Publications by authors named "Zeenat Mirza"

40 Publications

prediction and experimental validation of siRNAs targeting ORF1ab of MERS-CoV in Vero cell line.

Saudi J Biol Sci 2021 Feb 27;28(2):1348-1355. Epub 2020 Nov 27.

Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Post Box No-80216, Jeddah 21589, Saudi Arabia.

The Middle East Respiratory Syndrome Coronavirus is well known to cause respiratory syndrome and this virus was identified and isolated for the first time from Jeddah, Saudi Arabia in 2012 from infected patient. In this report, we have conducted the prediction, designing and evaluation of siRNAs targeting Middle East Respiratory Syndrome Coronavirus orf1ab gene to inhibit the virus replication. By using bioinformatics software, total twenty-one functional, off-target reduced siRNA were selected from four hundred and sixty-two siRNAs based on their greater potency and specificity. We have evaluated only seven siRNAs to analyze their performance and efficacy as antivirals by reverse transfection approach in Vero cells. There was no cytotoxicity of siRNAs at various concentrations was observed in Vero cells. Based on the real-time PCR results, better inhibition of viral replication was observed in the siRNA-1 and 4 as compared to other siRNAs. The results generated from this work provided suitable information about the efficacy of siRNAs which encouraged us to further evaluate the remaining siRNAs to determine their inhibitory effect on the virus replication. We concluded that the insilico prediction and designing resulted in the screening of potential siRNAs with better efficiency, and strength. This can be used to develop oligonucleotide-based antiviral therapeutics against MERS-CoV in the near future.
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http://dx.doi.org/10.1016/j.sjbs.2020.11.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833792PMC
February 2021

Designing and evaluation of MERS-CoV siRNAs in HEK-293 cell line.

J Infect Public Health 2021 Feb 29;14(2):238-243. Epub 2020 Dec 29.

Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Post Box, No-80216, Jeddah 21589, Saudi Arabia; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.

Background: The MERS-CoV was identified for the first time from Jeddah, Saudi Arabia in 2012 from a hospitalized patient. This virus has now been spread to 27 countries with a total of 858 deaths and 2494 confirmed cases and has become a serious concern for the human population. Camels are well known for the transmission of the virus to the human population.

Methods: In this report, we have discussed the designing, prediction, and evaluation of potential siRNAs against the orf1ab gene of MERS-CoV. The online software was used to predict and design the siRNAs and finally, total twenty-one siRNA were filtered out from four hundred and sixty-two sIRNAs as per their scoring and specificity criteria. We have used only ten siRNAs to evaluate their cytotoxicity and efficacy by reverse transfection approach in HEK-293-T cell lines.

Results: Based on the results and data generated; no cytotoxicity was observed for any siRNAs at various concentrations in HEK-293-T cells. The ct value of real-time PCR showed the inhibition of viral replication in siRNA-1, 2, 4, 6, and 9. The data generated provided the preliminary information and encouraged us to evaluate the remaining siRNAs separately as well as in combination to analyses the replication of MERS-CoV inhibition in other cell lines.

Conclusion: Based on the results obtained; it is concluded that the prediction of siRNAs using online software resulted in the filtration of potential siRNAs with high accuracy and strength. This technology can be used to design and develop antiviral therapy not only for MERS-CoV but also against other viruses.
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http://dx.doi.org/10.1016/j.jiph.2020.12.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771261PMC
February 2021

Discovery and Protein Modeling Studies of Novel Compound Mutations Causing Resistance to Multiple Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia.

Asian Pac J Cancer Prev 2020 12 1;21(12):3517-3526. Epub 2020 Dec 1.

College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS)/ KAIMRC/SSBMT, National Guards Health Affairs, Al-Ahsa, Kingdom of Saudi Arabia.

Objective: BCR-ABL fusion oncogene is the hallmark of chronic myeloid leukemia (CML), causing genomic instability which leads to accumulation of mutations in BCR-ABL as well as other genes. BCR-ABL mutations are the cause of tyrosine kinase inhibitors (TKIs) resistance in CML. Recently, compound BCR-ABL mutations have been reported to resist all FDA approved TKIs. Therefore, finding novel compound BCR-ABL mutations can help and clinically manage CML. Therefore, our objective was to find out novel drug-resistant compound BCR-ABL mutations in CML and carry out their protein modelling studies.

Methodology: Peripheral blood samples were collected from ten imatinib resistant CML patients receiving nilotinib treatment. BCR-ABL transcript mutations were investigated by employing capillary sequencing. Patient follow-up was carried out using European LeukemiaNet guidelines. Protein modeling  studies were carried out for new compound mutations using PyMol to see the effects of mutations at structural level.

Results: A novel compound mutation (K245N mutation along with G250W mutation) and previously known T351I utation was detected in two of the nilotinib resistance CML patients respectively while in the rest of 8 nilotinib responders, no resistant mutations were detected. Protein modelling studies indicated changes in BCR-ABL mutant protein which may have negatively impacted its binding with nilotinib leading to drug resistance.

Conclusion: We report a novel nilotinib resistant BCR-ABL compound mutation (K245N along with G250W mutation) which impacts structural modification in BCR-ABL mutant protein leading to drug resistance. As compound mutations pose a new threat by causing resistance to all FDA approved tyrosine kinase inhibitors in BCR-ABL+ leukemias, our study opens a new direction for in vitro characterization of novel BCR-ABL compound mutations and their resistant to second  generation and third generation TKIs.
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http://dx.doi.org/10.31557/APJCP.2020.21.12.3517DOI Listing
December 2020

Uncovering Potential Roles of Differentially Expressed Genes, Upstream Regulators, and Canonical Pathways in Endometriosis Using an In Silico Genomics Approach.

Diagnostics (Basel) 2020 Jun 19;10(6). Epub 2020 Jun 19.

King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia.

Endometriosis is characterized by ectopic endometrial tissue implantation, mostly within the peritoneum, and affects women in their reproductive age. Studies have been done to clarify its etiology, but the precise molecular mechanisms and pathophysiology remain unclear. We downloaded genome-wide mRNA expression and clinicopathological data of endometriosis patients and controls from NCBI's Gene Expression Omnibus, after a systematic search of multiple independent studies comprising 156 endometriosis patients and 118 controls to identify causative genes, risk factors, and potential diagnostic/therapeutic biomarkers. Comprehensive gene expression meta-analysis, pathway analysis, and gene ontology analysis was done using a bioinformatics-based approach. We identified 1590 unique differentially expressed genes (129 upregulated and 1461 downregulated) mapped by IPA as biologically relevant. The top upregulated genes were , , , , , , , and , and the top downregulated ones were , , , , , , , , and . The most perturbed canonical pathways were mitotic roles of Polo-like kinase, role of Checkpoint kinase proteins in cell cycle checkpoint control, and ATM signaling. Protein-protein interaction analysis showed a strong network association among FOS, EGR1, ZFP36, and JUNB. These findings provide a thorough understanding of the molecular mechanism of endometriosis, identified biomarkers, and represent a step towards the future development of novel diagnostic and therapeutic options.
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http://dx.doi.org/10.3390/diagnostics10060416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344784PMC
June 2020

Array comparative genomic hybridization based identification of key genetic alterations at 2p21-p16.3 (MSH2, MSH6, EPCAM), 3p23-p14.2 (MLH1), 7p22.1 (PMS2) and 1p34.1-p33 (MUTYH) regions in hereditary non polyposis colorectal cancer (Lynch syndrome) in the Kingdom of Saudi Arabia.

Saudi J Biol Sci 2020 Jan 15;27(1):157-162. Epub 2019 Jun 15.

Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.

Lynch syndrome is inherited in an autosomal dominant mode. Lynch syndrome is caused by impairment of one or more of the various genes (most frequently MLH1 and MSH2) involved in mismatch repair. In this study, whole genome comparative genomic hybridization array (array CGH) based genomic analysis was performed on twelve Saudi Lynch syndrome patients. A total of 124 chromosomal alterations (structural loss) were identified at mean log2 ratio cut off value of ±0.25. We also found structural loss in 2p21-p16.3, 3p23-p14.2, 7p22.1 and 1p34.1-p33 regions. These findings were subsequently validated by real time quantitative PCR showing downregulation of MSH2, MSH6, EPCAM, MLH1, PMS2 and MUTYH genes. These findings shall help in establishing database for alterations in mismatch repair genes underlying Lynch syndrome in Saudi population as well as to determine the incidence ratio of these disorders. Guided counselling will subsequently lead to the prevention and eradication of Lynch Syndrome in the local population.
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http://dx.doi.org/10.1016/j.sjbs.2019.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933242PMC
January 2020

Physical and chemical mutagens improved , strain ST20 for enhanced Phytase activity.

Saudi J Biol Sci 2019 Nov 11;26(7):1485-1491. Epub 2019 Jul 11.

Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia.

Objective: Phosphorous is an essential micronutrient of plants and involved in critical biological functions. In nature, phosphorous is mostly present in immobilized inorganic mineral and in the fixed organic form including phytic acid and phosphoesteric compounds. However, the bioavailability of bound phosphorous could be enhanced by the use of phosphate solubilizing microorganisms such as bacteria and fungi. The phytases are widespread in an environment and have been isolated from different sources comprising bacteria and fungi.

Methodology: In current studies, we show the successful use of gamma rays and EMS (Ethyl Methane Sulphonate) mutagenesis for enhanced activity of phytases in a fungal strain .

Results: We report an improved strain ST2 that could produce a clear halo zone around the colony, up to 24 mm. The maximum enzymatic activity was found of 382 U/mL on pH 5.5. However, the phytase activity was improved to 387 U/ml at 45 °C. We also report that the mutants produced through EMS showed the greater potential for phytase production.

Conclusion: The current study highlights the potential of EMS mutagenesis for strain improvement over physical mutagens.
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http://dx.doi.org/10.1016/j.sjbs.2019.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864213PMC
November 2019

A comparative study of bacterial diversity based on culturable and culture-independent techniques in the rhizosphere of maize ( L.).

Saudi J Biol Sci 2019 Nov 1;26(7):1344-1351. Epub 2019 Apr 1.

Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia.

Objective: Maize is an important crop for fodder, food and feed industry. The present study explores the plant-microbe interactions as alternative eco-friendly sustainable strategies to enhance the crop yield.

Methodology: Bacterial diversity was studied in the rhizosphere of maize by culture-dependent and culture-independent techniques by soil sampling, extraction of DNA, amplification of gene of interest, cloning of desired fragment and library construction.

Results: Culturable bacteria were identified as , , , and genera. For culture-independent approach, clone library of 16S ribosomal RNA gene was assembled and 100 randomly selected clones were sequenced. Majority of the sequences were related to Firmicutes (17%), Acidobacteria (16%), Actinobacteria (17%), Alpha-Proteobacteria (7%), Delta-proteobacteria (4.2%) and Gemmatimonadetes (4.2%) However, some of the sequences (30%) were novel that showed no homologies to phyla of cultured bacteria in the database. Diversity of diazotrophic bacteria in the rhizosphere investigated by analysis of PCR-amplified H gene sequence that revealed abundance of sequences belonging to genera (25%), (10%), (10%). The diazotrophic genera and related H sequences were also detected but no sequence related to was found showing biasness of the growth medium rather than relative abundance of diazotrophs in the rhizosphere.

Conclusion: The study provides a foundation for future research on focussed isolation of the and other diazotrophs found in higher abundance in the rhizosphere.
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http://dx.doi.org/10.1016/j.sjbs.2019.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864194PMC
November 2019

Nanoparticles-based drug delivery and gene therapy for breast cancer: Recent advancements and future challenges.

Semin Cancer Biol 2021 Feb 5;69:226-237. Epub 2019 Nov 5.

Department of Medical Lab Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.

Breast cancer (BC) is amongst the most lethal cancer among females and conventional treatment methods like surgery, radiotherapy and chemotherapy are not effective enough as expected and suffer concerns of low bioavailability, low cellular uptake, emerging resistance, and adverse toxicities. Gene therapy using free nucleic acids has potential to deal with key candidate genes of BC, but their effect is retarded due to poor cell uptake and instability in circulation. The rapidly evolving field of nanomedicine aiming targeted drug/gene delivery curtailing BC promises to overcome the limitations of conventional therapies. Nanoparticles can be game changer for BC gene therapy as they can be effective carrier of specific drug/gene by improving the circulation time, enhancing bioavailability, reducing the immune system based recognition chances, and delivering the gene regulator accurately. Herein, we discuss the mechanism of nanoparticles targeted drug delivery, recent advancement of therapeutic strategies of nanoparticles based carriers for small interfering RNA, and microRNA, and gene augmentation therapies in BC. We also discuss the future prospect and challenges of nanoparticle-based therapies for BC.
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http://dx.doi.org/10.1016/j.semcancer.2019.10.020DOI Listing
February 2021

Molecular analysis of V617F mutation in Janus kinase 2 gene of breast cancer patients.

Saudi J Biol Sci 2019 Sep 2;26(6):1123-1128. Epub 2019 Aug 2.

Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia.

Background: Breast cancer is a multifactorial disease with the highest frequency in females. Genetic and environmental factors can cause mutation in several genes like tyrosine kinase, JAK2 gene which may initiate cancer. Molecular analysis of mutations in the gene along with determination of environmental, clinical and haematological risk factors associated with breast cancer patients is need of hour to improve patient's healthcare. Somatic JAK2 valine-to-phenylalanine (617 codon) mutation is one of the widely prevalent mutations.

Methods: Blood was collected from seventy breast cancer patients after their consent. The questionnaire included risk factors, age group, locality, number of children, tumor type, family history, time of initial diagnosis, no of cycles/month, water conditions and exposure to radiations. Molecular analysis were carried out from genomic DNA using Sanger sequencing and allele-specific PCR to check the V617F point mutation.

Results: The breast cancer risk factors includes unfiltered water (68.57%), urban (58.57%), menopause (55.71%), family history of cancer (18.57%), tumor grades (II, 37.14% and III, 35.71%), consanguineous marriages (44.28%) and having more than 3-4 children (45.71%). Prevalence of breast cancer was higher after the age of 35 and maximum at 35-50. In allele-specific PCR of 70 patients, 25 patients were wild type (229 bp), 25 patients were with partially deleted gene (200 bp), and 20 patient had shown no or less than 40 bp size fragments. In Sanger's sequencing of 70 BC cases, 18% were found to be positive for V617F point mutation, including 6 homozygous (T/T) and 7 heterozygous (G/T) mutations at nucleotide position 1849 in exon 14 of the gene.

Conclusions: Environmental and clinical risk factors were associated with breast cancer which can be overcome by improving awareness of associated risks, health facilities and reducing stress.
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http://dx.doi.org/10.1016/j.sjbs.2019.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733781PMC
September 2019

Implications of advanced oxidation protein products (AOPPs), advanced glycation end products (AGEs) and other biomarkers in the development of cardiovascular diseases.

Saudi J Biol Sci 2019 Feb 27;26(2):334-339. Epub 2018 Aug 27.

Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.

Objective: To study the putative effects of Advanced Oxidation Protein Products (AOPPs) and Advanced Glycation End Products (AGEs) in the development and progression of cardiovascular disease (CVD).

Methodology: AGEs, AOPPs, e-NOS, lipid profile, circulating stress and inflammatory biomarkers were evaluated among fifty cardiovascular patients and fifty controls. Independent student's -test was done for statistical analysis.

Results: The malondialdehyde mean level in CVD patients (5.45 nmol/ml) was significantly higher than control (1.36 nmol/ml) (p value = 0.018). Nitric oxide in CVD patients (55.72 ng/ml) was remarkably increased as compared to normal subjects (19.19 ng/ml). A significant change in the mean serum level of AGEs in CVD patients (2.74 ng/ml) and normal individuals (0.85 ng/ml) was recorded (p value = 0.000). The AOPPs also showed significant increased levels in CVD group (132.07 ng/ml) in comparison with normal subjects (83.05 ng/ml) (p value = 0.011). The mean eNOS serum level in CVD group (15.50 U/L) was higher than control group (11.28 U/L) (p value = 0.004). Cardiovascular disease patients, in comparison with healthy controls, showed increased level of total cholesterol (5.48 mmol/L vs 4.45 mmol/L), triglycerides (2.59 mmol/L vs 1.24 mmol/L), and low density lipoprotein (2.47 mmol/L vs 2.31 mmol/L) along with decrease in high density lipoprotein (1.39 mmol/L vs 1.74 mmol/L). The mean MMP-11 serum levels in CVD group (98.69 ng/ml) was almost double of control group (45.60 ng/ml) (p value = 0.017). The mean serum level of TNF-α and IL1-α were 32.16 pg/ml and 6.64 pg/ml in CVD patient. The significant decreasing trend of SOD (p value = 0.041), CAT (p value = 0.018), GSH (p value = 0.036) and GRx (p value = 0.029) but increasing drift of GPx (0.023) level was observed in CVD patients.

Conclusion: This study provides strong evidence that CVD patients presented with elevated oxidative stress, enhanced inflammation and lipid profile in their serum. Therefore, the study strongly approves that AGEs, AOPPs, inflammatory and lipoxidative biomarkers hold predictive potential in causing and aggravating the disease, thus by controlling these factors CVD progression can be inhibited.
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http://dx.doi.org/10.1016/j.sjbs.2018.08.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717110PMC
February 2019

Isolation, characterization, and effect of phosphate-zinc-solubilizing bacterial strains on chickpea ( L.) growth.

Saudi J Biol Sci 2019 Jul 8;26(5):1061-1067. Epub 2019 Apr 8.

Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia.

Objective: Phosphate (P) and zinc (Zn) are essential plant nutrients required for nodulation, nitrogen-fixation, plant growth and yield. Mostly applied P and Zn nutrients in the soil are converted into unavailable form. A small number of soil microbes have the ability to transform unsolvable forms of P and Zn to an available form. P-Zn-solubilizing rhizobacteria are potential alternates for P and Zn supplement. In the present study, the effect of two P-Zn-solubilizing bacterial strains ( sp. strain AZ17 and sp. strain AZ5) was evaluated on the growth of chickpea plant.

Methodology: Both strains were purified from the rhizospheric soil of chickpea plant grown-up in sandy soil and rain-fed area (Thal desert). , both strains solubilize P and Zn as well both strain produce IAA and organic acids. In the field experiments, conducted in the rain-fed area, the positive influence of inoculation with both bacterial isolates AZ5 and AZ17 on chickpea growth was observed.

Results: The application of inoculum (strains AZ5 and AZ17) resulted in up to 17.47% and 17.34% increase in grain yield of both types of chickpea grown in fertilized and non-fertilized soil, respectively over non-inoculated control. Strain AZ5 was the most effective inoculum, increasing up to 17.47%, 16.04%, 26.32%, 22.53%, 26.12% and 22.59% in grain yield, straw weight, nodules number, dry weight of nodules, Zn uptake and P uptake respectively, over control.

Conclusion: These results indicated that sp. strain AZ5 and sp. strain AZ17 can serve as effective microbial inocula for chickpea, particularly in the rain-fed area.
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http://dx.doi.org/10.1016/j.sjbs.2019.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600776PMC
July 2019

Advancements in CRISPR/Cas9 technology-Focusing on cancer therapeutics and beyond.

Semin Cell Dev Biol 2019 12 31;96:13-21. Epub 2019 May 31.

Department of Medical Lab Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.

"CRISPR" is an abbreviation for Clustered Regularly Interspaced Short Palindromic Repeats, which are a characteristic of the bacterial defense system and Cas9 (or "CRISPR-associated") is a RNA-guided DNA endonuclease or molecular scissor, capable of cutting DNA strands. Both together forms the basis for CRISPR-Cas9 targeted genome editing technology and enables highly specific genomic modifications to an organism's DNA. Recent advent of high-throughput genomics has revolutionizing personalized medicine and enhanced our molecular understanding of human cancers. The development of the CRISPR/Cas9 tool has unveiled advancement of new, simplistic and efficient in vivo model systems in oncology. The usage of CRISPR/Cas9 gene editing systems for curing various cancers promises to be the next great biotechnological breakthrough in medicine. However, urgent attention is needed to assess the functional relevance of novel cancer-associated mutations and translate our molecular knowledge to therapeutics. Herein, we will review the development and applications of the exciting uses of the CRISPR/Cas9 technique for cancer research and therapy with focus on origin, progress, clinical trials, implications, and challenges ahead. Major ethical and safety concerns are perhaps unknown long term consequences of DNA manipulation and irreversibility of this procedure.
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http://dx.doi.org/10.1016/j.semcdb.2019.05.026DOI Listing
December 2019

Role of diagnostic factors associated with antioxidative status and expression of matrix metalloproteinases (MMPs) in patients with cancer therapy induced ocular disorders.

Saudi J Biol Sci 2018 Dec 12;25(8):1724-1728. Epub 2018 Aug 12.

King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

Background: Cancer patients when treated with different chemotherapeutic drugs often develop mild to severe sight threatening diseases during or after chemotherapy. The mechanism involved in the pathogenesis of ocular toxicities is poorly understood. Oxidative stress, inflammation and MMPs (angiogenic factor) are involved in the progression of chemotherapy related ocular disorders.

Materials And Methods: The concentration of oxidative stress markers such as MDA, NO and levels of different antioxidant molecules such as SOD, CAT, GSH, GPx, GPr, VIT A, VIT E and VIT C present in the serum of chemotherapy treated patients ( = 50) and in normal persons ( = 20) were estimated by the direct spectrophotometric method while the concentration of and MMP-9 activity were determined using human and MMP-9 ELISA kits.

Results: The concentration of SOD and CAT (0.356 ± 0.05 μg/dl and 1.26 ± 0.01 μmol/mol of protein) was significantly lower as compared to that (1.09 ± 0.03 μg/dl and 3.99 ± 0.04 μmol/mol of protein) in controls. The levels of GPx (0.06 ± 0.01 mmol/dl) in the cancer patients were much lower than those in the controls (0.78 ± 0.06 mmol/dl). Lower level of GSH (0.96 ± 0.003 μg/dl) in serum of the diseased group was observed as compared to healthy group (7.26 ± 1.40 μg/dl). The level of Vit A, Vit C and Vit E was lower in systemic circulation of cancer patients (109.99 ± 6.35 μg/ml, 1.26 ± 0.36 μg/ml and 1.29 ± 0.191 μg/ml) as compared to control subjects (166.35 ± 14.26 μg/ml, 3.25 ± 0.099 μg/ml and 6.354 ± 2.26 μg/ml) respectively. The concentration of nitric oxide was significantly higher in the cancer patients (45.26 ± 6.35 ng/ml) than that in the normal subjects (16.35 ± 3.26 ng/ml). The higher concentration of MDA (8.65 ± 3.26 nmol/ml) was observed in the patients than normal ones (1.254 ± 0.065 nmol/ml). The quantity of was significantly higher in chemotherapy treated patients (32.68 ± 4.33 pg/ml) as compared to the control group (20.979 ± 1.98 pg/ml). Significantly higher concentration of MMP-9 (40.26 ± 3.26 ng/ml) was observed in the cancer patients than the controls (7.256 ± 1.95 ng/ml).

Conclusion: Lower levels of antioxidant enzymes and non-enzymatic small molecules and higher levels of oxidative stress and inflammatory clinical parameters such as NO, MDA, and MMP-9 may be involved in the pathogenesis of systemic chemotherapy related ocular complications such as cataract, glaucoma, blepharitis, retinitis pigmentosa, macular degeneration, pterygium and retinal degeneration.
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http://dx.doi.org/10.1016/j.sjbs.2018.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303172PMC
December 2018

Design and Delivery of Therapeutic siRNAs: Application to MERS-Coronavirus.

Curr Pharm Des 2018 ;24(1):62-77

Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

Background: The MERS-CoV is a novel human coronavirus causing respiratory syndrome since April 2012. The replication of MERS-CoV is mediated by ORF 1ab and viral gene activity can be modulated by RNAi approach. The inhibition of virus replication has been documented in cell culture against multiple viruses by RNAi approach. Currently, very few siRNA against MERS-CoV have been computationally designed and published.

Methods: In this review, we have discussed the computational designing and delivery of potential siRNAs. Potential siRNA can be designed to silence a desired gene by considering many factors like target site, specificity, length and nucleotide content of siRNA, removal of potential off-target sites, toxicity and immunogenic responses. The efficient delivery of siRNAs into targeted cells faces many challenges like enzymatic degradation and quick clearance through renal system. The siRNA can be delivered using transfection, electroporation and viral gene transfer. Currently, siRNAs delivery has been improved by using advanced nanotechnology like lipid nanoparticles, inorganic nanoparticles and polymeric nanoparticles.

Conclusion: The efficacy of siRNA-based therapeutics has been used not only against many viral diseases but also against non-viral diseases, cancer, dominant genetic disorders, and autoimmune disease. This innovative technology has attracted researchers, academia and pharmaceuticals industries towards designing and development of highly effective and targeted disease therapy. By using this technology, effective and potential siRNAs can be designed, delivered and their efficacy with toxic effects and immunogenic responses can be tested against MERS-CoV.
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http://dx.doi.org/10.2174/1381612823666171109112307DOI Listing
September 2019

Identification of Electrophysiological Changes in Alzheimer's Disease: A Microarray Based Transcriptomics and Molecular Pathway Analysis Study.

CNS Neurol Disord Drug Targets 2017 ;16(9):1027-1038

Department of Anatomy, King Abdulaziz University Medical College, King Abdulaziz University, Jeddah, Saudi Arabia.

Background & Objective: Involvement of amyloid beta and tau proteins in pathogenesis of Alzheimer's disease (AD) has been studied extensively. However, electrophysiological activity, and cellular processes like membrane transport are mostly unstudied. Electrophysiological processes provide a bridge between brain activity and cognition, and show promise as translatable biomarkers in preclinical and clinical applications. Biochemical imbalance leads to change in glutamate-based neurotransmission, antioxidant capacity, and in membrane polarization-repolarization events, eventually, resulting in AD. We hypothesize that in AD, these processes are unified at a single metabolic hub and we carried out a holistic system-biology approach.

Method: In the present study, we integrated and analyzed multiple AD expression datasets from the GEO database to identify significant genes associated with electrophysiological pathways and attempted determination of interconnected canonical molecular pathways. Partek Genomic suite based expression analysis identified 200 significantly expressed genes using cut-off value of ≤ 0.05 and 2 fold change. Transducer of ERBB2, 2 (TOB2); lactotransferrin (LFT) and RAS-like, family 12 (RASL12) were most up-regulated genes, while neurofilament light polypeptide (NEFL); collagen, type V, alpha 2 (COL5A2); visinin-like 1 (VSNL1); cannabinoid receptor 1 (brain) (CNR1); neurofilament, medium polypeptide (NEFM); regulator of G-protein signaling 4 (RGS4), and synaptosomalassociated protein, 25kDa (SNAP25) were most down-regulated ones.

Conclusion: Interestingly, we found majority of transporter genes identified in dataset as downregulated. Ingenuity pathways analysis revealed glutamate receptor signaling, CREB signaling, dopamine- DARPP32 feedback in cAMP signaling, fMLP signaling in neutrophils, and synaptic long term potentiation pathway playing critical role in AD pathophysiology and having correlation with electrophysiological dysfunction.
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http://dx.doi.org/10.2174/1871527316666171023153837DOI Listing
March 2019

Genomic answers for recurrent spontaneous abortion in Saudi Arabia: An array comparative genomic hybridization approach.

Reprod Biol 2017 Jun 18;17(2):133-143. Epub 2017 Apr 18.

Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address:

To study the genomics/genetic factors associated with recurrent spontaneous abortion (RSA), as ∼50% of RSA are unexplained. However, chromosome abnormalities have been reported to play major role in RSA. We performed whole genome array-CGH based genomic analysis of forty four Saudi RSA patients to identify potential molecular and chromosomal abnormalities. We identified a total of 845 alterations, usually not detected by classic cytogenetic methods, in different genomic regions using a cut off value of -0.25 and 0.25 for structural loss and gain, whereas -1.0 and 0.58 were used for single copy number deletion and duplication respectively. We identified frequent (present at least in 10% of patients) alterations including three macro-alteration at 8p23.1, 10q11.21-q11.22 and 15q11.2 as well as large numbers of micro-deletions/amplifications with affected genes including 22q11.23 (GSTT1), 3p22.2 (CTDSPL), 6p21.32 (HLA), and 8p22 (MSR1). Pathway analysis of genes located in detected CNVs regions revealed the allograft rejection signaling, IL-4 signaling, and autoimmune thyroid disease signaling as the most significant canonical pathways associated with RSA. Whole genome array CGH technique can be used to identify potential genes, biofunctions and chromosomal abnormalities associated with RSA which is supported by our findings of a number of novel CNVs/genes (22q11.23/GSTT1, 3p22.2/CTDSPL, 6p21.32/HLA, 8p22/MSR1, and 14q32.33/AKT1) and pathways in patients affected with RSA. To improve diagnosis and treatment of RSA, a comprehensive procedure is needed for identification and validation of causative genes.
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http://dx.doi.org/10.1016/j.repbio.2017.03.003DOI Listing
June 2017

Possible Molecular Interactions of Bexarotene - A Retinoid Drug and Alzheimer's Aβ Peptide: A Docking Study.

Curr Alzheimer Res 2017 ;14(3):327-334

King Fahd Medical Research Center, PO Box-80216, King Abdulaziz University, Jeddah -21589, Saudi Arabia.

Background: Alzheimer's disease (AD) pathogenesis is primarily hallmarked by the production and accumulation of amyloid beta (Aβ) peptide. Along with the understanding of the neurodegenerative disease progression and its pathophysiological mechanisms, development of anti-Aβ targeted effective therapeutics is essential for AD management. Numerous therapeutic approaches targeting the production, toxicity and removal of Aβ are being attempted worldwide. Prime need is to design inhibitors which can slow down the Aβ aggregation process in a physiological environment. Bexarotene (targretin) is the first of the U.S. Food and Drug Administration approved oral retinoid X receptors (RXR)-selective retinoids, or rexinoids. It is effectively used for the treatment of advanced, refractory cutaneous T cell lymphoma, and also reportedly reduces Aβ levels in AD mouse models. Administration of bexarotene facilitates intracellular Aβ clearance via RXR regulated apolipoprotein E (ApoE) production.

Objective: To the best of our knowledge, this is the first structural attempt to find binding interactions of the drug bexarotene with monomeric Aβ peptide.

Method: We checked binding possibilities of bexarotene by using structural bioinformatics method.

Results: We found in our study the basic amino acids His13 and Lys 16 of Aβ peptide to be crucial for the interaction with bexarotene.

Conclusion: We speculate that direct binding of bexarotene to free Aβ peptide may lessen the concentration of free Aβ peptides in the brain and hamper the propensity of the peptide's clumping and aggregating behavior. Further experimental validation of the results of this study would be required for its therapeutic success.
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http://dx.doi.org/10.2174/1567205013666161114115344DOI Listing
October 2017

Cyclin D1 as a therapeutic target of renal cell carcinoma- a combined transcriptomics, tissue microarray and molecular docking study from the Kingdom of Saudi Arabia.

BMC Cancer 2016 09 30;16(Suppl 2):741. Epub 2016 Sep 30.

Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.

Background: Renal cell carcinoma (RCC) is a seventh ranked malignancy with poor prognosis. RCC is lethal at metastatic stage as it does not respond to conventional systemic treatments, and there is an urgent need to find out promising novel biomarkers for effective treatment. The goal of this study was to evaluate the biomarkers that can be potential therapeutic target and predict effective inhibitors to treat the metastatic stage of RCC.

Methods: We conducted transcriptomic profiling to identify differentially expressed genes associated with RCC. Molecular pathway analysis was done to identify the canonical pathways and their role in RCC. Tissue microarrays (TMA) based immunohistochemical stains were used to validate the protein expression of cyclinD1 (CCND1) and were scored semi-quantitatively from 0 to 3+ on the basis of absence or presence of staining intensity in the tumor cell. Statistical analysis determined the association of CCND1 expression with RCC. Molecular docking analyses were performed to check the potential of two natural inhibitors, rutin and curcumin to bind CCND1.

Results: We detected 1490 significantly expressed genes (1034, upregulated and 456, downregulated) in RCC using cutoff fold change 2 and p value < 0.05. Hes-related family bHLH transcription factor with YRPW motif 1 (HEY1), neuropilin 2 (NRP2), lymphoid enhancer-binding factor 1 (LEF1), and histone cluster 1 H3h (HIST1H3H) were most upregulated while aldolase B, fructose-bisphosphate (ALDOB), solute carrier family 12 (SLC12A1), calbindin 1 (CALB1) were the most down regulated genes in our dataset. Functional analysis revealed Wnt/β-catenin signaling as the significantly activated canonical pathway (z score = 2.53) involving cyclin D1 (CCND1). CCND1 was overexpressed in transcriptomic studies (FC = 2.26, p value = 0.0047) and TMA results also showed the positive expression of CCND1 in 53 % (73/139) of RCC cases. The ligands - rutin and curcumin bounded with CCND1 with good affinity.

Conclusion: CCND1 was one of the important upregulated gene identified in microarray and validated by TMA. Docking study showed that CCND1 may act as a potential therapeutic target and its inhibition could focus on the migratory, invasive, and metastatic potential of RCC. Further in vivo and in vitro molecular studies are needed to investigate the therapeutic target potential of CCND1 for RCC treatment.
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http://dx.doi.org/10.1186/s12885-016-2775-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073805PMC
September 2016

Panacea seed "Nigella": A review focusing on regenerative effects for gastric ailments.

Saudi J Biol Sci 2016 Jul 13;23(4):542-53. Epub 2014 Oct 13.

King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

Nigella sativa (NS) or black cumin is a dark, thin, and crescent-shaped, seeded shrub belonging to the Ranunculaceae family commonly growing on Mediterranean coasts in Saudi Arabia, northern Africa and Asia. They have amazing curative and therapeutic features that make them one of the most popular, safe, non-detrimental, and cytoprotective medicinal plant that can be used for prevention and treatment of many complicated diseases. Originally, N. sativa was used to treat migraines and allergy, and researches have shown its effectiveness in destroying cancer cells as well. The gastro protective effect of NS oil and its constituents has also been reported earlier; however, the complete perception on etiology and pathogenesis of gastric ulcer is not yet clear. Herein, we attempt to unveil some of the potential mechanisms exhibited by NS in preventing problems related to gastric ulcers. Gastric ailments like ulcers and tumors are the most common disorders of the gastro-intestinal tract in the present day life of the industrialized world. Gastric ulcer being a multifaceted problem exhibits complex etiology and is the fourth most common cause of cancer mortality. Drug interactions and toxicity are the main hindrances in chemotherapy. The existing merits and demerits of modern-day drugs make us turn toward the plant kingdom which may provide a valuable resource of novel potent natural compounds for pharmaceuticals or alternately, as dietary supplements. In this context, the revered phytotherapeutic N. sativa comes as a promising savior in today's times. This review aims to summarize, both the functional and disease-related effects in the area of gastroenterology.
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http://dx.doi.org/10.1016/j.sjbs.2014.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890198PMC
July 2016

Low expression of leptin and its association with breast cancer: A transcriptomic study.

Oncol Rep 2016 Jul 13;36(1):43-8. Epub 2016 May 13.

Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.

The incidence of breast cancer is alarmingly increasing worldwide and also among Saudi women. Obesity is linked with an increased cancer risk and studies have also revealed that leptin may be involved in breast tumorigenesis particularly among obese women. Numerous transcriptomic studies have been carried out worldwide; however, molecular studies among breast cancer patients of diverse ethnic groups from the Arabian Peninsula are scarce. In the present study, whole transcriptome analysis of 45 surgically resected breast tumors from Saudi Arabian female patients was carried out. Expression data were analyzed, and molecular networks and canonical pathways were identified. We identified 1,159 differentially expressed genes using p-value with a false discovery rate <0.05 and a fold-change >2 as a cut-off. Using ingenuity pathway analysis tool, we identified many canonical pathways that were implicated in breast cancer for the first time. Notably, along with other lipid metabolism molecules, leptin (LEP)was one of the most downregulated genes (fold cut-off, -7.03) with significant differences between the breast cancer and the control groups (p<0.0001) and was further confirmed in all the samples using qPCR. Transcriptomic profiling of breast cancer from a Saudi female population revealed downregulation of LEP. Molecular pathway analysis demonstrated the role of LEP and other associated molecules of the lipid metabolism pathway. Involvement of leptin and lipid metabolism in breast cancer was highlighted. The majority of cases presented were of late stage, stressing the need to educate individuals concerning early diagnostic testing and the life-style risk factors for breast cancer such as unhealthy diet and obesity.
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http://dx.doi.org/10.3892/or.2016.4806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899016PMC
July 2016

Global Expression Studies of Schizophrenic Brain: A Meta-Analysis Study Linking Neurological Immune System with Psychological Disorders.

CNS Neurol Disord Drug Targets 2016 ;15(4):477-88

King Fahd Medical Research Center, PO Box-80216, King Abdulaziz University, Jeddah -21589, Saudi Arabia.

Schizophrenia, a psychological disorder with enormous societal impact, is a result of abnormalities in gene expression and dysregulation of the immune response in the brain. Few studies have been conducted to understand its etiology, however, the exact molecular mechanism largely remains unknown, though some poorly understood theories abound. Present meta-study links the role of central nervous system, immunological system and psychological disorders by using global expression approach and pathway analysis. We retrieved genome-wide mRNA expression data and clinico-pathological information from five independent studies of schizophrenic patients from Gene Expression Omnibus database. We continued further with three studies having common platform. Our result showed a total of 527 differentially expressed genes of which 314 are up regulated and 213 are down regulated. After adjusting the sources of variation, we carried out pathway and gene ontology analysis, and observed alteration of 14-3-3-mediated signaling, γ-aminobutyric acid receptor signaling, role of nuclear factor of activated T-cells in regulation of the immune response, G beta gamma signaling, dopamine- and cyclic AMP-regulated phosphoprotein of relative molecular mass 32,000 feedback in cAMP signaling, complement system, axonal guidance signaling, dendritic cell maturation, cAMP response element-binding protein signaling in neurons and interleukin-1 signaling pathways and networks. Conclusively, our global gene expression pathway and gene set enrichment analysis studies suggest disruption of many common pathways and processes, which links schizophrenia to immune and central nervous system. Present meta-study links the role of central nervous system, immunological system and psychological disorders by using global expression approach and pathway analysis.
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http://dx.doi.org/10.2174/1871527315666160321105216DOI Listing
December 2016

Assessment of Radiation Induced Therapeutic Effect and Cytotoxicity in Cancer Patients Based on Transcriptomic Profiling.

Int J Mol Sci 2016 Feb 19;17(2):250. Epub 2016 Feb 19.

Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia.

Toxicity induced by radiation therapy is a curse for cancer patients undergoing treatment. It is imperative to understand and define an ideal condition where the positive effects notably outweigh the negative. We used a microarray meta-analysis approach to measure global gene-expression before and after radiation exposure. Bioinformatic tools were used for pathways, network, gene ontology and toxicity related studies. We found 429 differentially expressed genes at fold change >2 and p-value <0.05. The most significantly upregulated genes were synuclein alpha (SNCA), carbonic anhydrase I (CA1), X-linked Kx blood group (XK), glycophorin A and B (GYPA and GYPB), and hemogen (HEMGN), while downregulated ones were membrane-spanning 4-domains, subfamily A member 1 (MS4A1), immunoglobulin heavy constant mu (IGHM), chemokine (C-C motif) receptor 7 (CCR7), BTB and CNC homology 1 transcription factor 2 (BACH2), and B-cell CLL/lymphoma 11B (BCL11B). Pathway analysis revealed calcium-induced T lymphocyte apoptosis and the role of nuclear factor of activated T-cells (NFAT) in regulation of the immune response as the most inhibited pathways, while apoptosis signaling was significantly activated. Most of the normal biofunctions were significantly decreased while cell death and survival process were activated. Gene ontology enrichment analysis revealed the immune system process as the most overrepresented group under the biological process category. Toxicity function analysis identified liver, kidney and heart to be the most affected organs during and after radiation therapy. The identified biomarkers and alterations in molecular pathways induced by radiation therapy should be further investigated to reduce the cytotoxicity and development of fatigue.
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http://dx.doi.org/10.3390/ijms17020250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783980PMC
February 2016

A proteomics based approach for the identification of gastric cancer related markers.

Curr Pharm Des 2016 ;22(7):804-11

King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia.

Gastric cancer (GC) is the amongst the most common cancer types causing second largest number of cancer related deaths globally. GC is characterized as an aggressive malignancy which is very tough to be detected at an early stage. GC has been defined as a complex, multistep process involving multiple genetic and epigenetic alterations leading to aberrant expression of key regulating factors. GC according to WHO has been defined as malignant epithelial tumors of the gastric mucosa with glandular differentiation. About one half of the GCs are located in the lower stomach, and remaining is located in the corpus and fundus of the stomach (20%), lesser curvature (20%), cardia (10%) and greater curvature (3%). GC has been classified into intestinal and diffuse types based on epidemiological and clinico- and histopathological features. The etiology of GC is multifactorial and includes dietary as well as non-dietary factors. Despite a lot of research efforts, GC remains to be the cancer without clear symptoms at onset, poor prognosis, with metastasis and recurrence. Thus, there is an urgent need for identifying novel and diagnostic GC biomarkers and techniques with high sensitivity and specificity. In the present review, we provide a synopsis of proteomics based GC biomarkers discovered from various cancerous specimens such as blood, gastric fluid, tissues, cells and H. pylori infected cancer cell lines. The advent of proteomics based GC biomarkers will be a great asset for the early detection and treatment of GC.
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http://dx.doi.org/10.2174/1381612822666151209151848DOI Listing
October 2016

Conotoxins: Structure, Therapeutic Potential and Pharmacological Applications.

Curr Pharm Des 2016 ;22(5):582-9

King Fahd Medical Research Center, P.O. Box-80216, King Abdulaziz University, Jeddah -21589, Saudi Arabia.

Cone snails, also known as marine gastropods, from Conus genus produce in their venom a diverse range of small pharmacologically active structured peptides called conotoxins. The cone snail venoms are widely unexplored arsenal of toxins with therapeutic and pharmacological potential, making them a treasure trove of ligands and peptidic drug leads. Conotoxins are small disulfide bonded peptides, which act as remarkable selective inhibitors and modulators of ion channels (calcium, sodium, potassium), nicotinic acetylcholine receptors, noradrenaline transporters, N-methyl-D-aspartate receptors, and neurotensin receptors. They are highly potent and specific against several neuronal targets making them valuable as research tools, drug leads and even therapeutics. In this review, we discuss their gene superfamily classification, nomenclature, post-translational modification, structural framework, pharmacology and medical applications of the active conopeptides. We aim to give an overview of their structure and therapeutic potential. Understanding these aspects of conopeptides will help in designing more specific peptidic analogues.
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http://dx.doi.org/10.2174/1381612822666151124234715DOI Listing
October 2016

Molecular interaction of a kinase inhibitor midostaurin with anticancer drug targets, S100A8 and EGFR: transcriptional profiling and molecular docking study for kidney cancer therapeutics.

PLoS One 2015 19;10(3):e0119765. Epub 2015 Mar 19.

Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, PO BOX 80216, Jeddah, 21589, Saudi Arabia.

The S100A8 and epidermal growth factor receptor (EGFR) proteins are proto-oncogenes that are strongly expressed in a number of cancer types. EGFR promotes cellular proliferation, differentiation, migration and survival by activating molecular pathways. Involvement of proinflammatory S100A8 in tumor cell differentiation and progression is largely unclear and not studied in kidney cancer (KC). S100A8 and EGFR are potential therapeutic biomarkers and anticancer drug targets for KC. In this study, we explored molecular mechanisms of interaction profiles of both molecules with potential anticancer drugs. We undertook transcriptional profiling in Saudi KCs using Affymetrix HuGene 1.0 ST arrays. We identified 1478 significantly expressed genes, including S100A8 and EGFR overexpression, using cut-off p value <0.05 and fold change ≥2. Additionally, we compared and confirmed our findings with expression data available at NCBI's GEO database. A significant number of genes associated with cancer showed involvement in cell cycle progression, DNA repair, tumor morphology, tissue development, and cell survival. Atherosclerosis signaling, leukocyte extravasation signaling, notch signaling, and IL-12 signaling were the most significantly disrupted signaling pathways. The present study provides an initial transcriptional profiling of Saudi KC patients. Our analysis suggests distinct transcriptomic signatures and pathways underlying molecular mechanisms of KC progression. Molecular docking analysis revealed that the kinase inhibitor "midostaurin" has amongst the selected drug targets, the best ligand properties to S100A8 and EGFR, with the implication that its binding inhibits downstream signaling in KC. This is the first structure-based docking study for the selected protein targets and anticancer drug, and the results indicate S100A8 and EGFR as attractive anticancer targets and midostaurin with effective drug properties for therapeutic intervention in KC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0119765PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366044PMC
February 2016

Application of Proteomic Tools in Modern Nanotechnological Approaches Towards Effective Management of Neurodegenerative Disorders.

Curr Drug Metab 2015 ;16(5):376-88

King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia.

Neurodegeneration is the progressive loss of structure or function of neurons leading to neuronal death, usually associated with ageing. Some of the common neurodegenerative disorders include Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and Huntington's disease. Due to recent advancements in highthroughput technologies in various disciplines such as genomics, epigenomics, metabolomics and proteomics, there has been a great demand for detection of specific macromolecules such as hormones, drug residues, miRNA, DNA, antibodies, peptides, proteins, pathogens and xenobiotics at nano-level concentrations for in-depth understanding of disease mechanisms as well as for the development of new therapeutic strategies. The present review focuses on the management of agerelated neurodegenerative disorders using proteomics and nanotechnological approaches. In addition, this review also highlights the metabolism and disposition of nano-drugs and nano-enabled drug delivery in neurodegenerative disorders.
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http://dx.doi.org/10.2174/1389200216666141208153303DOI Listing
July 2016

Effect of electromagnetic radiations on neurodegenerative diseases- technological revolution as a curse in disguise.

CNS Neurol Disord Drug Targets 2014 ;13(8):1406-12

King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah - 21589, Kingdom of Saudi Arabia.

In the present developed world, all of us are flooded with electromagnetic radiations (EMR) emanating from generation and transmission of electricity, domestic appliances and industrial equipments, to telecommunications and broadcasting. We have been exposed to EMR for last many decades; however their recent steady increase from artificial sources has been reported as millions of antennas and satellites irradiate the global population round the clock, year round. Needless to say, these are so integral to modern life that interaction with them on a daily basis is seemingly inevitable; hence, the EMR exposure load has increased to a point where their health effects are becoming a major concern. Delicate and sensitive electrical system of human body is affected by consistent penetration of electromagnetic frequencies causing DNA breakages and chromosomal aberrations. Technological innovations came with Pandora's Box of hazardous consequences including neurodegenerative disorders, hearing disabilities, diabetes, congenital abnormalities, infertility, cardiovascular diseases and cancer to name few, all on a sharp rise. Electromagnetic non-ionizing radiations pose considerable health threat with prolonged exposure. Mobile phones are usually held near to the brain and manifest progressive structural or functional alterations in neurons leading to neurodegenerative diseases and neuronal death. This has provoked awareness among both the general public and scientific community and international bodies acknowledge that further systematic research is needed. The aim of the present review was to have an insight in whether and how cumulative electro-magnetic field exposure is a risk factor for neurodegenerative disorders.
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http://dx.doi.org/10.2174/1871527313666141023122340DOI Listing
July 2015

Gene expression analysis approach to establish possible links between Parkinson's disease, cancer and cardiovascular diseases.

CNS Neurol Disord Drug Targets 2014 ;13(8):1334-45

King Fahd Medical Research Center, King Abdulaziz University, PO Box - 80216, Jeddah - 21589, Kingdom of Saudi Arabia.

Non-communicable chronic diseases have been apparently established as threat to human health, and are currently the world's main killer. Cardiovascular diseases (CVD), cancer, diabetes and neurodegenerative diseases are collectively amounting to more than 60% of non-communicable disease burden across world. Tremendous advancements in healthcare enabled us to fight several health problems primarily infectious diseases. However, this increased longevity where in many cases an individual suffers from several such chronic diseases simultaneously, making treatment complex. Finding whether diseases can coexist in an individual by chance or there exists a possible association between them is vital. Our goal is to establish possible existing link among CVD, cancer and Parkinson's disease (PD) for better understanding of the associated molecular network. In this study, we integrated multiple dataset retrieved from the National Centre for Biotechnology Information's Gene Expression Omnibus database, and took a systems-biology approach to compare and distinguish the molecular network associated with PD, cancer and CVD. We identified 230, 308 and 1619 differentially expressed genes for CVD, cancer and PD dataset respectively using cut off p value<0.5 and fold change>2. We integrated these data with known pathways using Ingenuity Pathway Analysis tool and found following common pathways associated with all three diseases to be most affected; epithelial adherens junction signaling, remodelling of epithelial adherens junctions, role of BRCA1 in DNA damage response, sphingomyelin metabolism, 3- phosphoinositide biosynthesis, acute myeloid leukemia signaling, type I diabetes mellitus signaling, agrin interactions at neuromuscular junction, role of IL-17A in arthritis, and antigen presentation pathways. In conclusion, CVD, cancer and PD appear tightly associated at molecular level.
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http://dx.doi.org/10.2174/1871527313666141023122803DOI Listing
July 2015

Protein interactions between the C-terminus of Aβ-peptide and phospholipase A2--a structure biology based approach to identify novel Alzheimer's therapeutics.

CNS Neurol Disord Drug Targets 2014 ;13(7):1224-31

King Fahd Medical Research Center, P.B. No. 80216, King Abdulaziz University, Jeddah -21589, Saudi Arabia.

Amyloid β (Aβ) polypeptide plays a key role in determining the state of protein aggregation in Alzheimer's disease. The hydrophobic C-terminal part of the Aβ peptide is critical in triggering the transformation from α-helical to β- sheet structure. We hypothesized that phospholipase A2 (PLA2) may inhibit the aggregation of Aβ peptide by interacting with the peptide and keeping the two peptide chains apart. In order to examine the nature of interactions between PLA2 and Aβ peptide, we prepared and crystallized complex of Naja naja sagittifera PLA2 with the C-terminal hepta-peptide Val-Gly-Gly-Val-Val-Ile-Ala. The X-ray intensity data were collected to 2.04 A resolution and the structure was determined by molecular replacement and refined to the crystallographic R factor of 0.186. The structural analysis revealed that the peptide binds to PLA2 at the hydrophobic substrate binding cavity forming at least eight hydrogen bonds and approximately a two dozen Van der Waals interactions. The number and nature of interactions indicate that the affinity between PLA2 and the hepta-peptide is greater than the affinity between two Aβ peptide chains. Therefore, PLA2 is proposed as a probable ligand to prevent the aggregation of Aβ peptides.
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http://dx.doi.org/10.2174/1871527313666140917112248DOI Listing
July 2015

Transcriptomics study of neurodegenerative disease: emphasis on synaptic dysfunction mechanism in Alzheimer's disease.

CNS Neurol Disord Drug Targets 2014 ;13(7):1202-12

King Fahd Medical Research Center, PO Box-80216, King Abdulaziz University, Jeddah -21589, Saudi Arabia.

Alzheimer's disease (AD) is a common neurodegenerative disorder primarily affecting memory and thinking ability; caused by progressive degeneration and death of nerve cells. In this study, we integrated multiple dataset retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus database, and took a systems-biology approach to compare and distinguish the molecular network based synaptic dysregulation associated with AD in particular and neurodegenerative diseases in general. We first identified 832 differentially expressed genes using cut off P value <0.5 and fold change > 2, followed by gene ontology study to identify genes associated with synapse (n=95) [membrane associated guanylate kinase, 2, amyloid beta precursor protein, neurotrophic tyrosine kinase, receptor, type 2], synapse part [γ-aminobutyric acid A receptor, γ1], synaptic vesicle [glutamate receptor, ionotropic, α-amino-3-hydroxy-5- methyl-4-isoxazole propionic acid receptor 2, synaptoporin], pre- and post-synaptic density [neuronal calcium sensor 1, glutamate receptor, metabotropic 3]. We integrated these data with known pathways using Ingenuity Pathway Analysis tool and found following synapse associated pathways to be most affected; γ-aminobutyric acid receptor signaling, synaptic long term potentiation/depression, nuclear factor-erythroid 2-related factor 2-mediated oxidative stress response, huntington's disease signaling and Reelin signaling in neurons. In conclusion, synaptic dysfunction is tightly associated with the development and progression of neurodegenerative diseases like AD.
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http://dx.doi.org/10.2174/1871527313666140917113446DOI Listing
July 2015