Racemic Norlignans as Diastereoisomers from Ferula sinkiangensis Resins with Antitumor and Wound-Healing Promotion Activities.

Ferulasinkins A-D (1-4), four new norlignans, were isolated from the resins of Ferula sinkiangensis, a medicinal plant of the Apiaceae family. All of them were obtained as racemic mixtures, chiral HPLC was used to produce their (+)- and (-)-antipodes. The structures of these new compounds, including their absolute configurations, were elucidated by spectroscopic and computational methods. This isolation provides new insight into the chemical profiling of F. sinkiangensis resins beyond the well-investigated structure types such as sesquiterpene coumarins and disulfides. Compounds 2a and 3a were found to significantly inhibit the invasion and migration of triple-negative breast cancer (TNBC) cell lines via CCK-8 assay. On the other hand, the wound-healing assay also demonstrated that compounds 4a and 4b could promote the proliferation of human umbilical vein endothelial cells (HUVECs). Notably, the promoting effects of 4a and 4b were observed as more significant versus a positive control using basic fibroblast growth factor (bFGF).

SIRT1 Activation Promotes ß-Cell Regeneration by Activating Endocrine Progenitor Cells via AMPK Signaling-Mediated Fatty Acid Oxidation.

Induction of ß-cell regeneration from endogenous cells represents a highly promising strategy in stem cell-based treatment for patients with diabetes. Recently, calorie restriction has been shown to affect the regulation of tissue and cell regeneration, including ß cells, via metabolic related mechanisms. Here, we examined the potential utility of sirtuin 1 (SIRT1), a calorie restriction mimetic, for stimulating ß-cell regeneration and the underlying mechanisms of such stimulation. The present results showed that SIRT1 activation with SRT1720 promoted ß-cell regeneration in streptozotocin (STZ)-induced ß-cell-deficient neonatal rats. This beneficial effect involved enhanced activation of neurogenin3 (NGN3)-positive endocrine progenitors from pancreatic ductal cells, rather than an expansion of residual ß cells. A dynamic expression profile of SIRT1 was observed in endocrine progenitors both during ß-cell regeneration in neonatal rats and in the second transition phase of mouse pancreas development. Consistently, SRT1720 treatment upregulated endocrine progenitor differentiation in cultured pancreatic rudiments. Upregulation of NGN3 by SIRT1 activation was through stimulating AMP-activated protein kinase (AMPK) signaling-mediated fatty acid oxidation (FAO) in human pancreatic progenitor cells; AMPK inhibition abolished these effects. The present findings demonstrate a promotional effect of SIRT1 activation on ß-cell restoration and endocrine progenitor differentiation that involves regulation of AMPK signaling-mediated FAO. Stem Cells 2019;37:1416-1428.

Liquidambarines A - C, three new abietane diterpenoids from Liquidambar formosana Hance and their anti-inflammatory activities.

Liquidambarines A - C (1-3), three new abietane-type diterpenoids, together with five known compounds (4-8) were isolated from the resin of Liquidambar formosana Hance. Their structures were elucidated by the combination of spectroscopic and computational methods. We explored their anti-inflammatory potential by analyzing the protein expression of iNOS and COX-2. Compounds 1 and 3 exhibit significant anti-inflammatory activities without cytotoxicity. These experimental studies suggest these new abietane-type diterpenoids have the potential to be candidates for inflammation-associated diseases.

Seven diterpenoids from the resin of Pinus yunnanensis Franch and their anti-inflammatory activity.

Phytochemical investigation of the 95% ethanol extract from Pinus yunnanensis Franch resin induced the isolation of six previously unreported diterpenoids pinuyunnanacids K - N, P - Q, a nor-diterpenoid with a novel skeleton pinuyunnanacid O and six known analogues. Their structures were elucidated by spectroscopic analysis and computational methods, including nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, calculated NMR chemical shifts method and electronic circular dichroic (ECD) spectra. All the compounds were analyzed for anti-inflammatory activity through western blotting and cell viability, compounds 2, 10 and 12 significantly downregulated the protein expression of iNOS at the concentration of 40 µM. At the same time, compounds 10 and 12 decreased the expression of COX-2 in LPS-treated RAW264.7 (leukemia cells in mouse macrophage) cells at the concentration of 40 µM.

Irisin Is a Positive Regulator for Ferroptosis in Pancreatic Cancer.

Regulated cell death by way of ferroptosis involves iron-dependent accumulation of cellular reactive oxygen species (ROS). Ferroptosis is attracting attention as a potential therapeutic target for cancer treatments without drug resistance. The relationship between irisin, a myokine involved in autophagy and ROS metabolism, and ferroptosis is unclear. In this study, we used erastin-induced ferroptosis in PANC-1 cells to examine potential interactions of irisin with ferroptosis. Using western blots and reverse transcriptase polymerase chain reactions, we found that irisin can further exacerbate erastin-induced upregulation in free iron, lipid ROS levels, and glutathione depletion, relative to cells treated with erastin only. Conversely, removal of irisin limited erastin effects. Furthermore, irisin modulation of ferroptosis was associated with the expression changes in molecules important for ROS metabolism, iron metabolism, and the cysteine/glutamate antiporter system (system Xc -). These study findings suggest that irisin can act as a master factor of ferroptosis, and that potential implications for harnessing irisin-mediated ferroptosis for cancer treatment are warranted.

Alcohol ingestion induces pancreatic islet dysfunction and apoptosis via mediation of FGF21 resistance.

BACKGROUND: Disruption of ß-cell insulin secretion and viability caused by excessive ethanol consumption increases type 2 diabetes mellitus (T2DM) pathogenesis risk. Fibroblast growth factor 21 (FGF21) plays a significant role in regulating lipid and glucose homeostasis. Recently, FGF21, best known for its role in lipid and glucose homeostasis regulation, and its obligate co-receptor ß-klotho have been shown to inhibit ethanol ingestion and metabolism. It remains unclear whether heavy ethanol intake modulates islet FGF21 expression and function. This study investigated the relationship between ethanol exposure, FGF21, and islet function in vivo/ex vivo islet and in vitro cell models. METHODS: Mice were gavaged with 3.5 g/kg ethanol or saline for 1-3 weeks (long-term exposure). Human MIN6 cells and isolated islets were cultured and treated with 80 mM ethanol for 24 h (short-term exposure) to mimic excessive ethanol consumption. We applied the oral glucose tolerance test (OGTT), blood glucometry, enzyme-linked immunosorbent assay (ELISAs) for insulin and FGF21, glucose stimulated insulin secretion (GSIS) testing, reverse-transcription (RT)-polymerase chain reaction (PCR), and western blot experiments. RESULTS: Long-term ethanol treatment induced FGF21 resistance in mouse pancreatic islets. Moreover, ethanol exposure damaged insulin secretory ability and glucose homeostasis. In vitro and ex vivo experiments showed that short-term ethanol treatment upregulated the expression of FGF21 signaling pathway-related genes and proteins, without affecting ß-cell survival or function. CONCLUSIONS: Long-term ethanol consumption induces FGF21 resistance-mediated pancreatic ß-cell dysfunction, and thus diabetes pathogenesis risk.