Chemoprevention of intestinal tumorigenesis by the natural dietary flavonoid myricetin in APCMin/+ mice

forrás: https://www.oncotarget.com/article/11108/text/


2021-11-19 11:49:59


Myricetin is a natural dietary flavonoid compound. We evaluated the efficacy of myricetin against intestinal tumorigenesis in adenomatous polyposis coli multiple intestinal neoplasia (APCMin/+) mice. Myricetin was given orally once a day for 12 consecutive weeks. APCMin/+ mice fed with myricetin developed fewer and smaller polyps without any adverse effects. Histopathological analysis showed a decreased number of dysplastic cells and degree of dysplasia in each polyp. Immunohistochemical and western blot analysis revealed that myricetin selectively inhibits cell proliferation and induces apoptosis in adenomatous polyps. The effects of myricetin were associated with a modulation the GSK-3β and Wnt/β-catenin pathways. ELISA analysis showed a reduced concentration of pro-inflammatory cytokines IL-6 and PGE2 in blood, which were elevated in APCMin/+ mice. The effect of myricetin treatment was more prominent in the adenomatous polyps originating in the colon. Further studies showed that myricetin downregulates the phosphorylated p38 MAPK/Akt/mTOR signaling pathways, which may be the mechanisms for the inhibition of adenomatous polyps by myricetin. Taken together, our data show that myricetin inhibits intestinal tumorigenesis through a collection of biological activities. Given these results, we suggest that myricetin could be used preventatively to reduce the risk of developing colon cancers.


Effect of a Plant-derived Natural Compound, Flavin7, on the ERK Signaling Pathway in Immortalized Mouse Proximal Tubule Cells

forrás: http://medpublics.com/docs/egy_novenyi_eredetu_vegyulet_english.pdf


2021-02-08 12:45:05


Abstract. Background: Since MAP kinases represent an important pathway of transducing external stimuli to internal signals in cells, determining their possible role in cancer cells may offer a promising way for the treatment and prognosis of malignant diseases. Our previous experiments have shown that a flavonoid-rich solution, Flavin7, was able to diminish kidney tumor growth in vivo. Materials and Methods: Effects of Flavin7 on the MAPK signaling pathway were determined in immortalized mouse proximal tubule cells by determining cell viability, flow cytometric analysis, luciferase assays and Western blots. Results: At a nontoxic dose, Flavin7 markedly reduced phosphorylation of ERK and inhibited activity of its downstream targets such as Elk1 and CREB via inhibition of the ERK-kinase MEK1. Conclusion: Because of its ability to temporarily inhibit kidney tumor growth and activation of the MEK1/ERK pathway in vitro, further in vivo investigations may determine the potential role of Flavin7 in the treatment of malignancies. The mitogen-activated protein kinase (MAPK) cascade is a major signaling system by which cells transduce extracellular signals into intracellular responses. Many steps of this cascade are conserved, and homologs have been discovered in different species (1). The first three mammalian MAP kinases, ERK1, ERK2 and ERK3 were cloned in the early 1990s, facilitating the development of reagents for their study. It has become clear that ERK1 and ERK2 are among the protein kinases most commonly activated in signal transduction pathways. They have particularly been linked to cell proliferation, but have important roles in many other events (2-4). In mammalian cells, ERK1 and ERK2, often referred to as p44 and p42 MAP kinases, are the archetypal members of the MAPK family. Therefore, determining the possible role of MAPKs in cancer cells may offer a promising way for treatment and prognosis of cancerous diseases. According to recent results, activation of the ERK pathway is a frequent event in tumorigenesis. ERK has been implicated in cell initiation, tumor promotion and progression, invasion, metastasis, and regulation of apoptosis and angiogenesis, events that are essential for successful completion of developing a metastatic tumor (reviewed in 5). On the other hand, ERK activation is not unambiguously an advantage or a disadvantage for patients with cancerous diseases, since it has been shown to trigger cell proliferation and survival in normal cells, as well as in tumor cells. Flavonoids, found in great quantity in fruit extracts, are secondary metabolites of superior plants exhibiting antitumor effects. They are known to exert antioxidant and antiproliferative effects on tumor cells (6). Recent studies have speculated that the classical antioxidant activity of flavonoids is unlikely to be the sole explanation for their cellular effects. This hypothesis is based on several lines of reasoning: i) flavonoids are extensively metabolized in vivo, thus, their redox potentials are significantly altered (7), and ii) the concentrations of flavonoids and their metabolites accumulated in vivo are lower than those of small of antioxidant nutrients (8). Investigations have indicated that flavonoids may selectively interact with the MAPK signaling pathway due to their ability to inhibit tyrosine kinase activity (9, 10). A natural compound, Flavin7 (F7), composed of the extracts from seven different fruits, was investigated in our kidney tumor animal model (11). Ne/De tumor cells were transplanted underneath the renal capsule of 6- to 8-weekold Fisher344 rats and animals were treated with human 871 Correspondence to: Edit Nádasi, MD, Ph.D., Department of Public Health and Preventive Medicine, University of Pécs, 7624 Pécs, Szigeti u. 12, Hungary. Tel: +36 72 536394, Fax: +36 72 536395, e-mail: edit.nadasi@aok.pte.hu Key Words: Flavin7 extract, plant-derived natural compounds, mitogen-activated protein kinase pathway, anticarcinogenic effect. in vivo 21: 871-876 (2007) Effect of a Plant-derived Natural Compound, Flavin7, on the ERK Signaling Pathway in Immortalized Mouse Proximal Tubule Cells EDIT NÁDASI1,2, ISTVÁN EMBER2 and ISTVÁN ARANY1 1Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veteran HealthCare System, Little Rock, AR 72205, U.S.A.; 2Department of Public Health and Preventive Medicine, University of Pécs, 7624 Pécs, Hungary 0258-851X/2007 $2.00+.40 dose-equivalent F7 solution according to the manufacturer’s instructions. After two weeks of treatment rats were sacrificed and tumor growth was determined. F7 significantly (p<0.05) reduced tumor growth in vivo. Accordingly, the aim of this study was to determine whether F7 influences the ERK signaling pathway in immortalized mouse renal proximal tubule cells.

 


Zinc and respiratory tract infections: Perspectives for COVID‑19

forrás: https://www.spandidos-publications.com/ijmm/46/1/17


2021-01-22 09:50:43


In view of the emerging COVID‑19 pandemic caused by SARS‑CoV‑2 virus, the search for potential protective and therapeutic antiviral strategies is of particular and urgent interest. Zinc is known to modulate antiviral and antibacterial immunity and regulate inflammatory response. Despite the lack of clinical data, certain indications suggest that modulation of zinc status may be beneficial in COVID‑19. In vitro experiments demonstrate that Zn2+ possesses antiviral activity through inhibition of SARS‑CoV RNA polymerase. This effect may underlie therapeutic efficiency of chloroquine known to act as zinc ionophore. Indirect evidence also indicates that Zn2+ may decrease the activity of angiotensin‑converting enzyme 2 (ACE2), known to be the receptor for SARS‑CoV‑2. Improved antiviral immunity by zinc may also occur through up‑regulation of interferon α production and increasing its antiviral activity. Zinc possesses anti‑inflammatory activity by inhibiting NF‑κB signaling and modulation of regulatory T‑cell functions that may limit the cytokine storm in COVID‑19. Improved Zn status may also reduce the risk of bacterial co‑infection by improving mucociliary clearance and barrier function of the respiratory epithelium, as well as direct antibacterial effects against S. pneumoniae. Zinc status is also tightly associated with risk factors for severe COVID‑19 including ageing, immune deficiency, obesity, diabetes, and atherosclerosis, since these are known risk groups for zinc deficiency. Therefore, Zn may possess protective effect as preventive and adjuvant therapy of COVID‑19 through reducing inflammation, improvement of mucociliary clearance, prevention of ventilator‑induced lung injury, modulation of antiviral and antibacterial immunity. However, further clinical and experimental studies are required.

 


Computational screening of antagonists against the SARS-CoV-2 (COVID-19) coronavirus by molecular docking

forrás: http://medpublics.com/docs/computational_screening.pdf


2021-01-21 14:14:58


In the current spread of novel coronavirus (SARS-CoV-2), antiviral drug discovery is of great importance. AutoDock Vina was used to screen potential drugs by molecular docking with the structural protein and non-structural protein sites of new coronavirus. Ribavirin, a common antiviral drug, remdesivir, chloroquine and luteolin were studied. Honeysuckle is generally believed to have antiviral effects in traditional Chinese medicine. In this study, luteolin (the main flavonoid in honeysuckle) was found to bind with a high affinity to the same sites of the main protease of SARS-CoV-2 as the control molecule. Chloroquine has been proved clinically effective and can bind to the main protease; this may be the antiviral mechanism of this drug. The study was restricted to molecular docking without validation by molecular dynamics simulations. Interactions with the main protease may play a key role in fighting against viruses. Luteolin is a potential antiviral molecule worthy of attention

 


Roles of flavonoids against coronavirus infection

forrás: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385538/


2021-01-25 11:09:42


In terms of public health, the 21st century has been characterized by coronavirus pandemics: in 2002-03 the virus SARS-CoV caused SARS; in 2012 MERS-CoV emerged and in 2019 a new human betacoronavirus strain, called SARS-CoV-2, caused the unprecedented COVID-19 outbreak. During the course of the current epidemic, medical challenges to save lives and scientific research aimed to reveal the genetic evolution and the biochemistry of the vital cycle of the new pathogen could lead to new preventive and therapeutic strategies against SARS-CoV-2. Up to now, there is no cure for COVID-19 and waiting for an efficacious vaccine, the development of “savage” protocols, based on “old” anti-inflammatory and anti-viral drugs represents a valid and alternative therapeutic approach. As an alternative or additional therapeutic/preventive option, different in silico and in vitro studies demonstrated that small natural molecules, belonging to polyphenol family, can interfere with various stages of coronavirus entry and replication cycle. Here, we reviewed the capacity of well-known (e.g. quercetin, baicalin, luteolin, hesperetin, gallocatechin gallate, epigallocatechin gallate) and uncommon (e.g. scutellarein, amentoflavone, papyriflavonol A) flavonoids, secondary metabolites widely present in plant tissues with antioxidant and anti-microbial functions, to inhibit key proteins involved in coronavirus infective cycle, such as PLpro, 3CLpro, NTPase/helicase. Due to their pleiotropic activities and lack of systemic toxicity, flavonoids and their derivative may represent target compounds to be tested in future clinical trials to enrich the drug arsenal against coronavirus infections.


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