Posttranscriptional regulation of de novo lipogenesis by glucose-induced O-GlcNAcylation.

O-linked ß-N-acetyl glucosamine (O-GlcNAc) is attached to proteins under glucose-replete conditions; this posttranslational modification results in molecular and physiological changes that affect cell fate. Here we show that posttranslational modification of serine/arginine-rich protein kinase 2 (SRPK2) by O-GlcNAc regulates de novo lipogenesis by regulating pre-mRNA splicing. We found that O-GlcNAc transferase O-GlcNAcylated SRPK2 at a nuclear localization signal (NLS), which triggers binding of SRPK2 to importin α. Consequently, O-GlcNAcylated SRPK2 was imported into the nucleus, where it phosphorylated serine/arginine-rich proteins and promoted splicing of lipogenic pre-mRNAs. We determined that protein nuclear import by O-GlcNAcylation-dependent binding of cargo protein to importin α might be a general mechanism in cells. This work reveals a role of O-GlcNAc in posttranscriptional regulation of de novo lipogenesis, and our findings indicate that importin α is a "reader" of an O-GlcNAcylated NLS.

Liver transplantation for pediatric patients with congenital heart disease: A single-center study in mainland China.

BACKGROUND: Liver transplantation (LT) is a serious cardiovascular stressor for patients with end-stage liver disease (ESLD). Data on the effects of cardiovascular diseases on pediatric LT is limited. No study on LT for pediatric patients with ESLD combined with congenital heart disease (CHD) has been reported from mainland China. METHODS: A total of 1005 patients were included in this study. The Kaplan-Meier method with log-rank testing was used to evaluate survival outcomes between groups. Univariable and multivariable Cox regression models were used to determine the risk factors for patient and graft survival. RESULTS: The most common indication for LT was biliary atresia (BA 90.3%). The prevalence of CHD was 3.8% (38). 42 CHD were found in 38 patients. The incidence of death and graft loss was more common in the CHD group than in the no-CHD group (13.2% vs. 5.0%, p = .045 and 15.8% vs. 6.2%, p = .019, respectively). The 5-year patient survival and graft survival in the CHD group versus the no-CHD group was 86.8% versus 94.7% (log-rank p = .022) and 84.2% versus 93.5% (log-rank p = .015), respectively. No significant differences were observed in re-transplantation, hepatic artery thrombosis (HAT), and portal vein thrombosis (PVT). After adjusting for age, BMI, etiology of LT, and other confounding factors, we can still find that the presence of CHD was associated with patient and graft survival after LT. CONCLUSION: The presence of CHD was associated with higher mortality and lower graft survival after LT. If possible, the cardiac defects should be addressed prior to LT.

Monomeric compounds from natural products for the treatment of pulmonary fibrosis: a review.

Pulmonary fibrosis (PF) is the end stage of lung injury and chronic lung diseases that results in diminished lung function, respiratory failure, and ultimately mortality. Despite extensive research, the pathogenesis of this disease remains elusive, and effective therapeutic options are currently limited, posing a significant clinical challenge. In addition, research on traditional Chinese medicine and naturopathic medicine is hampered by several complications due to complex composition and lack of reference compounds. Natural product monomers, possessing diverse biological activities and excellent safety profiles, have emerged as potential candidates for preventing and treating PF. The effective anti-PF ingredients identified can be generally divided into flavonoids, saponins, polysaccharides, and alkaloids. Specifically, these monomeric compounds can attenuate inflammatory response, oxidative stress, and other physiopathological processes of the lung through many signaling pathways. They also improve pulmonary factors. Additionally, they ameliorate epithelial-mesenchymal transition (EMT) and fibroblast-myofibroblast transdifferentiation (FMT) by regulating multiple signal amplifiers in the lungs, thereby mitigating PF. This review highlights the significant role of monomer compounds derived from natural products in reducing inflammation, oxidative stress, and inhibiting EMT process. The article provides comprehensive information and serves as a solid foundation for further exploration of new strategies to harness the potential of botanicals in the treatment of PF.

A cross-sectional study on the mental health of patients with COVID-19 1 year after discharge in Huanggang, China.

OBJECTIVE: This study is aimed to investigate the mental health status of COVID-19 survivors 1 year after discharge from hospital and reveal the related risk factors. METHODS: From April 11 to May 11, 2021, 566 COVID-19 survivors in Huanggang city were recruited through their primary doctors. A total of 535 participants (94.5%) admitted to participate in the survey and completed the questionnaires. Five scales were applied including 7-Items Generalized Anxiety Disorder Scale, Patient Health Questionnaire-9, Impact of Event Scale-Revised, Pittsburgh Sleep Quality Index, and Fatigue Scale-14. The chi-square and the Fisher's exact test were used to evaluate the classification data, multivariate logistic regression was used to explore the related factors of sleep quality, fatigue, anxiety, depression, and post-traumatic stress disorder (PTSD). RESULTS: One year after being discharged, of the 535 COVID-19 survivors, 252 (47.1%) had poor sleep quality; 157 (29.3%) had the symptoms of fatigue; 84 (15.7%),112 (20.9%), and 130 (24.3%) suffered from symptoms of anxiety, depression, and PTSD, respectively. The logistic regression analysis showed that history of chronic disease was risk factor for poor sleep quality (OR 2.501; 95% CI, 1.618-3.866), fatigue (OR 3.284; 95% CI 2.143-5.033), PTSD (OR 2.323; 95% CI 1.431-3.773) and depression (OR 1.950; 95% CI 1.106-3.436) in COVID-19 survivors. Smoking contributed to the poor sleep quality (OR 2.005; 95% CI 1.044-3.850), anxiety (OR 4.491; 95% CI 2.276-8.861) and depression (OR 5.459; 95% CI 2.651-11.239) in survivors. Drinking influenced fatigue (OR 2.783; 95% CI 1.331-5.819) and PTSD (OR 4.419; 95% CI 1.990-9.814) in survivors. Compared with college-educated survivors, survivors with high school education were at higher risk for poor sleep quality (OR 1.828; 95% CI 1.050-3.181) and PTSD (OR 2.521; 95% CI 1.316-4.830), and survivors with junior high school education were at higher risk for PTSD (OR 2.078; 95% CI 1.039-4.155). Compared with overweight survivors (BMI ≥ 23.0), survivors with normal BMI (18.5-22.9) (OR 0.600; 95% CI 0.405-0.889) were at lower risk for fatigue. While being housewife (OR 0.390; 95% CI 0.189-0.803) was protective factor for fatigue and having more family members was protective factor for PTSD (OR 0.404 95% CI 0.250-0.653) in survivors. CONCLUSIONS: One year after infection, poor sleep quality, fatigue, anxiety, depression, and PTSD, still existed in a relatively high proportion of COVID-19 survivors. Chronic disease history was an independent risk factor for poor sleep quality, fatigue, depression, and PTSD. Participants with low education levels were more likely to have mental problems than the others. We should focus on the long-term psychological impact of COVID-19 on survivors, and the government should apply appropriate mental health services to offer psychiatric support.

Association between thyroid autoimmunity and the decline of ovarian reserve in euthyroid women.

RESEARCH QUESTION: Is thyroid autoimmunity (TAI) associated with the decline of ovarian reserve in euthyroid women? DESIGN: Case-control study. Data from 4302 euthyroid women with normal ovarian reserve (NOR) and low ovarian reserve (LOR), including biochemical premature ovarian insufficiency (POI) and overt POI, were retrospectively analysed. The prevalence and effect of TAI on ovarian reserve was evaluated between women with NOR and LOR. Status of ovarian insufficiency and TSH levels was further stratified for analysis. The correlation between anti-thyroid peroxidase antibody (TPOAb), anti-thyroglobulin antibody (TgAb) titres and ovarian reserve markers was also determined. RESULTS: The prevalence of positive TAI and TgAb was equally distributed between women with NOR and LOR (P = 0.080, P = 0.172); the prevalence of TPOAb positivity was higher in the LOR group (P = 0.005). After stratifying ovarian reserve and TSH, positive TAI, TPOAb and TGAb were significantly associated with overt POI when TSH was >2.5 µIU/ml (all P < 0.001); no association was observed with biochemical POI or overt POI when TSH was ≤2.5 µIU/ml. No correlation was found between TPOAb, TGAb titres and AMH (P = 0.218, P = 0.368, respectively), and bilateral AFC (P = 0.184, P = 0.315, respectively) in patients with LOR; only TPOAb titre was positively correlated with FSH (P = 0.039). CONCLUSIONS: Among the whole population of euthyroid women, TAI was not associated with low ovarian reserve but was significantly associated with overt POI in women with TSH>2.5 µIU/ml. Further basic studies on underlying mechanisms are needed.

Colchicine-Containing Nanoparticles Attenuates Acute Myocardial Infarction Injury by Inhibiting Inflammation.

PURPOSE: Anti-inflammatory therapy is important for reducing myocardial injury after acute myocardial infarction (MI). New anti-inflammatory drugs and their mechanism are necessary to be explored to improve clinical efficacy. We aimed to improve the efficacy of colchicine on attenuating MI injury by nano-drug delivery systems and to investigate the mechanism of anti-inflammatory. METHODS: A colchicine-containing delivery system based on calcium carbonate nanoparticles (ColCaNPs) was synthesized. The protection against MI by ColCaNPs was evaluated using an in vivo rat model established by ligating the left anterior descending coronary artery. Macrophage polarization and the levels of inflammatory cytokines were determined using immunohistochemistry, Western blot, and ELISA analysis. RESULTS: ColCaNP treatment showed about a 45% reduction in myocardial infarct size and attenuating myocardial fibrosis compared with groups without drug intervention after MI. Furthermore, ColCaNPs significantly decreased the levels of CRP, TNF-α, and IL-1ß in serum and the expression of proinflammatory cytokine in myocardial tissues after MI (p < 0.05). We also found that ColCaNPs notably restrained pyroptosis and inhibited inflammatory response by modulating on M1/M2 macrophage polarization and suppressing TLR4/NFκB/NLRP3 signal pathway. CONCLUSION: Colchicine-containing nanoparticles can protect against MI injury in a clinically relevant rat model by reducing inflammation. In addition, calcium carbonate nanoparticles can increase the cardioprotective effects of colchicine.

Efficacy and safety of soluble guanylate cyclase stimulators in patients with heart failure: A systematic review and meta-analysis.

Objective: To evaluate the efficacy and safety of soluble guanylate cyclase (sGC) stimulators in patients with heart failure (HF). Methods: A systematic literature search from several electronic databases (Web of Science, PubMed, Embase, Medline) was performed up until March 2021. Eligible studies included randomized controlled trials (RCTs) that compared sGC stimulators treatment with placebo. Data extracted from eligible RCTs were pooled using relative risk (RR) and weight mean difference (WMD) on random effect model or fixed effect model. Results: A total of eight RCTs involving 7225 patients met the inclusion criteria. For the efficacy endpoint, sGC stimulators significantly reduced HF-related hospitalization or cardiovascular (CV) death (RR = 0.92, 95%CI: 0.86-0.99; P = 0.03), but no relationship was found for 6-minute walking distance (6MWD) (SMD = 0.04, 95%CI: -0.09-0.17; P = 0.55). In addition, compared to control group, the change of NT-proBNP was statistically decreased in the riociguat group (SMD = -0.78, 95%CI: -1.09--0.47; P < 0.00), yet not in vericiguat group (SMD = 0.05, 95%CI: -0.19-0.28; P = 0.70). For the safety endpoint, there was no significant difference in all-cause mortality (RR = 0.98 95%CI: 0.88-1.09; P = 0.69) and serious adverse events (RR = 0.95, 95%CI: 0.892-1.02; P = 0.16) between SGC stimulants group and control group. Conclusion: The oral therapy with sGC stimulators including vericiguat and riociguat decreases the incidence of HF-related hospitalization or CV death with good tolerability and safety. The study did not support improvement in many parameters including 6MWD and NT-proBNP in HF patients.

Synthesis and cytotoxic activity of chalcone analogues containing a thieno[2,3-d]pyrimidin-2-yl group as the A-ring or B-ring.

Many natural or synthetic chalcones have potential anti-tumor activity. Here, we synthesized two series of chalcone analogues containing a thieno[2,3-d]pyrimidin-2-yl group and evaluated for their cytotoxic activity towards cultured human lung cancer A549 and colorectal HCT-116 cells. Among them, compound 8d was the most cytotoxic against HCT-116 cells, with an IC50 value of 2.65 µM. Analyses of the phenotypic changes induced by this compound found a dose-dependent accumulation of HCT-116 cells in sub-G1 phase, indicating that compound 8d might induce apoptosis. Furthermore, we found that 8d triggered mitochondrial membrane potential depolarization, promoted reactive oxygen species formation in HCT-116 cells, and increased the percentage of early and late apoptotic cells. Finally, immunoblotting indicated that 8d increased PARP-1 and caspases 3, 7 and 9 cleavage. These data suggest that compound 8d induces apoptosis via the mitochondrial death pathway.

Renal denervation improves cardiac function by attenuating myocardiocyte apoptosis in dogs after myocardial infarction.

BACKGROUND: Myocardial apoptosis is important in the pathogenesis and progression of myocardial infarction-induced heart failure (MI-HF). Renal sympathetic denervation (RDN) has become a promising therapeutic strategy for the treatment of HF. Previous studies have shown that RDN could improve heart function Yao et al. (Exp Ther Med 14:4104-4110, 2017). However, whether and how RDN regulates myocardial apoptosis in MI-HF is unclear. This study sought to evaluate the effects of RDN on cardiac function and apoptosis-related gene expression in MI-HF dogs. METHODS: Eighteen healthy mongrel dogs were randomly divided into control group(n = 6), model group(n = 6) and treatment group(n = 6). MI-HF was established in model group and treatment group by anhydrous alcohol embolization, after heart failure dogs in the treatment group and model group proceeded bilateral renal artery ablation and bilateral renal arteriography, respectively. The cardiac function parameters were evaluated by echocardiographic; the serum NT-BNP level was detected by ELISA; the degree of myocardial fibrosis was observed through masson staining; the expression of MMP-2, MMP-9 in the cardiac were got by immunohistochemistry. TUNEL method was used to observe cardiomyocyte apoptotsis and calculate the apoptosis index (AI). Relative expression of Bcl-2 and Bax, Caspase3 and GRP78 were detected using RT-PCR and Western Blot. Renal artery H&E staining and serum creatinine were conducted to access the efficacy and safety of RDN. RESULTS: Four weeks after RDN, the LVEDD, LVESD and LVEDP decreased, and the LVEF and LVSP increased in the treatment group compared with those in the control group (all P < 0.05). Moreover, NT-BNP, an indicator of cardiac function was decreased. Additionally, MMP-2 and MMP-9 levels in the myocardium decreased significantly in the treatment group. Furthermore, the levels of Bax, and caspase 3 decreased, while the level of Bcl-2 increased. Thus, myocardial apoptosis was attenuated in RDN treated dogs. We also found that the level of GRP78 which is activated in response to endoplasmic reticulum (ER) stress, was decreased. However, serum creatinine levels were not significantly different between the RND-treated dogs and the control dogs. CONCLUSION: Cardiac function was improved by RDN treatment through regulating apoptosis and ER stress in cardiomyocytes in dogs after MI.

Dietary oxidized tyrosine (O-Tyr) stimulates TGF-ß1-induced extracellular matrix production via the JNK/p38 signaling pathway in rat kidneys.

Oxidized tyrosine (O-Tyr) products have been detected in commercial food and have been demonstrated to induce liver injury in our previous study, but the precise mechanisms of the impact induced by dietary O-Tyr are still unclear. Kidney plays an important role in the metabolism of protein. Accumulation of O-Tyr products, especially the dityrosine (Dityr) and advanced oxidation protein products (AOPPs), in vivo was shown to be associated with many kidney diseases. Therefore, this study determined whether chronic exposure to dietary O-Tyr impaired renal function in rats. After O-Tyr treatment for 24 weeks, rats exhibited oxidative stress and protein oxidation in the kidneys, accompanied with inflammatory reaction and renal dysfunction. Elevated extracellular matrix (ECM) contents and the histological examination (HE and Masson stain) results indicated renal fibrosis. The Real-time PCR and Western blotting assay showed that O-Tyr activated phosphorylation of JNK/p38 and up-regulated the expression of transforming growth factor-ß1 (TGF-ß1) and Smad 2/3. These results suggest that dietary O-Tyr could induce oxidative stress, inflammation and renal fibrosis through JNK/p38/TGF-ß1 signaling pathway. Dityr (accounting for 22 % of the total O-Tyr material) may be responsible for the O-Tyr-induced injury. This study also provides a modified procedure for separation and purification of Dityr, the main oxidized product in O-Tyr.

Dityrosine administration induces dysfunction of insulin secretion accompanied by diminished thyroid hormones T3 function in pancreas of mice.

Oxidized tyrosine products are commonly found in food with high protein content and have been demonstrated to cause damage of liver and kidney in our previous studies. Dityrosine (Dityr) is a typical oxidized tyrosine product. Due to its structural homology with thyroid hormones T3, we assumed that one of the endocrine systems most likely considered in connection with its disruption by Dityr may be the T3 action. T3 plays important roles in insulin synthesis, and thyroid hormone resistance (RTH) is associated with the impairment of glucose metabolism. Therefore, this study determined whether Dityr exposure impaired T3 function in pancreas leading to glucose metabolism disruption. After 10-week gavage with Dityr, mice exhibited impaired glucose tolerance and disturbed energy metabolism. The elevated free THs content in plasma, the up-regulation of THs synthesis-specific genes expressions in thyroid glands, and the increased thyroid follicles histology shapes and areas indicated that Dityr enhanced the THs synthesis in thyroid glands. In addition, Dityr-induced RTH, which reflected as elevated plasma free THs in the presence of unsuppressed thyroid stimulating hormone. The mRNA downregulation of membrane transporter of T3 (MCT8) and co-activator factors (RXRα, Src-1), together with the decreased protein level of thyroid hormone receptor ß1 (TRß1) in pancreas illustrated that the activation ability of T3 to downstream gene involved in insulin synthesis was suppressed by Dityr. In MIN-6 cell experiment, T3 improved glucose-stimulated insulin secretion by upregulating mRNA levels of insulin synthesis-related genes (Ins2, MafA, Pdx1) and T3 action-related genes, as well as increasing protein level of TRß1. These data suggest that Dityr suppress T3-regulated insulin synthesis stimulated by glucose via an indirect way of decreasing sensibility to T3 in pancreas. All these findings indicate that Dityr can disrupt THs function in pancreas leading to glucose metabolism disorder.

[Effects of tyrosine oxidation products on redox state in myocardium of rats].

OBJECTIVE: To explore the effects of tyrosine oxidized products (TOP) on the redox state of rats myocardium and investigate the oxidative damage mechanism. METHODS: Male SD Rats were randomly assigned to three groups and treated respectively with normal diet (Group C), 440 mg/kg TOP (Group TOP), 440 mg/kg tyrosine oxidized products plus 5 mg/kg lipoic acid (Group TOP + LA). Indicators of oxidative stress in blood and myocardial were measured at the end of 6 weeks, 12 weeks and 24 weeks. RT-PCR was used to detect mRNA expression of Nrf2, Trx, NF-κB and AP-1 in myocardium. RESULTS: Compared to the control group (Group C), reactive oxygen species (ROS), carbonyl (PC), malondialdehyde (MDA), dityrosine (Dityr), 3-nitrotyrosine (3-NT) in rats blood and myocardium were all significantly increased in the TOP group (P < 0.05). Total antioxidant capacity (T-AOC), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), reducing glutathione (GSH) and oxidized glutathione (GSSG) levels all decreased significantly (P < 0.05). The mRNA expression of Nrf2, Trx-1, NF-κB, AP-1 RNA significantly up-regulated (P < 0.05) in the TOP group compared to the control. CONCLUSION: Tyrosine oxidized products impairs antioxidant defense system and lead to accumulation of protein oxidation products in rats myocardium. Moreover, lipoic acid performs a positive effect in the protective reaction, which may adjusted by regulation of redox signaling pathway.

Shaking table test on damage mechanism of bedrock and overburden layer slope based on the time-frequency analysis method.

To systematically analyze the damage caused by bedrock and overburden layer slope under seismic action, a set of large-scale shaking table test was designed and completed. Interpolation of the acceleration amplification coefficient, Hilbert-Huang transform and transfer function was adopted. The damage mechanisms of the bedrock and overburden layer slopes under seismic action are systematically summarized in terms of slope displacement, acceleration field, vibration amplitude, energy, vibration frequency, and damage level. The results show a significant acceleration amplification effect within the slope under seismic action and a localized amplification effect at the top and trailing edges of the slope. With an increase in the input seismic intensity, the difference in the vibration amplitude between the overburden layer and bedrock increased, low-frequency energy of the overburden layer was higher than that of the bedrock, and the vibration frequency of the overburden layer was smaller than that of the bedrock. These differences cause the interface to experience cyclic loading continuously, resulting in the damage degree of the overburden layer at the interface being larger than that of the bedrock, reduction of the shear strength, and eventual formation of landslides. The displacement in the middle of the overburden is always greater than that at the top. Therefore, under the action of an earthquake and gravity, the damage mode of the bedrock and overburden layer slope is such that the leading edge of the critical part pulls and slides at the trailing edge, and multiple tensile cracks are formed on the slope surface.

Knowledge mapping of links between dendritic cells and allergic diseases: A bibliometric analysis (2004-2023).

In this study, bibliometric analysis was carried out to comprehend the global research trends, hotspots, scientific frontiers, and output characteristics of the links between dendritic cells (DCs) and allergic diseases from 2004 to 2023. Publications and their recorded information were retrieved from the Web of Science Core Collection (WoSCC). VOSviewer and Citespace were used to visualize the hotspots and trends of research area. ChemBio 3D, Autodock tools, and Discovery Studio were used to visualize the molecular docking results of hotspots. A total of 4861 articles were retrieved. The number of publications (Np) was in a high and stable state. Years 2011 and 2017 were two peaks in Np. The largest contributor in terms of publications, scholars, and affiliations was the USA. The paper published in NATURE MEDICINE (IF: 82.9) and written by Trompette, A in 2006 had the highest global citation score (GCS). Keywords, such as "asthma," "t-cells," "inflammation," "expression," "atopic dermatitis," "food allergy," "gut microbiota," "murine model," and "cytokines related to immunity" appeared the most frequently. Most of the binding free energy of the key active components of Saposhnikovia divaricata docked with toll-like receptor proteins well. This bibliometric study aimed to help better comprehend the present state and make decisions from a macro viewpoint.

Methylation-driven mechanisms of allergic rhinitis during pollen and non-pollen seasons using integrated bioinformatics analysis.

Background: Allergic rhinitis (AR) is a widespread allergic airway disease that results from a complex interplay between genetic and environmental factors and affects approximately 10%-40% of the global population. Pollen is a common allergen, and exposure to pollen can cause epigenetic changes. However, the mechanism underlying pollen-induced DNA methylation changes and their potential effects on the allergic march are still unclear. The purpose of this study was to explore the methylation-driven mechanisms of AR during the pollen and non-pollen seasons using bioinformatics analysis and to investigate their relationship with asthma. Methods: We downloaded DNA methylation and gene expression data from the GEO database (GSE50387: GSE50222, GSE50101) and identified differentially methylated positions (DMPs) and differentially expressed genes (DEGs) during the pollen and non-pollen seasons using the CHAMP and limma packages. Through correlation analysis, we identified methylation-driven genes and performed pathway enrichment analysis to annotate their functions. We incorporated external data on AR combined with asthma (GSE101720) for analysis to identify key CpGs that promote the transformation of AR to asthma. We also utilized external data on olive pollen allergy (GSE54522) for analysis to validate the methylation-driven genes. Weighted correlation network analysis (WGCNA) was employed to identify gene modules significantly correlated with pollen allergy. We extracted genes related to the key methylation-driven gene ZNF667-AS1 from the significant module and performed pathway intelligent clustering using KOBAS-i. We also utilized gene set enrichment analysis to explore the potential function of ZNF667-AS1. Results: We identified 20 and 24 CpG-Gene pairings during the pollen and non-pollen seasons. After incorporating external data from GSE101720, we found that ZNF667-AS1 is a key gene that may facilitate the transformation of AR into asthma during the pollen season. This finding was further validated in another external dataset, GSE54522, which is associated with pollen allergy. WGCNA identified 17 modules, among which the blue module showed significant correlation with allergies. ZNF667-AS1 was located in the blue module. We performed pathway analysis on the genes correlated with ZNF667-AS1 extracted from the blue module and identified a prominent cluster of pathways in the KOBAS-i results, including Toll-like receptor (TLR) family, MyD88, MAPK, and oxidative stress. Gene set enrichment analysis around cg05508084 (paired with ZNF667-AS1) also indicated its potential involvement in initiating and modulating allergic inflammation from the perspective of TLR and MAPK signaling. Conclusion: We identified methylation-driven genes and their related pathways during the pollen and non-pollen seasons in patients with AR and identified key CpGs that promote the transformation of AR into asthma due to pollen exposure. This study provides new insights into the underlying molecular mechanisms of the transformation of AR to asthma.

Early-life antibiotic exposure promotes house dust mite-induced allergic airway inflammation by impacting gut microbiota and lung lipid metabolism.

Asthma is a chronic inflammatory respiratory disease. Early-life antibiotic exposure is a unique risk factor for the incidence and severity of asthma later in life. Perturbations in microbial-metabolite-immune interaction caused by antibiotics are closely associated with the pathogenesis of allergy and asthma. We investigated the effect of early intervention with common oral antibiotics on later asthma exacerbations and found that different antibiotic exposures can amplify different types of immune responses induced by HDM. Cefixime (CFX) promoted a biased type 2 inflammation, azithromycin (AZM) enhanced Th17 immune response, and cefuroxime axetil (CFA) induced eosinophils recruitment. Moreover, early-life antibiotic exposure can have short- and long-term effects on the abundance, composition, and diversity of the gut microbiota. In the model of CFX-promoted type 2 airway inflammation, fecal metabolomics indicated abnormal lipid metabolism and T cell response. Lipidomic also suggested allergic airway inflammation amplified by CFX is closely associated with abnormal lipid metabolism in lung tissues. Moreover, abnormalities in lipid metabolism-related genes (LMRGs) were found to have cellular heterogeneity be associated with asthma severity by bioinformatics analysis.

Ten-year follow-up of very-high risk hypertensive patients undergoing renal sympathetic denervation.

OBJECTIVES: Renal denervation (RDN) has been proven to be effective in lowering blood pressure (BP) in patients, but previous studies have had short follow-ups and have not examined the effects of RDN on major cardiovascular outcomes. This study aimed to demonstrate the effectiveness and safety of RDN in the long-term treatment of hypertension and to determine if it has an effect on cardiovascular outcomes. METHODS: All patients with resistant hypertension who underwent RDN between 2011 and 2015 at Tianjin First Central Hospital were included in the study. Patients were followed up at 1,5 and 10 years and the longest follow-up was 12 years. Data were collected on office BP, home BP, ambulatory BP monitoring (ABPM), renal function, antihypertensive drug regimen, major adverse events (including acute myocardial infarction, stroke, cardiovascular death and all cause death) and safety events. RESULTS: A total of 60 participants with mean age 50.37 ±â€Š15.19 years (43.33% female individuals) completed long-term follow-up investigations with a mean of 10.02 ±â€Š1.72 years post-RDN. Baseline office SBP and DBP were 179.08 ±â€Š22.05 and 101.17 ±â€Š16.57 mmHg under a mean number of 4.22 ±â€Š1.09 defined daily doses (DDD), with a reduction of -35.93/-14.76 mmHg as compared with baseline estimates ( P  < 0.0001). Compared with baseline, ambulatory SBP and DBP after 10-years follow-up were reduced by 14.31 ±â€Š10.18 ( P  < 0.001) and 9 ±â€Š4.35 ( P  < 0.001) mmHg, respectively. In comparison to baseline, participants were taking fewer antihypertensive medications ( P  < 0.001), and their mean heart rate had decreased ( P  < 0.001). Changes in renal function, as assessed by estimated glomerular filtration rate (eGFR) and creatinine, were within the expected rate of age-related decline. No major adverse events related to the RDN procedure were observed in long-term consequences. All-cause mortality and cardiovascular mortality rates were 10 and 8.34%, respectively, for the 10-year period. CONCLUSION: The BP-lowering effect of RDN was safely sustained for at least 10 years post-procedure. More importantly, to the best of my knowledge, this is the first study to explore cardiovascular and all-cause mortality at 10 years after RDN.

Molecular characterization of allergic constitution based on network pharmacology and multi-omics analysis methods.

The objective of this study was to identify critical pathways associated with allergic constitution. Shared genes among allergic rhinitis (AR), asthma (AA), and atopic dermatitis (AD) were extracted from the GWAS catalog. RNA-seq data of AR, AA, and AD from gene expression omnibus (GEO) database were preprocessed and subjected to differential gene expression analysis. The differentially expressed genes (DEGs) were merged using the Robust Rank Aggregation (RRA) algorithm. Weighted gene co-expression network analysis (WGCNA) was performed to identify modules associated with allergies. Components of Guominkang (GMK) were obtained from 6 databases and activate components were identified by SwissADME website. Utilizing the SwissTarget Prediction, PharmMapper, SymMap, and HERB, the targets of GMK were predicted and subsequently validated using gene chip data from our team previous study. Differentially expressed proteins (DEPs) related to the allergic constitution were also extracted based on a previous study. Pathway enrichment analysis was performed using KOBAS-i on the GWAS, RRA, WGCNA modules, DEPs, and GMK targets. P values from multi-omics datasets were combined by meta-analysis, and Bonferroni correction was applied. The significant pathways were further validated using Gene Set Enrichment Analysis (GSEA) with intervention data of GMK. The GWAS results yielded 172 genes. Four datasets AR1, AA1, AD1, and AD2 were acquired from GSE75011, GSE125916, and GSE184237. The RRA algorithm identified 19 upregulated and 20 downregulated genes. WGCNA identified 5 significant modules, with the blue and turquoise modules displaying a moderate correlation with allergies. By performing network pharmacology analysis, we identified 127 active ingredients of GMK and predicted 618 targets. Validation using gene chip data confirmed 107 GMK targets. Single-omics pathway analysis was conducted using KOBAS-i, and 39 significant pathways were identified across multiple omics datasets. GSEA analysis using GMK intervention data identified 11 of 39 significant pathways as the final key pathways associated with the allergic constitution. Through multi-omics integrated pathway analysis, we identified 11 critical pathways of allergic constitution, including TH1 and TH2 cell differentiation, TLR cascade, and TH17 cell differentiation. Identifying these pathways suggests that the observed alterations at the pathway level may play significant roles in the molecular characteristics of the allergic constitution.

Bufotalin attenuates pulmonary fibrosis via inhibiting Akt/GSK-3ß/ß-catenin signaling pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with no cure. Bufotalin (BT), an active component extracted from Venenum Bufonis, has been prescribed as a treatment for chronic inflammatory diseases. However, whether BT has antifibrotic properties has never been investigated. In this study, we report on the potential therapeutic effect and mechanism of BT on IPF. BT was shown to attenuate lung injury, inflammation, and fibrosis as well as preserve pulmonary function in bleomycin (BLM)-induced pulmonary fibrosis model. We next confirmed BT's ability to inhibit TGF-ß1-induced epithelial-mesenchymal transition (EMT) and myofibroblast activation (including differentiation, proliferation, migration, and extracellular matrix production) in vitro. Furthermore, transcriptional profile analysis indicated the Wnt signaling pathway as a potential target of BT. Mechanistically, BT effectively prevented ß-catenin from translocating into the nucleus to activate transcription of profibrotic genes. This was achieved by blunting TGF-ß1-induced increases in phosphorylated Akt Ser437 (p-Akt S437) and phosphorylated glycogen synthase kinase (GSK)-3ß Ser9 (p-GSK-3ß S9), thereby reactivating GSK-3ß. Additionally, the antifibrotic effects of BT were further validated in another in vivo model of radiation-induced pulmonary fibrosis. Collectively, these data demonstrated the potent antifibrotic actions of BT through inhibition of Akt/GSK-3ß/ß-catenin axis downstream of TGF-ß1. Thus, BT could be a potential option to be further explored in IPF treatment.