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We employed an untargeted proteo‐metabolomic approach to profile circulating biomarkers in plasma samples from the I‐Lan Longitudinal Aging Study, aiming to identify biomarkers and pathways associated with physio‐cognitive decline syndrome (PCDS). In 115 propensity score‐matched PCDS case–control pairs, pathway analyses implicated dysregulation of fatty acid metabolism and inflammation in PCDS pathogenesis. Sex‐specific associations were observed, with disruptions in central carbon metabolism (elevated PKM, MDH1, and GAPDH; decreased MINPP1) and tyrosine metabolism (decreased MIF, DBH; increased thyroxine) characterizing in men. In contrast, perturbations in glutathione and phenylalanine metabolism, including increased ANPEP, GSTP1, and decreased pyroglutamic acid, were identified in women. Results suggest that dysregulated energy and redox homeostasis likely contribute to PCDS development. Notably, ANPEP, PKM, and MIF emerged as potential biomarkers, elucidating the muscle–brain crosstalk framework. Our findings provide insights into potential molecular mechanisms underlying PCDS and the muscle–brain crosstalk, marking progress toward elucidating biomarkers in the journey of healthy aging. [ABSTRACT FROM AUTHOR]

Sphingosine-1-phosphate (S1P) has been known to promote endothelial cell (EC) proliferation and protect Syndecan-1 (SDC1) from shedding, thereby maintaining this antithrombotic signal. In the present study, we investigated the effect of S1P in the construction of a functional tissue-engineered blood vessel by using human endothelial cells and decellularized human umbilical vein (DHUV) scaffolds. Both human umbilical vein endothelial cells (HUVEC) and human cord blood derived endothelial progenitor cells (EPC) were seeded onto the scaffold with or without the S1P treatment. The efficacy of re-cellularization was determined by using the fluorescent marker CellTracker CMFDA and anti-CD31 immunostaining. The antithrombotic effect of S1P was examined by the anti-aggregation tests measuring platelet adherence and clotting time. Finally, we altered the expression of SDC1, a major glycocalyx protein on the endothelial cell surface, using MMP-7 digestion to explore its role using platelet adhesion tests in vitro. The result showed that S1P enhanced the attachment of HUVEC and EPC. Based on the anti-aggregation tests, S1P-treated HUVEC recellularized vessels when grafted showed reduced thrombus formation compared to controls. Our results also identified reduced SDC1 shedding from HUVEC responsible for inhibition of platelet adherence. However, no significant antithrombogenic effect of S1P was observed on EPC. In conclusion, S1P is an effective agent capable of decreasing thrombotic risk in engineered blood vessel grafts.Statement of significanceSphingosine-1phosphate (S1P) is a low molecular-weight phospholipid mediator that regulates diverse biological activities of endothelial cell, including survival, proliferation, cell barrier integrity, and also influences the development of the vascular system. Based on these characters, we the first time to use it as an additive during the process of a small caliber blood vessel construction by decellularized human umbilical vein and endothelial cell/endothelial progenitor. We further explored the function and mechanism of S1P in promoting revascularization and protection against thrombosis in this tissue engineered vascular grafts. The results showed that S1P could not only accelerate the generation but also reduce thrombus formation of small caliber blood vessel.

Describes the development and implementation process of a Web-based science museum in Taiwan. Topics include use of the Internet; lifelong distance learning; museums and the Internet; objectives of the science museum; funding; categories of exhibitions; analysis of Web users; homepage characteristics; graphics and the effect on speed; and future research. (LRW)

Summary: Skeletal muscle has emerged as one of the most important tissues involved in regulating systemic metabolism. The gastrocnemius is a powerful skeletal muscle composed of predominantly glycolytic fast‐twitch fibers that are preferentially lost among old age. This decrease in gastrocnemius muscle mass is remarkable during aging; however, the underlying molecular mechanism is not fully understood. Strikingly, there is a ~70% decrease in Cisd2 protein, a key regulator of lifespan in mice and the disease gene for Wolfram syndrome 2 in humans, within the gastrocnemius after middle age among mice. A proteomics approach was used to investigate the gastrocnemius of naturally aged mice, and this was compared to the autonomous effect of Cisd2 on gastrocnemius aging using muscle‐specific Cisd2 knockout (mKO) mice as a premature aging model. Intriguingly, dysregulation of calcium signaling and activation of UPR/ER stress stand out as the top two pathways. Additionally, the activity of Serca1 was significantly impaired and this impairment is mainly attributable to irreversibly oxidative modifications of Serca. Our results reveal that the overall characteristics of the gastrocnemius are very similar when naturally aged mice and the Cisd2 mKO mice are compared in terms of pathological alterations, ultrastructural abnormalities, and proteomics profiling. This suggests that Cisd2 mKO mouse is a unique model for understanding the aging mechanism of skeletal muscle. Furthermore, this work substantiates the hypothesis that Cisd2 is crucial to the gastrocnemius muscle and suggests that Cisd2 is a potential therapeutic target for muscle aging. [ABSTRACT FROM AUTHOR]

Conventional polyacrylamide hydrogels prepared from the free radical polymerization between acrylamide and N,N′-methylenebisacrylamide (NMBA) have been frequently used in the biochemical technique like the sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) to resolve protein mixtures. In this study, we have prepared an alternative polyacrylamide hydrogel from the cross-linking of acrylamide and N,N′-bisacrylylcystamine (BACy). In addition, we have compared the BACy-based hydrogel with the NMBA-based polyacrylamide hydrogel for their physical properties such as swelling ratio, shear modulus, crosslink density and morphology. Moreover, we further determined whether BACy-based polyacrylamide hydrogel could be applied to SDS-PAGE and proteomics research. The results showed that this type of hydrogel is capable of separating proteins and facilitates further in-gel protein digestion and the following protein identifications by mass spectrometry. In summary, our study provides a basis for the putative application of BACy-based hydrogels. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Chronic myelogenous leukemia (CML) is clinically treated with imatinib, which inhibits the kinase activity of the Bcr-Abl oncoprotein. However, imatinib resistance remains a common clinical issue. Andrographolide, the major compound of the medicinal plant Andrographis paniculata , was reported to exhibit anticancer activity. In this study, we explored the therapeutic potential of andrographolide and its derivative, NCTU-322, against both imatinib-sensitive and imatinib-resistant human CML cell lines. Both andrographolide and NCTU-322 downregulated the Bcr-Abl oncoprotein in imatinib-resistant CML cells through an Hsp90-dependent mechanism similar to that observed in imatinib-sensitive CML cells. In addition, NCTU-322 had stronger effects than andrographolide on downregulation of Bcr-Abl oncoprotein, induction of Hsp90 cleavage and cytotoxicity of CML cells. Notably, andrographolide and NCTU-322 could induce differentiation, mitotic arrest and apoptosis of both imatinib-sensitive and imatinib-resistant CML cells. Finally, the anticancer activity of NCTU-322 against imatinib-resistant CML cells was demonstrated in vivo. In summary, our data demonstrated that andrographolide and NCTU-322 inhibit Bcr-abl function via a mechanism different from that of imatinib, and they induced multiple anticancer effects in both imatinib-sensitive and resistant CML cells. Our findings demonstrate that andrographolide and NCTU-322 are potential therapeutic agents again CML. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the effects of minocycline on cognitive functions in neonatal rat after hypoxia exposure and the underlying mechanism. A model of hypoxic brain damage (HBD) was developed by exposing postnatal 1 day (P1) rats to systemic hypoxia. The rats were intraperitoneally injected with normal saline (Hy group) or minocycline (Hy + M group) 2 h after hypoxia exposure. Some other P1 rats that were not subjected to systemic hypoxia were used as normal control (NG group). The Y-maze test was used to evaluate learning and memory ability on postnatal day 30. Inflammatory mediators (Iba-1, IL-1β, TNF-α and TGF-β1), glutamate transporters (EAAT1 and EAAT2), total Tau and phosphorylated Tau (phosphorylation sites: Tyr18, Thr205, Thr231, Ser396 and Ser404) protein expressions in the hippocampus were detected by Western blot 7 d after hypoxic exposure. The results showed that hypoxia induced learning and memory impairments of the neonatal rats, and minocycline administration could reverse the effects of hypoxia. The protein expression levels of Iba-1, IL-1β, TNF-α, EAAT2 and Tau phosphorylated at T231 were increased, but the total Tau expression was decreased in the hippocampus of the rats from Hy group 7 d after hypoxia exposure. In the hypoxia-treated rats, minocycline down-regulated Iba-1, IL-1β, TNF-α and EAAT2 protein expressions significantly, but did not affect total Tau and phosphorylated Tau protein expressions. Our results suggest that minocycline can prevent cognitive deficits of rats with hypoxia exposure, and the underlying mechanism may involve the inhibition of neuroinflammation and dysfunctional glutamate transporters but not the regulation of the Tau hyperphosphorylation.