Publications by authors named "Mohamed A M Ali"

22 Publications

  • Page 1 of 1

The DEAD-box protein family of RNA helicases: sentinels for a myriad of cellular functions with emerging roles in tumorigenesis.

Authors:
Mohamed A M Ali

Int J Clin Oncol 2021 Mar 3. Epub 2021 Mar 3.

Department of Biochemistry, Faculty of Science, Ain Shams University, Abbassia, Cairo, 11566, Egypt.

DEAD-box RNA helicases comprise a family within helicase superfamily 2 and make up the largest group of RNA helicases. They are a profoundly conserved family of RNA-binding proteins, carrying a generic Asp-Glu-Ala-Asp (D-E-A-D) motif that gives the family its name. Members of the DEAD-box family of RNA helicases are engaged in all facets of RNA metabolism from biogenesis to decay. DEAD-box proteins ordinarily function as constituents of enormous multi-protein complexes and it is believed that interactions with other components in the complexes might be answerable for the various capacities ascribed to these proteins. Therefore, their exact function is probably impacted by their interacting partners and to be profoundly context dependent. This may give a clarification to the occasionally inconsistent reports proposing that DEAD-box proteins have both pro- and anti-proliferative functions in cancer. There is emerging evidence that DEAD-box family of RNA helicases play pivotal functions in various cellular processes and in numerous cases have been embroiled in cellular proliferation and/or neoplastic transformation. In various malignancy types, DEAD-box RNA helicases have been reported to possess pro-proliferation or even oncogenic roles as well as anti-proliferative or tumor suppressor functions. Clarifying the exact function of DEAD-box helicases in cancer is probably intricate, and relies upon the cellular milieu and interacting factors. This review aims to summarize the current data on the numerous capacities that have been ascribed to DEAD-box RNA helicases. It also highlights their diverse actions upon malignant transformation in the various tumor types.
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http://dx.doi.org/10.1007/s10147-021-01892-1DOI Listing
March 2021

DEAD-box RNA helicases: The driving forces behind RNA metabolism at the crossroad of viral replication and antiviral innate immunity.

Authors:
Mohamed A M Ali

Virus Res 2021 Feb 25;296:198352. Epub 2021 Feb 25.

Department of Biochemistry, Faculty of Science, Ain Shams University, Abbassia, 11566, Cairo, Egypt. Electronic address:

DEAD-box RNA helicases, the largest family of superfamily 2 helicases, are a profoundly conserved family of RNA-binding proteins, containing a distinctive Asp-Glu-Ala-Asp (D-E-A-D) sequence motif, which is the origin of their name. Aside from the ATP-dependent unwinding of RNA duplexes, which set up these proteins as RNA helicases, DEAD-box proteins have been found to additionally stimulate RNA duplex fashioning and to uproot proteins from RNA, aiding the reformation of RNA and RNA-protein complexes. There is accumulating evidence that DEAD-box helicases play functions in the recognition of foreign nucleic acids and the modification of viral infection. As intracellular parasites, viruses must avoid identification by innate immune sensing mechanisms and disintegration by cellular machinery, whilst additionally exploiting host cell activities to assist replication. The capability of DEAD-box helicases to sense RNA in a sequence-independent way, as well as the broadness of cellular roles performed by members of this family, drive them to affect innate sensing and viral infections in numerous manners. Undoubtedly, DEAD-box helicases have been demonstrated to contribute to intracellular immune recognition, function as antiviral effectors, and even to be exploited by viruses to support their replication. Relying on the virus or the viral cycle phase, a DEAD-box helicase can function either in a proviral manner or as an antiviral factor. This review gives a comprehensive perspective on the various biochemical characteristics of DEAD-box helicases and their links to structural data. It additionally outlines the multiple functions that members of the DEAD-box helicase family play during viral infections.
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http://dx.doi.org/10.1016/j.virusres.2021.198352DOI Listing
February 2021

Role of nanoparticles in osteogenic differentiation of bone marrow mesenchymal stem cells.

Cytotechnology 2020 Feb 13;72(1):1-22. Epub 2019 Nov 13.

Hormones Department, Medical Research Division, National Research Centre, 33 EL Bohouth St. (former EL -Tahrir st.), Dokki, Giza, P.O. 12622, Egypt.

The present study aimed to investigate the osteoinductive potentiality of some selected nanostructures; Hydroxyapatite (HA-NPs), Gold (Au-NPs), Chitosan (C-NPs), Gold/hydroxyapatite (Au/HA-NPs) and Chitosan/hydroxyapatite (CH-NPs) on bone marrow- derived mesenchymal stem cells (BM-MSCs). These nanostructures were characterized using transmission electron microscope and Zetasizer. MSCs were isolated from bone marrow of rat femur bones and their identity was documented by morphology, flow cytometry and multi-potency capacity. The influence of the selected nanostructures on the viability, osteogenic differentiation and subsequent matrix mineralization of BM-MSCs was determined by MTT assay, molecular genetic analysis and alizarin red S staining, respectively. MTT analysis revealed insignificant toxicity of the tested nanostructures on BM-MSCs at concentrations ranged from 2 to 25 µg/ml over 48 h and 72 h incubation period. Notably, the tested nanostructures potentiate the osteogenic differentiation of BM-MSCs as evidenced by a prominent over-expression of runt-related transcription factor 2 (Runx-2) and bone morphogenetic protein 2 (BMP-2) genes after 7 days incubation. Moreover, the tested nanostructures induced matrix mineralization of BM-MSCs after 21 days as manifested by the formation of calcium nodules stained with alizarin red S. Conclusively, these data provide a compelling evidence for the functionality of the studied nanostructures as osteoinductive materials motivating the differentiation of BM-MSCs into osteoblasts with the most prominent effect observed with Au-NPs and Au/HA-NPs, followed by CH-NPs.
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http://dx.doi.org/10.1007/s10616-019-00353-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002803PMC
February 2020

Cervical high-risk human papillomavirus infection among women residing in the Gulf Cooperation Council countries: Prevalence, type-specific distribution, and correlation with cervical cytology.

Cancer Cytopathol 2019 Sep 7;127(9):567-577. Epub 2019 Aug 7.

Department of Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

Background: The scarcity of updated data on the prevalence of cervical human papillomavirus (HPV) infection in the Gulf Cooperation Council (GCC) countries hampers the establishment of cervical cancer screening and HPV vaccination programs. The current study estimated the prevalence of cervical high-risk (HR) HPV infection among women residing in some countries of the GCC and analyzed the correlation between HR-HPV infection types and cytology results.

Methods: In total, 2478 women residing in the Kingdom of Saudi Arabia, Qatar, the United Arab Emirates, and Bahrain were enrolled in this study. Cervical specimens were subjected to simultaneous liquid-based cytology and HR-HPV DNA analysis.

Results: Of 2478 women, 520 (21%) tested positive for HR-HPV. Other non-HPV genotype 16 (HPV16)/HPV18 HR-HPV was the most frequently detected infection type, accounting for 63.7%. Non-Arab women had a significantly higher HR-HPV positivity rate compared with Arab women (31.6% vs 16.4%; P < .001). The HR-HPV positivity rate was highest among women residing in Qatar (31.3%), followed by women living in Bahrain (20%), the Kingdom of Saudi Arabia (17.2%), and the United Arab Emirates (14.7%). The overall prevalence of HR-HPV infections declined significantly with advancing age (P < .001). Women with abnormal cytology had a significantly higher HR-HPV positivity rate than those with normal cytology (50.6% vs 14.7%; P < .001). The HR-HPV positivity rate increased as the severity of the cytological lesion increased.

Conclusions: The current study provides updated data on HR-HPV prevalence in the GCC countries and delivers an evidence base for supporting the introduction of regional/national vaccination and screening programs in these countries.
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http://dx.doi.org/10.1002/cncy.22165DOI Listing
September 2019

Development of an efficient cell-based assay system for monitoring hepatitis C virus genotype 4a NS3/4A protease activity.

Indian J Pathol Microbiol 2019 Jul-Sep;62(3):391-398

Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.

Background: Hepatitis C virus (HCV) represents a serious worldwide healthcare problem. No protective vaccines against HCV have been developed yet due to the fact that HCV is rapidly mutable, allowing the virus to escape from the neutralizing antibodies. Understanding of HCV was initially hampered by the inability to achieve viral replication in cell culture. Given its essential roles in viral polyprotein processing and immune evasion, HCV NS3/4A protease is a prime target for antiviral chemotherapy. We aimed to establish in vivo cell-based assay system for monitoring the activity of NS3/4A protease from HCV genotype 4a, the predominant genotype in Egypt, and the Middle East. Furthermore, the developed system was used to evaluate the inhibitory potency of a series of computer-designed chemically-synthesized compounds against NS3/4A protease from HCV genotype 4a.

Materials And Methods: Native as well as mutant cleavage sites to NS3/4A protease were cloned in frame into β-galactosidase gene of TA cloning vector. The target specificity of HCV NS3/4A was evaluated by coexpression of β-galactosidase containing the protease cleavage site with NS3/4A protease construct in bacterial cells. The activity of β-galactosidase was colorimetrically estimated in the cell lysate using orthonitro phenyl β-D-galactopyanoside (ONPG) as a substrate.

Results And Conclusions: We successfully developed an efficient cell-based system based on the blue/white selection of bacterial cells that are able to express functional/nonfunctional β-galactosidase enzyme.
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http://dx.doi.org/10.4103/IJPM.IJPM_774_18DOI Listing
December 2019

Additive Diagnostic Yield of Homozygosity Regions Identified During Chromosomal microarray Testing in Children with Developmental Delay, Dysmorphic Features or Congenital Anomalies.

Biochem Genet 2020 Feb 4;58(1):74-101. Epub 2019 Jul 4.

Cytogenetics Unit, Al Borg Medical Laboratories, Jeddah, Kingdom of Saudi Arabia.

Chromosomal microarray (CMA) has emerged as a robust tool for identifying microdeletions and microduplications, termed copy number variants (CNVs). Nevertheless, data regarding its utility in different patient populations with developmental delay (DD), dysmorphic features (DF) and congenital anomalies (CA), is a matter of dense debate. Although regions of homozygosity (ROH) are not diagnostic of a specific condition, they may have pathogenic implications. Certain CNVs and ROH have ethnically specific occurrences and frequencies. We aimed to determine whether CMA testing offers additional diagnostic information over classical cytogenetics for identifying genomic imbalances in a pediatric cohort with idiopathic DD, DF, or CA. One hundred sixty-nine patients were offered cytogenetics and CMA simultaneously for etiological diagnosis of DD (n = 67), DF (n = 52) and CA (n = 50). CMA could identify additional, clinically significant anomalies as compared with cytogenetics. CMA detected 61 CNVs [21 (34.4%) pathogenic CNVs, 37 (60.7%) variants of uncertain clinical significance and 3 (4.9%) benign CNVs] in 44 patients. CMA identified one or more ROH in 116/169 (68.6%) patients. When considering pathogenic CNVs and aneuploidies as positive findings, 9/169 (5.3%) received a genetic diagnosis from cytogenetics, while 25/169 (14.8%) could have a genetic diagnosis from CMA. The identification of ROH was clinically significant in two cases (2/169), thereby, adding 1.2% to the diagnostic yield of CMA (16% vs. 5.3%, p < 0.001). CMA uncovers additional genetic diagnoses over cytogenetics, thereby, offering a much higher diagnostic yield. Our findings convincingly demonstrate the additive diagnostic value of clinically significant ROH identified during CMA testing, highlighting the need for careful clinical interpretation of these ROH.
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http://dx.doi.org/10.1007/s10528-019-09931-3DOI Listing
February 2020

Correlation between Antioxidant/Antimutagenic and Antiproliferative Activity of Some Phytochemicals.

Anticancer Agents Med Chem 2019 ;19(12):1481-1490

Department of Zoology, Faculty of Science, Ain Shams University, Abbassia 11566, Cairo, Egypt.

Background: Chemotherapeutic drugs have high toxicity associated with undesirable side-effects. Now, natural products are the most important anti-cancer agents because of their low toxicity and potential effectiveness.

Methods: The half maximal inhibitory concentration (IC50) of amygdalin, naringenin and ellagic acid against breast, colon, and liver cell lines was estimated. The antimutagenic, free radical-, superoxide radical-, and hydroxyl radical- scavenging activities of these phytochemicals were measured. The expression of p53, bid, bax, bcl2, and caspases 9, 3, and 7 was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in breast and liver cells. In addition, the active Caspase 3 protein was estimated in liver cells.

Results: Ellagic acid showed the highest antioxidant and antiproliferative activities. Amygdalin and naringenin with low and moderate antioxidant profiles showed a corresponding low and moderate cytotoxicity against cancer cell lines, respectively. Naringenin and ellagic acid had a significant antimutagenic activity which was detected by the Salmonella test. Ellagic acid offered a much better antimutagenic activity than naringenin. The apoptotic pathway evoked by ellagic acid in HepG2 and MCF-7 cells was investigated. The results showed that a caspase-dependent and a caspase-independent apoptosis occurred in MCF-7 and HepG2, respectively.

Conclusion: The antimutagenic/antioxidant properties are well correlated with the antiproliferative activity of the phytochemicals investigated. This study proved that some easy, quick and cheap assays could predict the antiproliferative activity of many nutraceuticals. Finally, this platform could help in the discovery of new anticancer agents where hundreds of compounds are investigated in the pipeline of drug discovery.
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http://dx.doi.org/10.2174/1871520619666190528091648DOI Listing
March 2020

Identification of novel small molecule inhibitors against the NS3/4A protease of hepatitis C virus genotype 4a.

Curr Pharm Des 2018 ;24(37):4484-4491

Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.

Background: Hepatitis C virus (HCV) infection poses a considerable threat to the public health. The current standard of care treatment with pegylated interferon-alpha in combination with ribavirin (PEG-IFN- α+RBV) is associated with significant side effects, poorly tolerated, and provides limited efficacy. The development of direct-acting antiviral agents (DAAs) targeting key viral enzymes essential for viral replication represents a significant milestone in the treatment of chronic HCV infection. Given its critical role in the viral polyprotein processing and the evasion of the host innate immunity, the NS3/4A protease has emerged as a promising drug target for the development of anti-HCV therapies. Although several potent NS3/4A protease inhibitors (PIs) have been approved or are in clinical development, the majority of currently available PIs have significant limitations related to untoward adverse events and a lack of pan-genotypic activity, indicating a continuing unmet medical need for the development and optimization of novel PIs with improved efficacy and tolerability, convenient dosing schedules, and shorter treatment durations.

Methods: The inhibitory efficacy of four computer-designed chemically-synthesized compounds was evaluated against in vitro-expressed NS3/4A protease from HCV genotype 4a, the most prevalent genotype in Egypt, using a fluorescence-based enzymatic assay.

Results: We successfully identified two non-macrocyclic small molecules, BE113 (7a) and BE114 (7b), which exhibited inhibitory activity against HCV NS3/4A protease from HCV genotype 4a.

Conclusion: The two compounds presented in this study may be promising inhibitors against NS3/4A protease of HCV genotype 4a and could be novel lead compounds for developing new therapeutics for the treatment of chronic HCV infection.
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http://dx.doi.org/10.2174/1381612825666181203153835DOI Listing
November 2019

Influence of IL-6, IL-10, IFN-γ and TNF-α genetic variants on susceptibility to diabetic kidney disease in type 2 diabetes mellitus patients.

Biomarkers 2019 Feb 31;24(1):43-55. Epub 2018 Aug 31.

c Internal Medicine Department , Amiri Hospital , Kuwait city , Kuwait.

Background: Data from previous studies on the role of inflammatory cytokines as biomarkers for diabetic kidney disease (DKD) are contradictory. The association of a particular inflammatory cytokine single nucleotide polymorphism (SNP) with susceptibility to DKD has not been consistently replicated. We aimed to investigate the utility of inflammatory cytokines as biomarkers for DKD in type 2 diabetes mellitus (T2DM) patients. Association of inflammatory cytokine gene SNPs with the development of DKD was also explored.

Subjects And Methods: One hundred and fifty-nine Kuwaiti subjects were recruited in this study, including 50 T2DM patients without DKD, 67 diabetic DKD patients and 42 healthy subjects. Plasma levels of interleukin-6 (IL-6), IL-10, interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) were measured by enzyme-linked immunosorbent assays. Nine SNPs, including 2 SNPs in IL-6, 3 SNPs in IL-10, 1 SNP in IFN-γ and 3 SNPs in TNF-α, were genotyped using TaqMan SNP genotyping assays.

Results: Diabetic DKD patients showed higher IL-6, IL-10, IFN-γ and TNF-α levels than those without DKD. Diabetic DKD patients had a significantly higher frequency of IL-10 - 1082 A allele than those without DKD (p = 0.001). No significant association of IL-6 - 174/-597 haplotypes with DKD risk was detected (p = 0.188). Distribution of IL-10 - 592/-819/-1082 haplotypes differ significantly between T2DM patients with/without DKD (p = 0.014). Diabetic DKD patients had a significantly lower frequency of IL-10 - 592C/-819C/-1082G haplotype than those without DKD (p = 0.002).

Conclusions: Although inflammatory cytokine genotypes and, more importantly, haplotypes may have the potential to identify those patients at risk of DKD, hence, improving DKD predisposition prediction, further investigations regarding their real clinical significance is warranted in a large cohort of patients.
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http://dx.doi.org/10.1080/1354750X.2018.1501761DOI Listing
February 2019

Time-course expression profile and diagnostic potential of a miRNA panel in exosomes and total serum in acute liver injury.

Int J Biochem Cell Biol 2018 07 5;100:11-21. Epub 2018 May 5.

Biochemistry Department, Faculty of Pharmacy, Cairo University, Egypt. Electronic address:

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.
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http://dx.doi.org/10.1016/j.biocel.2018.05.002DOI Listing
July 2018

The Synonymous Isocitrate Dehydrogenase 1 315C>T SNP Confers an Adverse Prognosis in Egyptian Adult Patients with NPM1-/CEBPA-Negative Acute Myeloid Leukemia.

Indian J Hematol Blood Transfus 2018 Apr 24;34(2):240-252. Epub 2017 Jul 24.

3Zoology Department, Faculty of Science, Ain Shams University, Cairo, Egypt.

Although the clinical features of isocitrate dehydrogenase () genetic aberrations have been well-characterized in acute myeloid leukemia (AML), definitive information on their prognostic significance is lacking. We aimed to explore the prognostic significance of gene alterations in an Egyptian cohort of adult patients with AML. Diagnostic peripheral blood samples from 51 AML patients were analyzed for the presence of mutations/SNPs in exon 4 of and genes using polymerase chain reaction amplification followed by direct sequencing. mutational status had no impact on event-free survival (EFS) and overall survival (OS), whereas the presence of 315C>T SNP was significantly associated with inferior EFS ( = 0.037) and OS ( = 0.034) as compared with wild-type . 315C>T SNP but not mutations is associated with unfavorable outcomes, suggesting that AML patients with 315C>T SNP can represent a new subgroup of patients which allows refined risk stratification.
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http://dx.doi.org/10.1007/s12288-017-0852-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884974PMC
April 2018

Extracellular miR-145, miR-223 and miR-326 expression signature allow for differential diagnosis of immune-mediated neuroinflammatory diseases.

J Neurol Sci 2017 Dec 15;383:188-198. Epub 2017 Nov 15.

Medical Molecular Genetics Department, National Research Centre, Cairo, Egypt.

Background: Although misdiagnosis of neuromyelitis optica spectrum disorder (NMOSD) with neuropsychiatric systemic lupus erythematosus (NPSLE) or multiple sclerosis (MS) is not infrequent, reliable biomarkers remains an unmet need. Extracellular microRNAs (miRNAs) represent a worthy avenue to identify biomarkers for differential diagnosis. We aimed to explore the potential role of some selected circulating miRNAs as biomarkers for the differential diagnosis in immune-mediated neuroinflammatory diseases.

Methods: A total of 80 subjects were enrolled in the present study, including 37 patients with MS (relapsing-remitting MS [RRMS; n=18] and secondary progressive MS [SPMS; n=19]), 10 patients with NMOSD and 10 patients with NPSLE as well as 23 healthy subjects. Serum expression levels of three selected miRNAs (miR-145, miR-223 and miR-326) were measured using quantitative real-time polymerase chain reaction (qRT-PCR). Whole blood expression levels of cellular immune response-relevant target genes, including signaling mother against decapentaplegic peptide 3 (SMAD3) and specificity protein 1 (SP1), were also measured using qRT-PCR.

Results: In comparison to healthy subjects, only miR-145 and miR-223 were significantly up-regulated in MS patients, whereas, all the analyzed miRNAs revealed insignificant upregulation in NMOSD patients. All the examined miRNAs were significantly down-regulated in NPSLE patients compared to healthy subjects. miR-145, miR-223 and miR-326 expression profile is a promising diagnostic biomarker for MS and NPSLE, but not for NMOSD. This expression profile is capable of differentiating not only among MS, NMOSD and NPSLE, but also between RRMS and SPMS.

Conclusion: Specific circulating miRNAs expression signature may have the potential to differentially diagnose immune-mediated neuroinflammatory diseases.
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http://dx.doi.org/10.1016/j.jns.2017.11.014DOI Listing
December 2017

Identification of host DEAD-box RNA helicases that regulate cellular tropism of oncolytic Myxoma virus in human cancer cells.

Sci Rep 2017 Nov 16;7(1):15710. Epub 2017 Nov 16.

The Biodesign Institute; Center for Immunotherapy, Vaccines, and Virotherapy; Arizona State University, Tempe, AZ, 85287-5401, USA.

Myxoma virus (MYXV), a Leporipoxvirus, is being developed as an oncolytic virotherapeutic for the treatment of a variety of human cancers. MYXV tropism for human cancer cells is largely mediated by intracellular signaling networks that regulate viral replication or innate antiviral response pathways. Thus, MYXV is fully or partially permissive for the majority of human cancer cells that harbor defects in antiviral signaling, but a minority are nonpermissive because the virus infection aborts before its completion. To identify host factors relevant for MYXV tropism in human cancer cells, we performed a small interfering RNA (siRNA) library screen targeting the 58 human DEAD-box RNA helicases in two permissive human cancer cells (HeLa and A549), one semi-permissive (786-0), and one nonpermissive cell line (PANC-1). Five host RNA helicases (DDX3X, DDX5, DHX9, DHX37, DDX52) were inhibitory for optimal replication and thus classified as anti-viral, while three other cellular RNA helicases (DHX29, DHX35, RIG-I) were identified as pro-viral or pro-cellular because knockdown consistently reduced MYXV replication and/or required metabolic functions of permissive cancer cells. These findings suggest that replication of MYXV, and likely all poxviruses, is dramatically regulated positively and negatively by multiple host DEAD-box RNA helicases.
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http://dx.doi.org/10.1038/s41598-017-15941-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5691082PMC
November 2017

Redox dysregulation, immuno-inflammatory alterations and genetic variants of BDNF and MMP-9 in schizophrenia: Pathophysiological and phenotypic implications.

Schizophr Res 2017 10 15;188:98-109. Epub 2017 Jan 15.

Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.

Background: Although a clear mechanism underlying the pathophysiology of schizophrenia (SZ) remains elusive, oxidative stress, inflammatory syndrome and immune activation have become an attractive hypothesis for explaining the pathophysiology of SZ. Data from prior studies on the role of matrix metalloproteinase 9 (MMP-9) and brain-derived neurotrophic factor (BDNF) single nucleotide polymorphisms (SNPs) in SZ are contradictory. We aimed to investigate whether oxidative stress, inflammatory and immune activation markers as well as MMP-9 levels may be implicated in SZ pathogenesis. The association of MMP-9 and BDNF SNPs with the clinical expression of SZ was examined.

Subjects And Methods: Ninety-four subjects were recruited, including 44 SZ patients and 50 healthy controls. Serum levels of thiobarbituric acid reactive substances (TBARS), protein carbonyl content (PCC), nitrite, C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), Beta-2 microglobulin (Β2M), complement component 3 (C3), C4 and MMP-9 were measured. The MMP-9 -1562C>T and BDNF196G>A SNPs were genotyped using polymerase chain reaction-restriction fragment length polymorphism assay. Psychopathology was assessed using the positive and negative syndrome scale (PANSS).

Results: SZ patients showed significantly higher TBARS, PCC, nitrite, CRP, IL-6, TNF-α, Β2M, C3 and MMP-9 levels than controls. In distinguishing SZ patients from healthy controls, CRP and MMP-9 yielded similar discriminatory performance, and both perform better than IL-6, Β2M, C3, nitrite, TBARS, PCC, TNF-α and C4. The MMP-9 -1562C>T SNP genotypes distribution didn't differ significantly between controls and SZ patients. As compared to controls, SZ patients harbor a significantly higher frequency of the BDNF196GG genotype and a lower frequency of the BDNF196GA/AA genotype. Patients carrying the MMP-9 -1562CC or BDNF196GG genotype revealed a significantly higher PANSS than those carrying MMP-9 -1562CT/TT or BDNF196GA/AA genotype. Male gender and the MMP-9 -1562CC genotype were identified as independent predictive factors for higher PANSS.

Conclusions: Redox dysregulation and alterations in the immuno-inflammatory pathways are major culprits in the pathogenesis of SZ. MMP-9 and BDNF SNPs are associated with the clinical phenotype of SZ and, thus, may be a useful marker predicting the phenotypic expression and prognosis of SZ patients.
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http://dx.doi.org/10.1016/j.schres.2017.01.016DOI Listing
October 2017

Ellagic and ferulic acids alleviate gamma radiation and aluminium chloride-induced oxidative damage.

Life Sci 2016 Sep 17;160:2-11. Epub 2016 Jul 17.

Radiation Biology Department, National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt.

Aim: Ionizing radiation interacts with biological systems through the generation of free radicals, which induce oxidative stress. Aluminium (Al) can negatively impact human health by direct interaction with antioxidant enzymes. Ellagic acid (EA) and Ferulic acid (FA) are plant polyphenolic compounds, have gained attention due to their multiple biological activities. To date, no studies investigating the antioxidant effect of EA/FA in a model involving both γ radiation and aluminium chloride (AlCl3) have been reported. Herein, we investigated the protective effect of EA and FA against oxidative stress induced by γ radiation and AlCl3 in rats.

Methods: Rats were divided into thirteen groups: a negative control group, 3 positive control groups (γ-irradiated, AlCl3-treated and γ-irradiated+AlCl3-treated) and 9 groups (3 γ-irradiated, 3 AlCl3-treated and 3 γ-irradiated+AlCl3-treated) treated with EA and/or FA. Liver function and lipid profile were assessed. Levels of lipid peroxidation, protein oxidation and endogenous antioxidants as well as the concentrations of copper, iron and zinc were estimated in liver tissue homogenate. Furthermore, liver tissue sections were histologically examined.

Results: Oral administration of EA and/or FA resulted in 1) amelioration of AlCl3 and/or γ-radiation-induced hepatic function impairment, dyslipidemia and hepatic histological alterations; 2) reduction in liver MDA and PCC levels; 3) elevation of liver CAT, GPx and SOD activity as well as GSH level; 4) elevation in liver Cu concentrations which was accompanied by a reduction in Fe and Zn concentrations.

Conclusions: Oral administration of EA and/or FA may be useful for ameliorating γ radiation and/or AlCl3-induced oxidative damage.
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http://dx.doi.org/10.1016/j.lfs.2016.07.006DOI Listing
September 2016

Presepsin is an early monitoring biomarker for predicting clinical outcome in patients with sepsis.

Clin Chim Acta 2016 Sep 25;460:93-101. Epub 2016 Jun 25.

Microbiology and Immunology Department, El-Maadi Military Hospital, Cairo, Egypt.

Despite their undoubted helpfulness in diagnosing sepsis, increased blood C-reactive protein (CRP) and procalcitonin (PCT) levels have been described in many noninfectious conditions. Presepsin is a soluble fragment of the cluster of differentiation 14 involved in pathogen recognition by innate immunity. We aimed to investigate the diagnostic and prognostic performance of presepsin in comparison to PCT and CRP in patients presenting with systemic inflammatory response syndrome (SIRS) and suspected sepsis. Seventy-six subjects were enrolled in this study, including 51 patients with SIRS as well as 25 healthy subjects. Plasma presepsin, PCT and CRP levels were serially measured on admission and at days 1, 3, 7 and 15. Presepsin and PCT yielded similar diagnostic accuracy, whereas presepsin performed significantly better than CRP. Presepsin and PCT showed comparable performance for predicting 28-day mortality, and both biomarkers performed significantly better than CRP. In septic patients, presepsin revealed earlier concentration changes over time when compared to PCT and CRP. Presepsin and PCT could differentiate between septic and non-septic patients with comparable accuracy and both biomarkers showed similar performance for predicting 28-day mortality. Early changes in presepsin concentrations might reflect the appropriateness of the therapeutic modality and could be useful for making effective treatment decisions.
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http://dx.doi.org/10.1016/j.cca.2016.06.030DOI Listing
September 2016

Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors: An Evolving Paradigm of Molecularly Targeted Therapy.

Authors:
Mohamed A M Ali

Mol Diagn Ther 2016 08;20(4):315-33

Department of Biochemistry, Faculty of Science, Ain Shams University, Abbassia, 11566, Cairo, Egypt.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent hematopoietic stem cells. CML was the first malignancy in which a unique chromosomal abnormality was identified and a pathophysiologic association was suggested. The hallmark of CML is a reciprocal chromosomal translocation between the long arms of chromosomes 9 and 22, t(9; 22)(q34; q11), creating a derivative 9q+ and a shortened 22q-. The latter, known as the Philadelphia (Ph) chromosome, harbors the breakpoint cluster region-abelson (BCR-ABL) fusion gene, encoding the constitutively active BCR-ABL tyrosine kinase that is necessary and sufficient for initiating CML. The successful implementation of tyrosine kinase inhibitors (TKIs) for the treatment of CML remains a flagship for molecularly targeted therapy in cancer. TKIs have changed the clinical course of CML; however, some patients nonetheless demonstrate primary or secondary resistance to such therapy and require an alternative therapeutic strategy. Therefore, the assessment of early response to treatment with TKIs has become an important tool in the clinical monitoring of CML patients. Although mutations in the BCR-ABL have proven to be the most prominent mechanism of resistance to TKIs, other mechanisms-either rendering the leukemic cells still dependent on BCR-ABL activity or supporting oncogenic properties of the leukemic cells independent of BCR-ABL signaling-have been identified. This article provides an overview of the current understanding of CML pathogenesis; recommendations for diagnostic tools, treatment strategies, and management guidelines; and highlights the BCR-ABL-dependent and -independent mechanisms that contribute to the development of resistance to TKIs.
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http://dx.doi.org/10.1007/s40291-016-0208-1DOI Listing
August 2016

Tissue CA125 and HE4 Gene Expression Levels Offer Superior Accuracy in Discriminating Benign from Malignant Pelvic Masses.

Asian Pac J Cancer Prev 2016 ;17(1):323-33

Clinical Pathology Department, National Cancer Institute, Cairo University, Egypt E-mail :

Background: Ovarian cancer remains a major worldwide health care issue due to the lack of satisfactory diagnostic methods for early detection of the disease. Prior studies on the role of serum cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) in detecting ovarian cancer presented conflicting results. New tools to improve the accuracy of identifying malignancy are urgently needed. We here aimed to evaluate the diagnostic utility of tissue CA125 and HE4 gene expression in comparison to serum CA125 and HE4 in discriminating benign from malignant pelvic masses.

Materials And Methods: One-hundred Egyptian women were enrolled in this study, including 60 epithelial ovarian cancer (EOC) patients and 20 benign ovarian tumor patients, as well as 20 apparently healthy women. Preoperative serum levels of CA125 and HE4 were measured by immunoassays. Tissue expression levels of genes encoding CA125 and HE4 were determined by quantitative real time polymerase chain reaction (qRT-PCR). The diagnostic performance of CA125 and HE4, measured either as mRNA or protein levels, was evaluated by receiver operating characteristic (ROC) curves.

Results: The serum CA125+HE4 combination and serum HE4, with area under the curve (AUC) values of 0.935 and 0.932, respectively, performed significantly better than serum CA125 (AUC=0.592; P<0.001). Tissue CA125 and HE4 (AUC=1) performed significantly better than serum CA125 (P<0.001), serum HE4 (P=0.016) and the serum CA125+HE4 combination (P=0.018).

Conclusions: Measurement of tissue CA125 and HE4 gene expression not only improves discriminatory performance, but also broadens the range of differential diagnostic possibilities in distinguishing EOC from benign ovarian tumors.
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http://dx.doi.org/10.7314/apjcp.2016.17.1.323DOI Listing
November 2016

Diagnostic utility of BNP, corin and furin as biomarkers for cardiovascular complications in type 2 diabetes mellitus patients.

Biomarkers 2015 21;20(6-7):460-9. Epub 2015 Oct 21.

d General Directorate of Human Resources Development, Ministry of Health , Gaza , Palestine.

Context: The number of patients with type 2 diabetes mellitus (T2DM) is progressively increasing, and diabetic cardiovascular complications have become a public health problem. Brain or B-type natriuretic peptide (BNP) is a cardiac hormone synthesized as a pre-pro-peptide. pro-BNP is produced by cleaving the signal peptide then two proprotein convertases, corin and furin cleave pro-BNP to form a biologically active hormone. Two corin single nucleotide polymorphisms (SNPs) have been reported to alter corin protein conformation and impair its biological activity.

Objective: We aimed to investigate the potential role of corin and furin in comparison to BNP as biomarkers for predicting cardiovascular complications in T2DM patients. The association of corin gene SNPs with corin levels was also examined.

Methods: Seventy-five subjects were recruited in this study, including 25 T2DM patients with complications, 25 T2DM patients without complications as well as 25 healthy subjects. Plasma BNP, corin and furin levels were measured using enzyme-linked immunosorbent assays. Two corin SNPs were genotyped using allele specific oligonucleotide-polymerase chain reaction.

Results: Both furin and BNP were found to be more sensitive than corin (80% versus 56%, p = 0.008), whereas furin showed higher specificity when compared to BNP (96% versus 84%, p = 0.041) and corin (96% versus 64%, p < 0.0001) in predicting cardiovascular complications in T2DM patients. Corin SNPs are not associated with corin levels, neither in the entire study cohort nor in the subgroup of T2DM patients with cardiovascular complications (p > 0.05).

Conclusions: Furin may be useful, either alone or in combination with other biomarkers, for cardiovascular risk stratification assessment in T2DM patients.
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http://dx.doi.org/10.3109/1354750X.2015.1093032DOI Listing
September 2016

Secreted Phosphoprotein 1 Promoter Genetic Variants Are Associated with the Response to Pegylated Interferon α Plus Ribavirin Combination Therapy in Egyptian Patients with Chronic Hepatitis C Virus Infection.

Gut Liver 2015 Jul;9(4):516-24

Internal Medicine Hospital, Armed Forces Medical Complex, Kobry Elqobba, Cairo, Egypt.

Background/aims: The T-helper 1 (TH1) immune reaction is essential for the eradication of hepatitis C virus (HCV) during pegylated interferon α (PEG-IFN-α)- and ribavirin (RBV)-based therapy in chronic HCV patients. Secreted phosphoprotein 1 (SPP1) was shown to be a crucial cytokine for the initiation of a TH1 immune response. We aimed to investigate whether SPP1 single nucleotide polymorphisms (SNPs) may influence sustained virological response (SVR) rates.

Methods: Two SNPs in the promoter region of SPP1 at the -443 C>T and -1748 G>A loci were genotyped in 100 patients with chronic HCV genotype 4 infection using a TaqMan SNP genotyping assay.

Results: Sixty-seven patients achieved a SVR, and 33 patients showed no SVR. Patients carrying the T/T genotype at the -443 locus showed a significantly higher SVR rate than those carrying the C/T or C/C genotype (83.67% vs. 50.98%, p<0.001). At the -1748 locus, the SVR rate was significantly higher in patients with the G/G genotype than in those with the A/A genotype (88.89% vs. 52.63%, p=0.028) and in patients with the G/A genotype than in those with the A/A genotype (85.29% vs. 52.63%, p=0.001).

Conclusions: SPP1 SNPs at -443 C>T and -1748 G>A loci may be useful markers for predicting the response to PEG-IFN-α-2b plus RBV therapy in Egyptian patients with chronic HCV genotype 4 infection.
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http://dx.doi.org/10.5009/gnl14162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477996PMC
July 2015

ABCB1 haplotypes but not individual SNPs predict for optimal response/failure in Egyptian patients with chronic-phase chronic myeloid leukemia receiving imatinib mesylate.

Med Oncol 2014 Nov 11;31(11):279. Epub 2014 Oct 11.

Department of Biochemistry, Faculty of Science, Ain Shams University, Abbassia, Cairo, 11566, Egypt,

Imatinib mesylate (IM) has so far been the standard of care for treating chronic myeloid leukemia (CML), but the initial striking efficacy of this drug has been overshadowed by the development of clinical resistance, which may in part be caused by pharmacogenetic variability. The ATP-binding cassette, subfamily B, member 1 (ABCB1) gene codes for P-glycoprotein (P-gp), a membrane-bound efflux transporter known to affect the pharmacokinetics of many drugs. IM is a substrate of the P-gp-mediated efflux. ABCB1 single nucleotide polymorphisms (SNPs) have been reported as modulators of ABCB1-mediated transport, affecting IM's bioavailability and consequently the treatment outcome of IM therapy. We aimed to examine the association between ABCB1 SNPs and the likelihood of achieving optimal response in IM-treated CML patients. Three ABCB1 SNPs (C1236T, G2677T, and C3435T) were genotyped in 100 Egyptian patients with CML undergoing IM therapy using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The optimal response rate did not differ significantly between C1236T, G2677T, or C3435T genotypes (P > 0.05). Optimal response rate was significantly different among patients with the CGC, TTT, TGC, CGT, TGT, CTC, CTT, and TTC haplotypes (P = 0.023). The 1236T-2677G-3435T haplotype was significantly associated with lower probability of achieving optimal response (P = 0.001). ABCB1 SNPs haplotype analysis should be taken into account in an attempt to get clearer insights into who is likely to respond optimally to IM for identifying CML patients who may not respond optimally to standard-dose IM therapy and potentially need an individualized therapeutic approach.
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http://dx.doi.org/10.1007/s12032-014-0279-yDOI Listing
November 2014

Value of vanin-1 assessment in adult patients with primary immune thrombocytopenia.

Platelets 2014 27;25(2):86-92. Epub 2013 Mar 27.

Clinical Hematology and Bone Marrow Transplant Unit, Internal Medicine Department, Faculty of Medicine, Ain Shams University , Cairo , Egypt .

The diagnosis of primary immune thrombocytopenia (ITP) is clinical and cannot be established by any specific laboratory assay. Perhaps the best diagnostic study is assessment of the patient's response to ITP therapy. Oxidative stress-related pathways were among the most significant chronic ITP-associated pathways. Overexpression of VNN1 gene, an oxidative stress sensor in epithelial cells, was most strongly associated with progression to chronic ITP. To address this issue, we tested the hypothesis that blood vanin-1 protein level could distinguish between chronic responders and non-responders ITP patients as well as between ITP patients and healthy controls. Vanin-1 protein levels were determined in peripheral blood leukocytes of 80 adult subjects (16 newly diagnosed ITP patients, 24 chronic responders ITP patients, 24 chronic non-responders ITP patients and 16 healthy controls) by enzyme-linked immunesorbent assay (ELISA). Blood vanin-1 protein levels were lower in controls (median = 18.39 ng) than in ITP patients (median = 58.78 ng) with a highly significant p value (p < 0.001). Vanin-1 levels were highly significantly elevated in newly diagnosed ITP patients (median = 188.62 ng) in comparison to chronic responders (median= 26.90 ng) and chronic non-responders (median = 73.87 ng). Vanin-1 level at a cut-off value of >20.73 ng was found to be 100% sensitive and 93.7% specific in discriminating between newly diagnosed ITP patients and healthy controls. Vanin-1 level was found to be 100% sensitive and 100% specific in differentiating between responders and non-responders with a cut-off value of ≤ 34.5 ng. Our results suggest that vanin-1 can distinguish between chronic responders and non-responders ITP patients as well as between newly diagnosed ITP patients and healthy controls. These findings demonstrate that vanin-1 may contribute to the pathogenesis of ITP, indicating that vanin-1 is an important target for further investigation.
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http://dx.doi.org/10.3109/09537104.2013.782484DOI Listing
October 2014