A new strategy for the treatment of Parkinson's disease: Discovery and bio-evaluation of the first central-targeting tyrosinase inhibitor.

The high level of tyrosinase leads to the generation of neuromelanin, further causing the abnormality of redox-related protein level and mediating the occurrence and development of Parkinson's disease (PD). However, the existing tyrosinase inhibitors are mostly natural product extracts or polyphenolic derivatives, which hindered them from penetrating the blood-brain barrier (BBB). Herein, we obtained a novel tyrosinase inhibitor, 2-06 (tyrosinase: monophenolase IC50 = 70.44 ± 22.69 µM, diphenolase IC50 = 1.89 ± 0.64 µM), through the structure-based screening method. The compound 2-06 presented good in vitro and in vivo safety, and can inhibit the tyrosinase and melanogenesis in B16F10. Moreover, this compound showed neuroprotective effects and Parkinsonism behavior improving function. 2-06 was proved to penetrate the BBB and enter the central nervous system (CNS). The exploration of the binding mode between 2-06 and tyrosinase provided the foundation for the subsequent structural optimization. This is the first research to develop a central-targeting tyrosinase inhibitor, which is crucial for in-depth study on the new strategy for utilizing tyrosinase inhibitors to treat PD.

Acute pulmonary embolism with electrocardiogram showing subtotal left main coronary artery occlusion: A case report.

When the electrocardiogram of acute pulmonary embolism is similar to that of acute myocardial infarction, it is difficult to distinguish between the two diseases quickly and effectively. We present the case of a 50-year-old man with acute pulmonary embolism. His electrocardiogram showed subtotal occlusion of the left main coronary artery with ST segment depression in I, II, aVF, V3 to V6, ST segment elevation in aVR, V1 and S1Q3T3. Invasive coronary angiography did not show coronary artery stenosis, then pulmonary angiography was performed quickly which showed massive bilateral acute pulmonary embolism. Electrocardiogram cannot effectively distinguish acute pulmonary embolism from subtotal occlusion of the left main coronary artery. For patients with hemodynamic instability, if ultrasound cannot be performed in time, the combination of invasive coronary angiography and pulmonary angiography can be an option to distinguish acute pulmonary embolism from subtotal occlusion of the left main coronary artery and to treat.

Association between chronic obstructive pulmonary disease and cardiovascular disease in adults aged 40 years and above: data from NHANES 2013-2018.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) are two major age-related diseases prevalent in the elderly. However, it is unclear whether there is a higher prevalence of one or more CVDs in COPD patients compared to those without COPD, and the magnitude of this increased prevalence. METHODS: This population-based cross-sectional study was conducted using data from the National Health and Nutrition Examination Survey (NHANES) 2013-2018 among American adults aged 40 years and above. Multivariable logistic regression models (including unadjusted model, minimally adjusted model, and fully adjusted model) were conducted to investigate the association between COPD and the prevalence of one or more CVDs, including coronary heart disease, heart failure, angina pectoris, heart attack, diabetes, and stroke. RESULTS: This study included 11,425 participants, consisting of 661 participants with COPD and 10,764 participants without COPD. COPD patients had a significantly higher prevalence of CVD than those without COPD (59.6% vs. 28.4%). After adjusting for covariates, COPD was significantly associated with the prevalence of one CVD (OR = 2.2, 95% CI = 1.6-3.0, p < 0.001), two or more CVDs (OR = 3.3, 95% CI = 2.2-5.0, p < 0.001), and three or more CVDs (OR = 4.3, 95% CI = 2.9-6.5, p < 0.001). CONCLUSIONS: Patients with COPD have a higher prevalence of one or more CVDs compared with those without COPD. Our findings highlight the importance of CVD prevention and management in patients with COPD.

High Ampacity On-Chip Wires Implemented by Aligned Carbon Nanotube-Cu Composite.

With the size of electronic devices shrinking to the nanometer scale, it is of great importance to develope new wire materials with higher current carrying capacity than traditional materials such as gold (Au) and copper (Cu). This is urgently needed for more efficient, compact and functional integrated chips and microsystems. To meet the needs of an atom chip, here we report a new solution by introducing super-aligned carbon nanotubes (SACNTs) into Cu thin films. The microwires exhibit an ultra-high current carrying capacity beyond the limit of the traditional Cu wires, reaching (1.7~2.6) × 107 A·cm-2. The first-principles calculation is used to obtain the band structural characteristics of the CNT-Cu composite material, and the principle of its I-V characteristic curve is analyzed. Driven by the bias voltage, a large number of carriers are injected into the CNT layer from Cu by the strong tunneling effect. Moreover, a variety of microwires can be designed and fabricated on demand for high compatibility with conventional microelectronics technology. The composite structures have great potential in high-power electronic devices, high-performance on-chip interconnecting, as well as other applications that have long-term high-current demands, in addition to atom chips.

CBL knockdown protects cardiomyocytes against hypoxia-reoxygenation injury by downregulating GRB2 expression.

Myocardial ischemia-reperfusion injury (MIRI) is an event that follows a myocardial infarction. As such, close observation and appropriate patient management is paramount in the treatment process of interventional surgery. The pathogenesis of MIRI has not been fully elucidated. Therefore, the aim of the present study was to explore of novel targets for MIRI treatment whilst also determining their possible underlying mechanism of action. The plasma samples used in the present study were collected from 30 patients with ischemic cardiomyopathy and 30 healthy volunteers. H9c2 rat cardiomyoblasts were subjected to hypoxia and reoxygenation (H/R) modeling to establish an in vitro MIRI model. Initially, the expression levels of Cbl proto-oncogene (CBL) in ICM heart tissue, normal heart tissue, H/R-induced H9c2 cells and normal H9c2 cells were detected using quantitative PCR and western blotting. With the application of Cell Counting Kit-8, western blotting and Tunnel assay, the proliferation, oxidative stress and apoptosis of H/R-induced cells were assessed. Moreover, co-IP assay was employed to testify the interaction between CBL and GRB2. The present study revealed that CBL expression was upregulated in patients with ischemic cardiomyopathy and H/R-induced H9c2 cells in comparison with that in normal heart tissue and normal H9c2 cells, respectively. The genetic silence of CBL using small interfering RNA promoted the proliferation and oxidative stress of H/R-induced cells but repressed the apoptosis. The full-length wild-type of growth factor receptor-bound protein 2 (GRB2) was ligated into pcDNA3.1 to achieve GRB2 overexpression, which revealed that GRB2 overexpression reversed the effects of CBL knockdown on cells, suggesting that it may mediate these processes downstream. In conclusion, under hypoxic conditions, CBL knockdown promoted the proliferation and antioxidant capacity of cardiomyocytes whilst inhibiting apoptosis, by downregulating GRB2 expression. These findings revealed the underlying mechanism of action of this pathway, which can be exploited for the prevention or treatment of MIRI.

Acute ST-segment elevation myocardial infarction due to extrinsic compression of left coronary artery from pulmonary epithelioid hemangioendothelioma: A case report.

RATIONALE: Acute myocardial infarction is usually caused by coronary atherosclerotic plaque disruption (rupture or erosion), also including other uncommon etiologies. Pulmonary epithelioid hemangioendothelioma (PEH) is a rare low to intermediate malignant vascular tumor originating from vascular endothelial cells. Here, we report a rare case of acute ST-segment elevation myocardial infarction (STEMI) due to extrinsic compression of left coronary artery from PEH. PATIENT CONCERNS: A 63-year-old woman with pulmonary nodules received left pulmonary nodulectomy, and the pathological examination indicated PEH. Five months after the pulmonary nodulectomy, the patient was admitted due to progressive dyspnea. DIAGNOSIS: Electrocardiography showed the obvious ST-segment elevation in the leads I, aVL, and V1-3, and laboratory tests revealed the elevated level of cardiac troponin T. Emergent coronary angiography and the contrast-enhanced computed tomography scan conformed STEMI due to extrinsic compression of left coronary artery from PEH. INTERVENTIONS: The patient did not undergo further therapy after the pulmonary nodulectomy. During the present hospitalization, she received basic life support and nutritional support treatment. OUTCOMES: The patient deteriorated rapidly into multi-organ failure and eventually died. LESSONS: Acute STEMI could be caused by extrinsic compression of the coronary artery from the mass effects of PEH, and active therapy and close follow-up should be considered for patients with PEH.

Dulaglutide inhibits high glucose- induced endothelial dysfunction and NLRP3 inflammasome activation.

Activation of the NLRP3 inflammasome plays an important role in high glucose- induced endothelial dysfunction in patients with type 2 diabetes mellitus (T2DM). Dulaglutide, a newly developed glucagon-like peptide-1 receptor (GLP-1R) agonist, has been approved for the management of T2DM. In the current study, we aimed to investigate whether dulaglutide possesses a protective effect against high glucose- induced activation of the NLRP3 inflammasome. Our results indicate that dulaglutide treatment prevented high glucose- induced generation of reactive oxygen species (ROS) and protein carbonyl, as well as the expression of NADPH oxidase 4 (NOX-4) in human umbilical vein endothelial cells (HUVECs). Dulaglutide treatment could inhibit high glucose- induced release of lactate dehydrogenase (LDH) and the expression of TXNIP. Dulaglutide suppressed high glucose- induced activation of NLRP3 inflammasome by reducing the expression of NLRP3, ASC, and cleaved caspase 1 (P10). Notably, dulaglutide treatment suppressed high glucose- induced maturation of IL-1ß and IL-18. Mechanistically, our findings indicate that SIRT1 was involved in this process by showing that knockdown of SIRT1 by transfection with SIRT1 siRNA abolished the inhibitory effects of dulaglutide on IL-1ß and IL-18 secretion via suppression of NLRP3, ASC, and p10. These data suggest that dulaglutide might serve as a potential drug for the treatment of cardiovascular complications in T2DM patients.

Sp1-induced LncRNA CTBP1-AS2 is a novel regulator in cardiomyocyte hypertrophy by interacting with FUS to stabilize TLR4.

Cardiomyocyte hypertrophy is a heart response adapting to increasing cardiac load. Prolonged cardiomyocyte hypertrophy indicates a higher risk of heart failure or even cardiac death. Long noncoding RNAs have been largely reported to modulate human diseases. CTPB1-AS2 is a newly discovered lncRNA reported as an oncogene in papillary thyroid cancer, but its function in cardiomyocyte hypertrophy has never been probed. Toll-like receptor 4 (TLR4) is recognized to play important roles in cardiomyocyte hypertrophy. The present study aimed to investigate the role of CTBP1-AS2 in cardiomyocyte hypertrophy. First, we discovered the low expression of CTBP1-AS2 in normal heart tissues in GETx database. Then, we established cardiomyocyte hypertrophy models on mice and cardiomyocytes through transverse aortic constriction surgery and Ang II treatment. We revealed the up-regulation of CTBP1-AS2 and TLR4 in cardiomyocyte hypertrophy models. Also, we confirmed the positive correlation between CTBP1-AS2 and TLR4 expressions in cardiomyocyte hypertrophy tissues. Loss-of-function assays confirmed that inhibiting CTBP1-AS2 attenuated the Ang II-induced cardiomyocyte hypertrophy. Mechanism research showed that CTBP1-AS2 stabilized TLR4 mRNA by recruiting FUS. Rescue assays certified that CTBP1-AS2 regulated cardiomyocyte hypertrophy through TLR4. Finally, we found Sp1 as an upstream activator for CTBP1-AS2 expression. In conclusion, our study uncovered CTBP1-AS2 as a novel regulator of cardiomyocyte hypertrophy through regulating TLR4, providing a new potential treatment target for cardiomyocyte hypertrophy.

Modes Coupling Analysis of Surface Plasmon Polaritons Based Resonance Manipulation in Infrared Metamaterial Absorber.

Surface plasmon polaritons (SPPs) and standing wave modes provide interesting and exotic properties for infrared metamaterial absorbers. Coupling of these modes promises further development in this field but restricted by the complexity of modes analysis. In this work, we investigate the general phenomenon of modes coupling supported by a metal (with grating)-dielectric-metal sandwich structure based on rigorous coupled-wave analysis (RCWA) method and experiment results. Through the analysis of fundamental modes, a new approach based on the boundary conditions is introduced to reveal the coupling mechanism and the corresponding resonance shifting phenomenon with simple but rigorous derivations. The strong coupling between SPPs excited on the dielectric-metal interfaces and rigorous modes of standing waves in the dielectric layer can be manipulated to improve the detection sensitivity of sensors and emissivity efficiency of infrared emitters.

[Expression of peroxisome proliferator-activated receptor alpha and beta in peripheral blood mononuclear cells of non-vavular hypertensive atrial fibrillation patients].

OBJECTIVE: To determine the mRNA expressions of PPARalpha and PPARbeta in peripheral blood mononuclear cells of non-vavular hypertensive atrial fibrillation (AF) patients and elucidate its possible role in the pathogenesis of AF. METHODS: Peripheral blood samples were collected from 103 patients with hypertensive AF (persistent AF: 55, paroxysmal AF: 48) and 50 age-adjusted hypertension patients without AF. The mRNA expressions of PPARalpha, PPARbeta, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in monocytes were detected by using a Real time polymerase chain reaction. The concentrations of high sensitive C-reactive protein (CRP) and interleukin-1 (IL-1) were measured by immunoenzymetric method. RESULTS: The PPARalpha mRNA expression level was persistently decreased in hypertensive non-AF group, paroxysmal AF group, and persistent AF group (1.34 +/- 0.17, 1.09 +/- 0.23, 0.85 +/- 0.22), while the difference was statistically significant (P < 0.001; respectively). TNF-alpha mRNA, IL-6 mRNA,CRP and IL-1 persistently increased in hypertensive non-AF group, paroxysmal AF group, persistent AF group, also the difference was statistically significant (P < 0. 001; respectively). The difference of PPARbeta mRNA was not statistically significant between non-AF group, paroxysmal AF group and persistent AF group. Left atrial diameter (LAD) was in positive correlation with CRP, IL-1, IL-6 mRNA and TNF-alpha mRNA (P < 0.05). PPARalpha mRNA level was in negative correlation with CRP, IL-1, IL-6 mRNA and TNF-alpha mRNA, the correlation coefficient was -0.519, -0.532, -0.491 and -0.528, respectively (P < 0.05). CONCLUSION: In hypertensive patients with AF, increased inflammatory cytokines were associated with atrial remodeling and lead to the development of atrial fibrillation; PPARalpha was negatively correlated with these inflammatory cytokines and may play a vital role in the process of atrial fibrillation development.

[Changes in the prevalence of obesity and abdominal obesity in middle-aged Chengdu residents during 1992 and 2007].

OBJECTIVE: To analyze the changes in the prevalence of obesity and abdominal obesity in the middle-aged Chengdu residents during 1992 and 2007. METHODS: In 1992, a cohort of 1365 Chengdu residents were selected using a combination of nonrandom cluster sampling and intra-cluster random sampling stratified by age and gender for cardiovascular disease risk factor surveys. In 2007, 1061 of the selected residents completed a second survey. We analyzed the changes in the prevalence of obesity and abdominal obesity in the middle-aged residents using BMI and waist circumference as indicators. RESULTS: From 1992 to 2007, the BMI, waist circumference, prevalence of obesity and abdominal obesity of this cohort of respondents increased significantly (P < 0.05). The 2007 survey found significant higher BMI, waist circumference, and prevalence of obesity and abdominal obesity in the residents of 50-64 years old than those with the same age in 1992 (P < 0.05). The female respondents had consistently greater standardized prevalence of obesity and abdominal obesity than their male counterparts except for the abdominal obesity in the 2007 survey. CONCLUSION: Both prevalence of obesity and abdominal obesity are increasing in Chengdu residents, even after adjustment of age.

[Association of PPARgamma2 Pro12Ala polymorphism and cognitive dysfunction in hypertension patients].

OBJECTIVE: To study the relationship between PPARgamma2 Pro12Ala polymorphism and cognitive function in patients with primary hypertension. METHODS: This study enrolled 502 hypertensive patients of Chinese Han population from Jan 2008 to Feb 2009 in West China Hospital of Sichuan University. We collected the general data and applied the mini mental state examination (MMSE) to test the cognitive function and computed score. Total cholesterol (TC), triglyeride (TG), fasting plasma glucose (FPG) and postprandial blood sugar (PPBS), fasting insulin (FINS) and postprandial plasma insulin (PINS) were measured. PCR-RELP method was used to analysis the PPARgamma2 Pro12Ala gene polymorphism. RESULTS: Pro12Pro genotype was present in 88.6% of the patients and Prol2Ala genotype was present in 11.4% of the population. Allele frequencies were 94.3% for Pro allele and 5.7% for Ala allele. In cognitive normal group, the frequencies of PP and PA genotype were 328 (87.2%) and 48 (12.8%), while the frequencies of PP and PA genotypes in the cognitive dysfunction group were 126 (92.9%), 9 (7.1%) respectively. Analyzed by chi2 test, both the genotype frequency and the allele frequency of PPARy2 Pro12Ala polymorphism did not display statistical variability between the cognitive normal group and the cognitive dysfunction group, even eliminating the influence of age and sexuality. CONCLUSION: Pro12Ala polymorphism in PPARgamma2 with primary hypertension may not associate with cognitive impairment.

Downregulation of peroxisome proliferator-activated receptor-gamma expression in hypertensive atrial fibrillation.

BACKGROUND: Numerous evidence has suggested that either hypertension or atrial fibrillation (AF) is associated with systemic inflammation. Peroxisome proliferator-activated receptor-gamma (PPARgamma) has been proved to have anti-inflammatory effects and is implicated as a molecular pathway involved in many cardiovascular diseases, such as hypertension. The correlation between PPARgamma inflammation and AF is still unknown. METHODS: Using a case-control study design, 57 patients with hypertensive AF (persistent AF: 32, paroxysmal AF: 25) were included into the study groups. A total of 32 age-matched patients with hypertension, but without AF were selected as the control group. The expressions of PPARgamma, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) mRNA in monocytes were detected by using a reverse transcription-polymerase chain reaction (RT-PCR). Interleukin-1 (IL-1) was measured by immunoenzymetric methods. RESULTS: The PPARgamma mRNA was markedly decreased in the hypertensive AF group as compared with the hypertensive non-AF group, and it was significantly lower in persistent AF than paroxysmal AF (0.222 +/- 0.0702 vs 0.564 +/- 0.0436, P<0.01). TNF-alpha mRNA, IL-6 mRNA, and IL-1 were increased in patients with hypertensive AF compared to the non-AF group and it was even higher in persistent AF than in paroxysmal AF (0.721 +/- 0.0541 vs 0.530 +/- 0.0496, 0.567 +/- 0.044 vs 0.457 +/- 0.0505, 325.61 +/- 88.10 vs 190.65 +/- 59.38, respectively, P<0.01). TNF-alpha, IL-6, and IL-1 were in negative correlation with PPARgamma, the correlation coefficient was -0.854, -0.769, and -0.702, respectively (P<0.01). CONCLUSIONS: In hypertensive patients, increased inflammatory cytokines were associated with increased incidence of AF and atrial remodeling; PPARgamma may be involved in the pathogenesis of AF by regulation of inflammation.