In Caenorhabditis elegans (C. elegans), ablation of germline stem cells (GSCs) leads to infertility, which extends lifespan. It has been reported that aging and reproduction are both inextricably associated with metabolism. However, few studies have investigated the roles of polar small molecules metabolism in regulating longevity by reproduction. In this work, we combined the nuclear magnetic resonance (NMR) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) to profile the water-soluble metabolome in C. elegans. Comparing the metabolic fingerprint between two physiological ages among different mutants, our results demonstrate that aging is characterized by metabolome remodeling and metabolic decline. In addition, by analyzing the metabolic profiles of long-lived germline-less glp-1 mutants, we discovered that glp-1 mutants regulate the levels of many age-variant metabolites to attenuate aging, including elevated concentrations of the pyrimidine and purine metabolism intermediates and decreased concentrations of the citric acid cycle intermediates. Interestingly, by analyzing the metabolome of daf-16;glp-1 double mutants, our results revealed that some metabolic exchange contributing to germline-mediated longevity was mediated by transcription factor FOXO/DAF-16, including pyrimidine metabolism and the TCA cycle. Based on a comprehensive metabolic analysis, we provide novel insight into the relationship between longevity and metabolism regulated by germline signals in C. elegans.
Abstract Phytochromes initiate chloroplast biogenesis by activating genes encoding the photosynthetic apparatus, including photosynthesis-associated plastid-encoded genes ( PhAPG s). PhAPG s are transcribed by a bacterial-type RNA polymerase (PEP), but how phytochromes in the nucleus activate chloroplast gene expression remains enigmatic. We report here a forward genetic screen in Arabidopsis that identified NUCLEAR CONTROL OF PEP ACTIVITY (NCP) as a necessary component of phytochrome signaling for PhAPG activation. NCP is dual-targeted to plastids and the nucleus. While nuclear NCP mediates the degradation of two repressors of chloroplast biogenesis, PIF1 and PIF3, NCP in plastids promotes the assembly of the PEP complex for PhAPG transcription. NCP and its paralog RCB are non-catalytic thioredoxin-like proteins that diverged in seed plants to adopt nonredundant functions in phytochrome signaling. These results support a model in which phytochromes control PhAPG expression through light-dependent double nuclear and plastidial switches that are linked by evolutionarily conserved and dual-localized regulatory proteins.
Isoselagintamarlin A (1), a selaginellin analogue featured a rare benzofuran unit, was isolated from Selaginella tamariscina. Its complete structural assignment was established through a combination of high-field NMR technique and biomimetic synthesis. Notably, isoselagintamarlin A (1) was successfully synthesized via sequential oxidations and intramolecular cyclization.
Thirteen sesquiterpenes including eight new ones, magnodelavins A-H (1-8), were obtained from the 95 % ethanolic extract of the leaves of Magnolia delavayi Franch. The structures of the new compounds were determined by exhaustive 1 H-, 13 C-, 2D-NMR, UV, IR, and HR-ESI-MS data, as well as X-ray crystallographic analysis. Compounds 9 and 10 showed potent cytotoxic activities against HL-60, A-549, SMMC-7721, MCF-7, and SW480 human cancer cell lines in vitro using MTS assay.
Background TPM3 (tropomyosin 3) is an actin‐binding protein in vascular smooth muscle cells, where posttranslational modifications critically regulate its actin affinity, influencing cardiovascular function. Emerging evidence suggests that Khib (2‐hydroxyisobutyrylation) plays a significant role in the cardiovascular system. Histone deacetylase 3 (HDAC3) serves as an “eraser” of Khib marks. However, the impact of TPM3 de‐2‐hydroxyisobutyrylation on vascular contraction remains unclear. Methods and Results In this study, we employed mouse models and in vitro experiments to elucidate the mechanism by which phenylephrine‐induced HDAC3 activation drives vasoconstriction via de‐2‐hydroxyisobutyrylation of TPM3. Our findings demonstrate that phenylephrine triggers HDAC3 nuclear export and promotes its interaction with TPM3, resulting in decreased Khib modification and enhanced vasoconstriction. Coimmunoprecipitation experiments confirmed that phenylephrine reduces Khib levels on TPM3 in mouse aorta. Additionally, ex vivo vascular tension assays using mouse aortic rings revealed that treatment with the Khib donor, ethyl 2‐hydroxyisobutyrate, induces endothelium‐independent vasodilation and ameliorates hypertensive vascular dysfunction. Molecular docking and kinetic simulations identified Lys141 of TPM3 as the primary site targeted by HDAC3‐mediated de‐2‐hydroxyisobutyrylation. This was further validated by adenoviral transfection of isolated blood vessels with a Lys141‐mutated TPM3 construct, which abolished the effects of HDAC3 on TPM3 Khib modification and vascular contractility. Conclusions These findings underscore the critical role of TPM3 de‐2‐hydroxyisobutyrylation in vasoconstriction and suggest that modulating this posttranslational modification could provide a novel therapeutic strategy for hypertensive vascular dysfunction.
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