PMID: 

J Exp Clin Cancer Res. 2020 May 14 ;39(1):88. Epub 2020 May 14. PMID: 32410646

Abstract Title: 

Promotion of ubiquitination-dependent survivin destruction contributes to xanthohumol-mediated tumor suppression and overcomes radioresistance in human oral squamous cell carcinoma.

Abstract: 

BACKGROUND: Overexpression of survivin plays a crucial role in tumorigenesis and correlates with poor prognosis in human malignancies. Thus, survivin has been proposed as an attractive target for new anti-tumor interventions.METHODS: A natural product library was used for natural compound screening through MTS assay. The expression of survivin in oral squamous cell carcinoma (OSCC) and the inhibitory effect of xanthohumol (XN) on OSCC were examined by anchorage-dependent and -independent growth assays, immunoblot, immunofluorescence, immunohistochemical staining, ubiquitination analysis, co-immunoprecipitation assay, CRISPR-Cas9-based gene knockout, and xenograft experiment.RESULTS: Survivin is highly expressed in OSCC patient-derived tissues and cell lines. Knockout of survivin reduced the tumorigenic properties of OSCC cells in vitro and in vivo. With a natural compound screening, we identified that xanthohumol inhibited OSCC cells by reducing survivin protein level and activating mitochondrial apoptotic signaling. Xanthohumol inhibited the Akt-Wee1-CDK1 signaling, which in turn decreased survivin phosphorylation on Thr34, and facilitated E3 ligase Fbxl7-mediated survivin ubiquitination and degradation. Xanthohumol alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors.CONCLUSION: Our findings indicate that targeting survivin for degradation might a promising strategy for OSCC treatment.

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PMID: 

J Cancer. 2020 ;11(14):4047-4058. Epub 2020 Apr 6. PMID: 32368287

Abstract Title: 

Xanthohumol suppresses glioblastoma via modulation of Hexokinase 2 -mediated glycolysis.

Abstract: 

Deregulation of aerobic glycolysis is a common phenomenon in human cancers, including glioblastoma (GBM). In the present study, we demonstrated that the natural compound xanthohumol has a profound anti-tumor effect on GBM via direct inhibition of glycolysis. Xanthohumol suppressed cell proliferation and colony formation of GBM cells, and significantly impaired glucose metabolism via inhibiting Hexokinase 2 (HK2) expression. We demonstrated that down-regulation of c-Myc was required for xanthohumol-induced decrease of HK2. Xanthohumol destabilization of c-Myc, and promoted FBW7-mediated ubiquitination of c-Myc. Xanthohumol attenuated Akt activity and inhibited the activation of GSK3β, resulted in c-Myc degradation. Overexpression of Myr-Akt1 significantly rescued xanthohumol-mediated c-Myc inhibition and glycolysis suppression. Finally, the xanthohumol-mediated down-regulation of the PI3-K/Akt-GSK3beta-FBW7 signaling axis promoted the destabilization of c-Myc. Finally, the animal results demonstrated that xanthohumol substantially inhibited tumor growth. Collectively, xanthohumol appears to be a promising new anti-tumor agent with the therapeutic potential for GBM.

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PMID: 

Life Sci. 2020 May 15:117807. Epub 2020 May 15. PMID: 32422304

Abstract Title: 

Xanthohumol regulates miR-4749-5p-inhibited RFC2 signaling in enhancing temozolomide cytotoxicity to glioblastoma.

Abstract: 

AIMS: Xanthohumol (XN), a natural prenylated flavonoid isolated from Humulus lupulus L. (hops), possess the therapeutic effects in glioblastoma multiforme (GBM), which is a grade IV aggressive glioma in adults. However, low bioavailability and extractive yield limit the clinical applications of XN. To comprehensively investigate XN-mediated gene networks in inducing cell death is helpful for drug development and cancer research. Therefore, we aim to identify the detailed molecular mechanisms of XN's effects on exhibiting cytotoxicity for GBM therapy.METHODS AND KEY FINDINGS: XN significantly induced GBM cell death and enhanced temozolomide (TMZ) cytotoxicity, a first-line therapeutic drug of GBM. XN-mediated transcriptome profiles and canonical pathways were identified. DNA repair signaling, a well-established mechanism against TMZ cytotoxicity, was significantly correlated with XN-downregulated genes. Replication factor C subunit 2 (RFC2), a DNA repair-related gene, was obviously downregulated in XN-treated cells. Higher RFC2 levels which occupied poor patient survival were also observed in high grade GBM patients and tumors. Inhibition of RFC2 reduced cell viability, induced cell apoptosis, and enhanced both XN and TMZ cytotoxicity. By intersecting array data, bioinformatic prediction, and in vitro experiments, microRNA (miR)-4749-5p, a XN-upregulated microRNA, was identified to target to RFC2 3'UTR and inhibited RFC2 expression. A negative correlation existed between miR-4749-5p and RFC2 in GBM patients. Overexpression of miR-4749-5p significantly promoted XN- and TMZ-mediated cytotoxicity, and reduced RFC2 levels.SIGNIFICANCE: Consequently, we suggest that miR-4749-5p targeting RFC2 signaling participates in XN-enhanced TMZ cytotoxicity of GBM. Our findings provide new potential therapeutic directions for future GBM therapy.

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PMID: 

Int J Mol Sci. 2020 Apr 3 ;21(7). Epub 2020 Apr 3. PMID: 32260306

Abstract Title: 

Therapeutic Effect of Seaweed Derived Xanthophyl Carotenoid on Obesity Management; Overview of the Last Decade.

Abstract: 

Present-day lifestyles associated with high calorie-fat intake and accumulation, as well as energy imbalance, have led to the development of obesity and its comorbidities, which have emerged as some of the major health issues globally. To combat the disease, many studies have reported the anti-obesity effects of natural compounds in foods, with some advantages over chemical treatments. Carotenoids, such as xanthophyll derived from seaweeds, have attracted the attention of researchers due to their notable biological activities, which are associated mainly with their antioxidant properties. Their involvement in oxidative stress modulation, the regulation of major transcription factors and enzymes, and their antagonistic effects on various obesity parameters have been examined in both in vitro and in vivo studies. The present review is a collation of published research over the last decade on the antioxidant properties of seaweed xanthophyll carotenoids, with a focus on fucoxanthin and astaxanthin and their mechanisms of action in obesity prevention and treatment.

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PMID: 

Environ Toxicol. 2020 May 25. Epub 2020 May 25. PMID: 32449842

Abstract Title: 

Fucoxanthin treatment inhibits nasopharyngeal carcinoma cell proliferation through induction of autophagy mechanism.

Abstract: 

Nasopharyngeal carcinoma (NPC) arises from the epithelium of the nasopharyngeal mucosa. Elderly people above the age of 65 years are more susceptible to NPC. Nasopharyngectomy is the renowned treatment procedure to NPC; however, it is too risky due to its complicated surgical procedure. Other treatment methods also reported with serious side effects such brain injury; hence, the alternative anticancer drug without any side effects was needed. Fucoxanthin is a carotenoid derived from marine algae with the numerous pharmacological functions. This study aims to examine the inhibitory potential in NPC cell proliferation via apoptosis and autophagy. The cytotoxicity of fucoxanthin on C666-1 cells was observed by theMTT assay. The expression of autophagy-linked proteins was assessed with immunoblotting analysis. The expression of autophagy protein LC3 was estimated using immunocytochemical analysis in C666-1 and GFP-LC3 transfected cells. Furthermore, the fucoxanthin-treated C666-1 cells were analyzed with TUNEL assay. The apoptotic level in the fucoxanthin-treated C666-1 cells was evaluated using acridine orange staining. Fucoxanthin significantly increased the expression of autophagy-linked proteins which is clearly depicted in the immunoblotting analysis and immunocytochemical analysis of GFP-tagged LC3 protein. The results of TUNEL assay of fucoxanthin-treated C666-1 in the presence autophagy inhibitors demonstrated the induction of autophagy by fucoxanthin. Acridine orange staining results of C666-1 confirmed fucoxanthin decreases the expression of autophagy-linked proteins during stressed condition thereby causes apoptosis. Our overall results authentically conclude that fucoxanthin induces autophagy and apoptosis in NPC cell line, and it can be ideal agent to treat nasopharyngeal cancer in future with further investigations.

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PMID: 

Int J Biol Macromol. 2020 May 21. Epub 2020 May 21. PMID: 32446898

Abstract Title: 

Studies on isolation, characterization of fucoidan from brown algae Turbinaria decurrens and evaluation of it's in vivo and in vitro anti-inflammatory activities.

Abstract: 

In the present study, the anti-nociception and anti-inflammatory activity of fucoidan isolated from T. Decurrens on formalin induced paw-edema in mice model were investigated. The extracted fucoidan contain 54.86% of total sugar, 23.51% of sulfate and 3.4% of protein. The monosaccharide composition analysis revealed that fucoidan encompassed of fucose (59.3%), galactose (12.6%), mannose (9.6%), rhamnose (6.4%) and xylose (11.4%). Further, the structural characterization was done by UV-visible spectroscopy, X-ray diffraction, FT-IR andHNMR analysis. The fucoidan reduced the licking time thereby suggesting anti-nociceptive effect and decreased the size of paw swelling in the formalin induced inflammatory edema condition. The isolated fucoidan could significantly decreased the MDA and also increase the SOD, CAT, GPx, GST and GSH activity in paw edema tissue of formalin injected mice. Furthermore, fucoidan administration retained p65/NF-κB transcription factor in the cytosol thereby showing down regulation of the gene expression of pro-inflammatory mediators such as IL-1β, COX-2and MMP-9 in fucoidan treated mice. The anti-inflammatory effect of fucoidan was attributed to its capacity on modulating the levels of enzymatic antioxidants, master regulator NF-κB and pro-inflammatory cytokines. The fucoidan has reduced LPS induced cytotoxicity in IC-21 macrophage at a dose depended on manner.

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PMID: 

Inflammation. 2020 Mar 24. Epub 2020 Mar 24. PMID: 32212036

Abstract Title: 

Immunomodulating Properties of Carrageenan from Tichocarpus crinitus.

Abstract: 

Several in vivo immunotropic effects ofκ/β-carrageenan isolated from the red algae Tichocarpus crinitus were studied, by orally administering it at 100 mg/kg/day to mice for 7 days. Serum levels of IFN-γ, IL-12, IL-1β, and IL-4 were measured. Carrageenan's ability to influence development of LPS-induced inflammation was also assessed. Oral administration of κ/β-carrageenan increased serum levels of all the studied cytokines at least twice in comparison to the intact mice, while intraperitoneal LPS injection at 1 mg/kg increased concentration of only the pro-inflammatory cytokines: IFN-γ, IL-12, and IL-1β. Furthermore, κ/β-carrageenan demonstrated a higher efficacy at inducing IFN-γ production than LPS. Previous 7-day-long oral carrageenan administration impaired development of LPS-induced inflammation: level of IL-1β dropped below that found in intact mice, while IFN-γ and IL-12 concentrations were at least 40% lower than in mice with LPS-induced inflammation. Murine peritoneal macrophages were also affected by the oral administration of the κ/β-carrageenan: their motility was increased, and morphology altered. In sum, we have demonstrated that κ/β-carrageenan, when administered orally, is not only not immunologically inert, but at the dose of 100 mg/kg possesses pharmacologically exploitable effects.

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PMID: 

Mar Drugs. 2020 Apr 22 ;18(4). Epub 2020 Apr 22. PMID: 32331442

Abstract Title: 

The Comparative Analysis of Antiviral Activity of Native and Modified Fucoidans from Brown AlgaeIn Vitro and In Vivo.

Abstract: 

The enzymatic depolymerization of fucoidans from brown algae allowed the production of their standardized derivatives with different biological activities. This work aimed to compare the antiviral activities of native (FeF) and modified with enzyme (FeHMP) fucoidans from. The cytotoxicity and antiviral activities of the FeF and FeHMP against herpes viruses (HSV-1, HSV-2), enterovirus (ECHO-1), and human immunodeficiency virus (HIV-1) in Vero and human MT-4 cell lines were examined by methylthiazolyltetrazolium bromide (MTT) and cytopathic effect (CPE) reduction assays, respectively. The efficacy of fucoidans in vivo was evaluated in the outbred mice model of vaginitis caused by HSV-2. We have shown that both FeF and FeHMP significantly inhibited virus-induced CPE in vitro and were more effective against HSV. FeF exhibited antiviral activity against HSV-2 with a selective index (SI)>40, and FeHMP with SI˃ 20, when they were added before virus infection or at the early stages of the HSV-2 lifecycle. Furthermore, in vivo studies showed that after intraperitoneal administration (10 mg/kg), both FeF and FeHMP protected mice from lethal intravaginal HSV-2 infection to approximately the same degree (44-56%). Thus, FeF and FeHMP have comparable potency against several DNA and RNA viruses, allowing us to consider the studied fucoidans as promising broad-spectrum antivirals.

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PMID: 

Mar Drugs. 2020 May 13 ;18(5). Epub 2020 May 13. PMID: 32414158

Abstract Title: 

Anti-Influenza A Virus Activity of Rhamnan Sulfate from Green Algaein Mice with Normal and Compromised Immunity.

Abstract: 

Influenza viruses cause a significant public health burden each year despite the availability of anti-influenza drugs and vaccines. Therefore, new anti-influenza virus agents are needed. Rhamnan sulfate (RS) is a sulfated polysaccharide derived from the green alga. Here, we aimed to demonstrate the antiviral activity of RS, especially against influenza A virus (IFV) infection, in vitro and in vivo. RS showed inhibitory effects on viral proliferation of enveloped viruses in vitro. Evaluation of the anti-IFV activity of RS in vitro showed that it inhibited both virus adsorption and entry steps. The oral administration of RS in IFV-infected immunocompetent and immunocompromised mice suppressed viral proliferation in both mouse types. The oral administration of RS also had stimulatory effects on neutralizing antibody production. Fluorescent analysis showed that RS colocalized with M cells in Peyer's patches, suggesting that RS bound to the M cells and may be incorporated into the Peyer's patches, which are essential to intestinal immunity. In summary, RS inhibits influenza virus infection and promotes antibody production, suggesting that RS is a potential candidate for the treatment of influenza virus infections.

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PMID: 

Biomed Pharmacother. 2020 May 1 ;127:110178. Epub 2020 May 1. PMID: 32371317

Abstract Title: 

Microalgae extracts: Potential anti-Trypanosoma cruzi agents?

Abstract: 

INTRODUCTION: Chagas disease, caused by the protozoan parasiteTrypanosoma cruzi, has no effective treatment available. On the other hand, microalgae are aquatic organisms that constitute an interesting reservoir of biologically active metabolites. Moreover, some species of green and red algae present anti-protozoan activity. Our aim was to study the antiparasitic effects of aqueous, methanolic and ethanolic extracts from different microalgae.METHODS AND RESULTS: Our results show that the methanolic extracts of S. obliquus and T. suecica as well as the ethanolic extracts of C. reinhardtii and T. suecica present trypanocidal activity on the infective extracellular trypomastigotes and intracellular amastigotes. In addition, the ethanolic extract of C. reinhardtii potentiates the activity of the conventional antichagasic drug nifurtimox. In order to identify some potential compounds with trypanocidal activity, we performed a phytochemical screening analyzing the presence of phenolic compounds, pigments and terpenoids.CONCLUSION: The different microalgae extracts, particularly the ethanolic extract ofC. reinhardtii, are promising potential candidates for the development of future natural antichagasic drugs.

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