Browsing by Author "Dhapola, Rishika"
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Item Antiplatelet drugs: Potential therapeutic options for the management of neurodegenerative diseases(John Wiley and Sons Inc, 2023-05-03T00:00:00) Beura, Samir K.; Dhapola, Rishika; Panigrahi, Abhishek R.; Yadav, Pooja; Kumar, Reetesh; Reddy, Dibbanti H.; Singh, Sunil K.The blood platelet plays an important role but often remains under-recognized in several vascular complications and associated diseases. Surprisingly, platelet hyperactivity and hyperaggregability have often been considered the critical risk factors for developing vascular dysfunctions in several neurodegenerative diseases (NDDs) like Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. In addition, platelet structural and functional impairments promote prothrombotic and proinflammatory environment that can aggravate the progression of several NDDs. These findings provide the rationale for using antiplatelet agents not only to prevent morbidity but also to reduce mortality caused by NDDs. Therefore, we thoroughly review the evidence supporting the potential pleiotropic effects of several novel classes of synthetic antiplatelet drugs, that is, cyclooxygenase inhibitors, adenosine diphosphate receptor antagonists, protease-activated receptor blockers, and glycoprotein IIb/IIIa receptor inhibitors in NDDs. Apart from this, the review also emphasizes the recent developments of selected natural antiplatelet phytochemicals belonging to key classes of plant-based bioactive compounds, including polyphenols, alkaloids, terpenoids, and flavonoids as potential therapeutic candidates in NDDs. We believe that the broad analysis of contemporary strategies and specific approaches for plausible therapeutic treatment for NDDs presented in this review could be helpful for further successful research in this area. � 2023 Wiley Periodicals LLC.Item Apoptosis in Alzheimer�s disease: insight into the signaling pathways and therapeutic avenues(Springer, 2023-04-26T00:00:00) Kumari, Sneha; Dhapola, Rishika; Reddy, Dibbanti HariKrishnaAlzheimer�s disease (AD) is characterized by the accumulation of hyperphosphorylated tau and amyloid-? (A?) protein resulting in synaptic loss and apoptosis. A? and tau deposition trigger apoptotic pathways that result in neuronal death. Apoptosis is considered to be responsible for manifestations associated with AD under pathological conditions. It regulates via extrinsic and intrinsic pathways. It activates various proteins including Bcl-2 family proteins like Bax, Bad, Bid, Bcl-XS, Bcl-XL and caspases comprising of initiator, effector and inflammatory caspases carried out through a cascade of events that finally lead to cell disintegration. The apoptotic elements interact with trophic factors, signaling molecules including Ras-ERK, JNK, GSK-3?, BDNF/TrkB/CREB and PI3K/AKT/mTOR. Ras-ERK signaling is involved in the progression of cell cycle and apoptosis. JNK pathway is also upregulated in AD which results in decreased expression of anti-apoptotic proteins. JAK-STAT triggers caspase-3 mediated apoptosis leading to neurodegeneration. The imbalance between autophagy and apoptosis is regulated by PI3K/Akt/mTOR pathway. GSK-3? is involved in the stimulation of pro-apoptotic factors resulting in dysregulation of apoptosis. Drugs like filgrastim, epigallocatechin gallate, curcumin, nicergoline and minocycline are under development which target these pathways and modulate the disease condition. This study sheds light on apoptotic pathways that are cardinal for neuronal survival and perform crucial role in the occurrence of AD along with the trends in therapeutics targeting apoptosis induced AD. To develop prospective treatments for AD, it is desirable to elucidate potential targets including restoration apoptotic balance, regulation of caspases, Bcl-2 and other crucial proteins involved in apoptosis mediated AD. � 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Endoplasmic reticulum stress in Alzheimer's disease: Molecular mechanisms and therapeutic prospects(Elsevier Inc., 2023-07-29T00:00:00) Nagar, Pushank; Sharma, Prajjwal; Dhapola, Rishika; Kumari, Sneha; Medhi, Bikash; HariKrishnaReddy, DibbantiAlzheimer's disease (AD) is a progressive neurodegenerative condition that leads to memory loss and cognitive impairment over time. It is characterized by protein misfolding as well as prolonged cellular stress, such as perturbing calcium homeostasis and redox management. Numerous investigations have proven that endoplasmic reticulum failure may exhibit exacerbation of AD pathogenesis in AD patients, in-vivo and in-vitro models. The endoplasmic reticulum (ER) participates in a variety of biological functions including folding of protein, quality control, cholesterol production, and maintenance of calcium balance. A diverse range of physiological, pathological and pharmacological substances can interfere with ER activity and thus lead to exaggeration of ER stress. The unfolded protein response (UPR), an intracellular signaling network is stimulated due to ER stress. Three stress sensors found in the endoplasmic reticulum, the PERK, ATF6, and IRE1 transducers detect protein misfolding in the ER and trigger UPR, a complex system to maintain homeostasis. ER stress is linked to many of the major pathological processes that are seen in AD, including presenilin1 and 2 (PS1 and PS2) gene mutation, tau phosphorylation and ?-amyloid formation. The role of ER stress and UPR in the pathophysiology of AD implies that they can be employed as potent therapeutic target. This study shows the relationship between ER and AD and how the pathogenesis of AD is influenced by the impact of ER stress. An effective method for the prevention or treatment of AD may involve therapeutic strategies that modify ER stress pathways. � 2023 Elsevier Inc.Item Implicative role of cytokines in neuroinflammation mediated AD and associated signaling pathways: Current progress in molecular signaling and therapeutics(Elsevier Ireland Ltd, 2023-10-30T00:00:00) Kumari, Sneha; Dhapola, Rishika; Sharma, Prajjwal; Singh, Sunil K.; Reddy, Dibbanti HariKrishnaAlzheimer's Disease (AD) is one of the most devastating age-related disorder causing significant social and economic burden worldwide. It affects the cognitive and social behavior of individuals and characterized by accumulation of A?, phosphorylated tau and cytokines formation. The synthesis and release of cytokines are regulated by specific groups of immune and non-immune cells in response to microglia or astrocyte activation through multiple pathways. Physiologically, microglia assert an anti-inflammatory, quiescent state with minimal cytokine expression and little phagocytic activity in motion to carry out their housekeeping role to eliminate pathogens, aggregated A? and tau protein. However, they develop a phagocytic nature and overexpress cytokine gene modules in response to certain stimuli in AD. Microglia and astrocytes upon chronic activation release an enormous amount of inflammatory cytokines due to interaction with formed A? and neurofibrillary tangle. Gut microbiota dysbiosis also stimulates the release of inflammatory cytokines contributing to AD pathogenesis. In addition, the dysregulation of few signaling pathways significantly influences the development of disease, and the pace of advancement also rises with age. This review sheds light on multiple pathways results into neuroinflammation triggered by activated cytokines worsening AD pathology and making it an appropriate target for AD treatment. This review also included drugs targeting different neuroinflammation pathways under clinical and preclinical studies that are found to be effective in attenuating the disease pathology. � 2023 Elsevier B.V.Item Nanotherapeutics for Parkinson's disease using metal nanocomposites(CRC Press, 2023-10-19T00:00:00) Dhapola, Rishika; Sharma, Prajjwal; Kumari, Sneha; Nagar, Pushank; Medhi, Bikash; Reddy, Dibbanti Harikrishna[No abstract available]Item Neuroinflammation in Alzheimer�s Disease: Current Progress in Molecular Signaling and Therapeutics(Springer, 2022-08-20T00:00:00) Thakur, Sujata; Dhapola, Rishika; Sarma, Phulen; Medhi, Bikash; Reddy, Dibbanti HariKrishnaAlzheimer�s disease, a neurodegenerative disease with amyloid beta accumulation as a major hallmark, has become a dire global health concern as there is a lack of clear understanding of the causative agent. It is a major cause of dementia which is increasing exponentially with age. Alzheimer�s disease is marked by tau hyperphosphorylation and amyloid beta accumulation that robs people of their memories. Amyloid beta deposition initiated a spectrum of microglia-activated neuroinflammation, and microglia and astrocyte activation elicited expressions of various inflammatory and anti-inflammatory cytokines. Neuroinflammation is one of the cardinal features of Alzheimer�s disease. Pro-inflammatory cytokine signaling plays multifarious roles in neurodegeneration and neuroprotection. Induction of proinflammatory signaling leads to discharge of immune mediators which affect functions of neurons and cause cell death. Sluggish anti-inflammatory system also contributes to neuroinflammation. Numerous pathways like NF?B, p38 MAPK, Akt/mTOR, caspase, nitric oxide, and COX are involved in triggering brain immune cells like astrocytes and microglia to secrete inflammatory cytokines such as tumor necrosis factor, interleukins, and chemokines and participate in Alzheimer�s disease pathology. PPAR-? agonists tend to boost the phagocytosis of amyloid beta and decrease the inflammatory cytokine IL-1?. Recent findings suggest the cross-link between gut microbiota and neuroinflammation contributing in AD which has been explained in this study. The role of cellular, molecular pathways and involvement of inflammatory mediators in neuroinflammation has also been described; targeting them could be a potential therapeutic strategy for treatment of AD. � 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Recent Advances in Molecular Pathways and Therapeutic Implications Targeting Mitochondrial Dysfunction for Alzheimer�s Disease(Springer, 2021-11-02T00:00:00) Dhapola, Rishika; Sarma, Phulen; Medhi, Bikash; Prakash, Ajay; Reddy, Dibbanti HariKrishnaAlzheimer�s disease (AD) is a neurodegenerative disorder which leads to mental deterioration due to aberrant accretion of misfolded proteins in the brain. According to mitochondrial cascade hypothesis, mitochondrial dysfunction is majorly involved in the pathogenesis of AD. Many drugs targeting mitochondria to treat and prevent AD are in different phases of clinical trials for the evaluation of safety and efficacy as mitochondria are involved in various cellular and neuronal functions. Mitochondrial dynamics is regulated by fission and fusion processes mediated by dynamin-related protein (Drp1). Inner membrane fusion takes place by OPA1 and outer membrane fusion is facilitated by mitofusin1 and mitofusin2 (Mfn1/2). Excessive calcium release also impairs mitochondrial functions; to overcome this, calcium channel blockers like nilvadipine are used. Another process acting as a regulator of mitochondrial function is mitophagy which is involved in the removal of damaged and non-functional mitochondria however this process is also altered in AD due to mutations in Presenilin1 (PS1) and Amyloid Precursor Protein (APP) gene. Mitochondrial dynamics is altered in AD which led to the discovery of various fission protein (like Drp1) inhibitors and drugs that promote fusion. Modulations in AMPK, SIRT1 and Akt pathways can also come out to be better therapeutic strategies as these pathways regulate functions of mitochondria. Oxidative phosphorylation is major generator of Reactive Oxygen Species (ROS) leading to mitochondrial damage; therefore reduction in production of ROS by using antioxidants like MitoQ, Curcumin and Vitamin Eis quiteeffective. � 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Recent advances in molecular pathways and therapeutic implications targeting neuroinflammation for Alzheimer�s disease(Springer Science and Business Media Deutschland GmbH, 2021-11-23T00:00:00) Dhapola, Rishika; Hota, Subhendu Shekhar; Sarma, Phulen; Bhattacharyya, Anusuya; Medhi, Bikash; Reddy, Dibbanti HariKrishnaAlzheimer�s disease (AD) is a major contributor of dementia leading to the degeneration of neurons in the brain with major symptoms like loss of memory and learning. Many evidences suggest the involvement of neuroinflammation in the pathology of AD. Cytokines including TNF-? and IL-6 are also found increasing the BACE1 activity and expression of NF?B resulting in generation of A? in AD brain. Following the interaction of A? with microglia and astrocytes, other inflammatory molecules also get translocated to the site of inflammation by chemotaxis and exaggerate neuroinflammation. Various pathways like NF?B, p38 MAPK, Akt/mTOR, caspase, nitric oxide and COX trigger microglia to release inflammatory cytokines. PPAR? agonists like pioglitazone increases the phagocytosis of A? and reduces inflammatory cytokine IL-1?. Celecoxib and roficoxib like selective COX-2 inhibitors also ameliorate neuroinflammation. Non-selective COX inhibitor indomethacin is also potent inhibitor of inflammatory mediators released from microglia. Mitophagy process is considered quite helpful in reducing inflammation due to microglia as it promotes the phagocytosis of over activated microglial cells and other inflammatory cells. Mitophagy induction is also beneficial in the removal of damaged mitochondria and reduction of infiltration of inflammatory molecules at the site of accumulation of the damaged mitochondria. Targeting these pathways and eventually ameliorating the activation of microglia can mitigate neuroinflammation and come out as a better therapeutic option for the treatment of Alzheimer�s disease. � 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG.Item Redefining oxidative stress in Alzheimer's disease: Targeting platelet reactive oxygen species for novel therapeutic options(Elsevier Inc., 2022-08-01T00:00:00) Beura, Samir Kumar; Dhapola, Rishika; Panigrahi, Abhishek Ramachandra; Yadav, Pooja; Reddy, Dibbanti Harikrishna; Singh, Sunil KumarAlzheimer's disease (AD), a progressive neurodegenerative disorder, is considered one of the most common causes of dementia worldwide, accounting for about 80 % of all dementia cases. AD is manifested by the extraneuronal deposition of senile plaques of amyloid beta (A?) and intraneuronal accumulation of neurofibrillary tangles of phosphorylated tau. The impaired proteostasis of these filamentous A? and tau is significantly regulated by reactive oxygen species (ROS). ROS-induced oxidative stress (OS) is the cardinal cause behind neuroinflammation-triggered neurodegeneration during AD. Besides ROS-induced neuro-inflammation, AD is also associated with cerebrovascular dysfunction, where platelet primarily plays a significant role in blood-vessel integrity and tissue repair. Though platelets are the circulatory cell fragments that play predominant roles in thrombosis and hemostasis, their contributions to other physiological functions are also being elucidated. Surprisingly, platelets contribute about 90 % of the circulatory A? and share striking similarities with neurons in several aspects, including different neurotransmitters and their cognate receptors, thus considering platelets as potential peripheral models for AD. Interestingly, platelet structural and functional dysfunctions are evident in AD, where ROS production is associated with platelet hyperactivity. Although activated platelet carries several vital enzymes and immunomodulatory molecules, which can potentially exacerbate OS-mediated neuronal damage, and neurodegeneration, their mechanism of action and mode of progression, are still obscure. Therefore, in this review, we have described the detailed role of OS and platelet in AD, addressing the therapeutic approach and molecular mechanism of platelet-mediated ROS generation as a contributing factor in aggravating the disease. � 2022 Elsevier Inc.