School Of Health Sciences
Permanent URI for this communityhttps://kr.cup.edu.in/handle/32116/102
Browse
12 results
Search Results
Item Understanding the neuronal synapse and challenges associated with the mitochondrial dysfunction in mild cognitive impairment and Alzheimer's disease(Elsevier B.V., 2023-09-13T00:00:00) Verma, Harkomal; Gangwar, Prabhakar; Yadav, Anuradha; Yadav, Bharti; Rao, Rashmi; Kaur, Sharanjot; Kumar, Puneet; Dhiman, Monisha; Taglialatela, Giulio; Mantha, Anil KumarSynaptic mitochondria are crucial for maintaining synaptic activity due to their high energy requirements, substantial calcium (Ca2+) fluctuation, and neurotransmitter release at the synapse. To provide a continuous energy supply, neurons use special mechanisms to transport and distribute healthy mitochondria to the synapse while eliminating the damaged mitochondria from the synapse. Along the neuron, mitochondrial membrane potential (?) gradient exists and is highest in the somal region. Lower ? in the synaptic region renders mitochondria more vulnerable to oxidative stress-mediated damage. Secondly, mitochondria become susceptible to the release of cytochrome c, and mitochondrial DNA (mtDNA) is not shielded from the reactive oxygen species (ROS) by the histone proteins (unlike nuclear DNA), leading to activation of caspases and pronounced oxidative DNA base damage, which ultimately causes synaptic loss. Both synaptic mitochondrial dysfunction and synaptic failure are crucial factors responsible for Alzheimer's disease (AD). Furthermore, amyloid beta (A?) and hyper-phosphorylated Tau, the two leading players of AD, exaggerate the disease-like pathological conditions by reducing the mitochondrial trafficking, blocking the bi-directional transport at the synapse, enhancing the mitochondrial fission via activating the mitochondrial fission proteins, enhancing the swelling of mitochondria by increasing the influx of water through mitochondrial permeability transition pore (mPTP) opening, as well as reduced ATP production by blocking the activity of complex I and complex IV. Mild cognitive impairment (MCI) is also associated with decline in cognitive ability caused by synaptic degradation. This review summarizes the challenges associated with the synaptic mitochondrial dysfunction linked to AD and MCI and the role of phytochemicals in restoring the synaptic activity and rendering neuroprotection in AD. � 2023 Elsevier B.V. and Mitochondria Research Society. All rights reserved.Item Targeting Mitochondria as a Novel Disease-Modifying Therapeutic Strategy in Cancer(Springer Singapore, 2022-09-28T00:00:00) Bhatti, Gurjit Kaur; Pahwa, Paras; Gupta, Anshika; Sidhu, Inderpal Singh; Navik, Uma Shanker; Reddy, P. Hemachandra; Bhatti, Jasvinder SinghMitochondria are essential for the metabolism of energy, regulation of apoptosis, and cell signaling. Overproduction of reactive oxidation species (ROS) in mitochondria is one of the indications of cancer cells. Moreover, this boosts the proliferation of cancerous cells by causing genomic instability and altering gene expressions. Mitochondrial and nuclear DNA mutations caused by oxidative damage impair the mechanism of oxidative phosphorylation and can lead to more mitochondrial ROS output, genome instability, and cancer development. The classic approach to target mitochondria of cancerous cells with novel targeted therapeutics helps in targeting the mitochondrial apoptotic proteins and changing energy metabolism. A key benefit of selective drug delivery is that it reduces the drug�s toxicity and increases specificity. A better understanding of the mitochondrial role in tumor growth will help design more therapeutic agents with better selectivity. � Springer Nature Singapore Pte Ltd. 2022.Item Mitochondria-targeted drug delivery systems for the effective treatment of neurodegenerative disorders(Elsevier, 2022-03-18T00:00:00) Khare, Vaishali; Gupta, Surbhi; Bisht, Preeti; Garabadu, DebapriyaMitochondria are known to be the powerhouse of the cell. Its dysfunction leads to several alterations in cellular physiology. Mitochondrial dysfunction is a well-documented process in the pathophysiology of neurodegeneration and neurodegenerative disorders. The interplay between mitochondrial dysfunction and oxidative stress is well suggested in the pathophysiology of neurodegenerative disorders. The activation of autophagy is also well established along with the mitochondrial impairment in neurodegenerative disorders. The relationship between mitochondrial dysfunction and excitotoxicity is also well established in the pathophysiology of neurodegenerative disorders. Enhanced apoptosis and necrosis is well established along with mitochondrial dysfunction in the pathophysiology of neurodegenerative disorders. Several synthetic and herbal drugs have been established in the management of mitochondrial dysfunction-induced neurodegenerative disorders. Little information is available about the formulations of the established mitochondria-targeted drugs in the management of neurodegenerative disorders. Therefore, critical attention is required in the development of mitochondria-targeted drug delivery systems for therapeutic and diagnostic applications in neurodegenerative disorders. � 2022 Elsevier Inc. All rights reserved.Item Targeting Mitochondria as a Novel Disease-Modifying Therapeutic Strategy in Cancer(Springer Nature, 2022-01-31T00:00:00) Bhatti, Gurjit Kaur; Pahwa, Paras; Gupta, Anshika; Navik, Uma Shanker; Reddy, P. Hemachandra; Bhatti, Jasvinder SinghMitochondria are important for the metabolism of energy, regulation of apoptosis and cell signaling. Overproduction of reactive oxidation species (ROS) in mitochondria is one of the indications of cancer cells; moreover, this boosts the proliferation of cancerous cells by causing genomic instability and altering gene expressions. Mitochondrial and nuclear DNA mutations, caused by oxidative damage which impairs the mechanism of oxidative phosphorylation, can lead to more mitochondrial ROS output, genome instability, and the development of the cancer. Classic approach to target mitochondria of cancerous cells with novel-targeted therapeutics helps in targeting the mitochondrial apoptotic proteins and changing energy metabolism. Key benefit of selective drug delivery is it reduces the toxicity of drug and increases specificity. Better understanding of mitochondrial role in tumor growth will help to design more therapeutic agents with better selectivity. � Springer Nature Singapore Pte Ltd. 2022.Item Quercetin Exhibits ?7nAChR/Nrf2/HO-1-Mediated Neuroprotection Against STZ-Induced Mitochondrial Toxicity and Cognitive Impairments in Experimental Rodents(Springer, 2021-09-23T00:00:00) Singh, Niraj Kumar; Garabadu, DebapriyaThe objective of the present study was to investigate the ?7nAChR-mediated Nrf2-dependant protective activity against streptozotocin (STZ)-induced brain mitochondrial toxicity in Alzheimer�s disease (AD)-like rats. STZ (3�mg/kg) was injected through an intracerebroventricular route to induce AD-like dementia. Repeated Quercetin (50�mg/kg, i.p.) administration attenuated cognitive impairments in the STZ-challenged animals during Morris water-maze and Y-maze tests. Quercetin significantly mitigated the STZ-induced increase in cholinergic dysfunction, such as the increase in acetylcholinesterase activity, decrease in acetylcholine level, and activity of choline acetyltransferase, and increase in amyloid-beta aggregation and mitochondrial toxicity in respect of mitochondrial bioenergetics, integrity, and oxidative stress in memory-challenged rat hippocampus, prefrontal cortex and, amygdala. Further, Quercetin significantly attenuated STZ-induced reduction in the ?7nAChRs and HO-1 expression levels in the selected rat brain regions. On the contrary, trigonelline (10�mg/kg, i.p.) and methyllycaconitine (2�mg/kg; i.p.) abolished the neuroprotective effects of Quercetin against STZ-induced behavioral, molecular, and biochemical alterations in the AD-like animals. Hence, Quercetin exhibits ?7nAChR/Nrf2/HO-1-mediated neuroprotection against STZ-challenged AD-like animals. Thus, Quercetin could be considered as a potential therapeutic option in the management of AD. Graphical Abstract: [Figure not available: see fulltext.] � 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Targeting dynamin-related protein-1 as a potential therapeutic approach for mitochondrial dysfunction in Alzheimer's disease(Elsevier B.V., 2023-06-29T00:00:00) Bhatti, Jasvinder Singh; Kaur, Satinder; Mishra, Jayapriya; Dibbanti, Harikrishnareddy; Singh, Arti; Reddy, Arubala P.; Bhatti, Gurjit Kaur; Reddy, P. HemachandraAlzheimer's disease (AD) is a neurodegenerative disease that manifests its pathology through synaptic damage, mitochondrial abnormalities, microRNA deregulation, hormonal imbalance, increased astrocytes & microglia, accumulation of amyloid ? (A?) and phosphorylated Tau in the brains of AD patients. Despite extensive research, the effective treatment of AD is still unknown. Tau hyperphosphorylation and mitochondrial abnormalities are involved in the loss of synapses, defective axonal transport and cognitive decline in patients with AD. Mitochondrial dysfunction is evidenced by enhanced mitochondrial fragmentation, impaired mitochondrial dynamics, mitochondrial biogenesis and defective mitophagy in AD. Hence, targeting mitochondrial proteins might be a promising therapeutic strategy in treating AD. Recently, dynamin-related protein 1 (Drp1), a mitochondrial fission protein, has gained attention due to its interactions with A? and hyperphosphorylated Tau, altering mitochondrial morphology, dynamics, and bioenergetics. These interactions affect ATP production in mitochondria. A reduction in Drp1 GTPase activity protects against neurodegeneration in AD models. This article provides a comprehensive overview of Drp1's involvement in oxidative damage, apoptosis, mitophagy, and axonal transport of mitochondria. We also highlighted the interaction of Drp1 with A? and Tau, which may contribute to AD progression. In conclusion, targeting Drp1 could be a potential therapeutic approach for preventing AD pathology. � 2023Item Oncogenic metabolic reprogramming in breast cancer: focus on signaling pathways and mitochondrial genes(Springer, 2023-05-11T00:00:00) Malayil, Rhuthuparna; Chhichholiya, Yogita; Vasudeva, Kanika; Singh, Harsh Vikram; Singh, Tashvinder; Singh, Sandeep; Munshi, AnjanaOncogenic metabolic reprogramming impacts the abundance of key metabolites that regulate signaling and epigenetics. Metabolic vulnerability in the cancer cell is evident from the Warburg effect. The research on metabolism in the progression and survival of breast cancer (BC) is under focus. Oncogenic signal activation and loss of�tumor suppressor are important regulators of tumor cell metabolism. Several intrinsic and extrinsic factors contribute to metabolic reprogramming. The molecular mechanisms underpinning metabolic reprogramming in BC are extensive and only partially defined. Various signaling pathways involved in the metabolism play a significant role in the modulation of BC. Notably, PI3K/AKT/mTOR pathway, lactate-ERK/STAT3 signaling, loss of the tumor suppressor Ras, Myc, oxidative stress, activation of the cellular hypoxic response and acidosis contribute to different metabolic reprogramming phenotypes linked to enhanced glycolysis. The alterations in mitochondrial genes have also been elaborated upon along with their functional implications. The outcome of these active research areas might contribute to the development of novel therapeutic interventions and the remodeling of known�drugs. � 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.Item Let-7a induces metabolic reprogramming in breast cancer cells via targeting mitochondrial encoded ND4(BioMed Central Ltd, 2021-11-27T00:00:00) Sharma, Praveen; Sharma, Vibhuti; Ahluwalia, Tarunveer Singh; Dogra, Nilambra; Kumar, Santosh; Singh, SandeepBackground and objectives: MicroRNA (miRNA) that translocate from the nucleus to mitochondria are referred to as mitochondrial microRNA (mitomiR). Albeit mitomiRs have been shown to modulate gene expression, their functional impact within mitochondria is unknown. The main objective of this study is to investigate whether the mitochondrial genome is regulated by miR present inside the mitochondria. Methods and results: Here, we report mitomiR let-7a regulates mitochondrial transcription in breast cancer cells and reprogram the metabolism accordingly. These effects were mediated through the interaction of let-7a with mtDNA, as studied by RNA pull-down assays, altering the activity of Complex I in a cell line-specific manner. Our study, for the first time, identifies the role of mitomiR (let-7a) in regulating the mitochondrial genome by transcriptional repression and its contribution to regulating mitochondrial metabolism of breast cancer cells. Conclusion: These findings uncover a novel mechanism by which mitomiR regulates mitochondrial transcription. � 2021, The Author(s).Item Small regulatory molecules acting big in cancer: Potential role of mito-miRs in cancer(Bentham Science Publishers, 2019) Sharma P.; Bharat; Dogra N.; Singh S.MicroRNAs [miRNAs] are short, non-coding, single stranded RNA molecules regulating gene expression of their targets at the posttranscriptional level by either degrading mRNA or by inhibiting translation. Previously, miRNAs have been reported to be present inside the mitochondria and these miRNAs have been termed as mito-miRs. Origin of these mito-miRs may either be from mitochondrial genome or import from nucleus. The second class of mito-miRs makes it important to unravel the involvement of miRNAs in crosstalk between nucleus and mitochondria. Since miRNAs are involved in various physiological processes, their deregulation is often associated with disease progression, including cancer. The current review focuses on the involvement of miRNAs in different mitochondrial mediated processes. It also highlights the importance of exploring the interaction of miRNAs with mitochondrial genome, which may lead to the development of small regulatory RNA based therapeutic options.Item Potential Mitochondrial-Specific Function Of piRNAs(Central University of Punjab, 2018) Paul, Shouvik; Singh, SandeepPiwi-interacting RNAs (piRNAs) are (26-31 nt) small noncoding RNAs processed from their longer precursor transcripts with the help of Piwi proteins. There are more than 30,000 piRNA genes present in the human genome which now turns out to be emerging player in both homeostasis and diseases. Localization of piRNA and PIWI in the repeat region of the mammalian nuclear genome in germ cells has been reported, although localization and potential functional role of piRNA in the mammalian mitochondrial genome are largely unknown. We have taken 111 piRNA sequences found in the MCF-7 mitochondrial genome, which is obtained by NGS analysis for alignment study. Resulting piRNA have been aligned with DQ112870 North American Homo sapiens mitochondrion genome for studying post- transcriptional roles of piRNA.