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Inflammatory diseases have become increasingly prevalent throughout the world. Coronavirus disease 2019 (COVID‐19), which has recently become pandemic, also exhibits hyperinflammation and cytokine release syndrome. To address inflammation‐related diseases, numerous molecular targets have been explored in preclinical studies and clinical trials. Among them, the protease‐activated receptors (PARs) that belong to G protein‐coupled receptors are one of the most popular classes of drug targets, participating in inflammatory signalling and diseases. PARs activation can trigger downstream intracellular signalling to modulate a variety of inflammatory responses in multiple systems, including nervous, respiratory, digestive, circulatory, urinary and immune systems. Importantly, there are the Yin‐Yang effects, comprising anti‐ and pro‐inflammatory roles, of PARs activation in different types of inflammations, and these are context‐dependent. Alternatively, it was recently revealed that PARs not only modulate inflammatory‐related tumour progression, but also participate in inflammatory cytokine release related to COVID‐19 via direct interaction with severe acute respiratory syndrome coronavirus 2 protein, suggesting that PARs also participate in other diseases via inflammatory responses. In this review, we renew and discuss the findings of PARs as molecular targets for treating inflammatory diseases, highlighting the novel roles of PARs and facilitating a better understanding of their designated values in the specific inflammatory environment. [ABSTRACT FROM AUTHOR]

Older age and underlying conditions such as diabetes/obesity or immunosuppression are leading host risk factors for developing severe complications from COVID‐19 infection. The pathogenesis of COVID‐19‐related cytokine storm, tissue damage, and fibrosis may be interconnected with fundamental aging processes, including dysregulated immune responses and cellular senescence. Here, we examined effects of key cytokines linked to cellular senescence on expression of SARS‐CoV‐2 viral entry receptors. We found exposure of human umbilical vein endothelial cells (HUVECs) to the inflammatory cytokines, TNF‐α + IFN‐γ or a cocktail of TNF‐α + IFN‐γ + IL‐6, increased expression of ACE2/DPP4, accentuated the pro‐inflammatory senescence‐associated secretory phenotype (SASP), and decreased cellular proliferative capacity, consistent with progression towards a cellular senescence‐like state. IL‐6 by itself failed to induce substantial effects on viral entry receptors or SASP‐related genes, while synergy between TNF‐α and IFN‐γ initiated a positive feedback loop via hyper‐activation of the JAK/STAT1 pathway, causing SASP amplification. Breaking the interactive loop between senescence and cytokine secretion with JAK inhibitor ruxolitinib or antiviral drug remdesivir prevented hyper‐inflammation, normalized SARS‐CoV‐2 entry receptor expression, and restored HUVECs proliferative capacity. This loop appears to underlie cytokine‐mediated viral entry receptor activation and links with senescence and hyper‐inflammation. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) continues to ravage communities across the world. Despite its primary effect on the respiratory system, the virus does not solely impact those with underlying lung conditions as initially predicted. Indeed, prognosis is worsened (often fatal) in patients with pre‐existing hyperinflammatory responses (e.g., hypertension, obesity and diabetes), yet the mechanisms by which this occurs are unknown. A number of psychological conditions are associated with inflammation, suggesting that these may also be significant risk factors for negative outcomes of COVID‐19. In this review, we evaluate preclinical and clinical literature suggesting that chronic stress‐induced hyperinflammation interacts synergistically with COVID‐19‐related inflammation, contributing to a potentially fatal cytokine storm syndrome. In particular, we hypothesize that both chronic stress and COVID‐19‐related hyperinflammation are a product of glucocorticoid insufficiency. We discuss the devastating effects of SARS‐CoV‐2 on structural and functional aspects of the biological stress response and how these induce exaggerated inflammatory responses, particularly interleukin (IL)‐6 hypersecretion. We postulate that chronic stress should be considered a significant risk factor for adverse COVID‐19‐related health outcomes, given overlapping peripheral and central immune dysregulation in both conditions. We conclude by discussing how people with a history of chronic stress could mitigate their risk for COVID‐19 complications, identifying specific strategies that can be implemented during self‐isolation. [ABSTRACT FROM AUTHOR]

Curcumin is the effective ingredient of turmeric, sometimes used as a painkiller in traditional medicine. It has extensive biological properties such as anti‐inflammatory and antioxidant activities. SARS‐CoV‐2 is a betacoronavirus developing severe pneumonitis. Inflammasome is one of the most important components of innate immunity, which exacerbates inflammation by increasing IL‐1β and IL‐18 production. Studies on viral infections have shown overactivity of inflammasome and thus the occurrence of destructive and systemic inflammation in patients. NLRP3 inflammasome has been shown to play a key role in the pathogenesis of viral diseases. The proliferation of SARS‐CoV‐2 in a wide range of cells can be combined with numerous observations of direct and indirect activation of inflammasome by other coronaviruses. Activation of the inflammasome is likely to be involved in the formation of cytokine storm. Curcumin regulates several molecules in the intracellular signal transduction pathways involved in inflammation, including IBB, NF‐kBERK1,2, AP‐1, TGF‐β, TXNIP, STAT3, PPARγ, JAK2‐STAT3, NLRP3, p38MAPK, Nrf2, Notch‐1, AMPK, TLR‐4 and MyD‐88. Due to anti‐inflammatory and anti‐inflammasome properties without any special side effects, curcumin can potentially play a role in the treatment of COVID‐19 infection along with other drug regimens. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is uncontrollably spread all over the world. The host immune responses strongly try to confront it with all the potential cells and cytokines. With chronically condition of SARS‐CoV‐2, natural killer cells and T cells become exhausted and decreasing their count leads to lymphopenia. Inability to eradicate the infected organ makes hyperinitiation of the immune system, which releases the excessive inflammatory cytokines to compensate the exhausted one as well as the low lymphocytes counts; it consequently leads to the cytokine storm syndrome. These mechanisms and the potential therapeutic targeting are discussed in this paper. [ABSTRACT FROM AUTHOR]