The Severity of Obstructive Sleep Apnea Increases the Risk of Arteriosclerosis.

BACKGROUND: Obstructive sleep apnea (OSA) is a common disorder worldwide. It is associated with myocardial remodeling and arteriosclerosis in patients with hypertension. Our study investigated the relationship between OSA severity and arteriosclerosis and blood pressure in an Asian population. METHODS: We enrolled 365 subjects from July 2018 to December 2020 at Ruijin Hospital. We recorded data from the medical history and collected blood samples from all participants. We performed 24-hour ambulatory Blood Pressure (BP) monitoring and Carotid-femoral pulse wave velocity (cf-PWV) measurements. Overnight polysomnography (PSG) was performed using Respironics Alice PDxSleepware. RESULTS: PSG was performed in a total of 365 subjects; mean age of 49.1 ± 12.8 years and Body Mass Index (BMI) 28.1 ± 3.8 kg/m2. The majority (89.3%) were male. The office systolic BP was significantly higher in the moderate to severe group than mild OSA group (148 ± 21 mmHg vs 139 ± 19 mmHg, p < 0.01). The subjects with moderate to severe OSA presented higher cf-PWV values than those in the mild group (10.03 ± 3.67 m/s vs 7.62 ± 1.48 m/s, p < 0.01). BMI was significantly higher in the moderate to severe than the mild OSA groups (28.3 ± 4.0 kg/m2 vs 27.5 ± 3.2 kg/m2, p < 0.05). The Pearson correlation showed that the apnea-hypopnea index (AHI) was significantly and positively correlated with cf-PWV (r = 0.217, p < 0.01), Age (r = 0.148, p < 0.01), BMI (r = 0.228, p < 0.01) and HbA1c (r = 0.172, p < 0.01). After adjusting for age, BMI, low density lipoprotein cholesterin (LDL-c), FGB, AHI, estimated Glomerular Filtration Rate (eGFR), Night BP, office diastolic BP and Day BP in Logistic regression model, AHI (OR = 1.03, 95% CI: 1.01-1.05) and office diastolic pressure (OR = 1.04, 95% CI: 1.00-1.08) and age (OR = 1.12, 95% CI: 1.06-1.19) were independent risk factors for arteriosclerosis. CONCLUSIONS: The severity of OSA was positively correlated with pulse wave velocity. AHI, office BP and age were independent risk factors for arteriosclerosis.

miR-200c overexpression inhibits the invasion and tumorigenicity of epithelial ovarian cancer cells by suppressing lncRNA HOTAIR in mice.

Epithelial ovarian cancer (EOC) is a common ovarian cancer in gynecological cancers today. It has been found that microRNAs and long-chain noncoding RNA (lncRNA) regulate the gene transcriptional expression in cells. However, it is not well understood that the upstream and downstream regulatory molecules of lncRNA HOX antisense intergenic RNA (HOTAIR). The effects of miR-200c overexpression on the invasion and nude mouse tumorigenicity, as well as lncRNA HOTAIR and snail expression of EOC SKOV3 cells, should be further explored. The expression of miR-200c and lncRNA HOTAIR was detected by reverse transcription PCR (RT-PCR) in EOC SKOV3 cells. The whole miR-200c gene fragment was cloned into a lentiviral plasmid vector. The miR-200c expression in transducted SKOV3 cells with reconstructed miR-200c lentivirus was significantly higher than the negative control (P < .01). The lentivirus-miR-200c-SKOV3 cells show that the invasion ability was significantly decreased compared with the negative control (P < .01). The nude mouse tumorigenicity was significantly decreased compared with that of the control group (P < .01). The snail protein expression in lentivirus-miR-200c-SKOV3 xenograft tumor was significantly decreased compared with the negative control lentivirus-SKOV3 group (P < .05). The miR-200c overexpression significantly decreased the expressions of lncRNA HOTAIR and snail, but increased E-cadherin expression in the lentivirus-miR-200c transducted SKOV3 cells of xenograft tumor, compared with the negative control (P < .05). The miR-200c overexpression in SKOV3 cells with transducted lentivirus-miR-200c can inhibit lncRNA HOTAIR expression, decrease snail, increase E-cadherin and significantly reduce the invasion and tumorigenicity of EOC SKOV3 cells. These results suggest that the miR-200c and lncRNA HOTAIR could be effective therapeutic targets for human epithelial ovarian cancer treatment.

Central aortic pressure improves prediction of cardiovascular events compared to peripheral blood pressure in short-term follow-up of a hypertensive cohort.

Objective: The aim of this study was to assess indices of a comprehensive panel of central aortic pressure and arterial stiffness for prediction of cardiovascular events in a hypertensive cohort.Methods: Noninvasive measurements of central aortic blood pressure, brachial pressure, wave reflection augmentation index, pressure amplification, pulse wave velocity (PWV) and carotid intima-media thickness (IMT) were obtained in 675 hypertensive patients (age 61 ± 9 years, 425 males) for a mean follow-up period 25 ± 4 months. The primary endpoints were defined as cardiovascular disease (CVD) events or death from CVD.Results: After adjusting for confounding factors, central systolic (cSBP) and pulse pressure (cPP) showed higher hazard ratios (HR/10 mmHg) for cardiovascular events (CV) compared to peripheral pressure indices (pSBP, pPP) at age >60 years (cSBP: HR = 1.18, pSBP: HR = 1.17, p = 0.034; cPP: HR = 1.28, pPP: HR = 1.2, p = 0.019). Each SD increase in IMT and in central augmented pressure (cAP) entailed a 1.4 times higher risk of increased total events in elderly patients (age >60 years). For males, each SD increase in cAP was associated with 1.36 times higher risk of increased total events. For females, each SD increase in cAIx and cAP was associated with 0.4 and 0.5 times lower risk of increased total and major CV, respectively. This sex difference is most likely due to lack of age-related increase of cAIx in females after age >60 years compared to males.Conclusions: Central pressure improved prediction of CVD compared to peripheral pressure during a relatively short-term follow up of approximately 2 years at age >60 years.

Hexokinase II promotes the Warburg effect by phosphorylating alpha subunit of pyruvate dehydrogenase.

OBJECTIVE: Tumor cells rely heavily on glycolysis regardless of oxygen tension, a phenomenon called the Warburg effect. Hexokinase II (HKII) catalyzes the first irreversible step of glycolysis and is often overexpressed in tumor cells. Mitochondrial HKII couples glycolysis and oxidative phosphorylation while maintaining mitochondrial membrane integrity. In this study, we investigated the role of HKII in promoting the Warburg effect in cancer cells. METHODS: HKII-mediated phosphorylation of the alpha subunit of pyruvate dehydrogenase (PDHA1) was tested in HEK293T cells and clear cell renal cell carcinoma (ccRCC) specimens using gene knockdown, western blotting, immunohistochemistry, and immunofluorescence. RESULTS: It was determined that HKII could not only transform glucose into glucose-6-phosphate, but also transfer the phosphate group of ATP onto PDHA1. In addition, it was found that HKII increased the phosphorylation of Ser293 on PDHA1, decreasing pyruvate dehydrogenase (PDH) complex activity and thus rerouting the metabolic pathway and promoting the Warburg effect. The overexpression of HKII correlated with the phosphorylation of PDHA1 and disease progression in ccRCC. CONCLUSIONS: The data presented here suggest that HKII is an important biomarker in the evaluation and treatment of cancer.

Neurotoxicity of Combined Exposure to the Heavy Metals (Pb and As) in Zebrafish (Danio rerio).

Lead (Pb) and arsenic (As) are commonly occurring heavy metals in the environment and produce detrimental impacts on the central nervous system. Although they have both been indicated to exhibit neurotoxic properties, it is not known if they have joint effects, and their mechanisms of action are likewise unknown. In this study, zebrafish were exposed to different concentrations of Pb (40 µg/L, 4 mg/L), As (32 µg/L, 3.2 mg/L) and their combinations (40 µg/L + 32 µg/L, 4 mg/L + 3.2 mg/L) for 30 days. The histopathological analyses showed significant brain damage characterized by glial scar formation and ventricular enlargement in all exposed groups. In addition, either Pb or As staining inhibited the swimming speed of zebrafish, which was enhanced by their high concentrations in a mixture. To elucidate the underlying mechanisms, we examined changes in acetylcholinesterase (AChE) activity, neurotransmitter (dopamine, 5-hydroxytryptamine) levels, HPI axis-related hormone (cortisol and epinephrine) contents and neurodevelopment-related gene expression in zebrafish brain. The observations suggest that combined exposure to Pb and As can cause abnormalities in swimming behavior and ultimately exacerbate neurotoxicity in zebrafish by interfering with the cholinergic system, dopamine and 5-hydroxytryptamine signaling, HPI axis function as well as neuronal development. This study provides an important theoretical basis for the mixed exposure of heavy metals and their toxicity to aquatic organisms.

ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice.

Cardiac macrophage contributes to the development of cardiac fibrosis, but factors that regulate cardiac macrophages transition and activation during this process remains elusive. Here we show, by single-cell transcriptomics, lineage tracing and parabiosis, that cardiac macrophages from circulating monocytes preferentially commit to macrophage-to-myofibroblast transition (MMT) under angiotensin II (Ang II)-induced hypertension, with accompanying increased expression of the RNA N6-methyladenosine demethylases, ALKBH5. Meanwhile, macrophage-specific knockout of ALKBH5 inhibits Ang II-induced MMT, and subsequently ameliorates cardiac fibrosis and dysfunction. Mechanistically, RNA immunoprecipitation sequencing identifies interlukin-11 (IL-11) mRNA as a target for ALKBH5-mediated m6A demethylation, leading to increased IL-11 mRNA stability and protein levels. By contrast, overexpression of IL11 in circulating macrophages reverses the phenotype in ALKBH5-deficient mice and macrophage. Lastly, targeted delivery of ALKBH5 or IL-11 receptor α (IL11RA1) siRNA to monocytes/macrophages attenuates MMT and cardiac fibrosis under hypertensive stress. Our results thus suggest that the ALKBH5/IL-11/IL11RA1/MMT axis alters cardiac macrophage and contributes to hypertensive cardiac fibrosis and dysfunction in mice, and thereby identify potential targets for cardiac fibrosis therapy in patients.

Arterial Stiffness as a Predictor of the Index of Atherosclerotic Cardiovascular Disease in Hypertensive Patients.

OBJECTIVE: The aim of this study was to evaluate the predictive value of carotid-femoral pulse wave velocity (cfPWV) and cardiovascular disease in the hypertensive population in China and to determine the specific cfPWV cut-off value for assessing future cardiovascular disease (CVD) risk. METHODS: This cross-sectional study included 630 hospital patients with primary hypertension and multiple cardiovascular risk factors or complications involving damage to clinical target organs. The study was conducted between July 2007 and October 2008. Atherosclerotic cardiovascular disease (ASCVD) risk calculations were computed according to criteria presented by the American College of Cardiology and the American Heart Association. Patients were stratified by a predefined risk threshold of 10% and divided into two groups: ASCVD ≥ 10% or ASCVD < 10%. cfPWV was used as a marker of arterial stiffness. A receiver operating characteristics (ROC) curve was applied to establish the optimal cfPWV cut-off point to differentiate between participants with and without ASCVD risk. RESULTS: In the study cohort of 630 patients (age 63.55.2 ± 8.6 years, 61.7% male) with primary hypertension, the pressure indices (augmented pressure, augmentation index [AIx], aortic pulse pressure, aortic systolic pressure [SBP]) and Framingham Risk Scores (FRS) were greater in females than in males (p < 0.001); ASCVD risk scores and peripheral diastolic pressure (DBP) were higher in males (p < 0.05). All hemodynamic indices showed a significant positive correlation with ASCVD risk scores and FRS; AIx was not correlated with ASCVD risk scores. In multivariate logistic analysis, cfPWV was significantly associated with ASCVD risk (OR: 1.324, 95% confidence interval: 1.119-1.565, p < 0.001) after adjusting for age, gender, smoking, body mass index, total cholesterol, fasting blood glucose, antihypertensive treatment, statin treatment, and DBP. In the ROC analysis, the area under the curve was 0.758 and 0.672 for cfPWV and aortic SBP (p < 0.001 and p < 0.001, respectively); the optimal critical value of cfPWV and aortic SBP was 12.45 m/s (sensitivity 63.2%, specificity 77.8%) and 124.5 mmHg (sensitivity 63.9%, specificity 65.3%). CONCLUSIONS: cfPWV is significantly correlated with the risk of ASCVD. The best cut-off value of cfPWV for assessing future CVD risk in the hypertensive population in China is 12.45 m/s.

Improving Nutritional Status Was Associated with Decreasing Disease Severity and Shortening of Negative Conversion Time of PCR Test in Non-ICU Patients with COVID-19.

Background: Nutrition is an important prevention in old patients with COVID-19. However, in China, there are few studies on the correlation between nutrition and COVID-19. Methods: A total of 148 hospitalized COVID-19 (65.7 ± 16.0 [range: from 21 to 101] years old) patients were enrolled in this study. The information of demographic, biochemical results, vaccination doses, types of COVID-19, PCR test negative conversion time, and scores of Mini Nutritional Assessment Short Form (MNA-SF) for evaluating nutritional status were recorded. We first explored the relationships between MNA-SF performance and the severities of COVID-19 in the groups with non-vaccinated, vaccinated, and all the patients using multivariable ordinal logistic regression. Further, we explored the relationships between performance of MNA-SF and the time of negative conversion of PCR in the groups with non-vaccinated, vaccinated, and all the patients using COX proportional hazards survival regression. Results: Group of patients with malnutrition or at risk of malnutrition group was associated with older of the age, those who had not been vaccinated, in fewer people who were asymptomatic type and in more people who showed longer of the negative conversion time of PCR, lower of the BMI, and the lower of the hemoglobin level. Each additional increase of one point of MNA-SF was associated with a 17% decrease in the odds of a worse type of COVID-19 in all patients, and the significant result exists in non-vaccinated patients. One point increase of MNA-SF was associated with increased 11% of hazard ratios of turning negative of PCR and well-nourished group was associated with increased 46% of hazard ratio of turning negative of PCR. Conclusion: Higher nutrition is associated with less severity of COVID-19, especially in the non-vaccinated group. Higher nutrition is also associated with shorter time of turning negative of PCR in non-ICU COVID-19 patients.

Developmental Neurotoxicity of Difenoconazole in Zebrafish Embryos.

Difenoconazole is a type of triazole fungicide that is widely used in the treatment of plant diseases. Triazole fungicides have been shown in several studies to impair the development of the nervous system in zebrafish embryos. There is still little known about difenoconazole-induced neurotoxicity in fish. In this study, zebrafish embryos were exposed to 0.25, 0.5, and 1 mg/L of difenoconazole solution until 120 h post-fertilization (hpf). The difenoconazole-exposed groups showed concentration-dependent inhibitory tendencies in heart rate and body length. Malformation rate and spontaneous movement of zebrafish embryos increased, and the locomotor activity decreased in the highest exposure group. The content of dopamine and acetylcholine was reduced significantly in difenoconazole treatment groups. The activity of acetylcholinesterase (AChE) was also increased after treatment with difenoconazole. Furthermore, the expression of genes involved in neurodevelopment was remarkably altered, which corresponded with the alterations of neurotransmitter content and AChE activity. These results indicated that difenoconazole might affect the development of the nervous system through influencing neurotransmitter levels, enzyme activity, and the expression of neural-related genes, ultimately leading to abnormal locomotor activity in the early stages of zebrafish.

Comparison of Risk of Target Organ Damage in Different Phenotypes of Arterial Stiffness and Central Aortic Blood Pressure.

Objectives: The aim of this study was to explore the risk of target organ damage (TOD) in different groups based on carotid-femoral pulse wave velocity (cfPWV) and central aortic blood pressure (CBP) in different populations. Methods: The study cohort was divided into four groups according to the status of cfPWV and CBP [Group (cfPWV/CBP): high cfPWV and high CBP; Group (cfPWV): high cfPWV and normal CBP; Group (CBP): normal cfPWV and high CBP; Group (control): normal cfPWV and normal CBP]. TOD was determined by the assessment of carotid intima-media thickness (CIMT) abnormality, chronic kidney disease (CKD), microalbuminuria, and left ventricular hypertrophy (LVH). Results: A total of 1,280 patients (mean age 53.14 ± 12.76 years, 64.1% male patients) were recruited in this study. Regarding Group (control) as reference, LVH was significantly higher in Group (cfPWV) and Group (CBP) [OR 2.406, 95% CI (1.301-4.452), P < 0.05; OR 2.007, 95% CI (1.335-3.017), P < 0.05]; microalbuminuria was significantly higher in Group (cfPWV/CBP) and Group (CBP) [OR 3.219, 95% CI (1.630-6.359), P < 0.05; OR 3.156, 95% CI (1.961-5.079), P < 0.05]. With age stratified by 60 years, the risk of CKD was significantly higher in Group (cfPWV/CBP) [OR 4.019, 95% CI (1.439-11.229), P < 0.05]. Conclusion: Different phenotypes based on the status of cfPWV and CBP were associated with different TOD. Individuals with both cfPWV and CBP elevated have a higher risk of microalbuminuria.

Comparison of Influence of Blood Pressure and Carotid-Femoral Pulse Wave Velocity on Target Organ Damage in Hypertension.

Objectives: Assessment of target organ damage (TOD) is an important part of the diagnosis and evaluation of hypertension. Carotid-femoral pulse wave velocity (cf-PWV) is considered to be the gold-standard for noninvasive arterial stiffness assessment. This study aims to analyze the risk of TOD in people with different phenotypes of peripheral blood pressure and cf-PWV. Methods: The study cohort was recruited from December 2017 to September 2021 at Ruijin Hospital in Shanghai. It was divided into 4 groups according to peripheral blood pressure (pBP) and cf-PWV. TOD was assessed as carotid intima-media thickness (CIMT), chronic kidney disease (CKD), urinary albumin-creatinine ratio (ACR), estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI). Results: A total of 1,257 subjects (mean age 53.13 ± 12.65 years, 64.2% males) was recruited. Age, body mass index (BMI) and fasting blood glucose (FBG), as well as peripheral systolic blood pressure (pSBP), peripheral diastolic blood pressure (pDBP), peripheral pulse pressure (pPP) were significantly different in the four groups (P < 0.01). eGFR, ACR, LVMI and CIMT were significantly different among different groups (P < 0.01). The risk of ACR abnormality was significantly higher in the group with elevated pBP (P = 0.005, OR 2.264, 95%CI 1.277-4.016; and in the group with elevated pBP and cf-PWV (P = 0.003, OR 1.482, 95%CI 1.144-1.920), while left ventricular hypertrophy (LVH) was significantly higher in the group with elevated cf-PWV (P = 0.002, OR 1.868, 95%CI 1.249-2.793). Conclusion: Different profiles based on the status of PBP and cf-PWV associated with different TOD. Individuals with higher pBP have an increased risk of ACR abnormality, while individuals with only cf-PWV elevated have a higher risk of LVH.

Association between Brachial-Ankle Pulse Wave Velocity as a Marker of Arterial Stiffness and Body Mass Index in a Chinese Population.

Objectives: Arterial stiffness is widely accepted as an important predictor of cardiovascular disease (CVD) development. While obesity is generally associated with increased CVD risk, there is evidence that overweight patients with existing CVD may have better clinical outcomes than their lean counterparts. Our study sought to observe any potential association between brachial−ankle pulse wave velocity (BAPWV), a marker of arterial stiffness related to CVD risk, and Body Mass Index (BMI), a crude and widely used measure of obesity. Methods: Adult individuals (n = 857) assessed for routine CV risk were included and grouped according to their BMI (<25 kg/m2: normal; 25−30 kg/m2: overweight, ≥30 kg/m2: obese). Their anthropometric parameters, brachial cuff pressures, and BAPWV were measured. Results: Brachial pressure was significantly higher as BMI increased. BAPWV showed a positive linear association with systolic (r = 0.66, p < 0.01), mean (r = 0.60, p < 0.01), diastolic (r = 0.51, p < 0.01), and pulse (r = 0.53, p < 0.01) pressures. However, a linear relationship between BMI and BAPWV was only apparent in males aged <50 years (p = 0.01) and in females aged ≥50 years (p < 0.01). In individuals with similar brachial systolic pressure, BAPWV was higher in normal-weight subjects compared to overweight−obese ones. Conclusions: This conflicting finding is attributed to an overestimation of the degree of arterial stiffness as a measure of CVD risk in individuals with a less 'healthy' BMI. This suggests that BMI may not the appropriate obesity indicator to assess CV risk. Our finding emphasizes the importance of establishing a non-linear relationship between CVD risk, age, and BMI, taking into account apparent sex differences, to predict future CV events. While this finding may suggest a lower degree of stiffness in large arteries of overweight−obese subjects compared to their normal-weight counterparts, the potential implications for individuals with higher BMI need be explored further.

Relationship between Arterial Stiffness and Renal Function Determined by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) Equations in a Chinese Cohort Undergoing Health Examination.

Background: The association between arterial stiffness and cardiovascular risk in CKD and ESRD patients is well established. However, the relationship between renal function estimation and properties of large arteries is unclear due to the four different methods used to quantify glomerular filtration. This study investigated the relationship between carotid-femoral pulse wave velocity (c-fPWV), as a measure of arterial stiffness, and accepted metrics of renal function. Methods: This cross-sectional study was conducted in 431 health examination individuals in China, enrolled from January 2017 to June 2019. c-fPWV and blood pressure were measured, and blood samples were obtained for all participants. Four different methods were used to determine the estimated glomerular filtration rate (eGFR) as described by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations: (i) CKD-EPISCr formula based on SCr, (ii) CKD-EPICysC formula based on CysC, (iii) CKD-EPISCr/CysC formula based on Cr and CysC, and (iv) MDRD. Results: Of all of the study participants (average age 53.1 ± 13.0 years, 68.1% male), 23.7% had diabetes mellitus and 66.6% had hypertension. The average eGFR values determined by the CKD-EPISCr, CKD-EPICysC, CKD-EPISCr/CysC, and MDRD equations were 91.9 ± 15.6, 86.8 ± 21.4, 89.6 ± 18.3, and 90.7 ± 16.6 ml/min/1.73m2, respectively. c-fPWV was significantly and negatively correlated with eGFR determined by CKD-EPISCr (r = -0.336, P < 0.001), CKD-EPICysC (r = -0.385, P < 0.001), CKD-EPISCr/CysC (r = -0.378, P < 0.001), and MDRD (r = -0.219, P < .001) equations. After adjusting for confounding factors, c-fPWV remained significantly and negatively correlated with eGFR determined by the CKD-EPICysC equation (ß = -0.105, P = 0.042) and significantly and positively correlated with age (ß = 0.349, P ≤ 0.01), systolic pressure (ß = 0.276, P ≤ 0.01), and hypoglycemic drugs (ß = 0.101, P = 0.019). Conclusion: In a health examination population in China, c-fPWV is negatively correlated with eGFR determined by four different equations; however, only the metric of eGFR determined by the equation for CKD-EPICysC showed an independent relation with c-fPWV.

Disparate Associations of 24-h Central Aortic and Brachial Cuff Blood Pressure With Hypertension-Mediated Organ Damage and Cardiovascular Risk.

Objective: Aim of this study was to evaluate the associations of non-invasive central aortic and peripheral (brachial) blood pressure (BP) for Hypertension-mediated organ damage (HMOD) and atherosclerotic cardiovascular disease (ASCVD) risk. Methods: We evaluated associations of HMOD with 24-h ambulatory blood pressure monitoring (ABPM) of central aortic and peripheral BP indices in patients with primary hypertension and presence of several cardiovascular risk factors. BP measurements were performed by means of a non-invasive automated oscillometric device (Mobil-O-Graph). HMOD was defined as the presence of carotid intima-media thickness (IMT) above normal values and/or carotid plaque, left ventricular hypertrophy (LVH), and/or renal abnormalities as assessed by urine albumin/creatinine ratio above normal values and/or estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2. Results: In the study cohort of 273 (age 55.2 ± 13.4 years, 71.8% male) patients with primary hypertension, documented HMOD was present in 180 (65.9%), LVH in 70 (25.6%), increased IMT in 129 (47.3%). Fifty-six patients (20.5%) had kidney organ damage (20.5% albuminuria and 2.6% impaired eGFR). When accounting for confounding factors (age, sex, body-mass-index, antihypertensive treatment, smoking, triacylglycerol, statin treatment, glucose, hypoglycemic therapy, or heart rate) only peripheral 24-h pulse pressure (PP) maintained statistical significance with HMOD indices (OR: 1.126, 95% CI: 1.012~1.253; p = 0.029). Using ASCVD risk score as the independent continuous variable in multiple linear regression, 24-h central systolic pressure (SBP) (ß = 0.179; 95% CI:0.019~0.387; p = 0.031), daytime central PP (ß = 0.114; 95% CI:0.070~0.375; p = 0.005, night-time central SBP (ß = 0.411; 95% CI:0.112~0.691; p = 0.007) and night-time PP (ß = 0.257; 95% CI:0.165~0.780; p = 0.003) were all positively associated with ASCVD risk. Conclusions: Blood pressure obtained by 24-h ABPM was better correlated with HMOD than office BP. Whilst 24-h peripheral BP showed a stronger association with HMOD than 24-h central BP, the prognostic value of 24-h central BP for the 10-year ASCVD risk was superior to 24-h peripheral BP.

The presence of polystyrene nanoplastics enhances the MCLR uptake in zebrafish leading to the exacerbation of oxidative liver damage.

The accumulation of diminutive plastic waste in the environment, including microplastics and nanoplastics, has threatened the health of multiple species. Nanoplastics can adsorb the pollutants from the immediate environment, and may be used as carriers for pollutants to enter organisms and bring serious ecological risk. To evaluate the toxic effects of microcystin-LR (MCLR) on the liver of adult zebrafish (Danio rerio) in the presence of 70 nm polystyrene nanoplastics (PSNPs), zebrafish were exposed to MCLR alone (0, 0.9, 4.5 and 22.5 µg/L) and a mixture of MCLR + PSNPs (100 µg/L) for three months. The results indicated that groups with combined exposure to MCLR and PSNPs further enhanced the accumulation of MCLR in the liver when compared to groups only exposed to MCLR. Cellular swelling, fat vacuolation, and cytoarchitectonic damage were observed in zebrafish livers after exposure to MCLR, and the presence of PSNPs exacerbated these adverse effects. The results of biochemical tests showed the combined effect of MCLR + PSNPs enhanced MCLR-induced hepatotoxicity, which could be attributed to the altered levels of reactive oxygen species, malondialdehyde and glutathione, and activities of catalase. The expression of genes related to antioxidant responses (p38a, p38b, ERK2, ERK3, Nrf2, HO-1, cat1, sod1, gax, JINK1, and gstr1) was further performed to study the mechanisms of MCLR combined with PSNPs aggravated oxidative stress of zebrafish. The results showed that PSNPs could improve the bioavailability of MCLR in the zebrafish liver by acting as a carrier and accelerate MCLR-induced oxidative stress by regulating the levels of corresponding enzymes and genes.

Shikonin Inhibits Non-Small-Cell Lung Cancer H1299 Cell Growth through Survivin Signaling Pathway.

Overexpressed survivin is associated with worse survival of several types of human tumors. In this study, the antitumor activity of shikonin in non-small-cell lung cancer (NSCLC) by regulating survivin pathway was investigated. Results showed that shikonin inhibited the NSCLC H1299 cell proliferation in a dose-dependent manner. Moreover, shikonin fits well with survivin by molecular docking. Shikonin also inhibited the mRNA expression and protein level of survivin in H1299 cells. Shikonin arrested H1299 cell cycle at the G0/G1 phase by regulating CDK/cyclin family members. In addition, shikonin regulated the expression of X-linked inhibitor of apoptosis- (XIAP-) mediated caspases 3 and 9, thus leading to the damage of mitochondrial membrane potential and induction of H1299 cell apoptosis. Overall, shikonin inhibited H1299 cell growth by inducing apoptosis and blocking the cell cycle. The underlying mechanism involves targeting survivin, which subsequently regulates the protein expression of XIAP/caspase 3/9, CDK2/4, and cyclin E/D1. Thus, shikonin, a survivin inhibitor, is a promising therapeutic strategy in NSCLC treatment.

MIA SH3 Domain ER Export Factor 3 Deficiency Prevents Neointimal Formation by Restoring BAT-Like PVAT and Decreasing VSMC Proliferation and Migration.

Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) and excessive accumulation of dysfunctional PVAT are hallmarks of pathogenesis after angioplasty. Recent genome-wide association studies reveal that single-nucleotide polymorphism (SNP) in MIA3 is associated with atherosclerosis-relevant VSMC phenotypes. However, the role of MIA3 in the vascular remodeling response to injury remains unknown. Here, we found that expression of MIA3 is increased in proliferative VSMCs and knockdown of MIA3 reduces VSMCs proliferation, migration, and inflammation, whereas MIA3 overexpression promoted VSMC migration and proliferation. Moreover, knockdown of MIA3 ameliorates femoral artery wire injury-induced neointimal hyperplasia and increases brown-like perivascular adipocytes. Collectively, the data suggest that MIA3 deficiency prevents neointimal formation by decreasing VSMC proliferation, migration, and inflammation and maintaining BAT-like perivascular adipocytes in PVAT during injury-induced vascular remodeling, which provide a potential therapeutic target for preventing neointimal hyperplasia in proliferative vascular diseases.

Female Gender Is Associated with Higher Susceptibility of Weight Induced Arterial Stiffening and Rise in Blood Pressure.

Arterial stiffness is an important predictor of cardiovascular events, independent of traditional risk factors. Stiffening of arteries, though an adaptive process to hemodynamic load, results in substantial increase in the pulsatile hemodynamic forces that detrimentally affects the microcirculation perfusing the vital organs such as the brain, heart and kidneys. Studies have proposed that arterial stiffness precedes and may contribute to the development of hypertension in individuals with obesity. Our study sought to determine the gender-based effects on arterial stiffening in obesity which may predispose to the development of hypertension. We found female sex is associated with higher susceptibility of weight-related arterial stiffening and rise in blood pressure in obesity. Women had significantly higher carotid-femoral pulse wave velocity (CF-PWV) with higher body mass index (BMI) status (normal: 7.9 ± 2 m/s; overweight: 9.1 ± 2 m/s; obese: 9 ± 2 m/s, p < 0.001), whereas it was similar in males across all BMI categories. The linear association between arterial stiffness and BMI following adjustment for age and brachial systolic and diastolic blood pressure (BP), remained significant in females (ß = 0.06; 95% CI 0.01 to 0.1; p < 0.05) but not in males (ß = 0.04; 95% CI -0.01 to 0.1; p > 0.05). The mean CF-PWV values increased by 0.1 m/s for every 1 kg/m2 increase in BMI in the female subjects in the age adjusted linear model, while such effect was not seen in the male subjects. In line with arterial stiffening, the overweight and obese females demonstrated significantly higher systolic brachial BP. (BP difference: ΔBP 9-11 mmHg, p < 0.01) and central systolic pressure (ΔBP 8-10 mmHg, p < 0.05) compared to their lean counterparts, unlike the male subjects. Our results suggest that female gender is associated with higher susceptibility of weight-related arterial stiffening and rise in blood pressure.

The joint effect of parental exposure to microcystin-LR and polystyrene nanoplastics on the growth of zebrafish offspring.

The coexistence of nanoplastics (NPs) and various pollutants in the environment has become a problem that cannot be ignored. In order to identify the microcystin-LR (MCLR) bioaccumulation and the potential impacts on the early growth of F1 zebrafish (Danio rerio) offspring in the presence of polystyrene nanoplastics (PSNPs), PSNPs and MCLR were used to expose adult zebrafish for 21days. The exposure groups divided into MCLR (0, 0.9, 4.5 and 22.5µgL-1) alone groups and PSNP (100µgL-1) and MCLR co-exposure groups. F1 embryos were collected and developed to 120 h post-fertilization (hpf) in clear water. Compared with the exposure to MCLR only, the combined exposure increased the parental transfer of MCLR to the offspring and subsequently exacerbated the growth inhibition of F1 larvae. Further research clarified that combined exposure of PSNPs and MCLR could reduce the levels of thyroxine (T4) and 3, 5, 3'-triiodothyronine (T3) by altering the expression of hypothalamus-pituitary-thyroid (HPT) axis-related genes, eventually leading to growth inhibition of F1 larvae. Our results also exhibited combined exposure of PSNPs and MCLR could change the transcription of key genes of the GH/IGF axis compared with MCLR single exposure, suggesting the GH/IGF axis was a potential target for the growth inhibition of F1 larvae in PSNPs and MCLR co-exposure groups. The present study highlights the potential risks of coexistence of MCLR and PSNPs on development of fish offspring, and the environmental risks to aquatic ecosystems.

Preparation of Electrochemical Sensor Based on Zinc Oxide Nanoparticles for Simultaneous Determination of AA, DA, and UA.

ZnO nanoparticles (NPs) were synthesized using a hydrothermal method. Scanning electron microscope (SEM) and X-ray diffraction have been used for characterizing the synthesized ZnO NPs. An electrochemical sensor was fabricated using ZnO NPs-modified glassy carbon electrode for simultaneous determination of ascorbic acid (AA), dopamine (DA), and uric acid (UA). The proposed electrochemical sensor exhibited excellent detection performance toward three analytes, demonstrating that it can potentially be applied in clinical applications. The results indicated the ZnO NPs-modified electrode can detect AA in the concentrations range between 50 and 1,000 µM. The ZnO NPs-modified electrode can detect DA in the concentrations range between 2 and 150 µM. The ZnO NPs-modified electrode can detect UA in the concentrations range between 0.2 and 150 µM. The limits of detections of AA, DA, and UA using ZnO NPs-modified electrode were calculated to be 18.4, 0.75, and 0.11 µM, respectively.