Cucurbitacin: As a candidate against Cytokine Storm in Severe COVID-19 Infection

The severity of SARS-CoV-2 infection is marked by elevated cytokines and chemokines levels like interleukin 6 (IL-6), interferon-gamma (IFN-γ), tumour necrosis factor (TNF), IL-2 and monocyte chemotactic protein 1. This hyperactive pro-in lammatory response identi ied as the Cytokine Storm (CS) complicates the disease leading to extensive damage of the host tissue, Acute RespiratoryDistress Syndrome (ARDS), which further result inmultiple organ failures. CS is very critical for the disease progression and is responsible for high death rate in an infected patient. Accordingly, various therapeutic modalities are currently investigated for their effectiveness in subsiding the hyper-in lammatory syndrome either using immunomodulatory agents or anti-in lammatory therapies. Phytochemical (herbal) compounds are demonstrated to possess anti-in lammatory, antimicrobial or antioxidants properties. Various signalling pathways and molecules exacerbating the in lammation state complicate the pathophysiology of COVID-19. Cucurbitacins are tetracyclic bioactive phytochemical compounds found in cucurbitaceous plants. More than 100 species of cucurbitacins possess various pharmacological properties, including anti-in lammatory. Cucurbitacin E and R have shown to be down-regulated the expression of TNF alpha and IL-1beta. Cucurbitacin II B also alleviates the expression of TNF-α as well as IFN-γ and IL-6. Cucurbitacin1 has the potential to reduce the oxidative stress-induced with the reactive oxygen species, and thus prevents cardiovascular damage. Thus cucurbitacins may be pharmacologically manipulated to establish its clinical ef icacy in minimizing the disease state and improvising the prognosis of the patients.

complicates the disease leading to extensive damage of the host tissue, Acute Respiratory Distress Syndrome (ARDS), which further result in multiple organ failures. CS is very critical for the disease progression and is responsible for high death rate in an infected patient. Accordingly, various therapeutic modalities are currently investigated for their effectiveness in subsiding the hyper-in lammatory syndrome either using immunomodulatory agents or anti-in lammatory therapies. Phytochemical (herbal) compounds are demonstrated to possess anti-in lammatory, antimicrobial or antioxidants properties. Various signalling pathways and molecules exacerbating the in lammation state complicate the pathophysiology of COVID-19. Cucurbitacins are tetracyclic bioactive phytochemical compounds found in cucurbitaceous plants. More than 100 species of cucurbitacins possess various pharmacological properties, including anti-in lammatory. Cucurbitacin E and R have shown to be down-regulated the expression of TNF alpha and IL-1beta. Cucurbitacin II B also alleviates the expression of TNF-α as well as IFN-γ and IL-6. Cucurbitacin1 has the potential to reduce the oxidative stress-induced with the reactive oxygen species, and thus prevents cardiovascular damage. Thus cucurbitacins may be pharmacologically manipulated to establish its clinical ef icacy in minimizing the disease state and improvising the prognosis of the patients.

INTRODUCTION
The COVID-19 pandemic commenced across the globe due to the spread of positive-sense ssRNA novel coronavirus 2019 (also known as SARS-CoV-2). The disease severity is marked by elevated cytokines and chemokines levels like interleukin 6 (IL-6), interferon-gamma (IFN-γ), tumour necrosis factor (TNF), IL-2 and monocyte chemotactic protein 1 etc. Such hyperactive pro-in lammatory response is identi ied as the Cytokine Storm (CS) that complicates the disease leading to extensive damage of the host tissue, Acute Respiratory Distress Syndrome (ARDS) and may result in mul-tiple organ failures. CS is very critical for the disease progression and is responsible for high death rate in an infected patient (Zhou et al., 2020). Accordingly, various therapeutic modalities are currently investigated for their effectiveness in subsiding the hyper-in lammatory syndrome either using immunomodulatory agents or antiin lammatory therapies. Phytochemical (herbal) compounds are demonstrated to possess antiin lammatory, antimicrobial or antioxidants properties. Cucurbitacins are tetracyclic bioactive phytochemical compounds found in cucurbitaceous plants. More than 100 species of cucurbitacins possess various pharmacological properties, including anti-in lammatory (Aeri et al., 2015).
SARS-CoV-2 binding to toll likes receptors upregulates IL-1 beta by formation and activation of pro-IL-1 and in lammasome respectively. Hypersecretion of IL-1beta aggravates the in lammation in the lung inducing ibrosis in the pulmonary tissue (Conti et al., 2020). In an in-vitro study cucurbitacin E down-regulated the expression of TNF alpha and IL-1beta by repressing the nuclear factorkappa B (NF-kB) translocation. This inhibition of pro-in lammatory cytokines may be due to disruption in the actin cytoskeleton of the cells inhibiting NF-kB translocation (Qiao et al., 2013). In a rat model of adjunct arthritis, cucurbitacin R also suppressed TNF alpha and IL-1beta via suppression of the signal transducer and activator of transcription 3 (STAT3) signalling (Escandell et al., 2007).
Various signalling pathways and molecules exacerbating the in lammation state complicate the pathophysiology of COVID-19. Cucurbitacins may be pharmacologically manipulated to establish its clinical ef icacy in minimizing the disease state and improvising the prognosis of the patients. However, the effect of these compounds on the human body and its metabolism needs further investigations. Besides, research experts in phytochemical compounds may explore the antiviral properties of cucurbitacins.

CONCLUSIONS
The interleukin 6 (IL-6), interferon-gamma (IFNγ), tumour necrosis factor (TNF), IL-2 and monocyte chemotactic protein 1 are few of the cytokines and chemokines, known to be elevated in SARS-CoV-2 infection. Various therapeutic modalities using phytochemical compounds are currently investigated for their effectiveness in subsiding the hyperin lammatory syndrome. Cucurbitacin E and R have shown to be down-regulated the expression of TNF alpha and IL-1beta. Cucurbitacin II B also alleviates the expression of TNF-α as well as IFN-γ and IL-6. Cucurbitacin1 has the potential to reduce the oxidative stress-induced with the reactive oxygen species, and thus prevents cardiovascular damage. Thus cucurbitacins may be pharmacologically manipulated to establish its clinical ef icacy in minimizing the disease state and improvising the prognosis of the patients.