PMID: 

Obesity (Silver Spring). 2019 Apr ;27(4):542-550. Epub 2019 Feb 14. PMID: 30767409

Abstract Title: 

Attenuation of Postmeal Metabolic Indices with Red Raspberries in Individuals at Risk for Diabetes: A Randomized Controlled Trial.

Abstract: 

OBJECTIVE: This study investigated the effect of red raspberry intake on meal-induced postprandial metabolic responses in individuals who have overweight or obesity with prediabetes and insulin resistance (PreDM-IR), and in metabolically healthy individuals (Reference).METHODS: Thirty-two adults (PreDM-IR, n = 21; Reference, n = 11) were randomized to a controlled, three-arm, single-blinded, crossover trial. Participants were provided 0 g of frozen red raspberries (Control), 125 g of frozen red raspberries (RR-125) (~1 cup), or 250 g of frozen red raspberries (RR-250) (~2 cups), with a challengebreakfast meal (high carbohydrate/moderate fat) on three separate days. Multiple blood samples were collected up to 8 hours post breakfast with a final blood sample at 24 hours. A snack was provided at 6 hours.RESULTS: Breakfast containing RR-125 and RR-250 significantly reduced 2-hour insulin area under the curve, and RR-250 reduced peak insulin, peak glucose, and 2-hour glucose AUC compared with Control in the PreDM-IR group (P  0.05). No significant meal-related differences were observed for oxidative stress or inflammatory biomarkers.CONCLUSIONS: Our findings suggest that red raspberries aid in postmeal glycemic control in individuals with PreDM-IR, reducing glycemic burden with less insulin, which may be related to improved tissue insulin sensitivity.

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PMID: 

Metabolites. 2019 Mar 21 ;9(3). Epub 2019 Mar 21. PMID: 30901937

Abstract Title: 

Flavan-3-ols Content in Red Raspberry Leaves Increases under Blue Led-Light Irradiation.

Abstract: 

Berry fruits are well known to contain large amounts of polyphenol compounds. Among them, flavan-3-ol derivatives are a group of secondary metabolism compounds currently attracting a great deal of attention owing to their health benefits. Not only the fruits, but also the leaves of raspberry plants, are highly esteemed for tea making around the world and are largely used for food. In this report, we discuss the results of our study on the effect of light and temperature on polyphenol accumulation in raspberry leaves. When raspberry was cultivated in a plant factory unit and light intensity, wavelength, and temperature were varied, the amount of total polyphenol increased under blue light. Quantitative determination of (+)-catechin, (⁻)-epicatechin, procyanidin B4, flavan-3-ol trimer, which are flavan-3-ol derivatives, was carried out using HPLC, whereby we confirmed their increase under blue light. Semi-quantitative RT-PCR showed correlation between chalcone synthase (CHS) gene expression and the amounts of the compounds measured in the leaves.

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PMID: 

Free Radic Res. 2019 Jun ;53(6):680-693. Epub 2019 Jun 4. PMID: 31106605

Abstract Title: 

Chlorogenic acid prevents paraquat-induced apoptosis via Sirt1-mediated regulation of redox and mitochondrial function.

Abstract: 

Paraquat (PQ) is a widely used agro-chemical in agriculture and highly toxic to humans. Although the mechanism of PQ poisoning is not clear, it has been well documented that reactive oxygen species (ROS) generation and apoptosis play pivotal roles. Alternatively, chlorogenic acid (CA) is a biologically active dietary polyphenol, playing several therapeutic roles. However, it is not known whether CA has protective effect on PQ-induced apoptosis. Here, we investigated the effect of CA in preventing PQ-induced apoptosis and explored the underlying mechanisms. A549 cells were pretreated with 100µM CA for 24 h and then exposed to 160 µM PQ for 24 h. We found that CA was effective in preventing PQ-induced apoptotic features, including the release of cytochrome c from the mitochondria to cytoplasm, the cleavages of caspase 3 and caspase 9, and the increases in levels of Bcl-2-associatedX protein (Bax) and intracellular calcium ions. CA alleviated ROS production and prevented the reduction of antioxidant capacity in cells exposed to PQ by increasing NF-E2-related factor 2 (Nrf2), superoxide dismutase 2 (SOD2) and glutathione levels. In addition, CA also attenuated PQ-induced alterations of mitochondrial structure and function (such as the decreases in membrane potential and adenosine triphosphate level), and the impaired autophagic flux was improved by CA. Down-regulation of sirtuin 1 (Sirt1) by short hairpin RNA reversed the protective effects of CA. Thus, CA may be viewedas a potential drug to treat PQ-induced lung epithelial cell apoptosis and other disorders with similar pathologic mechanisms.

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PMID: 

Biomed Res Int. 2019 ;2019:6769789. Epub 2019 Apr 18. PMID: 31139644

Abstract Title: 

Chlorogenic Acid Attenuates Dextran Sodium Sulfate-Induced Ulcerative Colitis in Mice through MAPK/ERK/JNK Pathway.

Abstract: 

Objective: Observe the protective effect of chlorogenic acid on dextran sulfate-induced ulcerative colitis in mice and explore the regulation of MAPK/ERK/JNK signaling pathway.Methods: Seventy C57BL/6 mice (half males and half females) were randomly divided into 7 groups, 10 in each group: control group (CON group), UC model group (UC group), and sulfasalazine-positive control group (SASP group), chlorogenic acid low dose group (CGA-L group), chlorogenic acid medium dose group (CGA-M group), chlorogenic acid high dose group (CGA-H group), and ERK inhibitor + chlorogenic acid group (E+CGA group). The effects of chlorogenic acid on UC were evaluated by colon mucosa damage index (CMDI), HE staining, immunohistochemistry, ELISA, and Western blot. The relationship between chlorogenic acid and MAPK/ERK/JNK signaling pathway was explored by adding ERK inhibitor.Results: The UC models were established successfully by drinking DSS water. Chlorogenic acid reduces DSS-induced colonic mucosal damage, inhibits DSS-induced inflammation, oxidative stress, and apoptosis in colon, and reduces ERK1/2, p -ERK, p38, p-p38, JNK, and p-JNK protein expression. ERK inhibitor U0126 reversed the protective effect of chlorogenic acid on colon tissue.Conclusion: Chlorogenic acid can alleviate DSS-induced ulcerative colitis in mice, which can significantly reduce tissue inflammation and apoptosis, and its mechanism is related to the MAPK/ERK/JNK signaling pathway.

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PMID: 

Naunyn Schmiedebergs Arch Pharmacol. 2019 Oct ;392(10):1293-1309. Epub 2019 Jun 12. PMID: 31190087

Abstract Title: 

Neuroprotective effect of chlorogenic acid in global cerebral ischemia-reperfusion rat model.

Abstract: 

The ischemic cascade is initiated in the hypoperfused region of the brain that leads to neuronal cell death. Identification of multi-target inhibitor against prominent molecular mediators of ischemic cascade might be a suitable strategy to combat cerebral ischemic stroke. The present study is designed to evaluate the neuroprotective efficacy of chlorogenic acid (CGA) in the global cerebral ischemic rat model. The effective dose of CGA was evaluated on the basis of reduction in cerebral infarction area percentage, Evans blue extravasation, and restoration of brain water content. The expression of tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), and caspase-3 was evaluated by immunohistochemistry and morphological and cellular alterations in the cortex were observed by brain histology. The level of glutamate, calcium, and nitrate in different regions of the brain, as well as cerebrospinalfluid (CSF), was evaluated. The level of calcium and nitrate was compared with ifenprodil-an antagonist of N-methyl-D-aspartate receptor (NMDAR) and 7-nitroindazole-an inhibitor of neuronal nitric oxide synthase (nNOS) respectively. Further, molecular docking was performed to compare the inhibitionpotential of CGA against NMDAR and nNOS with their inhibitors. Dose optimization results revealed that intranasal administration of CGA (10 mg/kg b.w.) significantly reduced the cerebral infarction area, Evans blue extravasation and restored the brain water content compared with ischemia group. Italso significantly reduced the calcium, nitrate, and glutamate levels compared with ischemia group in the cortex, hippocampus cerebellum, and CSF. Immunohistochemical analysis revealed that CGA significantly reduced the expression of TNF-α, iNOS, and caspase-3 as compared with the ischemia group.In molecular docking study, CGA displayed similar binding interaction as that of Ifenprodil and 7-nitroindazole with NMDAR and nNOS respectively. The current findings suggest that the treatment with CGA confers neuroprotection in global ischemic insult by inhibiting and downregulating the differentmolecular markers of cerebral ischemia.

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PMID: 

Food Chem Toxicol. 2019 Nov ;133:110751. Epub 2019 Aug 4. PMID: 31390532

Abstract Title: 

Chlorogenic acid attenuates cadmium-induced intestinal injury in Sprague-Dawley rats.

Abstract: 

Chronic exposure to cadmium (Cd) causes remarkable damage to the liver and gastrointestinal tract. Previous studies have revealed that chlorogenic acid (CGA) could improve the intestinal barrier integrity for weaned rats. Hence, this study sought to investigate the protective effects of CGA from pure reagent and sunflower seed extract (SSE) on growth performance, antioxidant indicators, inflammatory biomarkers and intestinal barrier function in Cd treated rats. A total of 32 Sprague-Dawley female rats with similar weights were randomly allotted to four treatments: control, CdCl(6 mg/kg BW), co-treatment of Cd (6 mg/kg BW) and pure CGA (50 mg/kg BW), and co-treatment of Cd (6 mg/kg BW) and SSE (50 mg/kg BW) for 14 days. The data indicated that, CGA or SSE with Cd sequestration and good antioxidative ability decreased Cd absorption and accumulation in the jejunum and increased fecal Cd levels in Cd-exposed rats. Compared with the Cd group, co-treatment with CGA or SSE also alleviated inflammation, ameliorated the villus damage, reversed the disruption of tight junctions, and recovered weight gain of rats. These results suggest that CGA or SSE can protect the intestinal barrier, which is related to the alleviation of Cd-induced oxidative stress and growth decrease.

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PMID: 

Chemosphere. 2019 Oct 15 ;241:125092. Epub 2019 Oct 15. PMID: 31683443

Abstract Title: 

Obesogen effect of bisphenol S alters mRNA expression and DNA methylation profiling in male mouse liver.

Abstract: 

Environmental pollution is increasingly considered an important factor involved in the obesity incidence. Endocrine disruptors (EDs) are important actors in the concept of DOHaD (Developmental Origins of Health and Disease), where epigenetic mechanisms play crucial roles. Bisphenol A (BPA), a monomer used in the manufacture of plastics and resins is one of the most studied obesogenic endocrine disruptor. Bisphenol S (BPS), a BPA substitute, has the same obesogenic properties, acting at low doses with a sex-specific effect following perinatal exposure. Since the liver is a major organ in regulating body lipid homeostasis, we investigated gene expression and DNA methylation under low-dose BPS exposure. The BPS obesogenic effect was associated with an increase of hepatic triglyceride content. These physiological disturbances were accompanied by genome-wide changes in gene expression (1366 genes significantly modified more than 1.5-fold). Gene ontology analysis revealed alteration of gene cascades involved in protein translation and complement regulation. It was associated with hepatic DNA hypomethylation in autosomes and hypermethylation in sex chromosomes. Although no systematic correlation has been found between gene repression and hypermethylation, several genes related to liver metabolism were either hypermethylated (Acsl4, Gpr40, Cel, Pparδ, Abca6, Ces3a, Sgms2) or hypomethylated (Soga1, Gpihbp1, Nr1d2, Mlxipl, Rps6kb2, Esrrb, Thra, Cidec). In specific cases (Hapln4, ApoA4, Cidec, genes involved in lipid metabolism and liver fibrosis) mRNA upregulation was associated with hypomethylation. In conclusion, we show for the first time wide disruptive physiological effects of low-dose of BPS, which raises the question of its harmlessness as an industrial substitute for BPA.

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PMID: 

Sci Rep. 2019 Nov 4 ;9(1):15948. Epub 2019 Nov 4. PMID: 31685870

Abstract Title: 

Bisphenol S rapidly depresses heart function through estrogen receptor-β and decreases phospholamban phosphorylation in a sex-dependent manner.

Abstract: 

The health effects of the endocrine disruptor Bisphenol A (BPA) led to its partial replacement with Bisphenol S (BPS) in several products including food containers, toys, and thermal paper receipts. The acute effects of BPS on myocardial contractility are unknown. We perfused mouse hearts from both sexes for 15 min with physiologically relevant doses of BPS or BPA. In females BPS (1 nM) decreased left ventricular systolic pressure by 5 min, whereas BPA (1 nM) effects were delayed to 10 min. BPS effects in male mice were attenuated. In both sexes ER-β antagonism abolished the effects of BPS. Cardiac myofilament function was not impacted by BPS or BPA in either sex, although there were sex-dependent differences in troponin I phosphorylation. BPS increased phospholamban phosphorylation at S16 only in female hearts, whereas BPA reduced phosphorylation in both sexes. BPA decreased phospholamban phosphorylation at T17 in both sexes while BPS caused dephosphorylation only in females. This is the first study to compare sex differences in the acute myocardial response to physiologically relevant levels of BPS and BPA, and demonstrates a rapid ability of both to depress heart function. This study raises concerns about the safety of BPS as a replacement for BPA.

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PMID: 

Sci Rep. 2019 Nov 5 ;9(1):16005. Epub 2019 Nov 5. PMID: 31690802

Abstract Title: 

Bisphenol S and Bisphenol A disrupt morphogenesis of MCF-12A human mammary epithelial cells.

Abstract: 

Breast cancer is one of the most common cancers diagnosed in women worldwide. Genetic predisposition, such as breast cancer 1 (BRCA1) mutations, account for a minor percentage of the total breast cancer incidences. And thus, many life style factors have also been linked to the disease such as smoking, alcohol consumption and obesity. Emerging studies show that environmental pollutants may also play a role. Bisphenol-A (BPA) has been suspected to contribute to breast cancer development, and has been shown to affect mammary gland development amongst other effects. This prompted its replacement with other bisphenol analogs such as, bisphenol-S (BPS). In this study we used the human mammary epithelial cells, MCF-12A, grown in extracellular matrix to investigate the ability of BPA and BPS to disrupt mammary epithelial cells organization. We show that both BPA and BPS were equipotent in disrupting the organization of the acinar structures, despite BPS being less oestrogenic by other assays. Further, treatment with both compounds enabled the cells to invade the lumen of the structures. This study shows that BPS and BPA are environmental pollutants that may affect mammary development and may contribute to the development of breast cancer.

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PMID: 

Eur J Neurosci. 2019 Aug 22. Epub 2019 Aug 22. PMID: 31437868

Abstract Title: 

Chlorogenic acid ameliorates memory loss and hippocampal cell death after transient global ischemia.

Abstract: 

Chlorogenic acid (CGA) is known to have antioxidant potentials, yet the effect of CGA on brain ischemia has not been sufficiently understood. Brain ischemia such as transient global ischemia disrupts many areas of the brain of rats, including the hippocampus. Male Wistar rats were randomly assigned into five groups, that is, sham-operated (SO), bilateral common carotid occlusion (BCCO), and BCCO+ 15, 30, and 60 mg/kg bw CGA groups (CGA15, CGA30, and CGA60, respectively). Brain ischemia was induced in Wistar rats with BCCO for 20 min followed by intraperitoneal injection of CGA. The rats were examined for the spatial memory in a Morris water maze test on the 3rd day and were euthanized on the 10th day after BCCO. The total number of pyramidal cells was estimated, and the mRNA expressions of Bcl2, Bax, caspase-3, SOD2, SOD1, GPx, ET-1, eNOS, CD31, and VEGF-A were measured. The BCCO group spent less time and distance in the target quadrant than any other group in the spatial memory retention test. The CA1 pyramidal cell numbers in the BCCO and CGA15 groups were lower than in the CGA30 and CGA60 groups. The mRNA expressions of Bcl2, SOD2, and CD31 in the BCCO group were lower than in the CGA15, CGA30, and CGA60 groups. The ET-1 expression was higher in the BCCO and CGA15 groups than in the SO, CGA30, and CGA60 groups. CGA improves the spatial memory and prevents the CA1 pyramidal cell death after BCCO by increasing Bcl2, SOD2, and CD31 expressions and decreasing ET-1 expression.

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