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Article: The Biology of Toll-Like Receptor 9 and Its Role in Cancer.

Alzahrani, Badr

Critical reviews in eukaryotic gene expression

2021 Volume 30, Issue 5, Page(s) 457–474

Abstract: Toll-like receptor 9 (TLR9) plays a fundamental role in innate immune responses through pathogen-associated and danger-associated molecular pattern recognition. Ligand recognition by TLR9 results in activation of several signaling pathways, including ... ...

Abstract	Toll-like receptor 9 (TLR9) plays a fundamental role in innate immune responses through pathogen-associated and danger-associated molecular pattern recognition. Ligand recognition by TLR9 results in activation of several signaling pathways, including those involving nuclear factor-kappa B, mitogen-activated protein kinases, and interfer-on-regulatory factors, which promote secretion of proinflammatory cytokines and type I interferons. TLR9 is expressed by immune-mediated cells and in clinical specimens and cell lines of various human cancers. TLR9 appears to act as a double-edged sword in cancer, with some studies indicating that it is associated with increased malignancy and others indicating that it contributes to immune response against cancer. At present, the mechanisms underlying the role of TLR9 in cancer pathophysiology are not completely clear, although various TLR9 agonists and antagonists are being tested in in vitro and in vivo cancer models as well as clinical trials. This review summarizes the current state of knowledge regarding TLR9 features, isoforms, structure, ligands, and signaling, and discusses the roles of TLR9 in cancer pathogenesis. Recent efforts to utilize TLR9 agonists and antagonists as potential anticancer immunotherapy agents are also highlighted.
MeSH term(s)	Cytokines/metabolism ; Humans ; Inflammation Mediators/metabolism ; Neoplasms/metabolism ; Neoplasms/physiopathology ; Signal Transduction ; Toll-Like Receptor 9/agonists ; Toll-Like Receptor 9/antagonists & inhibitors ; Toll-Like Receptor 9/physiology
Chemical Substances	Cytokines ; Inflammation Mediators ; TLR9 protein, human ; Toll-Like Receptor 9
Language	English
Publishing date	2021-01-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1071345-1
ISSN	1045-4403
ISSN	1045-4403
DOI	10.1615/CritRevEukaryotGeneExpr.2020036214
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Article ; Online: The Role of miRNAs, circRNAs and Their Interactions in Development and Progression of Hepatocellular Carcinoma: An Insilico Approach

Ishaq, Yasmeen / Ikram, Aqsa / Alzahrani, Badr / Khurshid, Sana

Genes (Basel). 2022 Dec. 21, v. 14, no. 1

2022

Abstract: Hepatocellular carcinoma (HCC) is a type of malignant tumor. miRNAs are noncoding RNAs and their differential expression patterns are observed in HCC-induced by alcoholism, HBV and HCV infections. By acting as a competing endogenous RNA (ceRNA), circRNA ... ...

Abstract	Hepatocellular carcinoma (HCC) is a type of malignant tumor. miRNAs are noncoding RNAs and their differential expression patterns are observed in HCC-induced by alcoholism, HBV and HCV infections. By acting as a competing endogenous RNA (ceRNA), circRNA regulates the miRNA function, indirectly controlling the gene expression and leading to HCC progression. In the present study, data mining was performed to screen out all miRNAs and circRNA involved in alcohol, HBV or HCV-induced HCC with statistically significant (≤0.05%) expression levels reported in various studies. Further, the interaction of miRNAs and circRNA was also investigated to explore their role in HCC due to various causative agents. Together, these study data provide a deeper understanding of the circRNA–miRNA regulatory mechanisms in HCC. These screened circRNA, miRNA and their interactions can be used as prognostic biomarkers or therapeutic targets for the treatment of HCC.
Keywords	alcohol abuse ; alcohols ; biomarkers ; gene expression ; gene expression regulation ; hepatoma ; microRNA ; therapeutics
Language	English
Dates of publication	2022-1221
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes14010013
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Development of a tetravalent subunit vaccine against dengue virus through a vaccinomics approach.

Basheer, Amina / Jamal, Syed Babar / Alzahrani, Badr / Faheem, Muhammad

Frontiers in immunology

2023 Volume 14, Page(s) 1273838

Abstract: Dengue virus infection (DVI) is a mosquito-borne disease that can lead to serious morbidity and mortality. Dengue fever (DF) is a major public health concern that affects approximately 3.9 billion people each year globally. However, there is no vaccine ... ...

Abstract	Dengue virus infection (DVI) is a mosquito-borne disease that can lead to serious morbidity and mortality. Dengue fever (DF) is a major public health concern that affects approximately 3.9 billion people each year globally. However, there is no vaccine or drug available to deal with DVI. Dengue virus consists of four distinct serotypes (DENV1-4), each raising a different immunological response. In the present study, we designed a tetravalent subunit multi-epitope vaccine, targeting proteins including the structural protein envelope domain III (EDIII), precursor membrane proteins (prM), and a non-structural protein (NS1) from each serotype by employing an immunoinformatic approach. Only conserved sequences obtained through a multiple sequence alignment were used for epitope mapping to ensure efficacy against all serotypes. The epitopes were shortlisted based on an IC50 value <50, antigenicity, allergenicity, and a toxicity analysis. In the final vaccine construct, overall, 11 B-cell epitopes, 10 HTL epitopes, and 10 CTL epitopes from EDIII, prM, and NS1 proteins targeting all serotypes were selected and joined via KK, AAY, and GGGS linkers, respectively. We incorporated a 45-amino-acid-long B-defensins adjuvant in the final vaccine construct for a better immunogenic response. The vaccine construct has an antigenic score of 0.79 via VaxiJen and is non-toxic and non-allergenic. Our refined vaccine structure has a Ramachandran score of 96.4%. The vaccine has shown stable interaction with TLR3, which has been validated by 50 ns of molecular dynamics (MD) simulation. Our findings propose that a designed multi-epitope vaccine has substantial potential to elicit a strong immune response against all dengue serotypes without causing any adverse effects. Furthermore, the proposed vaccine can be experimentally validated as a probable vaccine, suggesting it may serve as an effective preventative measure against dengue virus infection.
MeSH term(s)	Animals ; Humans ; Dengue Virus ; Vaccines, Combined ; Vaccines, Subunit ; Epitopes, B-Lymphocyte ; Dengue/prevention & control ; Virus Diseases
Chemical Substances	Vaccines, Combined ; Vaccines, Subunit ; Epitopes, B-Lymphocyte
Language	English
Publishing date	2023-11-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1273838
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Article ; Online: The Role of miRNAs, circRNAs and Their Interactions in Development and Progression of Hepatocellular Carcinoma: An

Ishaq, Yasmeen / Ikram, Aqsa / Alzahrani, Badr / Khurshid, Sana

Genes

2022 Volume 14, Issue 1

Abstract	Hepatocellular carcinoma (HCC) is a type of malignant tumor. miRNAs are noncoding RNAs and their differential expression patterns are observed in HCC-induced by alcoholism, HBV and HCV infections. By acting as a competing endogenous RNA (ceRNA), circRNA regulates the miRNA function, indirectly controlling the gene expression and leading to HCC progression. In the present study, data mining was performed to screen out all miRNAs and circRNA involved in alcohol, HBV or HCV-induced HCC with statistically significant (≤0.05%) expression levels reported in various studies. Further, the interaction of miRNAs and circRNA was also investigated to explore their role in HCC due to various causative agents. Together, these study data provide a deeper understanding of the circRNA-miRNA regulatory mechanisms in HCC. These screened circRNA, miRNA and their interactions can be used as prognostic biomarkers or therapeutic targets for the treatment of HCC.
MeSH term(s)	Humans ; Carcinoma, Hepatocellular/pathology ; MicroRNAs/genetics ; MicroRNAs/metabolism ; RNA, Circular/genetics ; RNA, Circular/metabolism ; Liver Neoplasms/pathology ; Hepatitis C
Chemical Substances	MicroRNAs ; RNA, Circular
Language	English
Publishing date	2022-12-21
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes14010013
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Article: An In Silico Deep Learning Approach to Multi-Epitope Vaccine Design: A Hepatitis E Virus Case Study.

Ikram, Aqsa / Alzahrani, Badr / Zaheer, Tahreem / Sattar, Sobia / Rasheed, Sidra / Aurangzeb, Muhammad / Ishaq, Yasmeen

Vaccines

2023 Volume 11, Issue 3

Abstract: Hepatitis E Virus (HEV) is a major cause of acute and chronic hepatitis. The severity of HEV infection increases manyfold in pregnant women and immunocompromised patients. Despite the extensive research on HEV in the last few decades, there is no widely ... ...

Abstract	Hepatitis E Virus (HEV) is a major cause of acute and chronic hepatitis. The severity of HEV infection increases manyfold in pregnant women and immunocompromised patients. Despite the extensive research on HEV in the last few decades, there is no widely available vaccine yet. In the current study, immunoinformatic analyses were applied to predict a multi-epitope vaccine candidate against HEV. From the ORF2 region, 41 conserved and immunogenic epitopes were prioritized. These epitopes were further analyzed for their probable antigenic and non-allergenic combinations with several linkers. The stability of the vaccine construct was confirmed by molecular dynamic simulations. The vaccine construct is potentially antigenic and docking analysis revealed stable interactions with TLR3. These results suggest that the proposed vaccine can efficiently stimulate both cellular and humoral immune responses. However, further studies are needed to determine the immunogenicity of the vaccine construct.
Language	English
Publishing date	2023-03-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines11030710
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Article ; Online: Therapeutic Impact of ODN2088 to Block TLR9 Activity in Induced Liver Fibrosis Mice.

Alzahrani, Badr / A M Alameen, Ayman / Tantawy, Ahmed

Pakistan journal of biological sciences : PJBS

2021 Volume 24, Issue 1, Page(s) 122–131

Abstract: Background and objective: Liver fibrosis is the result of an excessive accumulation of extracellular matrix that develops when inflammation and chronic injury form scar tissue in the liver. Toll-like receptor 9 (TLR9) plays a central role in the innate ... ...

Abstract	Background and objective: Liver fibrosis is the result of an excessive accumulation of extracellular matrix that develops when inflammation and chronic injury form scar tissue in the liver. Toll-like receptor 9 (TLR9) plays a central role in the innate immune response by recognition of pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). This study aimed to show the therapeutic effects of TLR9 antagonist oligonucleotide (ODN) 2088 on liver fibrogenesis. Materials and methods: Mice were injected intraperitoneally with carbon tetrachloride (CCl4) or corn oil twice weekly for up to 8 weeks. Mice were also injected with CpG ODN 2088 (50 μg/20 g) daily for the last 4 weeks. At sacrifice, the serum level of liver enzyme activity was measured. Expression of pro-inflammatory and pro-fibrotic biomarkers was analyzed in liver tissue. Results: TLR9 antagonist, CpG ODN 2088, remarkably decreased the haptic inflammation and fibrosis during CCl4 administration. Treatment with CpG ODN 2088 resulted in reduced serum Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST). That was paralleled with inhibition in the production of intrahepatic inflammatory and fibrotic factors including collagen, α-Smooth Muscle Actin (SMA), Transforming Growth Factor-beta (TGF-β), interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α). Proliferation (Ki-67) and apoptosis (caspase-3) markers were highly suppressed after CpG ODN 2088 administration. Conclusion: Our results indicate that TLR9 antagonist, ODN 2088, showed protective effects against hepatics inflammation and fibrosis in the CCl4-induced fibrosis model. These observations suggest that ODN 2088 can be a potential therapeutic target for liver fibrosis treatment.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/pharmacology ; Carbon Tetrachloride ; Caspase 3/metabolism ; Chemical and Drug Induced Liver Injury/etiology ; Chemical and Drug Induced Liver Injury/metabolism ; Chemical and Drug Induced Liver Injury/pathology ; Chemical and Drug Induced Liver Injury/prevention & control ; Cytokines/metabolism ; Disease Models, Animal ; Inflammation Mediators/metabolism ; Ki-67 Antigen/metabolism ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Liver Cirrhosis/chemically induced ; Liver Cirrhosis/metabolism ; Liver Cirrhosis/pathology ; Liver Cirrhosis/prevention & control ; Male ; Mice, Inbred BALB C ; Oligodeoxyribonucleotides/pharmacology ; Signal Transduction ; Toll-Like Receptor 9/antagonists & inhibitors ; Toll-Like Receptor 9/metabolism ; Mice
Chemical Substances	Anti-Inflammatory Agents ; Cytokines ; Inflammation Mediators ; Ki-67 Antigen ; Mki67 protein, mouse ; Oligodeoxyribonucleotides ; Tlr9 protein, mouse ; Toll-Like Receptor 9 ; iCpG-ODN ; Carbon Tetrachloride (CL2T97X0V0) ; Casp3 protein, mouse (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-)
Language	English
Publishing date	2021-02-20
Publishing country	Pakistan
Document type	Journal Article
ISSN	1812-5735
ISSN (online)	1812-5735
DOI	10.3923/pjbs.2021.122.131
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Article: In-silico

Saleem, Tayyab / Jamal, Syed Babar / Alzahrani, Badr / Basheer, Amina / Wajid Abbasi, Sumra / Ali, Mahwish / Rehman, Ashfaq Ur / Faheem, Muhammad

Frontiers in molecular biosciences

2023 Volume 10, Page(s) 1098217

Abstract: Naegleria ... ...

Abstract	Naegleria fowleri
Language	English
Publishing date	2023-02-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2023.1098217
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Article: Determination of serum tumor necrosis factor-alpha (TNF-α) levels in metabolic syndrome patients from Saudi population.

Ullah, Muhammad Ikram / Alzahrani, Badr / Alsrhani, Abdullah / Atif, Muhammad / Alameen, Ayman Ali Mohammed / Ejaz, Hasan

Pakistan journal of medical sciences

2021 Volume 37, Issue 3, Page(s) 700–705

Abstract: Objectives: To detect the relationship between serum tumor necrosis factor-alpha (TNF-α) and metabolic syndrome (MetS) components in patients of the Saudi population.: Methods: This cross-sectional study was carried out at Jouf University Saudi ... ...

Abstract	Objectives: To detect the relationship between serum tumor necrosis factor-alpha (TNF-α) and metabolic syndrome (MetS) components in patients of the Saudi population. Methods: This cross-sectional study was carried out at Jouf University Saudi Arabia from September 2019 to August 2020 and comprised of 183 individuals (91 cases and 92 controls). The blood samples were drawn from the patients visiting two tertiary care settings of Al Jouf province. Biochemical analysis was conducted on various instruments, and serum TNF-α was measured by the ELISA method. Results: The levels of serum glucose fasting, lipid profile, HbA1c and body mass index (BMI) were raised significantly in cases of MetS than controls (p = 0.001). Serum TNF-α was significantly higher in patients (58.04 ± 15.44) than controls (48.81 ± 10.30). It was correlated with the BMI, blood HbA1c, serum fasting glucose (SFG) and serum high density lipoprotein (HDL). The weak positive correlation was found with BMI (r = 0.18; p = 0.01), serum glucose (r = 0.21; p = 0.007) and HbA1c (r = 0.14; p = 0.04), but found negative association with serum HDL (r = -0.18; p = 0.01). Conclusion: The serum TNF-α was raised in metabolic syndrome patients than the healthy controls. It was positively associated with high BMI, serum fasting glucose, and HbA1c and found linked and negatively linked to low HDL levels in MetS patients in the Saudi population.
Language	English
Publishing date	2021-05-19
Publishing country	Pakistan
Document type	Journal Article
ZDB-ID	2032827-8
ISSN	1681-715X ; 1682-024X ; 1017-4699
ISSN (online)	1681-715X
ISSN	1682-024X ; 1017-4699
DOI	10.12669/pjms.37.3.3897
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Article ; Online: Assessment of risk factors for deep vein thrombosis associated with natural anticoagulants and fibrinolytic regulatory proteins.

Abdalhabib, Ezeldine K / Jackson, Denise E / Alzahrani, Badr / Elfaki, Elyasa / Hamza, Alneil / Alanazi, Fehaid / Ali, Elryah I / Algarni, Abdulrahman / Ibrahim, Ibrahim Khider

Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis

2022 Volume 33, Issue 3, Page(s) 149–152

Abstract: Deep vein thrombosis (DVT) is a critical condition and a potential cause of mortality and morbidity in Africa and worldwide with a high recurrence rate. The study was designed to assess the roles of natural anticoagulants and fibrinolytic regulatory ... ...

Abstract	Deep vein thrombosis (DVT) is a critical condition and a potential cause of mortality and morbidity in Africa and worldwide with a high recurrence rate. The study was designed to assess the roles of natural anticoagulants and fibrinolytic regulatory factors in the development of DVT in Sudanese patients. A case-control study was conducted in Omdurman Teaching Hospital, Khartoum State over a period of 1 year. The study enrolled 200 patients diagnosed with DVT and 200 age-matched and gender-matched controls. Demographic data and data on acquired risk factors were collected using a semi-structured questionnaire. Protein C (PC), protein S (PS), antithrombin III (AT-III), thrombin-activable fibrinolysis inhibitor (TAFI), and plasminogen activator inhibitor-1 (PAI-1) were measured in patients and controls. Among the patients with DVT, 5.5% had PC deficiency, 8.5% had PS deficiency, and 3% had AT-III deficiency. Elevated TAFI and PAI-1 levels were demonstrated in 1.5 and 0.5% of patients, respectively. Risk factors for DVT (overweight, surgical history, and family history of DVT) were remarkably higher in patients than in controls. Among the female participants, pregnancy and usage of oral contraceptive pills were the highest associated risk factors for DVT. The findings concluded that the early assessment of risk factors, including the measurements of natural inhibitors, can predict the occurrence of DVT before it is actually detected in patients.
MeSH term(s)	Anticoagulants/pharmacology ; Case-Control Studies ; Female ; Fibrinolysis ; Humans ; Plasminogen Activator Inhibitor 1 ; Pregnancy ; Risk Factors ; Venous Thrombosis/etiology
Chemical Substances	Anticoagulants ; Plasminogen Activator Inhibitor 1
Language	English
Publishing date	2022-03-02
Publishing country	England
Document type	Journal Article
ZDB-ID	1033551-1
ISSN	1473-5733 ; 0957-5235
ISSN (online)	1473-5733
ISSN	0957-5235
DOI	10.1097/MBC.0000000000001116
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Zs.A 2920: Show issues

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Article ; Online: Integrated analysis to study the interplay between post-translational modifications (PTM) in hepatitis C virus proteins and hepatocellular carcinoma (HCC) development.

Ikram, Aqsa / Rauff, Bisma / Alzahrani, Badr / Awan, Faryal Mehwish / Obaid, Ayesha / Naz, Anam / Kakar, Salik Javed / Janjua, Hussnain Ahmed

Scientific reports

2022 Volume 12, Issue 1, Page(s) 15648

Abstract: Many PTMs dysregulation is known to be the major cause of many cancers including HCV induced HCC. PTMs of hepatitis C virus (HCV) regions NS3/4A, NS5A and NS5B are crucial for proper protein functions and replication that directly affect the generation ... ...

Abstract	Many PTMs dysregulation is known to be the major cause of many cancers including HCV induced HCC. PTMs of hepatitis C virus (HCV) regions NS3/4A, NS5A and NS5B are crucial for proper protein functions and replication that directly affect the generation of infectious virus particles and completion of its life cycle. In this study, we have performed comprehensive analysis of PTMs within HCV non-structural proteins (NS3/4A, NS5A and NS5B) through bioinformatics analysis to examine post-translational crosstalk between phosphorylation, palmitoylation, methylation, acetylation and ubiquitination sites in selected viral proteins. Our analysis has revealed many highly putative PTMs sites that are also conserved among major genotypes conferring the importance of these sites. We have also analysed viral 3D structures in their modified and unmodified forms to address extent and signatures of structural changes upon PTM. This study provides evidence that PTMs induce significant conformational changes and make viral proteins more stable. To find the potential role of PTMs in HCV induced HCC, docking analysis between selected viral proteins and p38-MAPK has been performed which also confirms their strong association with HCV induced HCC. The major findings proposed that PTMs at specific sites of HCV viral proteins could dysregulate specific pathways that cause the development of HCC.
MeSH term(s)	Carcinoma, Hepatocellular ; Hepacivirus/genetics ; Hepatitis C/complications ; Humans ; Liver Neoplasms ; Protein Processing, Post-Translational ; Viral Proteins/genetics
Chemical Substances	Viral Proteins
Language	English
Publishing date	2022-09-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-19854-6
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