PMID: 

Adv Neurobiol. 2020 ;24:615-646. PMID: 32006377

Abstract Title: 

Dietary Phytochemicals as Neurotherapeutics for Autism Spectrum Disorder: Plausible Mechanism and Evidence.

Abstract: 

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with symptoms ranging from lack of social interaction and communication deficits to rigid, repetitive, and stereotypic behavior. It has also been associated with comorbidities such as anxiety, aggression, epilepsy, deficit in sensory processing, as well as ADHD (attention deficit hyperactivity disorder). Apart from several behavioral and cognitive complications arising as a result of central nervous system dysfunction, there are various physiological comorbidities such as immune system deregulation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and gastrointestinal complications which can worsen existing behavioral complications. There are no available treatments for these physiological comorbidities. The prevalence of gastrointestinal complications in ASD ranges from 9% to 70% and it correlates with behaviors consistent with the autistic endophenotype indicating that these are one of the major comorbidities associated with ASD. A strong connection of gut-brain cross talk occurs as a result of gut dysbiosis responsible for excessive production of short-chain fatty acids such as propanoic acid (PPA) by abnormal gut flora in ASD patients. This worsens behavioral, neurochemical, and mitochondrial dysfunction occurring in ASD. These physiological comorbidities are responsible for the generation of free radical species that cause immune system dysfunction leading to synthesis of various pro-inflammatory cytokines and chemokines. This in turn causes activation of microglia. Dietary phytochemicals are thought to be safer and useful as an alternative neurotherapeutic moiety. These compounds provide neuroprotection by modulating signaling pathways such as Nrf2, NF-κB, MAPK pathway or Sirtuin-FoxO pathway. There has been recent evidence in scientific literature regarding the modulation of gut-brain cross talk responsible for behavioral, biochemical, and mitochondrial dysfunction as well as cellular and behavioral sensory alterations by dietary phytochemicalssuch as curcumin, resveratrol, naringenin, and sulforaphane. These dietary phytochemicals can be formulated in novel brain-targeted delivery systems which overcome their limitation of low oral bioavailability and short half-life leading to prolonged action. Till date, not much work has been done onthe development of brain-targeted neurotherapeutics for ASD. In this chapter we discuss plausible mechanisms and evidence from our own and other scientific research for the utilization of curcumin, resveratrol, naringenin, and sulforaphane as neurotherapeutics for ASD.

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PMID: 

Med Sci Monit. 2020 Feb 1 ;26:e919558. Epub 2020 Feb 1. PMID: 32005795

Abstract Title: 

Bauerane Induces S-Phase Cell Cycle Arrest, Apoptosis, and Inhibition of Proliferation of A549 Human Lung Cancer Cells Through the Phosphoinositide 3-Kinase (PI3K)/AKT and Signal Transducer and Activator of Transcription 3 (STAT3) Signaling Pathway.

Abstract: 

BACKGROUND Bauerane is a triterpenoid derived from the dandelion root (Taraxacum officinale). This study aimed to investigate the effects of bauerane on cell proliferation of A549 human lung cancer cells and the molecular mechanisms involved. MATERIAL AND METHODS A549 human lung adenocarcinoma cells and normal MRC-5 lung fibroblasts were grown in culture and treated with increasing doses of bauerane at 0, 2.5, 5, 10, 20, 40, 80, and 160µM. The MTT assay was used to measure cell proliferation. Cell apoptosis was assessed by 4', 6-diamidino-2-phenylindole (DAPI), and acridine orange/ethidium bromide (AO/EB) staining. The cell cycle was evaluated by flow cytometry. Western blot measured the protein expression levels of cytochrome c,Bax, cyclin B1, Bcl-2, PI3K, p-PI3K, Akt, p-Akt, and STAT3 proteins. RESULTS Bauerane inhibited the proliferation of A549 lung cancer cells in a dose-dependent manner, with an IC₅₀ of 10 µM, with no cytotoxicity for MRC-5 cells. Bauerane treatment induced apoptosis of A549 cells, which was associated with the upregulation of Bax and down-regulation of Bcl-2. Bauerane induced S-phase arrest of A549 cells, which was dose-dependent and associated with reduced expression of cyclin B1. The findings from Western blot showed that bauerane inhibited the phosphorylation of PI3K/AKT and STAT3 signaling pathways. CONCLUSIONS Bauerane inhibited the proliferation of A549 lung cancer cells in vitro and induced cell apoptosis and cell cycle arrest in a dose-dependent manner.

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PMID: 

Brain Sci. 2020 Jan 6 ;10(1). Epub 2020 Jan 6. PMID: 31935983

Abstract Title: 

Inhibitory Effects of Myricetin on Lipopolysaccharide-Induced Neuroinflammation.

Abstract: 

Microglial activation elicits an immune response by producing proinflammatory modulators and cytokines that cause neurodegeneration. Therefore, a plausible strategy to prevent neurodegeneration is to inhibit neuroinflammation caused by microglial activation. Myricetin, a natural flavanol, induces neuroprotective effects by inhibiting inflammation and oxidative stress. However, whether myricetin inhibits lipopolysaccharide (LPS)-induced neuroinflammation in hippocampus and cortex regions is not known. To test this, we examined the effects of myricetin on LPS-induced neuroinflammation in a microglial BV2 cell line. We found that myricetin significantly downregulated several markers of the neuroinflammatory response in LPS-induced activated microglia, including inducible nitric oxide (NO) synthase (iNOS), cyclooxygenase-2 (COX-2), and proinflammatory modulators and cytokines such as prostaglandin E2 (PGE), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α). Moreover, myricetin suppressed the expression of c-Jun NH2-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK), which are components of the mitogen-activated protein kinase (MAPK) signaling pathway. Furthermore, myricetin inhibited LPS-induced macrophages and microglial activation in the hippocampus and cortex of mice. Based on our results, we suggest that myricetin inhibits neuroinflammation in BV2 microglia by inhibiting the MAPK signaling pathway and the production of proinflammatory modulators and cytokines. Therefore, this could potentially be used for the treatment of neuroinflammatory diseases.

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PMID: 

J Nutr Biochem. 2019 Dec 23 ;78:108328. Epub 2019 Dec 23. PMID: 31952013

Abstract Title: 

Myricetin inhibits endometriosis growth through cyclin E1 down-regulation in vitro and in vivo.

Abstract: 

Endometriosis is a benign gynecological condition prevalent among reproductive-aged women. Although active research and studies have been carried out to discover new drugs, surgery and hormone therapy are still the gold standard for endometriosis treatment. Nowadays, various flavonoids are considered long-term supplements for different diseases. Myricetin, a flavonol, has antiproliferative, anti- or pro-oxidant, and anticancer effects in gynecological diseases. Here, we reveal for the first time, to our knowledge, the antigrowth effects of myricetin in endometriosis. Myricetin inhibited cell proliferation and cell cycle progression of human VK2/E6E7 and End1/E6E7 cells and induced apoptosis, with the loss of mitochondrial membrane potential and accumulation of reactive oxygen species and calcium ions. Additionally, myricetin decreased the activation of AKT and ERK1/2 proteins, whereas it induced p38 activation in both cell lines. Moreover, myricetin decreased lesion size in the endometriosis mouse model via Ccne1 inhibition. Thus, myricetin has antiproliferative effects on endometriosis through cell cycle regulation.

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PMID: 

Bioorg Med Chem Lett. 2012 Jun 15 ;22(12):4049-54. Epub 2012 Apr 25. PMID: 22578462

Abstract Title: 

Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13.

Abstract: 

Severe acute respiratory syndrome (SARS) is an infectious disease with a strong potential for transmission upon close personal contact and is caused by the SARS-coronavirus (CoV). However, there are no natural or synthetic compounds currently available that can inhibit SARS-CoV. We examined the inhibitory effects of 64 purified natural compounds against the activity of SARS helicase, nsP13, and the hepatitis C virus (HCV) helicase, NS3h, by conducting fluorescence resonance energy transfer (FRET)-based double-strand (ds) DNA unwinding assay or by using a colorimetry-based ATP hydrolysis assay. While none of the compounds, examined in our study inhibited the DNA unwinding activity or ATPase activity of human HCV helicase protein, we found that myricetin and scutellarein potently inhibit the SARS-CoV helicase protein in vitro by affecting the ATPase activity, but not the unwinding activity, nsP13. In addition, we observed that myricetin and scutellarein did not exhibit cytotoxicity against normal breast epithelial MCF10A cells. Our study demonstrates for the first time that selected naturally-occurring flavonoids, including myricetin and scultellarein might serve as SARS-CoV chemical inhibitors.

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PMID: 

Exp Physiol. 2020 Jan 31. Epub 2020 Jan 31. PMID: 32003913

Abstract Title: 

Melissa officinalis L. hydro-alcoholic extract inhibits anxiety and depression through prevention of central oxidative stress and apoptosis.

Abstract: 

NEW FINDINGS: What is the central question of this study? Prolonged stress exposure induces detrimental changes in the brain structure, and increases the vulnerability to develop psychiatric disorders. The central question of this study is how Melissa officinalis L. ameliorates anxiety- and depressive-like behavior of mice. What is the main finding and its importance? Melissa officinalis L. possessed anxiolytic and anti-depressant effects, which could mainly mediate through its antioxidant and anti-apoptotic properties.ABSTRACT: Objective This study evaluated the effects of hydro-alcoholic extract of Melissa officinalis (HAEMO) on anxiety- and depressive-like behaviors, oxidative stress, and apoptosis markers in the restraint-stress exposed mice. Methods In order to induce depression-like model, mice were subjected to restraint-stress (3 h dayfor 14 days) and received normal saline or HAEMO (50, 75, and 150 mg kg day) for 14 days. The administered doses of HAEMO were designated based on one the main phenolic compounds present in the extract, rosmarinic acid (RA), concentration (2.55 mg kgat lowest dose), other phytochemical analysis including assays for antioxidant activity, total phenols, and flavonoids contents were also carried out. The behavioral changes in the open field task, elevated plus maze, tail suspension, and forced swimming tests were evaluated. Also, malondialdehyde (MDA) levels and enzyme activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx), and total antioxidant capacity were assessed in the prefrontal cortex (PFC) and hippocampus (HIP). Moreover, levels of Bcl-2, Bax, and caspase 3, in the brain as well as serum concentration of corticosterone (CORT), were evaluated. Results HAEMO (75 and 150 mg kg) significantly reversed anxiety- and depressive-like behaviors. Also, the HAEMO reduced MDA levels, enhanced enzymatic antioxidant activities, and restored serum levels of CORT. The immunoblotting analysis also demonstrated that HAEMO decreased levels of pro-apoptotic markers and increased anti-apoptotic protein levels in the PFC and HIP of restraint-stress exposed mice. Conclusion Our findings suggested that HAEMO reduced inflammation and had anxiolytic and antidepressant effects in mice. This article is protected by copyright. All rights reserved.

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PMID: 

Adv Pharm Bull. 2020 Jan ;10(1):13-19. Epub 2019 Dec 11. PMID: 32002357

Abstract Title: 

An Overview of the Cellular Mechanisms of Flavonoids Radioprotective Effects.

Abstract: 

Considering the remarkable application of radiotherapy in the treatment and diagnosis of various diseases and even nuclear war, it is important to protect healthy tissues and people at risk from the radiation. Currently, there is no ideal and safe radioprotective agent available and we are seeing a great effort to find these agents from natural sources. Phenolic compounds, as well as flavonoid, are presented widely as the second metabolite in plants and they have been considered for investigation according to their benefits for human health, healing and preventing many disorders. The major bioactive benefits of flavonoids include antioxidant, anti-inflammatory, anti-tumor, anti-aging, anti-bacterial and viral, neuroprotection and radioprotective effects. Their lower toxicity and oral administration have made it suitable for radiotherapy patient, radiation, military forces, and even the general public. This review attempts to provide a summary of the main molecular mechanisms involved in flavonoid radio-protective effects. Data of these studies will provide a comprehensive perspective to flavonoids and can help to optimize their effects in radioprotection procedures.

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PMID: 

BMC Infect Dis. 2017 02 13 ;17(1):144. Epub 2017 Feb 13. PMID: 28193191

Abstract Title: 

Effective inhibition of MERS-CoV infection by resveratrol.

Abstract: 

BACKGROUND: Middle East Respiratory Syndrome coronavirus (MERS-CoV) is an emerging viral pathogen that causes severe morbidity and mortality. Up to date, there is no approved or licensed vaccine or antiviral medicines can be used to treat MERS-CoV-infected patients. Here, we analyzed the antiviral activities of resveratrol, a natural compound found in grape seeds and skin and in red wine, against MERS-CoV infection.METHODS: We performed MTT and neutral red uptake assays to assess the survival rates of MERS-infected Vero E6 cells. In addition, quantitative PCR, western blotting, and immunofluorescent assays determined the intracellular viral RNA and protein expression. For viral productivity, we utilized plaque assays to confirm the antiviral properties of resveratrol against MERS-CoV.RESULTS: Resveratrol significantly inhibited MERS-CoV infection and prolonged cellular survival after virus infection. We also found that the expression of nucleocapsid (N) protein essential for MERS-CoV replication was decreased after resveratrol treatment. Furthermore, resveratrol down-regulated the apoptosis induced by MERS-CoV in vitro. By consecutive administration of resveratrol, we were able to reduce the concentration of resveratrol while achieving inhibitory effectiveness against MERS-CoV.CONCLUSION: In this study, we first demonstrated that resveratrol is a potent anti-MERS agent in vitro. We perceive that resveratrol can be a potential antiviral agent against MERS-CoV infection in the near future.

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PMID: 

Evid Based Complement Alternat Med. 2005 06 ;2(2):209-215. Epub 2005 Apr 7. PMID: 15937562

Abstract Title: 

Inhibition of SARS-CoV 3C-like Protease Activity by Theaflavin-3,3'-digallate (TF3).

Abstract: 

SARS-CoV is the causative agent of severe acute respiratory syndrome (SARS). The virally encoded 3C-like protease (3CL(Pro)) has been presumed critical for the viral replication of SARS-CoV in infected host cells. In this study, we screened a natural product library consisting of 720 compounds for inhibitory activity against 3CL(Pro). Two compounds in the library were found to be inhibitive: tannic acid (IC(50) = 3 microM) and 3-isotheaflavin-3-gallate (TF2B) (IC(50) = 7 microM). These two compounds belong to a group of natural polyphenols found in tea. We further investigated the 3CL(Pro)-inhibitory activity of extracts from several different types of teas, including green tea, oolong tea, Puer tea and black tea. Our results indicated that extracts from Puer and black tea were more potent than that from green or oolong teas in their inhibitory activities against 3CL(Pro). Several other known compositions in teas were also evaluated for their activities in inhibiting 3CL(Pro). We found that caffeine, (-)-epigallocatechin gallte (EGCg), epicatechin (EC), theophylline (TP), catechin (C), epicatechin gallate (ECg) and epigallocatechin (EGC) did not inhibit 3CL(Pro) activity. Only theaflavin-3,3'-digallate (TF3) was found to be a 3CL(Pro) inhibitor. This study has resulted in the identification of new compounds that are effective 3CL(Pro) inhibitors.

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PMID: 

Metabolites. 2019 Jul 11 ;9(7). Epub 2019 Jul 11. PMID: 31336728

Abstract Title: 

Metabolic Regulation of Glycolysis and AMP Activated Protein Kinase Pathways during Black Raspberry-Mediated Oral Cancer Chemoprevention.

Abstract: 

Oral cancer is a public health problem with an incidence of almost 50,000 and a mortality of 10,000 each year in the USA alone. Black raspberries (BRBs) have been shown to inhibit oral carcinogenesis in several preclinical models, but our understanding of how BRB phytochemicals affect the metabolic pathways during oral carcinogenesis remains incomplete. We used a well-established rat oral cancer model to determine potential metabolic pathways impacted by BRBs during oral carcinogenesis. F344 rats were exposed to the oral carcinogen 4-nitroquinoline-1-oxide in drinking water for 14 weeks, then regular drinking water for six weeks. Carcinogen exposed rats were fed a 5% or 10% BRB supplemented diet or control diet for six weeks after carcinogen exposure. RNA-Seq transcriptome analysis on rat tongue, and mass spectrometry and NMR metabolomics analysis on rat urine were performed. We tentatively identified 57 differentially or uniquely expressed metabolites and over 662 modulated genes in rats being fed with BRB. Glycolysis and AMPK pathways were modulated during BRB-mediated oral cancer chemoprevention. Glycolytic enzymes,,,,, andas well as the PKA-AMPK pathway genes,,,, andwere downregulated by BRBs during oral cancer chemoprevention. Furthermore, the glycolysis metabolite glucose-6-phosphate decreased in BRB-administered rats. Our data reveal the novel metabolic pathways modulated by BRB phytochemicals that can be targeted during the chemoprevention of oral cancer.

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