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Paracha U.Z.,Hajvery University | Fatima K.,IQ Institute of Infection and Immunity | Alqahtani M.,King Abdulaziz University | Chaudhary A.,King Abdulaziz University | And 3 more authors.
Virology Journal | Year: 2013

The disproportionate imbalance between the systemic manifestation of reactive oxygen species and body's ability to detoxify the reactive intermediates is referred to as oxidative stress. Several biological processes as well as infectious agents, physiological or environmental stress, and perturbed antioxidant response can promote oxidative stress. Oxidative stress usually happens when cells are exposed to more electrically charged reactive oxygen species (ROS) such as H2O2 or O2-. The cells' ability to handle such pro-oxidant species is impeded by viral infections particularly within liver that plays an important role in metabolism and detoxification of harmful substances. During liver diseases (such as hepatocellular or cholestatic problems), the produced ROS are involved in transcriptional activation of a large number of cytokines and growth factors, and continued production of ROS and Reactive Nitrogen Species (RNS) feed into the vicious cycle. Many human viruses like HCV are evolved to manipulate this delicate pro- and antioxidant balance; thus generating the sustainable oxidative stress that not only causes hepatic damage but also stimulates the processes to reduce treatment of damage. In this review article, the oxidant and antioxidant pathways that are perturbed by HCV genes are discussed. In the first line of risk, the pathways of lipid metabolism present a clear danger in accumulation of viral induced ROS. Viral infection leads to decrease in cellular concentrations of glutathione (GSH) resulting in oxidation of important components of cells such as proteins, DNA and lipids as well as double strand breakage of DNA. These disorders have the tendency to lead the cells toward cirrhosis and hepatocellular carcinoma in adults due to constant insult. We have highlighted the importance of such pathways and revealed differences in the extent of oxidative stress caused by HCV infection. © 2013 Paracha et al.


Shah F.A.,Quaid-i-Azam University | Fatima K.,IQ Institute of Infection and Immunity | Sabir S.,Allama Iqbal Open University | Ali S.,Quaid-i-Azam University | And 2 more authors.
Medicinal Chemistry Research | Year: 2015

The discovery and optimization of a novel triorganotin(IV) complexes with anti-HCV properties are presented. Organotin(IV) moiety has the ability to bind phosphate group of RNA backbone. The organotin(IV) moiety is bonded with ligands and groups, which are known for inhibiting HCV enzymes. Triorganotin(IV) complexes were synthesized and evaluated for their potency against HCV by using luciferase assay. Structure-activity relationship studies led to the identification of Tributyltannic[3-(3′4′dichlorophenylamido)propanoate] (compound 1) as a potent HCV inhibitor, with log IC50 values 0.79 nM in the cell-based assay. Triorganotin(IV) complexes containing chlorine and nitro group display higher potency. Gaussia luciferase Assay shows that among triorganotin(IV) derivatives, butyl substituted triorganotin(IV) complexes are more active than methyl- and phenyl-substituted complexes. Graphical abstract: HCV infection can lead to hepatocellular carcinoma, and is a major reason for liver transplantation. The worldwide prevalence of chronic HCV infection is estimated to be approaching 270-300 million people, but patients and physicians are still waiting for effective anti-HCV drugs. With this background, organotin(IV) complexes are synthesized and screened against HCV using Gaussia luciferase assay. Organotin(IV) complexes are selected due to their ability to interact with both DNA constituents and enzymes. [Figure not available: see fulltext.] © 2014 Springer Science+Business Media New York.


Mathew S.,Jamal Mohamed College | Mathew S.,King Abdulaziz University | Mathew S.,Bharathidasan University | Ali A.,King Abdulaziz University | And 11 more authors.
Infection, Genetics and Evolution | Year: 2014

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and is advanced by severe viral hepatitis B or C (HBV or HCV) as well as alcoholic liver disease. Many patients with early disease are asymptomatic therefore HCC is frequently diagnosed late requiring costly surgical resection or transplantation. The available non-invasive detections systems are based on the clinical utility of alpha fetoprotein (AFP) measurement, together with ultrasound and other more sensitive imaging techniques. The hallmark of liver disease and its propensity to develop into fully blown HCC is depended on several factors including the host genetic make-up and immune responses. While common symptoms involve diarrhea, bone pain, dyspnea, intraperitoneal bleeding, obstructive jaundice, and paraneoplastic syndrome, the evolution of cell and immune markers is important to understand viral induced liver cancers in humans. The circulating miRNA, cell and immune based HCC biomarkers are imperative candidates to successfully develop strategies to restrain liver injury. The current molecular genetics and proteomic analysis have lead to the identification of number of key biomarkers for HCC for earlier diagnosis and more effective treatment of HCC patients. In this review article, we provide latest updates on the biomarkers of HBV or HCV-associated HCC and their co-evolutionary relationship with liver cancer. © 2014 Elsevier B.V.


Ali A.,King Abdulaziz University | Abdel-Hafiz H.,King Abdulaziz University | Suhail M.,King Abdulaziz University | Al-Mars A.,University of Colorado at Denver | And 7 more authors.
World Journal of Gastroenterology | Year: 2014

Hepatocellular carcinoma (HCC) is one of the leading causes of death induced by cancer in the modern world and majority of the cases are related to chronic hepatitis B virus (HBV) infection. HBV-encoded X protein (HBx) is known to play a pivotal role in the pathogenesis of viral induced HCC. HBx is a multifunctional protein of 17 kDa which modulates several cellular processes by direct or indirect interaction with a repertoire of host factors resulting in HCC. HBX might interfere with several cellular processes such as oxidative stress, DNA repair, signal transduction, transcription, protein degradation, cell cycle progression and apoptosis. A number of reports have indicated that HBx is one of the most common viral ORFs that is often integrated into the host genome and its sequence variants play a crucial role in HCC. By mutational or deletion analysis it was shown that carboxy terminal of HBx has a likely role in protein-protein interactions, transcriptional transactivation, DNA repair, cell, signaling and pathogenesis of HCC. The accumulated evidence thus far suggests that it is difficult to understand the mechanistic nature of HBx associated HCC, and HBx mediated transcriptional transactivation and signaling pathways may be a major determinant. This article addresses the role of HBx in the development of HCC with particular emphasis on HBx mutants and their putative targets. © 2014 Baishideng Publishing Group Inc. All rights reserved.


Suhail M.,King Abdulaziz University | Abdel-Hafiz H.,Aurora University | Ali A.,King Abdulaziz University | Fatima K.,IQ Institute of Infection and Immunity | And 5 more authors.
World Journal of Gastroenterology | Year: 2014

Chronic active hepatitis (CAH) is acknowledged as an imperative risk factor for the development of liver injury and hepatocellular carcinoma. The histological end points of CAH are chronic inflammation, fibrosis and cirrhosis which are coupled with increased DNA synthesis in cirrhotic vs healthy normal livers. The potential mechanism involved in CAH includes a combination of processes leading to liver cell necrosis, inflammation and cytokine production and liver scaring (fibrosis). The severity of liver damage is regulated by Hepatitis B virus genotypes and viral components. The viral and cellular factors that contribute to liver injury are discussed in this article. Liver injury caused by the viral infection affects many cellular processes such as cell signaling, apoptosis, transcription, DNA repair which in turn induce radical effects on cell survival, growth, transformation and maintenance. The consequence of such perturbations is resulted in the alteration of bile secretion, gluconeogenesis, glycolysis, detoxification and metabolism of carbohydrates, proteins, fat and balance of nutrients. The identification and elucidation of the molecular pathways perturbed by the viral proteins are important in order to design effective strategy to minimize and/or restore the hepatocytes injury. © 2014 Baishideng Publishing Group Inc. All rights reserved.


PubMed | Bharathidasan University, COMSATS Institute of Information Technology, Jamal Mohamed College, King Abdulaziz University and IQ Institute of Infection and Immunity
Type: Journal Article | Journal: PloS one | Year: 2015

The current standard care therapy for hepatitis C virus (HCV) infection consists of two regimes, namely interferon-based and interferon-free treatments. The treatment through the combination of ribavirin and pegylated interferon is expensive, only mildly effective, and is associated with severe side effects. In 2011, two direct-acting antiviral (DAA) drugs, boceprevir and telaprevir, were licensed that have shown enhanced sustained virologic response (SVR) in phase III clinical trial, however, these interferon-free treatments are more sensitive to HCV genotype 1 infection. The variable nature of HCV, and the limited number of inhibitors developed thus aim in expanding the repertoire of available drug targets, resulting in targeting the virus assembly therapeutically.We conducted this study to predict the 3D structure of the p7 protein from the HCV genotypes 3 and 4. Approximately 63 amino acid residues encoded in HCV render this channel sensitive to inhibitors, making p7 a promising target for novel therapies. HCV p7 protein forms a small membrane known as viroporin, and is essential for effective self-assembly of large channels that conduct cation assembly and discharge infectious virion particles.In this study, we screened drugs and flavonoids known to disrupt translation and production of HCV proteins, targeted against the active site of p7 residues of HCV genotype 3 (GT3) (isolatek3a) and HCV genotype 4a (GT4) (isolateED43). Furthermore, we conducted a quantitative structure-activity relationship and docking interaction study.The drug NB-DNJ formed the highest number of hydrogen bond interactions with both modeled p7 proteins with high interaction energy, followed by BIT225. A flavonoid screen demonstrated that Epigallocatechin gallate (EGCG), nobiletin, and quercetin, have more binding modes in GT3 than in GT4. Thus, the predicted p7 protein molecule of HCV from GT3 and GT4 provides a general avenue to target structure-based antiviral compounds.We hypothesize that the inhibitors of viral p7 identified in this screen may be a new class of potent agents, but further confirmation in vitro and in vivo is essential. This structure-guided drug design for both GT3 and GT4 can lead to the identification of drug-like natural compounds, confirming p7 as a new target in the rapidly increasing era of HCV.


Qashqari H.,King Abdulaziz University | Al-Mars A.,King Abdulaziz University | Chaudhary A.,King Abdulaziz University | Abuzenadah A.,King Abdulaziz University | And 6 more authors.
Infection, Genetics and Evolution | Year: 2013

Hepatitis C virus (HCV) is one of the foremost causes of chronic liver disease affecting over 300. million globally. HCV contains a positive-stranded RNA of ~9600. nt and is surrounded by the 5' and 3'untranslated regions (UTR). The only successful treatment regimen includes interferon (IFN) and ribavirin. Like many other viruses, HCV has also evolved various mechanisms to circumvent the IFN response by blocking (1) downstream signaling actions via STAT1, STAT2, IRF9 and JAK-STAT pathways and (2) repertoire of IFN Stimulatory Genes (ISGs). Several studies have identified complex host demographic and genetic factors as well as viral genetic heterogeneity associated with outcomes of IFN therapy. The genetic predispositions of over 2000 ISGS may render the patients to become resistant, thus identification of such parameters within a subset of population are necessary for management corollary. The ability of various HCV genotypes to diminish IFN antiviral responses plays critical role in the establishment of chronic infection at the acute stage of infection, thus highlighting importance of the resistance in HCV treated groups. The recently defined role of viral protein such as C, E2, NS3/NS4 and NS5A proteins in inducing the IFN resistance are discussed in this article. How the viral and host genetic composition and epistatic connectivity among polymorphic genomic sites synchronizes the evolutionary IFN resistance trend remains under investigation. However, these signals may have the potential to be employed for accurate prediction of therapeutic outcomes. In this review article, we accentuate the significance of host and viral components in IFN resistance with the aim to determine the successful outcome in patients. © 2013 Elsevier B.V.


Shah F.A.,Quaid-i-Azam University | Fatima K.,IQ Institute of Infection and Immunity | Sabir S.,Allama Iqbal Open University | Ali S.,Quaid-i-Azam University | Qadri I.,King Abdulaziz University
Applied Organometallic Chemistry | Year: 2014

Gaussia luciferase assay was used to measure the anti-hepatitis C (anti-HCV) potency of tributyltin(IV)[3-(3′,5′-dimethylphenylamido) propanoate] in infected Huh 7.5 cells (human hepatocellular cell). Interaction of the organotin(IV) complex with cetyl N,N,N-trimethylammonium bromide (CTAB) micelles was studied using UV-visible and steady-state florescence spectroscopy. The anti-HCV study showed a log IC50 value of 0.96 nm for the complex. The complex-CTAB interaction parameter showed that partition of the complex from bulk water to the CTAB micelle was a spontaneous process, and the red shift in visible spectra of the complex confirmed its increased solubility into micelles. © 2013 John Wiley & Sons, Ltd.


PubMed | Allama Iqbal Open University Islamabad, King Abdulaziz University, IQ Institute of Infection and Immunity and Quaid-i-Azam University
Type: | Journal: Journal of photochemistry and photobiology. B, Biology | Year: 2016

Four new triorganotin(IV) complexes with general formula R3SnL (R=C4H9, C6H5, and L=3-[(fluorophenylamido)]propenoic acid, 3-[(fluorophenylamido)]propanoic acid) were synthesized and characterized by elemental analyses, FT-IR, NMR ((1)H, (13)C and (119)Sn), mass spectrometry and single crystal X-ray structural analysis. The disappearance of the OH peak of the carboxylic acid in the FT-IR and NMR spectra of the compounds conform the formation of the compound and suggests that the complexation occurs via oxygen atoms of the carboxylate moiety. FT-IR date shows the bidentate nature of the carboxylate moiety of the ligand as the value in all complexes is less than 250. Crystallographic data for compound 2 showed that tin has distorted tetrahedral geometry with 433.42 angle around the central tin atom. The compounds (1-4) bind to DNA, resulting hypochromism shifts in UV-visible spectroscopy suggesting an intercalative mode of interactions. The compound-DNA interaction results (UV-visible and Viscometery) encourage using the compounds against HCV. The compounds (1-4) were screened for anti-HCV activity using Huh7.5 cell (human hepatoma cell) by the Gaussia Luciferase Assay and found to be biologically active. Based on Gaussia Luciferase Assay, compound 3 (Tributylstannic [3-(2-fluorophenylamido)propionate]) was taken for quantitative analysis by QRT-PCR using the serum of HCV patients and was found to have substantial anti-HCV activity. This work, demonstrated that compound 3 may be used as a potential anti-HCV agent in the future.


Fatima K.,IQ Institute of Infection and Immunity | Qadri I.,King Abdulaziz University
Journal of Infection in Developing Countries | Year: 2013

On 22 Feb 2013, the Polio Monitoring Cell of Pakistan announced that the 2012-2013 polio campaign ended, and that 1.6 million children could not be vaccinated due to security concerns in several regions where polio workers had been killed. Those who could not be vaccinated included 50,000 children from the Federally Administrated Tribal Area (FATA), 150,000 form Khyber Pakhtoon Khao, 400,000 from a Quetta, 400,000 from Karachi, and a small number from the Rawalpindi District. These statistics are worrying, as several districts in the large metropolitan cities of Karachi and Quetta were also excluded. The fear of advanced medicine, ideas, or complex devices is a new phenomenon in many conservative and poor countries such as Pakistan, Afghanistan, Sudan, and Somalia. To safeguard the safety of the rest of the world, the failure in the implementation of WHO guidelines for vaccination must be regulated by the UN. There are a number of reasons for the phobias surrounding vaccination, but as technology continues to evolve at such a rapid rate, those with self-determined ideologies cannot cope with such advances. They become vocal to gain popularity and prevent the use of these technologies and medicine by creating and spreading rumors and propaganda of expediency. The struggle to vaccinate children is not easily understood by anyone living in the developed world. The irrational fear of vaccines and the lack of vaccination pose a serious global health risk and must be curbed through a wide variety of pro-vaccination media and religious campaigns. © 2013 Fatima et al.

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