| Reference | [1]. J Cell Mol Med. 2019 Sep;23(9):6479-6493. doi: 10.1111/jcmm.14543. Epub 2019 Jul 21.<br />
Procyanidin B2 inhibits the activation of hepatic stellate cells and angiogenesis via the Hedgehog pathway during liver fibrosis.<br />
Feng J(1)(2), Wang C(1), Liu T(2), Li J(1), Wu L(2), Yu Q(2)(3), Li S(2), Zhou Y(2)(3), Zhang J(2)(3), Chen J(2)(3), Ji J(2), Chen K(2), Mao Y(4), Wang F(5), Dai W(1)(2)(6)(7), Fan X(8), Wu J(1), Guo C(2).<br />
Author information: (1)Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai, China. (2)Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. (3)Shanghai Tenth Hospital, School of Clinical Medicine of Nanjing Medical University, Shanghai, China. (4)Department of Gerontology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. (5)Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. (6)Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China. (7)Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China. (8)Department of Gastroenterology, Jinshan Hospital of Fudan University, Jinshan, Shanghai, China.<br />
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.<br />
DOI: 10.1111/jcmm.14543 PMCID: PMC6714206 PMID: 31328391 [Indexed for MEDLINE]<br />
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[2]. Front Immunol. 2019 Aug 7;10:1895. doi: 10.3389/fimmu.2019.01895. eCollection 2019.<br />
Procyanidin B2 Activates PPARγ to Induce M2 Polarization in Mouse Macrophages.<br />
Tian Y(1), Yang C(1), Yao Q(1), Qian L(2), Liu J(1), Xie X(1), Ma W(1), Nie X(2), Lai B(1), Xiao L(1), Wang N(2)(3).<br />
Author information: (1)Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China. (2)The Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China. (3)College of Basic Medical Sciences, Dalian Medical University, Dalian, China.<br />
Procyanidins, a subclass of flavonoids found in commonly consumed foods, possess potential anti-inflammatory activity. Manipulation of M1/M2 macrophage homeostasis is an effective strategy for the treatment of metabolic inflammatory diseases. The objective of this study was to determine the effect of procyanidins on macrophage polarization. Procyanidin B2 (PCB2), the most widely distributed natural procyanidins, enhanced the expressions of M2 macrophage markers (Arg1, Ym1, and Fizz1). PCB2 activated peroxisome proliferator-activated receptor γ (PPARγ) activity and increased the expressions of PPARγ target genes (CD36 and ABCG1) in macrophages. Inhibition of PPARγ using siRNA or antagonist GW9662 attenuated the PCB2-induced expressions of M2 macrophage markers. In addition, we identified cognate PPAR-responsive elements (PPREs) within the 5'-flanking regions of the mouse Arg1, Ym1, and Fizz1 genes. Furthermore, macrophages isolated from db/db diabetic mice showed lower expressions of M2 markers. PCB2 effectively restored the Arg1, Ym1, and Fizz1 expressions in a PPARγ-dependent manner. These findings support the notion that PCB2 regulated macrophage M2 polarization via the activation of PPARγ. Our results provide a new mechanism by which procyanidins exert their beneficial anti-inflammatory effects.<br />
DOI: 10.3389/fimmu.2019.01895 PMCID: PMC6693435 PMID: 31440258 [Indexed for MEDLINE]<br />
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[3]. Redox Biol. 2020 Oct;37:101728. doi: 10.1016/j.redox.2020.101728. Epub 2020 Sep 15.<br />
Procyanidin B2 mitigates endothelial endoplasmic reticulum stress through a PPARδ-Dependent mechanism.<br />
Nie X(1), Tang W(2), Zhang Z(3), Yang C(3), Qian L(1), Xie X(3), Qiang E(1), Zhao J(2), Zhao W(3), Xiao L(4), Wang N(5).<br />
Author information: (1)Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China. (2)Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China; Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, China. (3)Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, China. (4)Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, China. Electronic address: [email protected]. (5)Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China. Electronic address: [email protected].<br />
Hyperglycemia-induced endothelial endoplasmic reticulum (ER) stress is implicated in the pathophysiology of diabetes and its vascular complications. Procyanidins are enriched in many plant foods and have been demonstrated to exert several beneficial effects on diabetes, cardiovascular and other metabolic diseases. In the present study, we investigated the effect of procyanidin B2 (PCB2), the most widely distributed natural procyanidin, on ER stress evoked by high glucose in endothelial cells (ECs) and the underlying mechanisms. We showed that PCB2 mitigated the high glucose-activated ER stress pathways (PERK, IRE1α and ATF6) in human vascular ECs. In addition, we found that PCB2 attenuated endothelial ER stress via the activation of peroxisome proliferator-activated receptor δ (PPARδ). We demonstrated that PCB2 directly bound to and activated PPARδ. Conversely, GSK0660, a selective PPARδ antagonist, attenuated the suppressive effect of PCB2 on the ER stress signal pathway. Functionally, PCB2 ameliorated the high glucose-impaired endothelium-dependent relaxation in mouse aortas. The protective effect of PCB2 on vasodilation was abolished in the aortas pretreated with GSK0660 or those from the EC-specific PPARδ knockout mice. Moreover, the protective effects of PCB2 on ER stress and endothelial dysfunction required the inter-dependent actions of PPARδ and AMPK. Collectively, we demonstrated that PCB2 mitigated ER stress and ameliorated vasodilation via a PPARδ-mediated mechanism beyond its classic action as a scavenger of free radicals. These findings further highlighted the novel roles of procyanidins in intervening the ER stress and metabolic disorders related to endothelial dysfunction.<br />
DOI: 10.1016/j.redox.2020.101728 PMCID: PMC7509074 PMID: 32961442 [Indexed for MEDLINE]<br />
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[4]. Free Radic Biol Med. 2018 Oct;126:269-286. doi: 10.1016/j.freeradbiomed.2018.08.024. Epub 2018 Aug 22.<br />
Procyanidin B2 ameliorates free fatty acids-induced hepatic steatosis through regulating TFEB-mediated lysosomal pathway and redox state.<br />
Su H(1), Li Y(1), Hu D(1), Xie L(1), Ke H(1), Zheng X(1), Chen W(2).<br />
Author information: (1)Department of Food Science and Nutrition, National Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing, Zhejiang University, Hangzhou 310058, China. (2)Department of Food Science and Nutrition, National Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].<br />
Procyanidin B2, a naturally occurring phenolic compound, has been reported to exert multiple beneficial functions. However, the effect of procyanidin B2 on free fatty acids (FFAs)-induced hepatic steatosis remains obscure. The present study is therefore aimed to elucidate the protective effect of procyanidin B2 against hepatic steatosis and its underlying mechanism. Herein, we reported that procyanidin B2 attenuated FFAs-induced lipid accumulation and its associated oxidative stress by scavenging excessive ROS and superoxide anion radicals, blocking loss of mitochondrial membrane potential, restoring glutathione content, and increasing activity of antioxidant enzymes (GPx, SOD and CAT) in hepatocytes. Procyanidin B2 mechanistically promoted lipid degradation via modulation of transcription factor EB (TFEB), a master regulator of lysosomal pathway. Molecular docking analysis indicated a possible ligand-binding position of procyanidin B2 with TFEB. In addition, administration of procyanidin B2 resulted in a significant reduction of hepatic fat accumulation in high-fat diet (HFD)-induced obese mice, and also ameliorated HFD-induced metabolic abnormalities, including hyperlipidemia and hyperglycemia. It was confirmed that procyanidin B2 prevented HFD-induced hepatic fat accumulation through down-regulating lipogenesis-related gene expressions (PPARγ, C/EBPα and SREBP-1c), inhibiting pro-inflammatory cytokines production (IL-6 and TNF-α) and increasing antioxidant enzymes activity (GPx, SOD and CAT). Moreover, hepatic fatty acids analysis indicated that procyanidin B2 caused a significant increase in the levels of palmitic acid, oleic acid and linoleic acid. Intriguingly, procyanidin B2 restored the decreased nuclear TFEB expression in HFD-induced liver steatosis and up-regulated its target genes involved in lysosomal pathway (Lamp1, Mcoln, Uvrag), which suggested a previously unrecognized mechanism of procyanidin B2 on ameliorating HFD-induced hepatic steatosis. Taken together, our results demonstrated that procyanidin B2 attenuated FFAs-induced hepatic steatosis through regulating TFEB-mediated lysosomal pathway and redox state, which had important implications that modulation of TFEB might be a potential therapeutic strategy for hepatic steatosis and procyanidin B2 could represent a promising novel agent in the prevention and treatment of non-alcoholic fatty liver disease (NAFLD).<br />
DOI: 10.1016/j.freeradbiomed.2018.08.024 PMID: 30142454 [Indexed for MEDLINE]<br />
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[5]. Aging (Albany NY). 2020 Aug 15;12(15):15638-15655. doi: 10.18632/aging.103726. Epub 2020 Aug 15.<br />
Protection of procyanidin B2 on mitochondrial dynamics in sepsis associated acute kidney injury via promoting Nrf2 nuclear translocation.<br />
Liu JX(1), Yang C(1), Liu ZJ(2), Su HY(2), Zhang WH(2), Pan Q(1), Liu HF(1).<br />
Author information: (1)Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, Guangdong, China. (2)Guangdong Medical University, Zhanjiang 524023, Guangdong, China.<br />
In septic acute kidney injury (SAKI), the positive feedback between damaged mitochondria and accumulation of reactive oxygen species results in cell and tissue damage through multiple mechanisms. Removing the damaged mitochondria or neutralizing the reactive oxygen species has been considered beneficial to alleviating cell damage. The antioxidant Procyanidin B2 has been reported to inhibits reactive oxygen species and thereby reduces cell injury. However, it is unclear whether this effect is associated with clearance of damaged mitochondria. Here, we evaluated the efficacy of procyanidin B2 on SAKI, and focused on its effects on mitochondrial dynamics and removing damaged mitochondria via mitophagy. The results showed that the renal function, renal tubular cell vacuolization and oxidative stress were decreased in SAKI mice treated with procyanidin B2, moreover, skewed mitochondrial fusion/fission, mitochondrial mediated apoptosis and impaired mitophagy were improved in SAKI mice treated with procyanidin B2. In mechanism, the improvement of procyanidin B2 on mitochondrial dynamics were associated with increased nuclear translocation of the transcription factor, Nrf2. In summary, our findings highlighted that the protective efficacy of procyanidin B2 in reducing cellular damage in SAKI, and mechanisms improving mitochondrial dynamics and quality control at least in part by promoting Nrf2 translocation into the nucleus.<br />
DOI: 10.18632/aging.103726 PMCID: PMC7467384 PMID: 32805725 [Indexed for MEDLINE]<br />
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