BITS Faculty Publications
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Item Universum least squares twin parametric-margin support vector machine(IEEE, 2020-07) Richhariya, BharatUniversum based algorithms involve universum samples in the classification problem to improve the generalization performance. In order to provide prior information about data, we utilized universum data to propose a novel classification algorithm. In this paper, a novel parametric model for universum based twin support vector machine is presented for classification problems. The proposed model is termed as universum least squares twin parametric-margin support vector machine (ULSTPMSVM). The solution of ULSTPMSVM involves a system of linear equations. This makes the ULSTPMSVM efficient w.r.t. training time. In order to verify the performance of the proposed model, various experiments are carried out on real world benchmark datasets. Statistical tests are performed to verify the significance of the proposed method. The proposed ULSTPMSVM performed better than existing algorithms in terms of classification accuracy and training time for most of the datasets. Moreover, an application of proposed ULSTPMSVM is presented for classification of Alzheimer's disease data.Item Diagnosis of Alzheimer's disease using universum support vector machine based recursive feature elimination (USVM-RFE)(Elsevier, 2020-05) Richhariya, BharatAlzheimer's disease is one of the most common causes of death in today's world. Magnetic resonance imaging (MRI) provides an efficient and non-invasive approach for diagnosis of Alzheimer's disease. Efficient feature extraction techniques are needed for accurate classification of MRI images. Motivated by the work on support vector machine based recursive feature elimination (SVM-RFE) [16], we propose a novel feature selection technique to incorporate prior information about data distribution in the recursive feature elimination process. Our method is termed as universum support vector machine based recursive feature elimination (USVM-RFE). The proposed method provides global information about data in the RFE process as compared to the local approach of feature selection in SVM-RFE. We also present the application of feature selection and classification algorithms on both voxel based as well as volume based morphometry analysis of structural MRI images (ADNI database). Feature selection is performed using MRI data of brain tissues such as gray matter, white matter, and cerebrospinal fluid. USVM-RFE provides improvement over SVM-RFE in classification of control normal (CN), mild cognitive impairment (MCI), and Alzheimer's disease (AD) subjects. Moreover, better accuracy is obtained by USVM-RFE with lesser number of features in comparison to SVM-RFE. This leads to identification of prominent brain regions for feature selection and classification of MRI images. The highest accuracies obtained by our method for classification of CN vs AD, CN vs MCI, and MCI vs AD are 100%, 90%, and 73.68%, respectively.Item (Re)Formulating rotigotine: a potential molecule with unmet needs(Future Science Group, 2023-01) Pandey, Murali Monohar; Chitkara, DeepakRotigotine (RTG), a non-ergoline D3/D2/D1 dopamine receptor agonist, is indicated for Parkinson’s disease (PD) and restless leg syndrome (RLS)[1]. It also has an affinity toward serotonin (5-HT1A, 5-HT2B, and 5-HT7) and α2B-adrenergic receptors [2]. At present, RTG is commercially available as an extended-release transdermal patch since it shows poor oral bioavailability because of its extensive first-pass metabolism [3]. Although successfully marketed, RTG potential has not been fully utilized owing to the challenges and drawbacks associated with its delivery. For instance, the absolute bioavailability from the transdermal patch is reported to be only 37%. The absolute bioavailability of transdermal patches varies depending on its site of application [3]. Moreover, RTG forms crystals in the transdermal patch upon storage and shows variations in drug release and bioavailability as wellItem Mechanistic Insights of Meglitinides Drug Repurposing and Delivery to Brain for Metabolic Syndrome Linked Neurodegenerative Disease(Alzheimer's Association, 2023-07) Taliyan, RajeevMetabolic syndrome (MS) includes clusters of metabolic disorders and type 2 DM (T2DM) is most common MS which cause insulin resistance (IR). The IR mediated dysregulation of signaling cascades in brain increase the production and secretion of Aβ, p-tau which prompt to Alzheimer’s (AD). Therefore, repaglinide (REP) a meglitinides drug is used, which act by targeting ATP binding cassette and evidence indicated that REP increase neuronal survival via upregulating ATF-6 gene and blocking the DREAM. Thus, there is huge possibility that REP regulate and modulate the expression of pro-apoptotic protein, anti-apoptotic protein, calcium homeostasis and may eventually reduce the neuronal cell death.Item Orchestration of the circadian clock and its association with Alzheimer's disease: Role of endocannabinoid signaling(Elsevier, 2022-01) Taliyan, RajeevCircadian rhythms are 24-hour natural rhythms regulated by the suprachiasmatic nucleus, also known as the "master clock". The retino-hypothalamic tract entrains suprachiasmatic nucleus with photic information to synchronise endogenous circadian rhythms with the Earth’s light-dark cycle. However, despite the robustness of circadian rhythms, an unhealthy lifestyle and chronic photic disturbances cause circadian rhythm disruption in the suprachiasmatic nucleus’s TTFL loops via affecting glutamate and γ-aminobutyric acid-mediated neurotransmission in the suprachiasmatic nucleus. Recently, considerable evidence has been shown correlating CRd with the incidence of Alzheimer's disease. The present review aims to identify the existence and signalling of endocannabinoids in CRd induced Alzheimer's disease through retino-hypothalamic tract- suprachiasmatic nucleus-cortex. Immunohistochemistry has confirmed the expression of cannabinoid receptor 1 in the suprachiasmatic nucleus to modulate the circadian phases of the master clock. Literature also suggests that cannabinoids may alter activity of suprachiasmatic nucleus by influencing the activity of their major neurotransmitter γ-aminobutyric acid or by interacting indirectly with the suprachiasmatic nucleus’s two other major inputs i.e., the geniculo-hypothalamic tract-mediated release of neuropeptide Y and serotonergic inputs from the dorsal raphe nuclei. Besides, the expression of cannabinoid receptor 2 ameliorates cognitive deficits via reduction of tauopathy and microglial activation. In conclusion, endocannabinoids may be identified as a putative target for correcting CRd and decelerating Alzheimer’s disease.Item Therapeutic Approaches to Alzheimer’s Type of Dementia: A Focus on FGF21 Mediated Neuroprotection(Bentham Science, 2019) Taliyan, RajeevNeurodegenerative disorders are the most devastating disorder of the nervous system. The pathological basis of neurodegeneration is linked with dysfunctional protein trafficking, mitochondrial stress, environmental factors and aging. With the identification of insulin and insulin receptors in some parts of the brain, it has become evident that certain metabolic conditions associated with insulin dysfunction like Type 2 diabetes mellitus (T2DM), dyslipidemia, obesity etc., are also known to contribute to neurodegeneration mainly Alzheimer’s Disease (AD). Recently, a member of the fibroblast growth factor (FGF) superfamily, FGF21 has proved tremendous efficacy in diseases like diabetes mellitus, obesity and insulin resistance (IR). Increased levels of FGF21 have been reported to exert multiple beneficial effects in metabolic syndrome. FGF21 receptors are present in certain areas of the brain involved in learning and memory. However, despite extensive research, its function as a neuroprotectant in AD remains elusive. FGF21 is a circulating endocrine hormone which is mainly secreted by the liver primarily in fasting conditions. FGF21 exerts its effects after binding to FGFR1 and co-receptor, β-klotho (KLB). It is involved in regulating energy via glucose and lipid metabolism. It is believed that aberrant FGF21 signalling might account for various anomalies like neurodegeneration, cancer, metabolic dysfunction etc. Hence, this review will majorly focus on FGF21 role as a neuroprotectant and potential metabolic regulator. Moreover, we will also review its potential as an emerging candidate for combating metabolic stress induced neurodegenerative abnormalities.Item Epigenetics in Neurodegenerative Diseases: The Role of Histone Deacetylases(Bentham Science, 2019) Taliyan, RajeevImbalance in histone acetylation levels and consequently the dysfunction in transcription are associated with a wide variety of neurodegenerative diseases. Histone proteins acetylation and deacetylation is carried out by two opposite acting enzymes, histone acetyltransferases and histone deacetylases (HDACs), respectively. In-vitro and in-vivo animal models of neurodegenerative diseases and post mortem brains of patients have been reported overexpressed level of HDACs. In recent past numerous studies have indicated that HDAC inhibitors (HDACIs) might be a promising class of therapeutic agents for treating these devastating diseases. HDACs being a part of repressive complexes, the outcome of their inhibition has been attributed to enhanced gene expression due to heightened histone acetylation. Beneficial effects of HDACIs has been explored both in preclinical and clinical studies of these diseases. Thus, their screening as future therapeutics for neurodegenerative diseases has been widely explored.Item Liposomes: An emerging carrier for targeting Alzheimer's and Parkinson's diseases(Elsevier, 2022-06) Murugesan, SankaranarayananThe function of the brain can be affected by various factors that include infection, tumor, and stroke. The major disorders reported with altered brain function are Alzheimer's disease (AD), Parkinson's disease (PD), dementia, brain cancer, seizures, mental disorders, and other movement disorders. The major barrier in treating CNS disease is the blood-brain barrier (BBB), which protects the brain from toxic molecules, and the cerebrospinal fluid (CSF) barrier, which separates blood from CSF. Brain endothelial cells and perivascular elements provide an integrated cellular barrier, the BBB, which hamper the invasion of molecules from the blood to the brain. Even though many drugs are available to treat neurological disorders, it fails to reach the desired site with the required concentration. In this purview, liposomes can carry required concentrations of molecules intracellular by diverse routes such as carrier-mediated transport and receptor-mediated transcytosis. Surface modification of liposomes enables them to deliver drugs to various brain cells, including neurons, astrocytes, oligodendrocytes, and microglia. The research studies supported the role of liposomes in delivering drugs across BBB and in reducing the pathogenesis of AD and PD. The liposomes were surface-functionalized with various molecules to reach the cells intricated with the AD or PD pathogenesis. The targeted and sustained delivery of drugs by liposomes is disturbed due to the antibody formation, renal clearance, accelerated blood clearance, and complement activation–related pseudoallergy (CARPA). Hence, this review will focus on the characteristics, surface functionalization, drug loading, and biodistribution of liposomes respective to AD and PD. In addition, the alternative strategies to overcome immunogenicity are discussed briefly.Item Identification of Azelastine and Carvedilol as Cholinesterase Inhibitors via Structure-Based Virtual Screening of FDA-approved Drugs(Wiley, 2023-07) Jadhav, Hemant R.The structure-based virtual screening (SBVS) has gained immense importance in early drug discovery. Herein, we report the SBVS-driven identification of new cholinesterase inhibitors from a library of FDA-approved small molecule drugs (n=1760). The in vitro validation of top SBVS hits provided azelastine, dronedarone, and iloperidone as acetylcholinesterase (AChE) inhibitors with IC50 values of 9.2, 18.2, and 23.0 μM, respectively. The in vitro screening of top actives in the butyrylcholinesterase (BChE) inhibition assay provided carvedilol as a potent BChE inhibitor with an IC50 of 0.8 μM. Azelastine also inhibits BChE with IC50 of 4.89 μM, indicating its dual ChE inhibition activity. Azelastine and carvedilol also inhibit the self-aggregation of Aβ1–42 with IC50 values of 4.6 and 2.2 μM, respectively. Both drugs cross blood-brain barrier (BBB), as indicated by the parallel artificial membrane permeation assay. Results presented herein warrant exploring the repurposing potential of azelastine and carvedilol for Alzheimer's disease.Item Design, Synthesis and Evaluation of 2,4,6-substituted Pyrimidine Derivatives as BACE-1 Inhibitor: Plausible Lead for Alzheimer’s Disease(Bentham Science, 2021) Jadhav, Hemant R.Alzheimer’s disease is one of the most common neurodegenerative disorder afflicting a large mass of population. BACE-1 (β-secretase) is an aspartyl protease of the amyloidogenic pathway considered responsible for Alzheimer’s disease (AD). Since it catalyzes the rate-limiting step of Aβ-42 production from amyloid precursor protein (APP), its inhibition is considered a viable therapeutic strategy. We have reported the design of small molecular weight compounds supposed to be blood brain permeable as BACE-1 inhibitors. The clue for the design of this series is drawn from the previously designed series from our research group.