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Now showing 1 - 10 of 20
  • PublicationMetadata only
    Andrographolide Inhibits Proliferation of Colon Cancer SW-480 Cells via Downregulating Notch Signaling Pathway
    (2020-07-01T00:00:00Z) Khan, Imran; KHAN, IMRAN
    Background: Recently Notch signaling pathway has gained attention as a potential therapeutic target for chemotherapeutic intervention. However, the efficacy of previously known Notch inhibitors in colon cancer is still unclear. The purpose of this study was to investigate the effect of andrographolide on aberrantly activated Notch signaling in SW-480 cells in vitro. Methods: The cytostatic potential of andrographolide on SW-480 cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay, morphology assessment and colony formation assay. The apoptotic activity was evaluated by FITC Annexin V assay, 4',6-diamidino-2-phenylindole (DAPI), Hoechst, Rhodamine 123 and Mito Tracker CMXRos staining. Scratch assay for migratory potential assessment. 7'-Dichlorodihydrofluorescein Diacetate (DCFH-DA) staining was used to evaluate the Reactive Oxygen Species (ROS) generation. Relative mRNA expression of Bax, Bcl2, NOTCH 1 and JAGGED 1 was estimated by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). Cell cycle phase distribution was evaluated Annexin V-FITC/PI staining. Results: MTT assay demonstrated dose and time dependent cytoxicity of andrographolide on SW-480 cells. It also inhibited the migratory and colony forming potential of SW-480 cells. Furthermore, andrographolide also showed disruption of mitochondrial membrane potential and induced apoptosis through nuclear condensation. Flow cytometric evaluation showed andrographolide enhanced early and late apoptotic cells and induced upregulation of proapoptotic (Bax and Bad) and downregulation of antiapoptotic Bcl2 in treated SW-480 cells. Andrographolide augmented intracellular ROS generation and induced G0/G1 phase cell cycle arrest in colon cancer SW480 cells. Furthermore, andrographolide repressed the Notch signaling by decreasing the expression of NOTCH 1 and JAGGED 1. Conclusion: Our findings suggested that andrographolide constraint the growth of SW-480 cells through the inhibition of Notch signaling pathway.
  • PublicationMetadata only
    Understanding and Targeting the Colon Cancer Pathogenesis: A Molecular Perspective
    (2022-01-01) KHAN I.; KHAN, IMRAN
    Colorectal cancer (CRC) one of the leading cause of cancer-related deaths worldwide. With the presently available knowledge on CRC, it is understood that the underlying is a complex process. The complexity of CRC lies in aberrant activation of several cellular signaling pathways that lead to activation and progression of CRC. In this context, recent studies have pointed towards the role of developmental pathways like; hedgehog (HH), wingless-related integration site (WNT/??-catenin) and Notch pathways that play a crucial role in maintenance and homeostasis of colon epithelium. Moreover, the deregulation of these signaling pathways has also been associated with the pathogenesis of CRC. Therefore, in the search for better therapeutic options, these pathways have emerged as potential targets. The present review attempts to highlight the role of HH, WNT/??-catenin and Notch pathways in colon carcinogenesis.
  • PublicationMetadata only
    Thymoquinone Enhances the Effect of Gamma Knife in B16-F10 Melanoma Through Inhibition of Phosphorylated STAT3
    BACKGROUND: Patients with brain metastasis from melanoma have a dismal prognosis with poor survival time. Gamma Knife (GK) is an effective treatment to control brain metastasis from melanoma. Thymoquinone (TQ) has emerged as a potential therapeutic option due to its antiproliferative effects on various cancers. The purpose of the study was to assess the effect of GK on B16-F10 melanoma cells in vitro and intracerebral melanoma in vivo, and its synergistic effect in combination with TQ.
  • PublicationMetadata only
    Glycyrrhizin induces reactive oxygen species-dependent apoptosis and cell cycle arrest at G(0)/G(1) in HPV18(+) human cervical cancer HeLa cell line
    (2018-01-01T00:00:00Z) Farooqui, Arshi; Khan, Fahad; Khan, IMRAN; Ansari, Irfan A.; KHAN, IMRAN
    Cervical cancer is the fourth most common cancer among women worldwide and is a major cause of morbidity and mortality. High-risk Human Papilloma Virus (mostly type 16 & 18) infection is the primary risk factor for the development of cervical carcinoma. The quest for strong, safe and cost effective natural antiproliferative agents that could reduce cervical cancer have been focussed now a day. Recently, glycyrrhizin, a triterpene glycoside (saponin) from licorice (Glycyrrhiza glabra Linn.), has been shown to exhibit potent antiproliferative and anticancer properties in a few preliminary studies. However, potential of this compound in cervical cancer has not been elucidated yet. Therefore the objective of this study was to analyze the antiproliferative and apoptotic properties of glycyrrhizin in human cervical cancer HeLa cells. Our results showed that glycyrrhizin exposure significantly reduced the cell viability of HeLa cells with a concomitant increase in nuclear condensation and DNA fragmentation in a dose dependent manner. The intracellular ROS generation assay showed dose-related increment in ROS production induced by glycyrrhizin. Glycyrrhizin also induced apoptosis in cervical cancer cells by exerting mitochondrial depolarization. Cell cycle study showed that glycyrrhizin induced cell cycle arrest in G(0)/G1 phase of cell cycle in a dose dependent manner. Thus, this study confirms the efficacy of glycyrrhizin in cervical cancer cells which could be an adjunct in the better prevention and management of cervical cancer worldwide.
  • PublicationMetadata only
    Investigating the Mechanism of Inhibition of Cyclin-Dependent Kinase 6 Inhibitory Potential by Selonsertib: Newer Insights Into Drug Repurposing
    (2022-05-26) Baig M. H.; Yousuf M.; Khan M. I.; KHAN I.; Ahmad I.; Alshahrani M. Y.; Hassan M. I.; Dong J.; KHAN, IMRAN
    Copyright © 2022 Baig, Yousuf, Khan, Khan, Ahmad, Alshahrani, Hassan and Dong.Cyclin-dependent kinases (CDKs) play significant roles in numerous physiological, and are considered an attractive drug target for cancer, neurodegenerative, and inflammatory diseases. In the present study, we have aimed to investigate the binding affinity and inhibitory potential of selonsertib toward CDK6. Using the drug repurposing approach, we performed molecular docking of selonsertib with CDK6 and observed a significant binding affinity. To ascertain, we further performed essential dynamics analysis and free energy calculation, which suggested the formation of a stable selonsertib-CDK6 complex. The in-silico findings were further experimentally validated. The recombinant CDK6 was expressed, purified, and treated with selonsertib. The binding affinity of selonsertib to CDK6 was estimated by fluorescence binding studies and enzyme inhibition assay. The results indicated an appreciable binding of selonsertib against CDK6, which subsequently inhibits its activity with a commendable IC50 value (9.8 μM). We concluded that targeting CDK6 by selonsertib can be an efficient therapeutic approach to cancer and other CDK6-related diseases. These observations provide a promising opportunity to utilize selonsertib to address CDK6-related human pathologies.
  • PublicationMetadata only
    Herbal Medicine for Glioblastoma:Current and Future Prospects.
    (2020-01-29T00:00:00Z) Khan, I; Mahfooz, S; Hatiboglu, MUSTAFA AZİZ; KHAN, IMRAN; HATİBOĞLU, MUSTAFA AZİZ
  • PublicationMetadata only
    Potential role of lycopene in targeting proprotein convertase subtilisin/kexin type-9 to combat hypercholesterolemia
    (2017-07-01T00:00:00Z) Alvi, Sahir Sultan; Ansari, Irfan A.; Khan, IMRAN; Iqbal, Johar; Khan, M. Salman; KHAN, IMRAN
    Proprotein convertase subtilisin/kexin type 9 (PCSK-9) is a serine protease of the proprotien convertase (PC) family that has profound effects on plasma low density lipoprotein cholesterol (LDL-C) levels, the major risk factor for coronary heart disease (CHD), through its ability to mediate LDL receptor (LDL-R) protein degradation and reduced recycling to the surface of hepatocytes. Thus, the current study was premeditated not only to evaluate the role of lycopene in targeting the inhibition of PCSK-9 via modulation of genes involved in cholesterol homeostasis in HFD rats but also to examine a correlation between HFD induced inflammatory cascades and subsequent regulation of PCSK-9 expression. Besides the effect of lycopene on hepatic PCSK-9 gene expression, PPI studies for PCSK-9-Lycopene complex and EGF-A of LDL-R were also performed via molecular informatics approach to assess the dual mode of action of lycopene in LDL-R recycling and increased removal of circulatory LDL-C. We for the first time deciphered that lycopene treatment significantly down-regulates the expression of hepatic PCSK-9 and HMGR, whereas, hepatic LDL-R expression was significantly up-regulated. Furthermore, lycopene ameliorated inflammation stimulated expression of PCSK-9 via suppressing the expression of inflammatory markers. The results from our molecular informatics studies confirmed that lycopene, while occupying the active site of PCSK-9 crystal structure, reduces the affinity of PCSK-9 to complex with EGF-A of LDL-R, whereas, atorvastatin makes PCSK-9-EGF-A complex formation more feasible than both of PCSK-9-EGF-A alone and Lycopene-PCSK-9-EGF-A complex. Based on above results, it can be concluded that lycopene exhibits potent hypolipidemic activities via molecular mechanisms that are either identical (HMGR inhibition) or distinct from that of statins (down-regulation of PCSK-9 mRNA synthesis). To the best of our knowledge, this is the first report that lycopene has this specific biological property. Being a natural, safer and alternative therapeutic agent, lycopene could be used as a complete regulator of cholesterol homeostasis and ASCVD.
  • PublicationMetadata only
    Carvacrol Induces Reactive Oxygen Species (ROS)-mediated Apoptosis Along with Cell Cycle Arrest at G(0)/G(1) in Human Prostate Cancer Cells
    (2017-01-01T00:00:00Z) Khan, Fahad; Khan, IMRAN; Farooqui, Arshi; Ansari, Irfan A.; KHAN, IMRAN
    Carvacrol, a major monoterpenoid phenol from Origanum and Thymus species, has been shown to exhibit antiproliferative and anticancer properties in a few recent studies. Nevertheless, detailed mechanism of the action of this compound in prostate cancer has not been elucidated yet. Therefore, in the current study, we examined the anticancer activity and mechanism of the action of carvacrol against human prostate cancer cells. It was found that the treatment of DU145 cells with carvacrol decreased cell viability in a concentration and time-dependent manner. The antiproliferative action of carvacrol leads to induction of apoptosis as confirmed by nuclear condensation, Annexin V-FITC/PI positive cells, and caspase-3 activation. In addition, carvacrol augmented reactive oxygen species generation and disruption in the mitochondrial membrane potential which has not been reported in the previous studies of carvacrol with prostate cancer. Moreover, carvacrol-induced apoptosis of prostate cancer cells was also accompanied by significant amount of growth arrest at the G(0)/G(1) phase of the cell cycle which has also not been documented previously. To sum up, this study has established that carvacrol could be a promising chemotherapeutic agent and could have a direct practical implication and translational relevance to prostate cancer patients as Origanum consumption may retard prostate cancer progression.
  • PublicationMetadata only
    Prediction of functionally significant single nucleotide polymorphisms in PTEN tumor suppressor gene: An in silico approach
    (2017-09-01T00:00:00Z) Khan, IMRAN; Ansari, Irfan A.; Singh, Pratichi; Dass, Febin Prabhu J.; KHAN, IMRAN
    The phosphatase and tensin homolog (PTEN) gene plays a crucial role in signal transduction by negatively regulating the PI3K signaling pathway. It is the most frequent mutated gene in many human-related cancers. Considering its critical role, a functional analysis of missense mutations of PTEN gene was undertaken in this study. Thirty five nonsynonymous single nucleotide polymorphisms (nsSNPs) within the coding region of the PTEN gene were selected for our in silico investigation, and five nsSNPs (G129E, C124R, D252G, H61D, and R130G) were found to be deleterious based on combinatorial predictions of different computational tools. Moreover, molecular dynamics (MD) simulation was performed to investigate the conformational variation between native and all the five mutant PTEN proteins having predicted deleterious nsSNPs. The results of MD simulation of all mutant models illustrated variation in structural attributes such as root-mean-square deviation, root-mean-square fluctuation, radius of gyration, and total energy; which depicts the structural stability of PTEN protein. Furthermore, mutant PTEN protein structures also showed a significant variation in the solvent accessible surface area and hydrogen bond frequencies from the native PTEN structure. In conclusion, results of this study have established the deleterious effect of the all the five predicted nsSNPs on the PTEN protein structure. Thus, results of the current study can pave a new platform to sort out nsSNPs that can be undertaken for the confirmation of their phenotype and their correlation with diseased status in case of control studies. (C) 2016 International Union of Biochemistry and Molecular Biology, Inc.
  • PublicationMetadata only
    Profiling Deleterious Non-synonymous SNPs of Smoker-s Gene CYP1A1
    (2013-12-01T00:00:00Z) Ramesh, A. Sai; Khan, IMRAN; Farhan, Md.; Thiagarajan, Padma; KHAN, IMRAN
    CYP1A1 gene belongs to the cytochrome P450 family and is known better as smokers- gene due to its hyperactivation as a consequence of long term smoking. The expression of CYP1A1 induces polycyclic aromatic hydrocarbon production in the lungs, which when over expressed, is known to cause smoking related diseases, such as cardiovascular pathologies, cancer, and diabetes. Single nucleotide polymorphisms (SNPs) are the simplest form of genetic variations that occur at a higher frequency, and are denoted as synonymous and non-synonymous SNPs on the basis of their effects on the amino acids. This study adopts a systematic in silico approach to predict the deleterious SNPs that are associated with disease conditions. It is inferred that four SNPs are highly deleterious, among which the SNP with rs17861094 is commonly predicted to be harmful by all tools. Hydrophobic (isoleucine) to hydrophilic (serine) amino acid variation was observed in the candidate gene. Hence, this investigation aims to characterize a candidate gene from 159 SNPs of CYP1A1.