Correlation between obesity and early vascular aging in middle-aged and young adult health check-up populations. / ä¸­é’å¹´å¥åº·ä½“æ£€äººç¾¤è‚¥èƒ–ä¸Žæ—©å‘è¡€ç®¡è€åŒ–çš„ç›¸å ³æ€§.

OBJECTIVES: The obesity rate among middle-aged and young adults in China is increasing annually, and the incidence of cardiovascular diseases is becoming more prevalent in younger populations. However, it has not yet been reported whether obesity is associated with early vascular aging (EVA). This study aims to explore the correlation between obesity and EVA in middle-aged and young adult health check-up populations, providing a reference for the prevention of cardiovascular diseases. METHODS: A total of 15 464 middle-aged and young adults aged 18-59 who completed brachial-ankle pulse wave velocity (baPWV) test in the Third Xiangya Hospital of Central South University from January to December 2020 were included. Among them, 1 965 individuals with normal blood pressure and no cardiovascular risk factors were selected as the healthy population. The baPWV thresholds for determining EVA in each age group for males and females were calculated based on the baPWV values of the healthy population. The number and percentage of individuals meeting the EVA criteria in the middle-aged and young adult health check-up populations were statistically analyzed by age and gender. The differences in obesity indicators [visceral adiposity index (VAI), body mass index (BMI), waist circumference (WC)] between the EVA and non-EVA groups for males and females were compared. Using EVA as the dependent variable, VAI, BMI, and WC were included as independent variables in a Logistic model to analyze the correlation between each obesity indicator and EVA before and after adjusting for other influencing factors. Furthermore, the correlation between each obesity indicator and EVA in each age group was analyzed. RESULTS: In the health check-up populations, the detection rate of EVA in different age groups was 1.65%-10.92% for males, and 1.16%-10.50% for females, the detection rate of EVA increased with age in both males and females. Except for the 40-<50 age group, the EVA detection rate was higher in males than in females in all other age groups. Regardless of gender, obesity indicators VAI, BMI, and WC were significantly higher in the EVA group than in the non-EVA group (all P<0.01). Before and after adjusting for other influencing factors, VAI and WC were both correlated with EVA (both P<0.05). BMI was a risk factor for EVA before adjusting for other influencing factors (P<0.01), but after adjustment, the correlation between BMI and EVA was not statistically significant (P=0.05). After adjusting for other influencing factors, the correlation between VAI and EVA was statistically significant in the 18-<40 and 50-<60 age groups (both P<0.05), while the correlation between BMI and WC with EVA was not statistically significant (both P>0.05). In the 40-<50 age group, the correlation between VAI and BMI with EVA was not statistically significant (both P>0.05), but the correlation between WC and EVA was statistically significant (P<0.01). CONCLUSIONS: VAI is closely related to the occurrence of EVA in middle-aged and young adults aged 18-<40 and 50-<60 years, while WC is closely related to the occurrence of EVA in those aged 40-<50 years.

Distance-Selected Topochemical Dehydro-Diels-Alder Reaction of 1,4-Diphenylbutadiyne toward Crystalline Graphitic Nanoribbons.

Solid-state topochemical polymerization (SSTP) is a promising method to construct functional crystalline polymeric materials, but in contrast to various reactions that happen in solution, only very limited types of SSTP reactions are reported. Diels-Alder (DA) and dehydro-DA (DDA) reactions are textbook reactions for preparing six-membered rings in solution but are scarcely seen in solid-state synthesis. Here, using multiple cutting-edge techniques, we demonstrate that the solid 1,4-diphenylbutadiyne (DPB) undergoes a DDA reaction under 10-20 GPa with the phenyl as the dienophile. The crystal structure at the critical pressure shows that this reaction is "distance-selected". The distance of 3.2 Å between the phenyl and the phenylethynyl facilitates the DDA reaction, while the distances for other DDA and 1,4-addition reactions are too large to allow the bonding. The obtained products are crystalline armchair graphitic nanoribbons, and hence our studies open a new route to construct the crystalline carbon materials with atomic-scale control.

Novel role of PKR in palmitate-induced Sirt1 inactivation and endothelial cell senescence.

Endothelial cell senescence is regarded as a vital characteristic of cardiovascular diseases. Elevated palmitate (PA) is an independent risk factor of cardiovascular diseases, but its role in endothelial cell senescence is currently unknown. During the course of studying the prosenescent role of PA, we discovered a key role of dsRNA-dependent protein kinase [protein kinase R (PKR)] in endothelial senescence. Exposure of human umbilical vein endothelial cells (HUVECs) to PA-induced cell senescence is characterized by increased levels of senescence-associated ß-galactose glucosidase activity, excessive production of reactive oxygen species production, impaired cellular proliferation, and G1 phase arrest. This phenomenon is associated with an increase of PKR autophosphorylation and decreased activity of sirtuin 1 (Sirt1), a pivotal antisenescent factor. PKR inactivation by PKR siRNA or its phosphorylation inhibitor 2-aminopurine significantly attenuated PA-induced HUVEC senescence by reversing Sirt1 activity and its downstream signaling. Moreover, to study the regulatory mechanism between PKR and Sirt1, we found that PKR promotes JNK activation to inhibit Sirt1 activity and that this effect could be reversed by the JNK inhibitor SP600125. These findings provide evidence that PKR mediates PA-induced HUVEC senescence by inhibiting Sirt1 signaling. Our study provides novel insights into the actions and mechanisms of PKR in endothelial senescence. NEW & NOTEWORTHY This study first provides a novel observation that dsRNA-dependent protein kinase (PKR) mediates palmitate-induced sirtuin 1 inactivation and subsequent human umbilical vein endothelial cell senescence. Most importantly, these new findings will provide a potential therapeutic strategy to improve free fatty acid-induced endothelial senescence by targeting PKR in cardiovascular diseases.

What is the impact of PCSK9 rs505151 and rs11591147 polymorphisms on serum lipids level and cardiovascular risk: a meta-analysis.

BACKGROUND: PCSK9 rs505151 and rs11591147 polymorphisms are identified as gain- and loss-of-function mutations, respectively. The effects of these polymorphisms on serum lipid levels and cardiovascular risk remain to be elucidated. METHODS: In this meta-analysis, we explored the association of PCSK9 rs505151 and rs11591147 polymorphisms with serum lipid levels and cardiovascular risk by calculating the standardized mean difference (SMD) and odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Pooled results analyzed under a dominant genetic model indicated that the PCSK9 rs505151 G allele was related to higher levels of triglycerides (SMD: 0.14, 95% CI: 0.02 to 0.26, P = 0.021, I2 = 0) and low-density lipoproteins cholesterol (LDL-C) (SMD: 0.17, 95% CI: 0.00 to 0.35, P = 0.046, I2 = 75.9%) and increased cardiovascular risk (OR: 1.50, 95% CI: 1.19 to 1.89, P = 0.0006, I2 = 48%). The rs11591147 T allele was significantly associated with lower levels of total cholesterol (TC) and LDL-C (TC, SMD: -0.45, 95% CI: -0.57 to -0.32, P = 0.000, I2 = 0; LDL-C, SMD: -0.44, 95% CI: -0.55 to -0.33, P = 0.000, I2 = 0) and decreased cardiovascular risk (OR: 0.77, 95% CI: 0.60 to 0.98, P = 0.031, I2 = 59.9) in Caucasians. CONCLUSIONS: This study indicates that the variant G allele of PCSK9 rs505151 confers increased triglyceride (TG) and LDL-C levels, as well as increased cardiovascular risk. Conversely, the variant T allele of rs11591147 protects carriers from cardiovascular disease susceptibility and lower TC and LDL-C levels in Caucasians. These findings provide useful information for researchers interested in the fields of PCSK9 genetics and cardiovascular risk prediction not only for designing future studies, but also for clinical and public health applications.

[Role of high mobility group protein B1 in IL-1α-induced endothelial cell senescence].

OBJECTIVE: To explore the effect of interleukin-1α (IL-1α) on the senescence of human umbilical vein endothelial cells (HUVECs) and the function of high mobility group protein 1 (HMGB1).
 Methods: HUVECs were randomly divided into a control group, a IL-1α group (10 ng/mL IL-1α), a HMGB1 group (100 ng/mL HMGB1), and a HMGB1+IL-1α group (100 ng/mL of HMGB1 plus 10 ng/mL of IL-1α). Senescence associated ß-galactosidase (SA ß-gal) staining was used to assess the number of senescent cells, Western blot were performed to detect the protein levels of silent information regulator 1(SIRT1), and quantitative real-time PCR (qRT-PCR) was used to detect the mRNA levels of p53, p21 and p16.
 Results: Compared with the control group, the number of SA ß-gal positive cells were significantly increased in the IL-1α group (P<0.05), while the expression of SIRT1 protein significantly decreased (P<0.01). Compared with the IL-1α group, the expression of SA ß-gal positive cells in the HMGB1+IL-1α group was decreased and the mRNA levels of p21 and p53 were down-regulated (all P<0.05), however, there was no statistical significance in the mRNA expression of p16 (P>0.05).
 Conclusion: IL-1α can induce the senescence of HUVECs, and HMGB1 may inhibit IL-1α-induced endothelial cell senescence via p53-p21 pathway.

[Progress in the study on roles of cathepsin in hypertension].

Cardiovascular remodeling or dysfunction-induced abnormal cardiac output, blood volume and peripheral vascular resistance is an important pathophysiological mechanism for the occurrence and development of hypertension. Cathepsins are widely expressed in human various tissue and cells and they are involved in the pathogenesis of hypertension through activation of renin - angiotensin system, degradation of cytoplasmic matrix, proliferation of smooth muscle cell and hypertrophy of myocyte. The clinical studies have found that cathepsins can be used as a biomarker for hypertension. In recent years, the studies on the functions and mechanisms of cathepsins have provided a new sight and strategy for treatment of hypertension.

[Effect of NLRP3 inflammasome on vascular diseases].

The NLRP3 inflammasome, a protein complex belonging to the family of nucleotide-binding and oligomerization domain like receptors (NLRs), plays a vital role in the innate immune system. It promotes pro-caspase 1 cleavage into active caspase-1, which contributes to maturation and releases of IL-1ß and IL-18 in response to the harmful signals and participates in the host immune response and sterile inflammation. Recently a large number of studies have shown that NLRP3 inflammasome closely relates to the pathogenesis of the vascular diseases. NLRP3 inflammasome, which involves in the sterile inflammation of the vascular wall, plays an important role in the pathogenesis of main, middle and small arteries.

Identification of MTCH1 as a novel prognostic indicator and therapeutic target in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) emerges as the third leading cause of cancer mortality, contributing to approximately 830,000 deaths annually. The mechanisms driving its pathogenesis remain largely elusive. Through bioinformatic scrutiny, Mitochondrial Carrier 1 (MTCH1), a component of the mitochondrial carrier family, has been pinpointed as potentially pivotal in HCC evolution. Examination of The Cancer Genome Atlas (TCGA) database indicated a pronounced increase in MTCH1 expression within HCC tissues versus normal liver counterparts. Subsequent analyses, utilizing both Kaplan-Meier mapper and Gene Expression Profiling Interactive Analysis (GEPIA) datasets, associated elevated MTCH1 levels with reduced overall survival (OS) and disease-free survival (DFS). Complementary in vitro assessments confirmed that MTCH1 downregulation suppresses HCC cell proliferation and notably diminishes HCC xenograft tumor growth in murine models. Additional explorations, including Gene Set Enrichment Analysis (GSEA), STRING database interrogation, and quantitative PCR (qPCR) experiments, suggest MTCH1's involvement in HCC progression via the CDK-RB-E2F signaling axis. Collectively, these insights endorse MTCH1 as a promising therapeutic target for HCC, underscoring its significance in the disease's molecular framework and potential treatment innovation.

Role of pyroptosis-related cytokines in the prediction of lung cancer.

Objectives: Lung cancer is the leading cause to induce cancer-related mortality. Effective biomarkers for prediction the occurrence of lung cancer is urgently needed. Our previous studies indicated that pyroptosis-related cytokines TNF-α, IFN-γ, MIP-1α, MIP-1ß, MIP-2 and IP-10 is important to influence the efficacy of chemotherapy drug in lung cancer tissues. But the role of pyroptosis-related cytokines in prediction the occurrence of lung cancer is still unknown. Methods: Blood samples were collected from 258 lung cancer patients at different stage and 80 healthy volunteers. Serum levels of pyroptosis-related cytokines including TNF-α, IFN-γ, MIP-1α, MIP-1ß, MIP-2 and IP-10 were measured by Cytometric Bead Array (CBA). ROC curve was performed to evaluate the cut-off value and diagnosis value for prediction and diagnosis of lung cancer. Results: Compared with control group, the levels of IP-10, MIP-1α, MIP-1ß, MIP-2 and TNF-α were significantly higher in lung cancer patients (45.5 (37.1-56.7): 57.2 (43.0-76.5), 34.4 (21.8-75.2): 115.4 (96.6-191.2), 49.3 (25.6-78.7): 160.5 (124.9-218.6), 22.6 (17.8-31.2): 77.9 (50.1-186.5), 3.80 (2.3-6.2): 10.3 (5.7-16.6)), but the level of IFN-γ was decreased in the patients (12.38 (9.1-27.8): 5.9 (3.5-9.7)). All the above cytokines were significantly associated with the diagnosis of lung cancer, and the AUC values of IFN-γ, IP-10, MIP-1α, MIP-1ß, MIP-2, and TNF-α were 0.800, 0.656, 0.905, 0.921, 0.914, and 0.824. And the AUC can rise to 0.986 after combining the above factors, and the sensitivity and specificity also up to 96.7 % and 93.7 %, respectively. Additionally, TNF-α (r = 0.400, P < 0.01), MIP-2 (r = 0.343, P < 0.01), MIP-1α (r = 0.551, P < 0.01) and MIP-1ß (r = 0.403, p < 0.01) were positively associated with occurrence of lung cancer, but IFN-γ (r = -0.483, p < 0.01) was negatively associated with occurrence of lung cancer. As far as the potential of early diagnosis of lung cancer, TNF-α (AUC = 0.577), MIP-1α (AUC = 0.804) and MIP-1ß (AUC = 0.791) can predict the early stage of lung cancer, and combination of the above three cytokines has a better predictive efficiency (AUC = 0.854). Conclusion: Our study establishes a link between the levels of IP-10, MIP-1α, MIP-1ß, MIP-2, TNF-α and IFN-γ and diagnosis of lung cancer. Besides, we observed a synergistic effect of these five pyroptosis-related cytokines in diagnosing lung cancer patient, suggesting their potential as biomarkers for lung cancer diagnosis. Moreover, the combination of TNF-α, MIP-1α and MIP-1ß are also potential predictors for the early diagnosis of lung cancer.

PKR deficiency delays vascular aging via inhibiting GSDMD-mediated endothelial cell hyperactivation.

Vascular aging is an independent risk factor for cardiovascular diseases, but the regulatory mechanism is not clearly understood. In this study, we found that endothelial PKR activity is elevated in aging aorta tissues, which is accompanied with increased endothelial cell hyperactivation, IL-1ß and HMGB1 release and vascular smooth muscle cell (VSMC) phenotype transforming. Global knockout of PKR exhibits significantly delayed vascular aging compared to wild-type mice at the same age. In vitro, using PKR siRNA or the cell hyperactivation inhibitor glycine or disulfiram can effectively inhibit H2O2 or palmitic acid-induced endothelial cell hyperactivation, IL-1ß and HMGB1 release and co-cultured VSMC phenotype transforming. These results demonstrate that endothelial PKR activation induces GSDMD-mediated endothelial cell hyperactivation to release HMGB1 and IL-1ß, which promotes the phenotype transforming of VSMC and subsequent accelerates the process of vascular aging. These discoveries will help to explore the new drug target to inhibit vascular aging.

PKR deficiency alleviates pulmonary hypertension via inducing inflammasome adaptor ASC inactivation.

Pulmonary hypertension is a progressive fatal disease that currently has no specific therapeutic approaches. In this study, dsRNA-dependent protein kinase (PKR) was considered a candidate molecule in pulmonary hypertension. We demonstrated that PKR is activated in the endothelium of experimental pulmonary hypertension models. Deletion of PKR or treatment with the PKR activation inhibitor C16 inhibited the development of pulmonary hypertension. To explore the mechanism of PKR in pulmonary hypertension, we detected its downstream signaling and found that PKR knockout represses apoptosis-associated speck-like protein containing CARD (ASC) activation to inhibit high mobility group box 1 (HMGB1) and interleukin-1 beta release. To further explore whether ASC mediates the pro-pulmonary hypertension role of PKR, we used ASC deletion mice and found that ASC deletion inhibits the development of pulmonary hypertension and the release of HMGB1 and interleukin-1 beta. Furthermore, we co-cultured pulmonary arterial endothelial cells (PAECs) and pulmonary arterial smooth muscle cells (PASMCs) and found that endothelial PKR promotes PASMCs proliferation through the release of HMGB1 and interleukin-1 beta. In conclusion, these data indicate that endothelial PKR promotes the excessive proliferation of PASMCs by inducing ASC activation to release HMGB1 and interleukin-1 beta, which lead to the development of pulmonary hypertension. Our study will provide a novel insight that PKR is a potential target in the future treatment of pulmonary hypertension.

Herbicide Resistance: Another Hot Agronomic Trait for Plant Genome Editing.

Weeds have continually interrupted crop plants since their domestication, leading to a greater yield loss compared to diseases and pests that necessitated the practice of weed control measures. The control of weeds is crucial to ensuring the availability of sufficient food for a rapidly increasing human population. Chemical weed control (herbicides) along with integrated weed management (IWM) practices can be the most effective and reliable method of weed management programs. The application of herbicides for weed control practices calls for the urgency to develop herbicide-resistant (HR) crops. Recently, genome editing tools, especially CRISPR-Cas9, have brought innovation in genome editing technology that opens up new possibilities to provide sustainable farming in modern agricultural industry. To date, several non-genetically modified (GM) HR crops have been developed through genome editing that can present a leading role to combat weed problems along with increasing crop productivity to meet increasing food demand around the world. Here, we present the chemical method of weed control, approaches for herbicide resistance development, and possible advantages and limitations of genome editing in herbicide resistance. We also discuss how genome editing would be effective in combating intensive weed problems and what would be the impact of genome-edited HR crops in agriculture.

Scalable High-Pressure Synthesis of sp2-sp3 Carbon Nanoribbon via [4 + 2] Polymerization of 1,3,5-Triethynylbenzene.

Pressure-induced polymerization of aromatics is an effective method to construct extended carbon materials, including the diamond-like nanothread and graphitic structures, but the reaction pressure of phenyl is typically around 20 GPa and too high to be applied for large-scale preparation. Here by introducing ethynyl to phenyl, we obtained a sp2-sp3 carbon nanoribbon structure by compressing 1,3,5-triethynylbenzene (TEB), and the reaction pressure of phenyl was successfully decreased to 4 GPa, which is the lowest reaction pressure of aromatics at room temperature. Using experimental and theoretical methods, we figured out that the ethynylphenyl of TEB undergoes [4 + 2] dehydro-Diels-Alder (DDA) reaction with phenyl upon compression at an intermolecular C···C distance above 3.3 Å, which is much longer than those of benzene and acetylene. Our research suggested that the DDA reaction between ethynylphenyl and phenyl is a promising route to decrease the reaction pressure of aromatics, which allows the scalable high-pressure synthesis of nanoribbon materials.

Pressure Gradient Squeezing Hydrogen out of MnOOH: Thermodynamics and Electrochemistry.

Pressure of gigapascal (GPa) is a robust force for driving phase transitions and chemical reactions with negative volume change and is intensely used for promoting combination/addition reactions. Here, we find that the pressure gradient between the high-pressure region and the ambient-pressure environment in a diamond anvil cell is an even stronger force to drive decomposition/elimination reactions. A pressure difference of tens of GPa can "push" hydrogen out from its compounds in the high-pressure region to the environment. More importantly, in transition metal hydroxides such as MnOOH, the protons and electrons of hydrogen can even be separated via different conductors, pushed out by the high pressure, and recombine outside under ambient conditions, producing continuous current. A pressure-gradient-driven battery is hence proposed. Our investigation demonstrated that a pressure gradient is a special and powerful force to drive decomposition and electrochemical reactions.

l-Homocysteine-induced cathepsin V mediates the vascular endothelial inflammation in hyperhomocysteinaemia.

BACKGROUND AND PURPOSE: Vascular inflammation, including the expression of inflammatory cytokines in endothelial cells, plays a critical role in hyperhomocysteinaemia-associated vascular diseases. Cathepsin V, specifically expressed in humans, is involved in vascular diseases through its elastolytic and collagenolytic activities. The aim of this study was to determine the effects of cathepsin V on l-homocysteine-induced vascular inflammation. EXPERIMENTAL APPROACH: A high methionine diet-induced hyperhomocysteinaemic mouse model was used to assess cathepsin V expression and vascular inflammation. Cultures of HUVECs were challenged with l-homocysteine and the cathepsin L/V inhibitor SID to assess the pro-inflammatory effects of cathepsin V. Transfection and antisense techniques were utilized to investigate the effects of cathepsin V on the dual-specificity protein phosphatases (DUSPs) and MAPK pathways. KEY RESULTS: Cathepsin L (human cathepsin V homologous) was increased in the thoracic aorta endothelial cells of hyperhomocysteinaemic mice; l-homocysteine promoted cathepsin V expression in HUVECs. SID suppressed the activity of cathepsin V and reversed the up-regulation of inflammatory cytokines (IL-6, IL-8 and TNF-α), adhesion and chemotaxis of leukocytes and vascular inflammation induced by l-homocysteine in vivo and in vitro. Increased cathepsin V promoted the degradation of DUSP6 and DUSP7, phosphorylation and subsequent nuclear translocation of ERK1/2, phosphorylation of STAT1 and expression of IL-6, IL-8 and TNF-α. CONCLUSIONS AND IMPLICATIONS: This study has identified a novel mechanism, which shows that l-homocysteine-induced upregulation of cathepsin V mediates vascular endothelial inflammation under high homocysteine condition partly via ERK1/2 /STAT1 pathway. This mechanism could represent a potential therapeutic target in hyperaemia-associated vascular diseases. LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Construction and verification of CYP3A5 gene polymorphisms using a Saccharomyces cerevisiae expression system to predict drug metabolism.

The present study evaluated the ability of a Saccharomyces cerevisiae expression system to predict the pharmacokinetic (PK) activity of a calcium channel blocker in patients with distinct cytochrome P450 3A5 (CYP3A5) polymorphisms. The blood pressure lowering activity of amlodipine in 57 hypertensive patients with CYP3A5*1/*1, CYP3A5*1/*3, CYP3A5*4 and CYP3A5*6 polymorphisms was evaluated by the current study. Subsequently, a Saccharomyces cerevisiae expression system for CYP3A5 gene polymorphisms was constructed to examine the PK activity of CYP3A5*1/*1, CYP3A5*4 and CYP3A5*6 polymorphisms. This system was used to predict the PK of amlodipine and was compared with the in vivo data from different gene polymorphism groups. The blood pressure lowering activity of amlodipine in hypertensive patients varied among CYP3A5 polymorphisms. The in vivo results demonstrated that CYP3A5*6 exhibited the highest metabolic rate, followed by CYP3A5*1/*1, CYP3A5*4 and CYP3A5*1/*3. The difference between CYP3A5*6 and CYP3A5*1/*1 was not statistically significant (P=0.5). In accordance with in vivo data, CYP3A5*1/*1 exhibited the highest in vitro metabolic rate, followed by CYP3A5*6 and CYP3A5*4. With the exception of the comparison between CYP3A5*6 and CYP3A5*1/*1, polymorphisms exhibited statistically significant differences compared with CYP3A5*1/*1 (P<0.05). The Saccharomyces cerevisiae expression system may be a cost effective and potentially useful tool for assessing the PK activity of drugs that are metabolized by CYP3A5.