Exopolysaccharide production by Lactobacillus plantarum T10 is responsible for the probiotic activity in enhancing intestinal barrier function in vitro and in vivo.

Lactobacillus probiotics exert their effects in a strain-specific and metabolite-specific manner. This study aims to identify lactobacilli that can effectively enhance the intestinal barrier function both in vitro and in vivo and to investigate the underlying metabolite and molecular mechanisms involved. Nine Lactobacillus isolates were evaluated for their ability to enhance the IPEC-J2 cellular barrier function and for their anti-inflammatory and anti-apoptotic effects in IPEC-J2 cells after an enterotoxigenic Escherichia coli challenge. Of the nine isolates, L. plantarum T10 demonstrated significant advantages in enhancing the cellular barrier function and displayed anti-inflammatory and anti-apoptotic activities in vitro. The bioactivities of L. plantarum T10 were primarily attributed to the production of exopolysaccharides, which exerted their effects through the TLR-mediated p38 MAPK pathway in ETEC-challenged IPEC-J2 cells. Furthermore, the production of EPS by L. plantarum T10 led to the alleviation of dextran sulfate sodium-induced colitis by reducing intestinal damage and enhancing the intestinal barrier function in mice. The EPS is classified as a heteropolysaccharide with an average molecular weight of 23.0 kDa. It is primarily composed of mannose, glucose, and ribose. These findings have practical implications for the targeted screening of lactobacilli used in the production of probiotics and postbiotics with strain-specific features of exopolysaccharides.

Allochroic cluster light-emitting diodes based on unique µ3-tetraphosphine Cu3X3 crowns with tunable excited states.

Multicomponent excited states endow copper iodide clusters with allochroic properties under diverse stimuli. However, crystal states are required, and cluster stimulus sensitivity hampers electroluminochromism. We developed PhQPCu3X3 (X = Cl, Br, and I) with the first µ3-bridging tetraphosphine ligand, whose Cu3X3 crowns were exposed to external stimulus. The increased proportion of Cu3X3 results in equal contributions of cluster- and ligand-centered components to excited states, the former of which is highly sensitive to grind, vapor, and, especially, electric stimuli, due to semi-exposed Cu3X3. Through vacuum evaporation and vapor fumigation of cluster-based emissive layers, the diodes' electroluminescence colors changed from yellow to white. Joule heat during device operation induced further color variation to orange, corresponding to Commission Internationale de l'Eclairage coordinates of PhQPCu3I3 changed from (0.44 ± 0.1, 0.34 ± 0.1) to (0.57 ± 0.1, 0.42 ± 0.1). These results demonstrate the superiority of luminescent clusters in accurate excited-state modulation, holding promise for wide applications.

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) alleviate excessive autophagy of ovarian granular cells through VEGFA/PI3K/AKT/mTOR pathway in premature ovarian failure rat model.

BACKGROUND: Premature ovarian failure (POF) is one of the leading causes of female infertility and is accompanied by abnormal endocrine, seriously affecting female quality of life. Previous studies have demonstrated that mesenchymal stem cells (MSCs) transplantation is a promising therapeutic strategy for POF. However, the mechanism remains obscure. This study aims to investigate the therapeutic effect of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on ovarian function in the POF rat model and explore the underlying mechanisms. METHODS: The ovarian function was evaluated by ovarian morphology, histology, estrous cycle, hormone levels (AMH, E2, FSH, and LH), and fertility ability to investigate the effect of hUC-MSCs on the POF rats model. The cytokines levels were assayed in serum using protein array to explore the mechanisms of hUC-MSCs therapy for POF. The excessive autophagy levels were evaluated using a co-culture system of 3D MSCs spheroids with human ovarian granulosa cell line (KGN) or primary ovarian granulosa cells (GCs) to understand the paracrine effect of hUC-MSCs on GCs. The related proteins expression of autophagy and PI3K/AKT/mTOR pathway was detected using Western Blotting and/or in various inhibitors supplement to further demonstrate that vascular endothelial growth factor A (VEGFA) secreted by hUC-MSCs can alleviate excessive autophagy of ovarian GCs via PI3K/AKT/mTOR signaling pathway. The ovarian culture model in vitro was applied to confirm the mechanism. RESULTS: The ovarian function of POF and the excessive autophagy of ovarian GCs were restored after hUC-MSCs transplantation. The protein array result demonstrated that VEGF and PI3K/AKT might improve ovarian function. in vitro experiments demonstrated that VEGFA secreted by hUC-MSCs could decrease oxidative stress and inhibit excessive autophagy of ovarian GCs via PI3K/AKT/mTOR pathway. The ovarian culture model results confirmed this mechanism in vitro. CONCLUSION: The hUC-MSCs can alleviate excessive autophagy of ovarian GCs via paracrine VEGFA and regulate the PI3K/AKT/mTOR signaling pathway, thereby improving the ovarian function of POF.

Activation of the p62-Keap1-Nrf2 pathway protects against oxidative stress and excessive autophagy in ovarian granulosa cells to attenuate DEHP-induced ovarian impairment in mice.

Di-(2-ethylhexyl) phthalate (DEHP) is widely used in various plastics but has been demonstrated to cause female reproductive toxicity. However, the exact mechanism underlying the ovarian damage induced by DEHP remains unclear. In this study, DEHP was administered orally to 5-week-old female mice for 30 days at doses of 0, 250, 500, and 1000 mg/kg/day. The findings demonstrated that DEHP exposure disrupted ovarian function and follicular development as well as induced oxidative stress and autophagy in ovarian granulosa cells (GCs). Further, 200 µM mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP in vivo, induced autophagy in both human ovarian granulosa cells line (KGN) and mouse primary GCs within 24 h in vitro. However, it did not affect the p62-dependent autophagy flux. Furthermore, MEHP-induced autophagy was inhibited by the autophagy inhibitor 3-MA and exacerbated by the autophagy activator rapamycin, indicating that MEHP induces excessive autophagy in GCs. Subsequently, we found that MEHP-induced autophagic cell death was primarily attributed to oxidative damage from elevated intracellular ROS levels. Meanwhile, MEHP exposure induced nuclear translocation of erythroid-derived factor 2-related factor (Nrf2), a key regulator of antioxidant activity resulting in activating antioxidant effects. Interestingly, we also found that MEHP-induced increase in p62 competitively binds Keap1, thereby facilitating nuclear translocation of Nrf2 and establishing a positive feedback loop in antioxidant regulation. Therefore, this study demonstrated that inhibition of Nrf2 could aggravate oxidative damage and enhance excessive autophagy caused by MEHP, while activation of Nrf2 could reverse the trend. These findings have also been reinforced in studies of cultured ovaries in vitro. Our study suggests that the p62-Keap1-Nrf2 pathway may serve as a potential protective mechanism against DEHP-induced oxidative stress and excessive autophagy in mouse GCs.

Prognostic value of interleukin-34 and interleukin-38 in patients with newly diagnosed atrial fibrillation.

Background: Interleukin (IL)-34 and IL-38 are associated with cardiovascular disease (CVD). However, their involvement in atrial fibrillation (AF) and AF-associated adverse events remains uncertain. Therefore, we aimed to investigate their association with various AF prognostic factors in a cohort study and assessed their predictive value for the prognosis of patients with AF. Methods: Patients with new-onset non-valvular AF were consecutively enrolled between 2013 and 2015 at the Department of Cardiovascular Medicine of the Southwest Hospital of the Army Medical University (Third Military Medical University) in Chongqing, China. The endpoints included stroke and all-cause mortality. The baseline levels of plasma IL-34, IL-38, NT-proBNP, high-sensitivity cardiac troponin T (hs-cTnT), and GDF-15 were measured and their correlation with AF-related adverse events were analyzed in a Cox proportional-hazards regression model. The C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to evaluate the performance of the AF prognostic models. Decision curve analysis (DCA) was used to evaluate the clinical net benefit of the original and modified models. Results: A total of 299 patients with new-onset AF were enrolled. During the median follow-up time of 28 (IQR: 27, 29) months, the higher levels of IL-34 were associated with a lower risk of stroke, and the higher levels of IL-38 were associated with an increased risk of all-cause death (all adjusted P < 0.05). In addition, elevated hs-cTnT and NT-proBNP concentrations were associated with a higher risk of stroke and all-cause mortality (all adjusted P < 0.05). Furthermore, the CHA2DS2-VASc score combined with IL-38 and NT-proBNP significantly improved the C-statistic, IDI, and NRI (all P < 0.01). There was no statistically significant difference (all P > 0.05) in the discrimination power between the preference models and the ABC (age, biomarkers, and clinical history) score for the two prognostic outcomes. Conclusion: Our results suggested that IL-34 and IL-38 were independently associated with stroke and all-cause mortality in patients with AF. Moreover, adding IL-38 and NT-proBNP to the CHA2DS2-VASc score significantly improved its predictive ability of AF-related all-cause death. Finally, the preference model performed equally well as the ABC score in predicting AF prognosis.