Role of Staphylococcus aureus's Buoyant Density in the Development of Biofilm Associated Antibiotic Susceptibility.

Biofilms are clusters of microorganisms that form at various interfaces, including those between air and liquid or liquid and solid. Due to their roles in enhancing wastewater treatment processes, and their unfortunate propensity to cause persistent human infections through lowering antibiotic susceptibility, understanding and managing bacterial biofilms is of paramount importance. A pivotal stage in biofilm development is the initial bacterial attachment to these interfaces. However, the determinants of bacterial cell choice in colonizing an interface first and heterogeneity in bacterial adhesion remain elusive. Our research has unveiled variations in the buoyant density of free-swimming Staphylococcus aureus cells, irrespective of their growth phase. Cells with a low cell buoyant density, characterized by fewer cell contents, exhibited lower susceptibility to antibiotic treatments (100 µg/mL vancomycin) and favored biofilm formation at air-liquid interfaces. In contrast, cells with higher cell buoyant density, which have richer cell contents, were more vulnerable to antibiotics and predominantly formed biofilms on liquid-solid interfaces when contained upright. Cells with low cell buoyant density were not able to revert to a more antibiotic sensitive and high cell buoyant density phenotype. In essence, S. aureus cells with higher cell buoyant density may be more inclined to adhere to upright substrates.

PD-Like Pathogenesis in Caenorhabditis elegans Intestinally Infected with Nocardia farcinica and the Underlying Molecular Mechanisms.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the abnormal aggregation of α-synuclein (α-syn) and the loss of dopaminergic neurons. Although microbial infection has been implicated in the pathogenesis of PD, the associated virulence factors and the underlying molecular mechanisms require further elucidation. Here, we found that intestinal infection with Nocardia farcinica induced a series of PD-like symptoms in Caenorhabditis elegans, such as the accelerated degeneration of dopaminergic neurons, impaired locomotion capacity, and enhanced α-syn aggregation, through the disturbance of mitochondrial functions. To identify the potential virulence factors involved in these effects, we knocked out the nbtB/C and nbtS genes in N. farcinica, which are localized in the gene clusters responsible for nocobactin biosynthesis. The deletion of either gene partially rescued the degenerative effects of wild-type N. farcinica on dopaminergic neurons by attenuating mitochondrial dysfunction. LC-MS analysis further identified a decrease in the abundance of several siderophores in the two mutants, including nocobactin NA-a, nocobactin NA-b, and nocardimicin B. Collectively, our results demonstrated that intestinal N. farcinica infection in C. elegans facilitates PD-like pathogenesis and provides novel evidence for the involvement of pathogenic bacteria in neurodegenerative diseases via non-neuroinvasive mechanisms.

Role and molecular regulatory mechanisms of Hippo signaling pathway in Caenorhabditis elegans and mammalian cell models of Alzheimer's disease.

Although there is increasing evidence for the involvement of Hippo signaling in Alzheimer's disease (AD), the detailed functions and regulatory mechanisms are not fully understood, given the diverse biological effects of this pathway. In the present work, we used Caenorhabditis elegans and mammalian cell models to investigate changes in the Hippo signaling pathway in response to Aß and the downstream effects on AD development. Aß1-42 production in the AD models decreased phosphorylation of the upstream CST-1/WTS-1 kinase cascade and promoted an interaction between LIN-10 and YAP-1, leading to the nuclear translocation of YAP-1 and inducing gene transcription in conjunction with the transcription factor EGL-44. The YAP-1/EGL-44 complex suppressed the autophagy-lysosome pathway by modulating mTOR signaling, which enhanced Aß1-42 accumulation and promoted AD progression. These results demonstrate for the first time that crosstalk between Hippo and mTOR signaling contributes to AD development by enhancing Aß production, resulting in inhibition of Hippo signaling and autophagy-lysosome pathway and Aß accumulation, suggesting potential therapeutic targets for the treatment or prevention of AD.

Trimethylated chitosan-coated flexible liposomes with resveratrol for topical drug delivery to reduce blue-light-induced retinal damage.

LED-related blue-light-induced damage can cause eye diseases. However, drug delivery in patients with ocular diseases is faced with various challenges. In this study, we developed flexible liposomes based on trimethylated chitosan (TMC-Lipo) to deliver resveratrol for the treatment of retinal diseases. Flexible liposomes can easily cross various biological barriers. Chitosan and its derivatives have adhesive properties and are widely used in mucoadhesive drug delivery systems. Therefore, we wrapped flexible liposomes with trimethylated chitosan via electrostatic adsorption. The charge of the flexible liposomes became positive after encapsulation in TMC, and they remained stable in artificial tears. We assessed the safety of TMC-Lipo in cellular and zebrafish experiments and found that it can be safely used. In addition, treatment with TMC-Lipo significantly reduced H2O2-induced damage to ARPE-19 cells, restored mitochondrial membrane potential, and protected the cells. TMC-Lipo more easily reached the posterior ocular segment of the mice than liposome nanoparticles and attenuated blue-light-induced retinal cytopathy. Our study demonstrates that effective eye drop formulations can be developed based on trimethylated chitosan, which provides a promising approach for the treatment of ocular diseases.

Joint effect of overweight/obesity and tobacco exposure on hypertension in children aged 6-17 years: a cross-sectional study.

Aim: To assess the individual effects of overweight/obesity and tobacco exposure, and their combined effects on hypertension in children. Methods: This cross-sectional study included 6,339 children aged 6-17 years from National Health and Nutrition Examination Surveys 1999-2018. Participants' height, weight and blood pressure (BP) were measured by trained technicians. Hypertension was defined as: mean systolic BP (SBP) and/or diastolic BP (DBP) ≥ 90th percentile for sex, age, and height (for children aged 1-13 years), and SBP ≥120 mmHg and/or a DBP ≥80 mmHg (for adolescents aged 13-17 years); or self-reported having been diagnosed with hypertension or taking antihypertensive medication. Gender- and age-specific body mass index (BMI) cut-points were used to define overweight/obesity: "overweight" was defined as a BMI > 1 standard deviation (SD); "obesity" was defined as BMI > 2SD; and "thinness" was defined as BMI < -2SD. Tobacco exposure was defined as having serum cotinine levels >0.05 µg/L or reporting the presence of at least one smoker in the household. Weighted univariate and multivariate logistic regression models were used to assess overweight/obesity and tobacco exposure with the odds of hypertension, and the combined effects of overweight/ obesity and tobacco exposure on hypertension, followed by strata-specific analyses. Odds ratios (OR) with 95% confidence intervals (CI) were calculated. Results: The prevalence of overweight/obesity and tobacco exposure was significantly higher in the hypertension group than in the non-hypertension group. Overweight/obesity (OR = 1.67, 95%CI: 1.26-2.21/ OR = 2.38, 95%CI: 1.67-3.39) and tobacco exposure (OR = 1.58, 95%CI: 1.16-2.14) were associated with a higher odd of hypertension in children, respectively. Additionally, we also observed the combined effect between overweight (OR = 3.05, 95%CI: 1.96-4.75)/obesity (OR = 3.68, 95%CI: 2.24-6.03) and tobacco exposure were related to hypertension odds in children, with a significant effect in different populations. Conclusion: There may exist joint effect of overweight/obesity and tobacco exposure on the odds of hypertension in American children. These findings offer an insight that early weight control and reduction of tobacco exposure may be important to reduce odds of hypertension in children.

Shengjie Tongyu Decoction Regulates Cardiomyocyte Autophagy Through Modulating ROS-PI3K/Akt/mTOR Axis by LncRNA H19 in Diabetic Cardiomyopathy.

Context: Diabetic cardiomyopathy (DCM) is particularly dangerous in diabetes mellitus (DM). The Shengjie Tongyu decoction (SJTYD) is a well-known, traditional Chinese medicinal formulation that practitioners use to treat myocardial diseases in China; however, its role in DCM remain unclear. Objective: The study intended to investigate: (1) SJTYD's role in the treatment of DCM and its underlying mechanisms, (2) the association of autophagy with DCM, and (3) the involvement of mammalian target of rapamycin (mTOR) signaling in the regulation of DCM. Design: The research team performed an animal study. Setting: The study took place in the Department of Endocrinology in the No. 2 ward-Traditional and Complementary Medicine(TCM) of the China-Japan Friendship Hospital in Beijing, China. Animals: The animals were 60 C57/BL6 mice weighing 200-250 g. Intervention: To determine the role of SJTYD in treating DCM, the research team established a mouse model of DM using streptozotocin (STZ). The team randomly divided the mice into three groups with 20 mice each: (1) a negative control group, which didn't receive injections of STZ or treatment with SJTYD; (2) a model group, the Model group, which received injections of STZ but didn't receive treatment with SJTYD; and (3) an SJTYD group, which received injections of STZ and treatment with SJTYD. Outcome Measures: The research team: (1) conducted a differential analysis to identify the differentially expressed genes; (2) performed deep sequencing of the long noncoding RNAs (lncRNAs) expressed in cardiomyocytes from the control, Model, and SJTYD groups ; (3) performed a bioinformatics analysis; (4) used the ultrasonic and pathological, transmission electron microscopy (TEM) test as well as a Western blot to evaluate cardiac function, myocardial-injury areas, and autophagy in vivo; (5) transfected primary cardiomyocytes treated them with lncRNA H19 and SJTY 3-MA to establish SJTYD subgroups in which the H19 protected against DCM and the 3-MA inhibited autophagy; and (6) carried out immunofluorescence staining and Western blot to test the phosphorylated levels of phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) as well as autophagy levels in vitro. Results: The bioinformatics analysis indicated that SJTYD significantly modulated lncRNA H19 as well as the mTOR pathway. The vevo2100's results indicated the SJTYD reversed the cardiac-dysfunction parameters in DCM. The Masson' staining, TEM, and Western blot demonstrated that the SJTYD could suppress the myocardial-injury areas as well as the numbers of autophagosomes and the expression proteins of autophagy in vivo. The SJTYD promoted the phosphorylated-levels of PI3K, AKT, and mTOR and decreased the levels of autophagy proteins. LC3A-II and Beclin-1; lncRNA H19 amplified the SJTYD's role; and 3-MA reversed those effects, as tested using immunofluorescence and Western blot in primary cardiomyocytes. Conclusions: The SJTYD can protect against diabetic myocardial injury by inhibiting cardiomyocyte autophagy through the activation of lncRNA H19, reactive oxygen species (ROS), and the PI3K/Akt/mTOR signaling pathway. SJTYD may be an effective strategy to ameliorate diabetic myocardial injuries.

Is intrauterine hematoma associated with adverse pregnancy and obstetric outcomes of ART singletons? A systematic review and meta-analysis.

The objective of our meta-analysis was to estimate the effect of intrauterine hematoma (IUH) on obstetric and pregnancy outcomes of assisted reproductive technology (ART) pregnancies. Four electronic databases were searched up to December 2021 to find studies reporting relevant outcomes of ART pregnancies with IUH. Dichotomous data were expressed as odds ratios (OR) with 95% confidence intervals (CI). Continuous data were expressed as weighted mean difference (WMD) with 95% CI. A total of six observational studies were included in this meta-analysis. Our data suggested that IUH in pregnancies achieved by ART are not associated with increased risks of miscarriage, low birth weight, placenta previa, or premature rupture of membranes. Similar birthweight was noted between the two groups. However, IUH was associated with significantly shorter gestational age at delivery (GA) as well as higher risks of preterm birth. Subgroup analyses have found that the presence of retroplacental haematoma was associated with an increased risk of miscarriage. IUH may be associated with decreased GA and an increased risk of preterm birth. Therefore, Women diagnosed with IUH should be offered increased surveillance during the course of their pregnancy.

Advances and Prospects of Prolamine Corn Protein Zein as Promising Multifunctional Drug Delivery System for Cancer Treatment.

Zein is a type of prolamine protein that is derived from corn, and it has been recognized by the US FDA as one of the safest biological materials available. Zein possesses valuable characteristics that have made it a popular choice for the preparation of drug carriers, which can be administered through various routes to improve the therapeutic effect of antitumor drugs. Additionally, zein contains free hydroxyl and amino groups that offer numerous modification sites, enabling it to be hybridized with other materials to create functionalized drug delivery systems. However, despite its potential, the clinical translation of drug-loaded zein-based carriers remains challenging due to insufficient basic research and relatively strong hydrophobicity. In this paper, we aim to systematically introduce the main interactions between loaded drugs and zein, administration routes, and the functionalization of zein-based antitumor drug delivery systems, in order to demonstrate its development potential and promote their further application. We also provide perspectives and future directions for this promising area of research.

Glycyrrhetinic acid suppresses breast cancer metastasis by inhibiting M2-like macrophage polarization via activating JNK1/2 signaling.

BACKGROUND: Breast cancer metastasis is leading cause of cancer death among women worldwide. Tumor-associated macrophages (TAMs) have been considered as potential targets for treating breast cancer metastasis because they promote tumor growth and development. Glycyrrhetinic acid (GA) is one of the most important phytochemicals of licorice which has shown promising anti-cancer efficacies in pre-clinical trials. However, the regulatory effect of GA on the polarization of TAMs remains elusive. PURPOSE: To investigate the role of GA in regulating the polarization of M2 macrophages and inhibiting breast cancer metastasis, and to further explore its underlying mechanisms of action. STUDY DESIGN: IL-4 / IL-13-treated RAW 264.7 and THP-1 cells were used as the M2-polarized macrophages in vitro. A 4T1 mouse breast cancer model and the tail vein breast cancer metastasis model were applied to study the effect of GA on breast cancer growth and metastasis in vivo. RESULTS: In vitro studies showed that GA significantly inhibited IL-4 / IL 13-induced M2-like polarization in RAW 264.7 and THP-1 macrophages without affecting M1-like polarization. GA strongly decreased the expression of M2 macrophage markers CD206 and Arg-1, and reduced the levels of the pro-angiogenic molecules VEGF, MMP9, MMP2 and IL-10 in M2 macrophages. GA also increased the phosphorylation of JNK1/2 in M2 macrophages. Moreover, GA significantly suppressed M2 macrophage-induced cell proliferation and migration in 4T1 cancer cells and HUVECs. Interestingly, the inhibitory effects of GA on M2 macrophages were abolished by a JNK inhibitor. Animal studies showed that GA significantly suppressed tumor growth, angiogenesis, and lung metastasis in BALB/c mice bearing breast tumor. In tumor tissues, GA reduced the number of M2 macrophages but elevated the proportion of M1 macrophages, accompanied by activation of JNK signaling. Similar results were found in the tail vein breast cancer metastasis model. CONCLUSION: This study demonstrated for the first time that GA could effectively suppress breast cancer growth and metastasis by inhibiting macrophage M2 polarization via activating JNK1/2 signaling. These findings indicate that GA could be served as the lead compound for the future development of anti-breast cancer drug.

Topical treatment of tea saponin stabilized silybin nanocrystal gel reduced oxidative stress in UV-induced skin damage.

UV-induced peroxidation is a significant factor in skin damage. Some natural products have been utilized to protect the skin. However, most of them suffer from issues such as poor bioavailability. A promising strategy is to prepare them as safe and convenient gels. In this study, we constructed Silybin Nanocrystal Gel (SIL-NG). Tea saponin, a spatial stabilizer that we have previously reported, was used to prepare SIL-NS and subsequently combined with xanthan gum to prepare SIL-NG with an excellent safety profile. This nanogel with a natural stabilizer has a suitable ductility and shows a good safety profile in vitro and in vivo. In L929 cells, SIL-NG was able to reduce H2O2-induced ROS levels. In addition, SIL-NG exhibited better antioxidant activity compared to SIL-NS. SIL-NG was able to reduce UVB irradiation-induced oxidative damage in mice, significantly increase SOD activity, and reduce MDA levels. In conclusion, our work gives a new perspective on the treatment of UV skin damage using natural ingredients.

Gegen Qinlian standard decoction alleviated irinotecan-induced diarrhea via PI3K/AKT/NF-κB axis by network pharmacology prediction and experimental validation combination.

BACKGROUND: The frequently occurred chemotherapy-induced diarrhea (CID) caused by irinotecan (CPT-11) administration has been the most representative side-effects of CPT-11, resulting in the chemotherapy suspension or failure. Our previous studies indicated that Gegen Qinlian formula exhibited a significant alleviation effect on CPT-11-induced diarrhea. However, referencing to Japanese Kampo medicine, the TCM standard decoction would supply the gap between ancient preparation application and modern industrial production. METHODS: The LC-MS technology combined with network pharmacology was employed to identify the active ingredients and mechanisms of GQD standard decoction for CPT-11-induced diarrhea. The anti-inflammatory activities associated with intestinal barrier function of GQD standard decoction were studied by SN-38 activated NCM460 cells in vitro and CPT-11-induced diarrhea in vivo. Proteins involved in inflammation, mRNA levels, disease severity scores, and histology involved in intestinal inflammation were analysed. RESULTS: There were 37 active compounds were identified in GQD standard decoction. Network pharmacology analyses indicated that PI3K-AKT signaling pathway were probably the main pathway of GQD standard decoction in CPT-11-induced diarrhea treatment, and PIK3R1, AKT1, NF-κB1 were the core proteins. Moreover, we found that the key proteins and pathway predicted above was verified in vivo and in vitro experiments, and the GQD standard decoction could protect the cellular proliferation in vitro and ameliorate CPT-11-induced diarrhea in mice model. CONCLUSIONS: This study demonstrated the molecular mechanism of 37 active ingredients in GQD standard decoction against CPT-11-induced diarrhea. And the core proteins and pathway were validated by experiment. This data establishes the groundwork for particular molecular mechanism of GQD standard decoction active components, and this research can provide a scientific reference for the TCM therapy of CID.

N-Trimethylated chitosan coating white adipose tissue vascular-targeting oral nano-system for the enhanced anti-obesity effects of celastrol.

Oral nanoparticles (NPs) are more suitable for obesity control compared to NPs administered intravenously, as their convenience increases patient compliance. Herein, we developed an oral nano-system to improve the anti-obesity efficacy of celastrol (Cel). The observed enhanced efficacy was mediated by zein core NPs decorated with adipose-homing peptides that were coated with N-trimethylated chitosan. The optimized Cel/AHP-NPs@TMC exhibited spherical morphology by TEM, as well as narrow size distribution (221.76 ± 6.73 nm) and adequate stability in a gastrointestinal environment. Based on the combined delivery advantages of AHP-NPs@TMC - i.e., improved cellular internalization within Caco-2 cells and enhanced white adipose tissue (WAT) vascular targeting - Cel/AHP-NPs@TMC significantly reduced the body weight, blood lipid levels, adipose inflammation, and WAT distribution in diet-induced obese mice without side-effects. In short, this study provides clear evidence that TMC-based oral NPs can effectively improve celastrol for obesity treatment.

Relationship between NUDT21 mediated alternative polyadenylation process and tumor.

Alternative polyadenylation (APA) is a molecular process that generates diversity at the 3' end of RNA polymerase II transcripts from over 60% of human genes. APA and microRNA regulation are both mechanisms of post-transcriptional regulation of gene expression. As a key molecular mechanism, Alternative polyadenylation often results in mRNA isoforms with the same coding sequence but different lengths of 3' UTRs, while microRNAs regulate gene expression by binding to specific mRNA 3' UTRs. Nudix Hydrolase 21 (NUDT21) is a crucial mediator involved in alternative polyadenylation (APA). Different studies have reported a dual role of NUDT21 in cancer (both oncogenic and tumor suppressor). The present review focuses on the functions of APA, miRNA and their interaction and roles in development of different types of tumors.NUDT21 mediated 3' UTR-APA changes can be used to generate specific signatures that can be used as potential biomarkers in development and disease. Due to the emerging role of NUDT21 as a regulator of the aforementioned RNA processing events, modulation of NUDT21 levels may be a novel viable therapeutic approach.

Effects of Baicalin on Alopecia and the Associated Mechanism.

The aim of the present study was to explore the potential pharmacological mechanism of baicalin by combining network pharmacology prediction and the experimental verification of alopecia. Networks of baicalin-associated targets and alopecia-related genes were constructed using the STRING database. Potential targets and pathways associated with the therapeutic efficacy of baicalin were identified via enrichment analysis using Cytoscape and the database for annotation, visualization and integrated discovery (Metascape). The back hair of C57BL/6J mice was removed with depilatory cream to verify the therapeutic effect of baicalin. Human hair dermal papilla cells (HHDPCs) were used to explore the mechanism of action of baicalin. Network pharmacology analysis revealed that the potential targets of baicalin mainly include protein serine/threonine kinase, Src protein, epidermal growth factor receptor, and insulin-like growth factor 1 (IGF1), which were indicated to mediate neutrophil degranulation and regulation of cell-cell adhesion, vesicle lumen, cytoplasmic vesicle, membrane raft, and endopeptidase activity. Multiple pathways were identified, such as proteoglycans in cancer, PI3K/AKT, and forkhead box O signaling pathways. Following baicalin treatment for the experimental mice, the coverage, length, and weight of the hair increased in a baicalin dose-dependent manner. Moreover, the histological evaluation showed that the number of hair follicles increased after baicalin treatment and melanin formation were pronounced. In addition, baicalin induced an increase in the phosphorylated p-AKT, p-glycogen synthase kinase-3ß, p-PI3K, TGF-ß1, and vascular endothelial growth factor levels. Furthermore, the activation levels of key protein p-AKT were increased. Baicalin induced the proliferation of HHDPCs in vitro and significantly upregulated p-AKT, IGF1, and alkaline phosphatase. In conclusion, the present study revealed that the pharmacological mechanisms of baicalin in alopecia therapy were associated with the proliferation of DPCs, the activation of the AKT pathway, and the transmission of downstream signals, indicating that baicalin is a potential drug candidate for the clinical treatment of hair loss.

Small G protein RAC-2 regulates forgetting via the JNK-1 signalling pathway in Caenorhabditis elegans.

Although forgetting was once regarded as a passive decline in memory and an occasional source of embarrassment, recent research suggests that it is an active biological process of removing outdated or irrelevant memories via activation of specific genes and signal transduction pathways. Rho family G proteins are known to have a role in synaptic plasticity mediated by the actin cytoskeleton. However, the current study reveals that another Rho guanosine triphosphate enzyme (GTPase), RAC-2, facilitates the occurrence of forgetting in Caenorhabditis elegans independent of actin dynamics. Functioning downstream of RAC-2 in the same signalling pathway, JNK-1 and its phosphorylated protein are required to positively regulate forgetting. The pan-neuronal rescue of RAC-2 or JNK-1, instead of AWC neuron-specific expression, reverses the delayed forgetting caused by the rac-2 mutation, which indicates that the involvement of RAC-2/JNK-1 in more than AWCs must be required. In summary, our work elucidates the action of the Rho GTPase RAC-2 and downstream JNK-1 as a potential novel pathway in forgetting in C. elegans.

MicroRNA-320-3p promotes the progression of acute pancreatitis by blocking DNMT3a-mediated MMP8 methylation in a targeted manner.

In this research, we screened out two genes upregulated in mice with acute pancreatitis (AP) by gene sequencing: microRNA (miR)-320-3p and matrix metalloprotease 8 (MMP8). This study was designed to determine whether miR-320-3p and MMP8 participate in AP development and explore the mechanisms, with a new idea for clinical diagnosis and treatment of AP. Expression of miR-320-3p, DNA methyltransferase 3a (DNMT3a), and MMP8 in mouse pancreatic tissues and AR42J cells was tested by RT-qPCR and western blot assays. Pancreatic pathological changes, serum amylase and lipase, and inflammatory factors in mouse serum and cell supernatant were measured by hematoxylin-eosin staining, automation analyzer, and enzyme-linked immunosorbent assay, respectively. Cell proliferation and apoptosis were determined by CCK-8 assay and flow cytometry. The interaction between miR-320-3p, DNMT3a, and MMP8 was verified by luciferase activity assay, ChIP-qPCR, and MSP assay. High expression of miR-320-3p and MMP8, and low expression of DNMT3a were observed in pancreatic tissues of AP mice and caerulein-induced AP cellular model. Downregulation of miR-320-3p alleviated injury of mouse pancreas, reduced the levels of serum amylase and lipase, and blocked inflammatory factor levels in AP mice. In caerulein-induced AP cellular models, inhibiting miR-320-3p facilitated proliferation and inhibited apoptosis. Upregulation of MMP8 resulted in the opposite results, which could be reversed by simultaneous inhibition of miR-320-3p. miR-320-3p targeted DNMT3a, and downregulating miR-320-3p promoted DNMT3a expression. Moreover, DNMT3a promoted DNA methylation in MMP8 promoter region, thereby inhibiting MMP8 expression in AP mouse and cellular models. This research suggests that miR-320-3p inhibits DNMT3a to reduce MMP8 methylation and increase MMP8 expression, thereby promoting AP progression.

A real-world cost-effectiveness analysis of nebulized budesonide and intravenous methylprednisolone in acute exacerbation of chronic obstructive pulmonary disease.

Objective: To assess the cost-effectiveness of nebulized budesonide and intravenous methylprednisolone in the treatment of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a real-world setting. Materials and methods: Data from 291 patients with AECOPD were collected from the information system of a tertiary hospital in China. Patients were categorized into two groups: those treated with nebulized budesonide (n = 148) and those treated with intravenous methylprednisolone (n = 143). Clinical efficacy and the rate of no readmission within 1 year after discharge were used as effect indicators, and a cost-effectiveness analysis was conducted from the perspective of the Chinese healthcare system. Logistic regression, generalized linear regression, and bootstrap methods were used for sensitivity analyses. Results: There was no statistical difference between the budesonide and methylprednisolone groups in clinical efficacy rates (94.6% vs. 93.7%). The cost-minimization analysis shows that budesonide is not cost-effective owing to higher total cost. In terms of readmission rates, budesonide was again not cost-effective, with an incremental cost-effectiveness ratio (ICER) of 22276.62 CNY, which is higher than the willingness to pay (WTP) of 20206.20 CNY, the mean per admission expenditure in China. The sensitivity analyses confirm that these results are robust. Conclusion: Compared with intravenous methylprednisolone, nebulized budesonide is not a cost-effective strategy for AECOPD patients in China.

Inhibitory effects of LOXL2 knockdown on cellular functions of liver cancer stem cells.

Background: Lysyl oxidase-like 2 (LOXL2) plays a role in tumor microenvironment formation and metastasis of hepatocellular carcinoma (HCC), which has a high mortality burden. Liver cancer stem cells (LCSCs) are related with the major malignant phenotypes of HCC. The function of LOXL2 in regulation of LCSCs remains unknown. Methods: CD133+HepG2 and CD133+Hep3B cells were sorted by fluorescence-activated cell sorting (FACS) from two human hepatoblastoma cell lines. Spheroid formation, apoptosis, cell cycle, as well as transwell assays were performed upon LOXL2 knockdown in CD133+HepG2 and CD133+Hep3B cells. Protein and mRNA levels were quantified by Western blotting, immunofluorescence and reverse transcription-PCR (RT-PCR). Results: Knockdown of LOXL2 decreased spheroid formation, migration and invasion (P<0.05), also induced apoptosis (P<0.05) and cell cycle arrest (P<0.05) in CD133+HepG2 and CD133+Hep3B cells. Knockdown of LOXL2 effectively inhibited expression of the anti-apoptosis proteins baculoviral inhibitor of apoptosis protein (IAP) repeat-containing 3 (BIRC3) and murine double minute 2 (MDM2) (P<0.01), as well as autophagy marker microtubule-associated protein 1 light chain 3 B (LC3B) and autophagy gene ATG5 in CD133+HepG2 and CD133+Hep3B cells (P<0.01). Conclusions: The results revealed that LOXL2 inhibition could reduce the proliferation and expansion of LCSCs, making LOXL2 inhibitors an attractive and novel therapeutic strategy of HCC.

LncRNA H19 inhibits ER stress induced apoptosis and improves diabetic cardiomyopathy by regulating PI3K/AKT/mTOR axis.

OBJECTIVE: Extensive studies have shown that ERS may be implicated in the pathogenesis of DCM. We explored the therapeutic effects of lncRNAH19 on DCM and its effect on ERS-associated cardiomyocyte apoptosis. METHODS: C57/BL-6j mice were randomly divided into 3 groups: non-DM group (controls), DM group (DCM), and lncRNAH19 overexpression group (DCM+H19 group). The effect of H19 on cardiac function was detected. The effect of H19 on cardiomyocyte apoptosis and cardiac fibrosis in DM was examined. Differentially expressed genes (DEGs) and activated pathways were examined by bioinformatics analysis. STRING database was applied to construct a PPI network using Cytoscape software. The expression of p-PERK, p-IRE1, ATF6, CHOP, cleaved caspase-3, -9, -12 and BAX proteins in cardiac tissue was used to determine the ERS-associated apoptotic indicators. We established the HG-stimulated inflammatory cell model. The expression of p-PERK and CHOP in HL-1 cells following HG was determined by immunofluorescence labeling. The effects of H19 on ERS and PI3K/AKT/mTOR pathway were also detected. RESULTS: H19 improved left ventricular dysfunction in DM. H19 could reduce cardiomyocytes apoptosis and improve fibrosis in vivo. H19 could reduce the expression of p-PERK, p-IRE1α, ATF6, CHOP, cleaved caspase-3, cleaved caspase-9, cleaved caspase-12, and BAX proteins in cardiac tissues. Furthermore, H19 repressed oxidative stress, ERS and apoptosis in vitro. Moreover, the effect of H19 on ERS-associated apoptosis might be rescued by LY294002 (the specific inhibitor for PI3K and AKT). CONCLUSION: H19 attenuates DCM in DM and ROS, ERS-induced cardiomyocyte apoptosis, which is associated with the activation of PI3K/AKT/mTOR signaling pathway.

From Static to Dynamic: A Review on the Role of Mucus Heterogeneity in Particle and Microbial Transport.

Mucus layers (McLs) are on the front line of the human defense system that protect us from foreign abiotic/biotic particles (e.g., airborne virus SARS-CoV-2) and lubricates our organs. Recently, the impact of McLs on human health (e.g., nutrient absorption and drug delivery) and diseases (e.g., infections and cancers) has been studied extensively, yet their mechanisms are still not fully understood due to their high variety among organs and individuals. We characterize these variances as the heterogeneity of McLs, which lies in the thickness, composition, and physiology, making the systematic research on the roles of McLs in human health and diseases very challenging. To advance mucosal organoids and develop effective drug delivery systems, a comprehensive understanding of McLs' heterogeneity and how it impacts mucus physiology is urgently needed. When the role of airway mucus in the penetration and transmission of coronavirus (CoV) is considered, this understanding may also enable a better explanation and prediction of the CoV's behavior. Hence, in this Review, we summarize the variances of McLs among organs, health conditions, and experimental settings as well as recent advances in experimental measurements, data analysis, and model development for simulations.