Myricetin: A review of the most recent research.

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CLpro) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CLpro. Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CLpros, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands.

Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease.

Flavonoids represent an important group of bioactive compounds derived from plant-based foods and beverages with known biological activity in cells. From the modulation of inflammation to the inhibition of cell proliferation, flavonoids have been described as important therapeutic adjuvants against several diseases, including diabetes, arteriosclerosis, neurological disorders, and cancer. Cancer is a complex and multifactor disease that has been studied for years however, its prevention is still one of the best known and efficient factors impacting the epidemiology of the disease. In the molecular and cellular context, some of the mechanisms underlying the oncogenesis and the progression of the disease are understood, known as the hallmarks of cancer. In this text, we review important molecular signaling pathways, including inflammation, immunity, redox metabolism, cell growth, autophagy, apoptosis, and cell cycle, and analyze the known mechanisms of action of flavonoids in cancer. The current literature provides enough evidence supporting that flavonoids may be important adjuvants in cancer therapy, highlighting the importance of healthy and balanced diets to prevent the onset and progression of the disease.

The Hallmarks of Flavonoids in Cancer

Globally, traditional herbal medicines have played a vital role in health systems, and are used to treat various acute and chronic conditions without or minimal toxic effect. Herbal plants are often used as a natural remedy to cure various health problems including tuberculosis, cancer, diabetes mellitus, heart diseases, wound healing, asthma, pharyngitis, hypertension etc. Plants rich in bioactive phytomedicine compounds such as alkaloids, flavonoids, tannins and polyphenols have been used to cure illnesses because of their various pharmacological properties. India is always known to be rich depository of medicinal plants and various forms of herbal medicine practices are considered as “living tradition”. However, there is no collective report on the significant Indian medicinal plants and their current progress in medicinal plant research. Hence, the prime focus of this review is to identify and report the majorly used Indian medicinal plants that have grown in India and neighboring countries based on a complete research survey of local and international research articles. The review mainly summarizes the prominent Indian medicinal plants, their extract and its corresponding pharmacological properties such as anti-microbial, antioxidant, anti-diabetic, and anti-cancer etc. The significance of this review is aimed to provide a detailed and collective scientific evaluation of the key phytocompounds and its pharmacological action for the possible development of new ethnomedicine in the future.

Therapeutic and pharmacological efficacy of selective Indian medicinal plants – A review

The prostaglandins constitute a family of lipids of 20 carbon atoms that derive from polyunsaturated fatty acids such as arachidonic acid. Traditionally, prostaglandins have been linked to inflammation, female reproductive cycle, vasodilation, or bronchodilator/bronchoconstriction. Recent studies have highlighted the involvement of these lipids in cancer. In this review, existing information on the prostaglandins associated with different types of cancer and the advances related to the potential use of them in neoplasm therapies have been analyzed. We can conclude that the effect of prostaglandins depends on multiple factors, such as the target tissue, their plasma concentration, and the prostaglandin subtype, among others. Prostaglandin D2 (PGD2) seems to hinder tumor progression, while prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2α) seem to provide greater tumor progression and aggressiveness. However, more studies are needed to determine the role of prostaglandin I2 (PGI2) and prostaglandin J2 (PGJ2) in cancer due to the conflicting data obtained. On the other hand, the use of different NSAIDs (non-steroidal anti-inflammatory drugs), especially those selective of COX-2 (cyclooxygenase 2), could have a crucial role in the fight against different neoplasms, either as prophylaxis or as an adjuvant treatment. In addition, multiple targets, related to the action of prostaglandins on the intracellular signaling pathways that are involved in cancer, have been discovered. Thus, in depth research about the prostaglandins involved in different cancer and the different targets modulated by them, as well as their role in the tumor microenvironment and the immune response, is necessary to obtain better therapeutic tools to fight cancer.

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The Role of Prostaglandins in Different Types of Cancer.

Anti-tumor effects and associated molecular mechanisms of myricetin.

Combined chemotherapy with cyclooxygenase-2 (COX-2) inhibitors in treating human cancers: Recent advancement

The compound 3,3′,4′,5,5′,7-hexahydroxyflavone (myricetin) is a natural flavonoid with antitumour activity. Most of the studies on myricetin have focused on the induction of tumour cell apoptosis, and little is known about the regulatory effects of myricetin on autophagy in colorectal cancer. Here, we studied the effects of myricetin on colon cancer cell proliferation, apoptosis and autophagy. We detected colon cancer cell apoptosis induced by myricetin via flow cytometry and Hoechst 33258 staining. Transmission electron microscopy was performed to observe the morphological changes associated with autophagy. The expression levels of apoptosis-, autophagy- and PI3K/Akt/mTOR signalling-related proteins were measured by Western blot analysis. This study confirmed that myricetin inhibits the proliferation of 4 kinds of colon cancer cell lines. Myricetin induced cell apoptosis and autophagy by inhibiting PI3K/Akt/mTOR signalling pathway. In addition, the inhibition of autophagy with 3-methyladenine (3-MA) promoted the apoptosis of myricetin-treated colon cancer cells. Considering that myricetin induces apoptosis and autophagy in colon cancer cells, myricetin may become a viable candidate for chemotherapy; it could be used to exert tumour inhibitory effects alone or as adjuvant chemotherapy to inhibit autophagy. These studies may provide further evidence for the potential use of myricetin in the treatment of colon cancer.

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Min Jiang

Papers

Anti-tumor effects and associated molecular mechanisms of myricetin.

Combined chemotherapy with cyclooxygenase-2 (COX-2) inhibitors in treating human cancers: Recent advancement

Myricetin induces apoptosis and autophagy by inhibiting PI3K/Akt/mTOR signalling in human colon cancer cells.