A pH switchable hydrophilic fluorescent BODIPY sodium disulfonate for Fe3+ multicolor detection: Experimental and DFT studies.

BODIPY-based chemosensors are widely used owing to merits like good selectivity, high fluorescence quantum yield, and excellent optical stability. As such, a pH-switchable hydrophilic fluorescent probe, BODIPY-PY-(SO3Na)2, was developed for detection of Fe3+ ion in aqueous solutions. BODIPY-PY-(SO3Na)2 revealed strong fluorescence intensity and was responsive to pH value in the range of 6.59-1.96. Additionally, BODIPY-PY-(SO3Na)2 showed good selectivity and sensitivity towards Fe3+. A good linear relationship for Fe3+ detection was obtained from 0.0 µM to 50.0 µM with low detecting limit of 6.34 nM at pH 6.59 and 2.36 nM at pH 4.32, respectively. The response to pH and detection of Fe3+ induced obvious multicolor changes. BODIPY-PY-(SO3Na)2 can also be utilized to quantitatively detect Fe3+ in real water sample. Different mechanisms of Fe3+ detection at investigated pH values were unraveled through relativistic density functional theory (DFT) calculations in BODIPY-PY-(SO3Na)2 and experiments of coexisting cations, anions and molecules. These results enabled us to gain a deeper understanding of the interactions between BODIPY-PY-(SO3Na)2 and Fe3+ and provide valuable fundamental information for design of efficient multicolor chemosensors for Fe3+ as well.

Wenshen Xiaozheng Tang alleviates fibrosis in endometriosis by regulating differentiation and paracrine signaling of endometrium-derived mesenchymal stem cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Wenshen Xiaozheng Tang (WXT), a traditional Chinese medicine (TCM) decoction, is effective for treating endometriosis. However, the effect of WXT on endometrium-derived mesenchymal stem cells (eMSCs) which play a key role in the fibrogenesis of endometriosis requires further elucidation. AIMS OF THE STUDY: The aim of this study was to clarify the potential mechanism of WXT in improving fibrosis in endometriosis by investigating the regulation of WXT on differentiation and paracrine of eMSCs. MATERIALS AND METHODS: The nude mice with endometriosis were randomly divided into model group, WXT group and mifepristone group. After 21 days of treatment, the lesion volume was calculated. Fibrosis in the lesions was evaluated by Masson staining and expression of fibrotic proteins. The differentiation of eMSCs in vivo was explored using a fate-tracking experiment. To further clarify the regulation of WXT on eMSCs, primary eMSCs from the ectopic lesions of endometriosis patients were isolated and characterized. The effect of WXT on the proliferation and differentiation of ectopic eMSCs was examined. To evaluate the role of WXT on the paracrine activity of ectopic eMSCs, the conditioned medium (CM) from ectopic eMSCs pretreated with WXT was collected and applied to treat ectopic endometrial stromal cells (ESCs), after which the expression of fibrotic proteins in ectopic ESCs was assessed. In addition, transcriptome sequencing was used to investigate the regulatory mechanism of WXT on ectopic eMSCs, and western blot and ELISA were employed to determine the key mediator. RESULTS: WXT impeded the growth of ectopic lesions in nude mice with endometriosis and reduced collagen deposition and the expression of fibrotic proteins fibronectin, collagen I, α-SMA and CTGF in the endometriotic lesions. The fate-tracking experiment showed that WXT prevented human eMSCs from differentiating into myofibroblasts in the nude mice. We successfully isolated eMSCs from the lesions of patients with endometriosis and demonstrated that WXT suppressed proliferation and myofibroblast differentiation of ectopic eMSCs. Moreover, the expression of α-SMA, collagen I, fibronectin and CTGF in ectopic ESCs was significantly down-regulated by the CM of ectopic MSCs pretreated with WXT. Combining the results of RNA sequencing, western blot and ELISA, we found that WXT not only reduced thrombospondin 4 expression in ectopic eMSCs, but also decreased thrombospondin 4 secretion from ectopic eMSCs. Thrombospondin 4 concentration-dependently upregulated the expression of collagen I, fibronectin, α-SMA and CTGF in ectopic ESCs, indicating that thrombospondin 4 was a key mediator of WXT in inhibiting the fibrotic process in endometriosis. CONCLUSION: WXT improved fibrosis in endometriosis by regulating differentiation and paracrine signaling of eMSCs. Thrombospondin 4, whose release from ectopic eMSCs is inhibited by WXT, may be a potential target for the treatment of endometriosis.

Elucidating ferroptosis mechanisms in heart failure through transcriptomics, single-cell sequencing, and experimental validation.

BACKGROUND: The mechanisms underlying ferroptosis in heart failure (HF) remain incompletely understood. METHODS: This study analyzed the heart failure dataset from the Gene Expression Omnibus to identify differentially expressed ferroptosis-related genes (DFRGs). Key DFRGs were selected using LASSO regression and SVM-RFE machine learning techniques. Their diagnostic accuracy was evaluated via ROC curve analysis. Single-cell sequencing data, heart failure cell, and mouse models were utilized to validate these key DFRGs. Additionally, potential non-coding RNAs targeting these genes were predicted, and analyses for gene set enrichment, immune cell infiltration, and drug targeting were conducted. RESULTS: A total of 127 DFRGs were identified, with 83 downregulated and 44 upregulated compared to controls. Seven key DFRGs (PTGS2, BECN1, SLC39A14, QSOX1, MLST8, TMSB4X, KDM4A) were identified, showing high diagnostic accuracy (AUC 0.988) in the GSE5406 dataset. GO and KEGG analyses linked these genes to ferroptosis, FoxO signaling, and autophagy pathways. A ceRNA network identified 217 miRNAs and 243 lncRNAs potentially targeting these genes, and 64 drugs were predicted as potential targets. Single-cell sequencing and in vitro experiments revealed differential expression of SLC39A14 and QSOX1, which was further confirmed in vivo. CONCLUSION: This study provides novel insights into the role of ferroptosis in heart failure by identifying and validating DFRGs that exhibit differential expression across various cell types. The differential expression patterns of these genes, particularly SLC39A14 and QSOX1, indicate their potential involvement in the pathophysiological mechanisms contributing to HF. These findings offer new insights for the development of targeted therapies for HF.

Exposure-Response-Based Multiattribute Clinical Utility Score Framework to Facilitate Optimal Dose Selection for Oncology Drugs.

PURPOSE: The advent of new therapeutic modalities highlighted deficiencies in the traditional maximum tolerated dose approach for oncology drug dose selection and prompted the Food and Drug Administration (FDA)'s Project Optimus initiative, which suggests that sponsors take a holistic approach, including efficacy, safety, and pharmacokinetic (PK) and pharmacodynamic data, in conjunction with integrated exposure-response (ER) analyses. However, this method comes with an inherent challenge of the collation of the multisource data. To address this issue, an ER-based clinical utility score (CUS) framework, combining benefit and risk into a single measurement, was developed. METHODS: Model-predicted outcomes for each clinically relevant end point, informed by ER modeling, are converted to a CUS using a user-defined utility function. Thereafter, individual CUS is integrated into a single score with user-defined weighting for each end point. The user-defined weighting feature allows the user to incorporate expert knowledge/understanding into weighing the product's benefit versus risk profile. RESULTS: To validate the framework, data were leveraged from over 50 oncology programs from 2019 to 2023 on the basis of FDA new drug application/biologics license application review packages and/or related literature studies. Five representative cases were selected for in-depth evaluation. Results showed that the optimal benefit-risk ratio (highest CUS) was consistently observed at PK exposures synonymous with recommended doses. A recurring theme across cases was a greater emphasis on safety over efficacy in oncology drug dose determination. CONCLUSION: The ER-based CUS framework offers a strategic tool to navigate the complexities of dose selection in oncology programs. It serves as a pillar to the importance of integrative data analysis, aligning with the vision of Project Optimus, and demonstrates its potential in guiding dose optimization by balancing therapeutic benefits against risk.

The effect of different power radiofrequency ablations in treatment and postoperative pain in patients with atrial fibrillation: a retrospective study.

BACKGROUND: There has been no consensus on what power of radiofrequency energy can be used to produce the best surgical results in patients with atrial fibrillation. In addition, patients undergoing local anesthesia and fentanyl analgesia may experience pain when radiofrequency ablation is performed. This study investigated the effect of different power radiofrequency ablations in treatment and postoperative pain in patients with atrial fibrillation. METHODS: A retrospective study was performed with 60 patients who underwent radiofrequency ablation for atrial fibrillation between January and June 2023. Patients were divided into 2 groups according to the power of the radiofrequency ablation catheter used, with 30 patients in the conventional power group (35 W) and 30 patients in the high-power group (50 W). The cardiac electrophysiological indexes and postoperative pain of the 2 groups were compared. RESULTS: Most of the procedural key parameters between the 2 groups had no significant differences. However, the total application time during radiofrequency ablation and pulmonary vein isolation time in the high-power group were significantly shorter than those in the conventional power group (p < 0.001). Patients in the high-power group reported significantly less pain than those in the conventional power group in the immediate postoperative period and the late postoperative period (p < 0.001). CONCLUSIONS: High-power radiofrequency ablation showed a shorter treatment time, and could reduce postoperative pain compared to conventional power ablation.

Altitude-related features and prognosis in patients with reversible splenial lesion syndrome.

INTRODUCTION: RESLES (Reversible splenial lesion syndrome) can be observed secondary to various diseases, and intramyelinic edema may play a crucial role in the pathogenesis of SCC (Splenium of the corpus callosum). Some studies have suggested that hypoxic-ischaemic encephalopathy may constitute a risk factor for SCC lesions. However, the potential impact of high-altitude environments on SCC, especially during chronic exposure, remain obscure. METHODS: Our study included 19 patients who satisfied the diagnostic criteria of RESLES at high altitudes. Ten low-altitude patients with RESLES were included as controls. All participants received MRI (Magnetic resonance imaging) scans twice. Routine blood tests, liver, kidney and thyroid function, coagulation function, electrolytes and vitamins were detected during hospitalization and before discharge. In addition, the patients were followed up in May 2023. RESULTS: Hypoxic environments at high altitudes may increase the risk of RESLES. The two groups showed different clinical symptoms. High-altitude patients had significantly higher CRP levels than low-altitude patients. The lesion size in high-altitude patients showed a positive correlation with SaO2 levels. However, the patients at low altitudes had positive correlation trends between lesion size and several inflammatory markers (WBC, NEU and CRP). All patients had a benign prognosis that may not be affected by the use of prednisone acetate. CONCLUSIONS: Hypoxic environments at high altitudes may play a role in the aetiology of RESLES. Additionally, RESLES is a reversible disease and the administration of glucocorticoids may be dispensable for its treatment.

Cellular and molecular biology of posttranslational modifications in cardiovascular disease.

Cardiovascular disease (CVD) has now become the leading cause of death worldwide, and its high morbidity and mortality rates pose a great threat to society. Although numerous studies have reported the pathophysiology of CVD, the exact pathogenesis of all types of CVD is not fully understood. Therefore, much more research is still needed to explore the pathogenesis of CVD. With the development of proteomics, many studies have successfully identified the role of posttranslational modifications in the pathogenesis of CVD, including key processes such as apoptosis, cell metabolism, and oxidative stress. In this review, we summarize the progress in the understanding of posttranslational modifications in cardiovascular diseases, including novel protein posttranslational modifications such as succinylation and nitrosylation. Furthermore, we summarize the currently identified histone deacetylase (HDAC) inhibitors used to treat CVD, providing new perspectives on CVD treatment modalities. We critically analyze the roles of posttranslational modifications in the pathogenesis of CVD-related diseases and explore future research directions related to posttranslational modifications in cardiovascular diseases.

Optimized nanopesticide delivery of thiamethoxam to cowpeas (Vigna unguiculata) controls thrips (Megalurothrips usitatus) and reduces toxicity to non-target worker bees (Apis mellifera).

Thrips [Megalurothrips usitatus (Bagnall)] (Thysanoptera: Thripidae) is a pest that poses a serious challenge to global crop production and food supply, especially to the cowpea industry. Nano-delivery systems have broad application prospects in the prevention and control of pests in agriculture. Herein, three types of amino acid (AA) modified polysuccinimide nano-delivery carriers (PSI-GABA, PSI-ASP and PSI-GLU) were constructed with a diameter of approximately 150 nm to load thiamethoxam (THX), which enhanced THX effective distribution and use with cowpea plants. Significantly, the PSI-GLU nanocarrier effectively delivered THX to cowpea plant tissues following 6 h of soil application. Compared with commercial THX suspension (SC), the THX content in the leaves of cowpea plants was increased by 2.3 times. Confocal laser scanning microscopy revealed that the FITC-labeled PSI-GLU nanocarrier reached the leaves through the vascular system after being absorbed by the roots of cowpea plants. The PSI-GLU nanocarrier decreased the LC50 of THX from 11.45 to 7.79 mg/L and significantly enhanced the insecticidal effect. The PSI-GLU nanocarrier also improved the safety of THX to worker bees at 48 h, and moreover showed a growth-promoting effect on cowpea seedlings. These results demonstrated that the PSI-GLU nano-delivery carrier has promising uses on improving the effective utilization of THX for the sustainable control of thrips and reducing the risk to non-target pollutions.

Superconductivity in Diamond-Like BC15.

Advancing the compositional space of a compound class can result in intriguing superconductors, such as LaH10. Herein, we performed a comprehensive first-principles structural search on a binary B-C system with various chemical compositions. The identified diamond-like BC15, named d-BC15, is thermodynamically superior to the synthesized BC3 and BC5. Interestingly, d-BC15 shows anisotropic superconductivity resulting from three distinct Fermi surfaces. Its predicted critical temperature (Tc) is 43.6 K at ambient pressure, beyond the McMillan limit. d-BC15 reaches a maximum of around 75 K at 0.43% hole doping due to the substantially enhanced density of states at the Fermi level. Additionally, d-BC15 demonstrates superhard characteristics with a Vickers hardness of 75 GPa. The calculated tensile and shear stresses are 72 and 73 GPa, respectively. The combination of high superconductivity and superhardness in d-BC15 offers new insights into the design of multifunctional materials.

Role of bacterial pathogens in microbial ecological networks in hydroponic plants.

Plant-associated microbial communities are crucial for plant growth and health. However, assembly mechanisms of microbial communities and microbial interaction patterns remain elusive across vary degrees of pathogen-induced diseases. By using 16S rRNA high-throughput sequencing technology, we investigated the impact of wildfire disease on the microbial composition and interaction network in plant three different compartments. The results showed that pathogen infection significantly affect the phyllosphere and rhizosphere microbial community. We found that the primary sources of microbial communities in healthy and mildly infected plants were from the phyllosphere and hydroponic solution community. Mutual exchanges between phyllosphere and rhizosphere communities were observed, but microbial species migration from the leaf to the root was rarely observed in severely infected plants. Moreover, wildfire disease reduced the diversity and network complexity of plant microbial communities. Interactions among pathogenic bacterial members suggested that Caulobacter and Bosea might be crucial "pathogen antagonists" inhibiting the spread of wildfire disease. Our study provides deep insights into plant pathoecology, which is helpful for the development of novel strategies for phyllosphere disease prediction or prevention.

Effectiveness and safety of emergency transcatheter aortic valve replacement in patients with severe aortic stenosis complicated by cardiogenic shock: A systematic review and meta-analysis.

BACKGROUND: The application of transcatheter aortic valve replacement (TAVR) has been developed on different populations in many clinical studies. However, research dedicated to the application of emergency TAVR in patients with aortic stenosis (AS) experiencing cardiogenic shock is limited. OBJECTIVE: To investigate the safety and effectiveness of emergency TAVR in AS patients with circulatory collapse. METHODS: Studies on the application of emergency TAVR in AS patients with cardiogenic shock were screened from PubMed, Web of Science, and Embase databases. Two researchers independently screened the literature-extracted data and conducted a meta-analysis was conducted using STATA 16.0 software. RESULTS: 17 studies comprising 36,886 patients undergoing emergency TAVR and 8,530 patients undergoing emergency SAVR or BAV. Emergency TAVR showed no difference in valve implantation success rate compared to elective TAVR. At 30-day endpoints comparison, emergency TAVR exhibited significantly higher all-cause mortality and readmission rates than elective TAVR (RR=2.73 95 %CI 2.04-3.65, P < 0.01; RR=1.2 95 %CI 0.9-1.6, P < 0.01), but reduced mortality risk compared to emergency SAVR/BAV (RD=-0.15 95 %CI -0.25 to -0.04, P = 0.005). At one year post-operation, people with emergency TAVR continued to have higher all-cause mortality than elective TAVR (RR=1.55 95 %CI 1.37-1.74, P < 0.01) but similar with emergency SAVR/BAV (RD=-0.04 95 %CI -0.33 to 0.25, P = 0.796). Rates of severe bleeding and new-onset renal dialysis were higher after emergency TAVR, compared to elective TAVR, while the incidences of permanent pacemaker implantation, severe paravalvular leakage and stroke were similar. CONCLUSION: Despite emergency TAVR having higher readmission and mortality rates compared to elective TAVR, it is a relatively safe and effective treatment in cases of cardiogenic shock compared to emergency BAV/SAVR.

Mediating role of inner strength in the relationship between medication literacy and medication adherence among kidney transplant patients. / å† åœ¨åŠ›é‡åœ¨è‚¾ç§»æ¤æ‚£è€ è¯ç‰©ç´ å »ä¸Žæœè¯ä¾ä»Žæ€§å ³ç³»ä¸­çš„ä¸­ä»‹ä½œç”¨ï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Compared with long-term renal replacement therapy, kidney transplantation is the ideal treatment for end-stage renal disease (ESRD), significantly extending patient life and improving quality of life. Kidney transplant patients need to adhere to lifelong immunosuppressive medication regimens, but their medication adherence is generally poor compared with other organ transplant recipients. Medication adherence is closely related to medication literacy and psychological status, yet related studies are limited. This study aims to investigate the current status of medication adherence, inner strength, and medication literacy in kidney transplant patients, analyze the relationships among these 3 factors, and explore the mediating role of inner strength in the relationship between medication literacy and medication adherence. METHODS: A cross-sectional survey was conducted from March to October 2023 involving 421 patients aged≥18 years who visited kidney transplantation outpatient clinics at 4 tertiary hospitals in Hunan Province. The inner strength, medication literacy, and medication adherence of kidney transplant patients were investigated using the Inner Strength Scale (ISS), the Chinese version of the Medication Literacy Assessment in Spanish and English (MedLitRxSE), and the Chinese version of the Morisky Medication Adherence Scale-8 (C-MMAS-8), respectively. Univariate analysis was performed to examine the effects of demographic and clinical data on medication adherence. Correlation analysis was conducted to explore the relationships among medication literacy, medication adherence, and inner strength. Significant variables from univariate and correlation analyses were further analyzed using multiple linear regression, and the mediating effect of inner strength was explored. RESULTS: Among the 421 questionnaires collected, 408 were valid, with an effective rate of 96.91%. The scores of C-MMAS-8, MedLitRxSE, and ISS were 6.64±1.16, 100.63±14.67, and 8.47±4.03, respectively. Among the 408 patients, only 86 (21.08%) patients had a high level of medication adherence, whereas 230 (56.37%) patients had a medium level of medication adherence, and 92 (22.55%) patients had poor medication adherence. Univariate analysis indicated that the kidney transplant patients' age, marital status, education levels, years since their kidney transplant operation, number of hospitalizations after the kidney transplant, and adverse drug reactions showed significant differences in medication adherence (all P<0.05). Correlation analysis showed that inner strength positively correlated with both medication literacy (r=0.183, P<0.001) and medication adherence (r=0.201, P<0.001). Additionally, there was a positive correlation between medication adherence and medication literacy (r=0.236, P<0.001). Inner strength accounted for 13.22% of the total effect in the mediating role between medication literacy and medication adherence. CONCLUSIONS: The level of medication adherence among kidney transplant patients needs improvement, and targeted intervention measures are essential. Inner strength mediates the relationship between medication literacy and medication adherence in these patients. Healthcare professionals should focus on enhancing medication literacy and supporting patients' inner strength to improve medication adherence.

The clinical effect of endoscopic and open surgery in the treatment of thyroid cancer and their effect on the blood coagulation state: a comparative study.

Purpose: This study was performed to compare the therapeutic efficacy of endoscopic surgery and open surgery and their effects on postoperative blood coagulation state in patients with thyroid cancer, and to provide evidence for the prevention measurement of thrombosis in the perioperative period. Methods: One hundred patients with thyroid cancer who received treatment in our hospital from January 2021 to December 2021, were randomly divided into an endoscopic group and an open surgery group, with 50 patients in each group. The patients in the open surgery group were treated by traditional open surgery, while patients in the endoscopic group accepted endoscopic surgery. The clinically therapeutic effect and blood coagulation of the 2 groups were compared. Results: Intraoperative blood loss and length of hospital stay were lower, and operative time was longer in the endoscopic group than in the open surgery group (P < 0.05). The 24-hour postoperative fibrinogen and D-dimer levels were higher in both groups than in the preoperative period, while PT was shorter (P < 0.05). There were no significant differences in postoperative complications and follow-up between the 2 groups (P > 0.05), but the incidence of complications, postoperative metastases, and thrombosis was relatively low in the endoscopic group. Conclusion: In the treatment of patients with thyroid cancer, endoscopic surgery has the advantages of less blood loss, fewer complications, and so on. Endoscopic and open surgery can lead to a hypercoagulable state, but the effect of endoscopic surgery is better than that of open surgery.

Lanthanum chloride exerts therapeutic potential for chronic kidney disease by suppressing nanohydroxyapatite-induced mitophagy and mitochondria-mediated apoptosis.

OBJECTIVE: To investigate the protective effect of lanthanum chloride on kidney injury in chronic kidney disease and its mechanism. METHODS: 1. Patients with CKD stage 2-5 were selected to analyze the effect of lanthanum-containing preparations on CKD. 2. Sixty healthy male Wistar rats were randomly divided into control group, model group, lanthanum chloride groups (0.03 ng/kg, 0.1 ng/kg, 0.3 ng/kg, q.3d., i.v.), and lanthanum carbonate group (0.3 g/kg, q.d., p.o.). The model group was given 2 % adenine suspension (200 mg/kg, q.d., p.o.) for the first two weeks, followed by adenine (200 mg/kg, b.i.d., p.o.) for 2 weeks, and all animals were sacrificed after eight weeks of administration. 3. The serum and kidneys of rats in each group were collected to detect the oxidative stress indicators and the expressions of LC3B-Ⅱ/Ⅰ, p62, Bcl-2, Bax, Caspase-3 and Cleaved Caspase-3. 4. Human renal tubular epithelial cells (HK-2 cells) were divided into control group, model group, lanthanum chloride group, pyrophosphate (PPI) group, chloroquine (CQ) group, rapamycin group, doxorubicin (DOX) group and N-acetyl-L-cysteine (NAC) group. The mitochondrial status, mitophagy and apoptosis levels were detected. RESULTS: 1.Lanthanum-containing preparations can significantly reduce the biochemical indexes of kidney injury in patients with CKD. 2. In the model group, the glomerular and renal tubular edema, the mitochondria were short and round, and the expression of LC3B-Ⅱ/Ⅰ and Bax increased, while the expression of P62, Bcl-2 and Caspase-3 decreased, and there was a significant improvement in the administration group, especially the 0.1 ng/kg group and lanthanum carbonate group. 3. In the HK-2 cell model group, mitochondrial membrane potential decreased, morphology changed and the results were reversed by lanthanum chloride. CONCLUSION: Lanthanum chloride may alter the morphology of nano-hydroxyapatite, thereby inhibiting its induced mitophagy and mitochondria-mediated apoptosis, and ultimately improve CKD renal injury effectively.

Biocontrol of citrus fungal pathogens by lipopeptides produced by Bacillus velezensis TZ01.

Citrus diseases caused by fungal pathogens drastically decreased the yield and quality of citrus fruits, leading to huge economic losses. Given the threats of chemical pesticides on the environment and human health, biocontrol agents have received considerable attention worldwide as ecofriendly and sustainable alternative to chemical fungicides. In the present study, we isolated a Bacillus velezensis strain TZ01 with potent antagonistic effect against three citrus pathogenic fungi: Diaporthe citri, Colletotrichum gloeosporioides and Alternaria alternata. The culture supernatant of this strain exhibited remarkable antifungal activity on potato dextrose agar plates and detached leaves of five citrus varieties. Treatment with TZ01 culture supernatant obviously affected the hyphal morphology and caused nucleic acid leakage. The crude lipopeptides (LPs) extracted from the culture supernatant were found as the major active ingredients, and could maintain the activity under a wide range of temperature and pH and ultraviolet radiation. Furthermore, the type of LPs, produced in vitro, were explored. Whole-genome sequencing of TZ01 revealed secondary metabolite gene clusters encoding synthetases for non-ribosomal peptides and polyketide production, and gene clusters responsible for the synthesis of three important LPs (surfactin, iturin, and fengycin) were identified in the genome. The liquid chromatography-mass spectrometry analysis confirmed the presence of various homologs of surfactin A, bacillomycin D, and fengycin A in the extracted LPs. Taken together, these results contribute to the possible biocontrol mechanisms of B. velezensis strain TZ01, as well as providing a promising new candidate strain as a biological control agent for controlling citrus fungal pathogens.

Causal role of gut microbiota, serum metabolites, immunophenotypes in myocarditis: a mendelian randomization study.

Background: The intricate relationship among gut microbiota, serum metabolites, and immunophenotypes may significantly impact myocarditis. However, direct causal links between these domains and myocarditis are not well understood. Methods: The study performed Mendelian randomization (MR) analysis using genetic data from public sources. Exposure data included 211 gut microbiota, 486 serum metabolites, and 731 immunophenotypes from Mibiogen, the Metabolomics GWAS server, and GWAS catalog databases. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables based on established criteria. Myocarditis data from GWAS (427,911 participants, 24, 180, 570 SNPs) were used as the outcome variable. MR analysis was conducted using Inverse Variance Weighting (IVW), with Cochran's Q test for heterogeneity and Egger's intercept to assess horizontal pleiotropy. Results: 9 gut microbiota, 10 serum metabolites, and 2 immunophenotypes were negatively associated with myocarditis risk. In contrast, 5 gut microbiota, 12 serum metabolites, and 7 immunophenotypes were positively associated with myocarditis risk (all, P < 0.05). Sensitivity analyses confirmed the stability of these results. Conclusion: This MR study suggests that gut microbiota, serum metabolites, and immunophenotypes may causally influence myocarditis risk. These findings provide genetic evidence for myocarditis etiology and could inform future precision prevention and treatment strategies.

Network Pharmacology and in vitro Experimental Verification on Intervention of Oridonin on Non-Small Cell Lung Cancer.

OBJECTIVE: To explore the key target molecules and potential mechanisms of oridonin against non-small cell lung cancer (NSCLC). METHODS: The target molecules of oridonin were retrieved from SEA, STITCH, SuperPred and TargetPred databases; target genes associated with the treatment of NSCLC were retrieved from GeneCards, DisGeNET and TTD databases. Then, the overlapping target molecules between the drug and the disease were identified. The protein-protein interaction (PPI) was constructed using the STRING database according to overlapping targets, and Cytoscape was used to screen for key targets. Molecular docking verification were performed using AutoDockTools and PyMOL software. Using the DAVID database, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted. The impact of oridonin on the proliferation and apoptosis of NSCLC cells was assessed using cell counting kit-8, cell proliferation EdU image kit, and Annexin V-FITC/PI apoptosis kit respectively. Moreover, real-time quantitative PCR and Western blot were used to verify the potential mechanisms. RESULTS: Fifty-six target molecules and 12 key target molecules of oridonin involved in NSCLC treatment were identified, including tumor protein 53 (TP53), Caspase-3, signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase kinase 8 (MAPK8), and mammalian target of rapamycin (mTOR). Molecular docking showed that oridonin and its key target molecules bind spontaneously. GO and KEGG enrichment analyses revealed cancer, apoptosis, phosphoinositide-3 kinase/protein kinase B (PI3K/Akt), and other signaling pathways. In vitro experiments showed that oridonin inhibited the proliferation, induced apoptosis, downregulated the expression of Bcl-2 and Akt, and upregulated the expression of Caspase-3. CONCLUSION: Oridonin can act on multiple targets and pathways to exert its inhibitory effects on NSCLC, and its mechanism may be related to upregulating the expression of Caspase-3 and downregulating the expressions of Akt and Bcl-2.

Association of hepatitis B core antibody level and hepatitis B surface antigen clearance in HBeAg-negative patients with chronic hepatitis B.

Predicting hepatitis B surface antigen (HBsAg) clearance is important for chronic hepatitis B (CHB) patients receiving pegylated interferon-alfa (Peg-IFN) therapy. We aimed to determine the predictive value of serum hepatitis B core antibody (anti-HBc) for HBsAg clearance. A total of 189 HBeAg-negative CHB patients who received Peg-IFN based therapy were retrospectively included and classified into two groups: nucleos(t)ide analogues (NAs) add-on Peg-IFN group (add-on group, n = 94) and Peg-IFN combined with NAs or Peg-IFN monotherapy group (combination or monotherapy group, n = 95). After 48 weeks of treatment, 27.5% (52/189) and 15.9% (30/189) of patients achieved HBsAg clearance and seroconversion, respectively. Patients in the combination or monotherapy group tended to achieve relatively higher HBsAg clearance (31.6% vs. 23.4%, p = 0.208) and seroconversion (21.1% vs. 10.6%, p = 0.050) rates than those in the add-on group. In combination or monotherapy group, anti-HBc levels at week 12 were lower in patients with HBsAg clearance (9.0 S/CO vs. 9.9 S/CO, p < 0.001) and seroconversion (8.8 S/CO vs. 9.8 S/CO, p < 0.001) than those without. Anti-HBc level at week 12 was an independent predictor of HBsAg clearance and seroconversion. Patients with lower anti-HBc levels at week 12 showed a more significant decline in HBsAg levels during treatment. Combination of anti-HBc at week 12 and baseline HBsAg could identify over 70% of patients who achieved HBsAg clearance after 48 weeks of treatment. In addition to HBsAg, anti-HBc level could be used as a promising marker for selecting HBeAg-negative CHB patients who are more likely to respond to Peg-IFN-based therapy.

Anti-oxidative mesoporous polydopamine-based hypotensive nano-eyedrop for improved glaucoma management.

Conventional hypotensive eye drops remain suboptimal for glaucoma management, primarily due to their limited intraocular bioavailability and the growing concern regarding ocular surface side effects. Therefore, there is an urgent need to develop innovative intraocular pressure (IOP)-lowering formulations that not only possess enhanced corneal penetration ability but also provide ocular surface protection. Herein, anti-oxidative mesoporous polydopamine nanoparticles (MPDA NPs) were explored as a nano-carrier for Brimonidine to address the above issues. Nearly monodisperse MPDA NPs with obvious nanopores were successfully prepared by template-removal method and used for encapsulation of Brimonidine benefiting from their high specific surface area. Interestingly, the PEGylated and drug loaded MPDA-PEG@Brim NPs showed a near neutral surface charge, which is expected to enhance intraocular drug delivery. Consequently, much higher concentration of Brimonidine in the aqueous humor was found after topical administration of MPDA-PEG@Brim nano-dispersion as compared to free Brimonidine solution. Accordingly, superior IOP reduction effect was achieved for the nano-formulation in both hypertensive and normotensive rat eyes. Moreover, MPDA-PEG NPs showed good capability in scavenging diverse free radicals, alleviating intracellular oxidative stress, and mitigating ocular surface oxidative level in a mouse model of preservative-induced dry eye. In addition, the excellent biosafety of this novel Brimonidine nanodrug was confirmed both in vitro and in vivo. Therefore, the present work may shed light on the development of next generation hypotensive formulations for extended ocular surface protection and glaucoma management.

Bioinformatics analysis of the mechanisms of traumatic brain injury-associated dementia based on the competing endogenous RNA.

RATIONALE: Traumatic brain injury (TBI) is a critical condition associated with cognitive impairments, including dementia. This study is aimed to construct a long noncoding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) network based on bioinformatics analysis and explore molecular mechanisms underlying post-TBI dementia. METHODS: GSE104687 and GSE205661 datasets were downloaded from Gene Expression Omnibus database. Molecular Signatures Database (MSigDB) was used to search oxidative stress-, metabolism- and immune-related genes as the target gene datasets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were carried out for functional annotation and enrichment analysis. A TBI mouse model was built to validate the expression of NF2, PLXNA2, NCBP2 and U2SURP in brain tissues. RESULTS: A total of 7 differentially expressed lncRNAs (DElncRNAs) and 191 DEmRNAs were obtained. Subsequent to differential expression (DE) analysis, a lncRNA-miRNA-mRNA network was established. Notably, 13 key DEmRNAs were identified, potentially playing pivotal roles in the pathogenesis of TBI-induced dementia. By comparing the target gene datasets with 13 DEmRNAs, we identified 4 target genes that overlap with the 13 DEGmRNAs, namely NF2, PLXNA2, NCBP2 and U2SURP. Functional enrichment analysis highlighted the involvement of neuronal projections in the dementia-enriched cluster, while the protective cluster showed associations with protein synthesis and ubiquitination pathways. Importantly, we explored potential drug interventions based on interactions with the above 4 target genes. Additionally, drug interaction prediction showed that NF2 could interact with SELUMETINIB, EVEROLIMUS and TEMSIROLIMUS. CONCLUSION: Our study provides insights into the complex regulatory networks underlying post-TBI dementia and suggests a potential role for three classes of drugs in managing dementia symptoms in TBI-induced dementia.