serum FSH, Estradiol (E2) and anti-Müllerian hormone (AMH) levels were measured by enzyme-linked immunosorbent assay (ELISA).

RESULTS: This study revealed that the low AMH level was highly significantly related to the poor ovarian response (p < 0.001). Furthermore, the frequency of the ESR2 (AA) genotype and the FSHR (Ala307Ala) genotypes were highly significantly associated with the poor ovarian response (p < 0.001).

CONCLUSION: The AMH level in combination with the ESR2 and the FSHR gene polymorphisms predict the poor ovarian response to COH in Egyptian women.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02640976.

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