Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, which has been a topic of major concern for global human health. The challenge to restrain the COVID-19 pandemic is further compounded by the emergence of several SARS-CoV-2 variants viz. B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta), which show increased transmissibility and resistance towards vaccines and therapies. Importantly, there is convincing evidence of increased susceptibility to SARS-CoV-2 infection among individuals with dysregulated immune response and comorbidities. Herein, we provide a comprehensive perspective regarding vulnerability of SARS-CoV-2 infection in patients with underlying medical comorbidities. We discuss ongoing vaccine (mRNA, protein-based, viral vector-based, etc.) and therapeutic (monoclonal antibodies, small molecules, plasma therapy, etc.) modalities designed to curb the COVID-19 pandemic. We also discuss in detail, the challenges posed by different SARS-CoV-2 variants of concern (VOC) identified across the globe and their effects on therapeutic and prophylactic interventions.

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Tumor Necrosis Factor-α canonically induces the activation of NF-κB and associated gene product cellular FLICE-like inhibitory protein (cFLIP L ) to promote cell survival. Previously, we demonstrated that ectopic expression of the Fas associated death domain (FADD) diminishes the expression of cFLIP L and transduces caspases-8 mediated apoptosis, independent of FasL stimulation in HEK 293T cells. However, the underlying molecular mechanism of FADD mediated ablation of cFLIP and NF-κB signaling to determining the fate of cell death or survival remains elusive. Here, we explored a novel molecular mechanism of FADD mediated apoptotic cell death that was directed by ubiquitination of cFLIP L and inhibition of NF-κB activation, independent of TNF-α stimulation. We found that induced expression of FADD firmly interacts with procaspase-8 and precludes cFLIP L to from the death inducing signaling complex (DISC). In addition, FADD negatively regulates cellular inhibitor of apoptosis protein 2 (cIAP2) and Bcl-2. Furthermore, FADD restrains cIAP2 expression and interacts with RIP1 and procaspase-8 to accomplish apoptotic cell death signaling. Interestingly, FADD was also found to promote JNK1 mediated activation of E3 ubiquitin ligase ITCH to degrade cFLIP L that may lead to commencement of apoptosis. Thus, FADD is an important regulator for determining the fate of cell death or survival.Fas associated death domain (FADD) is a pivotal signaling component of death receptor (DR) mediated apoptosis. DRs such as Fas (CD95/Apo) and tumor necrosis factor receptor 1 (TNFR1) (p55/CD120a), belongs to the TNF receptor super family that contain cytoplasmic death domain (DD) to execute downstream signal transduction 1 . Upon binding of ligand to the cell surface receptors, the DD of cell surface receptor homophilically interacts with the DD of FADD and induces oligomerization of DED (death effector domain) of FADD with apical caspases such as, procaspase 8/10 to form a death-inducing signaling complex (DISC) 2 . In the downstream, DISC facilitates processing and catalytic activation of caspases-8/10 to transduces downstream signaling of apoptosis 3 . However, the catalytic activation of caspase-8/10 has been negatively regulated by the anti-apoptotic protein Cellular Flice like inhibitory protein (cFLIP) to abrogate apoptotic instigation 4 . Although FADD is a multifunctional protein and its Fas ligand mediated proapoptotic function has been well studied 5,6 . However, the cellular dynamics of FADD and cFLIP in the regulation of cell death and survival by TNFR signaling remains elusive. TNF receptor (TNFR) signaling elicits both non-apoptotic and apoptotic response by the formation of two sequential complexes depending upon the stimulation of the TNF-α . The components of complex I constituted with TRADD, TRAF2, cIAPs and RIP1 activates NF-κ B signaling for promoting cell survival. However, the subsequent dissociation of RIP1 from complex I and association with FADD and procaspase-8 initiates formation of pro-apoptotic complex II that...

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic which has been a topic of major concern to global human health. The challenge to restrain the COVID-19 pandemic is further compounded by the emergence of several SARS-CoV-2 variants viz. B.1.1.7, B.1.351, P1 and, B.1.617., which show in-creased transmissibility and resistance towards vaccines and therapies. Importantly, the likelihood of susceptibility to SARS-CoV-2 infection among individuals with dysregulated immune response or comorbidities needs greater attention. Herein, we provide a comprehensive perspective regarding ongoing vaccine (mRNA, protein-based, viral vector based etc.) and therapeutic (mono-clonal antibodies, small molecules, plasma therapy, etc.) modalities designed to curb the COVID-19 pandemic. We also discuss in detail the challenges posed by different SARS-CoV-2 variants of concern (VOC) identified across the globe and their effects on therapeutic and prophylactic interventions.

An alteration in susceptibility to apoptosis not only contributes to promotion of malignancy but can also enhance drug resistance in response to anticancer therapies. HA14-1 is a small molecule which has the potential of inducing apoptosis in cancerous cells. HA14-1 manifests an antagonistic effect on antiapoptotic protein Bcl-2 and consequently induces cell death in various cancerous cell lines. However, it is also known to generate ROS and toxic response in the cells upon decomposition. Elevated level of ROS is responsible for oxidative stress and other pathological consequences, if not metabolized properly. The aim of the present study was to examine the synergistic effect of curcumin in promoting apoptosis by regulating the HA14-1 mediated ROS generation, toxicity, oxidative stress, and autophagy in human embryonic kidney cells. Our study demonstrates that curcumin efficiently scavenges HA14-1 mediated generation of ROS and toxic response resulting in augmentation of apoptosis in HEK 293T cells by promoting inhibition of antiapoptotic proteins and process of autophagy. Thus curcumin along with HA14-1 regulates cell proliferation by disruption of the antiapoptotic signaling mechanism. This approach could serve as a promising strategy for therapeutic potential to overcome their adverse effects.