Association between nocturnal blood pressure phenotype and adverse cardiovascular prognosis in patients with coronary heart disease and hypertension.

Nocturnal blood pressure and nighttime dipping patterns are associated with the occurrence of cardiovascular events. However, there is few research on whether riser pattern is associated with the poor prognosis of patients with coronary heart disease (CHD) and hypertension independent of nighttime systolic blood pressure (SBP). This prospective and observational clinical study included 568 hospitalized patients with CHD and hypertension. All patients underwent 24-h ambulatory blood pressure (BP) monitoring during their hospitalization. Multivariate adjusted Cox proportional hazard models were utilized to examine the associations of nocturnal blood pressure and dipping status with primary endpoint events. Additionally, Harrell's C-statistics were employed to compare the discriminative ability of each model. During the 1-year follow-up period, 64 (11.3%) primary endpoint events were recorded, including 55 (9.7%) atherosclerotic cardiovascular disease (ASCVD) events. After adjusting for demographic and clinical risk variables, nighttime SBP was significantly related to the risk of incident primary endpoint events [per 20 mm Hg increase: hazard ratio (HR) = 1.775, 95% confidence interval (CI) 1.256-2.507]. The riser pattern group exhibited a significantly higher risk for primary endpoint events compared to the dipper pattern group, even after adjusting for office SBP (HR: 2.687, 95% CI: 1.015-7.110, p = .047). Furthermore, the addition of nighttime SBP or dipping status to the base model yielded statistically significant increments in C-statistic values (p = .036 and p = .007). However, adding both nighttime SBP and dipping status did not significantly enhance the model's performance in predicting the risk of primary endpoint events and ASCVD events according to the C-index (p = .053 and p = .054), which meant that the riser pattern group did not exhibit a significantly higher risk for primary endpoint events compared to the dipper pattern group after adjusting for nighttime SBP. In conclusion, nocturnal SBP and riser pattern demonstrated an association with adverse prognosis in patients with CHD and hypertension. Notably, nocturnal SBP proved to be a more reliable predictor than dipping status.

Association between apolipoprotein B/A1 ratio and quantities of tissue prolapse on optical coherence tomography examination in patients with atherosclerotic cardiovascular disease.

Atherosclerotic cardiovascular disease (ASCVD) continues to be a major health concern globally. Apolipoprotein (Apo) B/A1 ratio is a reliable predictor of ASCVD and an important factor in assessing the risk of myocardial infarction. Tissue prolapse (TP) is defined as the tissue extrusion into the lumen through the stent struts after implantation, which is a significant factor for poor short-term outcomes such as acute and subacute thrombosis, severe myocardial necrosis, and vulnerable plaque. Therefore, the aim of this study was to investigate the relationship between Apo B/A1, plaque vulnerability, and tissue prolapse on optical coherence tomography (OCT). This study enrolled 199 patients with atherosclerotic cardiovascular disease (ASCVD) who underwent percutaneous coronary intervention (PCI). Both pre- and post-procedural optical coherence tomography (OCT) examinations were conducted to assess TP volume and plaque morphology. Logistic regression analyses were performed to identify potential risk factors for tissue prolapse volume. Receiver operator characteristic (ROC) curve analysis was carried out to evaluate the value of the Apo B/A1 ratio for tissue prolapse volume. The high Apo B/A1 ratio group showed a larger TP volume (P = 0.001) and a higher percentage of plaque rupture and erosion in comparison to the low Apo B/A1 ratio group (P = 0.022 and P = 0.008). The high Apo B/A1 ratio group and the high TP volume group also had a higher proportion of thin-cap fibroatheroma (TCFA) (P = 0.046, P = 0.021). Multivariate logistic regression analysis revealed that both Apo B/A1 ratio (odds ratio [OR]: 1.041, 95% confidence interval [CI] 1.007-1.076; P = 0.019) and TCFA (OR: 3.199, 95%CI 1.133-9.031; 0.028) were significantly related to high TP volume. Furthermore, the area under the curve (AUC) for predictive value of TP volume was 0.635 for Apo B/A1 (95% CI 0.554-0.717, P = 0.002) compared to 0.615 for low density lipoprotein cholesterol (LDL-C) (95% CI 0.533-0.697, P = 0.008). The Apo B/A1 ratio is an independent predictor of TP volume on OCT and is related to plaque vulnerability.

The pan-cancer multi-omics landscape of key genes of sialylation combined with RNA-sequencing validation.

BACKGROUND: Sialylation, the process of salivary acid glycan synthesis, plays a pivotal function in tumor growth, immune escape, tumor metastasis, and resistance to drugs. However, the association between sialylation and prognosis, tumor microenvironment (TME), and treatment response in a variety of cancers remains unclear. METHODS: A comprehensive survey of the expression profile, prognostic value, and genetic and epigenetic alterations of sialylation-related genes was performed in pan-cancer. Subsequently, the single-sample gene set enrichment analysis (ssGSEA) algorithm was used to compute sialylation pathway scores in pan-cancer. Correlations of sialylation pathway scores with clinical features, prognosis, and TME were evaluated using multiple algorithms. Finally, the efficacy of the sialylation pathway score in determining the effect of immunotherapy was evaluated. The expression of sialylation-related genes were verified by RNA-sequencing. RESULTS: Significant differences were observed in sialylation-related genes expression between tumors and adjacent normal tissues for most cancer types. Sialylation pathway scores differed according to the type of tumor, where the poor prognosis was correlated with high sialylation pathway scores in uveal melanoma (UVM) and pancreatic adenocarcinoma (PAAD). In addition, sialylation pathway scores were positively associated with the ImmuneScore, StromalScore and immune-related pathways. Moreover, the level of immune cells infiltration was higher in tumors with higher sialylation pathway scores. Finally, patients with high sialylation pathway scores were more sensitive to immunotherapy. CONCLUSION: Sialylation-related genes are essential in pan-cancer. The sialylation pathway score may be used as a biomarker in oncology patients.

MitoQ ameliorates PM2.5-induced pulmonary fibrosis through regulating the mitochondria DNA homeostasis.

Pulmonary fibrosis is a severe pulmonary disease, and may related to PM2.5 exposure. Our study aims to explore the pathogenesis of PM2.5-induced pulmonary fibrosis, and MitoQ protective effect in this process. Our results find that inflammatory cells aggregation and pulmonary fibrosis in mice lung after PM2.5 exposure. Moreover, Collagen I/III overproduction, EMT and TGF-ß1/Smad2 pathway activation in mice lung and BEAS-2B after PM2.5 exposure. Fortunately, these changes were partially ameliorated after MitoQ treatment. Meanwhile, severe oxidative stress, mitochondrial homeostasis imbalance, overproduction of 8-oxoG (7,8-dihydro-8-oxoguanine), as well as the inhibition of SIRT3/OGG1 pathway have founded in mice lung or BEAS-2B after PM2.5 exposure, which were alleviated by MitoQ treatment. Collectively, our study found that oxidative stress, especially mitochondrial oxidative stress participates in the PM2.5-induced pulmonary fibrosis, and MitoQ intervention had a protective effect on this progress. Moreover, mitochondrial DNA homeostasis might participate in the pulmonary fibrosis caused by PM2.5 exposure. Our study provides a novel pathogenesis of PM2.5-caused pulmonary fibrosis and a possible targeted therapy for the pulmonary diseases triggered by PM2.5.

Sand Discharge Simulation and Flow Path Optimization of a Particle Separator.

A numerical simulation method is used to optimize the removal of sand from a helicopter engine particle separator. First, the classic configuration of a particle separator based on the literature is simulated using two boundary conditions. The results show that the boundary conditions for the total pressure inlet and mass flow outlet are much more closely aligned with the experimental environment. By modifying the material at the front of the shroud, the separation efficiencies of coarse Arizona road dust (AC-Coarse) and MIL-E-5007C (C-Spec) can be improved to 93.3% and 97.6%, respectively. Configuration modifications of the particle separator with dual protection can increase the separation efficiencies of AC-Coarse and C-Spec to 91.7% and 97.7%.

Prognostic value of hysterosalpingography after salpingostomy in patients with hydrosalpinx.

To assess whether post-hysterosalpingography evaluation was associated with pregnancy rate and to identify independent risk factors for pregnancy success after salpingostomy in patients with hydrosalpinx. A retrospective analysis was conducted on the clinical data of 47 patients diagnosed with hydrosalpingography (HSG) in our hospital from 2015 to 2018. These patients received laparoscopic surgery and another salpingography within 2 months after surgery. According to the fallopian tube conditions evaluated by HSG before and after surgery, the patients could be divided into two groups. According to the pregnancy rate and postoperative HSG of patients with hydrosalpinx after laparoscopy, the total pregnancy rate of the tubal improved group was 65.62%, while that of the non-improved group was 20%, with statistical significance (p < 0.05). We found that hysterosalpingography after salpingostomy in patients with hydrosalpinx can provide reference for clinical treatment and improve the prognosis of patients.

Postoperative HSG improvement was an independent risk factor for pregnancy rate in patients with hydrosalpinx after laparoscopic surgery. Impact statementWhat is already known on this subject? Fallopian tube obstruction is an important cause of female infertility. Current studies have shown that most spontaneous pregnancies in patients with hydrosalpinx after salpingostomy occur within 18 months, however, pregnancy rates and outcomes vary from report to report.What do the results of this study add? Many studies have shown that hydrosalpinx reduces the success rate of natural pregnancy and embryo transfer, but the mechanism of hydrosalpinx affecting pregnancy remains unclear. This study explored the mechanism of successful pregnancy through hysterosalpingography after salpingostomy in patients with hydrosalpinx.What are the implications of these findings for clinical practice and/or further research? To evaluate the prognosis of patients with hydrosalpinx after laparoscopic salpingostomy by hysterosalpingography (HSG), and to reflect the improvement according to the postoperative pregnancy rate of the patients. To provide clinical personalized treatment plan.

Acute or chronic inflammation role in gastrointestinal oncology.

The following letter to the editor highlights the review titled "Inflammatory bowel disease-related colorectal cancer: Past, present and future perspectives" in World J Gastrointest Oncol 2022 March 15; 14(3): 547-567. It is necessary to explore the role of inflammation in promoting tumorigenesis and development of gastrointestinal cancers.

Melatonin alleviates PM2.5 -induced glucose metabolism disorder and lipidome alteration by regulating endoplasmic reticulum stress.

Exposure to fine particulate matter (PM2.5 ) was associated with an increased incidence of liver metabolic disease. Melatonin has been shown to prevent liver glucolipid metabolism disorders. However, whether melatonin could rescue PM2.5 -induced liver metabolic abnormalities remains uncertain. This study was to evaluate the mitigating effect of melatonin on PM2.5 -accelerated hepatic glucose metabolism imbalance in vivo and in vitro. Schiff periodic acid shiff staining and other results showed that PM2.5 led to a decrease in hepatic glycogen reserve and an increase in glucose content, which was effectively alleviated by melatonin. Targeted lipidomics is used to identify lipid biomarkers associated with this process, including glycerolipids, glycerophospholipids, and sphingolipids. In addition, gene microarray and quantitative polymerase chain reaction analysis of ApoE-/- mice liver suggested that PM2.5 activated the miR-200a-3p and inhibited DNAJB9, and the targeting relationship was verified by luciferase reports for the first time. Further investigation demonstrated that DNAJB9 might motivate endoplasmic reticulum (ER) stress by regulating Ca2+ homeostasis, thus altering the protein expression of GSK3B, FOXO1, and PCK2. Meanwhile, melatonin effectively inhibited miR-200a-3p and glucose metabolism disorder. Knockout of miR-200a-3p in L02 cells revealed that miR-200a-3p is indispensable in the damage of PM2.5 and the therapeutic effect of melatonin. In summary, melatonin alleviated PM2.5 -induced liver metabolic dysregulation by regulating ER stress via miR-200a-3p/DNAJB9 signaling pathway. Our data provide a prospective targeted therapy for air pollution-related liver metabolism disorders.

Combined exposure to PM2.5 and high-fat diet facilitates the hepatic lipid metabolism disorders via ROS/miR-155/PPARγ pathway.

Environmental fine particulate matter (PM2.5), which has attracted worldwide attention, is associated with the progression of metabolic-associated fatty liver disease (MAFLD). However, it is unclear whether dietary habit exacerbate liver damage caused by PM2.5. The current study aimed to investigate the combined negative effects of PM2.5 and high-fat diet (HFD) on liver lipid metabolism in C57BL/6J mice. Histopathological and Oil-Red O staining analysis illustrated that PM2.5 exposure resulted in increased liver fat content in HFD-fed C57BL/6J mice, but not in standard chow diet (STD)-fed mice. And there was a synergistic effect between PM2.5 and HFD on hepatic lipotoxicity. The increased ROS levels and augmented oxidative damage were evaluated in liver tissue of mice treated with PM2.5 and HFD together. In addition, excessive ROS production could activate the miR-155/peroxisome proliferator-activated receptor gamma (PPARγ) pathway, including up-regulation of lipid accumulation-related protein expressions of recombinant liver X receptor alpha (LXRα), sterol regulatory element binding protein-1 (SREBP-1), stearoyl-CoA desaturase-1 (SCD1), fatty acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC1).The use of miR-155 inhibitors demonstrated the indispensable role of miR-155 in the activation of lipid-regulated proteins by PM2.5 and palmitic acid (PA). Collectively, altering high-fat dietary habits could protect against MAFLD motivated by air pollution, and miR-155 might be an effective preventive and therapeutic target for this process.

PM2.5 induce the defective efferocytosis and promote atherosclerosis via HIF-1α activation in macrophage.

Epidemiological studies demonstrate that fine particulate matter (PM2.5) promotes the development of atherosclerosis. However, the mechanism insight of PM2.5-induced atherosclerosis is still lacking. The aim of this study was to explore the biological effects of hypoxia-inducible factor 1α (HIF-1α) on PM2.5-triggered atherosclerosis. The vascular stiffness, carotid intima-media thickness (CIMT), lipid and atherosclerotic lesion were increased when von Hippel-Lindau (VHL)-null mice were exposed to PM2.5. Yet, knockout of HIF-1α markedly decreased the PM2.5-triggered atherosclerotic lesion. We firstly performed microarray analysis in PM2.5-treated bone morrow-derived macrophages (BMDMs), which showed that PM2.5 significantly changed the genes expression patterns and affected biological processes such as phagocytosis, apoptotic cell clearance, cellular response to hypoxia, apoptotic process and inflammatory response. Moreover, the data showed knockout of HIF-1α remarkably relieved PM2.5-induced defective efferocytosis. Mechanistically, PM2.5 inhibited the level of genes and proteins of efferocytosis receptor c-Mer tyrosine kinase (MerTK), especially in VHL-null BMDMs. In addition, PM2.5 increased the genes and proteins of a disintegrin and metallopeptidase domain 17 (ADAM17), which caused the MerTK cleavage to form soluble MerTK (sMer) in plasma and cellular supernatant. The sMer was significantly up-regulated in plasma of VHL-null PM2.5-exposed mice. Moreover, PM2.5 could induce defective efferocytosis and activate inflammatory response through MerTK/IFNAR1/STAT1 signaling pathway in macrophages. Our results demonstrate that PM2.5 could induce defective efferocytosis and inflammation by activating HIF-1α in macrophages, ultimately resulting in accelerating atherosclerotic lesion formation and development. Our data suggest HIF-1α in macrophages might be a potential target for PM2.5-related atherosclerosis.

Melatonin Alleviates PM2.5-Induced Hepatic Steatosis and Metabolic-Associated Fatty Liver Disease in ApoE-/- Mice.

Background: Exposure to fine particulate matter (PM2.5) is associated with the risk of developing metabolic-associated fatty liver disease (MAFLD). Melatonin is the main secreted product of the pineal gland and has been reported to prevent hepatic lipid metabolism disorders. However, it remains uncertain whether melatonin could protect against PM2.5-induced MAFLD. Methods and Results: The purpose of our study was to investigate the mitigating effects of melatonin on hepatic fatty degeneration accelerated by PM2.5 in vivo and in vitro. Histopathological analysis and ultrastructural images showed that PM2.5 induced hepatic steatosis and lipid vacuolation in ApoE-/- mice, which could be effectively alleviated by melatonin administration. Increased ROS production and decreased expression of antioxidant enzymes were detected in the PM2.5-treated group, whereas melatonin showed recovery effects after PM2.5-induced oxidative damage in both the liver and L02 cells. Further investigation revealed that PM2.5 induced oxidative stress to activate PTP1B, which in turn had a positive feedback regulation effect on ROS release. When a PTP1B inhibitor or melatonin was administered, SP1/SREBP-1 signalling was effectively suppressed, while Nrf2/Keap1 signalling was activated in the PM2.5-treated groups. Conclusion: Our study is the first to show that melatonin alleviates the disturbance of PM2.5-triggered hepatic steatosis and liver damage by regulating the ROS-mediated PTP1B and Nrf2 signalling pathways in ApoE-/- mice. These results suggest that melatonin administration might be a prospective therapy for the prevention and treatment of MAFLD associated with air pollution.

Discovery of Potent and Orally Bioavailable Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for the Treatment of Osteosarcoma.

Platelet-derived growth factor receptors (PDGFRs) are now considered promising targets for the treatment of osteosarcoma. Herein, the design, synthesis, and structure-activity relationships (SAR) of novel pyrimidine-2,4-diamine derivatives that selectively inhibit PDGFRα/ß kinases have been studied. The screening cascades revealed that 7m was the preferred compound among these derivatives, with IC50 values of 2.4 and 0.9 nM for PDGFRα and PDGFRß, respectively. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) experiment revealed that 7m has a substantial cytotoxic effect against all osteosarcoma cancer cell lines; 7m also displayed robust antitumor effects and low toxicity in a xenograft model. Additionally, 7m showed excellent bioavailability (F = 62.9%), suitable half-life (T1/2 = 2.12 h), satisfactory metabolic stability, and weak CYP isoform inhibitory activity, suggesting that 7m is a potential drug candidate for PDGFR-driven osteosarcoma.

The mitochondria-targeted antioxidant MitoQ attenuated PM2.5-induced vascular fibrosis via regulating mitophagy.

Short-term PM2.5 exposure is related to vascular remodeling and stiffness. Mitochondria-targeted antioxidant MitoQ is reported to improve the occurrence and development of mitochondrial redox-related diseases. At present, there is limited data on whether MitoQ can alleviate the vascular damage caused by PM2.5. Therefore, the current study was aimed to evaluate the protective role of MitoQ on aortic fibrosis induced by PM2.5 exposure. Vascular Doppler ultrasound manifested PM2.5 damaged both vascular function and structure in C57BL/6J mice. Histopathological analysis found that PM2.5 induced aortic fibrosis and disordered elastic fibers, accompanied by collagen I/III deposition and synthetic phenotype remodeling of vascular smooth muscle cells; while these alterations were partially alleviated following MitoQ treatment. We further demonstrated that mitochondrial dysfunction, including mitochondrial reactive oxygen species (ROS) overproduction and activated superoxide dismutase 2 (SOD2) expression, decreased mitochondrial membrane potential (MMP), oxygen consumption rate (OCR), ATP and increased intracellular Ca2+, as well as mitochondrial fragmentation caused by increased Drp1 expression and decreased Mfn2 expression, occurred in PM2.5-exposed aorta or human aortic vascular smooth muscle cells (HAVSMCs), which were reversed by MitoQ. Moreover, the enhanced expressions of LC3II/I, p62, PINK1 and Parkin regulated mitophagy in PM2.5-exposed aorta and HAVSMCs were weakened by MitoQ. Transfection with PINK1 siRNA in PM2.5-exposed HAVSMCs further improved the effects of MitoQ on HAVSMCs synthetic phenotype remodeling, mitochondrial fragmentation and mitophagy. In summary, our data demonstrated that MitoQ treatment had a protective role in aortic fibrosis after PM2.5 exposure through mitochondrial quality control, which regulated by mitochondrial ROS/PINK1/Parkin-mediated mitophagy. Our study provides a possible targeted therapy for PM2.5-induced arterial stiffness.

Acute exposure to PM2.5 triggers lung inflammatory response and apoptosis in rat.

Severe haze events, especially with high concentration of fine particulate matter (PM2.5), are frequent in China, which have gained increasing attention among public. The purpose of our study was explored the toxic effects and potential damage mechanisms about PM2.5 acute exposure. Here, the diverse dosages of PM2.5 were used to treat SD rats and human bronchial epithelial cell (BEAS-2B) for 24 h, and then the bioassays were performed at the end of exposure. The results show that acute exposure to diverse dosages of PM2.5 could trigger the inflammatory response and apoptosis. The severely oxidative stress may contribute to the apoptosis. Also, the activation of Nrf2-ARE pathway was an important compensatory process of antioxidant damage during the early stage of acute exposure to PM2.5. Furthermore, the HO-1 was suppression by siRNA that promoted cell apoptosis triggered by PM2.5. In other words, enhancing the expression of HO-1 may mitigate the cell apoptosis caused by acute exposure to PM2.5. In summary, our findings present the first time that prevent or mitigate the damage triggered by PM2.5 through antioxidant approaches was a promising strategy.

Metabolomic characteristics of hepatotoxicity in rats induced by silica nanoparticles.

Silica nanoparticles (SiNPs) have become one of the most widely studied nanoparticles in nanotechnology for environmental health and safety. Although many studies have devoted to evaluating the hepatotoxicity of SiNPs, it is currently impossible to predict the extent of liver lipid metabolism disorder by identifying changes in metabolites. In the present study, 40 male Sprague-Dawley (SD) rats were randomly divided into control group and 3 groups with different doses (1.8 mg/kg body weight (bw), 5.4 mg/kg bw, 16.2 mg/kg bw), receiving intratracheal instillation of SiNPs. Liver tissue was taken for lipid level analysis, and serum was used for blood biochemical analysis. Then, the metabolites changes of liver tissue in rats were systematically analyzed using 1H nuclear magnetic resonance (1H NMR) techniques in combination with multivariate statistical analysis. SiNPs induced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride (TG) elevation in treated groups; TG and low-density lipoprotein cholesterol (LDL-C) were significantly higher in SiNPs-treated groups of high-dose, however high-density lipoprotein cholesterol (HDL-C) showed a declining trend in liver tissue. The orthogonal partial least squares discriminant analysis (OPLS-DA) scores plots revealed different metabolic profiles between control and high-dose group (Q2 =0.495, R2Y=0.802, p = 0.037), and a total of 11 differential metabolites. Pathway analysis indicated that SiNPs treatment mainly affected 10 metabolic pathways including purine metabolism, glucose-alanine cycle and metabolism of various amino acids such as glutamate, cysteine and aspartate (impact value>0.1, false discovery rate (FDR)< 0.05). The result indicated that exposure to SiNPs caused liver lipid metabolism disorder in rats, the biochemical criterions related to lipid metabolism changed significantly. The obviously changed metabolomics in SiNPs-treated rats mostly occurred in amino acids, organic acids and nucleosides.

Melatonin ameliorates PM2.5 -induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis.

Fine particulate matter (PM2.5 ) exposure is correlated with the risk of developing cardiac fibrosis. Melatonin is a major secretory product of the pineal gland that has been reported to prevent fibrosis. However, whether melatonin affects the adverse health effects of PM2.5 exposure has not been investigated. Thus, this study was aimed to investigate the protective effect of melatonin against PM2.5 -accelerated cardiac fibrosis. The echocardiography revealed that PM2.5 had impaired both systolic and diastolic cardiac function in ApoE-/- mice. Histopathological analysis demonstrated that PM2.5 induced cardiomyocyte hypertrophy and fibrosis, particularly perivascular fibrosis, while the melatonin administration was effective in alleviating PM2.5 -induced cardiac dysfunction and fibrosis in mice. Results of electron microscopy and confocal scanning laser microscope confirmed that melatonin had restorative effects against impaired mitochondrial ultrastructure and augmented mitochondrial ROS generation in PM2.5 -treated group. Further investigation revealed melatonin administration could significantly reverse the PM2.5 -induced phenotypic modulation of cardiac fibroblasts into myofibroblasts. For the first time, our study found that melatonin effectively alleviates PM2.5 -induced cardiac dysfunction and fibrosis via inhibiting mitochondrial oxidative injury and regulating SIRT3-mediated SOD2 deacetylation. Our findings indicate that melatonin could be a therapy medicine for prevention and treatment of air pollution-associated cardiac diseases.

The critical role of endothelial function in fine particulate matter-induced atherosclerosis.

Ambient and indoor air pollution contributes annually to approximately seven million premature deaths. Air pollution is a complex mixture of gaseous and particulate materials. In particular, fine particulate matter (PM2.5) plays a major mortality risk factor particularly on cardiovascular diseases through mechanisms of atherosclerosis, thrombosis and inflammation. A review on the PM2.5-induced atherosclerosis is needed to better understand the involved mechanisms. In this review, we summarized epidemiology and animal studies of PM2.5-induced atherosclerosis. Vascular endothelial injury is a critical early predictor of atherosclerosis. The evidence of mechanisms of PM2.5-induced atherosclerosis supports effects on vascular function. Thus, we summarized the main mechanisms of PM2.5-triggered vascular endothelial injury, which mainly involved three aspects, including vascular endothelial permeability, vasomotor function and vascular reparative capacity. Then we reviewed the relationship between PM2.5-induced endothelial injury and atherosclerosis. PM2.5-induced endothelial injury associated with inflammation, pro-coagulation and lipid deposition. Although the evidence of PM2.5-induced atherosclerosis is undergoing continual refinement, the mechanisms of PM2.5-triggered atherosclerosis are still limited, especially indoor PM2.5. Subsequent efforts of researchers are needed to improve the understanding of PM2.5 and atherosclerosis. Preventing or avoiding PM2.5-induced endothelial damage may greatly reduce the occurrence and development of atherosclerosis.

BCR selection and affinity maturation in Peyer's patch germinal centres.

The antigen-binding variable regions of the B cell receptor (BCR) and of antibodies are encoded by exons that are assembled in developing B cells by V(D)J recombination1. The BCR repertoires of primary B cells are vast owing to mechanisms that create diversity at the junctions of V(D)J gene segments that contribute to complementarity-determining region 3 (CDR3), the region that binds antigen1. Primary B cells undergo antigen-driven BCR affinity maturation through somatic hypermutation and cellular selection in germinal centres (GCs)2,3. Although most GCs are transient3, those in intestinal Peyer's patches (PPs)-which depend on the gut microbiota-are chronic4, and little is known about their BCR repertoires or patterns of somatic hypermutation. Here, using a high-throughput assay that analyses both V(D)J segment usage and somatic hypermutation profiles, we elucidate physiological BCR repertoires in mouse PP GCs. PP GCs from different mice expand public BCR clonotypes (clonotypes that are shared between many mice) that often have canonical CDR3s in the immunoglobulin heavy chain that, owing to junctional biases during V(D)J recombination, appear much more frequently than predicted in naive B cell repertoires. Some public clonotypes are dependent on the gut microbiota and encode antibodies that are reactive to bacterial glycans, whereas others are independent of gut bacteria. Transfer of faeces from specific-pathogen-free mice to germ-free mice restored germ-dependent clonotypes, directly implicating BCR selection. We identified somatic hypermutations that were recurrently selected in such public clonotypes, indicating that affinity maturation occurs in mouse PP GCs under homeostatic conditions. Thus, persistent gut antigens select recurrent BCR clonotypes to seed chronic PP GC responses.

Subacute exposure of PM2.5 induces airway inflammation through inflammatory cell infiltration and cytokine expression in rats.

Accumulating evidences support that exposure to fine particulate matter (PM2.5) could cause inflammation of the airway, but its underlying mechanisms are less known. Our study aimed to explore the potential effect of non-canonical NF-κB signaling pathway in airway inflammation, which caused by PM2.5, and the possible regulatory relationship between miR-6747-5p and NF-κB2. The histological analysis from in vivo study manifested that PM2.5 could induce the exudation and infiltration of polymorphonuclear leukocytes (PMNs). Immunohistochemistry results of lung tissues showed that PM2.5 increased ICAM-1, 6Ckine, SDF-1 and BAFF positive staining with a dose-dependent manner. In addition, PM2.5 could induce the p52 nuclear translocation to trigger non-canonical NF-κB signaling pathway in lung tissues and BEAS-2B cells. Targetscan reporter gene assay showed that there was a target regulatory relationship between miR-6747-5p and NF-κB2. Besides, the chemical mimics of miR-6747-5p weakened the activation of non-canonical NF-κB signaling pathway induced by PM2.5. In summary, exposure to PM2.5 could trigger airway inflammation by activating the non-canonical NF-κB signaling pathway, which may be related to the negative feedback regulation mechanism of miR-6747-5p. Our findings will give new ideas into the toxic effects of airway inflammation triggered by PM2.5.