PMID: 

Mol Carcinog. 2020 Feb ;59(2):168-178. Epub 2019 Nov 25. PMID: 31763724

Abstract Title: 

Upregulation of DKK3 by miR-483-3p plays an important role in the chemoprevention of colorectal cancer mediated by black raspberry anthocyanins.

Abstract: 

It is reported that black raspberry (BRB) anthocyanins could act as a potential chemopreventive agent for colorectal cancer (CRC). However, the underlying mechanism by which BRB anthocyanins inhibits the carcinogenesis of CRC cells has not been elucidated. The abnormal expression of microRNAs (miRNAs) that target important tumor suppressor genes is usually associated with CRC development. In this study, we explored whether BRB anthocyanins could affect the expression of certain miRNAs in an azoxymethane (AOM)/dextran sulphate sodium (DSS)-induced CRC mouse model and human CRC cell lines. miRNA microarray analysis was used to determine the differences in miRNA expression between AOM/DSS-induced mice fed with a diet supplemented without or with BRB anthocyanins. The expression of one particular miRNA, miR-483-3p, was found to decrease dramatically in AOM/DSS-induced mice that were fed with a diet supplemented with BRB anthocyanins. Subsequent quantitative real-time polymerase chain reaction and Western blot analyses showed that the reduced expression of miR-483-3p was accompanied by an increased expression of Dickkopf 3 (DKK3), a potential target of miR-483-3p as predicted by bioinformatic analysis. The protein and messenger RNA levels of DKK3 were significantly upregulated when the miR-483-3p level was reduced by a miR-483-3p-specific inhibitor, suggesting that DKK3 might be the target gene of miR-483-3p. In addition, the downstream factors of the DKK3 signaling pathway, which included Wnt/β-catenin, also played a role in the miR-483-3p-mediated anticancer effect of BRB anthocyanins. Thus, miR-483-3p might be a potential target in BRB anthocyanin-mediated prevention of CRC.

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PMID: 

Cancer Prev Res (Phila). 2020 Jan 22. Epub 2020 Jan 22. PMID: 31969344

Abstract Title: 

Black Raspberry Inhibits Oral Tumors in Mice Treated with the Tobacco Smoke Constituent Dibenzo(def,p)chrysene via Genetic and Epigenetic Alterations.

Abstract: 

We previously reported that the environmental pollutant and tobacco smoke constituent dibenzo[def,p]chrysene (DBP) induced DNA damage, altered DNA methylation and induced oral squamous cell carcinoma (OSCC) in mice. In the present study, we showed that 5% dietary black raspberry (BRB) significantly reduced (p

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PMID: 

PLoS One. 2019 ;14(8):e0220548. Epub 2019 Aug 12. PMID: 31404064

Abstract Title: 

The implication of the crosstalk of Nrf2 with NOXs, and HMGB1 in ethanol-induced gastric ulcer: Potential protective effect is afforded by Raspberry Ketone.

Abstract: 

Ethanol consumption is one of the common causative agents implicated in gastric ulcer development. Oxidative stress plays a major role in the induction and development of gastric ulceration. NADPH oxidases (NOXs) and Nuclear factor erythroid 2-related factor 2 (Nrf2) are key players in ethanol-induced ulcers. High-mobility group box 1 (HMGB1), a ubiquitous nuclear protein, mediates various inflammation functions. However, the role of HMGB1 in ethanol-induced gastric ulcer is not yet elucidated. Raspberry Ketone (RK) is a natural phenolic compound with antioxidant and anti-inflammatory properties. In the present study, absolute ethanol (7.5 ml/kg) was used to induce gastric ulceration in rats. Raspberry Ketone (RK) (50 mg/kg) was given orally one hour before the administration of absolute ethanol. Interestingly, ethanol-induced gastric ulcer was associated with Nrf2 downregulation, which was correlated with NOX-1, 2 NOX-4, and HMGB1 upregulation, and was significantly reversed by RK pre-treatment. RK pre-treatment provided 80% gastroprotection. Gastroprotective properties of RK were mediated via antioxidant, anti-inflammatory (suppression of NF-kB and tumor necrosis factor-α), and antiapoptotic activities (reduction of Bax/Bcl2 ratio). Gastroprotective properties of RK were confirmed by histopathological examination. In conclusion, this study is the first to provide evidence to the role of HMGB1 in ethanol-induced gastric ulcer, and the crosstalk of Nrf2, NOXs and HMGB1. It also demonstrates that RK represents a promising gastroprotective activity comparable to omeprazole.

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PMID: 

Toxicol Res (Camb). 2019 Sep 1 ;8(5):663-676. Epub 2019 Jul 1. PMID: 31588343

Abstract Title: 

Hepatoprotective activity of raspberry ketone is mediatedinhibition of the NF-κB/TNF-α/caspase axis and mitochondrial apoptosis in chemically induced acute liver injury.

Abstract: 

Raspberry Ketone (RK) is a natural phenolic compound which is marketed nowadays as a popular weight-reducing remedy, with reported antioxidant and anti-inflammatory activities. However, its biological activity is not fully elucidated. Hepatotoxicity is the leading cause of acute liver failure in Europe and North America, and its management is still challenging. Therefore, this study aimed to assess the therapeutic detoxification activity of RK against liver injuryand to explore the underlying mechanisms using carbon tetrachloride (CCl)-induced hepatotoxicity as a model. First, a dose-response study using 4 different doses, 25, 50, 100, and 200 mg kgday, of RK was conducted. RK was administered for 5 days as a pretreatment, followed by a single dose of CCl(1 ml kg, 1 : 1 v/v CCl : olive oil)The RK dose of 200 mg kgshowed the greatest protective effect and was selected for further investigations. CClhepatotoxicity was confirmed by elevation of liver enzymes, and histopathological examination. CCl-induced oxidative stress was evident from increased lipid peroxidation measured as thiobarbituric acid reactive substances (TBARS) along with depleted superoxide dismutase (SOD), reduced glutathione (GSH), and total antioxidant capacity (TAC). Increased oxidative stress was associated with increased cytochrome c expression with subsequent activation of caspase-9 and caspase-3, in addition to DNA fragmentation reflecting apoptosis. CClalso induced the expression of inflammatory cytokines (NF-κB and TNF-α). Interestingly, RK hepatoprotective activity was evident from the reduction of liver enzymes, and maintenance of hepatocyte integrity and microstructures as evaluated by histopathological examination using H and E, and transmission electron microscopy. The antioxidant activity of RKwas demonstrated by the increase of TAC, SOD, and GSH, with a concomitant decrease of the TBARS level. Moreover, RK pretreatment inhibited CCl-induced upregulation of inflammatory mediators. RK antiapoptotic activity was indicated by the reduction of the expression of cytoplasmic cytochrome-C, a decrease of caspases, and inhibition of DNA fragmentation. In conclusion, this study demonstrates that RK is a promising hepatoprotective agent. The underlying mechanisms include antioxidant, anti-inflammatory, and anti-apoptotic activities. This is the first study reporting RK hepatoprotective activity in acute hepatic injury and approves its antiapoptotic effect in the liver.

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PMID: 

Biochem Pharmacol. 2020 Jan 10 ;174:113795. Epub 2020 Jan 10. PMID: 31926937

Abstract Title: 

Curcumol enhances the sensitivity of doxorubicin in triple-negative breast cancer via regulating the miR-181b-2-3p-ABCC3 axis.

Abstract: 

Chemoresistance is a major cause of recurrence and poor prognosis in triple-negative breast cancer (TNBC) patients. The essential oil of Rhizoma Curcumae has been recently reported to enhance the chemosensitivity of cancer cells. However, few reports have systematically illuminated the mechanism. Curcumol is the major component of the essential oil of Rhizoma Curcumae. Therefore, we wondered whether curcumol combined with chemotherapy could increase the anticancer effects. In the present study, we evaluated the anticancer effects of doxorubicin and curcumol alone or in combination by a series of growth proliferation and apoptosis assays in TNBC cells. Our results showed that curcumol enhanced the sensitivity of MDA-MB-231 cells to doxorubicin in vitro and in vivo. Through miRNA-seq, we found that miR-181b-2-3p was involved in the curcumol-mediated promotion of doxorubicin-sensitivity in both parental and doxorubicin-resistant MDA-MB-231 (MDA-MB-231/ADR) cells. Further study showed that miR-181b-2-3p suppressed ABCC3 expression by targeting its 3'UTR. More importantly, we identified that overexpression of miR-181b-2-3p sensitized MDA-MB-231/ADR cells to doxorubicin by inhibiting the drug efflux transporter ABCC3. Furthermore, we found that NFAT1 could be activated by curcumol. In addition, ChIP assay results revealed that NFAT1 could directly bind to the promoter region of miR-181b-2-3p. Finally, using PDX models, we identified that curcumol could enhance sensitivity to doxorubicin to suppress tumor growth by the miR-181b-2-3p-ABCC3 axis in vivo. Taken together, our study provides novel mechanistic evidence for curcumol-mediated sensitization to doxorubicin in TNBC, and it highlights the potential therapeutic usefulness of curcumol as an adjunct drug in TNBC patients with doxorubicin-resistance.

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PMID: 

Phytother Res. 2020 Jan 27. Epub 2020 Jan 27. PMID: 31989700

Abstract Title: 

Curcumol may reverse early and advanced liver fibrogenesis through downregulating the uPA/uPAR pathway.

Abstract: 

Previous studies have suggested strong antifibrotic activity of curcumol in the liver; the underlying mechanisms of which, however, remain largely unknown. Aiming to investigate the role of curcumol in regulating early and advanced liver fibrosis, we designed a rat model with advanced liver fibrosis and cell model with an initial fibrotic stage. Model rats induced by CCland alcohol presented advanced liver fibrosis with complete fibrous septa. The administration of curcumol (25 mg/kg or 50 mg/kg) resulted in reversal of liver fibrosis. Leptin-administrated liver sinusoidal endothelial cells presented defenestration and basement membrane components deposition, including laminin (LN) and type IV collagen (Col IV), the characteristics of capillarization by scanning electron microscopy and immunofluorescence assays. After treatment with curcumol (12.5, 25, or 50 mg/L), defenestration was restored and the levels of LN and Col IV were decreased, consistent with the rat model. Quantitative polymerase chain reaction and Western blot results revealed that increased levels of urokinase plasminogen activator (uPA)/ uPA receptor (uPAR) were observed both in vivo and in vitro, curcumol significantly reduced uPA/uPAR at both the mRNA and protein levels. Reduction of uPA/uPAR may be synergistic with matrix metallopeptidase 13 to reverse liver fibrogenesis. In conclusion, curcumol protects liver from phenotypic changes in the early and advanced fibrogenesis, possibly through uPA/uPAR pathway.

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PMID: 

Complement Ther Med. 2020 Jan ;48:102283. Epub 2019 Dec 17. PMID: 31987259

Abstract Title: 

The effects of curcumin supplementation on liver function, metabolic profile and body composition in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials.

Abstract: 

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Curcumin is the anti-inflammatory, antioxidant, anti-diabetic and also anti-hyperlipidemia agent and uses as herbal medicine for treating liver diseases.OBJECTIVE: The present systematic review and meta-analysis was conducted to investigate the effects of curcumin supplementation on metabolic markers and anthropometric parameters in patients with (NAFLD).METHODS: PubMed, Embase, Scopus, Web of Science and Cochrane Library were systematically searched to identify relevant randomized controlled trials (RCTs) investigating the effects of curcumin supplementation on the arms of this study in patients with NAFLD up to September 2019. Mean difference (MD) was pooled using a random effects model. Potential publication bias was assessed using Egger's weighted regression tests.RESULTS: After excluding irrelevant records, 9 RCTs included in this meta-analysis. Pooled results of included studies indicated a significant reduction in alanine transaminase (ALT), aspartate transaminase (AST), serum total cholesterol (TC), low density lipoprotein (LDL), fasting blood sugar (FBS), HOMA-IR, serum insulin and waist circumference (WC), but not in serum triglyceride (TG), high density lipoprotein (HDL), HbA1c, body weight and body mass index (BMI) following curcumin supplementation. Additionally, age- and baseline TC-based subgroup analysis indicated a significant reduction in TG and also duration- and dosage-based showed a significant change in BMI.CONCLUSION: The current study revealed that curcumin supplementation has favorable effect on metabolic markers and anthropometric parameters in patients with NAFLD.

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PMID: 

Environ Toxicol. 2020 Jan 29. Epub 2020 Jan 29. PMID: 31995279

Abstract Title: 

Pomegranate extract inhibits migration and invasion of oral cancer cells by downregulating matrix metalloproteinase-2/9 and epithelial-mesenchymal transition.

Abstract: 

Discovering drug candidates for the modulation of metastasis is of great importance in inhibiting oral cancer malignancy. Although most pomegranate extract applications aim at the antiproliferation of cancer cells, its antimetastatic effects remain unclear, especially for oral cancer cells. The aim of this study is to evaluate the change of two main metastasis characters, migration and invasion of oral cancer cells. Further, we want to explore the molecular mechanisms of action of pomegranate extract (POMx) at low cytotoxic concentration. We found that POMx ranged from 0 to 50 μg/mL showing low cytotoxicity to oral cancer cells. In the case of oral cancer HSC-3 and Ca9-22 cells, POMx inhibits wound healing migration, transwell migration, and matrix gel invasion. Mechanistically, POMx downregulates matrix metalloproteinase (MMP)-2 and MMP-9 activities and expressions as well as epithelial-mesenchymal transition (EMT) signaling. POMx upregulates extracellular signal-regulated kinases 1/2 (ERK1/2), but not c-Jun N-terminal kinase (JNK) and p38 expression. Addition of ERK1/2 inhibitor (PD98059) significantly recovered the POMx-suppressed transwell migration and MMP-2/-9 activities in HSC-3 cells. Taken together, these findings suggest to further test low cytotoxic concentrations of POMx as a potential antimetastatic therapy against oral cancer cells.

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PMID: 

Biomolecules. 2019 Aug 26 ;9(9). Epub 2019 Aug 26. PMID: 31454995

Abstract Title: 

The Inhibitory Effect of Cordycepin on the Proliferation of MCF-7 Breast Cancer Cells, and its Mechanism: An Investigation Using Network Pharmacology-Based Analysis.

Abstract: 

is a well-known medicinal mushroom. It is non-toxic and has clinical health benefits including cancer inhibition. However, the anticancer effects ofcultured in brown rice on breast cancer have not yet been reported. In this study, we simultaneously investigated the anticancer effects of cordycepin and an extract ofcultured in brown rice on MCF-7 human breast cancer cells using a cell viability assay, cell staining with Hoechst 33342, and an image-based cytometric assay. Theconcentrate exhibited significant MCF-7 cell inhibitory effects, and its ICvalue was 73.48µg/mL. Cordycepin also exhibited significant MCF-7 cell inhibitory effects, and its ICvalue was 9.58µM. We applied network pharmacological analysis to predict potential targets and pathways of cordycepin. The gene set enrichment analysis showed that the targets of cordycepin are mainly associated with the hedgehog signaling, apoptosis, p53 signaling, and estrogen signaling pathways. We further verified the predicted targets related to the apoptosis pathway using western blot analysis. Theconcentrate and cordycepin exhibited the ability to induce apoptotic cell death by increasing the cleavage of caspase-7 -8, and -9, increasing the Bcl-2-associated X protein/ B-cell lymphoma 2 (Bax/Bcl-2) protein expression ratio, and decreasing the protein expression of X-linked inhibitor of apoptosis protein (XIAP) in MCF-7 cells. Consequently, theconcentrate and cordycepin exhibited significant anticancer effects through their ability to induce apoptosis in breast cancer cells.

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PMID: 

Afr Health Sci. 2019 Jun ;19(2):2156-2163. PMID: 31656500

Abstract Title: 

Polysaccharides obtained fromofattenuated doxorubicin-induced cytotoxic effects in chemotherapy.

Abstract: 

Objectives: militaris has been used as a herbal tonic in traditional Chinese medicine, which could be surface liquid-cultured forproduction. To evaluate the potential of polysaccharides obtained fromof(PS-MCM) for attenuation of side-effects of chemotherapy.Methods: Doxorubicin was used to induce cytotoxicity in THP-1 monocytes and EL-4 T cells, and the effects of PS-MCM on cell viability and cytokine production were detected on doxorubicin-treated THP-1 and EL-4 cells.Results: PS-MCM reduced doxorubicin-induced cell death and promoted cell proliferation in THP-1 and EL-4 cells. Moreover, PS-MCM elevated the level of cytokines associated with immune-modulation of THP-1 and EL-4 cells.Conclusion: These findings indicate that PS-MCM has potential for development as a functional food to counteract side effects of chemotherapy.

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