Causal relationship between genetic proxies for calcium channel blockers and the risk of depression: a drug-target Mendelian randomization study.

Background: Calcium channel blockers (CCBs) are widely used in the clinical management of hypertension. Depression, a common comorbidity of hypertension, is an important issue in the management of hypertension. However, the impact of CCBs on depression risk remains controversial. We aim to investigate the causal effect of CCBs on depression through drug-target Mendelian randomization (MR) analysis. Methods: To proxy CCBs, we utilized the genetic variations located in or around drug target genes that were related to systolic blood pressure (SBP). Coronary artery disease (CAD) served as the positive control outcome. Genetic summary data of SBP, CAD, and depression were obtained from genome-wide association studies (GWAS) based on European population. Inverse variance weighted (IVW) method was applied as the main analysis to estimate the causal effect. Cochran's Q test, MR-Egger intercept, MR pleiotropy residual sum and outlier (MR-PRESSO) and leave-one-out sensitivity analysis were used to test the robustness of the results. Meta-analysis was applied to further confirm whether causal relationships existed between CCBs and depression. Results: The IVW results failed to reveal any causal relationship between genetic proxies for CCBs and depression (P > 0.05). Cochran's Q test showed no evidence of heterogeneity (P > 0.05). The MR-Egger intercept test suggested no evidence of directional pleiotropy, and the MR pleiotropy residual sum and outlier (MR-PRESSO) global test for horizontal pleiotropy was also not significant (P > 0.05). Leave-one-out analysis did not reveal any genetic variant that influenced the results. In addition, the meta-analysis further confirmed the absence of a causal relationship. Conclusion: The present study indicates no association of genetic proxies for CCBs with depression. Further studies are necessary to provide definitive evidence.

ACAT1 promotes proliferation and metastasis of bladder cancer via AKT/GSK3ß/c-Myc signaling pathway.

Acetyl-CoA acetyltransferase 1 (ACAT1) plays a significant role in the regulation of gene expression and tumorigenesis. However, the biological role of ACAT1 in bladder cancer (BLCA) has yet to be elucidated. This research aimed to elucidate the bioinformatics features and biological functions of ACAT1 in BLCA. Here, we demonstrate that ACAT1 is elevated in BLCA tissues and is correlated with specific clinicopathological features and an unfavorable prognosis for survival in BLCA patients. ACAT1 was identified as an independent risk factor in BLCA. Phenotypically, both in vitro and in vivo, ACAT1 knockdown suppressed BLCA cell proliferation and migration, while ACAT1 overexpression had the opposite effect. Mechanistic assays revealed that ACAT1 enhances BLCA cell proliferation and metastasis through the AKT/GSK3ß/c-Myc signaling pathway by modulating the cell cycle and EMT. Taken together, the results of our study reveal that ACAT1 is an oncogenic driver in BLCA that enhances tumor proliferation and metastasis, indicating its potential as a diagnostic and therapeutic target for this disease.

Self-Recovery of a Buckling BaTiO3 Ferroelectric Membrane.

The characteristic of self-recovery holds significant implications for upholding performance stability within flexible electronic devices following the release of mechanical deformation. Herein, the dynamics of self-recovery in a buckling inorganic membrane is studied via in situ scanning probe microscopy technology. The experimental results demonstrate that the ultimate deformation ratio of the buckling BaTiO3 ferroelectric membrane is up to 88%, which is much higher than that of the buckling SrTiO3 dielectric membrane (49%). Combined with piezoresponse force microscopy and phase-field simulations, we find that ferroelectric domain transformation accompanies the whole process of buckling and self-recovery of the ferroelectric membrane, i.e., the presence of the nano-c domain not only releases part of the elastic energy of the membrane but also reduces the interface mismatch of the a/c domain, which encourages the buckling ferroelectric membrane to have excellent self-recovery properties. It is conceivable that the evolution of ferroelectric domains will play a greater role in the regulation of the mechanical properties of ferroelectric membranes and flexible devices.

Development and validation of a nomogram for arterial stiffness.

Even though as a gold standard for noninvasive measurement of arterial stiffness, carotid-femoral pulse wave velocity (cfPWV) is not widely used in primary healthcare institutions due to time-consuming and unavailable equipment. The aim of this study was to develop a convenient and low-cost nomogram model for arterial stiffness screening. A cross-sectional study was undertaken in the department of general practice, the First Affiliated Hospital of Fujian Medical University. Arterial stiffness was defined as cfPWV ≥ 10 m/s. A total of 2717 participants were recruited to construct the nomogram using the least absolute shrinkage and selection operator and logistic regressions. Receiver operating characteristic (ROC) curve, calibration curve, decision curve analysis, clinical impact curve were used to evaluate the performance of the model. The model was validated internally and externally (399 participants) by bootstrap method. Arterial stiffness was identified in 913 participants (33.60%). Age, sex, waist to hip ratio, systolic blood pressure, duration of diabetes, heart rate were selected to construct the nomogram model. Good discrimination and accuracy were exhibited with area under curve of 0.820 (95% CI 0.803-0.837) in ROC curve and mean absolute error = 0.005 in calibration curve. A positive net benefit was shown in decision curve analysis and clinical impact curve. A satisfactory agreement was displayed in internal validation and external validation. The low cost and user-friendly nomogram is suitable for arterial stiffness screening in primary healthcare institutions.

Ultralow Tip-Force Driven Sizable-Area Domain Manipulation through Transverse Flexoelectricity.

Deterministic control of ferroelectric domain is critical in the ferroelectric functional electronics. Ferroelectric polarization can be manipulated mechanically with a nano-tip through flexoelectricity. However, it usually occurs in a very localized area in ultrathin films, with possible permanent surface damage caused by a large tip-force. Here it is demonstrated that the deliberate engineering of transverse flexoelectricity offers a powerful tool for improving the mechanical domain switching. Sizable-area domain switching under an ultralow tip-force can be realized in suspended van der Waals ferroelectrics with the surface intact, due to the enhanced transverse flexoelectric field. The film thickness range for domain switching in suspended ferroelectrics is significantly improved by an order of magnitude to hundreds of nanometers, being far beyond the limited range of the substrate-supported ones. The experimental results and phase-field simulations further reveal the crucial role of the transverse flexoelectricity in the domain manipulation. This large-scale mechanical manipulation of ferroelectric domain provides opportunities for the flexoelectricity-based domain controls in emerging low-dimensional ferroelectrics and related devices.

Increased Plasma Homocysteine Levels Are Associated with Left Ventricular Hypertrophy in Hypertensive Patients with Normal Renal Function.

INTRODUCTION: Renal function has an important bearing on plasma homocysteine levels. Plasma homocysteine is related to left ventricular hypertrophy (LVH). However, it remains unclear whether the association between plasma homocysteine levels and LVH is influenced by renal function. This study aimed to investigate relationships among left ventricular mass index (LVMI), plasma homocysteine levels, and renal function in a population from southern China. METHODS: A cross-sectional study was performed in 2,464 patients from June 2016 to July 2021. Patients were divided into three groups based on gender-specific tertiles of homocysteine levels. LVMI ≥115 g/m2 for man or ≥95 g/m2 for woman was defined as LVH. RESULTS: LVMI and the percentage of LVH were increased, while estimated glomerular filtration rate (eGFR) was decreased with the increase in homocysteine levels, both significantly. Multivariate stepwise regression analysis showed that eGFR and homocysteine were independently associated with LVMI in patients with hypertension. No correlation was observed between homocysteine and LVMI in patients without hypertension. Stratified by eGFR, further analysis confirmed homocysteine was independently associated with LVMI (ß = 0.126, t = 4.333, p < 0.001) only in hypertensive patients with eGFR ≥90 mL/(min·1.73 m2), not with 60≤ eGFR <90 mL/(min·1.73 m2). Multivariate logistic regression indicated that in hypertensive patients with eGFR ≥90 mL/(min·1.73 m2), the patients in high tertile of homocysteine levels had a nearly twofold increased risk of occurring LVH compared with those in low tertile (high tertile: OR = 2.780, 95% CI: 1.945-3.975, p < 0.001). CONCLUSION: Plasma homocysteine levels were independently associated with LVMI in hypertensive patients with normal eGFR.

Lactate dehydrogenase is associated with flow-mediated dilation in hypertensive patients.

The level of lactate dehydrogenase (LDH) has been proved to be positively associated with albuminuria, which represents glomerular endothelial damage in hypertension (HTN). In this study, the relationship between LDH and endothelial function evaluated by flow-mediated dilation (FMD) was investigated in hypertensives. 1507 subjects (aged 61.2 ± 12.5 years) were enrolled. All hypertensives (n = 1216) were subdivided into 3 groups: LDH1 (lowest tertile of LDH, n = 399), LDH2 (mediate tertile of LDH, n = 409) and LDH3 (highest tertile of LDH, n = 408). Meanwhile, 291 normotensives served as controls. FMD of right anterior tibial artery was assessed by high-resolution color Doppler ultrasound. The level of LDH in hypertensives was significantly higher than normotensives (p < 0.001). Whereas, FMD was obviously more blunted in hypertensives (p < 0.001). There was an increasing trend of FMD < 8% from control, LDH1, LDH2 to LDH3 group (χ2 = 36.751, p < 0.001). Stepwise multiple liner regression analysis demonstrated an independent correlation between LDH and FMD in hypertensives (ß = - 0.145, p < 0.05). After stratified analysis, the relevance persisted in the male, young and middle-aged, hypertensives with grade 2 HTN, duration of HTN < 3 years, metabolic syndrome and those without statin therapy. In conclusion, the level of LDH was inversely correlated with FMD among hypertensives. Those hypertensives with increased LDH need to be scanned for target organ damage, such as microalbuminuria and endothelial dysfunction, and more frequent following up are also recommended.

Proteomics analysis in myocardium of spontaneously hypertensive rats.

Hypertension-related left ventricular hypertrophy is recognized as a good predictor of adverse cardiovascular events. However, the underlying mechanism of left ventricular hypertrophy is still not fully understood. This study employed liquid chromatography coupled with tandem mass spectrometry to investigate global changes in protein profile in myocardium of spontaneously hypertensive rat, a classical animal model of essential hypertension. There were 369 differentially expressed proteins in myocardium between spontaneously hypertensive rats and normotensive rats. Xenobiotic catabolic process, cholesterol binding and mitochondrial proton-transporting ATP synthase were found to be the most significantly enriched biological process, molecular function and cellular component terms of Gene Ontology, respectively. Drug metabolism-cytochrome P450 was revealed to be the most significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways. FYN proto-oncogene, Src family tyrosine kinase was found to have the most interactions with other proteins. Differentially expressed proteins involved in xenobiotic catabolic process, lipid transport and metabolism, mitochondrial function might be targets for further study of hypertension-related left ventricular hypertrophy.

Angle prediction model when the imaging plane is tilted about z-axis.

Computer Tomography (CT) is a complicated imaging system, requiring highly geometric positioning. We found a special artifact caused by detection plane tilted around z-axis. In short scan cone-beam reconstruction, this kind of geometric deviation result in half circle shaped fuzzy around highlighted particles in reconstructed slices. This artifact is distinct near the slice periphery, but deficient around the slice center. We generated mathematical models, and InceptionV3-R deep network to study the slice artifact features to estimate the detector z-axis tilt angle. The testing results are: mean absolute error of 0.08819 degree, the Root mean square error of 0.15221 degree and R-square of 0.99944. A geometric deviation recover formula was deduced, which can eliminate this artifact efficiently. This research enlarges the CT artifact knowledge hierarchy, and verifies the capability of machine learning in CT geometric deviation artifact recoveries.

The zinc transporter ZIP12 regulates monocrotaline-induced proliferation and migration of pulmonary arterial smooth muscle cells via the AKT/ERK signaling pathways.

BACKGROUND: The zinc transporter ZIP12 is a membrane-spanning protein that transports zinc ions into the cytoplasm from the extracellular space. Recent studies demonstrated that upregulation of ZIP12 is involved in elevation of cytosolic free zinc and excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) induced by hypoxia. However, the expression of ZIP12 and its role in pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT) in rats have not been evaluated previously. The aim of this study was to investigate the effect of ZIP12 on the proliferation and migration of PASMCs and its underlying mechanisms in MCT-induced PAH. METHODS: A PAH rat model was generated by intraperitoneal injection of 20 mg/kg MCT twice at one-week intervals. PASMCs were isolated from the pulmonary arteries of rats with MCT-induced PAH or control rats. The expression of ZIP12 and related molecules was detected in the lung tissues and cells. A ZIP12 knockdown lentivirus and an overexpressing lentivirus were constructed and transfected into PASMCs derived from PAH and control rats, respectively. EdU assays, wound healing assays and Western blotting were carried out to explore the function of ZIP12 in PASMCs. RESULTS: Increased ZIP12 expression was observed in PASMCs derived from MCT-induced PAH rats. The proliferation and migration of PASMCs from PAH rats were significantly increased compared with those from control rats. These results were corroborated by Western blot analysis of PCNA and cyclin D1. All these effects were significantly reversed by silencing ZIP12. Comparatively, ZIP12 overexpression resulted in the opposite effects as shown in PASMCs from control rats. Furthermore, selective inhibition of AKT phosphorylation by LY294002 abolished the effect of ZIP12 overexpression on enhancing cell proliferation and migration and partially suppressed the increase in ERK1/2 phosphorylation induced by ZIP12 overexpression. However, inhibition of ERK activity by U0126 resulted in partial reversal of this effect and did not influence an increase in AKT phosphorylation induced by ZIP12 overexpression. CONCLUSIONS: ZIP12 is involved in MCT-induced pulmonary vascular remodeling and enhances the proliferation and migration of PASMCs. The mechanism of these effects was partially mediated by enhancing the AKT/ERK signaling pathways.

Coronaviruses Nsp5 Antagonizes Porcine Gasdermin D-Mediated Pyroptosis by Cleaving Pore-Forming p30 Fragment.

Coronaviruses (CoVs) are a family of RNA viruses that typically cause respiratory, enteric, and hepatic diseases in animals and humans. Here, we use porcine epidemic diarrhea virus (PEDV) as a model of CoVs to illustrate the reciprocal regulation between CoV infection and pyroptosis. For the first time, we elucidate the molecular mechanism of porcine gasdermin D (pGSDMD)-mediated pyroptosis and demonstrate that amino acids R238, T239, and F240 within pGSDMD-p30 are critical for pyroptosis. Furthermore, 3C-like protease Nsp5 from SARS-CoV-2, MERS-CoV, PDCoV, and PEDV can cleave pGSDMD at the Q193-G194 junction to produce two fragments unable to trigger pyroptosis. The two cleaved fragments could not inhibit PEDV replication. In addition, Nsp5 from SARS-CoV-2 and MERS-CoV also cleave human GSDMD (hGSDMD). Therefore, we provide clear evidence that PEDV may utilize the Nsp5-GSDMD pathway to inhibit pyroptosis and, thus, facilitate viral replication during the initial period, suggesting an important strategy for the coronaviruses to sustain their infection. IMPORTANCE Recently, GSDMD has been reported as a key executioner for pyroptosis. This study first demonstrates the molecular mechanism of pGSDMD-mediated pyroptosis and that the pGSDMD-mediated pyroptosis protects host cells against PEDV infection. Notably, PEDV employs its Nsp5 to directly cleave pGSDMD in favor of its replication. We found that Nsp5 proteins from other coronaviruses, such as porcine deltacoronavirus, severe acute respiratory syndrome coronavirus 2, and Middle East respiratory syndrome coronavirus, also had the protease activity to cleave human and porcine GSDMD. Thus, we provide clear evidence that the coronaviruses might utilize Nsp5 to inhibit the host pyroptotic cell death and facilitate their replication during the initial period, an important strategy for their sustaining infection. We suppose that GSDMD is an appealing target for the design of anticoronavirus therapies.

Health beliefs associated with preventive behaviors against noncommunicable diseases.

OBJECTIVE: To investigate the relationship between health beliefs and preventive behaviors against noncommunicable diseases (NCDs). METHODS: A survey was conducted in Health Management Center of the First Affiliated Hospital of Fujian Medical University from August 2019 to December 2019. An structured questionnaire was designed to collect the data on sociodemographic characteristics, health belief model (HBM) constructs and NCD-related behaviors. Structural equation model was used to describe the relationship between health beliefs and the behaviors. RESULTS: Among 4453 participants, the most common unhealthy behaviors were sedentary living and working, mood disorders and staying up late. Female, aging, living in urban areas, good physical health were associated with healthy behaviors. HBM constructs including perceived barriers, self-efficacy, cues to action, perceived benefits, perceived severity, and perceived susceptibility were directly or indirectly related to NCD-related behaviors. Perceived barriers (effect coefficient=0.495) and self-efficacy (effect coefficient=0.435) were found to have the greatest impact on the behaviors. CONCLUSION: Health beliefs are verified to be associated with preventive behaviors against NCDs. PRACTICE IMPLICATIONS: Changing sedentary living and working, mood disorders and staying up late are the top priority of health education. Health education based on HBM, especially focusing on helping overcome difficulties and building confidence of behavior change, may be more effective for the prevention of NCDs.

Zinc-mediated activation of CREB pathway in proliferation of pulmonary artery smooth muscle cells in pulmonary hypertension.

BACKGROUND: Transcription factor CREB is involved in the development of pulmonary hypertension (PH). However, little is known about the role and regulatory signaling of CREB in PH. METHODS: A series of techniques, including bioinformatics methods, western blot, cell proliferation and luciferase reporter assay were used to perform a comprehensive analysis of the role and regulation of CREB in proliferation of pulmonary artery smooth muscle cells (PASMCs) in PH. RESULTS: Using bioinformatic analysis of the differentially expressed genes (DEGs) identified in the development of monocrotaline (MCT)- and hypoxia-induced PH, we found the overrepresentation of CRE-containing DEGs. Western blot analysis revealed a sustained increase in total- and phosphorylated-CREB in PASMCs isolated from rats treated with MCT. Similarly, an enhanced and prolonged serum-induced CREB phosphorylation was observed in hypoxia-pretreated PASMCs. The sustained CREB phosphorylation in PASMCs may be associated with multiple protein kinases phosphorylated CREB. Additionally, hierarchical clustering analysis showed reduced expression of the majority of CREB phosphatases in PH, including regulatory subunits of PP2A, Ppp2r2c and Ppp2r3a. Cell proliferation analysis showed increased PASMCs proliferation in MCT-induced PH, an effect relied on CREB-mediated transcriptional activity. Further analysis revealed the raised intracellular labile zinc possibly from ZIP12 was associated with reduced phosphatases, increased CREB-mediated transcriptional activity and PASMCs proliferation. CONCLUSIONS: CREB pathway was overactivated in the development of PH and contributed to PASMCs proliferation, which was associated with multiple protein kinases and/or reduced CREB phosphatases and raised intracellular zinc. Thus, this study may provide a novel insight into the CREB pathway in the pathogenesis of PH. Video abstract.

Transcription factor CREB plays an important role in the development of pulmonary hypertension (PH). However, paradoxical roles have been reported in the pathogenesis of PH, and the regulatory mechanisms of CREB activation in pulmonary artery smooth muscle cells (PASMCs) proliferation remained unknown. In this study, we showed that CRE-containing genes were overrepresented among the differentially expressed genes in experimental PH, which resulted from the sustained activation of CREB pathway. The sustained activation of CREB pathway may be associated with the activation of multiple protein kinases that positively regulate CREB and down-regulation of numerous phosphatases involved in CREB dephosphorylation. Additionally, we found that the proliferation of PAMSCs was dependent on the CREB-mediated transcriptional activity in experimental PH. Moreover, the raised intracellular labile zinc possibly from ZIP12 may be associated with reduced protein phosphatases, increased CREB-mediated transcriptional activity and PASMCs proliferation. Collectively, we found CREB-mediated transcriptional activity in the proliferation of PASMCs in PH, which may be associated with multiple protein kinases and/or reduced phosphatases and elevated intracellular zinc. This study may reveal a critical role of zinc-mediated activation of CREB pathway in the proliferation of PASMCs, thus providing a more comprehensive understanding of CREB pathway in the pathogenesis of PH.

Porcine Epidemic Diarrhea Virus Inhibits HDAC1 Expression To Facilitate Its Replication via Binding of Its Nucleocapsid Protein to Host Transcription Factor Sp1.

Porcine epidemic diarrhea virus (PEDV) is an enteric coronavirus causing acute intestinal infection in pigs, with high mortality often seen in neonatal pigs. The newborns rely on innate immune responses against invading pathogens because of lacking adaptive immunity. However, how PEDV disables the innate immunity of newborns toward severe infection remains unknown. We found that PEDV infection led to reduced expression of histone deacetylases (HDACs), especially HDAC1, in porcine IPEC-J2 cells. HDACs are considered important regulators of innate immunity. We hypothesized that PEDV interacts with certain host factors to regulate HDAC1 expression in favor of its replication. We show that HDAC1 acted as a negative regulator of PEDV replication in IPEC-J2 cells, as shown by chemical inhibition, gene knockout, and overexpression. A GC-box (GCCCCACCCCC) within the HDAC1 promoter region was identified for Sp1 binding in IPEC-J2 cells. Treatment of the cells with Sp1 inhibitor mithramycin A inhibited HDAC1 expression, indicating direct regulation of HDAC1 expression by Sp1. Of the viral proteins that were overexpressed in IPEC-J2 cells, the N protein was found to be present in the nuclei and more inhibitory to HDAC1 transcription. The putative nuclear localization sequence 261PKKNKSR267 contributed to its nuclear localization. The N protein interacted with Sp1 and interfered with its binding to the promoter region, thereby inhibiting its transcriptional activity for HDAC1 expression. Our findings reveal a novel mechanism of PEDV evasion of the host responses, offering implications for studying the infection processes of other coronaviruses. IMPORTANCE The enteric coronavirus porcine epidemic diarrhea virus (PEDV) causes fatal acute intestinal infection in neonatal pigs that rely on innate immune responses. Histone deacetylases (HDACs) play important roles in innate immune regulation. Our study found PEDV suppresses HDAC1 expression via the interaction of its N protein and porcine Sp1, which identified a novel mechanism of PEDV evasion of the host responses to benefit its replication. This study suggests that other coronaviruses, including SARS-CoV and SARS-CoV-2, also make use of their N proteins to intercept the host immune responses in favor of their infection.

Preparation and characterization of carboxymethylcellulose based citric acid cross-linked magnetic aerogel as an efficient dye adsorbent.

A low-cost, collectable, and efficient material is essential for adsorbing water pollution, such as dyes and heavy metal ions pollution. In this work, we proposed a novel strategy for the preparation of an efficient and collectable magnetic aerogel as adsorbent for dye. The magnetic aerogels were prepared from sodium carboxymethylcellulose (CMC) hydrogel using citric acid (CA) as the crosslinker, followed by vacuum freeze-drying technique to obtain aerogels. The effects of magnetic Fe3O4 nanoparticle contents on the adsorption properties of the aerogels were investigated. The results show that the as-prepared magnetic composite aerogels exhibit porous structure and display good adsorption and collectable performance for methylene blue (MB) in water with the removal rate of 97.5% in 6 h. The maximum compress strength and absorption capacity of the magnetic aerogel with 1 wt% Fe3O4 nanoparticle loading for MB is 0.13 MPa and 83.6 mg/g, respectively. Aerogels with Fe3O4 nanoparticles exhibited magnetism which enables the aerogels to easily collect. This excellent structure stability and collectability guarantees long-term integrity and floatability of the magnetic aerogels in water.

Development of a nomogram for screening the risk of left ventricular hypertrophy in Chinese hypertensive patients.

Left ventricular hypertrophy (LVH) is an important risk factor for cardiovascular morbidity and mortality in hypertensives. Therefore, early identification of at-risk patients is necessary. The objective of this study was to estimate the risk of LVH among Chinese hypertensives by designing a nomogram. 832 hypertensives were divided into two groups based on the presence of LVH. The least absolute shrinkage and selection operator (LASSO) regression and multivariable logistic regression were successively applied for optimal variable selection and nomogram construction. Discrimination power, calibration, and clinical usefulness were evaluated using the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis. Internal validation was performed using the bootstrap method. The nomogram included five predictors, namely gender, duration of hypertension, age, body mass index (BMI), and systolic blood pressure. The area under the ROC curve (AUC) was 0.724 (95% CI: 0.687-0.761), indicating moderate discrimination. The calibration curve showed an excellent agreement between the predicted LVH and the actual LVH probability. The risk threshold between 5% and 72% according to the decision curve analysis, and the nomogram is clinically beneficial. Internal validation by bootstrapping with 1000 samples showed a good C-index of 0.715, which suggested that the predictive abilities for the training set and testing set were in consistency. Our study proposed a nomogram that can be utilized to assess the LVH risk rapidly for Chinese hypertensives. This tool could be useful in identifying patients at high risk for LVH. Further studies are required to ascertain the stability and applicability of this nomogram.

Relationship between lactate dehydrogenase and albuminuria in Chinese hypertensive patients.

Lactate dehydrogenase (LDH) has been reported to be positively correlated with albuminuria assessed by urinary albumin-to-creatinine ratio (UACR) in patients with sickle cell disease; both LDH and albuminuria are positively associated with the severity of hypertension (HTN). Here, a cross-sectional study was performed to investigate the association between LDH and albuminuria in Chinese hypertensives. A total of 1169 Chinese individuals (aged 58.0 ± 11.5 years, 60.4% male), who were admitted to our hospital, were included in this study. Based on the level of LDH, all hypertensives (n = 802) were divided into three groups: HTN1 (lowest tertile of LDH, n = 264), HTN2 (mediate tertile of LDH, n = 268), and HTN3 (highest tertile of LDH, n = 270). Hypertensives with hyperhomocysteinemia were defined as hypertensives with homocysteine ≥15µmol/L. Meanwhile, 367 normotensives served as controls. Compared with normotensives, the levels of LDH and UACR were significantly higher in hypertensives (p < .05). There was an increasing trend of albuminuria (UACR ≥30 mg/g) from control, HTN1, HTN2 to HTN3 group (4% vs. 12.1% vs. 14.9% vs. 19.6%, χ2  = 38.886, p < .001). Stepwise multiple regression analysis showed an independent association between LDH and UACR in patients with HTN (ß = 0.085, p < .05), but not in normotensives. After further stratification in hypertensive patients, this correlation remained in the male (ß = 0.161, p < .001), elderly (age ≥65 years, ß = 0.174, p < .001) and especially hypertensives with hyperhomocysteinemia (ß = 0.402, p < .001). LDH combined with white blood cell (WBC) counts was observed to have better discrimination for albuminuria than creatinine united with cystatin C in hypertensives according to receiver operation characteristic curves (area under curve: 0.637 vs. 0.535, z = 2.563, p = .0104). In conclusion, the level of LDH was associated with albuminuria in Chinese patients with HTN, particularly in hypertensives with hyperhomocysteinemia. LDH combined with WBC provided better prediction of albuminuria than routine renal function assessment in hypertensives. Further studies are needed to confirm LDH as an early marker for the risk of kidney involvement among hypertensives.

Relationship between high-normal albuminuria and arterial stiffness in Chinese population.

High-normal albuminuria is related to the morbidity and mortality of cardiovascular disease. Arterial stiffness has been regarded as a predictor of cardiovascular disease. However, the relationship between high-normal albuminuria and arterial stiffness is uncertain in Chinese population. A total of 1343 Chinese participants (aged 58.9 ± 12.1 years, 63.53% male) were included in this study. High-normal albuminuria was defined as urinary albumin-to-creatinine ratio (UACR) above the median within normal albuminuria. Based on the level of UACR, all participants were divided into low-normal albuminuria group (UACR < 6.36 mg/g, n = 580), high-normal albuminuria group (6.36 mg/g ≤ UACR < 30 mg/g, n = 581), microalbuminuria (30 mg/g ≤ UACR < 300 mg/g, n = 162), and macroalbuminuria (UACR ≥ 300 mg/g, n = 20). Arterial stiffness was assessed by measuring carotid-femoral pulse wave velocity (cfPWV). With the increment of UACR, the level of cfPWV was increased gradually (P < .001). Stepwise multiple regression analysis showed that systolic blood pressure, age, serum creatinine, heart rate, logarithmic (LG)-transformed UACR, and fasting plasma glucose were independently associated with cfPWV in all subjects (P < .001). LG-UACR was found to be related to cfPWV in high-normal albuminuria and macroalbuminuria subjects. After further stratification in the high-normal albuminuria subjects, their relation remained in male, elderly over 65 years old, or normotensives. In summary, UACR is associated with arterial stiffness in subjects with proteinuria excretion in high normal level. High-normal albuminuria might be an early indicator of arterial stiffness, especially in male, elderly, or normotensives in Chinese population. Furthermore, age and blood pressure are still observed to be the most important risk factor of arterial stiffness.

Role of 20-hydroxyeicosatetraenoic acid in pulmonary hypertension and proliferation of pulmonary arterial smooth muscle cells.

OBJECTIVE: To investigate the level of 20-Hydroxyeicosatetraenoic acid (20-HETE) in model of pulmonary hypertension (PH) and its effect on the proliferation of pulmonary arterial smooth muscle cells (PASMCs). METHODS: Twenty male Sprague-Dawley rats were randomly divided into two groups, including control group and PH group. PH was induced by intra-peritoneal injection of 20 mg/kg monocrotaline (MCT) twice in a week in 10 rats, and control rats were given equal amount of saline. Mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy index (RVHI) and pulmonary vascular remodeling index (WA%, WT%) were assessed at the week 4. The levels of 20-HETE were analysed by liquid chromatography tandem-mass spectrometry (LC-MS/MS). EdU test was used to determine the proliferation of PASMCs. Intracellular levels of reactive oxygen species (ROS) were detected using DCFH-DA dye. RESULTS: (1) Prominent right ventricular hypertrophy and pulmonary vascular remodeling were verified in PH rats; (2) 20-HETE levels in lung tissue and serum were significantly lifted in PH rats; (3) Increased 20-HETE levels in cell culture supernatants were significantly noted in hypoxia condition; (4) Proliferation of PASMCs was induced by 20-HETE and hypoxia, and was inhibited by HET0016; (5) Production of ROS was elevated by 20-HETE and hypoxia, and was reduced by HET0016; CONCLUSION: Vascular remodeling was demonstrated in PH rats. 20-HETE levels were significantly increased in PH rats and under hypoxia condition. PASMCs proliferation and ROS production were elevated by 20-HETE and could be inhibited by HET0016, a specific inhibitor of 20-HETE. Taken together, changes in the level of 20-HETE may be related to the excessive proliferation of PASMCs in PH rats.

Transcriptomic analysis identifies Toll-like and Nod-like pathways and necroptosis in pulmonary arterial hypertension.

Inflammation and immunity play a causal role in the pathogenesis of pulmonary vascular remodelling and pulmonary arterial hypertension (PAH). However, the pathways and mechanisms by which inflammation and immunity contribute to pulmonary vascular remodelling remain unknown. RNA sequencing was used to analyse the transcriptome in control and rats injected with monocrotaline (MCT) for various weeks. Using the transcriptional profiling of MCT-induced PAH coupled with bioinformatics analysis, we clustered the differentially expressed genes (DEGs) and chose the increased expression patterns associated with inflammatory and immune response. We found the enrichment of Toll-like receptor (TLR) and Nod-like receptor (NLR) pathways and identified NF-κB-mediated inflammatory and immune profiling in MCT-induced PAH. Pathway-based data integration and visualization showed the dysregulated TLR and NLR pathways, including increased expression of TLR2 and NLRP3, and their downstream molecules. Further analysis revealed that the activation of TLR and NLR pathways was associated with up-regulation of damage-associated molecular patterns (DAMPs) and RIPK3-mediated necroptosis was involved in the generation of DAMPs in MCT-induced PAH. Collectively, we identify RIPK3-mediated necroptosis and its triggered TLR and NLR pathways in the progression of pulmonary vascular remodelling, thus providing novel insights into the mechanisms underlying inflammation and immunity in the pathogenesis of PAH.