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N6-methyladenosine (m6A) modification is a class of epitope modifications that has received significant attention in recent years, particularly in relation to its role in various diseases, including sepsis. Epigenetic research has increasingly focused on m6A modifications, which is influenced by the dynamic regulation of three protein types: ?Writers" (such as METTL3/METTL14/WTAP)-responsible for m6A modification; ?Erasers" (FTO and ALKBH5)-involved in m6A de-modification; and ?Readers" (YTHDC1/2, YTHDF1/2/3)-responsible for m6A recognition. Sepsis, a severe and fatal infectious disease, has garnered attention regarding the crucial effect of m6A modifications on its development. In this review, we attempted to summarize the recent studies on the involvement of m6A and its regulators in sepsis, as well as the significance of m6A modifications and their regulators in the development of novel drugs and clinical treatment. The potential value of m6A modifications and modulators in the diagnosis, treatment, and prognosis of sepsis has also been discussed.
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Simple and efficient total synthesis of homogeneous and chemically modified protein samples remains a significant challenge. Here, we report development of a convergent hybrid phase native chemical ligation (CHP-NCL) strategy for facile preparation of proteins. In this strategy, proteins are split into ~100-residue blocks, and each block is assembled on solid support from synthetically accessible peptide fragments before ligated together into full-length protein in solution. With the new method, we increase the yield of CENP-A synthesis by 2.5-fold compared to the previous hybrid phase ligation approach. We further extend the new strategy to the total chemical synthesis of 212-residue linker histone H1.2 in unmodified, phosphorylated, and citrullinated forms, each from eight peptide segments with only one single purification. We demonstrate that fully synthetic H1.2 replicates the binding interactions of linker histones to intact mononucleosomes, as a proxy for the essential function of linker histones in the formation and regulation of higher order chromatin structure.
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Homeobox (HOX) genes encode highly conserved transcription factors that play vital roles in embryonic development. DNA methylation is a pivotal regulatory epigenetic signaling mark responsible for regulating gene expression. Abnormal DNA methylation is largely associated with the aberrant expression of HOX genes, which is implicated in a broad range of human diseases, including cancer. Numerous studies have clarified the mechanisms of DNA methylation in both physiological and pathological processes. In this review, we focus on how DNA methylation regulates HOX genes and briefly discuss drug development approaches targeting these mechanisms.
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BACKGROUND: Ticks are disease vectors that are matters of worldwide concern. Antibiotic treatments have been used to explore the interactions between ticks and their symbiotic microorganisms. In addition to altering the host microbial community, antibiotics can have toxic effects on the host. RESULTS: In the tick Haemaphysalis longicornis, the engorged females showed reproductive disruption after microinjection of tetracycline Multi-omics approaches were implemented to unravel the mechanisms of tick reproductive inhibition in this study. There were no significant changes in bacterial density in the whole ticks on days 2 or 4 after tetracycline treatment, while the bacterial microbial community was significantly altered, especially on day 4. The relative abundances of the bacteria Staphylococcus, Bacillus, and Pseudomonas decreased after tetracycline treatment, while the relative abundances of Coxiella and Rhodococcus increased. Ovarian transcriptional analysis revealed a cumulative effect of tetracycline treatment, as there was a significant increase in the number of differentially expressed genes with treatment time and a higher number of downregulated genes. The tick physiological pathways including lysosome, extracellular matrix (ECM)-receptor interaction, biosynthesis of ubiquinone and other terpenoids-quinones, insect hormone biosynthesis, and focal adhesion were significantly inhibited after 4 days of tetracycline treatment. Metabolite levels were altered after tetracycline treatment, and the differences increased with treatment time. The differential metabolites were involved in a variety of physiological pathways; the downregulated metabolites were significantly enriched in the nicotinate and nicotinamide metabolism, galactose metabolism, and ether lipid metabolism pathways. CONCLUSIONS: These findings indicate that tetracycline inhibits tick reproduction through the regulation of tick bacterial communities, gene expression, and metabolic levels. The results may provide new strategies for tick control. This article is protected by copyright. All rights reserved.
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Nirmatrelvir is a specific antiviral targeting the main protease (Mpro) of SARS-CoV-2, and has been approved to treat COVID-191,2. As an RNA virus characterized by high mutation rates, whether SARS-CoV-2 will develop resistance to nirmatrelvir is a concern. Our previous studies have shown that several mutational pathways confer resistance to nirmatrelvir but some result in a loss of viral replicative fitness, which in turn are compensated by additional mutations3. The molecular mechanisms for this observed resistance are yet unknown. Here we combined biochemical and structural methods to demonstrate that mutations at the substrate binding pocket of the Mpro can allow SARS-CoV-2 to develop resistance to nirmatrelvir in two distinct ways. Comprehensive studies of 14 complex structures of Mpro mutants with drugs or substrate revealed that mutations at the S1 and S4 subsites significantly decreased inhibitor binding, while mutations at the S2 and S4' subsites unexpectedly increased protease activity. Both mechanisms contributed to nirmatrelvir resistance, whereas the latter compensated for the loss in enzymatic activity of the former, which in turn accounted for the restoration of viral replicative fitness as we have observed previously3. Such a profile was also observed for ensitrelvir, another clinically relevant Mpro inhibitor. These results shed light on the mechanisms by which SARS-CoV-2 evolves to develop resistance to the current generation of protease inhibitors and provide the basis for the design of next-generation Mpro inhibitors.
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Vitamin A (VitA) is an important fat-soluble vitamin which plays an important role in cell growth and individual development. However, the effect of VitA on the repair process of muscle injury and its molecular mechanism are still unclear. In this study, VitA and RA were first added to the culture medium of differentiated cells. We then detected cell differentiation marker proteins and myotube fusion. Moreover, the effects of VitA on RARα expression and nuclear translocation were further examined. The results showed that VitA significantly promoted the differentiation of C2C12, and the expression of RARα was significantly increased. Furthermore, VitA was injected into skeletal muscle injury in mice. HE staining and Western Blot results showed that VitA could significantly accelerate the repair of skeletal muscle injury and VitA increase the expression of RARα in mice. This study provides a theoretical basis for elucidating the regulation mechanism of VitA-mediated muscle development and the development of therapeutic drugs for muscle diseases in animals.
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Vitamina A , Vitaminas , Animais , Camundongos , Vitamina A/farmacologia , Músculo Esquelético , Western Blotting , Ciclo Celular , Receptor alfa de Ácido Retinoico/genéticaRESUMO
Unhealthy diets rich in fats and/or sugar are considered as the major external cause of the obesity epidemic, which is often accompanied by a significant decrease in gut hormone glucagon-like peptide-1 (GLP1) levels. Numerous studies have demonstrated notable contributions of the gut microbiota in this process. Nevertheless, the underlying mechanism still needs further investigation. The role of epigenetic modifications in gene expression and metabolism has been well demonstrated, with m6A methylation on RNAs being the most prevalent modification throughout their metabolism. In the present study, we found that the expressions of small intestinal Gcg and Pc3, two key genes regulating GLP1 expression, were significantly downregulated in obese mice, associated with reduced GLP1 level. Immunohistochemistry analysis indicated that a high-fat diet slightly increased the density of enteroendocrine L cells in the small intestine, implying that decreased GLP1 levels were not caused by the changes in L cell intensity. Instead, the small intestinal m6A level as well as the expression of known "writers", mettl3/14 and wtap, were found to be positively correlated with the expression of Gcg and Pc3. Fecal microbiota transplantation with feces from normal and obese mice daily to antibiotic-treated mice revealed that dysbiosis in diet-induced obesity was sufficient to reduce serum GLP1, small intestinal m6A level, and intestinal expressions of Gcg, Pc3, and writer genes (mettl3/14, wtap). However, as the most direct and universal methyl donor, the production of fecal S-adenosylmethionine was neither affected by the different dietary patterns nor their shaped microbiota. These results suggested that microbial modulation of the epitranscriptome may be involved in regulating GLP1 expression, and highlighted epitranscriptomic modifications as an additional level of interaction between diet and individual health.
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Dieta Hiperlipídica , Hormônios Gastrointestinais , Animais , Camundongos , Dieta Hiperlipídica/efeitos adversos , Peptídeo 1 Semelhante ao Glucagon , Camundongos Obesos , Intestino DelgadoRESUMO
Urban stormwater is a primary source of pollution for receiving water, but there is a shortage of studies on pollutant loads from urban catchments in cold regions. In this study, we coupled a build-up and wash-off model (in Mike Urban) with a climate change model to assess the impacts of climate change and urban densification on stormwater nitrogen loads (TN, TKN, NOx-N, and TAN) in an urban catchment in Canada. We calibrated and validated the Mike Urban model against observed event mean concentrations and nitrogen loads from 2010 to 2016. Results show that the nitrogen loads were mainly governed by rainfall intensity, rainfall duration, and antecedent dry days. Future precipitation data were downscaled using the Global Climate Models (GCMs), and three different Representative Concentration Pathways (RCP 2.5, RCP 4.5, and RCP 8.5) were used. Modeling results show that the TN, TKN, NOx-N, and TAN loads in 2050 will increase by 28.5 - 45.2% from May to September under RCP 2.5 compared to those from 2010 to 2016, by 34.6 - 49.9% under RCP 4.5, and by 39.4 - 53.5% under RCP 8.5. The increase of our projected TN load (from 1.33 to 2.93 kg·N/ha) is similar or slightly higher than the limited studies in other urban catchments. This study provides a reference for predicting stormwater nitrogen loads in urban catchments in cold regions.
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The present study examined whether brain activities of metaphorical restructuring could predict improvements in emotion and general self-efficacy (GSES). Sixty-two anxious graduates were randomly assigned to either the metaphor group (nâ¯=â¯31) or the literal group (nâ¯=â¯31). After completing the pretest (T1), the participants were first presented with micro-counseling dialogues (MCD) to guide metaphorical or literal restructuring, and their functional brain activities were simultaneously recorded. They then completed the posttest (T2) and 1â¯week's follow-up (T3). It was found that (1) compared with the literal group, the metaphor group had more insightful experiences, a greater increase in positive affect and GSES at T2, and a greater decrease in psychological distress at T2 and T3; (2) the metaphor group showed a greater activation in the left inferior frontal gyrus (IFG) and bilateral temporal gyrus, and further activation in the left hippocampus positively predicted T2 GSES scores while that in the IFG and left hippocampus positively predicted the reduction slope of distress over the three time points. One important limitation is that the results should be interpreted with caution when generalizing to clinical anxiety samples due to the participants were graduate students with anxiety symptoms rather than clinical sample. These results indicated that metaphor restructuring produced greater symptom improvements, and activation in the hippocampus and IFG could predict these symptom improvements. This suggests that the activation of the two regions during the restructuring intervention may be a neural marker for symptom improvements.
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Luteolin is a kind of natural flavonoid with great potential for lipid accumulation intervention. However, the poor water solubility and non-targeted release greatly diminish its efficiency. In this study, 4-aminophenyl ß-D-galactopyranoside (Gal-NH2)/mulberry leaf polysaccharides- lysozyme/luteolin nanoparticles (Gal-MPL/Lut) were fabricated via amide reaction, self-assembly process and electrostatic interaction. The nanoparticles could hepatic-target of Lut and enhance action on liver tissue by specific recognition of asialoglycoprotein receptor (ASGPR). Physicochemical characterization of the nanoparticles showed a spherical shape with a uniform particle size distribution (77.8 ± 2.6 nm) with a polydispersity index (PDI) of 0.22 ± 0.06. Subsequently, in HepG2 cells model, administration with hepatic-targeted Gal-MPL/Lut nanoparticles promoted the cellular uptake of Lut, and regulated lipid metabolism manifested by remarkably inhibiting total cholesterol (TC) and triglyceride (TG) expression levels through the modulation of PI3K/SIRT-1/FAS/CEBP-α signaling pathway. This study provides a promising strategy for a highly hepatic-targeted therapy to ameliorate lipid accumulation using natural medicines facilitated by nano-technology.
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Geminal cross couplings using multiple components enable the formation of several different bonds at one site in the building of tertiary and quaternary alkanes. Nevertheless, there are remaining issues of concern cleavage of two geminal bonds and control of selectivity present challenges. We report here the geminal cross couplings of three components by reactions of dihaloalkanes with organomagnesium and chlorosilanes or alkyl tosylates by Cr catalysis, affording the formation of geminal C-C/C-Si or C-C/C-C bonds in the creation of tertiary and quaternary alkanes. The geminal couplings are catalyzed by low-cost CrCl2, enabling the sluggishness of competitive Kumada-type side couplings and homocouplings of Grignard reagents, in achieving high chemoselectivity. Experimental and theoretical studies indicate that two geminal C-halide bonds are continuously cleaved by Cr to afford a metal carbene intermediate, which couples with a Grignard reagent, followed by silylation, in the formation of geminal C-C and C-Si bonds via a novel inner-sphere radical coupling mechanism. These three-component geminal cross couplings are value-addition to the synthesis of commercial drugs and bioactive molecules in medicinal chemistry.
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A novel organophotoredox/DABCO catalytic system for the fluoroalkylation of activated allylic acetates via radical-radical coupling is described. The method offers mild reaction conditions, high selectivity, and broad substrate compatibility and enabled diverse bioactive molecules, FDA-approved drugs, and amino acid derivatives to be incorporated into transformation. This study expands the synthetic toolbox for the construction of fluorine-containing molecules.
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The GLABROUS1 Enhancer Binding Protein (GeBP) gene family is pivotal in regulating plant growth, development, and stress responses. However, the role of GeBP in Brassica rapa remains unclear. This study identifies 20 BrGeBP genes distributed across 6 chromosomes, categorized into 4 subfamilies. Analysis of their promoter sequences reveals multiple stress-related elements, including those responding to drought, low temperature, methyl jasmonate (MeJA), and gibberellin (GA). Gene expression profiling demonstrates wide expression of BrGeBPs in callus, stem, silique, and flower tissues. Notably, BrGeBP5 expression significantly decreases under low-temperature treatment, while BrGeBP3 and BrGeBP14 show increased expression during drought stress, followed by a decrease. Protein interaction predictions suggest that BrGeBP14 homolog, At5g28040, can interact with DES1, a known stress-regulating protein. Additionally, microRNA172 targeting BrGeBP5 is upregulated under cold tolerance. These findings underscore the vital role of BrGeBPs in abiotic stress tolerance. Specifically, BrGeBP3, BrGeBP5, and BrGeBP14 show great potential for regulating abiotic stress. This study contributes to understanding the function of BrGeBPs and provides valuable insights for studying abiotic stress in B. rapa.
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Brassica rapa , Secas , Humanos , Brassica rapa/genética , Resistência à Seca , Cromossomos Humanos Par 6 , Temperatura Baixa , Proteínas de Ligação a DNARESUMO
OBJECTIVE: To investigate the risk factors associated with the peripheral venous catheter-related complication and infection in children with bronchopneumonia. METHODS: A total of 185 patients were divided into case group (n = 114) and control group (n = 71) according to the presence of catheter-related infection and complications related to indwelling needle. We performed a multivariate logistic regression analysis to explore the risk factors associated with the infection. RESULTS: Age was divided into 4 categories (0 < age ≤ 1, 1 < age ≤ 3, 3 < age ≤ 6, age > 6). The case group had a higher percentage of patients with 0 < age ≤ 1 than the control group (21% vs. 9.7%) and the age distribution was significant different between the two groups (P = 0.045). The case group had a longer retention time than the control group (≥ 3 days: 56% vs. 35%, P < 0.001). The results of binary logistics regression analysis revealed that the indwelling time and indwelling site were the factors that influenced the complications or bacterial infection. Among the three indwelling sites, the hand is more prone to infection and indwelling needle-related complications than the head (OR: 2.541, 95% CI 1.032 to 6.254, P = 0.042). The longer the indwelling time, the more likely the infection and indwelling needle related complications (OR: 2.646, 95% CI 1.759 to 3.979, P< 0.001). CONCLUSION: Indwelling time and indwelling site are the influencing factors of complications or bacterial infection, which should be paid more attention to prevent the catheter-related infection in children with bronchophenumonia.
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Broncopneumonia , Infecções Relacionadas a Cateter , Humanos , Criança , Infecções Relacionadas a Cateter/epidemiologia , Broncopneumonia/complicações , Broncopneumonia/epidemiologia , Cateteres , Fatores de Risco , AgulhasRESUMO
Opencast mining activities destroy native vegetation, directly impacting the carbon sequestration capacity of the regional ecosystem. Restoring tree species have significant impacts on carbon storage. However, changes in carbon storage across tree-level landscape and the impact of tree-level landscape transitions on carbon storage remain poorly described in the literature, and this information is urgently needed to support management decisions. In this study, we combined field data and remote sensing techniques to create field data-driven maps of the tree-level landscape. This enabled the assessment of carbon storage and quantification of the impact of tree-level landscape transitions on carbon storage. We founded that carbon storage rises in initial/stable stages, decreases in development stage during mining expansion and reclamation. The choice of restoration tree species significantly influenced carbon storage. Pinus tabuliformis-R. pseudoacacia accumulated more carbon storage, making it a more suitable model for ecological reclamation of Pingshuo opencast mine. Furthermore, changes in carbon storage are influenced by land-use policies. Land-use policies and reclamation efforts counterbalance carbon loss associated with construction. Various tree-level landscape transitions were examined, with Pinus tabuliformis transitions notably affecting carbon storage, offering insights for ecological reclamation planning. Our research provides a reference for carbon storage assessment in opencast mining areas, enhances understanding of carbon storage changes in mining areas, assists in formulating ecological reclamation plans, and contributes to the "dualcarbon" goals and climate change mitigation.
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OBJECTIVE: Osteoarthritis (OA) is a non-inflammatory degenerative joint disease that mainly involves articular cartilage damage and involves the whole joint tissue. However, the relationship between CD14 and CSF1R and osteoarthritis remains unclear. The aim of this study was to explore the important role of CD14 and CSF1R in osteoarthritis and provide a new direction for its prevention and treatment. METHOD: The osteoarthritis datasets GSE46750 and GSE82107 were downloaded from gene expression omnibus (GEO) database generated by GPL10558 and GPL570. R package limma was used to screen differentially expressed genes (DEDs). Weighted gene co-expression network analysis (WGCNA) was performed. The construction and analysis of a protein-protein interaction (PPI) network, functional enrichment analysis, gene set enrichment analysis (GSEA), and comparative toxicogenomics database (CTD) analysis were performed. TargetScan screened miRNAs that regulated central DEGs. RESULTS: 687 DEGs were identified. According to gene ontology (GO), they were mainly concentrated in inflammatory response, IL-17 signaling pathway, rheumatoid arthritis, exercise, and regulation of response to external stimuli. The enrichment items are similar to the GO Kyoto Encyclopedia of Gene and Genome (KEGG) enrichment items of DEGs. These were mainly concentrated in exercise, inflammatory response, defense response, collagen containing extracellular matrix, and receptor regulator activity. In an enrichment project of Metascape, GO had inflammatory response, SARS-CoV-2 signal pathway network map, PIDIL8CXCR1 pathway, regulation of bone remodeling and endochondral ossification. 20 core genes were obtained by PPI network construction and analysis. Gene expression heat map showed that core genes (C1QC, CSF1R, CD14, TYROBP, HLA-DRA, C1QB, FCER1G, S100A9, HCLS1, WAS, BTK, TREM1) were highly expressed in osteoarthritis synovial tissues and were low in normal synovial tissues. CTD analysis showed that twelve genes (C1QC, CSF1R, CD14, TYROBP, HLA-DRA, C1QB, FCER1G, S100A9, HCLS1, WAS, BTK, TREM1) were found to be associated with inflammation, necrosis, gout, acute myeloid leukemia and thrombocytopenia. CONCLUSION: CD14 and CSF1R are highly expressed in osteoarthritis and may be therapeutic targets for osteoarthritis.
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Yttrium aluminum garnet (YAG) crystals are an important gain medium in thin-sheet solid-state lasers, and their processing quality directly affects the performance of solid-state lasers. But it is difficult to achieve high efficiency and high quality of YAG crystals by traditional chemical mechanical polishing (CMP). In this study, we developed a new polishing slurry for photoassisted chemical mechanical polishing (PCMP) of YAG crystals. The polishing slurry is composed of peroxymonosulfate (PMS), manganese ferrite (MnFe2O4), alumina (Al2O3) abrasives, and deionized water. PCMP is conducted in an ultraviolet (UV) light environment. When employing this polishing slurry for PCMP processing of YAG crystals, the material removal rate (MRR) achieved 250 nm/min and the surface roughness achieved 0.35 nm Sa. The experiments verified that both UV light and MnFe2O4 can effectively activate PMS to produce active free radicals and further enhance the chemical action of the polishing slurry. X-ray photoelectron spectroscopy (XPS) analysis results indicated that active radicals reacted with the surface structure of the crystal and removed the aluminum-oxygen octahedron in large quantities from it. The structural defects reduced the surface hardness of the crystal, which means that active free radicals can modify the crystal surface materials.
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BACKGROUND: Atrial fibrillation (AF) is a prevalent and chronic cardiovascular disorder associated with various pathophysiological alterations, including atrial electrical and structural remodeling, disrupted calcium handling, autonomic nervous system dysfunction, aberrant energy metabolism, and immune dysregulation. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play a significant role in the pathogenesis of AF. OBJECTIVE: This discussion aims to elucidate the involvement of AF-related lncRNAs, with a specific focus on their role as miRNA sponges that modulate crucial signaling pathways, contributing to the progression of AF. We also address current limitations in AF-related lncRNA research and explore potential future directions in this field. Additionally, we summarize feasible strategies and promising delivery systems for targeting lncRNAs in AF therapy. CONCLUSION: In conclusion, targeting AF-related lncRNAs holds substantial promise for future investigations and represents a potential therapeutic avenue for managing AF.
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Hypertension is characterized by endothelial dysfunction and arterial stiffness, which contribute to the pathogenesis of atherosclerotic cardiovascular diseases. Nicotinamide adenine dinucleotide (NAD+) is an indispensable cofactor in all living cells that is involved in fundamental biological processes. However, in hypertensive patients, alterations in NAD+ levels and their relation with blood pressure (BP) elevation and vascular damage have not yet been studied. Here we reported that hypertensive patients exhibited lower NAD+ levels, as detected by high-performance liquid chromatography-mass spectrometry (HPLC-MS), in both peripheral blood mononuclear cells (PBMCs) and aortas, which was parallel to vascular dysfunction. NAD+ boosting therapy with nicotinamide mononucleotide (NMN) supplement reduced BP and ameliorated vascular dysfunction in hypertensive patients (NCT04903210) and AngII-induced hypertensive mice. Upregulation of CD38 in endothelial cells led to endothelial NAD+ exhaustion by reducing NMN bioavailability. Pro-inflammatory macrophages infiltration and increase in IL-1ß generation derived from pro-inflammatory macrophages resulted in higher CD38 expression by activating JAK1-STAT1 signaling pathway. CD38 KO, CD38 inhibitors treatment, or adeno-associated virus (AAV)-mediated endothelial CD38 knockdown lowered BP and improved vascular dysfunction in AngII-induced hypertensive mice. The present study demonstrated for the first time that endothelial CD38 activation and subsequently accelerated NAD+ degradation due to enhanced macrophage-derived IL-1ß production was responsible for BP elevation and vascular damage in hypertension. NAD+ boosting therapy can be used as a novel therapeutic strategy for the management of hypertensive patients.
