Decidual Stromal Cell Ferroptosis Associated with Abnormal Iron Metabolism Is Implicated in the Pathogenesis of Recurrent Pregnancy Loss.

Iron is necessary for various critical biological processes, but iron overload is also dangerous since labile iron is redox-active and toxic. We found that low serum iron and decidual local iron deposition existed simultaneously in recurrent pregnancy loss (RPL) patients. Mice fed with a low-iron diet (LID) also showed iron deposition in the decidua and adverse pregnancy outcomes. Decreased ferroportin (cellular iron exporter) expression that inhibited the iron export from decidual stromal cells (DSCs) might be the reason for local iron deposition in DSCs from low-serum-iron RPL patients and LID-fed mice. Iron supplementation reduced iron deposition in the decidua of spontaneous abortion models and improved pregnancy outcomes. Local iron overload caused ferroptosis of DSCs by downregulating glutathione (GSH) and glutathione peroxidase 4 levels. Both GSH and cystine (for the synthesis of GSH) supplementation reduced iron-induced lipid reactive oxygen species (ROS) and cell death in DSCs. Ferroptosis inhibitor, cysteine, and GSH supplementation all effectively attenuated DSC ferroptosis and reversed embryo loss in the spontaneous abortion model and LPS-induced abortion model, making ferroptosis mitigation a potential therapeutic target for RPL patients. Further study that improves our understanding of low-serum-iron-induced DSC ferroptosis is needed to inform further clinical evaluations of the safety and efficacy of iron supplementation in women during pregnancy.

Enrichment of antiplatelet peptides and removal of fishy odor from silver carp skin collagen hydrolysates by macroporous resins: pH value of loading sample affects the peptides separation.

Enrichment of antiplatelet peptides from silver carp skin collagen hydrolysates (CH) was studied using macroporous resins. Static adsorption showed that XAD-16 resin was the suitable resin due to its high adsorption capacity. The dynamic desorption of CH was studied on XAD-16 resin by ethanol gradient elution. Interestingly, pH value of loading sample had a great impact on the peptides separation. Results revealed that the yield and the antiplatelet activity of Ethl-20% fraction were highest at loading sample pH 6.0. The antiplatelet peptides were enriched in the 20% ethanol fraction with IC50 2.03 mg/mL compared to IC50 of CH, 4.7 mg/mL. Besides, the Ethl-20% fraction had a weakest fishy odor. Moreover, a series of peptides containing Hyp-Gly or Pro-Gly were identified from Ethl-20% fraction, which contributed to the antiplatelet activities. This study provided a simple and efficient method for large-scale separation enrichment of antiplatelet peptides as functional foods from CH.

A Collagen-Derived Oligopeptide from Salmo salar Collagen Hydrolysates Restrains Atherogenesis in ApoE-/- Mice via Targeting P2 Y12 Receptor.

SCOPE: Collagen hydrolysates have been reported with a variety of biological activities. The previous study has separated and identified a series of Hyp-Gly containing antiplatelet peptides from collagen hydrolysates from Salmo salar. But the target and underlying mechanism in platelets remains unknown. METHODS AND RESULTS: In this study, peptide OGEFG (OG-5) inhibits platelet aggregation especially induced by 2MeS-ADP and attenuates tail thrombosis formation by 30% in a dose-dependent manner, via apparent antagonism effects on P2 Y12 receptors to regulate Gßγi-PI3K-Akt signaling and Gαi-cAMP-VASP signaling is demonstrated. The molecular docking results also reveal a strong binding energy with the P2 Y12 receptor of peptide OG-5 (-10.70 kcal mol-1 ). In vitro study suggests that OG-5 inhibited the release of inflammatory cytokines in endothelial cells and macrophage cells, migration of vascular smooth muscle cell induced by ADP, which is highly released in ApoE-/- mice. Long-term administration of OG-5 significantly reduces atherosclerotic plaque formation without side effects in ApoE-/- mice, exhibiting a comparable effect with aspirin. CONCLUSION: These results reveal that collagen hydrolysates with OG-containing peptides have potential to be developed as an effective diet supplement to prevent the occurrence of atherogenesis and thrombotic disease.

Korean red ginseng alleviate depressive disorder by improving astrocyte gap junction function.

ETHNOPHARMACOLOGICAL RELEVANCE: Korean red ginseng (KRG), a processed product of Panax ginseng C. A. Mey, show significant anti-depressive effect in clinic. However, its mechanism is still unclear. AIM OF THE STUDY: Gap junction intercellular communication (GJIC) dysfunction is a potential pathogenesis of depression. Therefore, this study's objective is to investigate whether the antidepressant effect of KRG is related to GJIC. MATERIALS AND METHODS: Rat were restraint 8 h every day for 28 consecutive days to prepare depression models, and meanwhile, rats were intragastrically administrated with normal saline, KRG solutions (25, 50 or 100 mg/kg) or fluoxetine (10 mg/kg) 1 h before stress. The behavioral performance was determined by forced swimming test, sucrose preference test and open field test. GJIC was determined by the Lucifer yellow (LY) diffusion distance in prelimb cortex (PLC). In addition, the level of Cx43, one of executors of GJIC, was tested by Western blot. To find out the protective effect of KRG against GJIC dysfunction directly, rats were intracranially injected with carbenoxolone (CBX, blocker of GJIC), and meanwhile normal saline, KRG (100 mg/kg) or fluoxetine (10 mg/kg) was administered daily. The behavioral performance of these rats was detected, and the LY localization injection PLC area was used to detect the gap junction function. RESULTS: Chronic resistant stress (CRS) induced depressive symptoms, as manifested by prolonged immobility time in forced swimming test and decreased sucrose consumption ratio. Administration of KRG alleviated these depressive symptoms significantly. GJIC determination showed that KRG improved the LY diffusion and increased Cx43 level in prefrontal cortex (PFC) significantly, indicated that GJIC dysfunction was alleviated by the treatment of KRG. However, the astrocytes number was also increased by the treatment of KRG, which maybe alleviate depression-like symptoms by increasing the number of astrocytes rather than improving GJIC. Injection of CBX produced depressive symptoms and GJIC dysfunction, as manifested by decreased sucrose consumption ratio and prolonged immobility time in forced swimming test, but no astrocytes number changes, KRG also reversed depressive symptoms and GJIC dysfunction, suggested that the improvement of depressive-like symptoms was improved by GJIC. CONCLUSIONS: KRG alleviate depressive disorder by improving astrocytic gap junction function.