Cinnamtannin D1

[Condensed tannins from roots of Indigofera stachyodes].[Pubmed:34467724]

Zhongguo Zhong Yao Za Zhi. 2021 Aug;46(16):4131-4138.

Eleven condensed tannins were isolated from the roots of Indigofera stachyodes by various column chromatography techniques including silica gel, octadecyl silica(ODS), Sephadex LH-20, and semi-preparative high performance liquid chromatography(HPLC). These compounds were identified on the basis of physicochemical properties, nuclear magnetic resonance(NMR) and mass spectrometry(MS) data as stachyotannin A(1), epicatechin-(2beta-->O-->7,4beta-->8)-epiafzelechin-(4beta-->8)-catechin(2), Cinnamtannin D1(3), cinnamtannin B1(4), epicatechin-(2beta-->O-->7,4beta-->8)-epiafzelechin-(4alpha-->8)-epicatechin(5), gambiriin C(6), proanthocyanidin A1(7), proanthocyanidin A2(8), aesculitannin B(9), proanthocyanidin A4(10), and procyanidin B5(11). Compound 1 is a new compound. Compounds 2-11 were isolated from Indigofera for the first time. Furthermore, compounds 1, 2, and 4-11 showed inhibitory effects on thrombin-induced ATP release in platelets.

Cinnamtannin D1 Protects Pancreatic beta-Cells from Glucolipotoxicity-Induced Apoptosis by Enhancement of Autophagy In Vitro and In Vivo.[Pubmed:33125846]

J Agric Food Chem. 2020 Nov 11;68(45):12617-12630.

In our previous study, Cinnamtannin D1 (CD-1), one of the A-type procyanidin oligomers isolated from Cinnamomum tamala, was reported to have the activity of antiapoptosis in palmitic acid-treated pancreatic beta cells via alleviating oxidative stress in vitro. In this study, the aim was to further disclose its protective effect and underlying mechanisms against glucolipotoxicity-induced beta-cells apoptosis in vitro and in vivo. We found that CD-1 was able to dose-dependently and time-dependently activate autophagy in INS-1 pancreatic beta-cells. High glucose and palmitic acid (HG/PA)-induced apoptosis and autophagy impairment could be attenuated by CD-1 in INS-1 cells as well as primary cultured murine islets. We also demonstrated that CD-1-induced autophagy was through AMPK/mTOR/ULK1 pathway. Moreover, it was shown that the effects of CD-1 on activation of Keap1/Nrf2 antioxidant signaling pathway and the amelioration of inflammation, endoplasmic reticulum stress, and apoptosis were through autophagy induction in HG/PA-treated INS-1 cells. These protective effects in vivo and hypoglycemic activity of CD-1 were also observed in diabetic db/db mice. These findings have great significance in revealing the antidiabetic mechanisms of procyanidin oligomers and paving the way for their application in the treatment of diabetes.

Cinnamtannin D1 attenuates autoimmune arthritis by regulating the balance of Th17 and treg cells through inhibition of aryl hydrocarbon receptor expression.[Pubmed:31706010]

Pharmacol Res. 2020 Jan;151:104513.

The suppression of the abnormal systemic immune response constitutes a primary strategy for treatment of rheumatoid arthritis (RA); toward this end, the identification of natural compounds with immunosuppressive activity represents a promising strategy for RA drug discovery. Cinnamtannin D1 (CTD-1), a polyphenolic compound isolated from Cinnamomum tamala, was previously reported to possess good immunosuppressive activity. However, the beneficial effect of CTD-1 on RA is currently unknown. The aim of this study was to evaluate the anti-arthritic effect of CTD-1 in collagen-induced arthritis (CIA) mice and clarify the underlying mechanisms. CTD-1 treatment significantly alleviated the severity of CIA mice, affording reduced clinical scores and paw swelling, along with reduced inflammatory cell infiltration and cartilage damage in the joints; in addition, the serum levels of IL-17, IL-6, and IL-1beta were decreased whereas those of TGF-beta and IL-10 were increased. CTD-1-treated mice exhibited lower frequency of Th17 cells and higher frequency of Treg cells compared to those in untreated mice, indicating that the balance of Th17/Treg cells may serve as the target for CTD-1. Consistent with this, in ex vivo assays, CTD-1 inhibited Th17 cell differentiation through the downregulation of phospho-STAT3/RORgammat, whereas it promoted Treg differentiation by upregulating phospho-STAT5/Foxp3 in response to the stimulation of collagen type II. Moreover, in an in vitro naive CD4(+) T cell differentiation assay, CTD-1 directly inhibited Th17 cell differentiation and promoted Treg differentiation, suggesting that CTD-1 regulated the balance of Th17 and Treg cells to inhibit excessive immune response. Furthermore, the regulation effect of CTD-1 on Th17 and Treg cells was dependent on Ahr expression, as this effect was abolished when Ahr was knocked down and was impaired when Ahr was overexpressed. Together, our results indicated that CTD-1 treatment benefits CIA mice by regulating Th17 and Treg differentiation through the inhibition of AHR expression, and suggested a potential application of CTD-1 toward RA treatment.

Trimer procyanidin oligomers contribute to the protective effects of cinnamon extracts on pancreatic beta-cells in vitro.[Pubmed:27238208]

Acta Pharmacol Sin. 2016 Aug;37(8):1083-90.

AIM: Cinnamon extracts rich in procyanidin oligomers have shown to improve pancreatic beta-cell function in diabetic db/db mice. The aim of this study was to identify the active compounds in extracts from two species of cinnamon responsible for the pancreatic beta-cell protection in vitro. METHODS: Cinnamon extracts were prepared from Cinnamomum tamala (CT-E) and Cinnamomum cassia (CC-E). Six compounds procyanidin B2 (cpd1), (-)-epicatechin (cpd2), cinnamtannin B1 (cpd3), procyanidin C1 (cpd4), parameritannin A1 (cpd5) and Cinnamtannin D1 (cpd6) were isolated from the extracts. INS-1 pancreatic beta-cells were exposed to palmitic acid (PA) or H2O2 to induce lipotoxicity and oxidative stress. Cell viability and apoptosis as well as ROS levels were assessed. Glucose-stimulated insulin secretion was examined in PA-treated beta-cells and murine islets. RESULTS: CT-E, CC-E as well as the compounds, except cpd5, did not cause cytotoxicity in the beta-cells up to the maximum dosage using in this experiment. CT-E and CC-E (12.5-50 mug/mL) dose-dependently increased cell viability in both PA- and H2O2-treated beta-cells, and decreased ROS accumulation in H2O2-treated beta-cells. CT-E caused more prominent beta-cell protection than CC-E. Furthermore, CT-E (25 and 50 mug/mL) dose-dependently increased glucose-stimulated insulin secretion in PA-treated beta-cells and murine islets, but CC-E had little effect. Among the 6 compounds, trimer procyanidins cpd3, cpd4 and cpd6 (12.5-50 mumol/L) dose-dependently increased the cell viability and decreased ROS accumulation in H2O2-treated beta-cells. The trimer procyanidins also increased glucose-stimulated insulin secretion in PA-treated beta-cells. CONCLUSION: Trimer procyanidins in the cinnamon extracts contribute to the pancreatic beta-cell protection, thus to the anti-diabetic activity.

Cinnamtannin D1 from Rhododendron formosanum Induces Autophagy via the Inhibition of Akt/mTOR and Activation of ERK1/2 in Non-Small-Cell Lung Carcinoma Cells.[Pubmed:26567590]

J Agric Food Chem. 2015 Dec 9;63(48):10407-17.

In our previous study, ursolic acid present in the leaves of Rhododendron formosanum was found to possess antineoplastic activity. We further isolated and unveiled a natural product, Cinnamtannin D1 (CNT D1), an A-type procyanidin trimer in R. formosanum also exhibiting anticancer efficacy that induced G1 arrest (83.26 +/- 3.11% for 175 muM CNT D1 vs 69.28 +/- 1.15% for control, p < 0.01) and autophagy in non-small-cell lung carcinoma (NSCLC) cells. We found that CNT D1-mediated autophagy was via the noncanonical pathway, being beclin-1-independent but Atg5 (autophagy-related genes 5)-dependent. Inhibition of autophagy with a specific inhibitor enhanced cell death, suggesting a cytoprotective function for autophagy in CNT D1-treated NSCLC cells. Moreover, CNT D1 inhibited the Akt/mammalian target of the rapamycin (mTOR) pathway and activated the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway, resulting in induction of autophagy.

Structure Elucidation of Procyanidins Isolated from Rhododendron formosanum and Their Anti-Oxidative and Anti-Bacterial Activities.[Pubmed:26184152]

Molecules. 2015 Jul 15;20(7):12787-803.

Rhododendron formosanum is an endemic species distributed in the central mountains of Taiwan. In this study, the biological activities of major procyanidins isolated from the leaf extract of R. formosanum were investigated. Four compounds, including two procyanidin dimers, procyanidin A1 (1) and B3 (2), and two procyanidin trimmers, procyanidin C4 (4) and Cinnamtannin D1 (5), were isolated and identified on the basis of spectroscopic data. The structure of a new procyanidin dimer, rhodonidin A (3), was elucidated by 2D-NMR, CD spectrum and MS. The procyanidin trimmers and rhodonidin A are reported for the first time in Ericaceae. The biological activities of these procyanidins were evaluated using anti-bacterial and anti-oxidative assays. Only the new compound 3 demonstrated strong anti-bacterial activity against Staphylococcus aureus at an MIC value of 4 mug/mL. All compounds showed pronounced antioxidant activities and the activities are enhanced as the amount of OH groups in procyanidins increased. In conclusion, the pleiotropic effects of procyanidins isolated from the leaves of R. formosanum can be a source of promising compounds for the development of future pharmacological applications.

Immunosuppressive Effects of A-Type Procyanidin Oligomers from Cinnamomum tamala.[Pubmed:25530780]

Evid Based Complement Alternat Med. 2014;2014:365258.

Cinnamon barks extracts have been reported to regulate immune function; however, the component(s) in cinnamon barks responsible for this effect is/are not yet clear. The aim of this study is to find out the possible component(s) that can be used as therapeutic agents for immune-related diseases from cinnamon bark. In this study, the immunosuppressive effects of fraction (named CT-F) and five procyanidin oligomers compounds, cinnamtannin B1, Cinnamtannin D1 (CTD-1), parameritannin A1, procyanidin B2, and procyanidin C1, from Cinnamomum tamala or Cinnamomum cassia bark were examined on splenocytes proliferation model induced by ConA or LPS. Then, the effects of activated compound CTD-1 on cytokine production and 2,4-dinitrofluorobenzene (DNFB) induced delayed-type hypersensitivity (DTH) response were detected to evaluate the immunosuppressive activity of CTD-1. It was found that CT-F and CTD-1 significantly inhibited the splenocyte proliferation induced by ConA or LPS. CTD-1 dose-dependently reduced the level of IFN-gamma and IL-2 and intensively suppressed DNFB-induced DTH responses. These findings suggest that the immunosuppressive activities of cinnamon bark are in part due to procyanidin oligomers. CTD-1 may be a potential therapeutic agent for immune-related diseases.

Ischemia-induced endothelial cell swelling and mitochondrial dysfunction are attenuated by cinnamtannin D1, green tea extract, and resveratrol in vitro.[Pubmed:24773045]

Nutr Neurosci. 2015 Oct;18(7):297-306.

Polyphenols possess antioxidant and anti-inflammatory properties. Oxidative stress (OS) and inflammation have been implicated in the pathogenesis of cytotoxic brain edema in cerebral ischemia. In addition, OS and pro-inflammatory cytokines also damage the endothelial cells and the neurovascular unit. Endothelial cell swelling may contribute to a leaky blood-brain barrier which may result in vasogenic edema in the continued presence of the existing cytotoxic edema. We investigated the protective effects of polyphenols on cytotoxic cell swelling in bEND3 endothelial cultures subjected to 5 hours oxygen-glucose deprivation (OGD). A polyphenol trimer from cinnamon (Cinnamtannin D1), a polyphenol-rich extract from green tea, and resveratrol prevented the OGD-induced rise in mitochondrial free radicals, cell swelling, and the dissipation of the inner mitochondrial membrane potential. Monocyte chemoattractant protein (also called CCL2), a chemokine, but not tumor necrosis factor-alpha or interleukin-6, augmented the cell swelling. This effect of monochemoattractant protein 1-1 was attenuated by the polyphenols. Cyclosporin A, a blocker of the mitochondrial permeability transition pore, did not attenuate cell swelling but BAPTA-AM, an intracellular calcium chelator did, indicating a role of [Ca(2+)]i but not the mPT in cell swelling. These results indicate that the polyphenols reduce mitochondrial reactive oxygen species and subsequent cell swelling in endothelial cells following ischemic injury and thus may reduce brain edema and associated neural damage in ischemia. One possible mechanism by which the polyphenols may attenuate endothelial cell swelling is through the reduction in [Ca(2+)]i.

Flavonoids from Lindera glauca Blume as low-density lipoprotein oxidation inhibitors.[Pubmed:24499267]

Nat Prod Res. 2014;28(11):831-4.

In order to identify antioxidant flavonoids from Lindera glauca Blume, we performed phytochemical analysis of L. glauca Blume heartwood and isolated eight flavonoids - lindeglaucol (1), lindeglaucone (2), cilicicone B (3), tamarixetin 3-O-alpha-L-rhamnoside (4), procyanidin A2 (5), cinnamtannin B1 (6), Cinnamtannin D1 (7), and procyanidin A1 (8) - through repeated column chromatography over silica gel (SiO(2)), octadecyl silica gel (ODS) and Sephadex LH-20. The chemical structures of compounds 1-8 were elucidated from spectroscopic data (NMR, IR and MS). The low-density lipoprotein oxidation inhibitory activities of the isolated compounds were evaluated in vitro by using the thiobarbituric acid reactive substances assay. Compounds 5-8 exhibited high inhibition activity, comparable to the positive control butyl hydroxyl toluene. Compounds 2 and 3 were slightly less active, while 1 and 4 expressed low activity.