Clinical usefulness of metagenomic next-generation sequencing for Talaromyces marneffei diagnosis in China: a retrospective study.

PURPOSE: Metagenomic next-generation sequencing (mNGS) has been widely used in the diagnosis of infectious diseases. However, studies on Talaromyces marneffei detection using mNGS remain scarce. Therefore, this study aimed to explore the diagnostic performance of mNGS in T. marneffei. METHODS: Between March 2021 and June 2023, patients who were discharged with a final diagnosis of talaromycosis, or confirmed T. marneffei infection by mNGS, culture or pathological examination were included in the study. Culture and mNGS were performed simultaneously for all patients. Clinical data were retrieved for analysis. RESULTS: A total of 78 patients were enrolled, with 40 in the talaromycosis group and 38 in the suspected-talaromycosis group. In the talaromycosis group, mNGS showed a higher positivity rate(40/40, 100.0%) compared to culture(34/40, 85.0%)(P = 0.111). All patients in the suspected-talaromycosis group tested negative via culture, while mNGS yielded positive results. The T. marneffei reads in the talaromycosis group were significantly higher than in the suspected-talaromycosis group (4399 vs. 28, P < 0.001). In the suspected-talaromycosis group, of the four patients with low reads who did not receive antifungal therapy, one died and one lung lesion progressed; most patients(31/34, 91.2%) recovered after receiving appropriate antifungal therapy. CONCLUSION: mNGS proves to be a rapid and highly sensitive method for detecting T. marneffei. Higher reads of T. marneffei correspond to a higher likelihood of infection. However, cases with low reads necessitate a comprehensive approach, integrating clinical manifestations, laboratory tests, and imaging examinations to confirm T. marneffei infection.

Structurally diverse isoquinoline alkaloids from the barks of Alangium salviifolium (L. f.) Wangerin and their cytotoxicity.

Eleven undescribed isoquinoline alkaloids (1-8, 14, 15, and 24), along with 19 analogues (9-13, 16-23, and 25-30) were isolated from the barks of Alangium salviifolium. The structures of the undescribed compounds were elucidated through the analysis of their HR-ESI-MS, 1D and 2D NMR, IR, UV, and X-ray diffraction. The absolute configuration of 8 was established via the ECD calculation. Notably, compounds 1/2 and 3/4 were two pairs of C-14 epimers. The isolated alkaloids were evaluated for their cytotoxicity against various cancer cell lines, including SGC-7901, HeLa, K562, A549, BEL-7402, HepG2, and B16, ß-carboline-benzoquinolizidine (14-22) and cepheline-type (24-28) alkaloids exhibited remarkable cytotoxicity, with IC50 values ranging from 0.01 to 48.12 µM. Remarkably, compounds 17 and 21 demonstrated greater cytotoxicity than the positive control doxorubicin hydrochloride. Furthermore, a significant proportion of these bioactive alkaloids possess a C-1' epimer configuration. The exploration of their structure-activity relationship holds promise for directing future investigations into alkaloids derived from Alangium, potentially leading to novel insights and therapeutic advancements.

Efficacy and Safety of Neoadjuvant Subcutaneous Envafolimab in dMMR/MSI-H Locally Advanced Colon Cancer.

BACKGROUND: Neoadjuvant immunotherapy with programmed death-ligand 1 blockade for colon cancer, especially for mismatch repair-deficient (dMMR)/high microsatellite instability (MSI-H) colon cancer, has gained considerable attention recently. OBJECTIVE: This study aimed to assess the safety and efficacy of neoadjuvant subcutaneous envafolimab in patients with dMMR/MSI-H locally advanced colon cancer. METHODS: Patients with dMMR/MSI-H locally advanced colon cancer treated with envafolimab at Sun Yat-sen University Cancer Center and Yunnan Cancer Hospital from October 2021 to July 2023 were retrospectively reviewed and analyzed. The primary endpoint was the pathological complete response (CR) rate, and secondary endpoints were treatment-related adverse events and complete clinical response rate. RESULTS: Overall, 15 patients were analyzed. After neoadjuvant immunotherapy with envafolimab, six patients achieved a CR, with five partial responses, and four stable disease. Three patients achieving a complete clinical response chose to accept a "watch and wait" strategy, and surgery was performed in 12 patients. Postoperative pathology results revealed seven patients achieved pathological CRs, and five patients achieved tumor regression grade 2, with 66.7% of the total CR rate. The most common treatment-related adverse events were pruritus and rash (40%), with no severe cases. No recurrences occurred over a 7.9-month follow-up. CONCLUSIONS: Envafolimab yielded promising surgical outcomes and safety in dMMR/MSI-H locally advanced colon cancer, representing a promising treatment modality for this population.

Metabolomic insights into the profile, bioaccessibility, and transepithelial transport of polyphenols from germinated quinoa during in vitro gastrointestinal digestion/Caco-2 cell transport, and their prebiotic effects during colonic fermentation.

The health-promoting activities of polyphenols and their metabolites originating from germinated quinoa (GQ) are closely related to their digestive behavior, absorption, and colonic fermentation; however, limited knowledge regarding these properties hinder further development. The aim of this study was to provide metabolomic insights into the profile, bioaccessibility, and transepithelial transport of polyphenols from germinated quinoa during in vitro gastrointestinal digestion and Caco-2 cell transport, whilst also investigating the changes in the major polyphenol metabolites and the effects of prebiotics during colonic fermentation. It was found that germination treatment increased the polyphenol content of quinoa by 21.91%. Compared with RQ group, 23 phenolic differential metabolites were upregulated and 47 phenolic differential metabolites were downregulated in GQ group. Compared with RQ group after simulated digestion, 7 kinds of phenolic differential metabolites were upregulated and 17 kinds of phenolic differential metabolites were downregulated in GQ group. Compared with RQ group after cell transport, 7 kinds of phenolic differential metabolites were upregulated and 9 kinds of phenolic differential metabolites were downregulated in GQ group. In addition, GQ improved the bioaccessibilities and transport rates of various polyphenol metabolites. During colonic fermentation, GQ group can also increase the content of SCFAs, reduce pH value, and adjust gut microbial populations by increasing the abundance of Actinobacteria, Bacteroidetes, Verrucomicrobiota, and Spirochaeota at the phylum level, as well as Bifidobacterium, Megamonas, Bifidobacterium, Brevundimonas, and Bacteroides at the genus level. Furthermore, the GQ have significantly inhibited the activity of α-amylase and α-glucosidase. Based on these results, it was possible to elucidate the underlying mechanisms of polyphenol metabolism in GQ and highlight its beneficial effects on the gut microbiota.

Deletion of Tmem268 in mice suppresses anti-infectious immune responses by downregulating CD11b signaling.

Transmembrane protein 268 (TMEM268) is a novel, tumor growth-related protein first reported by our laboratory. It interacts with the integrin subunit ß4 (ITGB4) and plays a positive role in the regulation of the ITGB4/PLEC signaling pathway. Here, we investigated the effects and mechanism of TMEM268 in anti-infectious immune response in mice. Tmem268 knockout in mice aggravated cecal ligation and puncture-induced sepsis, as evidenced by higher bacterial burden in various tissues and organs, congestion, and apoptosis. Moreover, Tmem268 deficiency in mice inhibited phagocyte adhesion and migration, thus decreasing phagocyte infiltration at the site of infection and complement-dependent phagocytosis. Further findings indicated that TMEM268 interacts with CD11b and inhibits its degradation via the endosome-lysosome pathway. Our results reveal a positive regulatory role of TMEM268 in ß2 integrin-associated anti-infectious immune responses and signify the potential value of targeting the TMEM268-CD11b signaling axis for the maintenance of immune homeostasis and immunotherapy for sepsis and related immune disorders.

Comprehensive molecular characterization of long-term glioblastoma survivors.

Fewer than 5 % glioblastoma (GBM) patients survive over five years and are termed long-term survivors (LTS), yet their molecular background is unclear. The present cohort included 72 isocitrate dehydrogenase (IDH)-wildtype GBM patients, consisting of 35 LTS and 37 short-term survivors (STS), and we employed whole exome sequencing, RNA-seq and DNA methylation array to delineate this largest LTS cohort to date. Although LTS and STS demonstrated analogous clinical characters and classical GBM biomarkers, CASC5 (P = 0.002) and SPEN (P = 0.013) mutations were enriched in LTS, whereas gene-to-gene fusions were concentrated in STS (P = 0.007). Importantly, LTS exhibited higher tumor mutation burden (P < 0.001) and copy number (CN) increase (P = 0.013), but lower mutant-allele tumor heterogeneity score (P < 0.001) and CN decrease (P = 0.026). Additionally, LTS demonstrated hypermethylated genome (P < 0.001) relative to STS. Differentially expressed and methylated genes both enriched in olfactory transduction. Further, analysis of the tumor microenvironment revealed higher infiltration of M1 macrophages (P = 0.043), B cells (P = 0.016), class-switched memory B cells (P = 0.002), central memory CD4+ T cells (P = 0.031) and CD4+ Th1 cells (P = 0.005) in LTS. We also separately analyzed a subset of patients who were methylation class-defined GBM, contributing 70.8 % of the entire cohort, and obtained similar results relative to prior analyses. Finally, we demonstrated that LTS and STS could be distinguished using a subset of molecular features. Taken together, the present study delineated unique molecular attributes of LTS GBM.

Effectiveness of a school-based Life Gatekeeper Training Program on suicide prevention in China: protocol for a randomized controlled trial.

BACKGROUND: With suicide as a leading cause of death, the issue of children and adolescent suicide risks is in the spotlight today. To empower teachers in primary and secondary schools to serve as gatekeepers and to ensure the safety of children and adolescents, the systematically tailored and localized Life Gatekeeper suicide prevention program was designed for Chinese schools. OBJECTIVE: With the ultimate goal of preventing child and adolescent suicide, we aim to outline a research protocol for examining outcomes of the recently created standardized school-based Life Gatekeeper program in reducing teachers' stigma, increasing their knowledge, willingness to intervene, and perceived competence. METHODS: Participants will be recruited from eligible primary and secondary schools. Cluster sampling will be used to randomly assign each school to either the intervention group or the control group. The primary outcomes are stigma against suicide, suicide literacy, perceived competence, and willingness to intervene with suicidal individuals, which will be measured using the Stigma of Suicide Scale, the Literacy of Suicide Scale, and the Willingness to Intervene Against Suicide Questionnaire, respectively. Measurements will be taken at four time points, including pre-intervention, immediately after the intervention, 6-month follow-up, and 1-year follow-up. CONCLUSIONS: The current study features innovative implementation in the real world, by using a randomized controlled trial design to examine the effectiveness of a school-based gatekeeper program among primary and secondary school teachers, following a sequence of defined and refined steps. The research will also investigate the viability of a school-based gatekeeper program for primary and secondary school teachers that could be quickly and inexpensively implemented in a large number of schools.

Utilizing deep ocean water in yeast fermentation for enhanced mineral-rich biomass production and fermentative regulation by proteomics modulation.

Deep Ocean Water (DOW) is rich in minerals and serves as a natural source of nutrients. However, due to the inorganic nature of these minerals, cultivating yeast in DOW could aid in the fermentation process, and simultaneously, the yeast can assimilate the minerals from DOW, resulting in a mineral-enriched yeast biomass. Focusing on three DOW sources off the eastern coast of Taiwan (TT-1, HL-1, HL-2), we fermented various yeast strains of Saccharomyces cerevisiae. Therefore, this study investigates the effects of DOW on yeast growth, alcohol dehydrogenase activity, and the biological absorption of mineral ions by the yeast. Additionally, this research employs two-dimensional electrophoresis techniques to examine how the absorbed minerals influence the regulation of yeast proteins, thereby affecting biomass and metabolism. In the result, S. cerevisiae BCRC 21689 demonstrated a remarkable ability to bio-absorb minerals such as magnesium, calcium, potassium, and zinc from DOW, enhancing its growth and fermentation performance. Proteomic analysis revealed significant shifts in the expression of 21 proteins related to glycolytic and energy metabolism, alcohol metabolism, and growth regulation, all influenced by DOW's mineral-rich environment. This indicates that DOW's mineral content is a key factor in upregulating essential enzymes in glycolytic metabolism and alcohol dehydrogenase. An increase in proteins involved in synthesis and folding processes was also observed, leading to a substantial increase in yeast biomass. This study underscores the potential of DOW as a natural enhancer in yeast fermentation processes, enriching the yeast with diverse minerals and modulating proteomic expression to optimize yeast growth and fermentation.

Systematic review and network meta-analysis on the efficacy and safety of parmacotherapy for hand osteoarthritis.

OBJECTIVE: Hand osteoarthritis poses a significant health challenge globally due to its increasing prevalence and the substantial burden on individuals and the society. In current clinical practice, treatment options for hand osteoarthritis encompass a range of approaches, including biological agents, antimetabolic drugs, neuromuscular blockers, anti-inflammatory drugs, hormone medications, pain relievers, new synergistic drugs, and other medications. Despite the diverse array of treatments, determining the optimal regimen remains elusive. This study seeks to conduct a network meta-analysis to assess the effectiveness and safety of various drug intervention measures in the treatment of hand osteoarthritis. The findings aim to provide evidence-based support for the clinical management of hand osteoarthritis. METHODS: We performed a comprehensive search across PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials was conducted until September 15th, 2022, to identify relevant randomized controlled trials. After meticulous screening and data extraction, the Cochrane Handbook's risk of bias assessment tool was applied to evaluate study quality. Data synthesis was carried out using Stata 15.1 software. RESULTS: 21 studies with data for 3965 patients were meta-analyzed, involving 20 distinct Western medicine agents. GCSB-5, a specific herbal complex that mainly regulate pain in hand osteoarthritis, showed the greatest reduction in pain [WMD = -13.00, 95% CI (-26.69, 0.69)]. CRx-102, s specific medication characterized by its significant effect for relieving joint stiffness symptoms, remarkably mitigated stiffness [WMD = -7.50, 95% CI (-8.90, -6.10)]. Chondroitin sulfate displayed the highest incidence of adverse events [RR = 0.26, 95% CI (0.06, 1.22)]. No substantial variation in functional index for hand osteoarthritis score improvement was identified between distinct agents and placebo. CONCLUSIONS: In summary, GCSB-5 and CRx-102 exhibit efficacy in alleviating pain and stiffness in HOA, respectively. However, cautious interpretation of the results is advised. Tailored treatment decisions based on individual contexts are imperative.

Emerging Chemodynamic Nanotherapeutics for Cancer Treatment.

Chemodynamic therapy (CDT) has emerged as a transformative paradigm in the realm of reactive oxygen species -mediated cancer therapies, exhibiting its potential as a sophisticated strategy for precise and effective tumor treatment. CDT primarily relies on metal ions and hydrogen peroxide to initiate Fenton or Fenton-like reactions, generating cytotoxic hydroxyl radicals. Its notable advantages in cancer treatment are demonstrated, including tumor specificity, autonomy from external triggers, and a favorable side-effect profile. Recent advancements in nanomedicine are devoted to enhancing CDT, promising a comprehensive optimization of CDT efficacy. This review systematically elucidates cutting-edge achievements in chemodynamic nanotherapeutics, exploring strategies for enhanced Fenton or Fenton-like reactions, improved tumor microenvironment modulation, and precise regulation in energy metabolism. Moreover, a detailed analysis of diverse CDT-mediated combination therapies is provided. Finally, the review concludes with a comprehensive discussion of the prospects and intrinsic challenges to the application of chemodynamic nanotherapeutics in the domain of cancer treatment.

Behavioral responses to predator and heterospecific alarm calls are habitat-specific in Eurasian tree sparrows.

Acoustic communication plays a vital role in predator-prey interactions. Although habitat structure has been shown to affect anti-predator tactics, little is known about how animals vary their behaviors in response to predator calls or heterospecific alarm calls in different environments. Here we used sound playbacks to test the responses of Eurasian tree sparrows (Passer montanus) foraging in harvested/unharvested rice paddy and open residential area. In the first experiment, we tested their behavioral responses to dove calls, male common cuckoo (Cuculus canorus) calls, hawk-like calls mimicked by female common cuckoo, sparrowhawk (Accipiter nisus) calls, and human yell calls produced to scare birds (predator signal playbacks). In the second experiment, we tested their behavioral responses to the Japanese tit's (Parus minor) territorial songs and alarm calls (heterospecific alarm signal playbacks). Results showed that the tree sparrows had less fleeing in unharvested ripe rice paddy than in harvested rice paddy and open residential area. In predator signal playbacks, call type affected the escape behavior of sparrows in unharvested rice paddy and open residential area but not harvested rice paddy. In alarm signal playbacks, tit alarm calls evoked more fleeing than territorial songs in harvested rice paddy and open residential area but not unharvested rice paddy. These results suggest that anthropogenic habitat changes may influence avian anti-predator tactics.

Deep learning system for malignancy risk prediction in cystic renal lesions: a multicenter study.

OBJECTIVES: To develop an interactive, non-invasive artificial intelligence (AI) system for malignancy risk prediction in cystic renal lesions (CRLs). METHODS: In this retrospective, multicenter diagnostic study, we evaluated 715 patients. An interactive geodesic-based 3D segmentation model was created for CRLs segmentation. A CRLs classification model was developed using spatial encoder temporal decoder (SETD) architecture. The classification model combines a 3D-ResNet50 network for extracting spatial features and a gated recurrent unit (GRU) network for decoding temporal features from multi-phase CT images. We assessed the segmentation model using sensitivity (SEN), specificity (SPE), intersection over union (IOU), and dice similarity (Dice) metrics. The classification model's performance was evaluated using the area under the receiver operator characteristic curve (AUC), accuracy score (ACC), and decision curve analysis (DCA). RESULTS: From 2012 to 2023, we included 477 CRLs (median age, 57 [IQR: 48-65]; 173 men) in the training cohort, 226 CRLs (median age, 60 [IQR: 52-69]; 77 men) in the validation cohort, and 239 CRLs (median age, 59 [IQR: 53-69]; 95 men) in the testing cohort (external validation cohort 1, cohort 2, and cohort 3). The segmentation model and SETD classifier exhibited excellent performance in both validation (AUC = 0.973, ACC = 0.916, Dice = 0.847, IOU = 0.743, SEN = 0.840, SPE = 1.000) and testing datasets (AUC = 0.998, ACC = 0.988, Dice = 0.861, IOU = 0.762, SEN = 0.876, SPE = 1.000). CONCLUSION: The AI system demonstrated excellent benign-malignant discriminatory ability across both validation and testing datasets and illustrated improved clinical decision-making utility. CRITICAL RELEVANCE STATEMENT: In this era when incidental CRLs are prevalent, this interactive, non-invasive AI system will facilitate accurate diagnosis of CRLs, reducing excessive follow-up and overtreatment. KEY POINTS: The rising prevalence of CRLs necessitates better malignancy prediction strategies. The AI system demonstrated excellent diagnostic performance in identifying malignant CRL. The AI system illustrated improved clinical decision-making utility.

The Cd resistant mechanism of Proteus mirabilis Ch8 through immobilizing and detoxifying.

Cadmium (Cd) pollution is a serious global environmental problem, which requires a global concern and practical solutions. Microbial remediation has received widespread attention owing to advantages, such as environmental friendliness and soil amelioration. However, Cd toxicity also severely deteriorates the remediation performance of functional microorganisms. Analyzing the mechanism of bacterial resistance to Cd stress will be beneficial for the application of Cd remediation. In this study, the bacteria strain, up to 1400 mg/L Cd resistance, was employed and identified as Proteus mirabilis Ch8 (Ch8) through whole genome sequence analyses. The results indicated that the multiple pathways of immobilizing and detoxifying Cd maintained the growth of Ch8 under Cd stress, which also possessed high Cd extracellular adsorption. Firstly, the changes in surface morphology and functional groups of Ch8 cells were observed under different Cd conditions through SEM-EDS and FTIR analyses. Under 100 mg/L Cd, Ch8 cells exhibited aggregation and less flagella; the Cd biosorption of Ch8 was predominately by secreting exopolysaccharides (EPS) and no significant change of functional groups. Under 500 mg/L Cd, Ch8 were present irregular polymers on the cell surface, some cells with wrapping around; the Cd biosorption capacity exhibited outstanding effects (38.80 mg/g), which was mainly immobilizing Cd by secreting and interacting with EPS. Then, Ch8 also significantly enhanced the antioxidant enzyme activity and the antioxidant substance content under different Cd conditions. The activities of SOD and CAT, GSH content of Ch8 under 500 mg/L Cd were significantly increased by 245.47%, 179.52%, and 241.81%, compared to normal condition. Additionally, Ch8 significantly induced the expression of Acr A and Tol C (the resistance-nodulation-division (RND) efflux pump), and some antioxidant genes (SodB, SodC, and Tpx) to reduce Cd damage. In particular, the markedly higher expression levels of SodB under Cd stress. The mechanism of Ch8 lays a foundation for its application in solving soil remediation.

Factors influencing pathological changes in the liver tissue in hepatitis B virus carriers with low-level viremia.

OBJECTIVES: To investigate the optimal timing for initiating antiviral therapy in hepatitis B virus (HBV) carriers with low-level viremia (LLV). METHODS: We retrospectively enrolled 126 HBV carriers with LLV who underwent liver biopsy. Patients' clinical data, routine blood test results, portal vein diameter, splenic vein diameter and thickness, and measurements (LSM) within 1 week before liver biopsy were obtained. Single-factor and multifactor statistical methods were used to analyze factors that affected inflammation and fibrosis in pathological liver tissues. The receiver operating characteristic curve was used to analyze liver stiffness and HBV DNA levels to determine liver tissue inflammation and fibrosis. R -Studio software was used to draw nomograms, calibration plots, and model decision curves. RESULTS: Infection duration and HBV DNA levels affected liver tissue inflammation. Albumin(ALB), aspartate aminotransferase (AST), HBV DNA, liver stiffness, age, and splenic thickness affected liver fibrosis. The best cutoff value of the LSM for diagnosing liver inflammation and fibrosis was 7.45 (specificity, 92%). The best cutoff value of HBV DNA for diagnosing liver inflammation and fibrosis was 39.5 (specificity, 96%). HBV DNA,and splenic thickness affected the treatment decision in naive chronic hepatitis Bpatients with LLV CONCLUSIONS: HBV carriers with LLV have high incidences of liver tissue inflammation and fibrosis. The infection duration and HBV DNA levels affected liver inflammation whereas the ALB, AST AST levels, HBV DNA, LSM, age, and splenic thickness affected liver fibrosis. Eligible expansion of antiviral treatment indications is necessary, however, a universal treatment approach may be inefficient. HBV DNA can be a reference for initiating antiviral therapy.

Performance comparison of 6 in-hospital patient monitoring systems in the detection and alarm of ventricular cardiac arrhythmias.

Background: Patient monitoring devices are critical for alerting of potential cardiac arrhythmias during hospitalization; however, there are concerns of alarm fatigue due to high false alarm rates. Objective: The purpose of this study was to evaluate the sensitivity and false alarm rate of hospital-based continuous electrocardiographic (ECG) monitoring technologies. Methods: Six commonly used multiparameter bedside monitoring systems available in the United States were evaluated: B125M (GE HealthCare), ePM10 and iPM12 (Mindray), Efficia and IntelliVue (Philips), and Life Scope (Nihon Kohden). Sensitivity was tested using ECG recordings containing 57 true ventricular tachycardia (VT) events. False-positive rate testing used 205 patient-hours of ECG recordings containing no cardiac arrhythmias. Signals from ECG recordings were fed to devices simultaneously; high-severity arrhythmia alarms were tracked. Sensitivity to true VT events and false-positive rates were determined. Differences were assessed using Fisher exact tests (sensitivity) and Z-tests (false-positive rates). Results: B125M raised 56 total alarms for 57 annotated VT events and had the highest sensitivity (98%; P <.05), followed by iPM12 (84%), Life Scope (81%), Efficia (79%), ePM10 (77%), and IntelliVue (75%). B125M raised 20 false alarms, which was significantly lower (P <.0001) than iPM12 (284), Life Scope (292), IntelliVue (304), ePM10 (324), and Efficia (493). The most common false alarm was VT, followed by nonsustained VT. Conclusion: We found significant performance differences among multiparameter bedside ECG monitoring systems using previously collected recordings. B125M had the highest sensitivity in detecting true VT events and lowest false alarm rate. These results can assist in minimizing alarm fatigue and optimizing patient safety by careful selection of in-hospital continuous monitoring technology.

Combined ROS Sensitive Folate Receptor Targeted Micellar Formulations of Curcumin Effective Against Rheumatoid Arthritis in Rat Model.

Introduction: Rheumatoid arthritis (RA) is an inflammatory immune-mediated disease that involves synovitis, cartilage destruction, and even joint damage. Traditional agents used for RA therapy remain unsatisfactory because of their low efficiency and obvious adverse effects. Therefore, we here established RA microenvironment-responsive targeted micelles that can respond to the increase in reactive oxygen species (ROS) levels in the joint and improve macrophage-specific targeting of loaded drugs. Methods: We here prepared ROS-responsive folate-modified curcumin micelles (TK-FA-Cur-Ms) in which thioketal (TK) was used as a ROS-responsive linker for modifying polyethylene glycol 5000 (PEG5000) on the micellar surface. When micelles were in the ROS-overexpressing inflammatory microenvironment, the PEG5000 hydration layer was shed, and the targeting ligand FA was exposed, thereby enhancing cellular uptake by macrophages through active targeting. The targeting, ROS sensitivity and anti-inflammatory properties of the micelles were assessed in vitro. Collagen-induced arthritis (CIA) rats model was utilized to investigate the targeting, expression of serum inflammatory factors and histology change of the articular cartilage by micelles in vivo. Results: TK-FA-Cur-Ms had a particle size of 90.07 ± 3.44 nm, which decreased to 78.87 ± 2.41 nm after incubation with H2O2. The micelles exhibited in vitro targeting of RAW264.7 cells and significantly inhibited inflammatory cytokine levels. Pharmacodynamic studies have revealed that TK-FA-Cur-Ms prolonged the drug circulation and exhibited augmented cartilage-protective and anti-inflammatory effects in vivo. Conclusion: The unique ROS-responsive targeted micelles with targeting, ROS sensitivity and anti-inflammatory properties were successfully prepared and may offer an effective therapeutic strategy against RA.

Coordination-Driven Self-Assembly of Metal Ion-Antisense Oligonucleotide Nanohybrids for Chronic Bacterial Infection Therapy.

Bacterial infection poses a significant challenge to wound healing and skin regeneration, leading to substantial economic burdens on patients and society. Therefore, it is crucial to promptly explore and develop effective methodologies for bacterial infections. Herein, we propose a novel approach for synthesizing nanostructures based on antisense oligonucleotides (ASOs) through the coordination-driven self-assembly of Zn2+ with ASO molecules. This approach aims to provide effective synergistic therapy for chronic wound infections caused by Staphylococcus aureus (S. aureus). The resulting hybrid nanoparticles successfully preserve the structural integrity and biological functionalities of ASOs, demonstrating excellent ASO encapsulation efficiency and bioaccessibility. In vitro antibacterial experiments reveal that Zn-ASO NPs exhibit antimicrobial properties against Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. This antibacterial ability is attributed to the high concentration of metal zinc ions and the generation of high levels of reactive oxygen species. Additionally, the ftsZ-ASO effectively inhibits the expression of the ftsZ gene, further enhancing the antimicrobial effect. In vivo antibacterial assays demonstrate that the Zn-ASO NPs promote optimal skin wound healing and exhibit favorable biocompatibility against S. aureus infections, resulting in a residual infected area of less than 8%. This combined antibacterial strategy, which integrates antisense gene therapy and metal-coordination-directed self-assembly, not only achieves synergistic and augmented antibacterial outcomes but also expands the horizons of ASO coordination chemistry. Moreover, it addresses the gap in the antimicrobial application of metal-coordination ASO self-assembly, thereby advancing the field of ASO-based therapeutic approaches.

Therapeutic targeting of TNIK in papillary thyroid carcinoma: a novel approach for tumor growth suppression.

Papillary thyroid carcinoma (PTC) is a common endocrine malignancy. The pathology of PTC is far from clear. As a kinase that can be targeted, the role of TNIK in PTC has not been investigated. This study was focused on the effects and molecular mechanisms of TNIK in PTC. Both public datasets and clinical specimens were used to verify TNIK expression. The effects of TNIK were investigated in both cell lines and mice models. Transcriptome analysis was used to explore the underlying mechanism of TNIK. Immunofluorescence, wound healing, and qRT-PCR assays were used to validate the mechanism of TNIK in PTC. The therapeutic effects of TNIK inhibitor NCB-0846 were evaluated by flow cytometry, western blot, and subcutaneous xenografts mice. TNIK expression was upregulated in PTC tissues. TNIK knockdown could suppress cell proliferation and tumor growth in no matter cell models or nude mice. The transcriptome analysis, GO enrichment analysis, and GSEA analysis results indicated TNIK was highly correlated with cytoskeleton, cell motility, and Wnt pathways. The mechanistic studies demonstrated that TNIK regulated cytoskeleton remodeling and promoted cell migration. NCB-0846 significantly inhibited TNIK kinase activity, induced cell apoptosis, and activated apoptosis-related proteins in a dose-dependent manner. In addition, NCB-0846 inhibited tumor growth in tumor-bearing mice. In summary, we proposed a novel regulatory mechanism in which TNIK-mediated cytoskeleton remodeling and cell migration to regulate tumor progression in PTC. TNIK is a therapeutic target in PTC and NCB-0846 would act as a novel targeted drug for PTC therapy.

Supported of gold nanoparticles on carboxymethyl lignin modified magnetic nanoparticles as an efficient catalyst for reduction of nitroarenes and treatment of human melanoma.

This article represents the synthesis and characterizations of Au NPs immobilized and carboxymethyl lignin (CML) modified Fe3O4 nanoparticles (Fe3O4@CML/Au NPs) following a bio-inspired protocol without the participation of any toxic and harmful reductant or stabilizers. Following various physicochemical methodologies, such as FT-IR, FE-SEM, TEM, EDX, XRD, VSM, and ICP-OES, the textural characteristics and different structural aspects were evaluated. The Fe3O4@CML/Au NPs nanocomposite was subsequently explored towards the catalytic reduction of diverse aromatic nitro functions using green conditions. An excellent yield were achieved within very short reaction time. Nine recycling runs of the nanocatalyst were completed without a discernible loss of catalytic activity, thanks to its easy magnetic recovery. The DPPH assay was carried out to examine the antioxidant effectiveness. The Fe3O4@CML/Au NPs nanocomposite inhibited half of the DPPH in a 250 µg/mL solution. To measure the anti-human melanoma efficacy of Fe3O4@CML/Au NPs nanocomposite, MTT assay was applied on HT144, MUM2C, IPC-298 and SKMEL24 cell lines. Fe3O4@CML/Au NPs nanocomposite had high anti-human melanoma efficacy on above tumor cells. The best finding of anti-human melanoma properties of Fe3O4@CML/Au NPs nanocomposite was seen in the case of the SKMEL24 cell line. The IC50 of Fe3O4@CML/Au NPs nanocomposite was 137, 145, 185, and 125 µg/mL against HT144, MUM2C, IPC-298 and SKMEL24 cells, respectively. This research exhibited remarkable anti-human melanoma and antioxidant efficacies of Fe3O4@CML/Au NPs nanocomposite in the in vitro condition.

Targeting starvation therapy for diabetic bacterial infections with endogenous enzyme-triggered hyaluronan-modified nanozymes in the infection microenvironment.

The high-glycemic microenvironment of diabetic wounds promotes bacterial proliferation, leading to persistent infections and delayed wound healing. This poses a significant threat to human health, necessitating the development of new nanodrug visualization platforms. In this study, we designed and synthesized cascade nano-systems modified with targeted peptide and hyaluronic acid for diabetic infection therapy. The nano-systems were able to target the site of infection using LL-37, and in the microenvironment of wound infection, the hyaluronic acid shell of the nano-systems was degraded by endogenous hyaluronidase. This precise degradation released a cascade of nano-enzymes on the surface of the bacteria, effectively destroying their cytoskeleton. Additionally, the metals in the nano-enzymes provided a photo-thermal effect, accelerating wound healing. The cascade nano-visualization platform demonstrated excellent bactericidal efficacy in both in vitro antimicrobial assays and in vivo diabetic infection models. In conclusion, this nano-system employs multiple approaches including targeting, enzyme-catalyzed therapy, photothermal therapy, and chemodynamic therapy to kill bacteria and promote healing. The Ag@Pt-Au-LYZ/HA-LL-37 formulation shows great potential for the treatment of diabetic wounds.