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.

Dictyostelium discoideum, a unicellular eukaryote, exhibits multicellularity upon nutrient starvation and is a good model system for developmental studies, and for the study of various signal transduction pathways. Reactive oxygen species at low doses act as signaling molecules; however, at high doses they are known to cause DNA damage that results in the activation of poly(ADP-ribose) polymerase (PARP). We have earlier reported the high resistance of the unicellular stage of D. discoideum to oxidative stress, and we now show the response of this organism to oxidative stress and the role of PARP during development. We used hydroxylamine (HA) to induce in situ generation of H₂O₂ and monitored the effect of benzamide, a PARP inhibitor, on oxidative stress-induced changes in D. discoideum development. Interestingly, oxidative stress resulted in PARP activation within 5 min that was inhibited by benzamide. Oxidative stress-induced delay in developmental pattern was also partially restored by benzamide. We studied the long-term effects of PARP inhibition under oxidative stress, and our results demonstrated that spores formed under HA stress exhibited significant delay in germination in comparison to benzamide-pretreated HA-stressed cells. However, second-generation cells showed normal development, signifying that PARP inhibition has no deleterious effect on D. discoideum development under oxidative stress.

PARP Inhibitors in Cancer Therapy: Magic Bullets but Moving Targets

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.