Causal Effects of Asthma on Upper Airway Diseases and Allergic Diseases: A Two-Sample Mendelian Randomization.

INTRODUCTION: Asthma is associated with upper airway diseases and allergic diseases; however, the causal effects need to be investigated further. Thus, we performed this two-sample Mendelian randomization (MR) analysis to explore and measure the causal effects of asthma on allergic rhinitis (AR), vasomotor rhinitis (VMR), allergic conjunctivitis (AC), atopic dermatitis (AD), and allergic urticaria (AU). METHODS: The data for asthma, AR, VMR, AC, AD, and AU were obtained from large-scale genome-wide association studies summarized recently. We defined single-nucleotide polymorphisms satisfying the MR assumptions as instrumental variables. Inverse-variance weighted (IVW) approach under random-effects was applied as the dominant method for causal estimation. The weighted median approach, MR-Egger regression analysis, MR pleiotropy residual sum and outlier test, and leave-one-out sensitivity analysis were performed as sensitivity analysis. Horizontal pleiotropy was measured using MR-Egger regression analysis. Significant causal effects were attempted for replication and meta-analysis. RESULTS: We revealed that asthma had causal effects on AR (IVW, odds ratio [OR] = 1.93; 95% confidence interval [CI], 1.74-2.14; p < 0.001), VMR (IVW, OR = 1.40; 95% CI, 1.15-1.71; p < 0.001), AC (IVW, OR = 1.65; 95% CI, 1.49-1.82; p < 0.001), and AD (IVW, OR = 2.13; 95% CI, 1.82-2.49; p < 0.001). No causal effect of asthma on AU was observed. Sensitivity analysis further assured the robustness of these results. The evaluation of the replication stage and meta-analysis further confirmed the causal effect of asthma on AR (IVW OR = 1.81, 95% CI 1.62-2.02, p < 0.001), AC (IVW OR = 1.44, 95% CI 1.11-1.87, p < 0.001), and AD (IVW OR = 1.85, 95% CI 1.42-2.41, p < 0.001). CONCLUSIONS: We revealed and quantified the causal effects of asthma on AR, VMR, AC, and AD. These findings can provide powerful causal evidence of asthma on upper airway diseases and allergic diseases, suggesting that the treatment of asthma should be a preventive and therapeutic strategy for AR, VMR, AC, and AD.

Leonurine alleviates acetaminophen-induced acute liver injury by regulating the PI3K/AKT signaling pathway in mice.

Leonurine (Leo) is a natural alkaloid isolated from the herb Leonurus japonicus Houtt. (Leonuri) that has been shown to inhibit oxidative stress and inflammation. However, the role and mechanism of Leo in acetaminophen (APAP)-induced acute liver injury (ALI) remain unknown. In this study, we investigated the protective effect of Leo against APAP-induced ALI and elucidated the molecular mechanism. Here, we showed that the damage to mouse primary hepatocytes (MPHs) induced by APAP was attenuated by treatment with Leo, which promoted proliferation and inhibited oxidative stress injury, and Leo significantly improved APAP-induced ALI in mice. Leo could protect against APAP-induced ALI by reducing serum aspartate aminotransferase (AST) and alanine transaminase (ALT) levels, hepatic histopathological damage, liver cell necrosis, inflammation, and oxidative stress-induced damage in vivo and in vitro. Moreover, the results indicated that Leo relieved APAP-induced liver cell necrosis by reducing the expression of Bax and cleaved caspase-3 and increasing Bcl-2 expression. Leo alleviated APAP-induced oxidative stress-induced damage by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, which facilitated Nrf2 nuclear translocation and upregulated oxidative stress-related protein expression in liver tissues. Moreover, the results suggested that APAP-induced inflammation in the liver was suppressed by Leo by suppressing the Toll-like receptor 4 (TLR4) and NLR family pyrin domain containing 3 (NLRP3) pathways. In addition, Leo facilitated the activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway in the liver tissue of ALI mice. Network pharmacology, molecular docking, and western blotting showed that PI3K was a potential target of Leo in the treatment of ALI. Molecular docking and cellular thermal shift assay (CETSA) indicated that Leo could stably bind to the PI3K protein. In conclusion, Leo attenuated ALI, and reversed liver cell necrosis, the inflammatory response and oxidative stress-induced damage by regulating the PI3K/AKT signaling pathway.

Amplifying the efficacy of ALA-based prodrugs for photodynamic therapy using nanotechnology.

5-aminolevulinic acid (ALA) is a clinically approved prodrug involved in intracellular Heme biosynthesis to produce the natural photosensitizer (PS) Protoporphyrin IX (PpIX). ALA based photodynamic therapy (PDT) has been used to treat various malignant and non-malignant diseases. However, natural ALA has disadvantages such as weak lipophilicity, low stability and poor bioavailability, greatly reducing its clinical performance. The emerging nanotechnology is expected to address these limitations and thus improve the therapeutic outcomes. Herein, we summarized important recent advances in the design of ALA-based prodrugs using nanotechnology to improve the efficacy of PDT. The potential limitations and future perspectives of ALA-based nanomedicines are also briefly presented and discussed.

Mesopore-encaged active MnOx in nano-silica selectively suppresses lung cancer cells by inducing autophagy.

Autophagy induced by nanomaterials is one of the intracellular catabolic pathways that degrade and recycle the biomacromolecules and damaged organelles in cells and has emerged as a very promising pharmacological target critical to future drug development and anti-cancer therapy. Herein, we developed mesopore-encaged highly-dispersed active cluster-like MnOx in nanosilica entitled MnO-MS, with a size of around 130 nm. Our studies show that MnO-MS could not only obviously induce autophagy in both stable GFP-LC3 HeLa cells and GFP-LC3-mCherry HeLa cells but also could selectively inhibit lung cancer A549 cell growth at 11.19 µg mL-1 (IC50) while exhibiting little cytotoxicity in normal cells. Encouraged by these interesting results, a further mechanistic study reveals that reactive oxygen species (ROS) were excited by the active MnOx in nanosilica, leading to the disruption of mitochondrial membrane potential (MMP), enhancement of ATG5A/ATG16L/ATG4B/Beclin1, and finally, inhibition of the mTOR signaling pathways. Collectively, these findings indicate that MnO-MS-induced cell death via autophagy pathways in cancer cells. Furthermore, MnO-MS significantly inhibited tumor growth with minimal side effects in vivo, and it is envisioned that MnO-MS can be further developed as a potential autophagy inducer for the treatment of lung cancers.

Using a Two-Sample Mendelian Randomization Study Based on Genome-Wide Association Studies to Assess and Demonstrate the Causal Effects of Allergic Rhinitis on Chronic Lower Respiratory Diseases and Lung Function.

INTRODUCTION: Observational studies have reported that allergic rhinitis (AR) was associated with chronic lower respiratory diseases (CLRDs) and lung function; however, their causal effects remain elusive. Therefore, to investigate the causal effects of AR on CLRDs and lung function, we conducted the two-sample Mendelian randomization (MR) study. METHODS: The data for AR, asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, idiopathic pulmonary fibrosis (IPF), and the forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio were obtained from genome-wide association studies, which were large sample studies on people of European ancestry. In this study, single-nucleotide polymorphisms associated with AR were considered instrumental variables. We employed the inverse-variance weighted (IVW) method with random effects to evaluate causal effects, and the weighted median and MR-Egger methods were used for sensitivity analyses. Significant causal associations were attempted for replication and meta-analysis. RESULTS: In the discovery stage, we found that AR exhibited a significant causal effect on asthma (IVW, odds ratio [OR] = 16.91, 95% CI, 8.03-35.65, p < 0.001) and a suggestive effect on FEV1/FVC ratio (IVW, OR = 0.82, 95% CI, 0.68-0.99, p = 0.039). No causal effect of AR was observed on COPD, bronchiectasis, and IPF. In the replication stage, the causal effect of AR on asthma was replicated (IVW, OR = 11.57, 95% CI, 4.90-27.37, p < 0.001). The meta-analysis demonstrated that the combined OR of AR on asthma was 14.37 (IVW, 95% CI, 8.18-25.24, p < 0.001). CONCLUSIONS: We demonstrated and measured the causal effects of AR on asthma (OR = 14.37) and FEV1/FVC ratio (OR = 0.82), while there was no evidence to support a causal effect of AR on COPD, bronchiectasis, and IPF. These results suggest that AR tends to have a causal effect on lower airway disease of similar inflammatory types and can provide high-quality causal evidence for clinical practice as well as the pathogenesis and prevention of AR and asthma.

Causal relationships between potential risk factors and chronic rhinosinusitis: a bidirectional two-sample Mendelian randomization study.

PURPOSE: Smoking, alcohol consumption, allergic rhinitis (AR), asthma, and obesity are associated with chronic rhinosinusitis (CRS), albeit the causal relationships between them remain elusive. Therefore, we conducted a bidirectional two-sample Mendelian randomization (MR) study to investigate the bidirectional causal effects between these potential risk factors and CRS. METHODS: The data for daily cigarette consumption, age of smoking initiation, weekly alcohol consumption, AR, asthma, body mass index (BMI), and CRS were drawn from large sample size genome-wide association studies. Single-nucleotide polymorphisms associated with each exposure were considered instrumental variables in this study. We investigated causal effects by using the inverse-variance weighted (IVW) method with random effects, and weighted median and MR-Egger methods were used for sensitivity analyses. Pleiotropic effects were detected and corrected by the MR pleiotropy residual sum and outlier test and MR-Egger model. RESULTS: We found the causal effects of daily cigarette consumption (IVW, OR = 1.15, 95% CI 1.00-1.32, p = 0.046), AR (IVW, OR = 4.77, 95% CI 1.61-14.13, p = 0.005), asthma (IVW, OR = 1.45, 95% CI 1.31 - 1.60, p < 0.001), and BMI (IVW, OR = 1.05, 95% CI 1.00-1.09, p = 0.028) on CRS. Furthermore, we found a causal effect of CRS on asthma (IVW OR = 1.08, 95% CI 1.05-1.12, p < 0.001). CONCLUSIONS: We confirmed the causal effects of daily cigarette consumption, AR, asthma, and BMI on CRS, and the causal effect of CRS on asthma, while no causal relationship between age of smoking initiation, weekly alcohol consumption, and CRS was found. These findings are expected to provide high-quality causal evidence for clinical practice and the pathogenesis of CRS and asthma.

Development and Validation of a Clinical Prediction Model to Diagnose Sinonasal Inverted Papilloma Based on Computed Tomography Features and Clinical Characteristics.

Objectives: Sinonasal inverted papilloma (SNIP) is one of the most common benign tumors of the nasal cavity and sinuses and is at risk for recurrence and malignant transformation. It is crucial to precisely predict SNIP before surgery to determine the optimal surgical technique and prevent SNIP recurrence. This study aimed to evaluate the diagnostic value of computed tomography (CT) features and SNIP clinical characteristics and to develop and validate a clinically effective nomogram. Methods: Here, 267 patients with SNIP and 273 with unilateral chronic rhinosinusitis with/without nasal polyps were included. Patient's demographic and clinical characteristics (i.e., gender, age, nasal symptoms, history of sinus surgery, smoking, and alcohol dependence) and CT features (i.e., lobulated/wavy edge, air sign, focal hyperostosis, diffuse hyperostosis, focal osseous erosion, and CT values) were recorded. Independent risk factors were screened using logistic regression analysis. A nomogram model was developed and validated. Results: Logistic regression analysis showed that age, facial pain/headache, history of sinus surgery, lobulated/wavy edge, air sign, focal hyperostosis, focal osseous erosion, and CT values were independent predictors of SNIP. A nomogram comprising these 8 independent risk factors was established. The area under the curve (AUC) for the training set was .960 (95% CI, .942-.978) and the AUC for the validation set was .951 (95% CI, .929-.971). Conclusion: The obtained results suggested that the nomogram based on age, facial pain/headache symptoms, history of sinus surgery, and CT characteristics had an excellent diagnostic value for SNIP.

Association of obesity, triglyceride-glucose and its derivatives index with risk of hyperuricemia among college students in Qingdao, China.

Objective: To analyze and compare the associations of hyperuricemia (HUA) with obesity, triglyceride-glucose (TyG), and its derivatives in college students. To provide early guidance on risk predictors of HUA in college students. Methods: This study was a cross-sectional survey including 23,411 participants (age: 17-20 years). Investigators conducted face-to-face interview surveys and physical examinations. Automated biochemical methods were used to detect biochemical indicators such as serum uric acid (UA). Calculation of obesity, TyG, and their derivatives indices were performed. Logistic regression was used to analyze the relationship between different indexes and hyperuricemia. OR value and 95% CI were also calculated. ROC curve was used for assessing the predictive ability of different indices of hyperuricemia. Results: After adjusting for age, SBP, DBP, ALT, AST, TC, BUN, and CREA, multivariate logistic regression showed that the OR value of LAP in the obesity index was higher, especially in women (male OR: 4.347, 95%CI: 3.807, 4.964; female OR: 4.672, 95%CI: 3.800, 5.744). The other three quartiles of TyG derivatives were highly associated with hyperuricemia in men and women compared with the top quartile (all P< 0.05). The risk of hyperuricemia increased with an increase in quartiles. For college students, all indicators could distinguish the presence of hyperuricemia. For men, the area under the curve (AUC) of TyG-WC was the largest (AUC: 0.694; 95%CI: 0.684-0.704; P<0.05), according to the Maximum Youden index 0.290 with cut point value 477.853. In women, TyG-BMI showed a maximum AUC value of 0.702 (95%CI: 0.685-0.719; P<0.05), according to the maximum Youden index of 0.317 with cut point value 132.446. The TyG-WC, TyG-WHtR, TyG-LAP, and LAP indices also had relatively high AUC. Conclusion: In clinical practice, LAP, TYG, and their related derivatives may be used as sensitive indicators for HUA prediction in college students.

Engineered Cell-Penetrating Peptides for Mitochondrion-Targeted Drug Delivery in Cancer Therapy.

Mitochondrion is a promising target in cancer therapy. However, gaining access to this organelle is difficult due to the obstacles to cross the complicated mitochondrial membrane. Cell-penetrating peptides (CPPs) with mitochondrion-targeting ability, named mitochondrion-targeting peptides (MTPs), are efficient tools to deliver exogenous therapeutics into mitochondria. Herein, we report several new MTPs, which can be readily synthesized via resin-based solid-phase peptide synthesis. In particular, MTP3 (compound 5), consisting of three positively charged arginines and two D- and L- alternating naphthylalanines, demonstrated excellent mitochondrion-targeting ability with high Pearson's correlation coefficient, suggesting that MTP3 has good potential for mitochondrion-targeted drug delivery. As proof-of-concept, the feasibility of MTP3 was validated by the preparation of a mitochondrion-targeting prodrug (compound 17, doxorubicin-based prodrug). This prodrug was subsequently confirmed to be specifically transported to the mitochondria of tumor cells, where it was able to release the native doxorubicin upon intracellular GSH activation, leading to mitochondrial depolarization and eventually cell death. Importantly, compound 17 showed good cytotoxicity against human tumor cells while negligible toxicity towards normal cells, indicating its potential as a potent mitochondrial medicine for targeted cancer therapy. Our study thus opens a way for engineered CPPs to be used to deliver bioactive cargos in mitochondrion-targeted cancer therapy.

Recent advance on PTP1B inhibitors and their biomedical applications.

Protein Tyrosine Phosphatase 1B (PTP1B), as one of the most important members in PTP superfamily, plays a vital role in conducting various cellular functions. So far, PTP1B has been reported to be involved in the development of many diseases including obesity, diabetes, cancers and cardiovascular diseases. Development of potent and specific PTP1B inhibitors and studies on the structure-activity relationship (SAR) between their chemical structures and their biological activity have drawn increasing attention as they could not only modulate the PTP1B functions inside the cells but also provide useful lead compounds for the treatment of various PTP1B-associated diseases. To this end, we herein summarized the recent developments of PTP1B inhibitors, and different kinds of high-throughput screening strategies for the identification of potential PTP1B inhibitors as well as their potential biomedical applications, and we also provided some perspectives in the concluding remarks in this work.