Rajawat, Jyotika

Bone is a dynamic organ maintained by tightly regulated mechanisms. With old age, bone homeostasis, which is maintained by an intricate balance between bone formation and bone resorption, undergoes deregulation. Oxidative stress-induced DNA damage, cellular apoptosis, and cellular senescence are all responsible for this tissue dysfunction and the imbalance in the bone homeostasis. These cellular mechanisms have become a target for therapeutics to treat age-related osteoporosis. Genetic mouse models have shown the importance of senescent cell clearance in alleviating age-related osteoporosis. Furthermore, we and others have shown that targeting cellular senescence pharmacologically was an effective tool to alleviate age- and radiation-induced osteoporosis. Senescent cells also have an altered secretome known as the senescence associated secretory phenotype (SASP), which may have autocrine, paracrine, or endocrine function. The current review discusses the current and potential pathways which lead to a senescence profile in an aged skeleton and how bone homeostasis is affected during age-related osteoporosis. The review has also discussed existing therapeutics for the treatment of osteoporosis and rationalizes for novel therapeutic options based on cellular senescence and the SASP as an underlying pathogenesis of an aging bone.

Background: Activation of Poly (ADP-ribose) polymerase 1 (PARP1), a post-translational modifying enzyme, has been shown to be involved with several inflammatory and viral diseases. Objective: The goal of this review is to highlight the mechanisms underlying PARP1 activation during viral or infectious pathogenesis and to assess potential possibilities of using PARP1 inhibitors as a therapeutic countering of SARS-CoV-2 virus. Methods: An extensive bibliographic search was done using Pubmed, Mendeley and google scholar with key words. Pre-prints are reported with potential caveats and studies without experimental data were excluded. Results: Covid-19, a global pandemic; is associated with systemic surge of inflammatory cytokines resulting in severe inflammation of the lung, heart dysfunction, ischemia, and stroke. PARP1 regulates expression of NFkB and downstream cytokine production and its inhibition is known to attenuate the expression of inflammatory cytokines. PARP1 and other PARP family members regulate viral infection, replication, and virulence. The literature clearly suggests that PARP1 plays an important role in host-pathogen interactions and pathogenesis, with pre-clinical and in vitro studies supporting the idea that PARP1 inhibition may negatively affect viability of several viruses including the replication of the SARS-CoV and SARS-CoV-2 virus. Conclusion: The current review discusses mechanisms of PARP1 activation during viral infection, inflammatory diseases, cytokine expression and possibility of PARP1 in regulating cytokine storm and hyper-inflammation seen with Covid-19. Additionally, in vitro studies showing the negative regulation of SARS-CoV-2 virus replication by PARP inhibitors indicates a potential therapeutic role of PARP inhibitors for Covid-19 or its variants.

Poly (ADP-ribose) polymerase 1 (PARP1) is a post-translational modifying enzyme and is also known to act as transcription factor and co-activator. PARP1 has been shown to be involved with diseases resulting in increased inflammation and several viral diseases have also been associated with PARP1 activation. PARP1 facilitates influenza A virus entry in host cells by degrading interferon receptor type I. PARP1 regulates expression of NFkB and downstream cytokine production and its inhibition is known to attenuate the expression of inflammatory cytokines. Thus, PARP1 plays an important role in host-pathogen interactions and pathogenesis. Moreover, pre-clinical and in vitro studies have shown that PARP1 inhibition may affect viability of several viruses including affecting replication of the SARS-CoV virus, a distant relative of the SARS-CoV-2 virus, the one which caused the SARS epidemic of 2002. Covid-19 has been declared a global pandemic; with symptoms of the disease now not limited to respiratory distress alone. Severe inflammation is observed in the lungs leading to a surge of cytokine release systemically, affecting heart function, ischemia and stroke. Inflammatory cytokines which are associated with severe comorbidities and mortalities due to chronic diseases are being upregulated in an acute fashion. There is no immediate treatment, and only palliative care is being provided. The current review will discuss mechanisms of PARP1 activation during viral infection, inflammatory diseases, cytokine expression and possibility of PARP1 in regulating cytokine storm and hyper-inflammation seen with Covid-19.

Poly (ADP-ribose) polymerase 1 (PARP1) is a post-translational modifying enzyme and is also known to act as transcription factor and co-activator. PARP1 has been shown to be involved with diseases resulting in increased inflammation and several viral diseases have also been associated with PARP1 activation. PARP1 facilitates influenza A virus entry in host cells by degrading interferon receptor type I. PARP1 regulates expression of NFkB and downstream cytokine production and its inhibition is known to attenuate the expression of inflammatory cytokines. Thus, PARP1 plays an important role in host-pathogen interactions and pathogenesis. Moreover, pre-clinical and in vitro studies have shown that PARP1 inhibition may affect viability of several viruses including affecting replication of the SARS-CoV virus, a distant relative of the SARS-CoV-2 virus, the one which caused the SARS epidemic of 2002. Covid-19 has been declared a global pandemic; with symptoms of the disease now not limited to respiratory distress alone. Severe inflammation is observed in the lungs leading to a surge of cytokine release systemically, affecting heart function, ischemia and stroke. Inflammatory cytokines which are associated with severe comorbidities and mortalities due to chronic diseases are being upregulated in an acute fashion. There is no immediate treatment, and only palliative care is being provided. The current review will discuss mechanisms of PARP1 activation during viral infection, inflammatory diseases, cytokine expression and possibility of PARP1 in regulating cytokine storm and hyper-inflammation seen with Covid-19.