Frailty mediating the causality between leucocyte telomere length and mortality: a cohort study of 440,551 UK Biobank participants.

Introduction: Previous studies reported leucocyte telomere length (LTL) and frailty were associated with mortality, but it remains unclear whether frailty serves as a mediator in the relationship between leucocyte telomere length and mortality risk. This study aimed to evaluate how measuring LTL and frailty can support early monitoring and prevention of risk of mortality from the prospective of predictive, preventive, and personalized medicine (PPPM/3PM). Methods: We included 440,551 participants from the UK Biobank between the baseline visit (2006-2010) and November 30, 2022. The time-dependent Cox proportional hazards model was conducted to assess the association between LTL and frailty index with the risk of mortality. Furthermore, we conducted causal mediation analyses to examine the extent to which frailty mediated the association between LTL and mortality. Results: During a median follow-up of 13.74 years, each SD increase in LTL significantly decreased the risk of all-cause [hazard ratio (HR): 0.94, 95% confidence interval (CI): 0.93-0.95] and CVD-specific mortality (HR: 0.92, 95% CI: 0.90-0.95). The SD increase in FI elevated the risk of all-cause (HR: 1.35, 95% CI: 1.34-1.36), CVD-specific (HR: 1.47, 95% CI: 1.44-1.50), and cancer-specific mortality (HR: 1.22, 95% CI: 1.20-1.24). Frailty mediated approximately 10% of the association between LTL and all-cause and CVD-specific mortality. Conclusions: Our results indicate that frailty mediates the effect of LTL on all-cause and CVD-specific mortality. There findings might be valuable to predict, prevent, and reduce mortality through primary prevention and healthcare in context of PPPM. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00355-7.

Chronic exposure to 3,6-dichlorocarbazole exacerbates non-alcoholic fatty liver disease in zebrafish by disrupting lipid metabolism and inducing special lipid biomarker accumulation.

Most previous studies have focused primarily on the adverse effects of environmental chemicals on organisms of good healthy. Although global prevalence of non-alcoholic fatty liver disease (NAFLD) has reached approximately 25%, the impact of environmentally persistent organic chemicals on organisms with NAFLD is substantially unknown. Polyhalogenated carbazoles (PHCZs) as emerging contaminants have been frequently detected in the environment and organisms. In this study, we investigated the impact of the most frequently detected PHCZs, 3,6-dichlorocarbazole (36-CCZ), on zebrafish with high-fat diet (HFD)-induced NAFLD. After 4 weeks exposure to environmentally relevant concentrations of 36-CCZ (0.16-0.45 µg/L), the accumulation of lipid in zebrafish liver dramatically increased, and the transcription of genes involved in lipid synthesis, transport and oxidation was significantly upregulated, demonstrating that 36-CCZ had exacerbated the NAFLD in zebrafish. Lipidomic analysis indicated that 36-CCZ had significantly affected liver lipid metabolic pathways, mainly including glycerolipids and glycerophospholipids. Additionally, fifteen lipids were identified as potential lipid biomarkers for 36-CCZ exacerbation of NAFLD, including diacylglycerols (DGs), triglycerides (TGs), phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), phosphatidic acid (PA), and phosphatidylinositol (PI). These findings demonstrate that long-term exposure to 36-CCZ can promote the progression of NAFLD, which will contribute to raising awareness of the health risks of PHCZs.

Tissue-specific accumulation, depuration and histopathological effects of 3,6-dichlorocarbazole and 2,7-dibromocarbazole in adult zebrafish (Danio rerio).

Although polyhalogenated carbazoles have been detected with increasing frequency in aquatic ecosystems, their bioaccumulation in fish and corresponding pathological effects related to bioaccumulation are still unclear. Here, we investigated the tissue-specific accumulation, depuration, and histopathological effects of two typical PHCZs, 3,6-dichlorocarbazole (36-CCZ) and 2,7-dibromocarbazole (27-BCZ), in adult zebrafish at three levels (0, 0.15 µg/L (5 × environmentally relevant level), and 50 µg/L (1/10 LC50). The lowest concentrations of 36-CCZ (1.2 µg/g ww) and 27-BCZ (1.4 µg/g ww) were observed in muscle, and the greatest concentrations of 36-CCZ (3.6 µg/g ww) and 27-BCZ (4 µg/g ww) were detected in intestine among the tested tissues. BCFww of 36-CCZ and 27-BCZ in zebrafish ranged from 172.9 (muscle) to 606.6 (intestine) and 285.2 (muscle) to 987.5 (intestine), respectively, indicating that both 36-CCZ and 27-BCZ have high potential of bioaccumulation in aquatic system. The 0.15 µg/L level of 36-CCZ or 27-BCZ caused lipid accumulation in liver, while 50 µg/L of 36-CCZ or 27-BCZ induced liver lesions such as fibrous septa, cytolysis, and nuclear dissolution. Brain damage such as multinucleated cells and nuclear solidification were only observed at 50 µg/L of 27-BCZ. This study provided valuable information in assessing the health and ecological risks of 36-CCZ and 27-BCZ.

Role of AT-rich interaction domain 1A in gastric cancer immunotherapy: Preclinical and clinical perspectives.

The application of immune checkpoint inhibitor (ICI) using monoclonal antibodies has brought about a profound transformation in the clinical outcomes for patients grappling with advanced gastric cancer (GC). Nonetheless, despite these achievements, the quest for effective functional biomarkers for ICI therapy remains constrained. Recent research endeavours have shed light on the critical involvement of modified epigenetic regulators in the pathogenesis of gastric tumorigenesis, thus providing a glimpse into potential biomarkers. Among these regulatory factors, AT-rich interaction domain 1A (ARID1A), a pivotal constituent of the switch/sucrose non-fermentable (SWI/SNF) complex, has emerged as a promising candidate. Investigations have unveiled the pivotal role of ARID1A in bridging the gap between genome instability and the reconfiguration of the tumour immune microenvironment, culminating in an enhanced response to ICI within the landscape of gastric cancer treatment. This all-encompassing review aims to dissect the potential of ARID1A as a valuable biomarker for immunotherapeutic approaches in gastric cancer, drawing from insights garnered from both preclinical experimentation and clinical observations.

A two-sample Mendelian randomization study of atherosclerosis and dementia.

The causality between atherosclerosis and dementia remains unclear. This study aimed to explore the causal effect of atherosclerosis related indicators on dementia risk based on two-sample Mendelian randomization (MR) using summary statistics of genome-wide association studies (GWASs). The inverse variance weighted (IVW) method was performed as the main analysis, supplemented by different sensitivity analyses. Suggestive evidence indicated that peripheral arterial disease (PAD) (odds ratio (OR): 0.864, 95% confidence interval (CI): 0.797-0.937), coronary atherosclerosis (CoAS) (OR: 0.927, 95% CI: 0.860-0.998) and atherosclerosis, excluding cerebral, coronary, and PAD (ATHSCLE) (OR: 0.812, 95% CI: 0.725-0.909) were inversely associated with the risk of AD. The sensitivity analysis confirmed a suggestive reverse effect of ATHSCLE on the risk of frontotemporal dementia (FTD) (OR, 0.812, 95% CI, 0.725-0.909). Findings provide suggestive evidence that PAD, CoAS, and ATHSCLE might be associated with the risk of AD or FTD, which requires further exploration in larger samples.

Broussonin E against acute respiratory distress syndrome: the potential roles of anti-inflammatory.

We applied network pharmacology and molecular docking analyses to study the efficacy of Broussonin E (BRE) in acute respiratory distress syndrome (ARDS) treatment and to determine the core components, potential targets, and mechanism of action of BRE. The SwissTargetprediction and SEA databases were used to predict BRE targets, and the GeneCards and OMIM databases were used to predict ARDS-related genes. The drug targets and disease targets were mapped to obtain an intersecting drug target gene network, which was then uploaded into the String database for protein-protein interaction network analysis. The intersecting gene was also uploaded into the DAVID database for gene ontology enrichment analysis and Kyoto encyclopedia of genes and genomes pathway analysis. Molecular docking analysis was performed to verify the interaction of BRE with the key targets. Finally, to validate the experiment in vivo, we established an oleic acid-induced ARDS rat model and evaluated the protective effect of BRE on ARDS by histological evaluation and enzyme-linked immunosorbent assay. Overall, 79 targets of BRE and 3974 targets of ARDS were predicted, and 79 targets were obtained after intersection. Key genes such as HSP90AA1, JUN, ESR1, MTOR, and PIK3CA play important roles in the nucleus and cytoplasm by regulating the tumor necrosis factor, nuclear factor-κB, and PI3K-Akt signaling pathways. Molecular docking results showed that small molecules of BRE could freely bind to the active site of the target proteins. In vivo experiments showed that BRE could reduce ARDS-related histopathological changes, release of inflammatory factors, and infiltration of macrophages and oxidative stress reaction. BRE exerts its therapeutic effect on ARDS through target and multiple pathways. This study also predicted the potential mechanism of BRE on ARDS, which provides the theoretical basis for in-depth and comprehensive studies of BRE treatment on ARDS.

A nanodrug simultaneously inhibits pancreatic stellate cell activation and regulatory T cell infiltration to promote the immunotherapy of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix flooded with immune suppressive cells, resulting in extremely poor clinical response to immunotherapy. It has been revealed that the activation of pancreatic stellate cells (PSCs) makes considerable contributions to the immunological "cold" tumor microenvironment (TME). Herein, we developed a polyamino acid-based nanodrug incorporating the PSC activation inhibitor calcipotriol and anti-CXCL12 siRNA. The nanodrug was easily prepared with a small particle size and is capable of penetrating pancreatic tumors to inactivate PSCs and downregulate CXCL12. The in vivo results of orthotopic pancreatic tumor treatment demonstrated that codelivery of calcipotriol and anti-CXCL12 siRNA remodeled the PDAC TME with reduced extracellular matrix and decreased immunosuppressive T cells. Eventually, the infiltration of cytotoxic T cells was increased, thereby acting with immune checkpoint blockade (ICB) therapy for immunologically "cold" pancreatic tumors. In the present study, we propose a promising paradigm to improve the immunotherapy outcome of PDAC using nanodrugs that synchronously inhibit PSC activation and regulatory T-cell infiltration. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix (ECM) that impedes the tumor infiltration of therapeutic agents and cytotoxic T lymphocytes, resulting in a poor clinical response to immunotherapy. In the present study, we proposed a promising approach for enhanced immunotherapy of pancreatic cancer. Specifically, a nanodrug incorporating calcipotriol and anti-CXCL12 siRNA was synthesized to synchronously inactivate matrix-producing pancreatic stellate cells and suppress the infiltration of regulatory T cells. The reduced ECM removed the pathological barrier, preventing nanodrug penetration and effector T-cell infiltration, leading to a conversion of the immunosuppressive "cold" microenvironment to a "hot" microenvironment, which eventually boosted the immunotherapy of anti-PD-1 antibodies in pancreatic cancer.

PEG-Sheddable Nanodrug Remodels Tumor Microenvironment to Promote Effector T Cell Infiltration and Revise Their Exhaustion for Breast Cancer Immunotherapy.

Low infiltration of cytotoxic T lymphocytes and their exhaustion manifest the two concurrent main hurdles for achieving effective tumor immunotherapy of triple-negative breast cancer. It is found that Galectin-9 blockage can revise the exhaustion of effector T cells, meanwhile the repolarization of protumoral M2 tumor-associated macrophages (TAMs) into tumoricidal M1-like ones can recruit effector T cells infiltrating into tumor to boost immune responses. Herein, a sheddable PEG-decorated and M2-TAMs targeted nanodrug incorporating Signal Transducer and Activator of Transcription 6 inhibitor (AS) and anti-Galectin-9 antibody (aG-9) is prepared. The nanodrug responds to acidic tumor microenvironment (TME) with the shedding of PEG corona and the release of aG-9, exerting local blockade of PD-1/Galectin-9/TIM-3 interaction to augment effector T cells via exhaustion reversing. Synchronously, targeted repolarization of M2-TAMs into M1 phenotype by AS-loaded nanodrug is achieved, which promotes tumor infiltration of effector T cells and thus synergizes with aG-9 blockade to boost the therapeutic efficacy. Besides, the PEG-sheddable approach endows nanodrug with stealth ability to reduce immune-related adverse effects caused by AS and aG-9. This PEG sheddable nanodrug holds the potential to reverse the immunosuppressive TME and increase effector T cell infiltration, which dramatically enhances immunotherapy in highly malignant breast cancer.

Novel dual CAFs and tumour cell targeting pH and ROS dual sensitive micelles for targeting delivery of paclitaxel to liver cancer.

Tumour development is not only an independent event of genetic mutation and overgrowth of tumour cells but is the result of a synergistic interaction between a malignant tumour and its surrounding tumour stromal microenvironment. In this paper, we address the shortcomings of current tumour therapy by focussing on the tumour itself and the surrounding microenvironment to achieve a two-pronged targeting model. In this paper, a dual-targeting, pH/reactive oxygen species (ROS) sensitive nano-drug delivery system for tumour cells and CAFs was designed. A hyaluronic acid (HA) with CD44 receptor targeting on the surface of tumour cells was selected as the main carrier material, and a dipeptide Z-glycine-proline (ZGP) with specific targeting of fibroblast activating protein (FAP) on the surface of CAFs was modified on HA to achieve precise targeting of CAFs, open the physical barrier of tumour cells and improve the deep penetration effect of the tumour, while introducing thioketone bond and ketone condensation bond to take advantage of the highly reactive ROS and low pH microenvironment at the tumour site to achieve chemical bond breaking of nano micelles encapsulating paclitaxel (PTX), drug release, and thus drug aggregation at the tumour site and improved bioavailability of the drug.

Vascular endothelial growth factor and risk of malignant brain tumor: A genetic correlation and two-sample Mendelian randomization study.

Objective: The relationship between vascular endothelial growth factor (VEGF) and the risk of malignant brain tumors has always been a concern in the medical field. However, the causal inferences from published observational studies on this issue may be affected by confounders, coinheritability and reverse causality. We aimed to investigate the causal relationship between VEGF and different types of malignant brain tumors. Methods: Using publicly available summary data from genome-wide association studies (GWAS) of VEGF (n=16,112) and different types of malignant brain tumors (n=174,097-174,646), we adopted a standard two-sample bidirectional Mendelian randomization (MR) to estimate potential causal associations of circulating VEGF levels and the risk of malignant brain tumors. Inverse variance weighted (IVW) was used as the primary analysis method to estimate causality. MR-Egger regression, weighted median (WM), penalty weighted median (PWM), MR robust adjusted profile score (MR.RAPS) and causal analysis using summary effect estimates (CAUSE) methods were used in sensitivity analyses to verify the robustness of the findings. Meanwhile, we applied the MR pleiotropy residual sum and outlier (MR-PRESSO) test and PhenoScanner tool to identify and remove potential horizontal pleiotropic single nucleotide polymorphisms (SNPs). Additionally, linkage disequilibrium score regression (LDSC) analysis was conducted to assess the coinheritability of exposure and outcome. Results: A total of 6 (VEGF), 12 (malignant brain tumor), 13 (brain glioblastoma) and 12 (malignant neoplasm of meninges) SNPs were identified as valid instrumental variables. No evidence supported a causal relationship between circulating VEGF levels and the risk of malignant brain tumors (forwards: odds ratio (OR) = 1.277, 95% confidence interval (CI), 0.812~2.009; reversed: ß = 0.005, 95% CI, -0.029~0.038), brain glioblastoma (forwards: OR (95% CI) = 1.278(0.463~3.528); reversed: ß = 0.010, 95% CI, -0.002~0.022) and malignant neoplasm of meninges (forwards: OR (95% CI) = 0.831(0.486~1.421); reversed: ß = 0.010, 95% CI, -0.030~0.050) using the main IVW method. Outliers and pleiotropy bias were not detected by sensitivity analyses and pleiotropy-robust methods in any estimates. LDSC failed to identify genetic correlations between VEGF and different types of malignant brain tumors. Conclusions: Our findings reported no coinheritability and failed to provide evidence for causal associations between VEGF and the risk of different types of malignant brain tumors. However, certain subtypes of VEGF for which genetic predictors have not been identified may play a role and need to be further investigated.

T cell-mediated targeted delivery of tadalafil regulates immunosuppression and polyamine metabolism to overcome immune checkpoint blockade resistance in hepatocellular carcinoma.

BACKGROUND: Immune checkpoint blockade (ICB) monotherapy provides poor survival benefit in hepatocellular carcinoma (HCC) due to ICB resistance caused by immunosuppressive tumor microenvironment (TME) and drug discontinuation resulting from immune-related side effects. Thus, novel strategies that can simultaneously reshape immunosuppressive TME and ameliorate side effects are urgently needed. METHODS: Both in vitro and orthotopic HCC models were used to explore and demonstrate the new role of a conventional, clinically used drug, tadalafil (TA), in conquering immunosuppressive TME. In detail, the effect of TA on M2 polarization and polyamine metabolism in tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) was identified. After making clear the aforementioned immune regulatory effect of TA, we introduced a nanomedicine-based strategy of tumor-targeted drug delivery to make better use of TA to reverse immunosuppressive TME and overcome ICB resistance for HCC immunotherapy. A dual pH-sensitive nanodrug simultaneously carrying both TA and programmed cell death receptor 1 antibody (aPD-1) was developed, and its ability for tumor-targeted drug delivery and TME-responsive drug release was evaluated in an orthotopic HCC model. Finally, the immune regulatory effect, antitumor therapeutic effect, as well as side effects of our nanodrug combining both TA and aPD-1 were analyzed. RESULTS: TA exerted a new role in conquering immunosuppressive TME by inhibiting M2 polarization and polyamine metabolism in TAMs and MDSCs. A dual pH-sensitive nanodrug was successfully synthesized to simultaneously carry both TA and aPD-1. On one hand, the nanodrug realized tumor-targeted drug delivery by binding to circulating programmed cell death receptor 1-positive T cells and following their infiltration into tumor. On the other hand, the nanodrug facilitated efficient intratumoral drug release in acidic TME, releasing aPD-1 for ICB and leaving TA-encapsulated nanodrug to dually regulate TAMs and MDSCs. By virtue of the combined application of TA and aPD-1, as well as the efficient tumor-targeted drug delivery, our nanodrug effectively inhibited M2 polarization and polyamine metabolism in TAMs and MDSCs to conquer immunosuppressive TME, which contributed to remarkable ICB therapeutic efficacy with minimal side effects in HCC. CONCLUSIONS: Our novel tumor-targeted nanodrug expands the application of TA in tumor therapy and holds great potential to break the logjam of ICB-based HCC immunotherapy.

Genetic association and causal inference between lung function and venous thromboembolism.

BACKGROUND: Previous studies have indicated that lower lung function is related to a higher risk of venous thromboembolism (VTE). However, causal inferences may be affected by confounders, coheritability or reverse causality. We aimed to explore the causal association between lung function and VTE. METHODS: Summary data from public genome-wide association studies (GWAS) for lung function and VTE were obtained from published meta-analysis studies and the FinnGen consortium, respectively. Independent genetic variables significantly related to exposure were filtered as proxy instruments. We adopted linkage disequilibrium score regression (LDSC) and two-sample Mendelian randomization (MR) analyses to infer the genetic backgrounds and causal associations between different lung functions and VTE events. RESULTS: LDSC showed a genetic correlation between forced expiratory volume in one second (FEV1) and deep vein thrombosis (DVT) (rg = - 0.189, P = 0.005). In univariate MR (UVMR), there was suggestive evidence for causal associations of genetically predicted force vital capacity (FVC) with DVT (odds ratio (OR) 0.774; 95% confidence interval (CI) 0.641-0.934) via forwards analysis and genetically predicted pulmonary embolism (PE) with FVC (OR 0.989; 95% CI 0.979-0.999) via reverse analysis. Multivariate MR (MVMR) analyses of lung function-specific SNPs suggested no significant direct effects of lung function on VTE, and vice versa. Of note is the borderline causal effect of PE on FEV1 (OR 0.921; 95% CI 0.848-1.000). CONCLUSIONS: Our findings identified a coheritability of FEV1 (significant) and FVC (suggestive) with DVT. There was no convincing causal relationship between lung function and the risk of VTE events. The borderline causal effect of PE on FEV1 and the significant genetic correlation of FEV1 with DVT may have clinical implications for improving the quality of existing prevention and intervention strategies.

Reverse homodigital dorsoradial flaps for thumb coverage obtained good sensory recovery after a long time follow up.

Reverse homodigital dorsoradial flap (RHDF) of the thumb has become a qualified option for the reconstruction of thumb tissue defects. However, the sensory recovery of the flap in long term is still unknown. Therefore, this study focused on the sensory recovery of RHDFs for the coverage of thumb in hand after a long-term follow-up. From January 2010 to March 2011, 18 patients (14 men and four women) were treated consecutively with an RHDF. All the patients were followed up two times. The pain and cold intolerance of the flap were self-reported by the patients. The sensory recovery of the flap was evaluated using Semmes-Weinstein (SW) monofilament, moving two-point discrimination (M-2PD) and static two-point discrimination (S-2PD) tests. The average times of the first and second follow-up were 39 ± 4 and 88 ± 6 months, respectively. The mean value of SW monofilament sensitivity score and M-2PD at first follow-up was significantly higher than that of the second follow-up and contralateral thumb. The mean value of S-2PD at the second follow-up was significantly lower than that of the first follow-up and higher than that of the contralateral thumb. The cold intolerance severity score (CISS) at the first follow-up was higher than that at the second follow-up. No significant difference was found in terms of the pain between the two follow-ups. RHDFs without nerve coaptation for thumb coverage could obtain good sensory recovery after a long-term follow-up. Abbreviations: RHDF: reverse homodigital dorsoradial flap; CISS: cold intolerance severity score; SW: Semmes-Weinstein monofilament sensitivity score; M-2PD: moving two-point discrimination; S-2PD: static two-point discrimination; VAS: visual analog scale.

Large private shareholders, industrial policies and industrial loans of city commercial banks: Evidence from China.

We show that large private shareholders have an information advantage about their industry; this can alleviate the information asymmetry suffered by banks, and consequently, increase bank lending to these shareholders' industry. Using a sample of Chinese city commercial banks, we show that an increase in the large private shareholders' shareholding of banks increases bank lending to these shareholders' industry. Importantly, using Chinese local government industrial policy as a moderator, we find that industrial policies have a positive and significant moderating effect on the relationship between large private shareholders and banks' industry-specific lending. This relationship strengthens when local industrial policy supports these shareholders' industry. This helps explain why banks prefer the industries to which their large private shareholders belong to and how industrial policy affects bank credit allocation.

Network analysis-based strategy to investigate the protective effect of cepharanthine on rat acute respiratory distress syndrome.

Combined with Network Analysis (NA) and in vivo experimental methods, we explored and verified the mechanism of Cepharanthine (CEP) involved in the treatment of acute respiratory distress syndrome (ARDS). Potential targets of CEP were searched using the SwissTargetPrediction database. The pathogenic genes related to ARDS were obtained using the DisGeNET database. A protein-protein interaction network of common target genes of disease-compound was subsequently built and visualised. Functional enrichment analysis was performed through the Enrichr database. Finally, for in vivo experimental verification, we established an oleic acid-induced ARDS rat model, mainly through histological evaluation and the ELISA method to evaluate both the protective effect of CEP on ARDS and its effect on inflammation. A total of 100 genes were found to be CEP targeted genes, while 153 genes were found to be associated with ARDS. The PPI network was used to illustrate the link and purpose of the genes associated with CEP and ARDS, which contained 238 nodes and 2,333 links. GO and KEGG analyses indicated that inflammatory response and its related signalling pathways were closely associated with CEP-mediated ARDS treatment. Thus, a key CEP-gene-pathway-ARDS network was constructed through network analysis, including 152 nodes (5 targets and 6 pathways) and 744 links. The results of in vivo experiments showed that CEP could alleviate histopathological changes and pulmonary edema related to ARDS, in addition to reducing neutrophil infiltration and secretion of inflammatory cytokines, whilst increasing serum contents of ResolvinD1 and ResolvinE1. Thus, these effects enhance the anti-inflammatory responses. Thus, our results show that CEP can treat oleic acid-induced ARDS in rats via ResolvinE1 and ResolvinD1 signalling pathways that promote inflammation resolution, providing a new avenue to explore for the clinical treatment of ARDS.

Vascular endothelial growth factor and the risk of venous thromboembolism: a genetic correlation and two-sample Mendelian randomization study.

BACKGROUND: The relationship between vascular endothelial growth factor (VEGF) and the risk of venous thromboembolism (VTE) has always been one of the concerns in the medical field. However, the causal inferences from published observational studies on this issue may be affected by confounders or reverse causality. We performed a two-sample bidirectional Mendelian randomization (MR) to infer the associations between VEGF and VTE. METHODS: Summary statistics from genome-wide association studies (GWAS) for VEGF and VTE were obtained from published meta-analysis studies and the FinnGen consortium, respectively. Independent genetic variables significantly associated with exposure were selected as instrumental variables. Linkage disequilibrium score regression (LDSC) and five robust MR analytical approaches were conducted to estimate the genetic correlations and causal inference. The MR-Egger intercept, Cochran's Q, and MR pleiotropy residual sum and outlier (MR-PRESSO) were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on outcomes. Notably, replication analyses were performed using different subgroups of VTE. RESULTS: LDSC failed to identify genetic correlations between VEGF and VTE. Based on 9 SNPs, the circulating VEGF level was positively related to the risk of VTE using inverse variance weighting (IVW) method (odds ratio (OR) = 1.064, 95% confidence interval (CI), 1.009-1.122). Reverse MR analyses showed that genetic liability for VTE was not associated with increased VEGF level (ß = -0.021, 95% CI, -0.087-0.045). Pleiotropy-robust methods indicated no bias in any estimates. CONCLUSIONS: Our findings failed to detect coheritability between VEGF and VTE. The suggestive positive effect of the higher VEGF level on the VTE risk may have clinical implications, suggesting that VEGF as a possible predictor and therapeutic target for VTE prevention need to be further warranted.

D-tagatose protects against oleic acid-induced acute respiratory distress syndrome in rats by activating PTEN/PI3K/AKT pathway.

Acute respiratory distress syndrome (ARDS) is characterized by disruption of the alveolar-capillary barrier, resulting in severe alveolar edema and inflammation. D-tagatose (TAG) is a low-calorie fructose isomer with diverse biological activities whose role in ARDS has never been explored. We found that TAG protects lung tissues from injury in the oleic acid-induced rat model of ARDS. Seventeen male Sprague-Dawley rats were randomly assigned to 3 groups: Sham (n = 5), ARDS (n = 6), and TAG + ARDS (n = 6). The treatment groups were injected with oleic acid to induce ARDS, and the TAG + ARDS group was given TAG 3 days before the induction. After the treatments, the effect of TAG was evaluated by blood gas analysis and observing the gross and histological structure of the lung. The results showed that TAG significantly improved the oxygenation function, reduced the respiratory acidosis and the inflammatory response. TAG also improved the vascular permeability in ARDS rats and promoted the differentiation of alveolar type II cells, maintaining the stability of the alveolar structure. This protective effect of TAG on the lung may be achieved by activating the PTEN/PI3K/AKT pathway. Thus, TAG protects against oleic acid-induced ARDS in rats, suggesting a new clinical strategy for treating the condition.

The influence of the largest private shareholder on bank loans: Evidence from China.

We point out that the largest private shareholders can use their information advantage of the industry to influence banks' industry lending behavior. Using a sample of Chinese city commercial banks, we find that increasing of ownership stake of the largest private shareholders leads banks to lend more to their industries. Interestingly, the largest state-owned shareholders do not have this effect. More importantly, we confirmed the channel of the information advantage by analyzing the bank's industry NPL ratio and the listed company's maximum loan amount in the bank. Of course, the effect of the largest private shareholders is achieved by intervening in board decisions. In addition, the ownership structure can influence this effect.

Performance of a Three-Dimensional Electrochemical Reactor (3DER) on Bisphenol A Degradation.

This study constructed a three-dimensional electrochemical reactor (3DER) using meshed stainless steel sheets and titanic magnetite particles (TMP) to investigate bisphenol A (BPA) degradation through the synergistic action of electrical current and TMP. We examined some TMP characteristics, such as particle size, specific surface areas, X-ray diffraction, surface imaging, elemental constituents, and electrical resistivity. It was found that TMP was a micron-level material with excellent electrical conductivity, and it could be regarded as a magnetite-based material comprising Fe(II) and Fe(III). The single-factor experiment determined the optimal conditions for BPA removal in 3DER, specifically by introducing 200 ml of BPA-simulated wastewater (10 mg L-1) into 3DER. At the initial pH of 9.00, current and electrodes gap of 300 mA and 15 mm, respectively, and adding 1 ml of 0.5 M potassium peroxymonosulfate and 1 g TMP, > 98% of BPA was removed after 55 min of electrochemical reaction. In addition, liquid chromatography-mass spectrometry identified the intermediates formed during the BPA treatment, showing two possible pathways for BPA degradation. The final degradation intermediates were chain organics with simple molecular structures. This research provided an understanding of the potential application of 3DER for BPA removal in water.

Natural Compound Library Screening Identifies Oroxin A for the Treatment of Myocardial Ischemia/Reperfusion Injury.

Myocardial ischemia/reperfusion injury (MI/RI) is a serious pathophysiological process relating to cardiovascular disease. Oroxin A (OA) is a natural flavonoid glycoside with various biological activities. However, its effect on the pathophysiological process of MI/RI has not yet been reported. The aim of this study was to determine whether OA could alleviate MI/RI induced inflammation and pyroptosis in vivo and in vitro, providing a novel therapeutic regimen for the treatment of MI/RI. A high-throughput drug screening strategy was employed to test 2,661 natural compound libraries that can alleviate MI/RI in vivo and in vitro. The rat model of MI/RI was established by ligating the left anterior descending (LAD) coronary artery. H9c2 cells were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) to simulate MI/RI. The results show that OA is able to significantly inhibit apoptosis, pyroptosis and the inflammation response (TNF-α, IL-6, IL-8, IL-10, IL-1ß, IL-18) in vivo and in vitro, and reduce the release of myocardial enzymes (cTnI, cTnT, CK-MB, LDH, AST). In the rat MI/RI model, OA can not only improve cardiac function and reduce inflammatory cell infiltration but also reduce myocardial infarct size. The results revealed that OA is an effective remedy against MI/RI as it reduces the inflammatory response and inhibits pyroptosis. This may provide a new therapeutic target for the clinical treatment of MI/RI.