Browsing by Author "Luciano Saso"

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Alpha-synuclein interaction with mitochondria is the final mechanism of ferroptotic death induced by erastin in SH-SY5Y cells
(Taylor and Francis Ltd., 2024) Upasana Ganguly; Sukhpal Singh; Aritri Bir; Arindam Ghosh; Sankha Shubhra Chakrabarti; Reena V. Saini; Luciano Saso; Marco Bisaglia; Sasanka Chakrabarti
Ferroptosis has been characterized as a form of iron-dependent regulated cell death accompanied by an accumulation of reactive oxygen species and lipid oxidation products along with typical morphological alterations in mitochondria. Ferroptosis is activated by diverse triggers and inhibited by ferrostatin-1 and liproxstatin-1, apart from iron chelators and several antioxidants, and the process is implicated in multiple pathological conditions. There are, however, certain ambiguities about ferroptosis, especially regarding the final executioner of cell death subsequent to the accumulation of ROS. This study uses a typical inducer of ferroptosis such as erastin on SH-SY5Y cells, and shows clearly that ferroptotic death of cells is accompanied by the loss of mitochondrial membrane potential and intracellular ATP content along with an accumulation of oxidative stress markers. All these are prevented by ferrostatin-1 and liproxstatin-1. Additionally, cyclosporine A prevents mitochondrial alterations and cell death induced by erastin implying the crucial role of mitochondrial permeability transition pore (mPTP) activation in ferroptotic death. Furthermore, an accumulation of α-synuclein occurs during erastin induced ferroptosis which can be inhibited by ferrostatin-1 and liproxstatin-1. When the knock-down of α-synuclein expression is performed by specific siRNA treatment of SH-SY5Y cells, the mitochondrial impairment and ferroptotic death of the cells induced by erastin are markedly prevented. Thus, α-synuclein through the involvement of mPTP appears to be the key executioner protein of ferroptosis induced by erastin, but it needs to be verified if it is a generalized mechanism of ferroptosis by using other inducers and cell lines. © 2024 Informa UK Limited, trading as Taylor & Francis Group.
Oxidative Stress, Neuroinflammation, and NADPH Oxidase: Implications in the Pathogenesis and Treatment of Alzheimer's Disease
(Hindawi Limited, 2021) Upasana Ganguly; Upinder Kaur; Sankha Shubhra Chakrabarti; Priyanka Sharma; Bimal Kumar Agrawal; Luciano Saso; Sasanka Chakrabarti
NADPH oxidase as an important source of intracellular reactive oxygen species (ROS) has gained enormous importance over the years, and the detailed structures of all the isoenzymes of the NADPH oxidase family and their regulation have been well explored. The enzyme has been implicated in a variety of diseases including neurodegenerative diseases. The present brief review examines the body of evidence that links NADPH oxidase with the genesis and progression of Alzheimer's disease (AD). In short, evidence suggests that microglial activation and inflammatory response in the AD brain is associated with increased production of ROS by microglial NADPH oxidase. Along with other inflammatory mediators, ROS take part in neuronal degeneration and enhance the microglial activation process. The review also evaluates the current state of NADPH oxidase inhibitors as potential disease-modifying agents for AD. © 2021 Upasana Ganguly et al.
Role of oxidative stress in the pathogenesis of metabolic syndrome
(Elsevier, 2023) Sankha Shubhra Chakrabarti; Luciano Saso; Sapna Bala; Sarmistha Saha; Elisabetta Profumo; Brigitta Buttari; Sasanka Chakrabarti
Metabolic syndrome is a composite of the inter-related entities obesity, hypertension, insulin resistance, and dyslipidaemia which presents differently in different people. While risk factors of metabolic syndrome include over-nutrition and lack of physical activity, the interaction of these with genetic risk traits and individual phenotypic variations is responsible for the development of clinical manifestations. Mitochondrial dysfunction and oxidative stress have been reported widely to be a prominent part of the pathogenetic cascade of metabolic syndrome. In this chapter, we would discuss the entity of oxidative stress, the role it plays in the pathogenesis of metabolic syndrome, and also the relationship between oxidative stress and metabolic syndrome. Prominent tissue or organ-specific effects of oxidative stress with emphasis on the adipose tissue, skeletal muscle, liver, and the cardiovascular and endocrine systems would be described. We would also discuss the interplay between oxidative stress, inflammation, and insulin resistance and briefly about circulating oxidative stress markers and probable therapeutic strategies directed against oxidative stress which may be of benefit in metabolic syndrome. © 2024 Elsevier Inc. All rights reserved.
Should ACE2 be given a chance in COVID-19 therapeutics: A semi-systematic review of strategies enhancing ACE2
(Elsevier B.V., 2020) Upinder Kaur; Kumudini Acharya; Ritwick Mondal; Amit Singh; Luciano Saso; Sasanka Chakrabarti; Sankha Shubhra Chakrabarti
The severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) has resulted in almost 28 million cases of COVID-19 (Corona virus disease-2019) and more than 900000 deaths worldwide since December 2019. In the absence of effective antiviral therapy and vaccine, treatment of COVID-19 is largely symptomatic. By making use of its spike (S) protein, the virus binds to its primary human cell receptor, angiotensin converting enzyme 2 (ACE2) which is present in the pulmonary epithelial cells as well as other organs. SARS-CoV-2 may cause a downregulation of ACE2. ACE2 plays a protective role in the pulmonary system through its Mas-receptor and alamandine-MrgD-TGR7 pathways. Loss of this protective effect could be a major component of COVID-19 pathogenesis. An attractive strategy in SARS-CoV-2 therapeutics would be to augment ACE2 either directly by supplementation or indirectly through drugs which increase its levels or stimulate its downstream players. In this semi-systematic review, we have analysed the pathophysiological interplay between ACE and ACE2 in the cardiopulmonary system, the modulation of these two proteins by SARS-CoV-2, and potential therapeutic avenues targeting ACE-Ang II and ACE2-Ang (1–7) axes, that can be utilized against COVID-19 disease progression. © 2020 Elsevier B.V.
Targeting host cell proteases to prevent sars-cov-2 invasion
(Bentham Science Publishers, 2021) Upinder Kaur; Sankha Shubhra Chakrabarti; Bisweswar Ojha; Bhairav Kumar Pathak; Amit Singh; Luciano Saso; Sasanka Chakrabarti
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread worldwide and caused widespread devastation. In the absence of definitive therapy, symptomatic management remains the standard of care. Repurposing of many existing drugs, including several anti-viral drugs, is being attempted to tackle the COVID-19 pandemic. However, most of them have failed to show significant benefit in clinical trials. An attractive approach may be to target host proteases in-volved in SARS-CoV-2 pathogenesis. The priming of the spike (S) protein of the virus by proteolytic cleavage by the transmembrane serine protease-2 (TMPRSS2) is necessary for the fusion of the virus to the host cell after it binds to its receptor angiotensin converting enzyme-2 (ACE2). There are other proteases with varying spatiotemporal locations that may be important for viral entry and subsequent replication inside the cells, and these include trypsin, furin and cathepsins. In this report, we have discussed the tentative therapeutic role of inhibitors of TMPRSS2, cathepsin, trypsin, furin, plasmin, factor X and elastase in infection caused by SARS-CoV-2. Both available evidence, as well as hypotheses, are discussed, with emphasis on drugs which are approved for other indications such as bromhexine, ammonium chloride, nafamostat, camostat, tranexamic acid, epsilon amino-caproic acid, chloroquine, ulinastatin, aprotinin and anticoagulant drugs. Simultane-ously, novel compounds being tested and problems with using these agents are also discussed. © 2021 Bentham Science Publishers.