PMID: 

Heliyon. 2019 Aug ;5(8):e02371. Epub 2019 Aug 28. PMID: 31517099

Abstract Title: 

α-Lipoic acid exerts a primary prevention for the cardiac dysfunction in aortocaval fistula-created rat hearts.

Abstract: 

Aim: α-Lipoic acid exerts a powerful antioxidant effect by acting as a free radical scavenger and inducing endogenous antioxidants such as vitamin E and glutathione. In the present study, we examined the effects of α-lipoic acid on cardiac dysfunction in rat hearts with aortocaval fistulae.Main methods: Aortocaval fistulae were created between the abdominal aorta and inferior vena cava in male rats. Hemodynamic parameters were measured 14 days after surgery using an intravascular pressure transducer, and then these hearts were harvested for tissue weight measurement, pathological evaluation, and mRNA isolation.Results: In vehicle-treated rats, left ventricular end-diastolic pressure and left ventricular weight significantly increased at 14 days after fistula creation. Fistula-creation resulted in expression of 4-hydroxy-2-nonenal, NADPH oxidase subunit p67and BNP mRNA in a time-dependent manner in the left ventricle.Long-term treatment (initiated 2 days before surgery, and continued for 14 days after fistula creation; days -2 to 14) withα-lipoic acid (30 mg/kg/day) markedly suppressed the increases in left and right ventricular weight, and left ventricular end-diastolic pressure. α-Lipoic acid treatment from days -2 to 14 prominently prevented the expression of 4-hydroxy-2-nonenal and NADPH oxidase subunit p67, and significantly raised BNP mRNA levels. Short-term treatment withα-lipoic acid from day – 2 to 7 was effective in preventing cardiac enlargement and dysfunction, similar to long-term treatment, but treatment from days 7-14 was not effective.Conclusions: Treatment withα-lipoic acid can prevent cardiac hyperplasia and dysfunction, probably by inhibiting superoxide production and enhancing BNP mRNA expression in an early phase after fistula creation.

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PMID: 

Nutrients. 2019 Oct 19 ;11(10). Epub 2019 Oct 19. PMID: 31635029

Abstract Title: 

α-Lipoic Acid Inhibits IL-8 Expression by Activating Nrf2 Signaling in-infected Gastric Epithelial Cells.

Abstract: 

causes gastritis and gastric cancers. Oxidative stress is involved in the pathological mechanism of-induced gastritis and gastric cancer induction. Therefore, reducing oxidative stress may be beneficial for preventing the development of-associated gastric diseases. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a crucial regulator for the expression of antioxidant enzyme heme oxygenase-1 (HO-1), which protects cells from oxidative injury.α-Lipoic acid (α-LA), a naturally occurring dithiol, shows antioxidant and anti-inflammatory effects in various cells. In the present study, we examined the mechanism by which α-LA activates the Nrf2/HO-1 pathway, suppresses the production of pro-inflammatory cytokine interleukine-8 (IL-8), and reduces reactive oxygen species (ROS) in-infected AGS cells.α-LA increased the level of phosphorylated and nuclear-translocated Nrf2 by decreasing the amount of Nrf2 sequestered in the cytoplasm by complex formation with Kelch-like ECH1-associated protein 1 (KEAP 1). By using exogenous inhibitors targeting Nrf2 and HO-1, we showed that up-regulation of activated Nrf2 and of HO-1 results in the α-LA-induced suppression of interleukin 8 (IL-8) and ROS. Consumption of α-LA-rich foods may prevent the development of-associated gastric diseases by decreasing ROS-mediated IL-8 expression in gastric epithelial cells.

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PMID: 

Nutr Neurosci. 2019 Oct 4:1-14. Epub 2019 Oct 4. PMID: 31583983

Abstract Title: 

The effect ofhydroalcoholic extract on memory and lung changes induced by rats that inhaled paraquat.

Abstract: 

The effects of hydroalcoholic extract of() on memory changes, as well as lung injury due to inhaled paraqut (PQ) in rat, were examined.Control group of rat with saline aerosol administration, PQ groups with PQ aerosol (27 and 54 mg/m) administration, PQ groups treated with two doses of the extract (200 and 800 mg/kg/day) and dexamethasone (0.03 mg/kg/day) were studied. Shuttle box and Morris Water Maze (MWM) tests were carried out as well as oxidant, anti-oxidant markers, total and differential white blood cell (WBC) counts and cytokine levels in broncho-alveolar lavage (BALF).Inhaled PQ significantly increased the escape latency and travelled distance in MWM test, but the time spent in the target quadrant on the probe day was significantly reduced (

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PMID: 

Environ Toxicol. 2019 Oct 6. Epub 2019 Oct 6. PMID: 31587482

Abstract Title: 

Benzyl isothiocyanate promotes miR-99a expression through ERK/AP-1-dependent pathway in bladder cancer cells.

Abstract: 

Benzyl isothiocyanate (BITC), a bioactive natural product present in cruciferous vegetables, has been proved to prevent cancer progression through various mechanisms. In our previous report, we proved that BITC exhibits antitumor effects in bladder cancer by suppressing IGF1R, FGFR3, and mTOR, which is mediated by miR-99a expression. In this study, we identified the signal pathway involved in regulating miR-99a expression after BITC exposure in bladder cancer. Treatment with different BITC concentrations resulted in induction of miR-99a expression in bladder cancer cell lines. Activation of extracellular signal-regulated protein kinase (ERK) and c-jun N-terminal kinase was observed in bladder cancer after BITC treatment for 24 hours. Interestingly, by using a chemical inhibitor of candidate pathways, we found that only the ERK signal pathway is required for miR-99a expression. Furthermore, we evaluated the transcription factor that may contribute to miR-99a expression in response to BITC treatment. The results indicated that c-Jun/AP-1 was activated after BITC treatment. Moreover, we confirmed c-Jun/AP-1 activation through immunofluorescence and the luciferase reporter assay. The results showed that BITC treatment markedly improved nuclear translocation of c-Jun/AP-1 and luciferase activity dose dependently. Finally, pretreatment with the ERK inhibitor U0126 diminished c-Jun phosphorylation and transcriptional activation, suggesting that BITC elicits ERK/c-Jun signal transduction, which is responsible for miR-99a expression in bladder cancer. The present work identifies the mechanism involved in upregulation miR-99a after BITC treatment, which provides an explanation for BITC biological function in our previous work.

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PMID: 

Am J Chin Med. 2019 Oct 23:1-16. Epub 2019 Oct 23. PMID: 31645124

Abstract Title: 

Ginsenoside Rh2 Suppresses Breast Cancer Cell Proliferation by Epigenetically Regulating the Long Noncoding RNA C3orf67-AS1.

Abstract: 

Ginsenoside Rh2, a major bioactive ingredient abundant in red ginseng, has an antiproliferative effect on various cancer cells. In this study, we report a novel long noncoding RNA, C3orf67-AS1, which was identified as being hypermethylated at a CpG site of the promoter by Rh2 in MCF-7 cancer cells. Rh2-induced hypermethylation was responsible for the lower gene expression; the expression was recovered following treatment with a methyltransferase inhibitor, 5-aza-2-deoxycytidine. When C3orf67-AS1 was downregulated by a siRNA, the cell growth rate was decreased, demonstrating the RNA's oncogenic activity. Accordingly, breast cancer patients showed a lower methylation and higher expression level of C3orf67-AS1. Within 800 kb flanking C3orf67-AS1 on the chromosome, eight genes were found, and four genes including C3orf67 (the sense strand gene of C3orf67-AS1) were downregulated by Rh2. In particular, C3orf67 was downregulated when C3orf67-AS1 was suppressed by a siRNA; however, the expression of C3orf67-AS1 was not affected by C3orf67. Taken together, this study identifies a novel noncoding RNA, C3orf67-AS1, of which the expression could be suppressed by Rh2 via promoter methylation, thereby mediating the anti-proliferative effect of the ginsenoside.

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PMID: 

Cell Oncol (Dordr). 2019 Aug 2. Epub 2019 Aug 2. PMID: 31376137

Abstract Title: 

Phenethyl isothiocyanate hampers growth and progression of HER2-positive breast and ovarian carcinoma by targeting their stem cell compartment.

Abstract: 

PURPOSE: Isothiocyanates elicit anticancer effects by targeting cancer stem cells (CSCs). Here, we tested the antitumor activity of phenethyl-isothiocyanate (PEITC), either alone or in combination with trastuzumab, in HER2-positive tumor models.METHODS: We assessed the in vitro anticancer activity of PEITC, alone or combined with trastuzumab, in HER2-positive BT474, SKBR3, HCC1954 and SKOV3 cancer cells by measuring their sphere forming efficiency (SFE). The expression of the human/rodent CSC biomarkers aldehyde-dehydrogenase (ALDH) and CD29/CD24/Sca1was evaluated by cytofluorimetric analysis. The expression of wild type HER2 (WTHER2), its splice variant d16HER2 and NOTCH was analysed by quantitative RT-PCR and Western blotting. The in vivo activity of PEITC and trastuzumab was evaluated in mice orthotopically implanted with MI6 tumor cells transgenic for the human d16HER2 splice isoform. Magnetic resonance imaging/spectroscopy and immunohistochemistry were used to assess morpho-functional and metabolic profiles of treated versus untreated mice.RESULTS: We found that PEITC significantly impaired the SFE of HER2-positive human cancer cells by decreasing their ALDH-positive compartments. The anti-CSC activity of PEITC was demonstrated by a reduced expression/activation of established cancer-stemness biomarkers. Similar results were obtained with MI6 cells, where PEITC, alone or in combination with trastuzumab, significantly inhibited their SFE. We also found that PEITC hampered the in vivo growth of MI6 nodules by inducing hemorrhagic and necrotic intra-tumor areas and, in combination with trastuzumab, by significantly reducing spontaneous tumor development in d16HER2 transgenic mice.CONCLUSIONS: Our results indicate that PEITC targets HER2-positive CSCs and that its combination with trastuzumab may pave the way for a novel therapeutic strategy for HER2-positive tumors.

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PMID: 

Cell Commun Signal. 2019 Oct 16 ;17(1):127. Epub 2019 Oct 16. PMID: 31619257

Abstract Title: 

Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1-mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma.

Abstract: 

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Phloretin (PH) possesses anticancer, antitumor, and hepatoprotective effects, however, the effects and potential mechanisms of phloretin remain elusive.METHODS: Five HCC cells were tested in vitro for sensitivity to PH, Sorafenib (Sor) or both and the apoptosis, signal transduction and phosphatase activity were analyzed. To validate the role of SHP-1, we used PTP inhibitor III and SHP-1 siRNA. Further, we used purified SHP-1 proteins or HCC cells expressing deletion N-SH2 domain or D61A point mutants to study the PH efficacy on SHP-1. The `invivo studies were conducted using HepG2 and SK-Hep1 and Sor resistant HepG2and Huh7xenografts. Molecular docking was done with Swiss dock and Auto Dock Vina.RESULTS: PH inhibited cell growth and induced apoptosis in all HCC cells by upregulating SHP-1 expression and downregulating STAT3 expression and further inhibited pAKT/pERK signaling. PH activated SHP-1 by disruption of autoinhibition of SHP-1, leading to reduced p-STAT3level. PH induced apoptosis in two Sor-resistant cell lines and overcome STAT3, AKT, MAPK and VEGFR2 dependent Sor resistance in HCCs. PH potently inhibited tumor growth in both Sor-sensitive and Sor-resistant xenografts in vivo by impairing angiogenesis, cell proliferation and inducing apoptosis via targeting the SHP-1/STAT3 signaling pathway.CONCLUSION: Our data suggest that PH inhibits STAT3 activity in Sor-sensitive and -resistant HCCs via SHP-1-mediated inhibition of STAT3 and AKT/mTOR/JAK2/VEGFR2 pathway. Our results clearly indicate that PH may be a potent reagent for hepatocellular carcinoma and a noveltargeted therapy for further clinical investigations.

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PMID: 

Oxid Med Cell Longev. 2019 ;2019:1202676. Epub 2019 Aug 18. PMID: 31531177

Abstract Title: 

Malaysian Tualang Honey Inhibits Hydrogen Peroxide-Induced Endothelial Hyperpermeability.

Abstract: 

Malaysian Tualang honey (TH) is a known therapeutic honey extracted from the honeycombs of the Tualang tree (Koompassia excelsa) and has been reported for its antioxidant, anti-inflammatory, antiproliferative, and wound healing properties. However, the possible vascular protective effect of TH against oxidative stress remains unclear. In this study, the effects of TH on hydrogen peroxide- (HO-) elicited vascular hyperpermeability in human umbilical vein endothelial cells (HUVECs) and Balb/c mice were evaluated. Our data showed that TH concentrations ranging from 0.01% to 1.00% showed no cytotoxic effect to HUVECs. Induction with 0.5 mM HOwas found to increase HUVEC permeability, but the effect was significantly reversed attenuated by TH (

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PMID: 

Am J Physiol Renal Physiol. 2019 Sep 18. Epub 2019 Sep 18. PMID: 31532243

Abstract Title: 

Oral Delivery of Nanoparticle Urolithin A Normalizes Cellular Stress and Improves Survival in Mouse Model of Cisplatin-induced AKI.

Abstract: 

The popular anti-cancer drug cisplatin causes many adverse side-effects, the most serious of which is acute kidney injury (AKI). Emerging evidence from laboratory and clinical studies suggests that the AKI pathogenesis involves oxidative stress pathways; therefore, regulating such pathways may offer protection. Urolithin A (UA), a gut metabolite of the dietary tannin ellagic acid, possesses anti-oxidant properties, and has shown promise in mouse models of AKI. However, UA's therapeutic potential is constrained by poor bioavailability. We aimed to improve oral bioavailability of UA by formulating it into biodegradable nanoparticles that utilize a surface conjugated ligand targeting the gut-expressed transferrin receptor. Nanoparticle encapsulation of UA led to a 7-fold enhancement in oral bioavailability compared to native UA. Treatment with nanoparticle UA also significantly attenuated the histopathological hallmarks of cisplatin-induced AKI and reduced mortality by 63% in the mouse model. Expression analyses indicated that nanoparticle UA therapy coincided with oxidative stress mitigation and downregulation of Nrf2 and P53-inducible genes. Additionally, normalization of miRNA (miR-192-5p and miR-140-5p) implicated in AKI, PARP1 levels, anti-apoptotic signaling, intracellular NAD, and mitochondrial oxidative phosphorylation were observed in the treatment group. Our findings suggest that nanoparticles greatly increases the oral bioavailability of UA leading to improved survival rates in AKI mice, in part by reducing renal oxidative and apoptotic stress.

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PMID: 

Molecules. 2019 Oct 16 ;24(20). Epub 2019 Oct 16. PMID: 31623144

Abstract Title: 

Isoliquiritigenin Inhibits Ovarian Cancer Metastasis by Reversing Epithelial-to-Mesenchymal Transition.

Abstract: 

The epithelial-to-mesenchymal transition (EMT) plays a prominent role in cancer metastasis. Isoliquiritigenin (ISL), one of the flavonoids in licorice, has been shown to exhibit anticancer activities in many cancer types through various mechanisms. However, it is unknown whether ISL impacts the EMT process. Here, we show that ISL is able to suppress mesenchymal features of ovarian cancer SKOV3 and OVCAR5 cells, evidenced by an apparent morphological change from a mesenchymal to an epithelial phenotype and reduced levels of mesenchymal markers accompanied by the gain of E-cadherin expression. The suppression of EMT is also supported by the observed decrease in cell migration and in vitro invasion upon ISL treatment. Moreover, we show that ISL effectively blocks the intraperitoneal xenograft development of the SKOV3 cell line and prolonged the survival of tumor-bearing mice. These data suggest that ISL inhibits intraperitoneal ovary tumor development through the suppression of EMT, indicating that ISL may be an effective therapeutic agent against ovarian cancer.

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