Department Of Pharmacology
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Item Bacillus Calmette-Gu�rin Vaccine Attenuates Haloperidol-Induced TD-like Behavioral and Neurochemical Alteration in Experimental Rats(2023-11-20T00:00:00) Yedke, Narhari Gangaram; Upadhayay, Shubham; Singh, Randhir; Jamwal, Sumit; Ahmad, Sheikh F.; Kumar, PuneetTardive dyskinesia (TD) is a hyperkinetic movement disorder that displays unusual involuntary movement along with orofacial dysfunction. It is predominantly associated with the long-term use of antipsychotic medications, particularly typical or first-generation antipsychotic drugs such as haloperidol. Oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis are major pathophysiological mechanisms of TD. The BCG vaccine has been reported to suppress inflammation, oxidative stress, and apoptosis and exert neuroprotection via several mechanisms. Our study aimed to confirm the neuroprotective effect of the BCG vaccine against haloperidol-induced TD-like symptoms in rats. The rats were given haloperidol (1 mg/kg, i.p.) for 21 days after 1 h single administration of the BCG vaccine (2 � 107 cfu). Various behavioral parameters for orofacial dyskinesia and locomotor activity were assessed on the 14th and 21st days after haloperidol injection. On the 22nd day, all rats were euthanized, and the striatum was isolated to estimate the biochemical, apoptotic, inflammatory, and neurotransmitter levels. The administration of the BCG vaccine reversed orofacial dyskinesia and improved motor function in regard to haloperidol-induced TD-like symptoms in rats. The BCG vaccine also enhanced the levels of antioxidant enzymes (SOD, GSH) and reduced prooxidants (MDA, nitrite) and pro-apoptotic markers (Cas-3, Cas-6, Cas-9) in rat brains. Besides this, BCG treatment also restored the neurotransmitter (DA, NE, 5-HT) levels and decreased the levels of HVA in the striatum. The study findings suggest that the BCG vaccine has antioxidant, antiapoptotic, and neuromodulatory properties that could be relevant in the management of TD.Item Calcium channelopathies in neurodegenerative disorder: an untold story of RyR and SERCA(Taylor and Francis Ltd., 2023-11-16T00:00:00) Dhureja, Maanvi; Arthur, Richmond; Soni, Divya; Upadhayay, Shubham; Temgire, Pooja; Kumar, PuneetIntroduction: Recent neuroscience breakthroughs have shed light on the sophisticated relationship between calcium channelopathies and movement disorders, exposing a previously undiscovered tale focusing on the Ryanodine Receptor (RyR) and the Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA). Calcium signaling mainly orchestrates neural communication, which regulates synaptic transmission and total network activity. It has been determined that RyR play a significant role in managing neuronal functions, most notably in releasing intracellular calcium from the endoplasmic reticulum. Areas covered: It highlights the involvement of calcium channels such as RyR and SERCA in physiological and pathophysiological conditions. Expert opinion: Links between RyR and SERCA activity dysregulation, aberrant calcium levels, motor and cognitive dysfunction have brought attention to the importance of RyR and SERCA modulation in neurodegenerative disorders. Understanding the obscure function of these proteins will open up new therapeutic possibilities to address the underlying causes of neurodegenerative diseases. The unreported RyR and SERCA narrative broadens the understanding of calcium channelopathies in movement disorders and calls for more research into cutting-edge therapeutic approaches. � 2023 Informa UK Limited, trading as Taylor & Francis Group.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 Unlocking the therapeutic potential of natural stilbene: Exploring pterostilbene as a powerful ally against aging and cognitive decline(Elsevier Ireland Ltd, 2023-11-17T00:00:00) Dutta, Bhaskar Jyoti; Rakshe, Pratik Shankar; Maurya, Niyogita; Chib, Shivani; Singh, SanjivThe therapeutic potential of natural stilbenes, with a particular focus on pterostilbene (PTE), has emerged as a promising avenue of research targeting age-associated conditions encompassing cardiovascular diseases (CVD), diabetes mellitus (DM), and cognitive decline. This comprehensive investigation delves into the intricate mechanisms through which PTE, a polyphenolic compound abundant in grapes and blueberries, exerts its advantageous effects as an anti-aging agent. Central to its action is the modulation of hallmark aging processes, including oxidative damage, inflammatory responses, telomere attrition, and cellular senescence. PTE's ability to effectively penetrate the blood-brain barrier amplifies its potential for safeguarding neural health, thereby facilitating the regulation of neuronal signalling cascades, synaptic plasticity, and mitochondrial functionality. Through engagement with sirtuin proteins, it orchestrates cellular resilience, longevity, and metabolic equilibrium. Encouraging findings from preclinical studies portray PTE as a robust candidate for counteracting age-linked cognitive decline, augmenting memory consolidation, and potentially ameliorating neurodegenerative maladies such as Alzheimer's disease (AD). The synthesis of current scientific insights accentuates the promising translational prospects of PTE as a potent, naturally derived therapeutic agent against cognitive impairments associated with aging. Consequently, these collective findings lay a solid groundwork for forthcoming clinical inquiries and innovative therapeutic interventions in this realm. � 2023 Elsevier B.V.Item Therapeutic targeting of angiopoietins in tumor angiogenesis and cancer development(Elsevier B.V., 2023-10-21T00:00:00) Thapa, Komal; Khan, Heena; Kaur, Gagandeep; Kumar, Puneet; Singh, Thakur GurjeetThe formation and progression of tumors in humans are linked to the abnormal development of new blood vessels known as neo-angiogenesis. Angiogenesis is a broad word that encompasses endothelial cell migration, proliferation, tube formation, and intussusception, as well as peri-EC recruitment and extracellular matrix formation. Tumor angiogenesis is regulated by angiogenic factors, out of which some of the most potent angiogenic factors such as vascular endothelial growth factor and Angiopoietins (ANGs) in the body are produced by macrophages and other immune cells within the tumor microenvironment. ANGs have a distinct function in tumor angiogenesis and behavior. ANG1, ANG 2, ANG 3, and ANG 4 are the family members of ANG out of which ANG2 has been extensively investigated owing to its unique role in modifying angiogenesis and its tight association with tumor progression, growth, and invasion/metastasis, which makes it an excellent candidate for therapeutic intervention in human malignancies. ANG modulators have demonstrated encouraging outcomes in the treatment of tumor development, either alone or in conjunction with VEGF inhibitors. Future development of more ANG modulators targeting other ANGs is needed. The implication of ANG1, ANG3, and ANG4 as probable therapeutic targets for anti-angiogenesis treatment in tumor development should be also evaluated. The article has described the role of ANG in tumor angiogenesis as well as tumor growth and the treatment strategies modulating ANGs in tumor angiogenesis as demonstrated in clinical studies. The pharmacological modulation of ANGs and ANG-regulated pathways that are responsible for tumor angiogenesis and cancer development should be evaluated for the development of future molecular therapies. � 2023 Elsevier Inc.Item Apoptotic Cell Death in Cardiomyocytes Induced by Hypoxia from Cobalt Chloride Is Hastened by SGLT-1 Inhibition(Mary Ann Liebert Inc., 2023-09-19T00:00:00) Kanwal, Abhinav; Liu, Lu; Bansal, Puneet Kumar; Kumar, Hemant; Singh, Shailendra PratapIntroduction: Myocardial ischemia is responsible for the deaths of millions of people every year. Cardiac hypoxia reduces the efficiency with which the heart muscle pumps blood. When one or more of the coronary arteries abruptly and severely narrows or closes off, this is known as an acute coronary syndrome (ACS). Ischemia of the heart muscle can also cause potentially fatal arrhythmias. More information about this topic is required. Methods: The effects of SGLT-1 inhibition were studied using a different disease model, the cobalt chloride (CoCl2) hypoxia paradigm. The MTT assay was used to examine the effects of CoCl2 with and without Phlorizin (PZ) on glucose uptake, caspase activity, and metabolic/cytotoxic activities in SGLT-1 overexpressed H9C2 cells. Both SGLT-1 siRNA silencing and PZ treatment of SGLT-1 overexpressed neonatal rat cardiomyocytes were studied. Results and Discussion: Using flow cytometry, we were able to distinguish between metabolically active (PI-stained) and inactive (annexin-stained) live cells, as well as apoptotic (annexin-stained) and necrotic (PI-stained) cells. Caspase 3, 9, bcl-2, HIF-1a, and SGLT-1 expression, as well as oxidative stress, were examined using Western blotting. H9C2 cells showed increased caspase 3 and 9 activity in the CoCl2 group compared to the control, and these increases were further amplified by PZ cotreatment. PZ did not counteract CoCl2's effects of decreased glucose absorption and MTT activity. Conclusion: PZ increased cardiomyocyte apoptosis and decreased metabolic quiescent cells. PZ had no effect on the oxidative stress and necrosis that CoCl2 caused. CoCl2-induced SGLT-1 reduction leads to rapid apoptotic cell death. � Copyright 2023, Mary Ann Liebert, Inc., publishers 2023.Item 1,3-Oxazine as a Promising Scaffold for the Development of Biologically Active Lead Molecules(John Wiley and Sons Inc, 2023-10-16T00:00:00) Gupta, Nidhi; Saini, Vipin; Basavarajaiah, S.M.; Dar, Mohammad Ovais; Das, Rina; Dahiya, Randhir SinghHeterocyclic compounds form an important part of wide range of biologically active molecules. The heteroatom provides them specificity for various receptors. 1,3-oxazine has been considered as a privileged scaffold in many medicinal chemistry applications. Compounds having 1,3-oxazine moiety exhibit broad range of biological applications such as anticancer, antimicrobial, anti-inflammatory, antiplatelet, antitubercular and alpha-glucosidase inhibition activities. In this review, we consolidate the recent developments in the synthesis and biological activities of 1,3-oxazine containing compounds. Also, the structure activity relationship (SAR) studies of different derivatives exhibiting several biological activities are summarized. Database such as Science direct, Pubmed and Google scholar were searched using keywords �1,3-Oxazine�, �synthesis�, �derivatives�, and �biological activities�. The review would provide a lead for the development of competent candidates with 1,3-oxazine moiety having broad range of applications in the treatment of several human disorders. � 2023 Wiley-VCH GmbH.Item Advancing Cancer Immunotherapy: The Potential of mRNA Vaccines As a Promising Therapeutic Approach(John Wiley and Sons Inc, 2023-10-04T00:00:00) Goyal, Falak; Chattopadhyay, Anandini; Navik, Umashanker; Jain, Aklank; Reddy, P. Hemachandra; Bhatti, Gurjit Kaur; Bhatti, Jasvinder SinghmRNA vaccines have long been recognized for their ability to induce robust immune responses. The discovery that mRNA vaccines may also contribute to antitumor immunity has made them a promising therapeutic approach against cancer. Recent advances in understanding of immune system are precious in developing therapeutic strategies that target pathways involved in tumor survival and progression, leading to the most reliable therapeutic strategies in cancer treatment history. Among all traditional cancer treatments, cancer immunotherapies are less toxic and more effective, even in advanced or recurrent stages of cancer. Recent advancements in genomics and machine learning algorithms give new insight into vaccine development. mRNA vaccines are designed to interfere with stimulator of interferon genes (STING) and tumor-infiltrating lymphocytes pathways, activating more CD8+ T-cells involved in destroying tumor cells and inhibiting tumor growth. A stronger immune response can be achieved by incorporating immunological adjuvants alongside mRNA. Nonformulated or vehicle-based mRNA vaccines, when combined with adjuvants, efficiently express tumor antigens through antigen-presenting cells and stimulate both innate and adaptive immune responses. Codelivery with additional immunotherapeutic agents, such as checkpoint inhibitors, further enhances the efficacy of mRNA vaccines. This article focuses on the current clinical approaches and challenges to consider when developing mRNA-based vaccine technology for cancer treatment. � 2023 Wiley-VCH GmbH.Item Impact of noscapine on halting the progression of pentylenetetrazole induced kindling epilepsy in mice(John Wiley and Sons Inc, 2023-09-19T00:00:00) Gupta, Rishav; Soni, Divya; Upadhayay, Shubham; Dhureja, Maanvi; Kumar, PuneetEpilepsy is caused by an excessive recurrent excitatory neuronal firing, characterized by motor, psychomotor, and sensory impairments. Current therapies fail to produce 100% outcomes because of the complexity of the disease, poor diagnosis, and upsurge�to drug-resistant epilepsy. The study repurposed�the drug �noscapine��mainly known for its anti-tussive properties. For the management of epilepsy and its associated secondary complications. To confirm the effect of noscapine, adult mice were injected with pentylenetetrazole (PTZ) (35 mg/kg i.p.) on an alternate day for 29 days to induce epilepsy. Animals were pretreated with noscapine in three doses (5, 10, and 20 mg/kg i.p.) for 33 days. Various behavioural assessments like the open field test, Morris water maze, and tail suspension test were performed to observe animals' locomotor activity, spatial memory, and anxiety-depressive behaviour. On the 34th day, animals were sacrificed, and brains were removed for biochemical estimations. Prolonged PTZ treatment reduced locomotor, learning activity, and increased anxiety-depressive behaviour, which was further confirmed by reduced antioxidant levels such as reduced glutathione (GSH), superoxide dismutase (SOD), and catalase because of increased oxido-nitrosative stress, that is, malondialdehyde (MDA) and nitrite in the brain. In comparison, noscapine pretreatment attenuated PTZ-induced behavioural and biochemical changes in the animals. The results indicate that noscapine ameliorates the oxido-nitrosative stress. However, studies indicate that oxido-nitrosative stress is a significant concern for the GABAergic neurons and promotes the disease progression. Further studies are required to explore the molecular mechanism of noscapine, which might be a practical approach as a newer antiepileptic agent. � 2023 John Wiley & Sons Australia, Ltd.Item Understanding the Cross-Talk between the Ceramide Biosynthetic Pathway and Mitochondrial Function in Multiple Sclerosis and Demyelinating Disorders(Wiley-Hindawi, 2023-10-12T00:00:00) Amarjeet; Babu, Raja; Mohapatra, Abhipsa; Pancholi, Bhaskaranand; Garabadu, Debapriya; Sharma, Anjali; Sharma, Ashwani; Azad, Md. A. K.Myelin is a spiral compilation of uniformly thick membranes around the axon in an alternating fashion, and it is formed by a complicated process known as myelination. Myelin sheaths are responsible for various physiological functions such as metabolism, rapid nerve conduction, and maintaining ionic and water homeostasis in the brain. Lipid is one of the major components in the myelin, which includes cholesterol, ceramide, and their derivatives, such as galactosylceramide, sulfatide, and gangliosides. Ceramide and its derivatives are synthesised by various ceramide biosynthetic pathways such as de novo, salvage, sphingomyelinase, and recycling of exogenous ceramide. At an appropriate level, ceramide facilitates the development of the nervous system, cell proliferation, autophagy, and apoptosis, which are responsible for normal functioning, but when the level is altered from normal, it results in mitochondrial dysfunction or cell death through autophagy and apoptosis. The ceramide level increases, especially in the mitochondria. Ceramide level increases in response to oxidative stress which is mediated by inflammatory cytokines. Due to mitochondrial dysfunction, an energy-deficient condition is created because of disruption in the electron transport chain, which results in the death of neurons and glial cells, which subsequently cause demyelination and degeneration of axon. Losing myelin while axons remain relatively intact is the characteristic feature of demyelinating diseases. The primary element of demyelinating disorder is damage, malfunction, failure, or death of mitochondria. These disturbances may occur due to direct or indirect interaction of ceramide with mitochondria. There are several risk factors for demyelination, such as viruses, bacteria, fungi, trauma, obesity, vitamin D deficiency, and genetic and environmental factors. Thus, the review is mainly aimed towards the interaction between ceramide and mitochondria during demyelination. � 2023 Amarjeet et al.