PMID: 

Int J Biol Macromol. 2020 Mar 10. Epub 2020 Mar 10. PMID: 32169452

Abstract Title: 

Fucoidan increased the sensitivity to gefitinib in lung cancer cells correlates with reduction of TGFβ-mediated Slug expression.

Abstract: 

Gefitinib is a first tyrosine kinase inhibitor (TKI) designed with an EGFR tyrosine kinase for lung cancer targeted therapy. However, some lung cancer patients with wild-type EGFR (wtEGFR) or acquired secondary EGFR mutation showed lower response rate of gefitinib. In this study, we examined the efficacy of fucoidan on altering gefitinib-sensitivity on TKI-resistant lung cancer A549 and H1975 cells. We found that the simultaneous administration of fucoidan and gefitinib synergistically inhibited lung cancer cell viability via activating apoptotic response. Moreover, we found that fucoidan effectively downregulated expressions of mesenchymal-like molecules. Mechanistically, we demonstrated that fucoidan altered the gefitinib-inhibitory rate may result from induction of proteasome-dependent Slug degradation. Abolishment of TGFβ signaling enhanced gefitinib-inhibited cell viability and reduced N-cadherin, Twist and Slug levels. Moreover, knockdown of Slug contributed the increasing the gefitinib-sensitivity of H1975 cells. Our study is the first to find that fucoidan alters the gefitinib-sensitive of TKI-resistant cellsby reduction of TGFβ receptor-mediated expressions of mesenchymal-like molecules and induction of Slug degradation. Together, our current results indicate that combination of fucoidan and gefitinib may be a potential and effective therapeutic strategy in gefitinib non-sensitive lung cancer.

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PMID: 

Biomed Pharmacother. 2020 May ;125:109992. Epub 2020 Feb 25. PMID: 32084700

Abstract Title: 

Oral supplementation of fucoxanthin-rich brown algae extract ameliorates cisplatin-induced testicular damage in hamsters.

Abstract: 

Oxidative stress is recognized as a common pathology that affects up to half of all men infertile. Fucoxanthin possesses antioxidant activity, and several investigators have reported anti-inflammatory action. This study extracted powder of Sargassum glaucescens by acetone to obtained fucoxanthin rich-brown algae extract (FXE). The objective of this study was to evaluate the ameliorative effects of fucoxanthin extract from Sargassum glaucescens on lipopolysaccharide-induced inflammation in RAW264.7 macrophage cells and its protective effects of against Cisplatin (CP)-induced reproductive damage in hamsters. Eighty male Syrian hamsters were injected with and without CP, then daily oral gavage with various concentrations of fucoxanthin for 5 days. Treatment with FXE reduced the level of reactive oxygen species and malondialdehyde in RAW 264.7 cells and the rats' testis as well as protective effects on mitochondrial membrane potential. The FXE administration also improved testosterone level and alpha-glucosidase activity. The sperm count also increased after treated with FXE, whereas sperm abnormality was reduced. Histopathological analysis showed that FXE successfully improved the seminiferous tubules morphology. According to these findings, fucoxanthin extract from Sargassum glaucescens can be used as an alternative for the treatment of testicular damage.

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PMID: 

Am J Transl Res. 2020 ;12(1):203-247. Epub 2020 Jan 15. PMID: 32051749

Abstract Title: 

Fisetin regulates gut microbiota to decrease CCR9/CXCR3/CD4T-lymphocyte count and IL-12 secretion to alleviate premature ovarian failure in mice.

Abstract: 

Currently, there are no studies reporting the efficacy of fisetin in premature ovarian failure (POF). In this study, using mouse andmodels, we found that fisetin not only significantly reversed ovarian damage in POF mice, but also effectively increasedlifespan and fertility. Subsequently, we carried out 16S rRNA v3+v4 sequencing using fresh feces samples from each group of mice. Results showed that although there was no significant difference in the number of gut microbiomes between the different groups of mice, fisetin affected the diversity and distribution of gut microbiota in POF mice. Alpha and beta diversity analyses showed that in the gut of POF mice in the fisetin group, the bacterial count of uncultured_bacterium_f_Lachnospiraceae was significantly increased, while that ofwas significantly decreased. Finally, flow cytometry analysis showed that the numbers of CCR9/CXCR3/CD4T lymphocytes in the peripheral blood of POF mice in the fisetin group were significantly reduced, along with the number of CD4/interleukin (IL)-12cells. Therefore, our data suggested that fisetin regulates the distribution and bacterial counts ofand uncultured_bacterium_f_Lachnospiracea in POF mice, and reduces peripheral blood CCR9/CXCR3/CD4T-lymphocyte count and IL-12 secretion to regulate the ovarian microenvironment and reduce inflammation, thus exerting therapeutic effects against POF.

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PMID: 

Drug Des Devel Ther. 2020 ;14:773-782. Epub 2020 Feb 25. PMID: 32158195

Abstract Title: 

Fisetin Modulates Human Oral Squamous Cell Carcinoma Proliferation by Blocking PAK4 Signaling Pathways.

Abstract: 

Objective: Human oral squamous cell carcinoma (OSCC) is a major cause of mortality and morbidity worldwide. There is an urgent need to identify bioactive molecules and potential target genes that could inhibit carcinogenesis for OSCC therapy. Fisetin (3,7,3',4'-tetrahydroxyflavone), a naturally occurring flavonoid, has been previously shown to have anti-proliferative activities in OSCC; however, its molecular mechanism is unknown.Methods: Colony formation, cell viability, Boyden chamber, wound healing, and tumor xenograft assays were used to detect the impact of fisetin on OSCC cells in vitro and in vivo. Western blot analysis was used to examine the corresponding protein expression.Results: Fisetin treatment significantly inhibited proliferation and promoted apoptosis by repressing PAK4 expression. Moreover, fisetin treatment attenuated cell migration by blocking PAK4 signaling pathways. In addition, the tumor xenograft showed anti-tumor growth effects of fisetin exposure in vivo.Conclusion: Fisetin may represent a potential therapeutic strategy for human OSCC by targeting PAK4 signaling pathways.

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PMID: 

Front Pharmacol. 2020 ;11:162. Epub 2020 Feb 28. PMID: 32184730

Abstract Title: 

Fisetin Prevents Acetaminophen-Induced Liver Injury by Promoting Autophagy.

Abstract: 

Acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure in clinical and hospital settings. Fisetin (FST) is a phenolic compound derived from natural products such as fruit and vegetables. Our research investigated the protective mechanisms of FST in APAP-induced hepatic injuryand. Assessment of mouse serum levels of alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO) activity, malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) demonstrated the protective effects of FST toward APAP-induced liver injury. FST also reversed an APAP-induced decrease in mouse L-02 cell line viability. Our results also showed that FST significantly promoted APAP-induced autophagy and inhibited inflammasome activation bothand. We also found that silencing ATG5, using si-ATG5, reduced the protective effects of FST against APAP-induced hepatotoxicity and reversed the effects on autophagy. Finally, we used the autophagy inhibitor, 3-methyladenine (3-MA) to validate the involvement of autophagy in FST against APAP-induced hepatotoxicity. We demonstrated that FST prevented APAP-induced hepatotoxicity by increasing ATG5 expression, thereby promoting autophagy and inhibiting inflammasome activation.

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PMID: 

J Infect Dis. 1990 Dec ;162(6):1277-82. PMID: 2172402

Abstract Title: 

Adverse effects of aspirin, acetaminophen, and ibuprofen on immune function, viral shedding, and clinical status in rhinovirus-infected volunteers.

Abstract: 

A double-blind, placebo-controlled trial was conducted to study the effects of over-the-counter analgesic/antipyretic medications on virus shedding, immune response, and clinical status in the common cold. Sixty healthy volunteers were challenged intranasally with rhinovirus type 2 and randomized to one of four treatment arms: aspirin, acetaminophen, ibuprofen, or placebo. Fifty-six volunteers were successfully infected and shed virus on at least 4 days after challenge. Virus shedding, antibody levels, clinical symptoms and signs, and blood leukocyte levels were carefully monitored. Use of aspirin and acetaminophen was associated with suppression of serum neutralizing antibody response (P less than .05 vs. placebo) and increased nasal symptoms and signs (P less than .05 vs. placebo). A concomitant rise in circulating monocytes suggested that the suppression of antibody response may be mediated through drug effects on monocytes and/or mononuclear phagocytes. There were no significant differences in viral shedding among the four groups, but a trend toward longer duration of virus shedding was observed in the aspirin and acetaminophen groups.

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PMID: 

Clin Sci (Lond). 2020 Mar 27 ;134(6):571-592. PMID: 32129440

Abstract Title: 

Nobiletin exerts anti-diabetic and anti-inflammatory effects in an in vitro human model and in vivo murine model of gestational diabetes.

Abstract: 

Gestational diabetes mellitus (GDM) is a global health issue, whereby pregnant women are afflicted with carbohydrate intolerance with first onset during pregnancy. GDM is characterized by maternal peripheral insulin resistance, thought to be driven by low-grade maternal inflammation. Nobiletin, a polymethoxylated flavonoid, possesses potent glucose-sensitizing and anti-inflammatory properties; however, its effects in GDM have not been assessed. The present study aimed to determine the effects of nobiletin on glucose metabolism and inflammation associated with GDM in both in vitro human tissues and an in vivo animal model of GDM. In vitro, treatment with nobiletin significantly improved TNF-impaired glucose uptake in human skeletal muscle, and suppressed mRNA expression and protein secretion of pro-inflammatory cytokines and chemokines in human placenta and visceral adipose tissue (VAT). Mechanistically, nobiletin significantly inhibited Akt and Erk activation in placenta, and NF-κB activation in VAT. In vivo, GDM mice treated with 50 mg/kg nobiletin daily via oral gavage from gestational day (gd) 1-17 or via i.p. injections from gd 10-17 significantly improved glucose tolerance. Pregnant GDM mice treated with nobiletin from either gd 1-17 or gd 10-17 exhibited significantly suppressed mRNA expression of pro-inflammatory cytokines and chemokines in placenta, VAT and subcutaneous adipose tissue (SAT). Using a quantitative mass spectrometry approach, we identified differentially abundant proteins associated with the effect of nobiletin in vivo. Together, these studies demonstrate that nobiletin improves glucose metabolism and reduces inflammation associated with GDM and may be a novel therapeutic for the prevention of GDM.

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PMID: 

Phytother Res. 2020 Mar 17. Epub 2020 Mar 17. PMID: 32182635

Abstract Title: 

Dietary citrus and/or its extracts intake contributed to weight control: Evidence from a systematic review and meta-analysis of 13 randomized clinical trials.

Abstract: 

Randomized controlled trials, being published in English and investigating the associations of at least 4 weeks intervention of citrus and/or its extracts on weight loss among adults, were searched from PubMed, Web of Science, Scopus, and Cochrane by June 2019 to conduct a meta-analysis. Thirteen articles, including 921 participants, were selected and evaluated by modified Jadad scale. Pooled resultsby the random-effects model showed that citrus and/or its extracts administration significantly reduced 1.280 kg body weight (95% CI: -1.818 to -0.741, p = 0.000, I= 81.4%), 0.322 kg/mBMI (95% CI: -0.599 to -0.046, p = 0.022, I= 87.0%), 2.185 cm WC (95% CI: -3.804 to -0.566, p = 0.008, I= 98.3%), and 2.137 cm HC (95% CI: -3.775 to -0.500, p = 0.011, I= 96.2%), respectively, but no significantly decreased effects on WHR and body fat were observed. Subgroup analysis deduced the different effects of study location, intervention duration on body weight associated indices. No publication bias was observed. Our meta-analysis supported the beneficial effects of citrus and/or its extracts supplement on body weight control, and future well-designed studies are required to firmly establish the clinical efficacy of citrus and/or its extracts intervention on body weight.

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PMID: 

J Ethnopharmacol. 2020 Apr 24 ;252:112575. Epub 2020 Jan 15. PMID: 31953201

Abstract Title: 

Metabolites from the citrus extracts inhibit the activity of selected proteins in Indian Cobra (Naja naja) venom.

Abstract: 

ETHNOPHARMACOLOGICAL RELEVANCE: Snakebite is a severe problem in many parts of the world, specifically in tropical and subtropical regions. A range of medicinal plant extracts are administered for treating snake bite. Of the many common plants, extracts of Citrus species have been documented to be used for treating snake bite and have been shown to decrease the snake venom toxicity.AIM: The aim of the current work is to evaluate the utility of citrus peel extracts (Citrus aurantium L. and Citrus reticulate Blanco) in the management of Indian cobra envenomation.MATERIALS AND METHODS: Peels of citrus species were evaluated for their phospholipase A, protease and haemolytic inhibition properties. The phytochemicals present in the extract were inferred using GC-MS. In-vivo studies, using mice model, were done to confirm the inhibitory effect of the extracts. Molecular docking was used to understand the possible binding modes of selected phytochemicals to snake venom phospholipase.RESULTS: Citrus peel extracts are rich in polyphenols, flavonoids and tannins. The methanolic extract of Citrus aurantium L. and Citrus reticulate Blanco inhibits phospholipase (75%), protease (71%) and hemolysis (80%) activity of the venom. GC-MS analyses indicate the presence ofβ-sitosterol, n-hexadecanoic acid, eicosanoic acid, and flavone in both the extracts. In addition, C. reticulate extract contains α-tocopherol and squalene. Molecular docking revealed that α-tocopherol, spiro [androst-5-ene-17,1'-cyclobutan]-2'-one,3-hydroxy-(3β,17β)- and β-sitosterol acetatebind with moderate affinity to the catalytic site of phospholipase A2.CONCLUSION: The present study provides new molecular insight and scientific evidence on the utility of the methanolic extracts of citrus peels to neutralize the venom toxins of Naja naja.

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Serious doubts about the accuracy of COVID-19 testing methods, results, mortality rates, and the supposedly unique and extreme lethality of this virus are starting to emerge, even within mainstream media and government reporting. A recent study released by Italy’s national health authority found that nearly everyone who was pronounced dead from COVID-19 was already struggling with serious chronic disease(s).

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