Nontargeted Identification of Organic Components in Fine Particulate Matter Related to Lung Tumor Metastasis Based on an Adverse Outcome Pathway Strategy.

Emerging studies implicate fine particulate matter (PM2.5) and its organic components (OCs) as urgent hazard factors for lung cancer progression in nonsmokers. Establishing the adverse outcome pathway (AOP)-directed nontargeted identification method, this study aimed to explore whether PM2.5 exposure in coal-burning areas promoted lung tumor metastasis and how we identify its effective OCs to support traceability and control of regional PM2.5 pollution. First, we used a nude mouse model of lung cancer for PM2.5 exposure and found that the exposure significantly promoted the hematogenous metastases of A549-Luc cells in lung tissues and the adverse outcomes (AOs), with key events (KEs) including the changed expression of epithelial-mesenchymal transition (EMT) markers, such as suppression of E-cad and increased expression of Fib. Subsequently, using AOs and KEs as adverse outcome directors, we identified a total of 35 candidate chemicals based on the in vitro model and nontargeted analysis. Among them, tributyl phosphate (C12H27O4P), 2-bromotetradecane (C14H29Br), and methyl decanoate (C11H22O2) made greater contributions to the AOs. Finally, we clarified the interactions between these OCs and EMT-activating transcription factors (EMT-ATFs) as the molecular initiation event (MIE) to support the feasibility of the above identification strategy. The present study updates a new framework for identifying tumor metastasis-promoting OCs in PM2.5 and provides solid data for screening out chemicals that need priority control in polluted areas posing higher lung cancer risk.

Multilevel Screening Strategy to Identify the Hydrophobic Organic Components of Ambient PM2.5 Associated with Hepatocellular Steatosis.

Hepatic steatosis is the first step in a series of events that drives hepatic disease and has been considerably associated with exposure to fine particulate matter (PM2.5). Although the chemical constituents of particles matter in the negative health effects, the specific components of PM2.5 that trigger hepatic steatosis remain unclear. New strategies prioritizing the identification of the key components with the highest potential to cause adverse effects among the numerous components of PM2.5 are needed. Herein, we established a high-resolution mass spectrometry (MS) data set comprising the hydrophobic organic components corresponding to 67 PM2.5 samples in total from Taiyuan and Guangzhou, two representative cities in North and South China, respectively. The lipid accumulation bioeffect profiles of the above samples were also obtained. Considerable hepatocyte lipid accumulation was observed in most PM2.5 extracts. Subsequently, 40 of 695 components were initially screened through machine learning-assisted data filtering based on an integrated bioassay with MS data. Next, nine compounds were further selected as candidates contributing to hepatocellular steatosis based on absorption, distribution, metabolism, and excretion evaluation and molecular dockingin silico. Finally, seven components were confirmed in vitro. This study provided a multilevel screening strategy for key active components in PM2.5 and provided insight into the hydrophobic PM2.5 components that induce hepatocellular steatosis.

LRRC75A-AS1 delivered by M2 macrophage exosomes promotes cervical cancer progression via enhancing SIX1 expression.

We aimed to investigate potential roles of LRRC75A-AS1 delivered by M2 macrophage exosomes in inducing cervical cancer progression. We demonstrated LRRC75A-AS1 was highly expressed in exosomes from M2 macrophages which could be absorbed by Hela cells. M2 macrophage-derived exosomes promoted Hela cell proliferation, migration, invasion, and EMT process by delivering LRRC75A-AS1. LRRC75A-AS1 directly targeted and suppressed miR-429 in Hela cells. The regulation of cell functions by exosomes from LRRC75A-AS1-overexpressing M2 macrophages was abrogated by miR-429 mimics. miR-429 directly targeted and repressed SIX1 expression. SIX1 overexpression alleviated the modulation of cellular functions and STAT3/MMP-9 signaling by miR-429 mimics. Also, miR-429 overexpression or SIX1 silence repressed tumor formation and metastasis in nude mice, which was mitigated by exosomes from LRRC75A-AS1-overexpressing M2 macrophages. In conclusion, LRRC75A-AS1 delivered by M2 macrophage exosomes repressed miR-429 to elevate SIX1 expression and promote cervical cancer progression through activating the STAT3/MMP-9 axis.

Discovery of a first-in-class orally available HBV cccDNA inhibitor.

BACKGROUND & AIMS: The persistence of covalently closed circular DNA (cccDNA) in infected hepatocytes is the major barrier preventing viral eradication with existing therapies in patients with chronic hepatitis B. Therapeutic agents that can eliminate cccDNA are urgently needed to achieve viral eradication and thus HBV cure. METHODS: A phenotypic assay with HBV-infected primary human hepatocytes (PHHs) was employed to screen for novel cccDNA inhibitors. A HBVcircle mouse model and a uPA-SCID (urokinase-type plasminogen activator-severe combined immunodeficiency) humanized liver mouse model were used to evaluate the anti-HBV efficacy of the discovered cccDNA inhibitors. RESULTS: Potent and dose-dependent reductions in extracellular HBV DNA, HBsAg, and HBeAg levels were achieved upon the initiation of ccc_R08 treatment two days after the HBV infection of PHHs. More importantly, the level of cccDNA was specifically reduced by ccc_R08, while it did not obviously affect mitochondrial DNA. Additionally, ccc_R08 showed no significant cytotoxicity in PHHs or in multiple proliferating cell lines. The twice daily oral administration of ccc_R08 to HBVcircle model mice, which contained surrogate cccDNA molecules, significantly decreased the serum levels of HBV DNA and antigens, and these effects were sustained during the off-treatment follow-up period. Moreover, at the end of follow-up, the levels of surrogate cccDNA molecules in the livers of ccc_R08-treated HBVcircle mice were reduced to below the lower limit of quantification. CONCLUSIONS: We have discovered a small-molecule cccDNA inhibitor that reduces HBV cccDNA levels. cccDNA inhibitors potentially represent a new approach to completely cure patients chronically infected with HBV. IMPACT AND IMPLICATIONS: Covalently closed circular DNA (cccDNA) persistence in HBV-infected hepatocytes is the root cause of chronic hepatitis B. We discovered a novel small-molecule cccDNA inhibitor that can specifically reduce cccDNA levels in HBV-infected hepatocytes. This type of molecule could offer a new approach to completely cure patients chronically infected with HBV.

Novel treatment from a botanical formulation Si-Miao-Yong-an decoction inhibits vasa vasorum angiogenesis and stabilizes atherosclerosis plaques via the Wnt1/ß-catenin signalling pathway.

CONTEXT: Si-Miao-Yong-An (SMYA) has been widely used for the clinical treatment of atherosclerosis (AS). Yet, its complete mechanism of action is not fully understood. OBJECTIVE: To investigate the mechanism by which SMYA stabilizes AS plaques from the perspective of inhibiting vasa vasorum (VV) angiogenesis. MATERIALS AND METHODS: We used male ApoE-/- mice to establish an AS model. The mice were divided into model, SMYA (11.7 mg/kg/d), and simvastatin (SVTT) (2.6 mg/kg/d) groups. Mice were given SMYA or SVTT by daily gavage for 8 weeks. HE staining, immunofluorescence double-labelling staining, and immunohistochemical staining were used to observe the pathological changes in the plaques. Finally, the protein and mRNA expression levels of the Wnt1/ß-catenin signalling pathway were detected by Western blot and qRT-PCR, respectively. RESULTS: SMYA significantly attenuated cholesterol crystallization, and lipid accumulation in AS plaques, resulting in smaller plaque size (0.25 mm2 vs. 0.46 mm2), and lowering ratio of plaque to lumen area (20.04% vs. 38.33%) and VV density (50.64/mm2 vs. 98.02/mm2). Meanwhile, SMYA suppressed both the positive area percentage of Wnt1 (2.53 vs. 3.56), ß-catenin (3.33 vs. 5.65) and Cyclin D1 (2.10 vs. 3.27) proteins in the aortic root plaques, and mRNA expression of Wnt1 (1.38 vs. 2.09), ß-catenin (2.05 vs. 3.25) and Cyclin D1 (1.39 vs. 2.57). DISCUSSION AND CONCLUSIONS: SMYA has a protective effect against AS, which may be related to its anti-VV angiogenesis in plaques, suggesting that SMYA has the potential as a novel botanical formulation in the treatment of AS.

The NLRP3 inflammasome: Multiple activation pathways and its role in primary cells during ventricular remodeling.

Inflammasomes are a group of multiprotein signaling complexes located in the cytoplasm. Several inflammasomes have been identified, including NLRP1, NLRP2, NLRP3, AIM2, and NLRC4. Among them, NLRP3 was investigated in most detail, and it was reported that it can be activated by many different stimuli. Increased NLRP3 protein expression and inflammasome assembly lead to caspase-1 mediated maturation and release of IL-1ß, which triggers inflammation and pyroptosis. The activation of the NLRP3 inflammasome has been widely reported in studies of tumors and neurological diseases, but relatively few studies on the cardiovascular system. Ventricular remodeling (VR) is an important factor contributing to heart failure (HF) after myocardial infarction (MI). Consequently, delaying VR is of great significance for improving heart function. Studies have shown that the NLRP3 inflammasome plays an essential role in the process of VR. Here, we reviewed the latest studies on the activation pathway of the NLRP3 inflammasome, focusing on the effects of the NLRP3 inflammasome in primary cells during VR, and finally discuss future research directions in this field.

Activation of the Liver X Receptor Pathway Inhibits HBV Replication in Primary Human Hepatocytes.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) infection is ranked among the top health priorities worldwide. Accumulating evidence suggests that HBV infection and replication are closely associated with liver metabolism. The liver X receptors (LXRs), which belong to the superfamily of nuclear hormone receptors, are important physiological regulators of lipid and cholesterol metabolism. However, the association between the LXR pathway and HBV infection remains largely unclear. APPROACH AND RESULTS: In this study, the antiviral activity of LXR agonists was investigated using multiple HBV cellular models. We observed that in HBV-infected primary human hepatocytes (PHHs), synthetic LXR agonists (T0901317, GW3965, and LXR-623), but not an LXR antagonist (SR9238), potently inhibited HBV replication and gene expression, as demonstrated by substantial reductions in viral RNA, DNA, and antigen production following agonist treatment. However, covalently closed circular DNA (cccDNA) levels were not significantly reduced by the agonists. In addition, no rebound in viral replication was observed after treatment withdrawal, indicating a long-lasting inhibitory effect. These results suggest that LXR agonists decrease the transcriptional activity of cccDNA. In contrast, no significant anti-HBV effect was observed in HepG2-derived cell lines. Interestingly, LXR agonist treatment strongly reduced cholesterol 7α-hydroxylase 1 (CYP7A1) mRNA levels. Knockdown of CYP7A1 gene expression with small interfering RNA inhibited HBV activity in PHHs, suggesting CYP7A1 as a potential factor contributing to the antiviral effects of LXR agonists. CONCLUSIONS: We found that activation of the LXR pathway with synthetic LXR agonists could elicit potent anti-HBV activity in PHHs, possibly through sustained suppression of cccDNA transcription. Our work highlights the therapeutic potential of targeting the LXR pathway for the treatment of chronic HBV infection.

Clinical efficacy of lenvatinib for the treatment of radioiodine-refractory thyroid carcinoma: A systematic review and meta-analysis of clinical trials.

OBJECTIVE: To evaluate the efficacy of lenvatinib in the treatment of radioiodine-refractory thyroid carcinoma. BACKGROUND: Thyroid carcinoma is one of the top ten carcinomas worldwide. Clinically, thyroid cancers are managed with resections and adjuvant therapy with radioiodine. However, radioiodine is not effective for radioiodine-refractory (RR) thyroid carcinoma in some patients. Lenvatinib is a multi-kinase inhibitor for the treatment of RR thyroid carcinoma. Several clinical trials showed its efficacy in prolonging progression-free survival (PFS) and overall survival (OS). DESIGN, PATIENTS AND MEASUREMENTS: A systematic search was done on databases (PubMed, Embase, MEDLINE, Cochrane) on 8 June 2020. Search keywords were lenvatinib, thyroid carcinoma and randomized controlled trials. Clinical trials fulfilling the SELECT protocol were selected to evaluate the efficacy of lenvatinib in terms of prolongation of PFS, OS and objective response rate (ORR). The risk ratio and distribution of grade 3 or above adverse events were documented. RESULTS: Of the 3997 patients of mean age 62.5 years in fifteen selected studies, lenvatinib is associated with prolonged PFS (hazard ratio 0.24, 95% CI, 0.19-0.31, p < .001) and OS (hazard ratio 0.65, 95% CI, 0.52-0.81, p < .001). Compared with placebo, the risk ratio of ORR and incidence of grade 3 or above adverse events are 35.41 (95% CI, 19.42-64.58, p < .001) and 8.25 (95% CI, 6.50-10.46, p < .001), respectively. Subgroup analysis shows that lenvatinib is effective for all patients with RR thyroid carcinoma, regardless of age, histological subtypes, radiological subtypes and mutation status. CONCLUSION: Lenvatinib is effective in the treatment of RR thyroid carcinoma. Close monitoring of serious adverse events is recommended.

PhI(OAc)2-mediated trifluoromethylthiolation/oxidative cyclization of ynamides.

A PhI(OAc)2-mediated trifluoromethylthiolation/oxidative cyclization of ynamides with the Shen reagent has been established herein, providing a facile access to CF3S-substituted oxazolidine-2,4-diones bearing a quaternary carbon center in 38-85% yields with chemoselectivities of up to 99/1.

Direct Inhibition of Hepatitis B e Antigen by Core Protein Allosteric Modulator.

Hepatitis B e antigen (HBeAg) is an important immunomodulator for promoting host immune tolerance during chronic hepatitis B (CHB) infection. In patients with CHB, HBeAg loss and seroconversion represent partial immune control of CHB infection and are regarded as valuable endpoints. However, the current approved treatments have only a limited efficacy in achieving HBeAg seroconversion in HBeAg-positive patients. Hepatitis B virus (HBV) core protein has been recognized as an attractive antiviral target, and two classes of core protein allosteric modulator (CpAM) have been discovered: the phenylpropenamides (PPAs) and the heteroaryldihydropyrimidines (HAPs). However, their differentiation and potential therapeutic benefit beyond HBV DNA inhibition remain to be seen. Here, we show that in contrast to PPA series compound AT-130, a HAP CpAM, HAP_R01, reduced HBeAg levels in multiple in vitro and in vivo HBV experimental models. Mechanistically, we found that HAP_R01 treatment caused the misassembly of capsids formed by purified HBeAg in vitro. In addition, HAP_R01 directly reduces HBeAg levels by inducing intracellular precore protein misassembly and aggregation. Using a HAP_R01-resistant mutant, we found that HAP_R01-mediated HBeAg and core protein reductions were mediated through the same mechanism. Furthermore, HAP_R01 treatment substantially reduced serum HBeAg levels in an HBV mouse model. Conclusion: Unlike PPA series compound AT-130, HAP_R01 not only inhibits HBV DNA levels but also directly reduces HBeAg through induction of its misassembly. HAP_R01, as well as other similar CpAMs, has the potential to achieve higher anti-HBeAg seroconversion rates than currently approved therapies for patients with CHB. Our findings also provide guidance for dose selection when designing clinical trials with molecules from HAP series.

Mining the proliferative diabetic retinopathy-associated genes and pathways by integrated bioinformatic analysis.

PURPOSE: Diabetic retinopathy (DR) especially proliferative diabetic retinopathy (PDR) is a serious eye disease. We aimed to identify key pathway and hub genes associated with PDR by analyzing the expression of retinal fibrovascular tissue in PDR patients. METHODS: First raw data were downloaded from the Gene Expression Omnibus database. Median normalization was subsequently applied to preprocess. Differentially expressed genes (DEGs) analyzed with the Limma package. Weighted correlation network analysis (WGCNA) was utilized to build the co-expression network for all genes. Then, we compared the DEGs and modules filtered out by WGCNA. A protein-protein interaction network based on the STRING web site and the Cytoscape software was constructed by the overlapping DEGs. Next, the Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. Finally, we used the Comparative Toxicogenomics Database to identify some important pathways and hub genes tightly related to PDR. RESULTS: Functional enrichment analysis showed that the pathway of cytokine-cytokine receptor interaction was significantly related to PDR eight hub genes which were associated with pathway including tumor necrosis factor (TNF), tumor necrosis factor receptor superfamily member 12A (TNFRSF12A), C-C chemokine 20 (CCL20), chemokine (C-X-C motif) ligand 2 (CXCL2), oncostatin M (OSM) interleukin 10 (IL10), interleukin 15 (IL 15), and interleukin 1B (IL1B). CONCLUSIONS: We identified one pathway and eight hub genes, which were associated with PDR. The pathway provided references that will advance the understanding of mechanisms of PDR. Moreover, the hub genes may serve as therapeutic targets for precise diagnosis and treatment of PDR in the future.

HBVcircle: A novel tool to investigate hepatitis B virus covalently closed circular DNA.

BACKGROUND & AIMS: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) persists as a stable episome in infected hepatocytes and serves as a template for the transcription of all viral genes. Due to the narrow host range of HBV, the development of a robust mouse model that supports cccDNA-dependent viral replication is a key hurdle in the development of novel HBV therapeutics. This study aimed to develop a novel tool to investigate HBV cccDNA. METHODS: Through minicircle technology, HBVcircle, a recombinant cccDNA, was easily generated and extracted from a genetically engineered E. coli strain. We characterized the performance of HBVcircle in cell culture by transfection and in immunocompetent mice by hydrodynamic injection (HDI). RESULTS: We demonstrated that HBVcircle formed authentic cccDNA-like molecules in vitro in transiently transfected hepatic cells and in vivo in mouse liver after HDI. HBVcircle supported high levels and persistent HBV replication. In addition, we investigated different factors affecting HBV in vivo replication and persistence, including the host genetic background, vector design and dosage, viral genes and genotypes, and immune activation status. Furthermore, different classes of anti-HBV drugs were also assessed with the HBVcircle system. CONCLUSION: Compared with previous reported HBV mouse models which employ other viral vectors to introduce overlength HBV genomes, viral gene expression and associated phenotypes are entirely driven by cccDNA-like viral genomes in the HBVcircle mouse model. Therefore, the HBVcircle is a close mimic of cccDNA, and it represents a novel tool for addressing HBV cccDNA related biological questions and for anti-HBV drug discovery. LAY SUMMARY: To establish a mouse model that supports cccDNA-dependent transcription, a novel tool named HBVcircle, was developed with minicircle technology. HBVcircle formed authentic cccDNA-like molecules in hepatocytes, and supported high levels and persistent HBV replication in vivo. The HBVcircle is a close mimic of cccDNA, and it represents a novel tool for addressing HBV cccDNA related biological questions and for anti-HBV drug discovery.

Association between ATM gene polymorphisms, lung cancer susceptibility and radiation-induced pneumonitis: a meta-analysis.

BACKGROUND: Previous studies have suggested that DNA double-strand break (DSB) repair is an important protective pathway after damage. The ataxia telangiectasia mutated (ATM) gene plays an important role in the DNA DSB repair pathway. DNA damage is a major cytotoxic effect that can be caused by radiation, and the ability to repair DNA after damage varies among different tissues. Impaired DNA repair pathways are associated with high sensitivity to radiation exposure. Hence, ATM gene polymorphisms are thought to influence the risk of cancer and radiation-induced pneumonitis (RP) risk in cancer patients treated with radiotherapy. However, the results of previous studies are inconsistent. We therefore conducted this comprehensive meta-analysis. METHODS: A systematic literature search was performed in the PubMed, Embase, China National Knowledge Internet (CNKI) and Wanfang databases to identify studies that investigated the association between the ATM gene polymorphisms and both lung cancer and RP radiotherapy-treated lung cancer (the last search was conducted on Dec.10, 2015). The odds ratio (OR) and 95% confidence interval (CI) were used to investigate the strength of these relationships. Funnel plots and Begg's and Egger's tests were conducted to assess the publication bias. All analyses were performed in STATA 13.0 software. RESULTS: Ten eligible case-control studies (4731 cases and 5142 controls) on lung cancer susceptibility and four (192 cases and 772 controls) on RP risk were included. The results of the overall and subgroup analyses indicated that in the ATM gene, the rs189037 (-111G > A, -4519G > A), rs664677 (44831C > T, 49238C > T) and rs664143 (131,717 T > G) polymorphisms were significantly associated with lung cancer susceptibility (OR = 1.21, 95% CI = 1.04-1.39, P = 0.01; OR = 1.26, 95% CI = 1.06-1.49, P = 0.01; OR = 1.43, 95% CI = 1.15-1.78, P < 0.01). Additionally, the rs189037 variant was significantly associated with RP risk (OR = 1.74, 95% CI = 1.02-2.97, P = 0.04). No publication bias was found in the funnel plots, Begg's tests or Egger's tests. CONCLUSIONS: The results indicate that the ATM rs189037, rs664677 and rs664143 gene polymorphisms are risk factors for lung cancer, while the ATM rs189037 variant was significantly associated with RP risk.

Notch2 regulates BMP signaling and epithelial morphogenesis in the ciliary body of the mouse eye.

The ciliary body (CB) of the mammalian eye is responsible for secreting aqueous humor to maintain intraocular pressure, which is elevated in the eyes of glaucoma patients. It contains a folded two-layered epithelial structure comprising the nonpigmented inner ciliary epithelium (ICE), the pigmented outer ciliary epithelium (OCE), and the underlying stroma. Although the CB has an important function in the eye, its morphogenesis remains poorly studied. In this study, we show that conditional inactivation of the Jagged 1 (Jag1)-Notch2 signaling pathway in the developing CB abolishes its morphogenesis. Notch2 is expressed in the OCE of the CB, whereas Jag1 is expressed in the ICE. Conditional inactivation of Jag1 in the ICE or Notch2 in the OCE disrupts CB morphogenesis, but neither affects the specification of the CB region. Notch2 signaling in the OCE is required for promoting cell proliferation and maintaining bone morphogenetic protein (BMP) signaling, both of which have been suggested to be important for CB morphogenesis. Although Notch and BMP signaling pathways are known to cross-talk via the interaction between their downstream transcriptional factors, this study suggests that Notch2 maintains BMP signaling in the OCE possibly by repressing expression of secreted BMP inhibitors. Based on our findings, we propose that Jag1-Notch2 signaling controls CB morphogenesis at least in part by regulating cell proliferation and BMP signaling.

Dkk2/Frzb in the dermal papillae regulates feather regeneration.

Avian feathers have robust growth and regeneration capability. To evaluate the contribution of signaling molecules and pathways in these processes, we profiled gene expression in the feather follicle using an absolute quantification approach. We identified hundreds of genes that mark specific components of the feather follicle: the dermal papillae (DP) which controls feather regeneration and axis formation, the pulp mesenchyme (Pp) which is derived from DP cells and nourishes the feather follicle, and the ramogenic zone epithelium (Erz) where a feather starts to branch. The feather DP is enriched in BMP/TGF-ß signaling molecules and inhibitors for Wnt signaling including Dkk2/Frzb. Wnt ligands are mainly expressed in the feather epithelium and pulp. We find that while Wnt signaling is required for the maintenance of DP marker gene expression and feather regeneration, excessive Wnt signaling delays regeneration and reduces pulp formation. Manipulating Dkk2/Frzb expression by lentiviral-mediated overexpression, shRNA-knockdown, or by antibody neutralization resulted in dual feather axes formation. Our results suggest that the Wnt signaling in the proximal feather follicle is fine-tuned to accommodate feather regeneration and axis formation.

Macrolide antibiotics for treatment of asthma in adults: a meta-analysis of 18 randomized controlled clinical studies.

Mounting studies have been showed that long-term macrolides used in patients with asthma could improve the lung function and symptoms. However, a large number of studies have reported inconclusive results. The aim of this meta-analysis was to investigate the effect of macrolide antibiotics in patients with asthma. We have performed a search in PubMed, Embase, China National Knowledge Internet (CNKI), and Wanfang databases. The weighed mean difference (WMD) or standardized mean difference (SMD) was used to evaluate the pooled effect. Statistical analysis was performed by STATA 11.0 software. Totally 1306 patients were included in the meta-analysis. The overall results indicated that statistically significance of long-term macrolides therapy in patients with asthma on forced expiratory volume in 1 s (FEV1) (WMD: 0.11, P < 0.01), peak expiratory flow (PEF) (SMD: 0.25, P = 0.001), airway hyper-responsiveness (AHR) (SMD: 0.90, P = 0.04), forced vital capacity (FVC) (WMD: 0.18, P = 0.05) and FEV1/FVC (WMD: 1.93, P < 0.001), but no statistically significance on FEV1/predict, FVC/predict, symptom scores, quality of life scores (QOL), reliever inhaler puffs per 24 h, and cell counts in sputum and blood. The subgroup analysis indicated macrolides could increase FEV1 and PEF in Caucasian and Asian, decrease AHR in Caucasian, while cells counts of sputum improvement among Asian. Therefore, the study suggested that long-term marolides therapy in asthma may improved the FEV1, PEF, AHR, FVC, FEV1/FVC and cells counts in sputum, but it can't improve other lung function (FEV1/predict and FVC/predict) and clinical outcomes (such as symptom, quality of life etc.).

Polymorphisms in HLA-DRB1 gene and the risk of tuberculosis: a meta-analysis of 31 studies.

PURPOSE: The HLA-DRB1 gene polymorphisms have been implicated in susceptibility to tuberculosis (TB). However, a large number of studies have reported inconclusive results. This study was conducted to investigate the relationship of HLA-DRB1 gene polymorphisms and TB risk by a meta-analysis. METHODS: A search was performed in Embase, PubMed, Wanfang Database, and China National Knowledge Internet (CNKI) up to Jul 30, 2014. Odds ratio (OR) and 95% confidence interval (95% CI) were used to assess the association. Statistical analyses were calculated by STATA 11.0 software. RESULTS: All 31 articles involving 3,416 cases and 4,515 controls were identified. The pooled results indicated a significant association between HLA-DRB1*04 (OR 1.22, 95% CI 1.00-1.48, P = 0.048), *09 (OR 1.50, 95% CI 1.08-2.08, P = 0.016), *10 (OR 1.23, 95% CI 1.01-1.49, P = 0.035), *11 (OR 0.72, 95% CI 0.53-0.99, P = 0.044), *15 (OR 1.40, 95% CI 1.14-1.73, P = 0.001), and *16 (OR 1.33, 95% CI 1.08-1.63, P = 0.007) gene polymorphisms and TB risk. In addition, the results also show no significant association between HLA-DRB1*01 (P = 0.748), *03 (P = 0.947), *07 (P = 0.966), *08 (P = 0.440), *12 (P = 0.288), *13 (P = 0.241), and *14 (P = 0.551) gene polymorphisms and TB risk. CONCLUSIONS: This study suggested that the HLA-DRB1*04, *09, *10, *15, and *16 gene polymorphisms may contribute to the risk of TB, especially in the East Asian. But the HLA-DRB1*11 gene polymorphism may be a protective factor for TB risk. Unfortunately, there is no significant association between the HLA-DRB1*01, *03, *07, *08, *12, *13, and *14 gene polymorphisms and TB risk.

Macrophage migration inhibitory factor -173G/C gene polymorphism increases the risk of renal disease: a meta-analysis.

AIM: Macrophage migration inhibitory factor (MIF) -173G/C (rs755622) gene polymorphism has been associated with renal disease risk. However, lots of studies have reported inconclusive results. Therefore, we performed a meta-analysis to investigate the relationship between MIF -173G/C gene polymorphism and renal disease susceptibility. METHODS: We conducted a search in PubMed, Embase (OvidSP), Wanfang databases and China National Knowledge Internet (CNKI) up to 20 June 2014. Odds ratio (OR) and 95% confidence interval (95% CI) were used to test the association. Statistical analyses were performed with STATA version 11.0 software. RESULTS: In total, 2755 participants from eight case-control studies were included in this meta-analysis. The pooled results indicated the significant association between MIF -173G/C polymorphism and renal disease risk (CC + CG vs GG, OR = 1.77, P < 0.01; C vs G, OR = 3.94, P < 0.01). In the subgroup analysis, a significant relationship of MIF -173G/C gene polymorphism and renal disease risk in Asians and Caucasians were observed. Additionally, we found that the heterozygote (CG) may strongly increase renal disease risk in children, while the homozygote (CC) may increase the renal disease susceptibility more significantly in adults. Surprisingly, the results found a significant association between MIF -173G/C polymorphism and glucocorticoid resistance in child patients with idiopathic nephrotic syndrome (INS) (C vs G, OR: 3.83, P < 0.01). CONCLUSION: This study suggested that MIF -173G/C gene polymorphism may increase risk of renal disease, especially in children. Furthermore, the meta-analysis also indicated that this gene polymorphism may increase risk of glucocorticoid resistance in child patients with INS.

Chronic Inflammation in Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) is an increasingly prevalent disease that affects approximately 10-12% of the global population. Therefore, it is considered a public health priority. Persistent and systemic low-grade chronic inflammation (CI) is an important part of the poor prognosis in CKD, especially for patients with advanced disease. For example, CI worsens anemia and promotes atherosclerosis. Therefore, CI deserves our attention. SUMMARY: The formation of CI in CKD involves many aspects. Among them, the decline in the glomerular filtration rate leads to the influence of substances or inflammatory cytokines that should be cleared in time. In addition, oxidative stress, the gut, and the gut microbiota are also influencing factors. KEY MESSAGES: In this review, we highlight the mechanisms involved in the development of CI in CKD.

Research hotspots and frontiers in post-stroke dysphagia: a bibliometric analysis study.

Background: Dysphagia is a common complication of stroke that can result in serious consequences. In recent years, more and more papers on post-stroke dysphagia have been published in various journals. However, there is still a lack of bibliometric analysis of post-stroke dysphagia. This study visually analyzes the global research situation of post-stroke dysphagia from 2013 to 2022, aiming to explore the current research status, frontier trends, and research hotspots in this field. Methods: Articles and reviews relevant to post-stroke dysphagia were obtained and retrieved from the Web of Science core collection database in the last 10 years (from 2013 to 2022). CiteSpace and Microsoft Excel 2019 were used for bibliographic analysis. Results: A total of 1,447 articles were included in the analysis. The number of publications showed an overall upward trend, from 72 in 2013 to 262 in 2022. The most influential authors, institutions, journals, and countries were Hamdy S, University of London, Dysphagia, and the People's Republic of China. An analysis of keywords and the literature indicated that current studies in the field of post-stroke dysphagia focused on dysphagia and aspiration, dysphagia classification, dysphagia rehabilitation, and daily living. Conclusion: This bibliometric analysis reveals the latest advancements and emerging trends in the field of post-stroke dysphagia, spanning the years 2013 to 2022. It highlights the paramount importance of conducting large-scale randomized controlled trials examining the efficacy of dysphagia screening protocols and non-invasive intervention techniques in improving the quality of life for these patients. Such research efforts hold significant academic implications for the development of evidence-based treatment strategies in this field.