The ongoing COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a globally leading public health concern over the past two years. Despite the development and administration of multiple vaccines, the mutation of newer strains and challenges to universal immunity has shifted the focus to the lack of efficacious drugs for therapeutic intervention for the disease. As with SARS-CoV, MERS-CoV, and other non-respiratory viruses, flavonoids present themselves as a promising therapeutic intervention given their success in silico, in vitro, in vivo, and more recently, in clinical studies. This review focuses on data from in vitro studies analyzing the effects of flavonoids on various key SARS-CoV-2 targets and presents an analysis of the structure-activity relationships for the same. From 27 primary papers, over 69 flavonoids were investigated for their activities against various SARS-CoV-2 targets, ranging from the promising 3C-like protease (3CLpro) to the less explored nucleocapsid (N) protein; the most promising were quercetin and myricetin derivatives, baicalein, baicalin, EGCG, and tannic acid. We further review promising in silico studies featuring activities of flavonoids against SARS-CoV-2 and list ongoing clinical studies involving the therapeutic potential of flavonoid-rich extracts in combination with synthetic drugs or other polyphenols and suggest prospects for the future of flavonoids against SARS-CoV-2.

Promising Antiviral Activities of Natural Flavonoids against SARS-CoV-2 Targets: Systematic Review.

Morchella esculenta (M. esculenta) is a delicious edible mushroom prized for its special flavor and strong health promoting abilities. Several bioactive ingredients including polysaccharides, polyphenolic compounds, proteins, and protein hydrolysates all contribute to the biological activities of M. esculenta. Different polysaccharides could be extracted and purified depending on the extraction methods and M. esculenta studied. Monosaccharide composition of M. esculenta polysaccharides (MEP) generally includes mannose, galactose, and glucose, etc. MEP possess multiple bioactivities such as antioxidant, anti-inflammation, immunoregulation, hypoglycemic activity, atherosclerosis prevention and antitumor ability. Other components like polyphenols, protein hydrolysates, and several crude extracts are also reported with strong bioactivities. In terms of potential applications of M. esculenta and its metabolites as nutritional supplements and drug supplements, this review aims to comprehensively summarize the structural characteristics, biological activities, research progress, and research trends of the active ingredients produced by M. esculenta. Among the various biological activities, the substances extracted from both natural collected and submerged fermented M. esculenta are promising for antioxidants, immunomodulation, anti-cancer and anti-inflammatory applications. However, further researches on the extraction conditions and chemical structure of bioactive compounds produced by M. esculenta still need investigations.

Recent Advances on Bioactive Ingredients of Morchella esculenta.

Macrophage stimulation by pathogen-associated molecular patterns (PAMPs) like lipopolysaccharide (LPS) or lipoteichoic acid (LTA) drives a proinflammatory phenotype and induces a metabolic reprogramming to sustain the cell’s function. Nevertheless, the relationship between metabolic shifts and gene expression remains poorly explored. In this context, the metabolic enzyme ATP citrate lyase (ACLY), the producer of citrate-derived acetyl-coenzyme A (CoA), plays a critical role in supporting a proinflammatory response. Through immunocytochemistry and cytosol–nucleus fractionation, we found a short-term ACLY nuclear translocation. Protein immunoprecipitation unveiled the role of nuclear ACLY in NF-κB acetylation and in turn its full activation in human PBMC-derived macrophages. Notably, sepsis in the early hyperinflammatory phase triggers ACLY-mediated NF-κB acetylation. The ACLY/NF-κB axis increases the expression levels of proinflammatory genes, including SLC25A1—which encodes the mitochondrial citrate carrier—and ACLY, thus promoting the existence of a proinflammatory loop involving SLC25A1 and ACLY genes.

ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-κB Acetylation.

Human herpesviruses (HHVs) are large DNA viruses with highly infectious characteristics. HHVs can induce lytic and latent infections in their host, and most of these viruses are neurotropic, with the capacity to generate severe and chronic neurological diseases of the peripheral nervous system (PNS) and central nervous system (CNS). Treatment of HHV infections based on strategies that include natural products-derived drugs is one of the most rapidly developing fields of modern medicine. Therefore, in this paper, we lend insights into the recent advances that have been achieved during the past five years in utilizing flavonoids as promising natural drugs for the treatment of HHVs infections of the nervous system such as alpha-herpesviruses (herpes simplex virus type 1, type 2, and varicella-zoster virus), beta-herpesviruses (human cytomegalovirus), and gamma-herpesviruses (Epstein–Barr virus and Kaposi sarcoma-associated herpesvirus). The neurological complications associated with infections induced by the reviewed herpesviruses are emphasized. Additionally, this work covers all possible mechanisms and pathways by which flavonoids induce promising therapeutic actions against the above-mentioned herpesviruses.

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Shah Faisal

Papers

Antiviral activities of flavonoids.