Department Of Human Genetics And Molecular Medicine
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Item Design, Synthesis, and Anticancer Evaluation of Hemithioindigos via Inhibition of Human Topoisomerases(John Wiley and Sons Inc, 2023-11-06T00:00:00) Kaur, Manpreet; Suman, Prabhat; Arora, Sahil; Singh, Tashvinder; Munshi, Anjana; Singh, Sandeep; Kumar, RajHemithioindigos were designed as topoisomerase inhibitors, synthesized, and evaluated for their anticancer properties against lung (A549) and breast (MDA-MB-468 and MCF7) cancer cell lines. Among all the synthetics, three compounds exerted potential anticancer effects on A549 (lung) and MCF7 (breast) cancer cell lines at low micromolar concentrations. The results revealed that two of these compounds blocked the cancer cells at the G1/S phase, while the third compound showed moderate G2/M inhibition, leading to necrotic cell death. Finally, the topoisomerase inhibition assays revealed their potent Topo I/II inhibitory actions as one of the primary anticancer mechanisms. Molecular docking studies further corroborated these findings. � 2023 Wiley-VCH GmbH.Item Neuroimaging Genomics a Predictor of Major Depressive Disorder (MDD)(Springer, 2023-11-22T00:00:00) Jindal, Manav; Chhetri, Aakash; Ludhiadch, Abhilash; Singh, Paramdeep; Peer, Sameer; Singh, Jawahar; Brar, Rahatdeep Singh; Munshi, AnjanaDepression is a complex psychiatric disorder influenced by various genetic and environmental factors. Strong evidence has established the contribution of genetic factors in depression through twin studies and the heritability rate for depression has been reported to be 37%. Genetic studies have identified genetic variations associated with an increased risk of developing depression. Imaging genetics is an integrated approach where imaging measures are combined with genetic information to explore how specific genetic variants contribute to brain abnormalities. Neuroimaging studies allow us to examine both structural and functional abnormalities in individuals with depression. This review has been designed to study the correlation of the significant genetic variants with different regions of neural activity, connectivity, and structural alteration in the brain as detected by imaging techniques to understand the scope of biomarkers in depression. This might help in developing novel therapeutic interventions targeting specific genetic pathways or brain circuits and the underlying pathophysiology of depression based on this integrated approach can be established at length. � 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Assessment of Resting-state functional Magnetic Resonance Imaging Connectivity Among Patients with Major Depressive Disorder: A Comparative Study(SAGE Publications Inc., 2023-08-29T00:00:00) Singh, Paramdeep; Singh, Jawahar; Peer, Sameer; Jindal, Manav; Khokhar, Sunil; Ludhiadch, Abhilash; Munshi, AnjanaBackground: Resting-state functional connectivity analysis has a potential to unearth the putative neuronal underpinnings of various disorders of the brain. Major depressive disorder (MDD) is regarded as a disorder arising from alterations in functional networks of the brain. Purpose: There is paucity of literature on resting-state functional magnetic resonance imaging (Rs-fMRI) in MDD, especially from the Indian subcontinent. The purpose of our study was to elucidate the differences in Rs-fMRI connectivity between MDD patients and age and gender matched healthy controls (HC). Methods: In this prospective single institute-based study, the patients were recruited consecutively based on Hamilton depression rating scale (HAM-D). Age and gender matched HC were also recruited. Rs-fMRI and anatomical MRI images were acquired for all the subjects (MDD and HC group) and subsequent analysis was done using the CONN toolbox. Results: A total of 49 subjects were included in the final analysis (MDD = 28 patients, HC = 21). HAM-D score was noted to be 24.4 � 4.8 in the MDD group. There was no significant difference between MDD and HC groups as far as age, gender, employment status, and level of education is concerned. Region-of-interest-based analysis of Rs-fMRI data showed a significantly lower connectivity between the left insula and left nucleus accumbens and between left paracingulate gyrus and bilateral posterior middle temporal gyri in MDD group as compared to HC group. Conclusion: There is reduced connectivity between certain key regions of the brain in MDD patients, that is, between the left insular cortex and the left nucleus accumbens and between the left paracingulate gyrus and the bilateral posterior middle temporal gyrus. These findings could explain the basis of clinical features of MDD such as anhedonia, rumination of thoughts, reduced visuo-spatial comprehension, reduced language function, and response to external stimuli. � 2023 Indian Academy of Neurosciences (IAN).Item Translation and Validation of ID.Migraine Questionnaire to North-Indian Vernacular Languages(Wolters Kluwer Medknow Publications, 2023-09-11T00:00:00) Sahu, Prachi; Chaturvedi, Pragya; Khan, Rahul; Singla, Monika; Munshi, Anjana; Singh, GagandeepBackground: ID-Migraine is an established screening tool for migraine. Translation and validation in more languages can increase its reach and scope. Aim: To translate and validate ID-Migraine for screening migraine patients in two North-Indian vernacular languages, that is, Hindi and Punjabi. Methods: ID Migraine was translated into Hindi and Punjabi. Subjects with headaches in outpatient clinics were administered the questionnaire according to their preferred language of choice and referenced clinical evaluations, performed by an experienced neurologist, based on current the ICHD-3 diagnostic criteria. Results: One hundred subjects with complaints of headaches and 60 healthy controls were recruited after informed consent. Of the 100 subjects with headaches, 73 (73%) screened positive with a translated version of ID-Migraine, and 60 (60%) were eventually diagnosed with migraine without aura. The sensitivity of the Hindi version of ID-Migraine was 94% (95% confidence intervals, 79% to 99%); specificity, 56% (95% CI, 31% to 78%); positive predictive value, 79% (95% CI, 69% to 86%) and negative predictive value, 83% (95% CI, 55% to 95%). The Punjabi version demonstrated a sensitivity of 86% (95% CI, 68% to 96%); specificity, 43% (95% CI, 23% to 66%); PPV, 68% (95% CI, 58% to 76%); and NPV, 69% (95% CI, 44% to 86%). Conclusion: The translated versions of ID-Migraine demonstrated high sensitivity and fair specificity for screening migraine in Indian subjects who speak and understand Hindi and Punjabi. � 2023 Annals of Indian Academy of Neurology.Item Genomic Variation Affecting MPV and PLT Count in Association with Development of Ischemic Stroke and Its Subtypes(Springer, 2023-07-15T00:00:00) Ludhiadch, Abhilash; Sulena; Singh, Sandeep; Chakraborty, Sudip; Sharma, Dixit; Kulharia, Mahesh; Singh, Paramdeep; Munshi, AnjanaPlatelets play a significant role in the pathophysiology of ischemic stroke since they are involved in the formation of intravascular thrombus after erosion or rupture of the atherosclerotic plaques. Platelet (PLT) count and mean platelet volume (MPV) are the two significant parameters that affect the functions of platelets. In the current study, MPV and PLT count was evaluated using flow cytometry and a cell counter. SonoClot analysis was carried out to evaluate activated clot timing (ACT), clot rate (CR), and platelet function (PF). Genotyping was carried out using GSA and Sanger sequencing, and expression analysis was performed using RT-PCR. In silico analysis was carried out using the GROMACS tool and UNAFold. The interaction of significant proteins with other proteins was predicted using the STRING database. Ninety-six genes were analyzed, and a significant association of THPO (rs6141) and ARHGEF3 (rs1354034) was observed with the disease and its subtypes. Altered genotypes were associated significantly with increased MPV, decreased PLT count, and CR. Expression analysis revealed a higher expression in patients bearing the variant genotypes of both genes. In silico analysis revealed that mutation in the THPO gene leads to the reduced compactness of protein structure. mRNA encoded by mutated ARHGEF3 gene increases the half-life of mRNA. The two significant proteins interact with many other proteins, especially the ones involved in platelet activation, aggregation, erythropoiesis, megakaryocyte maturation, and cytoskeleton rearrangements, suggesting that they could be important players in the determination of MPV values. In conclusion, the current study demonstrated the role of higher MPV affected by genetic variation in the development of IS and its subtypes. The results of the current study also indicate that higher MPV can be used as a biomarker for the disease and altered genotypes, and higher MPV can be targeted for better therapeutic outcomes. � 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Genetic variations in tumor-suppressor miRNA-encoding genes and their target genes: focus on breast cancer development and possible therapeutic strategies(Springer Science and Business Media Deutschland GmbH, 2023-04-24T00:00:00) Chhichholiya, Yogita; Singh, Harsh Vikram; Singh, Sandeep; Munshi, AnjanaMicroRNAs (miRNAs) negatively affect gene expression by binding to their specific mRNAs resulting in either mRNA destruction or translational repression. The aberrant expression of various miRNAs has been associated with a number of human cancer. Oncogenic or tumor-suppressor miRNAs regulate a variety of pathways involved in the development of breast cancer (BC), including cell proliferation, apoptosis, metastasis, cancer recurrence, and chemoresistance. Variations in miRNA-encoding genes and their target genes lead to dysregulated gene expression resulting in the development and progression of BC. The various therapeutic approaches to treat the disease include chemotherapy, radiation therapy, surgical removal, hormone therapy, chemotherapy, and targeted biological therapy. The purpose of the current review is to explore the genetic variations in tumor-suppressor miRNA-encoding genes and their target genes in association with the disease development and prognosis. The therapeutic interventions targeting the variants for better disease outcomes have also been discussed. � 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.Item Oncogenic metabolic reprogramming in breast cancer: focus on signaling pathways and mitochondrial genes(Springer, 2023-05-11T00:00:00) Malayil, Rhuthuparna; Chhichholiya, Yogita; Vasudeva, Kanika; Singh, Harsh Vikram; Singh, Tashvinder; Singh, Sandeep; Munshi, AnjanaOncogenic metabolic reprogramming impacts the abundance of key metabolites that regulate signaling and epigenetics. Metabolic vulnerability in the cancer cell is evident from the Warburg effect. The research on metabolism in the progression and survival of breast cancer (BC) is under focus. Oncogenic signal activation and loss of�tumor suppressor are important regulators of tumor cell metabolism. Several intrinsic and extrinsic factors contribute to metabolic reprogramming. The molecular mechanisms underpinning metabolic reprogramming in BC are extensive and only partially defined. Various signaling pathways involved in the metabolism play a significant role in the modulation of BC. Notably, PI3K/AKT/mTOR pathway, lactate-ERK/STAT3 signaling, loss of the tumor suppressor Ras, Myc, oxidative stress, activation of the cellular hypoxic response and acidosis contribute to different metabolic reprogramming phenotypes linked to enhanced glycolysis. The alterations in mitochondrial genes have also been elaborated upon along with their functional implications. The outcome of these active research areas might contribute to the development of novel therapeutic interventions and the remodeling of known�drugs. � 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.Item Comprehensive analysis of culture conditions governing differentiation of MSCs into articular chondrocytes(Newlands Press Ltd, 2023-05-18T00:00:00) Singh, Harsh Vikram; Das, Lakshmana; Malayil, Rhuthuparna; Singh, Tashvinder; Singh, Sandeep; Goyal, Tarun; Munshi, AnjanaTreatment of osteoarthritic patients requires the development of morphologically and mechanically complex hyaline cartilage at the injury site. A tissue engineering approach toward differentiating mesenchymal stem cells into articular chondrocytes has been developed to overcome the drawbacks of conventional therapeutic and surgical procedures. To imitate the native micro and macro environment of articular chondrocytes, cell culture parameters such as oxygen concentration, mechanical stress, scaffold design, and growth factor signalling cascade regulation must be addressed. This review aims to illuminate the path toward developing tissue engineering approaches, accommodating these various parameters and the role these parameters play in regulating chondrogenesis for better articular cartilage development to treat osteoarthritis effectively. � 2023 Future Medicine Ltd.Item In silico phytochemical repurposing of natural molecules as entry inhibitors against RBD of the spike protein of SARS-CoV-2 using molecular docking studies(Inderscience Publishers, 2023-04-18T00:00:00) Gupta, Pawan; Gupta, Swati; Sinha, Sukrat; Sundaram, Shanthy; Sharma, Vishnu K.; Munshi, AnjanaThe receptor binding domain (RBD) of Spike-protein (S-protein) is responsible for virus entry via interaction with host protein ACE2 (angiotensin-converting enzyme 2), present on the cell surface of humans. Therefore, S-protein is an important target to block the entry of the SARS-CoV-2 into the cell for further growth. In the present study, phytochemical repurposing of natural molecules: narirutin, naringin, neohesperidin and hesperidin were performed against the RBD S-protein/ACE2 interface as well as the RBD of the S-protein using molecular docking. These natural molecules were found to have structural similarity to each other and had binding potential against the viral infections. It is first time reported here that the naringin and narirutin are having binding potential against both RBD S-protein/ACE2 interface and active site of RBD of S-protein using binding mode analysis. Hence, this study will open avenues for multitargeting similar natural molecules binding against the SARS-CoV-2 proteins as all reports are made in this single study. Copyright � 2023 Inderscience Enterprises Ltd.Item Brain metastasis in breast cancer: focus on genes and signaling pathways involved, blood�brain barrier and treatment strategies(Springer Science and Business Media Deutschland GmbH, 2023-03-10T00:00:00) Chhichholiya, Yogita; Ruthuparna, Malayil; Velagaleti, Harini; Munshi, AnjanaBreast cancer�(BC) is one of the most prevalent types of cancer in women. Despite advancement in early detection and efficient treatment, recurrence and metastasis continue to pose a significant risk to the life of BC patients. Brain metastasis�(BM) reported in 17�20 percent of BC patients is considered as a major cause of mortality and morbidity in these patients. BM includes various steps from primary breast tumor to secondary tumor formation. Various steps involved are primary tumor formation, angiogenesis, invasion, extravasation, and brain colonization. Genes involved in different pathways have been reported to be associated with BC cells metastasizing to the brain. ADAM8 gene, EN1 transcription factor, WNT, and VEGF signaling pathway have been associated with primary breast tumor; MMP1, COX2, XCR4, PI3k/Akt, ERK and MAPK pathways in angiogenesis; Noth, CD44, Zo-1, CEMIP, S0X2 and OLIG2 are involved in invasion, extravasation and colonization, respectively. In addition, the blood�brain barrier is also a key factor in BM. Dysregulation of cell junctions, tumor microenvironment and loss of function of microglia leads to BBB disruption ultimately resulting in BM. Various therapeutic strategies are currently used to control the BM in BC. Oncolytic virus therapy, immune checkpoint inhibitors, mTOR-PI3k inhibitors and immunotherapy have been developed to target various genes involved in BM in BC. In addition, RNA interference (RNAi) and CRISPR/Cas9 are novel interventions in the field of BCBM where research to validate these and clinical trials are being carried out. Gaining a better knowledge of metastasis biology is critical for establishing better treatment methods and attaining long-term therapeutic efficacies against BC. The current review has been compiled with an aim to evaluate the role of various genes and signaling pathways involved in multiple steps of BM in BC. The therapeutic strategies being used currently and the novel ones being explored to control BM in BC have also been discussed at length. � 2023, The Author(s), under exclusive licence to Federaci�n de Sociedades Espa�olas de Oncolog�a (FESEO).