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 β 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 β-cells apoptosis in vitro and in vivo. We found that CD-1 was able to dose-dependently and timedependently activate autophagy in INS-1 pancreatic β-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.

ABSTRACT Background Parkinson's disease (PD) is a common neurodegenerative disorder. Cinnamon procyanidin oligomers (CPOs) are flavonoids with many claimed health benefits. Objective This study aimed to elucidate the neuroprotection of A-type CPOs (CPO-A) and the underlying mechanisms in cultured cell and animal models of PD. Methods Thirty male mice (C57BL/6, 9-wk old) were assigned to 3 groups (n = 10), and were given daily gavage of saline [control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) groups] or CPO-A (150 mg/kg, CPO-A group) during days 1–15 and daily intraperitoneal injections of saline (control group) or MPTP (20 mg/kg; MPTP and MPTP + CPO-A groups) during days 11–15. After the motor behavior test, all mice were killed on day 16 to collect the substantia nigra (SN) for assaying the neuroprotective effects of CPO-A. SH-SY5Y cells were treated with 12.5 μM CPO-A for 2 h or 3 activators of stress-related kinases (5–25 μM) for 12–48 h followed by 1 mM 1-methyl-4-phenylpyridinium (MPP+) for assays of viability, morphology, and stress status. Results Compared with the control, the MPTP treatment decreased (P < 0.05) locomotor activity by 21%, and tyrosine hydroxylase (TH) positive neurons by 55% and Th mRNA concentration by 51% in the SN. The CPO-A treatment attenuated or restored (P < 0.05) these changes and inhibited (P < 0.05) the MPTP-induced activation of P38 mitogen-activated protein kinase (P38MAPK) and P53, along with the downstream expression of BCL-2 associated X protein (BAX) in the SN. In SH-SY5Y cells, the CPO-A treatment blocked (P < 0.01) the MPP+-induced accumulation of intracellular reactive oxygen species and neurotoxicity. However, this protection was abolished (P < 0.05) by activators of the P38MAPK/P53/BAX pathway. Conclusion CPO-A protected against MPP+-induced cytotoxicity in SH-SY5Y cells and MPTP-induced neurotoxicity in mice by regulating the P38MAPK/P53/BAX signaling. Our findings reveal a novel role and mechanism of a food flavonoid CPO-A in preventing neurodegeneration.

The rate-limiting enzyme of the 2-methyl-d-erythritol-4-phosphate (MEP) terpenoid biosynthetic pathway, 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR), provides the perfect target for screening new antibacterial substances. In this study, we tested the DXR inhibitory effect of 35 plant essential oils (EOs), which have long been recognized for their antimicrobial properties. The results show that the EOs of Zanbthoxylum bungeanum (ZB), Schizonepetae tenuifoliae (ST), Thymus quinquecostatus (TQ), Origanum vulgare (OV), and Eugenia caryophyllata (EC) displayed weak to medium inhibitory activity against DXR, with IC50 values of 78 μg/mL, 65 μg/mL, 59 μg/mL, 48 μg/mL, and 37 μg/mL, respectively. GC-MS analyses of the above oils and further DXR inhibitory activity tests of their major components revealed that eugenol (EC) and carvacrol (TQ and OV) possess medium inhibition against the protein (68.3% and 55.6%, respectively, at a concentration of 20 μg/mL), whereas thymol (ST, TQ, and OV), carveol (ZB), and linalool (ZB, ST, and OV) only exhibited weak inhibition against DXR, at 20 μg/mL (23%−26%). The results add more details to the antimicrobial mechanisms of plant EOs, which could be very helpful in the direction of the reasonable use of EOs in the food industry and in the control of phytopathogenic microbials.

1-Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is a key enzyme in the methylerythritol phosphate pathway for terpenoid biosynthesis. Furthermore, it is an ideal target for the screening of novel antibiotics because it is present in causative organisms, but absent from humans. To identify more lipophilic DXR inhibitors from natural resources, we tested the DXR inhibitory activity of five proanthocyanidins in this study. The results indicated that all these compounds specifically restrained the activity of DXR, with procyanid B2 exhibiting a relatively low effect against DXR (IC50 ∼ 305 μM) and procyanid C1 displaying moderate activity (IC50 75.1 μM). The other three compounds cinnamtannin A2, cinnamtannin B1, and cinnamtannin D1 (IC50 ∼ 89.3, 105.0, and 97.8 μM, respectively) showed DXR inhibitory effects that were slightly weaker than that of procyanid C1. In addition, based on the initial characterization, the structure–activity relationship of this series of compounds against DXR is discussed.

Cinnamon procyanidin oligomers (CPOs) are water-soluble components extracted from cinnamon. This study aims to explore the neuroprotection of B-type CPO (CPO-B) against 1-methyl-4-phenylpyridinium (MPP+)-mediated cytotoxicity and the molecular mechanisms underlying its protection. The results demonstrated that CPO-B showed protection by increasing cell viability, attenuating an intracellular level of reactive oxygen species, downregulating cleaved caspase-3 expression, and upregulating the Bcl-2/Bax ratio. Moreover, CPO-B completely blocked the dephosphorylation of extracellular, signal-regulated kinase 1 and 2 (Erk1/2) caused by MPP+. Treatment with an Erk1/2 inhibitor, SCH772984, significantly abolished the neuroprotection of CPO-B against MPP+. Taken together, we demonstrate that CPO-B from cinnamon bark provided protection against MPP+ in cultured SH-SY5Y cells, and the potential mechanisms may be attributed to its ability to modulate the dysregulation between pro-apoptotic and anti-apoptotic proteins through the Erk1/2 signaling pathway. Our findings suggest that the addition of cinnamon to food or supplements might benefit patients with PD.