Department of Pharmacy

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Now showing 1 - 9 of 9
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    Autophagy as a potential therapeutic target in regulating improper cellular proliferation
    (Frontiers Media, 2025-05) Chitkara, Deepak
    Autophagy is a degradative process that makes rapid turnover of old and impaired proteins and organelles possible. It is highly instigated by stress signals, like starvation, and contributes to the cell’s homeostasis. Autophagy performs a crucial function in keeping cell genomic integrity stable. Impaired autophagic flux is implicated in neurodegenerative diseases, abnormal ageing, and cancerous diseases. In diseases like cancer, autophagy performs a dualistic function; it can have both a tumor-suppressive and supportive role. Autophagy in the initial phases of tumorigenesis maintains the integrity of the genome and, if it fails, leads to cell death, thus having a tumor-suppressive role. Meanwhile, autophagy also imparts the function of the pro-survival mechanism in the latter stages of tumorigenesis and supports the cancerous cells in surviving conditions like hypoxia and increased oxidative stress. Autophagy also helps cancerous cells develop drug resistance in some cases. Thus, modulation of the autophagic mechanism is a possible therapeutic strategy in cancer therapy as its inhibition can sensitise cancer cells to anti-cancerous drugs. The promotion of autophagy, in some cases, can also safeguard cells from toxic protein aggregation and enhanced oxidative stress. Excessive autophagy can result in autophagic cell death. Autophagy also regulates several cellular processes and cell death pathways, like apoptosis. Therefore, an in-depth knowledge of the autophagy process and its regulating molecules is critically important. Pharmaceutical small molecules or cellular target modulation can help modulate the cellular autophagy process in the context of specific disease conditions.
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    ULK1 as a therapeutic target in kidney diseases: Current perspective
    (Taylor & Francis, 2024-11) Gaikwad, Anil Bhanudas
    Globally, ~850 million people are affected by different kidney diseases. The pathogenesis of kidney diseases is intricate, where autophagy is crucial for maintaining kidney homeostasis. Iteliminates damaged organelles, thus reducing renal lesions and allowing tissue regeneration. Therefore, targeting various autophagy proteins, e.g. Unc–51–like autophagy-activating kinase 1 (ULK1), is emerging as potential therapeutic strategy against kidney disease.
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    Management of inflammaging in kidney diseases: focusing on the current investigational drugs
    (Taylor & Francis, 2024-10) Gaikwad, Anil Bhanudas
    To improve kidney disease treatments, it is crucial to understand how inflammaging affects patients´ longevity. We could potentially slow down kidney disease progression and enhance longevity by targeting specific pathways involved in inflammaging with potential drugs.
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    Mechanism of interaction between autophagy and apoptosis in cancer
    (Springer, 2021-09) Shrivastava, Richa
    The mechanisms of two programmed cell death pathways, autophagy, and apoptosis, are extensively focused areas of research in the context of cancer. Both the catabolic pathways play a significant role in maintaining cellular as well as organismal homeostasis. Autophagy facilitates this by degradation and elimination of misfolded proteins and damaged organelles, while apoptosis induces canonical cell death in response to various stimuli. Ideally, both autophagy and apoptosis have a role in tumor suppression, as autophagy helps in eliminating the tumor cells, and apoptosis prevents their survival. However, as cancer proceeds, autophagy exhibits a dual role by enhancing cancer cell survival in response to stress conditions like hypoxia, thereby promoting chemoresistance to the tumor cells. Thus, any inadequacy in either of their levels can lead to tumor progression. A complex array of biomarkers is involved in maintaining coordination between the two by acting as either positive or negative regulators of one or both of these pathways of cell death. The resulting crosstalk between the two and its role in influencing the survival or death of malignant cells makes it quintessential, among other challenges facing chemotherapeutic treatment of cancer. In view of this, the present review aims to highlight some of the factors involved in maintaining their diaphony and stresses the importance of inhibition of cytoprotective autophagy and deletion of the intermediate pathways involved to facilitate tumor cell death. This will pave the way for future prospects in designing drug combinations facilitating the synergistic effect of autophagy and apoptosis in achieving cancer cell death.
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    Disulfiram potentiates docetaxel cytotoxicity in breast cancer cells through enhanced ROS and autophagy
    (Springer, 2020-07) Chowdhury, Rajdeep; Roy, Aniruddha
    Recent studies have demonstrated that autophagy plays a critical role in reducing the drug sensitivity of docetaxel (DTX) therapy. Disulfiram (DSF) has exhibited potent autophagy inducing activity in multiple studies. We hypothesized that DSF co-treatment could sensitize breast cancer cells to DTX therapy via autophagy modulation.
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    Proteostasis defects: Medicinal challenges of imperfect aging & neurodegeneration
    (Elsevier, 2023) Chitkara, Deepak
    A prolonged healthy life is based on the optimal activity of an organism’s organ systems, and healthy cells are at the core of this proper functioning. Cellular homeostasis is of utmost importance, and a cell deploys several cytoprotective mechanisms to maintain this balance. One such mechanism is protein quality control (PQC) to preserve proteostasis and maintain functionality of proteins. In PQC, the chaperone system and proteolytic pathways like autophagy and ubiquitin-proteasome system (UPS) are primary cell devices preventing misfolding/aggregation of proteins and clearing out toxic protein aggregates and dysfunctional organelles. Aging is an unavoidable biological phenomenon observed in many organisms that negatively affects the functionality of multiple organs systems, thus reducing the life span. It constitutes a significant risk factor for impairment of PQC elements and proteostasis disruption, linked with physiological dysfunction of organelles along with other anomalies. Aging presents various medicinal challenges as it affects multiple physiological processes at once. In aging, declined PQC capacity can lead to increased incidence of several age-associated diseases, including neurodegenerative disorders. Proper maintenance and modulation of these PQC elements present an attractive therapeutic intervention opportunity for such disorders. Here, we present PQC and its components as a system affected in imperfect aging, its potential for modulation to improve healthspan and counter aging associated disorders, along with challenges linked with inherent complex nature of aging biology.
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    The gut-brain connection in the pathogenicity of Parkinson disease: Putative role of autophagy
    (Elsevier, 2021-05) Taliyan, Rajeev
    Parkinson disease (PD) is a progressive movement functionality disorder resulting in tremor and inability to execute voluntary functions combined with the preponderant non-motor disturbances encompassing constipation and gastrointestinal irritation. Despite continued research, the pathogenesis of PD is not yet clear. The available class of drugs for effective symptomatic management of PD includes a combination of levodopa and carbidopa. In recent past, the link between gut with PD has been explored. According to recent preclinical evidence, pathogens such as virus or bacterium may initiate entry into the gut via the nasal cavity that may aggravate lewy pathology in the gut that eventually propagates and progresses towards the brain via the vagus nerve resulting in the prodromal non-motor symptoms. Additionally, experimental evidence also suggests that alpha-synuclein misfolding commences at a very early stage in the gut and is transported via the vagus nerve prior to seeding PD pathology in the brain. However, this progression and resultant deterioration of the neurones can effectively be altered by an autophagy inducer, Trehalose, although the mechanism behind it is still enigmatic. Hence, this review will mainly focus on analysing the basic components of the gut that might be responsible for aggravating lewy pathology, the mediator(s) responsible for transmission of PD pathology from gut to brain and the important role of trehalose in ameliorating gut dysbiosis related PD complications that would eventually pave the way for therapeutic management of PD.
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    Neuroprotective Effects of Trehalose and Sodium Butyrate on Preformed Fibrillar Form of α-Synuclein-Induced Rat Model of Parkinson’s Disease
    (ACS, 2021-07) Taliyan, Rajeev
    Therapeutic options for Parkinson’s disease (PD) are limited to a symptomatic approach, making it a global threat. Targeting aggregated alpha-synuclein (α-syn) clearance is a gold standard for ameliorating PD pathology, bringing autophagy into the limelight. Expression of autophagy related genes are under the regulation by histone modifications, however, its relevance in PD is yet to be established. Here, preformed fibrillar form (PFF) of α-syn was used to induce PD in wistar rats, which were thereafter subjected to treatment with trehalose (tre, 4g/kg, orally), a potent autophagy inducer and sodium butyrate (SB, 300 mg/kg, orally), a pan histone deacetylase inhibitor alone as well as in combination. The combination treatment significantly reduced motor deficits as evidenced after rotarod, narrow beam walk, and open field tests. Novel object location and recognition tests were performed to govern cognitive abnormality associated with advanced stage PD, which was overcome by the combination treatment. Additionally, with the combination, the level of pro-inflammatory cytokines were significantly reduced, along with elevated levels of dopamine and histone H3 acetylation. Further, mRNA analysis revealed that levels of certain autophagy related genes and proteins implicated in PD pathogenesis significantly improved after administration of both tre and SB. Immunofluorescence and H&E staining in the substantia nigra region mirrored a potential improvement after treatment with both tre and SB. Therefore, outcomes of the present study were adequate to prove that combinatorial efficacy with tre and SB may prove to be a formidable insight into ameliorating PD exacerbated by PFF α-syn as compared to its individual efficacy.
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    Fibroblast growth factor 21 and autophagy: A complex interplay in Parkinson disease
    (Elsevier, 2020-07) Taliyan, Rajeev
    Parkinson disease (PD) is a progressive and an age-dependent neurodegenerative disorder that predominantly affects the dopaminergic (DA) neuronal system in the substantia nigra (SN) region of the brain causing its deterioration over time. This deterioration gives rise to motor abnormalities in a PD affected patient causing tremor, bradykinesia, akinesia, postural instability, slurred speech etc. Recent research also enlightened that occurrence of non-motor dysfunctions in an individual initiate in the advanced stage of PD. It comprises mainly of cognitive dysfunction, constipation, sleep disorder, depression, anxiety etc. PD is known to affect at least 0.3% of the worldwide population and over 3% of those over 80 years of age. The predominant pathological hallmark of PD is aggregation of misfolded forms of alpha-synuclein (α-syn) in intraneuronal inclusions known as lewy bodies (LBs) in cell soma and in lewy neurites (LNs) in neuronal processes. α-syn is a presynaptic protein involved in neurotransmission. It is normally degraded by ubiquitin-proteasome system (UPS) and autophagy-lysosome system (ALS) [1]. UPS is responsible for the selective degradation of short-lived proteins and its dysfunction leads to the activation of ALS [2]. Exceptionally high affinities of the mutant forms of α-syn blocks the lysosomal uptake and inhibits its degradation via ALS [1]. This very well explains that ALS dysfunction is an important mechanism in neurodegeneration especially PD. Subsequently, blockage of ALS can aggravate various factors that can further complicate PD, the most important being endoplasmic reticulum (ER) stress [3]. ER stress is mainly a compensatory mechanism that is intended to preserve cellular function and neuronal survival [4] by activating PKR-like ER kinase (PERK), activating transcription factor(ATF)-6, inositol-requiring enzyme(IRE)-1 [5]. Phosphorylation of eukaryotic initiation factor 2-α (eIF2α), via activation by PERK, leads to translational induction of ATF4. Several studies have proved that stressors like starvation, autophagy dysfunction activates ATF4 which is also known to upregulate Fibroblast growth factor 21 (FGF21) [6].