PMID: 

Anticancer Res. 2019 Nov ;39(11):6115-6123. PMID: 31704839

Abstract Title: 

Shikonin-induced Apoptosis of Colon Cancer Cells Is Reduced by Peroxiredoxin V Expression.

Abstract: 

BACKGROUND/AIM: Colon cancer is the second most common deadliest malignancy in the world and better understanding of its underlying mechanisms is needed to improve clinical management. Natural plant extracts are gaining attention in the development of new therapeutic strategies against various cancer types. Shikonin is a naturally extracted naphthoquinone pigment with effects against cancer, including colon cancer.MATERIALS AND METHODS: In this study, we conducted a series of in vitro experiments to show the effects of Shikonin on colon cancer cell apoptosis. A colon cancer cell line with overexpression of peroxiredoxin V (PrxV) was constructed and the relationship of PrxV expression with Shikonin-induced cell apoptosis was investigated.RESULTS: Shikonin induced colon cancer cell apoptosis via regulation of mammalian target of rapamycin signaling. Shikonin-induced cell apoptosis was abrogated by overexpression of PrxV.CONCLUSION: According to the results obtained in this study, targeting PrxV may provide new insight for the successful management of colon cancer by inducing cell apoptosis.

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PMID: 

Zhongguo Zhong Yao Za Zhi. 2014 Mar ;39(6):1058-63. PMID: 24956851

Abstract Title: 

[Effect of paeonol on adhesive function of rat vascular endothelial cells induced by lipopolysaccharide and co-cultured with smooth muscle cells].

Abstract: 

OBJECTIVE: To observe the changes in the adhesive function of vascular endothelial cells (VEC) and rat monocytes induced by lipopolysaccharide (LPS) and co-cultured with smooth muscle cells (SMC) and the intervention effect of paeonol (Pae).METHOD: Primary rat vascular endothelial cells (VECs) and rat vascular smooth muscle cells (VSMCs) were cultured by predigesting and adhering tissue blocks. The VEC-VSMC co-culture model was established by Transwell chamber. LPS was used to induce VEC injury. MTT assay and LDH assay were used to determine the VEC activity. ELISA assay was used to detect IL-1beta and TNF-alpha secreted by the VEC. The immunocytochemistry assay was carried out to detect the expression of ICAM-1. The Rose Bengal Staining was used to test adhesive function between VECs and monocytes.RESULT: The concentration of LPS-induced VEC injury was 100 microg x L(-1), and the time was 7 h. after the intervention on the above cell model for 24 h, Paeonol (15, 30, 60 micromol x L(-1)) could effectively inhibit LPS-induced VEC injury and VEC injury, significantly enhance the survival rate of LPS-injured VECs, decrease IL-1beta and TNF-alpha secreted by the injured VEC, and reduce the expression of ICAM-1, so as to inhibit the adhesion of LPS-induced VECs and monocytes.CONCLUSION: Paeonol could inhibit IL-1beta and TNF-alpha expression to protect VECs from being injured by LPS, and reduce ICAM-1 expression to inhibit the adhesion between VECs and monocytes.

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PMID: 

Biomol Ther (Seoul). 2014 Jul ;22(4):341-6. PMID: 25143814

Abstract Title: 

Antitumor and Apoptosis Induction Effects of Paeonol on Mice Bearing EMT6 Breast Carcinoma.

Abstract: 

Paeonol is a major phenolic micromolecular component of Moutan cortex Radicis, a traditional Chinese Medicine. It has shown antitumor effects in previous studies; however, the underlying mechanisms remain unknown. This study investigated the mechanism by giving treatments of placebo, cyclophosphamide, paeonol of 150 and 300 mg/kg to 4 groups of mice bearing EMT6 breast cancer. Apoptosis in tumor cells were confirmed by morphology analysis, including hematoxylin, eosin staining and TUNEL staining. The results showed that the weight of EMT6 breast tumor was significantly reduced in the groups treated with both 150 and 300 mg/kg of paeonol. Immunohistochemical and Western blot results showed that the expression of Bcl-2 was down-regulated while the expression of Bax, caspase 8 and caspase 3 was up-regulated respectively. These results suggest that paeonol exhibits antitumor effects and the mechanism of the inhibition is via induction of apoptosis, regulation of Bcl-2 and Bax expression, and activation of caspase 8 and caspase 3.

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PMID: 

Mediators Inflamm. 2014 ;2014:651890. Epub 2014 Aug 3. PMID: 25165413

Abstract Title: 

Paeonol attenuates cigarette smoke-induced lung inflammation by inhibiting ROS-sensitive inflammatory signaling.

Abstract: 

Cigarette smoking causes persistent lung inflammation that is mainly regulated by redox-sensitive pathways. We have previously reported that cigarette smoke (CS) activates reactive oxygen species- (ROS-) sensitive mitogen-activated protein kinases (MAPKs)/nuclear factor-κB (NF-κB) signaling leading to induction of lung inflammation. Paeonol, the main phenolic compound present in the Chinese herb Paeonia suffruticosa, has antioxidant and anti-inflammatory properties. However, whether paeonol has similar beneficial effects against CS-induced lung inflammation remains unclear. Using a murine model, we showed that chronic CS exposure for 4 weeks caused pulmonary inflammatory infiltration, increased lung vascular permeability, elevated lung levels of chemokines, cytokines, and 4-hydroxynonenal (an oxidative stress biomarker), and induced lung inflammation; all of these CS-induced events were suppressed by chronic treatment with paeonol. Using human bronchial epithelial cells (HBECs), we demonstrated that cigarette smoke extract (CSE) sequentially increased extracellular and intracellular levels of ROS, activated the MAPKs/NF-κB signaling, and induced interleukin-8 (IL-8); all these CSE-induced events were inhibited by paeonol pretreatment. Our findings suggest a novel role for paeonol in alleviating the oxidative stress and lung inflammation induced by chronic CS exposure in vivo and in suppressing CSE-induced IL-8 in vitro via its antioxidant function and an inhibition of the MAPKs/NF-κB signaling.

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PMID: 

Pharmacology. 2014 ;93(5-6):286-95. Epub 2014 Aug 21. PMID: 25170865

Abstract Title: 

Paeonol attenuates advanced oxidation protein product-induced oxidative stress injury in THP-1 macrophages.

Abstract: 

BACKGROUND: Paeonol (2'-hydroxy-4'-methoxyacetophenone) is thought to possess a broad range of clinically curative effects that are likely mediated by its anti-inflammatory and antioxidant activities.AIMS: To elucidate the efficacy of paeonol's anti-inflammatory and antioxidant activities and the underlying mechanism of paeonol in advanced oxidation protein product (AOPP) stimulation of THP-1 macrophages.MATERIALS AND METHODS: After incubating cells with AOPP plus paeonol, nitric oxide (NO) production and the levels of inducible NO synthase (iNOS), receptor for advanced glycation end products (RAGE), CD36, scavenger receptor (SR)-A, and SR-B1 were calculated. Moreover, THP-1 macrophages were preincubated with paeonol, the free radical scavenger N-acetylcysteine (NAC), NADPH oxidase inhibitors [apocynin, diphenylene iodonium (DPI)], and the specific inhibitor of nuclear factor-κB pyrrolidine dithiocarbamate (PDTC) prior to incubation with AOPP, and the levels of intracellular reactive oxygen species (ROS) production and tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and monocyte chemotactic protein 1 (MCP-1) were determined.RESULTS: Paeonol increased NO production and the mRNA level of iNOS, whereas it decreased ROS production. ROS production was also effectively attenuated by apocynin, DPI, NAC, and PDTC. Furthermore, these inhibitors and paeonol could downregulate the mRNA and protein levels of proinflammatory cytokines (TNF-α, IL-1β, IL-6, and MCP-1). Paeonol significantly reduced the expression levels of RAGE and CD36 but increased the expression levels of SR-A and SR-B1.CONCLUSIONS: These results indicate that paeonol can decrease proinflammatory cytokines in THP-1 macrophages, likely through RAGE-, CD36-, SR-A-, and SR-B1-mediated signals involving NADPH oxidase-dependent ROS generation. This suggests that paeonol can be used as a therapeutic agent for diseases contributing to oxidative stress injury.

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PMID: 

Food Sci Nutr. 2019 Sep ;7(9):2948-2957. Epub 2019 Aug 2. PMID: 31572588

Abstract Title: 

Antiproliferative and cytotoxic effects of grape pomace and grape seed extracts on colorectal cancer cell lines.

Abstract: 

Grape pomace is the source of bioactive compounds (anthocyanins, flavonols, flavan-3-ols, and stilbenes) which exhibit antiproliferative actions on cell cultures. We have investigated the antitumoral effects of grape pomace and grape seed extracts on colon cancer cells (Caco-2, HT-29) and fibroblasts. Crude extracts prepared from white and red pomace, and grape seeds, reduced the viability and proliferation of Caco-2. HT-29 cells were resistant to these actions. Purified extracts were then prepared from the same sources and compared with the LDH test; again, all three extracts were active and purified extract from grape seed was the most potent and specific on Caco-2 cells. HT-29 cells were more sensitive to these purified extracts. The biological activity resided almost exclusively in the flavonol and flavan-3-ols subfractions, rather than the anthocyanin subfraction. Preliminary results on the mechanisms involved in these effects revealed downregulation of Myc gene expression in HT-29 and upregulation of Ptg2 in Caco-2 cells.

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PMID: 

Nutrients. 2019 Nov 4 ;11(11). Epub 2019 Nov 4. PMID: 31689935

Abstract Title: 

Grape Seed Extract Eliminates Visceral Allodynia and Colonic Hyperpermeability Induced by Repeated Water Avoidance Stress in Rats.

Abstract: 

Grape seed extract (GSE) is rich in polyphenols composed mainly of proanthocyanidins, which are known to attenuate proinflammatory cytokine production. Repeated water avoidance stress (WAS) induces visceral allodynia and colonic hyperpermeability via toll-like receptor 4 (TLR4) and proinflammatory cytokine pathways, which is a rat irritable bowel syndrome (IBS) model. Thus, we explored the effects of GSE on repeated WAS (1 h for 3 days)-induced visceral allodynia and colonic hyperpermeability in Sprague-Dawley rats. Paracellular permeability, as evaluated by transepithelial electrical resistance and flux of carboxyfluorescein, was analyzed in Caco-2 cell monolayers treated with interleukin-6 (IL-6) and IL-1β. WAS caused visceral allodynia and colonic hyperpermeability, and intragastric administration of GSE (100 mg/kg, once daily for 11 days) inhibited these changes. Furthermore, GSE also suppressed the elevated colonic levels of IL-6, TLR4, and claudin-2 caused by WAS. Paracellular permeability wasincreased in Caco-2 cell monolayers in the presence of IL-6 and IL-1β, which was inhibited by GSE. Additionally, GSE suppressed the claudin-2 expression elevated by cytokine stimulation. The effects of GSE on visceral changes appear to be evoked by suppressing colonic TLR4-cytokine signaling and maintaining tight junction integrity. GSE may be useful for treating IBS.

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PMID: 

Biol Trace Elem Res. 2019 Nov 7. Epub 2019 Nov 7. PMID: 31701464

Abstract Title: 

Grape Seed Proanthocyanidin Extract Mitigates Titanium Dioxide Nanoparticle (TiO-NPs)-Induced Hepatotoxicity Through TLR-4/NF-κB Signaling Pathway.

Abstract: 

With the progress of nanotechnology, the adverse effects of nanoscale materials are receiving much attention. Inhibition of toll-like receptor 4 (TLR-4)/nuclear factor kappa B (NF-κB) signaling is a hallmark for downregulating the expression of many inflammatory genes implicated in oxidative stress. Therefore, the present study aimed to demonstrate the influence of grape seed proanthocyanidin extract (GSE) on the hepatic TLR-4/ NF-κB signaling pathway in TiO-NP-induced liver damage in rats. Forty male Albino rats were divided into 4 groups (n = 10): G1 was used as a control, G2 received TiO-NPs (500 mg/kg/day orally) from the 17th to 30th day (acute toxicity), G3 received GSE (75 mg/kg/day orally) for 30 days, and G4 pre- and co-treated with GSE (for 30 days) and TiO-NPs (from the 17th to 30th day), with the aforementioned doses. TiO-NPs induced severe hepatic injury that was indicated by biochemical alterations in serum liver markers (acetylcholinesterase, ALT, ALP, total proteins, albumin, and direct bilirubin), oxidative stress indicators (MDA, GSH, and catalase), and histopathological alterations as well. Moreover, TiO-NPs triggered an inflammatory response via the upregulation of TLR-4, NF-κB, NIK, and TNF-α mRNA expressions. Pre- and co-treatments with GSE alleviated the detrimental effects of TiO-NPs which were enforced by the histopathological improvements. These results indicated that GSE effectively protected against TiO-NP-induced hepatotoxicity via the inhibition of TLR-4/NF-κB signaling and hence suppressed the production of pro inflammatory cytokines such as TNF-α and improved the antioxidant status of the rats.

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PMID: 

Brain Res Bull. 2014 Oct ;109:61-7. Epub 2014 Oct 5. PMID: 25286445

Abstract Title: 

Paeonol pretreatment attenuates cerebral ischemic injury via upregulating expression of pAkt, Nrf2, HO-1 and ameliorating BBB permeability in mice.

Abstract: 

BACKGROUND: Oxidative damage plays a pivotal role in the pathogenesis of cerebral ischemic stroke and may represent a target for treatment. Our previous studies have proved that nuclear factor E2-related factor 2 (Nrf2) and its downstream genes served as a key mechanism for protection against oxidative stress. Paeonol (PN) is reputed to possess a broad range of therapeutic properties probably by virtue of its antioxidative ability. However little is elucidated regarding the underlying mechanisms in ischemic stroke. The aim of this study was to explore PNs effect in ischemic injury and the role of the pAkt, Nrf2 and hemeoxygenase-1 (HO-1) in the mice brains of permanent middle cerebral artery occlusion (pMCAO).METHODS: Male CD-1 mice were subjected to pMCAO and randomly divided into five groups: Sham (sham-operated+0.9% saline), pMCAO (pMCAO+0.9% saline), Vehicle (pMCAO+vehicle), PN-L (pMCAO+PN 30 mg/kg) and PN-H (pMCAO+PN 60 mg/kg) groups. PN was pre-administered intragastrically once daily for 3 days and with the last administration at 30 min before the operation in the fourth day. Neurological deficit scores, brain water content and infarct volume were measured at 24h after pMCAO. Western blot and qRT-PCR were employed to determine the expressions of pAkt, Nrf2, HO-1 and claudin-5. Superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by spectrophotometer.RESULTS: Compared with Vehicle group, PN significantly alleviated neurological deficit, infarct volume and brain edema (P

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PMID: 

Mol Med Rep. 2015 Jul ;12(1):1506-14. Epub 2015 Mar 11. PMID: 25760096

Abstract Title: 

Paclitaxel resistance in MCF-7/PTX cells is reversed by paeonol through suppression of the SET/phosphatidylinositol 3-kinase/Akt pathway.

Abstract: 

Breast cancer is one of the most prevalent types of malignant tumor. Paclitaxel is widely used in the treatment of breast cancer; however, the major problem contributing to the failure of chemotherapy in breast cancer is the development of drug resistance. Therefore, it is necessary to identify novel therapeutic targets and reversal agents for breast cancer. In the present study, the protein expression levels of SET, protein phosphatase 2A (PP2A) and phosphatidylinositol 3-kinase (PI3K)/Akt pathway were determined in MCF-7/PTX human breast carcinoma paclitaxel-resistant cells using western blot analysis. Small interference RNAs (siRNAs) were used to knock down the gene expression of SET in MCF-7/PTX cells and the cell viability was assessed following treatment with paclitaxel, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays and flow cytometry. In addition, western blot analysis was used to determined PI3K/Akt pathway activity following SET knockdown. Furthermore, the reversal effects of paeonol on paclitaxel, and its underlying mechanisms of action, were investigated using western blot analysis and reverse transcription-quantitative polymerase chain reaction. The results demonstrated that increased levels of SET and PI3K/Akt pathway proteins were present in the MCF-7/PTX cells, compared with normal MCF-7 cells. Knockdown of SET significantly sensitized MCF-7/PTX cells to paclitaxel and induced cell apoptosis. In addition, the expression levels of the adenosine triphosphate binding cassette (ABC) transporter proteins were significantly reduced in the MCF-7/PTX cells compared with the normal MCF-7 cells. SET-induced paclitaxel resistance was found to be associated with the activation of the PI3K/Akt pathway. Paeonol significantly reduced the mRNA and protein expression levels of SET in the MCF-7/PTX cells. Furthermore, paeonol significantly sensitized the MCF-7/PTX to paclitaxel via regulation of ABC transporters, B cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein. In addition, paeonol inhibited SET-mediated paclitaxel resistance by attenuating PI3K/Akt pathway activity in the MCF-7/PTX cells. In conclusion, the results of the present study demonstrated that SET was associated with paclitaxel resistance in MCF-7/PTX cells, and that paeonol reversed paclitaxel resistance in MCF-7/PTX cells by downregulating the activity of the SET/PP2A/Akt pathway.

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