PMID: 

Molecules. 2019 May 22 ;24(10). Epub 2019 May 22. PMID: 31121820

Abstract Title: 

Zerumbone Protects against Carbon Tetrachloride (CCl)-Induced Acute Liver Injury in Mice via Inhibiting Oxidative Stress and the Inflammatory Response: Involving the TLR4/NF-κB/COX-2 Pathway.

Abstract: 

The natural compound Zerumbone (hereinafter referred to as ZER), a monocyclic sesquiterpenoid, has been reported to possess many pharmacological properties, including antioxidant and anti-inflammatory properties. This study aimed to investigate the underlying mechanism of ZER against acute liver injury (ALI) in CCl-induced mice models. ICR mice were pretreated intraperitoneally with ZER for five days, then received a CClinjection two hours after the last ZER administration and were sacrificed 24 h later. Examination of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and the histopathological analysis confirmed the hepatoprotective effect of ZER. Biochemical assays revealed that ZER pretreatment recovered the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), restored the glutathione (GSH) reservoir, and reduced the production of malondialdehyde (MDA), all in a dose-dependent manner. Furthermore, administration of ZER in vivo reduced the release amounts of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) and inhibited the increased protein levels of Toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-κB) p-p65, and cyclooxygenase (COX-2). Further studies in lipopolysaccharide (LPS)-induced Raw264.7 inflammatory cellular models verified that ZER could inhibit inflammation via inactivating theTLR4/NF-κB/COX-2 pathway. Thus, our study indicated that ZER exhibited a hepatoprotective effect against ALI through its antioxidant and anti-inflammatory activities and the possible mechanism might be mediated by the TLR4/NF-κB/COX-2 pathway. Collectively, our studies indicate ZER could be a potential candidate for chemical liver injury treatment.

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PMID: 

Can J Microbiol. 2019 Oct ;65(10):713-721. Epub 2019 Jun 3. PMID: 31158320

Abstract Title: 

Zerumbone inhibitsbiofilm formation and hyphal growth.

Abstract: 

biofilm formation is considered an important matter because it can lead to strong resistance to conventional antifungal agents. Hyphae formed bycan also act as an important virulence factor related to its biofilm. The objective of this study was to determine the effect of zerumbone, a monocyclic sesquiterpene extracted from(L.) Smith, againstbiofilm formation. Our results suggest that zerumbone possesses antifungal and antibiofilm activity that inhibits biofilm formation and eradicates preformed biofilm. Notably, zerumbone considerably reduced carbohydrate and DNA contents of biofilm matrix. In addition, zerumbone showed antivirulence effects by decreasing the growth of hyphae and inhibiting morphologic changes of. Furthermore, zerumbone significantly downregulated expression levels of biofilm-related and hyphae-specific genes, includingand. Since zerumbone suppresses biofilm formation and hyphae growth, these results indicate that zerumbone could be used as a potential candidate to treat and preventbiofilm-related infections.

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PMID: 

Molecules. 2019 Jul 13 ;24(14). Epub 2019 Jul 13. PMID: 31337024

Abstract Title: 

Zerumbone Induces Apoptosis in Breast Cancer Cells by Targetingαvβ3 Integrin upon Co-Administration with TP5-iRGD Peptide.

Abstract: 

Cell-penetrating peptides (CPPs) are highly promising tools to deliver therapeutic molecules into tumours.αVβ3 integrins are cell-matrix adhesion receptors, and are considered as an attractive target for anticancer therapies owing to their roles in the process of metastasis and angiogenesis. Therefore, this study aims to assess the effect of co-administration of zerumbone (ZER) and ZERencapsulated inhydroxypropyl-β-cyclodextrin with TP5-iRGD peptide towards cell cytotoxicity, apoptosis induction, and proliferation of normal and cancerous breast cells utilizing in vitro assays, as well as to study the molecular docking of ZER in complex with TP5-iRGD peptide. Cell viability assay findings indicated that ZER and ZERencapsulated in hydroxypropyl-β-cyclodextrin (ZER-HPβCD) inhibited the growth of estrogen receptor positivebreast cancer cells (ERMCF-7) at 72 h treatment with an inhibitory concentration (IC)of 7.51± 0.2 and 5.08 ± 0.2 µg/mL, respectively, and inhibited the growth of triple negative breast cancer cells (MDA-MB-231) with an ICof 14.96± 1.52 µg/mL and 12.18 ± 0.7 µg/mL, respectively. On the other hand, TP5-iRGD peptide showed no significant cytotoxicity on both cancer and normal cells. Interestingly, co-administration of TP5-iRGD peptide in MCF-7 cells reduced the ICof ZER from 7.51± 0.2 µg/mL to 3.13 ± 0.7 µg/mL and reduced the ICof ZER-HPβCD from 5.08 ± 0.2 µg/mL to 0.49 ± 0.004 µg/mL, indicating that the co-administration enhances the potency and increases the efficacy of ZER and ZER-HPβCD compounds. Acridine orange (AO)/propidium iodide (PI) staining under fluorescence microscopy showed evidence of early apoptosis after 72 hfrom the co-administration of ZER or ZER-HPβCD with TP5-iRGD peptide in MCF-7 breast cancer cells. The findings of the computational modelling experiment provide novel insights into the ZER interaction with integrin αvβ3 in the presence of TP5-iRGD, and this could explain why ZER has better antitumor activities when co-administered with TP5-iRGD peptide.

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PMID: 

Microb Pathog. 2019 Dec ;137:103768. Epub 2019 Oct 1. PMID: 31585154

Abstract Title: 

Efficacy of zerumbone against dual-species biofilms of Candida albicans and Staphylococcus aureus.

Abstract: 

Candida albicans and Staphylococcus aureus are the most common opportunistic pathogens that co-exist as mixed biofilms. Dual-species biofilms of C. albicans and S. aureus cause nosocomial medical device-related infections that are strongly resistant to antibiotics and host immune responses compared with mono-species biofilms. The purpose of this study was to describe the efficacy of zerumbone derived from Zingiber zerumbet (L.) Smith, on dual-species biofilm formation. This study examined the inhibitory effects of zerumbone on planktonic cell growth, adhesion and biofilm formation. The results demonstrated that zerumbone remarkably inhibited mono- and dual-species biofilms formed by C. albicans and S. aureus using the XTT [2,3-bis(2-smethoxy-4-nitro-5-sulfo-phenyl)-2H-tetrazolium-5-carboxanilide]-reduction assay. Furthermore, a significant decrease in biomass and cell density of dual-species biofilms following zerumbone treatment was confirmed using confocal laser scanning microscopy (CLSM). Therefore, our study suggests that zerumbone is a potential antimicrobial and antibiofilm agent indicated for the therapeutic management of nosocomial medical device-related infections induced by dual-species biofilms of C. albicans and S. aureus.

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PMID: 

Folia Neuropathol. 2019 ;57(3):277-284. PMID: 31588714

Abstract Title: 

Zerumbone promotes proliferation of endogenous neural stem cells in vascular dementia by regulating Notch signalling.

Abstract: 

INTRODUCTION: Present investigation determines the effect of zerumbone on the proliferation of stem cells in vascular dementia (VD) rats.MATERIAL AND METHODS: Vascular dementia was induced by cerebral ischemia and reperfusion through non-invasive clamp. Rats were treated with zerumbone 50 mg/kg and 100 mg/kg intraperitoneally 30 min for four weeks after the surgery. Cognitive functions are determined by the Morris water maze (MWM) test and neurological function score in VD rats. Moreover mediators of inflammation and parameters of oxidative stress were estimated in the brain tissue homogenate of ischemia-induced vascular dementia rats. The expression of proteins and mRNA expressions were determined by western blot assay and RT-PCR methods. Moreover histopathological changes were observed by H&E staining on the brain tissue of vascular dementia rats.RESULTS: There was a significant reduction in the cognitive function and neurological score in the zerumbone-treated group compared to the VD group of rats. Data of the study reveal that treatment with zerumbone attenuates the altered level of cytokines and markers of oxidative stress parameters in the brain tissue of VD rats. The expression of NICD, Hes-1 and Nestin proteins was significantly (p

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PMID: 

Alzheimers Dement (N Y). 2019 ;5:637-643. Epub 2019 Oct 22. PMID: 31687471

Abstract Title: 

Effect of zerumbone on scopolamine-induced memory impairment and anxiety-like behaviours in rats.

Abstract: 

Introduction: We investigated the effects of zerumbone (1 and 10 mg/kg) against hyperactivity, anxiety and memory impairment in scopolamine-induced dementia in Sprague-Dawley rats.Methods: Open field tests, elevated plus maze and Morris water maze were performed to assess general locomotor activity, anxiety-like behaviours and learning and memory processes respectively in rats pretreated with scopolamine.Results: Scopolamine-treated rats showed high total activity, stereotype, and total distance travelled in the open field arena, reduced number of entries to open arms, decreased the percentage of time spent in open arms and higher escape latency time in the Morris water maze test. Interestingly, single administration of zerumbone (1 and 10 mg/kg) reversed the hyperactivity, anxiety-like behaviours, and learning impairment effects of scopolamine in the three experimental model studied respectively.Discussion: Our findings demonstrated that the scopolamine-induced impairment of learning and memory was reversed by the administration of zerumbone. As a conclusion, our findings presented the positive effects of zerumbone on dementia-like behaviours in the animal model used and could possibly contribute for future research to manage hyperactivity, anxiety, and learning disabilities.

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PMID: 

Pharmacol Res. 2019 Nov 2 ;150:104489. Epub 2019 Nov 2. PMID: 31689519

Abstract Title: 

Phloretin ameliorates dextran sulfate sodium-induced ulcerative colitis in mice by regulating the gut microbiota.

Abstract: 

Phloretin, extracted from the pericarp and velamen of apples or pears, is a dihydrochalcone flavonoid with anti-bacterial and anti-inflammatory activities. It has been reported that phloretin has anti-inflammatory effects in ulcerative colitis (UC) mice. However, the role of the gut microbiota in the phloretin anti-UC process remains unclear. In this study, we observed that the anti-UC effect of phloretin was affected by co-housing, probably because of the transmissible nature of the gut micobiota. Through fecal micobiota transplantation (FMT), the effects of the gut microbiota on the anti-UC of phloretin were further confirmed. UC was induced in mice by administrating 3% dextran sulfate sodium (DSS) in drinking water for 7 days. Phloretin (60 mg/kg) was administered by gavage every day during the experiment. Fecal microbes (10CFU/mL) from phloretin-treated UC mice were administered by gavage to non-phloretin-treated UC mice for 7 days. The results showed that FMT, like phloretin, ameliorated UC by improving disease symptoms and colon inflammation, balancing inflammatory cytokines, maintaining intestinal barrier integrity, restoring systemic immune function, inhibiting NF-κB and NLRP3 inflammasome activation and ameliorating the oxidant stress. Both FMT and phloretin treatment increased the levels of Bacteroidetes, Alistipes and Lactobacillus and decreased those of Firmicutes, Oscillibacter and Ruminiclostridium_6. Correlation analysis between gut microbes and micro-environmental factors revealed that Alistipes abundance was negatively correlated with DAI, pathological score, and TNF-α, IL-6 and IL-1β levels, and Alistipes was more abundant in phloretin or FMT treated UC mice. Oscillibacter abundance was significantly positively correlated with IL-6 and IL-1β levels and pathological score, and Oscillibacter was increased in UC mice. Furthermore, network analysis of the dominant genera revealed that Alistipes abundance was negatively related to Oscillibacter abundance. In conclusion, this study suggests that the anti-UC effects of phloretin are achieved through regulation of the gut microbiota and phloretin has the potential to be developed as a promising agent for the treatment of UC.

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PMID: 

J Cancer. 2019 ;10(26):6543-6556. Epub 2019 Oct 21. PMID: 31777584

Abstract Title: 

Synergistic inhibition of lung cancer cells by EGCG and NF-κB inhibitor BAY11-7082.

Abstract: 

Lung cancer has a poor 5-year survival rate and is the leading cause of cancer-related deaths worldwide. Thus, the development of more efficient therapeutic strategies is urgently needed. Many studies have shown that EGCG, a major polyphenol found in green tea, has potential anticancer effects. The present study aims to investigate the molecular mechanism of EGCG-mediated inhibition of proliferation in lung cancer cells and to explore the effects of combined treatment with EGCG and an NF-κB inhibitor, BAY11-7082, in A549 and H1299 cells bothand. Our results showed that EGCG inhibits cell proliferation and migration and induces apoptosis in A549 and H1299 cells at relatively high concentrations (IC50=86.4µM for A549 cells and 80.6 µM for H1299 cells). These effects are partially achieved via inhibition of the NF-κB signaling pathway. Combined treatment with EGCG and BAY11-7082, a potent NF-κB inhibitor, shows significant synergistic effects at relatively low concentrations. The inhibition rate reached approximately 50% in cells treated for 72 h with 20 µM EGCG and 5 µM (A549 cells) or 2.5 µM BAY11-7082 (H1299 cells). This synergistic anti-tumor effect was also observed in a xenograft model. These results indicated that EGCG inhibits lung cancer cell proliferation by suppressing NF-κB signaling. Coadministration of EGCG and BAY11-7082 has a synergistic effect bothandand may serve as a novel therapeutic strategy for lung cancer.

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PMID: 

J Pharmacol Exp Ther. 2019 Dec ;371(3):663-674. Epub 2019 Oct 3. PMID: 31582423

Abstract Title: 

Epicatechin-3-Gallate Signaling and Protection against Cardiac Ischemia/Reperfusion Injury.

Abstract: 

At concentrations found in humans after ingestion of one to two cups of green tea, epicatechin-3-gallate (ECG) modulates Na/K-ATPase conformation and activity. Akin to ouabain, an archetypal Na/K-ATPase ligand of the cardiotonic steroid (CTS) family, ECG also activates protein kinase C epsilon type (PKCε) translocation and increases the force of contraction of the rat heart. This study evaluated whether, like ouabain, ECG also modulates Na/K-ATPase/Src receptor function and triggers pre- and postconditioning against ischemia/reperfusion (I/R) injury. In vitro, ECG activated the purified Na/K-ATPase/Src complex. In Langendorff-perfused rat hearts, submicromolar concentrations of ECG administered either before or after ischemia reduced infarct size by more than 40%, decreased lactate dehydrogenase release, and improved the recovery of cardiac function. ECG protection was blocked by PKCinhibition and attenuated by mitochondrial Kchannel inhibition. In a unique mammalian cell system with depleted Na/K-ATPase1 expression, ECG-induced PKCactivation persisted but protection against I/R was blunted. Taken together, these results reveal a Na/K-ATPase- and PKC-dependent mechanism of protection by ECG that is also distinct from the mechanism of action of ouabain. These ECG properties likely contribute to the positive impact of green tea consumption on cardiovaascular health and warrant further investigation into the role of cardiac Na/K-ATPase signaling in the cardioprotective effect of green tea consumption. SIGNIFICANCE STATEMENT: Consumption of green tea, the richest dietary source of ECG, is associated with a reduced risk of cardiac mortality. Antioxidant effects of ECG and other tea polyphenols are well known, but reported for concentrations well above dietary levels. Therefore, the mechanism underlying the cardioprotective effect of green tea remains incompletely understood. This study provides experimental evidence that ECG concentrations commonly detected in humans after consumption of a cup of tea trigger the Na/K-ATPase/Src receptor in a cell-free system, activate a CTS-like signaling pathway, and provide PKC-dependent protection against ischemia/reperfusion injury in rat hearts. Mechanistic studies in mammalian cells with targeted Na/K-ATPase depletion revealed that although Na/K-ATPase does not mediate ECG-induced PKCactivation, it is required for ECG-induced protection against ischemia/reperfusion injury.

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PMID: 

Cancers (Basel). 2019 Oct 5 ;11(10). Epub 2019 Oct 5. PMID: 31590367

Abstract Title: 

Targeting Glycolysis with Epigallocatechin-3-Gallate Enhances the Efficacy of Chemotherapeutics in Pancreatic Cancer Cells and Xenografts.

Abstract: 

Pancreatic cancer is a complex disease, in need of new therapeutic approaches. In this study, we explored the effect and mechanism of action of epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, alone and in combination with current chemotherapeutics on pancreatic cancer cell growth, focusing on glycolysis metabolism. Moreover, we investigated whether EGCG's effect is dependent on its ability to induce reactive oxygen species (ROS). EGCG reduced pancreatic cancer cell growth in a concentration-dependent manner and the growth inhibition effect was further enhanced under glucose deprivation conditions. Mechanistically, EGCG induced ROS levels concentration-dependently. EGCG affected glycolysis by suppressing the extracellular acidification rate through the reduction of the activity and levels of the glycolytic enzymes phosphofructokinase and pyruvate kinase. Cotreatment with catalase abrogated EGCG's effect on phosphofructokinase and pyruvate kinase. Furthermore, EGCG sensitized gemcitabine to inhibit pancreatic cancer cell growth in vitro and in vivo. EGCG and gemcitabine, given alone, reduced pancreatic tumor xenograft growth by 40% and 52%, respectively, whereas the EGCG/gemcitabine combination reduced tumor growth by 67%. EGCG enhanced gemcitabine's effect on apoptosis, cell proliferation, cell cycle and further suppressed phosphofructokinase and pyruvate kinase levels. In conclusion, EGCG is a strong combination partner of gemcitabine reducing pancreatic cancer cell growth by suppressing glycolysis.

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