Endothelial dysfunction is one of the main age‐related arterial phenotypes responsible for cardiovascular disease (CVD) in older adults. This endothelial dysfunction results from decreased ...bioavailability of nitric oxide (NO) arising downstream of endothelial oxidative stress. In this study, we investigated the protective effect of anthocyanins and the underlying mechanism in rat thoracic aorta and human vascular endothelial cells in aging models. In vitro, cyanidin‐3‐rutinoside (C‐3‐R) and cyanidin‐3‐glucoside (C‐3‐G) inhibited the d‐galactose (d‐gal)‐induced senescence in human endothelial cells, as indicated by reduced senescence‐associated‐β‐galactosidase activity, p21, and p16INK4a. Anthocyanins blocked d‐gal‐induced reactive oxygen species (ROS) formation and NADPH oxidase activity. Anthocyanins reversed d‐gal‐mediated inhibition of endothelial nitric oxide synthase (eNOS) serine phosphorylation and SIRT1 expression, recovering NO level in endothelial cells. Also, SIRT1‐mediated eNOS deacetylation was shown to be involved in anthocyanin‐enhanced eNOS activity. In vivo, anthocyanin‐rich mulberry extract was administered to aging rats for 8 weeks. In vivo, mulberry extract alleviated endothelial senescence and oxidative stress in the aorta of aging rats. Consistently, mulberry extract also raised serum NO levels, increased phosphorylation of eNOS, increased SIRT1 expression, and reduced nitrotyrosine in aortas. The eNOS acetylation was higher in the aging group and was restored by mulberry extract treatment. Similarly, SIRT1 level associated with eNOS decreased in the aging group and was restored in aging plus mulberry group. These findings indicate that anthocyanins protect against endothelial senescence through enhanced NO bioavailability by regulating ROS formation and reducing eNOS uncoupling.
Aging is known for its correlation with increased protein acetylation rates and the decline of sirtuin‐1 (SIRT1) deacetylation activity. This study demonstrated that anthocyanin‐rich mulberry extract reduces oxidative stress in aging vasculature and attenuates endothelial dysfunction through reversed inhibition of endothelial nitric oxide synthase (eNOS), serine phosphorylation, and SIRT1 expression, recovering NO level in senescence.
Summary
Germination requires sufficient water absorption by seeds, but excessive water in the soil inhibits plant growth. We therefore hypothesized that tolerance mechanisms exist that help young ...seedlings survive and develop in waterlogged conditions.
Many ATP‐BINDING CASSETTE TRANSPORTER subfamily G (ABCG) proteins protect terrestrial plants from harsh environmental conditions. To establish whether any of these proteins facilitate plant development under waterlogged conditions, we observed the early seedling growth of many ABCG transporter mutants under waterlogged conditions.
abcg5 seedlings exhibited severe developmental problems under waterlogged conditions: the shoot apical meristem was small, and the seedling failed to develop true leaves. The seedlings had a high water content and reduced buoyancy on water, suggesting that they were unable to retain air spaces on and inside the plant. Supporting this possibility, abcg5 cotyledons had increased cuticle permeability, reduced cuticular wax contents, and a much less dense cuticle layer than the wild‐type.
These results indicate that proper development of plants under waterlogged conditions requires the dense cuticle layer formed by ABCG5 activity.
See also the Editorial on this article by Sasidharan et al., 229: 5–7.
Pluripotent stem cells (PSCs) have distinct metabolic properties that support their metabolic and energetic needs and affect their stemness. In particular, high glycolysis is critical for the ...generation and maintenance of PSCs. However, it is unknown how PSCs maintain and acquire this metabolic signature. In this study, we found that core pluripotency factors regulate glycolysis directly by controlling the expression of glycolytic enzymes. Specifically, Oct4 directly governs Hk2 and Pkm2, which are important glycolytic enzymes that determine the rate of glycolytic flux. The overexpression of Hk2 and Pkm2 sustains high levels of glycolysis during embryonic stem cell (ESC) differentiation. Moreover, the maintenance of high glycolysis levels by Hk2 and Pkm2 overexpression hampers differentiation and preserves the pluripotency of ESCs in the absence of leukemia inhibitory factor. Overall, our study identifies a direct molecular connection between core pluripotency factors and ESC metabolic signatures and demonstrates the significance of metabolism in cell fate determination.
Lipotoxic hepatocyte injury is a primary event in non-alcoholic steatohepatitis (NASH), but the mechanisms of lipotoxicity are not fully defined. Sphingolipids and free cholesterol (FC) mediate ...hepatocyte injury, but their link in NASH has not been explored. We examined the role of free cholesterol and sphingomyelin synthases (SMSs) that generate sphingomyelin (SM) and diacylglycerol (DAG) in hepatocyte pyroptosis, a specific form of programmed cell death associated with inflammasome activation, and NASH.
Wild-type C57BL/6J mice were fed a high fat and high cholesterol diet (HFHCD) to induce NASH. Hepatic SMS1 and SMS2 expressions were examined in various mouse models including HFHCD-fed mice and patients with NASH. Pyroptosis was estimated by the generation of the gasdermin-D N-terminal fragment. NASH susceptibility and pyroptosis were examined following knockdown of SMS1, protein kinase Cδ (PKCδ), or the NLR family CARD domain-containing protein 4 (NLRC4).
HFHCD increased the hepatic levels of SM and DAG while decreasing the level of phosphatidylcholine. Hepatic expression of
but not
was higher in mouse models and patients with NASH. FC in hepatocytes induced
expression, and
knockdown prevented HFHCD-induced NASH. DAG produced by SMS1 activated PKCδ and NLRC4 inflammasome to induce hepatocyte pyroptosis. Depletion of
prevented hepatocyte pyroptosis and the development of NASH. Conditioned media from pyroptotic hepatocytes activated the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) in Kupffer cells, but
knockout mice were not protected against HFHCD-induced hepatocyte pyroptosis.
SMS1 mediates hepatocyte pyroptosis through a novel DAG-PKCδ-NLRC4 axis and holds promise as a therapeutic target for NASH.
•The mechanism by which users develop virtual friendships with intelligent personal assistants (IPAs) is investigated.•The two critical dimensions of para-friendship are self-disclosure and social ...support.•IPAs that provide a sense of intimacy, understanding, enjoyability, and involvement affect para-friendships.•Para-friendships strengthen users' intention to continue using IPAs.•The para-friendship mechanism differs according to the users' social isolation tendency.
Glucose limitation is a major stress condition that cells must respond to by altering their metabolism to ensure survival. Rsv1 is a zinc finger protein previously shown to be required for survival ...during stationary phase. In this study, we present a novel mechanism regulated by Rsv1 in the fission yeast Schizosaccharomyces pombe that is involved in altering glucose metabolic flux. We found that rsv1 gene expression is induced by Rst2 and Atf1, two transcription factors regulated by the cAMP‐dependent protein kinase (PKA) pathway and the mitogen‐activated protein kinase (MAPK) cascade, respectively. The downstream target genes of Rsv1 were identified by genome‐wide ChIP sequencing of Rsv1‐bound DNA sites and RNA sequencing analysis of Rsv1‐dependent transcripts that were differentially expressed under glucose starvation. Rsv1 directly regulated the expression of at least 21 genes that mostly encode transporters and proteins related to sugar metabolism. Among these, gcd1, which encodes glucose dehydrogenase in the gluconate shunt for the pentose phosphate pathway, was most remarkably repressed by Rsv1. The defect in survival of Δrsv1 mutant under glucose starvation condition was mitigated by additional deletion of a gcd1, idn1, or a gene for a putative lactonase (SPCC16c4.10), suggesting the critical importance of downregulating the gluconate shunt and pentose phosphate pathway for long‐term survival. These results show an intricate response to glucose starvation: increasing the synthesis of a transcription factor via two signal transduction pathways, which sheds light on the importance of remodeling a metabolic circuit to secure glucose for cell survival.
With glucose as major carbon source for most organisms, the control of intracellular sugar levels is central for cell survival. Woo‐Hyun Chung, Jung‐Hye Roe and colleagues investigated transcriptional regulation of Rsv1, a pivotal factor for viability in S.pombe under nutrient starvation conditions. They found regulation of Rsv1 by both the MAPK and cAMP/PKA pathway cascades. By performing genome‐wide sequencing for Rsv1 target genes, they revealed 21 target genes. Rsv1 binding under glucose starvation represses a glucose dehydrogenase in the gluconate shunt for the pentose phosphate pathway. Together, the authors reveal the importance of controlling metabolic glucose pathways for cell survival.
Targeted therapy based on protein–drug conjugates has attracted significant attention owing to its high efficacy and low side effects. However, efficient and stable drug conjugation to a protein ...binder remains a challenge. Herein, a chemoenzymatic method to generate highly stable and homogenous drug conjugates with high efficiency is presented. The approach comprises the insertion of the CaaX sequence at the C‐terminal end of the protein binder, prenylation using farnesyltransferase, and drug conjugation through an oxime ligation reaction. MMAF and an EGFR‐specific repebody are used as the antitumor agent and protein binder, respectively. The method enables the precisely controlled synthesis of repebody–drug conjugates with high yield and homogeneity. The utility of this approach is illustrated by the notable stability of the repebody–drug conjugates in human plasma, negligible off‐target effects, and a remarkable antitumor activity in vivo. The present method can be widely used for generating highly homogeneous and stable PDCs for targeted therapy.
A chemoenzymatic conjugation method that is based on enzymatic prenylation and oxime ligation is a simple and efficient means for generating highly stable and homogeneous protein–drug conjugates in a site‐specific manner. It can be generally applied to the conjugation of drugs to a wide range of protein binders, facilitating the development of targeted therapies with high efficacies and low off‐target effects.
Abstract
The COVID-19 pandemic caused disruptions of public life and imposed lockdown measures in 2020 resulted in considerable reductions of anthropogenic aerosol emissions. It still remains unclear ...how the associated short-term changes in atmospheric chemistry influenced weather and climate on regional scales. To understand the underlying physical mechanisms, we conduct ensemble aerosol perturbation experiments with the Community Earth System Model, version 2. In the simulations reduced anthropogenic aerosol emissions in February generate anomalous surface warming and warm-moist air advection which promotes low-level cloud formation over China. Although the simulated response is weak, it is detectable in some areas, in qualitative agreement with the observations. The negative dynamical cloud feedback offsets the effect from reduced cloud condensation nuclei. Additional perturbation experiments with strongly amplified air pollution over China reveal a nonlinear sensitivity of regional atmospheric conditions to chemical/radiative perturbations. COVID-19-related changes in anthropogenic aerosol emissions provide an excellent testbed to elucidate the interaction between air pollution and climate.
In South Korea, a November 2021 outbreak caused by severe acute respiratory syndrome coronavirus 2 Omicron variant originated from 1 person with an imported case and spread to households, ...kindergartens, workplaces, restaurants, and hospitals, resulting in 11 clusters within 3 weeks. An epidemiologic curve indicated rapid community transmission of the Omicron variant.
Understanding the biocompatibility of nanoparticles in dental materials is essential for their safe usage in the oral cavity. In this study, we investigated whether nanoparticles deposited on ...orthodontic latex rubber bands are involved in the induction of cytotoxicity. A method of stretching to three times (“3L”) the length of the latex rubber bands was employed to detach the particles using the original length (“L”) for comparison. The cytotoxicity tests were performed on extracts with mouse fibroblasts (L929) and human gingival fibroblasts (HGFs). Fourier transform infrared spectroscopy, ion chromatography, elemental analysis, and inductively coupled plasma mass spectrometry (ICP-MS) were performed to detect the harmful components in the extracts from rubber bands. There was a significant decrease in the cell viability in the “L” samples compared with the “3L” samples ( P < 0.05 ) in the L929 and HGF cells. This was due to the Ni single crystal nanoparticles (~50nm) from the inner surface of “L” samples that were detached in the “3L” samples as well as the Zn ion (~9 ppm) detected in the extract. This study revealed that the Ni nanoparticles, as well as Zn ions, were involved in the induction of cytotoxicity from the latex rubber bands.
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