BITS Faculty Publications
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Item Epigenetics in neurodegeneration: emerging biomarkers and translational insights(Elsevier, 2025-12) Taliyan, RajeevNeurodegenerative disorders (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), are characterized by progressive neuronal loss leading to cognitive, motor, and behavioral impairments. Despite available interventions such as medications, physical therapy, and surgery, effective disease-modifying therapies remain elusive, with most treatments limited to symptom management. The multifactorial etiology of NDDs involves genetic, environmental, and increasingly recognized epigenetic factors that alter gene expression and drive disease onset and progression. Epigenetic mechanisms such as DNA methylation, histone modification, and chromatin remodeling play central roles in neuronal development, brain aging, and neurodegeneration. Recent advances highlight the potential of epigenetic biomarkers as diagnostic and prognostic tools, enabling early detection, monitoring of disease progression, and evaluation of therapeutic response. Protein- and microRNA-based biomarkers in biofluids, including blood and cerebrospinal fluid, provide promising insights into disease pathology and may support precision medicine approaches. This review explores current progress in identifying and validating epigenetic biomarkers and discusses their therapeutic implications, underscoring their transformative potential for improving diagnosis and treatment strategies in NDDs.Item Current pharmacophore based approaches for the development of new anti-Alzheimer’s agents(Elsevier, 2024-11) Shukla, ParitoshAmyloid beta peptide (Aβ) and hyperphosphorylated neuronal tau proteins accumulate in neurofibrillary tangles in Alzheimer’s disease (AD), a chronic neurodegenerative illness. Chronic inflammation in the brain, which promotes disease progression, is another feature of the Alzheimer’s disease pathogenesis. Approximately 60–70 % of dementia cases are caused by AD. The development of effective therapies for the treatment of AD is urgently needed given the severity of the condition and its rapidly rising prevalence. Cholinesterase inhibitors, beta-amyloid (A-beta), tau inhibitors, and many other medications are currently used as preventive medicine for AD. These medications can temporarily suppress dementia symptoms but cannot halt or reverse the disease’s progression. Many international pharmaceutical companies have tried numerous times to develop an amyloid clearing medication based on the amyloid hypothesis, but without success. Therefore, the amyloid theory may not be entirely plausible. This review mainly covers the recent and important reported pharmacophores as the starting point to discuss already known targets like tau, butyrylcholinesterase, amyloid beta, and acetylcholinesterase and covers the literature between years 2019–2024.Item Emerging relationship between the gut microbiota and neurodegenerative disorders(Springer, 2024-08) Marathe, Sandhya Amol; Tare, MeghanaA growing body of evidence indicates that the multitude of organisms residing in our gut can profoundly affect our health. These organisms are loosely termed as gut microbiota and have been known to affect the function as well as the behavioral aspects of human health. Recent research shows that the microorganisms in our gut play a crucial role in determining our health and susceptibility to disease. Newly identified intricacies of connection between nervous system and gut microbiota are specially intriguing, since nervous system intersects and in a manner regulates almost every other function of the body. Interestingly, gut microbiota has been found to be affected in cases of nervous system disorders, including neurodegeneration, such as but not limited to Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis. The number of people worldwide with neurodegenerative disorders grows yearly, but effective treatments with few side effects remain limited. There is a new avenue of translational research, which evaluates the gut-brain-microbiome axis for management and therapeutic ideas for neurodegenerative disorders. It is therefore important to understand the newer intervention techniques using microbiota, which can be employed for holistic cure of neurodegenerative disorders. This chapter encompasses a comprehensive review of the relationship between gut microbiota in the context of specific neurodegenerative disorders.Item Converged avenues: depression and Alzheimer’s disease– shared pathophysiology and novel therapeutics(Springer, 2024-01) Mahesh, RadhakrishnanDepression, a highly prevalent disorder affecting over 280 million people worldwide, is comorbid with many neurological disorders, particularly Alzheimer’s disease (AD). Depression and AD share overlapping pathophysiology, and the search for accountable biological substrates made it an essential and intriguing field of research. The paper outlines the neurobiological pathways coinciding with depression and AD, including neurotrophin signalling, the hypothalamic–pituitary–adrenal axis (HPA), cellular apoptosis, neuroinflammation, and other aetiological factors. Understanding overlapping pathways is crucial in identifying common pathophysiological substrates that can be targeted for effective management of disease state. Antidepressants, particularly monoaminergic drugs (first-line therapy), are shown to have modest or no clinical benefits. Regardless of the ineffectiveness of conventional antidepressants, these drugs remain the mainstay for treating depressive symptoms in AD. To overcome the ineffectiveness of traditional pharmacological agents in treating comorbid conditions, a novel therapeutic class has been discussed in the paper. This includes neurotransmitter modulators, glutamatergic system modulators, mitochondrial modulators, antioxidant agents, HPA axis targeted therapy, inflammatory system targeted therapy, neurogenesis targeted therapy, repurposed anti-diabetic agents, and others. The primary clinical challenge is the development of therapeutic agents and the effective diagnosis of the comorbid condition for which no specific diagnosable scale is present. Hence, introducing Artificial Intelligence (AI) into the healthcare system is revolutionary. AI implemented with interdisciplinary strategies (neuroimaging, EEG, molecular biomarkers) bound to have accurate clinical interpretation of symptoms. Moreover, AI has the potential to forecast neurodegenerative and psychiatric illness much in advance before visible/observable clinical symptoms get precipitated.Item Novel gene therapy approaches for targeting neurodegenerative disorders: focusing on delivering neurotrophic genes(Springer, 2024-06) Taliyan, RajeevNeurodegenerative illnesses (NDDs) like Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, spinal muscular atrophy, and Huntington’s disease have demonstrated considerable potential for gene therapy as a viable therapeutic intervention. NDDs are marked by the decline of neurons, resulting in changes in both behavior and pathology within the body. Strikingly, only symptomatic management is available without a cure for the NDDs. There is an unmet need for a permanent therapeutic approach. Many studies have been going on to target the newer therapeutic molecular targets for NDDs including gene-based therapy. Gene therapy has the potential to provide therapeutic benefits to a large number of patients with NDDs by offering mechanisms including neuroprotection, neuro-restoration, and rectification of pathogenic pathways. Gene therapy is a medical approach that aims to modify the biological characteristics of living cells by controlling the expression of specific genes in certain neurological disorders. Despite being the most complex and well-protected organ in the human body, there is clinical evidence to show that it is possible to specifically target the central nervous system (CNS). This provides hope for the prospective application of gene therapy in treating NDDs in the future. There are several advanced techniques available for using viral or non-viral vectors to deliver the therapeutic gene to the afflicted region. Neurotrophic factors (NTF) in the brain are crucial for the development, differentiation, and survival of neurons in the CNS, making them important in the context of various neurological illnesses. Gene delivery of NTF has the potential to be used as a therapeutic approach for the treatment of neurological problems in the brain. This review primarily focuses on the methodologies employed for delivering the genes of different NTFs to treat neurological disorders. These techniques are currently being explored as a viable therapeutic approach for neurodegenerative diseases. The article exclusively addresses gene delivery approaches and does not cover additional therapy strategies for NDDs. Gene therapy offers a promising alternative treatment for NDDs by stimulating neuronal growth instead of solely relying on symptom relief from drugs and their associated adverse effects. It can serve as a long-lasting and advantageous treatment choice for the management of NDDs. The likelihood of developing NDDs increases with age as a result of neuronal degradation in the brain. Gene therapy is an optimal approach for promoting neuronal growth through the introduction of nerve growth factor genes.Item Chitinase-3-like-1: a multifaceted player in neuroinflammation and degenerative pathologies with therapeutic implications(Springer, 2025-01) Taliyan, RajeevChitinase-3-like-1 (CHI3L1) is an evolutionarily conserved protein involved in key biological processes, including tissue remodeling, angiogenesis, and neuroinflammation. It has emerged as a significant player in various neurodegenerative diseases and brain disorders. Elevated CHI3L1 levels have been observed in neurological conditions such as traumatic brain injury (TBI), Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD), multiple sclerosis (MS), Neuromyelitis optica (NMO), HIV-associated dementia (HAD), Cerebral ischemic stroke (CIS), and brain tumors. This review explores the role of CHI3L1 in the pathogenesis of these disorders, with a focus on its contributions to neuroinflammation, immune cell infiltration, and neuronal degeneration. As a key regulator of neuroinflammation, CHI3L1 modulates microglia and astrocyte activity, driving the release of proinflammatory cytokines that exacerbate disease progression. In addition to its role in disease pathology, CHI3L1 has emerged as a promising biomarker for the diagnosis and monitoring of brain disorders. Elevated cerebrospinal fluid (CSF) levels of CHI3L1 have been linked to disease severity and cognitive decline, particularly in AD and MS, highlighting its potential for clinical diagnostics. Furthermore, therapeutic strategies targeting CHI3L1, such as small-molecule inhibitors and neutralizing antibodies, have shown promise in preclinical studies, demonstrating reduced neuroinflammation, amyloid plaque accumulation, and improved neuronal survival. Despite its therapeutic potential, challenges remain in developing selective and safe CHI3L1-targeted therapies, particularly in ensuring effective delivery across the blood–brain barrier and mitigating off-target effects. This review addresses the complexities of targeting CHI3L1, highlights its potential in precision medicine, and outlines future research directions aimed at unlocking its full therapeutic potential in treating neurodegenerative diseases and brain pathologies.Item Neuroprotective Effect of 2-Aminoethoxydiphenyl Borate (2-APB) in Amyloid β-Induced Memory Dysfunction: A Mechanistic Study(Springer, 2020-11) Khare, Pragyanshuβ-Amyloid (Aβ) peptide is a characteristic feature of Alzheimer’s disease (AD) and accumulation of Aβ is associated with loss of synaptic plasticity and neuronal cell death. Aggregation of Aβ initiates numerous molecular signalling pathways leading to oxidative stress, mitochondrial dysfunction as well as an imbalance of calcium ion influx homeostasis. Recently, it has been shown that transient receptor potential melastatin 2 (TRPM2), a non-selective calcium-permeable cation channel has been postulated to play a vital role in the neuronal death, indicating the potential of TRPM2 inhibition in CNS disease. In this study, neuroprotective potential of 2-aminoethoxydiphenyl borate (2-APB), a broad-spectrum calcium channels blocker was investigated in Aβ-induced memory deficits in rats. In addition, effect of 2-APB on TRPM2 channels gene and protein expressions and also on calcium and memory related proteins was investigated in the hippocampus. Intracerebroventricular (I.C.V.) administration of Aβ (Aβ25–35, 10 μg) markedly induced cognitive impairment and upregulation of mRNA and protein expression of TRPM2 in the hippocampus. In addition, AChE activity was also increased in the cortex of the Aβ administered animals. Three-week treatment with 2-APB led to the down-regulation of TRPM2 mRNA and protein expression in the hippocampus and also improved the cognitive functions which was evident from the behavioral parameters. Moreover, 2-APB treatment also increased the calcium and memory associated proteins namely p-CaMKII, p-GSK-3β, p-CREB and PSD-95 in the hippocampus and reduced the mRNA level of calcium buffering proteins and calcineurin A (PPP3CA) in the hippocampus. Furthermore, 2-APB treatment significantly reduced the AChE activity in the cortex. Thus, our findings suggest the neuroprotective effect of 2-APB in Aβ-induced cognitive impairment.Item Futuristic aspect of nanocarriers on targeted delivery for dementia(Elsevier, 2023) Taliyan, RajeevAlzheimer’s disease (AD) is one of the most common neurodegenerative diseases. Analysis conducted over the past 20 years has shown that macromolecules accumulating in the brain known as Amyloid-β (Aβ) are fundamentally responsible for the chronic effects of the disease. Amyloid-β builds up in the brain, forming plaques, and clumps that block neuronal signaling and break down the connections between neurons. Many researchers have been looking at the involvement of tau, a protein that causes the production of “neurofibrillary tangles” in the brain, which is another signal of neuronal death. Proteolytic therapies for AD are one of the novel strategies where the proteolysis targeting chimera (PROTAC) is selectively initiating protein degradation within the cell. In this novel approach, these techniques are small-molecule PROTACs peptide, TH006, and Neprilysin-2 (NEP-2). The traditional drug delivery technologies confront difficulties in targeting specific parts of the brain. For drug discovery and development in order to make medications more effective in the brain and to have a specific action. The first line of defense for the brain is the blood–brain barrier, which is followed by the blood-cerebrospinal fluid barrier. These membranes are more than just barriers; they also serve as selectively permeable membranes, allowing particular molecules to invade the brain. These mechanisms all operate as impediments to effective drug delivery in the brain. As a result, improved strategies for facilitating the administration of such medications in the brain must be developed. Nanotechnology is now playing an important role in research, with a large number of nanoparticles intended to deliver drugs to specific target areas. Liposomes, dendrimers, microneedles, polymeric nanoparticles, and other nanoparticles are examples. Antibody-coated nanoparticles are a novel strategy to treating AD in the nanosystem.Item Epigenetic Regulation of Mammalian Target of Rapamycin Debilitates Insulin Resistance Associated Alzheimer Disease Condition in Rats(Research Square, 2021) Taliyan, RajeevInsulin resistance (IR) and accumulation of amyloid beta (Aβ) oligomers are potential causative factor for Alzheimer Disease (AD). Simultaneously, enhanced clearance level of these oligomers through autophagy activation bring novel insights into their therapeutic paradigm. Autophagy activation is negatively correlated with mammalian target of rapamycin (mTOR) and dysregulated mTOR level due to epigenetic alterations can further culminate towards AD pathogenesis. Therefore, in the current study we explored the neuroprotective efficacy of rapamycin and vorinostat in-vitro and in-vivo. Aβ1−42 treated SH-SY5Y cells were exposed to rapamycin (20µM) and vorinostat (4µM) to analyse mRNA expression of amyloid precursor protein (APP), brain derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), neuronal growth factor (NGF), beclin-1, microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate, lysosome-associated membrane protein 2 and microtubule associated protein 2. In order to develop IR condition, rats were fed a high fat diet (HFD) for 8weeks and then subjected to intracerebroventricular Aβ1−42 administration. Subsequently, their treatment was initiated with rapa (1mg/kg, i.p.) and vori (50mg/kg, i.p.) once daily for 28days. Morris water maze was performed to govern cognitive impairment followed by sacrification for subsequent biochemical and histological estimations. For all the measured parameters, a significant improvement was observed amongst the combination treatment group in contrast to that of the HFD + Aβ1−42 group and that of the groups treated with the drugs alone. Outcomes of the present study thus suggest that combination therapy with rapa and vori provide a prospective therapeutic approach to ameliorate AD symptoms exacerbated by IR.Item Epigenetic regulation and autophagy modulation debilitates insulin resistance associated Alzheimer’s disease condition in rats(Springer, 2022-01) Taliyan, Rajeev; Marathe, SandhyaInsulin resistance (IR) and accumulation of amyloid beta (Aβ) oligomers are potential causative factor for Alzheimer’s Disease (AD). Simultaneously, enhanced clearance level of these oligomers through autophagy activation bring novel insights into their therapeutic paradigm. Autophagy activation is negatively correlated with mammalian target of rapamycin (mTOR) and dysregulated mTOR level due to epigenetic alterations can further culminate towards AD pathogenesis. Therefore, in the current study we explored the neuroprotective efficacy of rapamycin (rapa) and vorinostat (vori) in-vitro and in-vivo. Aβ1–42 treated SH-SY5Y cells were exposed to rapa (20 μM) and vori (4 μM) to analyse mRNA expression of amyloid precursor protein (APP), brain derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), neuronal growth factor (NGF), beclin-1, microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate (LC3), lysosome-associated membrane protein 2 (LAMP2) and microtubule associated protein 2 (MAP2). In order to develop IR condition, rats were fed a high fat diet (HFD) for 8 weeks and then subjected to intracerebroventricular Aβ1–42 administration. Subsequently, their treatment was initiated with rapa (1 mg/kg, i.p.) and vori (50 mg/kg, i.p.) once daily for 28 days. Morris water maze was performed to govern cognitive impairment followed by sacrification for subsequent mRNA, biochemical, western blot and histological estimations. For all the measured parameters, a significant improvement was observed amongst the combination treatment group in contrast to that of the HFD + Aβ1–42 group and that of the groups treated with the drugs alone. Outcomes of the present study thus suggest that combination therapy with rapa and vori provide a prospective therapeutic approach to ameliorate AD symptoms exacerbated by IR.