Genome-wide detections for runs of homozygosity and selective signatures reveal novel candidate genes under domestication in chickens.

BACKGROUND: Indigenous chickens were developed through a combination of natural and artificial selection; essentially, changes in genomes led to the formation of these modern breeds via admixture events. However, their confusing genetic backgrounds include a genomic footprint regulating complex traits, which is not conducive to modern animal breeding. RESULTS: To better evaluate the candidate regions under domestication in indigenous chickens, we considered both runs of homozygosity (ROHs) and selective signatures in 13 indigenous chickens. The genomes of Silkie feather chickens presented the highest heterozygosity, whereas the highest inbreeding status and ROH number were found in Luhua chickens. Short ROH (< 1 Mb), were the principal type in all chickens. A total of 291 ROH islands were detected, and QTLdb mapping results indicated that body weight and carcass traits were the most important traits. An ROH on chromosome 2 covering VSTM2A gene was detected in 12 populations. Combined analysis with the Tajima's D index revealed that 18 genes (e.g., VSTM2A, BBOX1, and RYR2) were under selection and covered by ROH islands. Transcriptional analysis results showed that RYR2 and BBOX1 were specifically expressed in the heart and muscle tissue, respectively. CONCLUSION: Based on genome-wide scanning for ROH and selective signatures, we evaluated the genomic characteristics and detected significant candidate genes covered by ROH islands and selective signatures. The findings in this study facilitated the understanding of genetic diversity and provided valuable insights for chicken breeding and conservation strategies.

GPS2 ameliorates cigarette smoking-induced pulmonary vascular remodeling by modulating the ras-Raf-ERK axis.

BACKGROUND: Mitogen-activated protein kinase (MAPK)signaling-mediated smoking-associated pulmonary vascular remodeling (PVR) plays an important role in the pathogenesis of group 3 pulmonary hypertension (PH). And G protein pathway suppressor 2 (GPS2) could suppress G-protein signaling such as Ras and MAPK, but its role in cigarette smoking -induced PVR (CS-PVR) is unclear. METHODS: An in vivo model of smoke-exposed rats was constructed to assess the role of GPS2 in smoking-induced PH and PVR. In vitro, the effects of GPS2 overexpression and silencing on the function of human pulmonary arterial smooth cells (HPASMCs) and the underlying mechanisms were explored. RESULTS: GPS2 expression was downregulated in rat pulmonary arteries (PAs) and HPASMCs after CS exposure. More importantly, CS-exposed rats with GPS2 overexpression had lower right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), and wall thickness (WT%) than those without. And enhanced proliferation and migration of HPASMCs induced by cigarette smoking extract (CSE) can be evidently inhibited by overexpressed GPS2. Besides, GPS2siRNA significantly enhanced the proliferation, and migration of HPASMCs as well as activated Ras and Raf/ERK signaling, while these effects were inhibited by zoledronic acid (ZOL). In addition, GPS2 promoter methylation level in rat PAs and HPASMCs was increased after CS exposure, and 5-aza-2-deoxycytidine (5-aza) inhibited CSE-induced GPS2 hypermethylation and downregulation in vitro. CONCLUSIONS: GPS2 overexpression could improve the CS-PVR, suggesting that GPS2 might serve as a novel therapeutic target for PH-COPD in the future.

Chronic diesel exhaust exposure induced pulmonary vascular remodeling a potential trajectory for traffic related pulmonary hypertension.

BACKGROUND: As one of the most common traffic-related pollutants, diesel exhaust (DE) confers high risk for cardiovascular and respiratory diseases. However, its impact on pulmonary vessels is still unclear. METHODS: To explore the effects of DE exposure on pulmonary vascular remodeling, our study analyzed the number and volume of small pulmonary vessels in the diesel engine testers (the DET group) from Luoyang Diesel Engine Factory and the controls (the non-DET group) from the local water company, using spirometry and carbon content in airway macrophage (CCAM) in sputum. And then we constructed a rat model of chronic DE exposure, in which 12 rats were divided into the DE group (6 rats with 16-week DE exposure) and the control group (6 rats with 16-week clean air exposure). During right heart catheterization, right ventricular systolic pressure (RVSP) was assessed by manometry. Macrophage migration inhibitory factor (MIF) in lung tissues and bronchoalveolar lavage fluid (BALF) were measured by qRT-PCR and ELISA, respectively. Histopathological analysis for cardiovascular remodeling was also performed. RESULTS: In DET cohort, the number and volume of small pulmonary vessels in CT were positively correlated with CCAM in sputum (P<0.05). Rat model revealed that chronic DE-exposed rats had elevated RVSP, along with increased wall thickness of pulmonary small vessels and right the ventricle. What's more, the MIF levels in BALF and lung tissues were higher in DE-exposed rats than the controls. CONCLUSION: Apart from airway remodeling, DE also induces pulmonary vascular remodeling, which will lead to cardiopulmonary dysfunction.

Association between the Reduced Expression of RECK and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a recently discovered inhibitor of matrix metalloproteinase (MMP). There is a large number of chronic obstructive pulmonary disease (COPD) patients worldwide; however, the role of RECK on COPD has not been studied. This study explored the expression of RECK in COPD patients and its effect on neutrophil function to provide a new scientific basis for the prevention and treatment of COPD. METHOD: Fifty patients with acute exacerbation of COPD and fifty healthy controls were enrolled in the study. RECK was detected in lung tissue, sputum, and plasma of subjects as well as in BEAS-2B cells stimulated with cigarette smoke extract (CSE) by immunohistochemistry, ELISA, and qRT-PCR. Meanwhile, lung function (FEV1%pred) and inflammatory cytokines (IL-6 and IL-8) were examined, and correlation analysis was performed with RECK expression. The effect of RECK on proliferation, apoptosis, migration, and inflammatory cytokines and its potential mechanism was further quantified by neutrophil stimulated with recombinant human RECK protein (rhRECK) combined with CSE using CCK8, flow cytometry, Transwell assay, qRT-PCR, ELISA, and Western analysis. RESULTS: RECK was mainly expressed on airway epithelial cells in normal lung tissue and was significantly diminished in COPD patients. The levels of RECK in sputum and plasma were also significantly decreased in COPD patients. Pearson correlation analysis showed that RECK level in plasma was positively correlated with FEV1%pred (r = 0.458, p < 0.001) and negatively correlated with IL-6 and IL-8 (r = -0.386, -0.437; p = 0.006, 0.002) in COPD patients. The expression of RECK was decreased in BEAS-2B stimulated with CSE. The migration, inflammation, and MMP-9 expression of neutrophils were promoted by CSE, while inhibited by rhRECK. CONCLUSION: RECK is low expressed in COPD patients and negatively correlated with inflammation. It may inhibit the inflammation and migration of neutrophils by downregulating MMP-9.

Characterization of an imported HIV-1 A1/A7/G recombinant in China.

BACKGROUND: International migration has accelerated the HIV-1 spread across national borders, gradually reducing the restrictions on the geographical distribution of HIV-1 subtypes. Subtypes A and G are globally recognized as the third and sixth most dominant HIV-1 genotypes, mainly prevalent in Africa, but rarely detected in China. Here we reported an imported HIV-1 recombinant which was composed of sub-subtypes A1 and A7 of subtype A and subtype G genes in a Chinese female. This virus was the first HIV-1 recombinant including A7 genes reported in the world. CASE PRESENTATION: The near full-length genome (NFLG) was obtained from the plasma sample of the female in an HIV-1 molecular epidemiological survey with 853 participants in China. Phylogenetic analyses showed that this NFLG sequence contains three A7 segments, four G segments and one A1 segment with seven breakpoints, and all these segments were closely related to HIV-1 references circulating in Africa. The evidence from epidemiological investigation indicated that this female participant had a more-than-two-years heterosexual contact history with a fixed partner from Nigeria, a country in west Africa, which further supported the results of phylogenetic analyses. By the Bayesian phylogenetic analyses, the times of most recent common ancestors (tMRCA) of the partial pol gene (nt2308-3284, A7 region) and full-length vpr-vpu plus partial env gene (nt5534-6858, G region) were estimated around 1989 and 1984, respectively. CONCLUSIONS: In this study, by using the NFLG sequencing, we identified an imported HIV-1 A1/A7/G recombinant which was estimated to originate around 1980s in Africa and introduced into China with international migration. This study highlighted the complexity of the global HIV-1 epidemic, the necessity of using genome sequences to determine HIV-1 genotypes and the importance of real-time monitoring of HIV-1 infection among international migrants and travelers.

A Retrospective Study on the Clinical Characteristics and Computed Tomography, Biochemical, and Blood Parameters of Duodenal Papillary Diseases.

OBJECTIVE: This study was conducted to investigate the imaging information, laboratory data, and clinical characteristics of duodenal papillary malignancies, aiming to contribute to the early diagnosis of these diseases. METHODS: The clinical characteristics, laboratory data, and computed tomography (CT) findings of 17 patients with adenoma of the major duodenal papilla (the adenoma group) and 58 patients with cancer of the major duodenal papilla (the cancer group) were retrospectively analyzed. The measurement data were analyzed using t test and expressed as mean ± standard deviation. The counting data were analyzed using the χ2 test and expressed in n (%). Pearson correlation analysis was also conducted, and a scatter plot was drawn. RESULTS: There were significant differences in the diameter, shape, margin, and target sign of the major duodenal papilla, pancreatic duct diameter, common bile duct diameter, enhancement uniformity, fever, direct bilirubin, total bilirubin, carcinoembryonic antigen, carbohydrate antigen 19-9, and jaundice between the adenoma group and the cancer group (P < .01). The enhancement magnitude of the duodenal papilla was correlated with the lesion size, and the venous phase CT value of the enhanced scan was correlated with the duodenal papilla diameter (P < .05). Additionally, 12 patients in the cancer group suffered from malignant transformation of adenomas. CONCLUSION: Firstly, CT is of high value in the diagnosis of duodenal papilla diseases. Secondly, the enhancement magnitude of the duodenal papilla is correlated with the lesion size. Thirdly, patients with duodenal papilla adenomas have a risk of progression into adenocarcinoma, thereby requiring close follow-up.

NIS-Promoted Chemodivergent and Diastereoselective Synthesis of Pyrrolinyl and Cyclopentenyl Spiropyrazolones via Regulated Cyclization of Alkylidene Pyrazolones with Enamino Esters.

An N-iodosuccinimide-promoted annulation of alkylidene pyrazolones with enamino esters has been explored to construct a spiropyrazolone moiety through a Michael addition/iodination/intramolecular nucleophilic substitution sequence. When the reaction was performed in acetonitrile at 100 °C, it furnished pyrrolinyl spiropyrazolones exclusively in an anti configuration through N-attacking cyclization. When the reaction was performed in dimethyl sulfoxide at 80 °C in the presence of K2HPO4, it afforded cyclopentenyl spiropyrazolones exclusively in the syn configuration through C-attacking cyclization. A plausible mechanism has also been proposed.

Switchable Synthesis of Spirodihydroindolizines and Indolizines from Aurones and Pyridin-2-yl Active Methylene Compounds.

A novel and flexible domino reaction of aurones with pyridin-2-yl active methylene compounds promoted by I2/BF3 has been developed to afford spirodihydroindolizines and indolizines in a controllable manner. When the reaction was performed in 1,2-dichloroethane at 80 °C, a variety of spirodihydroindolizines were obtained, whereas it almost exclusively provided a series of indolizines when the reaction was performed in a mixed solvent of 1,2-dichloroethane and N,N-dimethylformamide at a relatively higher temperature of 100 °C. Being metal-free, excellent product selectivity, high atom economy, good functional group tolerance, and feasibility for large-scale synthesis are the salient features of the developed methodology.

Cannabidiol Inhibits Epithelial Ovarian Cancer: Role of Gut Microbiome.

Epithelial ovarian cancer is among the deadliest gynecological tumors worldwide. Clinical treatment usually consists of surgery and adjuvant chemo- and radiotherapies. Due to the high rate of recurrence and rapid development of drug resistance, the current focus of research is on finding effective natural products with minimal toxic side effects for treating epithelial ovarian tumors. Cannabidiol is among the most abundant cannabinoids and has a non-psychoactive effect compared to tetrahydrocannabinol, which is a key advantage for clinical application. Studies have shown that cannabidiol has antiproliferative, pro-apoptotic, cytotoxic, antiangiogenic, anti-inflammatory, and immunomodulatory properties. However, its therapeutic value for epithelial ovarian tumors remains unclear. This study aims to investigate the effects of cannabidiol on epithelial ovarian tumors and to elucidate the underlying mechanisms. The results showed that cannabidiol has a significant inhibitory effect on epithelial ovarian tumors. In vivo experiments demonstrated that cannabidiol could inhibit tumor growth by modulating the intestinal microbiome and increasing the abundance of beneficial bacteria. Western blot assays showed that cannabidiol bound to EGFR/AKT/MMPs proteins and suppressed EGFR/AKT/MMPs expression in a dose-dependent manner. Network pharmacology and molecular docking results suggested that cannabidiol could affect the EGFR/AKT/MMPs signaling pathway.

Prognostic and predictive value of examined lymph node count in stage III colorectal cancer: a population based study.

BACKGROUND: The role of tumor-draining lymph nodes in the progression of malignant tumors, including stage III colorectal cancer (CRC), is critical. However, the prognostic and predictive value of the number of examined lymph nodes (ELNs) are not fully understood. METHODS: This population-based study retrospectively analyzed data from 106,843 patients with stage III CRC who underwent surgical treatment and registered in three databases from 2004 to 2021. The Surveillance, Epidemiology, and End Results (SEER) cohort was divided using into training and test cohorts at a ratio of 3:2. We employed restricted cubic spline (RCS) curves to explore nonlinear relationships between overall survival (OS) and ELNs counts and performed Cox regression to evaluate hazard ratios across different ELNs count subtypes. Additional validation cohorts were utilized from the First Affiliated Hospital, Sun Yat-sen University and The Cancer Genome Atlas (TCGA) under the same criteria. Outcomes measured included OS, cancer-specific survival (CSS), and progression-free survival (PFS). Molecular analyses involved differential gene expression using the "limma" package and immune profiling through CIBERSORT. Tissue microarray slides and multiplex immunofluorescence (MIF) were used to assess protein expression and immune cell infiltration. RESULTS: Patients with higher ELNs counts (≥ 17) demonstrated significantly better long-term survival outcomes across all cohorts. Enhanced OS, CSS, and PFS were notably evident in the LN-ELN group compared to those with fewer ELNs. Cox regression models underscored the prognostic value of higher ELNs counts across different patient subgroups by age, sex, tumor differentiation, and TNM stages. Subtype analysis based on ELNs count revealed a marked survival benefit in patients treated with adjuvant chemotherapy in the medium and large ELNs counts (≥ 12), whereas those with fewer ELNs showed negligible benefits. RNA sequencing and MIF indicated elevated immune activation in the LN-ELN group, characterized by increased CD3+, CD4+, and CD8 + T cells within the tumor microenvironment. CONCLUSIONS: The number of ELNs independently predicts survival and the immunological landscape at the tumor site in stage III CRC, underscoring its dual prognostic and predictive value.

A WKNN Indoor Fingerprint Localization Technique Based on Improved Discrimination Capability of RSS Similarity.

There are various indoor fingerprint localization techniques utilizing the similarity of received signal strength (RSS) to discriminate the similarity of positions. However, due to the varied states of different wireless access points (APs), each AP's contribution to RSS similarity varies, which affects the accuracy of localization. In our study, we analyzed several critical causes that affect APs' contribution, including APs' health states and APs' positions. Inspired by these insights, for a large-scale indoor space with ubiquitous APs, a threshold was set for all sample RSS to eliminate the abnormal APs dynamically, a correction quantity for each RSS was provided by the distance between the AP and the sample position to emphasize closer APs, and a priority weight was designed by RSS differences (RSSD) to further optimize the capability of fingerprint distances (FDs, the Euclidean distance of RSS) to discriminate physical distance (PDs, the Euclidean distance of positions). Integrating the above policies for the classical WKNN algorithm, a new indoor fingerprint localization technique is redefined, referred to as FDs' discrimination capability improvement WKNN (FDDC-WKNN). Our simulation results showed that the correlation and consistency between FDs and PDs are well improved, with the strong correlation increasing from 0 to 76% and the high consistency increasing from 26% to 99%, which confirms that the proposed policies can greatly enhance the discrimination capabilities of RSS similarity. We also found that abnormal APs can cause significant impact on FDs discrimination capability. Further, by implementing the FDDC-WKNN algorithm in experiments, we obtained the optimal K value in both the simulation scene and real library scene, under which the mean errors have been reduced from 2.2732 m to 1.2290 m and from 4.0489 m to 2.4320 m, respectively. In addition, compared to not using the FDDC-WKNN, the cumulative distribution function (CDF) of the localization errors curve converged faster and the error fluctuation was smaller, which demonstrates the FDDC-WKNN having stronger robustness and more stable localization performance.

Aerobic CuBr2-Catalyzed Oxidative Coupling Reaction of Amidines with Exocyclic α,ß-Unsaturated Cycloketones for the Synthesis of Spiroimidazolines.

A CuBr2-catalyzed cascade reaction of amidines with exocyclic α,ß-unsaturated cycloketones was developed, affording a large variety of spiroimidazolines in moderate to excellent yields. The reaction process involved the Michael addition and copper(II)-catalyzed aerobic oxidative coupling, in which O2 from air acted as the oxidant and H2O was the sole byproduct.

The preventive and therapeutic effects of AAV1-KLF4-shRNA in cigarette smoke-induced pulmonary hypertension.

We found previously that KLF4 expression was up-regulated in cultured rat and human pulmonary artery smooth muscle cells (PASMCs) exposed to cigarette smoke (CS) extract and in pulmonary artery from rats with pulmonary hypertension induced by CS. Here, we aim to investigate whether CS-induced pulmonary hypertension (PH) is prevented and ameliorated by targeted pulmonary vascular gene knockdown of KLF4 via adeno-associated virus 1 (AAV1)-KLF4-shRNA in vivo in rat model. The preventive and therapeutic effects were observed according to the different time-point of AAV1-KLF4-shRNA intratracheal administration. We tested haemodynamic measurements of systemic and pulmonary circulations and observed the degree of pulmonary vascular remodelling. In the preventive experiment, KLF4 expression and some pulmonary circulation hemodynamic measurements such as right ventricular systolic pressure (RVSP), mean right ventricular pressure (mRVP), peak RV pressure rate of rise (dP/dt max) and right ventricle (RV) contractility index were increased significantly in the CS-induced PH model. While in the prevention group (AAV1-KLF4-shRNA group), RVSP, mRVP, dP/dt max and RV contractility index which are associated with systolic function of right ventricle decreased and the degree of pulmonary vascular remodelling relieved. In the therapeutic experiment, we observed a similar trend. Our findings emphasize the feasibility of sustained pulmonary vascular KLF4 gene knockdown using intratracheal delivery of AAV1 in an animal model of cigarette smoke-induced PH and determined gene transfer of KLF4-shRNA could prevent and ameliorate the progression of PH.

Tanshinone IIA inhibits the adipogenesis and inflammatory response in ox-LDL-challenged human monocyte-derived macrophages via regulating miR-130b/WNT5A.

Atherosclerosis is a kind of chronic cardiovascular disease, characterized by oxidized low-density lipoprotein (ox-LDL) accumulation in macrophage. Tanshinone IIA (Tan), a lipophilic pharmacologically activate compound from Salvia miltiorrhiza Bunge, has been indicated to exert cardioprotective roles. Nevertheless, the biological role of Tan and regulatory mechanism in atherosclerosis are not fully established. In present study, atherosclerosis model was established in THP-1-derived macrophages by treatment of ox-LDL. The adipogenesis was measured by Nile red staining. The expressions of inflammatory factors, microRNA-130b (miR-130b) and WNT5A were measured by quantitative real-time polymerase chain reaction or Western blot. The target association between miR-130b and WNT5A was explored via luciferase activity and RNA immunoprecipitation assay. The results showed that exposure of Tan inhibited ox-LDL-induced adipogenesis and expressions of interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-alpha in THP-1-derived macrophages. miR-130b expression was decreased in THP-1-derived macrophages treated by ox-LDL and its overexpression attenuated adipogenesis as well as inflammatory response. miR-130b knockdown reversed the regulatory effect of Tan on adipogenesis and inflammatory response in THP-1-derived macrophages stimulated by ox-LDL. In addition, WNT5A acted as a functional target of miR-130b and inhibited by Tan and miR-130b. As a conclusion, Tan decreased the adipogenesis and inflammatory response by mediating miR-130b and WNT5A, providing a novel theoretical foundation for treatment of atherosclerosis.

Inhibition of miR-181b-5p protects cardiomyocytes against ischemia/reperfusion injury by targeting AKT3 and PI3KR3.

Ischemic heart disease (IHD) is the most occurring cardiovascular-associated disease, which is a primary leading cause of cardiac disability and death worldwide. Myocardial ischemia/reperfusion injury (MI/RI) has been linked to IHD-induced cardiomyocytes apoptosis and tissue damage. The clinical studies have indicated that pathophysiologic mechanisms of MI/RI are associated with reactive oxygen species generation, calcium overload, energy metabolism disorder, neutrophil infiltration, and others. However, the genetic mechanism of MI/RI remains unclear. In this study, we successfully established the reproducing abnormal heart observed in rat, of IHD-induced MI/RI post operation. By using these rats, we illustrated that expression of miR-181b-5p was increased not only in both hypoxia/reoxygenation-cultured H9C2 but also heart of myocardial ischemia/reperfusion (MI/R) rat. Suppression of the miR-181b-5p cardiomyocytes apoptosis and rescued myocardial infarction. Additionally, our data indicated that miR-181b-5p negatively regulates the expression of AKT3 and PIK3R3 through directly binding with its 3'-untranslated region. More importantly, suppression of miR-181b-5p protects the cardiomyocytes apoptosis and tissue damage from MI/R via regulation of PIK3R3 and AKT3. Hence, our study indicates that miR-181b-5p is essential for MI/RI via regulation of PI3K/Akt signaling pathway and could be a potential therapeutic target in IHD.

Association of Modified-FOLFIRINOX-Regimen-Based Neoadjuvant Therapy with Outcomes of Locally Advanced Pancreatic Cancer in Chinese Population.

LESSONS LEARNED: Modification of FOLFIRINOX significantly improves safety and tolerability in Chinese patients with locally advanced pancreatic cancer.Patients with locally advanced pancreatic cancer benefit from neoadjuvant therapy and experience a much better survival than patients with upfront surgery. BACKGROUND: The objective of this study was to evaluate the efficacy of modified-FOLFIRINOX (mFOLFIRINOX) regimens in Chinese patients with locally advanced pancreatic cancer (LAPC) and to compare outcomes between patients with LAPC treated with mFOLFIRINOX-based neoadjuvant therapy (LAPC-N) and patients with LAPC who underwent upfront surgery (LAPC-S). METHODS: Forty-one patients with LAPC-N were enrolled prospectively. Imaging features, chemotherapy response, adverse events, perioperative complications, histology, and survival were analyzed. Seventy-four patients with resectable pancreatic cancer (RPC) (from April 2012 to November 2017) and 19 patients with LAPC-S (from April 2012 to March 2014) were set as observational cohorts, and data were collected retrospectively. LAPC-N patients with adequate response underwent surgical treatment, whereas continuous chemotherapy was given to LAPC-N patients who were not deemed resectable after treatment, and the response was re-evaluated every 2 months. RESULTS: Forty-one patients with LAPC received mFOLFIRINOX with a response rate of 37.1%. The most common severe adverse events were neutropenia and anemia. mFOLFIRINOX-based neoadjuvant therapy contributed to a remarkable decrease in CA19-9 level and tumor diameter. Fourteen LAPC-N patients underwent surgery (LAPC-N-S) after downstaging. Compared with LAPC-N-S cases, LAPC-S patients had longer operative time, more blood loss, and a higher risk of grade 5 complications. The median overall survival (OS) and progression-free survival (PFS) of LAPC-N-S patients were 27.7 months and 19.3 months, respectively, which were similar to those of patients with RPC (30.0 months and 23.0 months) and much longer than those of patients with LAPC-S (8.9 months and 7.6 months), respectively. CONCLUSION: Neoadjuvant chemotherapy such as the mFOLFIRINOX regimen can be recommended for Chinese patients with LAPC after dose modification. Patients with LAPC-N who underwent surgery obtained significantly improved survival compared with patients in the observational LAPC-S cohort, who did not undergo neoadjuvant therapy.

Role of RASEF hypermethylation in cigarette smoke-induced pulmonary arterial smooth muscle remodeling.

BACKGROUND: Pulmonary hypertension (PH) is a progressive and fatal disease. While cigarette smoke can change DNA methylation status, the role of such molecular alterations in smoke-associated PH is unclear. METHODS: A PH rat model was developed by exposing animals to cigarette smoke for 3 months. Right ventricular systolic pressure was measured with a right heart catheter. Histological changes (right ventricular hypertrophy index, medial wall thickness in pulmonary arteries (PAs)) and DNMT1 protein levels in rat PAs or primary human PA smooth muscle cells (HPASMCs) exposed to cigarette smoke extract were assessed. Methylation sequencing and MassArray® were used to detect genomic and RASEF promoter methylation status, respectively. After DNMT1 knockdown and cigarette smoke extract exposure, HPASMCs behavior (proliferation, migration) and RASEF methylation status were examined; RASEF mRNA expression was evaluated by real-time-polymerase chain reaction. RASEF overexpression viral vectors were used to assess the impact of RASEF on rat PH and HPASMCs remodeling. RESULTS: Higher right ventricular systolic pressure, medial wall thickness, and right ventricular hypertrophy index values were observed in the smoking group rats. Smoke exposure increased DNMT1 expression and RASEF methylation levels in rat PAs and HPASMCs. Cigarette smoke extract induced HPASMCs behavioral changes and RASEF hypermethylation followed by silencing, while DNMT1 knockdown markedly inhibited these changes. RASEF overexpression distinctly inhibited PH and HPASMCs remodeling, possibly through phospho-AKT (Ser473), PCNA, and MMP9 downregulation. CONCLUSIONS: Cigarette smoke caused PA remodeling in PH rats related to RASEF hypermethylation. These results expand our understanding of key epigenetic mechanisms in cigarette smoke-associated PH and potentially provide a novel therapeutic target for PH.

Role of C/EBPα hypermethylation in diesel engine exhaust exposure-induced lung inflammation.

Exposure to diesel engine exhaust (DEE) impairs lung function. But the underlying mechanisms are still not fully understood. The aim of this study was to investigate the effects of long-term DEE exposure on lung inflammation and the underlying mechanisms. Sprague-Dawley male rats were exposed to DEE with 3 mg/m3 of diesel exhaust particles (DEP) for 12 weeks. Then urine, blood, bronchoalveolar lavage fluid (BALF), and lung tissue were collected for the determination of biochemistry indexes, DNA methylation status, and histological changes in the lung. The results showed that the metabolites of polycyclic aromatic hydrocarbons (PAHs) 2-hydroxyphenanthrene (2-OHPh) and 9-OHPh, and 8-hydroxy-2'-deoxyguanosine (8-OHdG), and malondialdehyde (MDA) level were higher in urine of DEE-exposed rats than control group. The level of proinflammatory cytokines IL-8, IL-6, and TNF-α was significantly higher in serum (1.8, 3.5, and nearly 1.0-fold increase, respectively), BALF (2.2, 3.8, and 2.0-fold increase, respectively) and lung tissues (3.5, 4.3, and 2.4-fold increase, respectively) of DEE-exposed rats than control group. While the level of clara cell secretory protein (CC16) and pulmonary surfactant protein D (SP-D) with anti-inflammatory property was obviously lower in serum (reduction of 29% and 38%, respectively), BALF (reduction of 50% and 46%, respectively) and lung tissues (reduction of 50% and 55%, respectively) of DEE-exposed rats than control group. Exposure to DEE also resulted in significant increases in total white blood cell (WBC), neutrophil, eosinophil, and lymphocyte number in BALF. Airway inflammation and remolding were apparent in DEE group. The methylation level of CCAAT/enhancer-binding protein alpha (C/EBPα) promoter was markedly increased (about 3.2-fold increase), and its mRNA and protein expression were significantly decreased (about 62% and 68% decrease, respectively) in the lungs of DEE-exposed rats compared with the group. Further, cell experiments were performed to investigate the relationship between C/EBPα and CC16, and CC16 function under DEP conditions. The results showed that DEP inhibited CC16 expression via methylation of C/EBPα promoter, and the increase of CC16 level significantly relieved the proinflammatory effects caused by DEP exposure. In conclusion, our data indicated that long-term exposure to DEE can cause lung inflammation, at least in part via methylation of C/EBPα promoter, and inhibition of CC16 expression.

Measuring abnormal intrinsic brain activities in patients with retinal detachment using amplitude of low-frequency fluctuation: a resting-state fMRI study.

OBJECTIVE: The targets of this study were to access the alternations of spontaneous brain activity in RD patients by amplitude of low-frequency fluctuation (ALFF) method and to explore their relationships with clinical behavioral performance. METHODS: A total of 20 patients with RD (6 males and 14 females), and 20 healthy controls (HCs) (6 males and 14 females) were recruited, and were matched in sex and age. All participants finished the functional magnetic resonance imaging (fMRI) scanning. We applied the ALFF method to detect the spontaneous brain activity. Receiver operating characteristic (ROC) curve was applied to distinguish RD Patients from HCs. RESULTS: RD patients showed decreased ALFF values in the right occipital lobe and right medial frontal gyrus and increased ALFF values in the right frontal superior orbital and left inferior temporal gyrus when compared with HCs. In RD patients, we did not find any relationship between the mean ALFF values and the clinical behavioral performances. CONCLUSION: The RD patients exhibited abnormal spontaneous brain activity in vision and vision related brain regions, which might explore potential pathological mechanism of acute vision loss in RD patients.

Experimental investigation of nitric oxide removal from flue gas using hexamminecobalt(II) solution scrubbing in a pilot-scale facility.

An experimental investigation of operational parameters, including liquid/gas ratio (L/G), inlet nitric oxide (NO) concentration, reaction temperature, and pH value of absorbing agent, on NO removal efficiency with hexamminecobalt(II) solution scrubbing was conducted on a pilot-scale facility to search optimal operation conditions. The experimental results show that NO removal efficiency increased with the pH value of hexamminecobalt solution, while the improving rate dropped gradually. When the reaction temperature increased, the NO removal efficiency increased first and then decreased. At the same time, NO removal efficiency increased with the increasing of L/G and hexamminecobalt concentration, while the removal efficiency did not change much at low NO concentration. The pH of 10.4 and L/G of 16 L/m3 were close to the optimal operation conditions, and the scrubbing temperature fell within a reasonable operation temperature. The experimental results can be used as a reference for the design and operation of scaled-up industrial devices.