PMID: 

Nan Fang Yi Ke Da Xue Xue Bao. 2019 Jul 30 ;39(7):778-783. PMID: 31340909

Abstract Title: 

[Protective effect of procyanidin B2 on intestinal barrier and against enteritis in a mouse model of trinitrobenzene sulphonic acid-induced colitis].

Abstract: 

OBJECTIVE: To investigate the protective effect of procyanidin B2 (PCB2) on the intestinal barrier and against enteritis in mice with trinitrobenzene sulphonic acid (TNBS)-induced colitis and explore the possible mechanism.METHODS: A mouse model of TNBS-induced colitis was established in male Balb/c mice aged 6-8 weeks. The successfully established mouse models were randomly divided into PCB2 treatment group (=10) and model group (=10) and were treated with daily intragastric administration of PCB2 (100 mg/kg, 0.2 mL) and 0.2 mL normal saline, respectively. After 4 weeks, the disease symptoms, intestinal inflammation, intestinal mucosal cell barrier function and the changes in PI3K/AKT signaling were evaluated using HE staining, immunofluorescence assay and Western blotting.RESULTS: The disease activity index of the mice was significantly lower and the mean body weight was significantly greater in PCB2 group than in the model group in the 3rd and 4th weeks of intervention (< 0.05). The levels of colonic inflammation and intestinal mucosal inflammatory mediators IL-1β and TNF-α were significantly lower while IL-10 was significantly higher in PCB2 group than in the model group (< 0.05). Compared with those in the model group, the mice in PCB2 treatment group showed a significantly lower positive rate of bacterial translocation in the mesenteric lymph nodes and a lower thiocyanate-dextran permeability of the intestinal mucosa (< 0.05). Western blotting showed that PCB2 treatment significantly increased the expressions of claudin-1 and ZO-1 (< 0.05) and significantly lowered the expression levels of p-PI3K and p-AKT in the intestinal mucosa as compared with those in the model group (< 0.05).CONCLUSIONS: PCB2 suppresses intestinal inflammation and protects intestinal mucosal functions and structural integrity by inhibiting intestinal PI3K/AKT signaling pathway, suggesting the potential of PCB2 as a new drug for Crohn's disease.

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PMID: 

J Cell Mol Med. 2019 Jul 21. Epub 2019 Jul 21. PMID: 31328391

Abstract Title: 

Procyanidin B2 inhibits the activation of hepatic stellate cells and angiogenesis via the Hedgehog pathway during liver fibrosis.

Abstract: 

BACKGROUND: Liver fibrosis is a wound-healing process of liver featured by the over-deposition of extracellular matrix (ECM) and angiogenesis. However, the effective treatment is lacking. Procyanidin B2 (PB2) is a flavonoid extract abundant in grape seeds with anti-oxidant, anti-inflammatory and anti-cancer properties. The present study aimed to determine effects of PB2 on liver fibrosis.METHOD: The CCl4-induced mouse liver fibrosis model and a human hepatic stellate cell (HSC) line (LX2 cells) were used to study the activation, ECM production and angiogenesis of HSCs through Western blotting analysis, immunohistochemistry, immunofluorescence staining, flow cytometry and tubulogenesis assay. A Hedgehog (Hh) pathway inhibitor (cyclopamine) and Smoothened agonist (SAG) were used to investigate the role of PB2 on Hh pathway.RESULTS: The results showed that PB2 could inhibit the proliferation and induce apoptosis of HSCs. PB2 could also down-regulate the expressions of VEGF-A, HIF-1α, α-SMA, Col-1 and TGF-β1 of HSCs in vivo and in vitro. The application of SAG and cyclopamine proved that PB2 targets on Hh pathway.CONCLUSIONS: PB2 inhibited the Hh pathway to suppress the activation, ECM production and angiogenesis of HSCs, therefore reverses the progression of liver fibrosis in vivo and in vitro.

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PMID: 

Onco Targets Ther. 2019 ;12:4109-4118. Epub 2019 May 24. PMID: 31213831

Abstract Title: 

Grape seed procyanidin B2 promotes the autophagy and apoptosis in colorectal cancer cells via regulating PI3K/Akt signaling pathway.

Abstract: 

Colorectal cancer (CRC) is a major malignancy in China, which is the critical risk of people health. Many natural herbs extracts have been found to exhibit good therapeutic effect on CRC. Our previous study found that grape seed procyanidins B2 (PB2) would induce CRC cell death. However, the molecular mechanism underlying its anti-tumor effect on CRC remains unclear. Thereby, this study aimed to investigate the anti-tumor mechanism of PB2 on CRC.CCK-8, western blotting, flow cytometry, qRT-PCR and animal study were used in the current study.The in vitro and in vivo data demonstrated that PB2 could promote the apoptosis of CRC cells in a dose-dependent manner, which was significantly reversed by caspase 3 inhibitor. Meanwhile, PB2 dose-dependently induced autophagy in CRC cells, which was markedly attenuated by autophagy inhibitor 3-MA. In addition, PB2 dose-dependently inhibited the expressions of p-PI3K, p-Akt and p-mTOR in the cells.PB2 dose-dependently induced apoptosis and autophagy in CRC cells via downregulation of PI3K/Akt pathway. This study provided the experimental basis for further development of PB2 as a new effective anticancer drug for the patients with CRC.

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PMID: 

Foods. 2019 May 20 ;8(5). Epub 2019 May 20. PMID: 31137514

Abstract Title: 

Identification of the Components in aExtract Showing Inhibitory Activity against Influenza Virus Adsorption.

Abstract: 

We previously reported that extracts from plants of the Ericaceae genus, commonly known as the kind of blueberry, inhibited the early steps of influenza virus (IFV) infection to host cells, and that the activity was correlated with the total polyphenol content. Particularly potent inhibitory activity was observed for. In this study, we identified the active components ininvolved in the inhibition of IFV infection. We sequentially fractionated theextract using a synthetic adsorbent resin column. High inhibitory activity was observed for the fractions eluted with 30%, 40%, and 50% ethanol, and three peaks (peak A, B, and C) considered to represent polyphenols were identified in the fractions by HPLC analysis. Among these peaks, high inhibitory activity was detected for peak A and B, but not for peak C. These peaks were analyzed by LC/MS, which revealed that peak A contained procyanidin B2 and ferulic acid derivatives, whereas peak B contained two ferulic acid-hexosides, and peak C contained quercetin-3–rhamnoside and quercetin–pentoside–rhamnoside. It is already known that these polyphenols have anti-IFV activity, but we speculate that ferulic acid derivatives are the major contributors to the inhibition of the early steps of IFV replication, such as either adsorption or entry, observed for.

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PMID: 

Nutr Cancer. 2019 ;71(6):992-1006. Epub 2019 Apr 29. PMID: 31032639

Abstract Title: 

3,3'-Diindolylmethane Inhibits TNF-α- and TGF-β-Induced Epithelial-Mesenchymal Transition in Breast Cancer Cells.

Abstract: 

Epithelial-mesenchymal transition (EMT) is the initial event required by cancer cells. Thus, inhibition of the EMT process could have potential benefits for preventing the spread of cancers. The phytochemicals have been reported to have inhibitory activity against the EMT process in breast cancers, but the mechanism behind this effect has not been fully elucidated. 3,3'-Diindolylmethane (DIM) is a major indole derived from bioactive compounds in cruciferous vegetables. In this study, we examined the effects of DIM cotreatment together with TNF-α/TGF-β on the EMT process as well as the mechanisms underlying its effects on human breast cancer cells. DIM significantly enhanced the mRNA and protein expression of E-cadherin and occludin in MCF-7 cells. The protein expression levels of E-cadherin and occludin in MCF-7 cells were significantlydecreased after TNF-α/TGF-β treatment alone, but these effects were reversed by the DIM co-treatment. Furthermore, DIM with TNF-α/TGF-β co-treatment attenuated the phosphorylation of Smad2/3 and ERK1/2 proteins. DIM significantly inhibited the TNF-α/TGF-β-induced migration of breast cancer cells. Taken together, the results indicated that DIM effectively suppressed EMT processes through the inhibition of TNF-α/TGF-β-associated signaling pathways in breast cancer cells. Thus, DIM may be a novel preventive and/or therapeutic approach for the treatment of breast cancers.

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PMID: 

Oxid Med Cell Longev. 2018 ;2018:1421438. Epub 2018 May 2. PMID: 29854073

Abstract Title: 

Carnosic Acid, a Natural Diterpene, Attenuates Arsenic-Induced Hepatotoxicity via Reducing Oxidative Stress, MAPK Activation, and Apoptotic Cell Death Pathway.

Abstract: 

The present studies have been executed to explore the protective mechanism of carnosic acid (CA) against NaAsO-induced hepatic injury. CA exhibited a concentration dependent (1-4 M) increase in cell viability against NaAsO(12 M) in murine hepatocytes. NaAsOtreatment significantly enhanced the ROS-mediated oxidative stress in the hepatic cells both inandsystems. Significant activation of MAPK, NF-B, p53, and intrinsic and extrinsic apoptotic signaling was observed in NaAsO-exposed hepatic cells. CA could significantly counteract with redox stress and ROS-mediated signaling and thereby attenuated NaAsO-mediated hepatotoxicity. NaAsO(10 mg/kg) treatment caused significant increment in the As bioaccumulation, cytosolic ATP level, DNA fragmentation, and oxidation in the liver of experimental mice (= 6). The serum biochemical and haematological parameters were significantly altered in the NaAsO-exposed mice (= 6). Simultaneous treatment with CA (10 and 20 mg/kg) could significantly reinstate the NaAsO-mediated toxicological effects in the liver. Molecular docking and dynamics predicted the possible interaction patterns and the stability of interactions between CA and signal proteins. ADME prediction anticipated the drug-likeness characteristics of CA. Hence, there would be an option to employ CA as a new therapeutic agent against As-mediated toxic manifestations in future.

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PMID: 

Exp Eye Res. 2018 10 ;175:103-114. Epub 2018 Jun 18. PMID: 29928899

Abstract Title: 

Carnosic acid attenuates acrylamide-induced retinal toxicity in zebrafish embryos.

Abstract: 

Acrylamide (ACR) is a water-soluble chemical used widely in industry, which can be formed in tobacco smoke and in starchy foods cooked at high temperatures. ACR is considered to be a neurotoxin, genotoxin and carcinotoxin. Previous studies reported that ACR-exposed workers and experimental animals exhibited visual function defects, although the underlying mechanisms have not been elucidated. In this study, we found that zebrafish embryos exposed to 1 mM and 2 mM ACR showed significantly increased reactive oxygen species (ROS), decreased expression of the antioxidant genes Sod1, Sod2, Catalase, Gpx1 and Nrf2, reduced activity of superoxide dismutase (SOD) and catalase, and elevated malondialdehyde (MDA), compared with control embryos. ACR exposure caused loss of both rod and cone photoreceptor cells through Caspase-3-dependent apoptotis. When embryos were simultaneously exposed to ACR and the natural antioxidative substance carnosic acid (CA), the presence of the latter (10 μM) markedly counteracted the above ACR-induced toxic effects. Our data suggest that CA can protect photoreceptor cells against ACR-induced oxidative damage and has a potential for neuroprotection of visual function in humans exposed to ACR.

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PMID: 

J Neurotrauma. 2019 Jul 1 ;36(13):2147-2152. Epub 2019 Mar 26. PMID: 30672378

Abstract Title: 

Carnosic Acid Improves Outcome after Repetitive Mild Traumatic Brain Injury.

Abstract: 

In the majority of cases, the cognitive and behavioral impairments resulting from a mild traumatic brain injury (TBI) (also referred to as concussion) wane within days to weeks. In contrast, these impairments can persist for months to years after repetitive mild TBI (rmTBI). The cellular and molecular mechanisms underlying these impairments are not well understood. In the present study, we examined the consequences of rmTBI (three weight drops each separated by 72 h) on brain tissue respiration, pathology, and cognitive performance in mice. The transcription factor nuclear factor-erythroid 2-realted factor 2 (Nrf2) has been demonstrated to enhance the expression of numerous cytoprotective genes. Carnosic acid (CA) has been shown to activate Nrf2 and suppress the proinflammatory transcription factor nuclear factor kappa B (NF-κB). Because contemporaneous activation of cytoprotective genes and inhibition of proinflammatory genes can be beneficial, we questioned whether CA can be used to mitigate the pathobiology of rmTBI. The rmTBI increased hippocampal adenosine triphosphate-linked tissue respiration and proton leak that were unaffected by CA treatment. The rmTBI also caused significant motor and cognitive dysfunction, as tested using the foot fault, Barnes maze, and novel object recognition tasks. These impairments occurred in the absence of visible neuronal or dendritic loss. Post-rmTBI administration of CA significantly improved motor and cognitive function, and decreased Gfap and Iba1 immunoreactivities within white matter tracks. Taken together, these results show that rmTBI can cause cognitive impairments in the absence of overt neuronal pathologies, and post-injury treatment with CA can lessen some of these impairments.

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PMID: 

Int J Biol Macromol. 2019 Jul 26. Epub 2019 Jul 26. PMID: 31356939

Abstract Title: 

Interaction mechanism of carnosic acid against glycosidase (α-amylase and α-glucosidase).

Abstract: 

Inhibition the activity of glycosidase is an effective method for the treatment and prevention of diabetes. In this study, enzymatic kinetics, fluorescence spectrum experiment, starch granule digestion, molecular docking studies and animal's studies were used to investigate the interaction mechanism of carnosic acid against two glycosidase (α-amylase and α-glucosidase). Enzymatic kinetics showed that carnosic acid inhibited α-amylase activity in a competitive manner and α-glucosidase activity in a non-competitive manner. The half inhibitory concentrations (IC50) of carnosic acid to α-amylase and α- glucosidase were (1.12 ± 0.31) and (0.08 ± 0.17), respectively. The fluorescence quenching experiments showed that the intrinsic fluorescence of α-amylase or α-glucosidase was quenched by forming a complex with carnosic acid, and there was only one binding site between carnosic acid and glycosidase. The starch granules were no longer hydrolyzed by α-amylase after the addition of carnosic acid, which indicated that carnosic acid inhibited the activity of α-amylase. Molecular docking study showed that carnosic acid binds to the amino acid residues of glycosidase through hydrogen bond and van der Waals force, which leads to the change of the molecular conformation of glycosidase and thus reduces the activity of glycosidase. The experiment on mice showed that carnosic acid could effectively reduce postprandial blood glucose in mice.

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PMID: 

Fitoterapia. 2019 Jul 11:104266. Epub 2019 Jul 11. PMID: 31302251

Abstract Title: 

Sesquiterpene rich essential oil from Nepalese Bael tree (Aegle marmelos (L.) Correa) as potential antiproliferative agent.

Abstract: 

Aegle marmelos (L.) Corr. (Rutaceae), also known as Bael tree, is an herbal traditional remedy in the South East Asia. In the present work, the leaf essential oil distilled from a population collected in Nepal was analyzed for the chemical composition by GC-MS showing different phytochemical constituents compared with literature data. The obtained oil was rich in sesquiterpenes, mainlyβ-Caryophyllene (26%), whereas monoterpenes, known in literature as the major components, were present in little amounts. Due to richness in sesquiterpenes which are promising as anticancer drugs, the oil was tested against several human tumor cell lines namely pancreatic (PSN-1), colon (LoVo), lung (H157) and ovarian (2008) cells showing ICof 5.6 μg/ml, 6.5 μg/ml, 6.7 μg/ml and 2.3 μg/ml, respectively. In vivo distribution of oil was studied with a dose of 41.5 mg/kg in mice allowing the quantification of β-Caryophyllene, α-Humulene, γ-Muurulene and ar-Curcumene at 30 and 60 min after oral administration. Sesquiterpene were found in higer amount in, liver, kidney and heart whereas lung and blood contained lower levels. The tissue distribution study demonstrated that active sesquiterpenoids of the oil can efficiently reach different organs.

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