Exploration of 1-(indolin-1-yl)-2-(thiazol-2-yl)ethan-1-one derivatives as novel anti-HBV agent with potential TLR7-agonistic effect.

Hepatitis B virus (HBV) infection, as a serious global public health issue, is closely related to the immune dysfunction. Herein, thirty-seven 1-(indolin-1-yl)-2-(thiazol-4-yl)ethan-1-one derivatives were prepared as potential immunomodulatory anti-HBV agents. Anti-HBV activity evaluation confirmed compound 11a could significantly suppress the HBV DNA replication in both wild and resistant HBV stains, with IC50 values of 0.13 µM and 0.36 µM, respectively. Preliminary action mechanism studies showed that 11a had an inhibitory effect on cellular HBsAg secretion and could effectively activate TLR7, thereby inducing the secretion of TLR7-regulated cytokines IL-12, TNF-α and IFN-α in human PBMC cells. SPR analysis confirmed that 11a could bind to TLR7 protein with an affinity of 7.06 µM. MD simulation predicted that 11a could form tight interactions with residues in the binding pocket of TLR7. Physicochemical parameters perdition and pharmacokinetic analysis indicated that 11a displayed relatively favorable drug-like properties. Considering all the results, compound 11a might be a promising lead for developing novel immunomodulatory anti-HBV agents.

Prognostic marker CD27 and its micro-environmental in multiple myeloma.

BACKGROUND: The Cluster of Differentiation 27 (CD27) is aberrantly expressed in multiple myeloma (MM) -derived. This expression facilitates the interaction between tumor and immune cells within TME via the CD27-CD70 pathway, resulting in immune evasion and subsequent tumor progression. The objective of this study is to investigate the correlation between CD27 expression and the prognosis of MM, and to elucidate its potential relationship with the immune microenvironment. METHODS: In this research, CD27 expression in T cells within the 82 newly diagnosed MM microenvironment was assessed via flow cytometry. We then examined the association between CD27 expression levels and patient survival. Subsequent a series of bioinformatics and in vitro experiments were conducted to reveal the role of CD27 in MM. RESULTS: Clinical evidence suggests that elevated CD27 expression in T cells within the bone marrow serves as a negative prognostic marker for MM survival. Data analysis from the GEO database has demonstrated a strong association between MM-derived CD27 and the immune response, as well as the hematopoietic system. Importantly, patients with elevated levels of CD27 expression were also found to have an increased presence of MDSCs and macrophages in the bone marrow microenvironment. Furthermore, the PERK-ATF4 signaling pathway has been implicated in mediating the effects of CD27 in MM. CONCLUSIONS: We revealed that CD27 expression levels serve as an indicative marker for the prognosis of MM patients. The CD27- PERK-ATF4 is a promising target for the treatment of MM.

Green synthesis and multifunctional applications of nitrogen-doped carbon quantum dots via one-step hydrothermal carbonization of Curcuma zedoaria.

Low-dimensional (<10 nm) semiconductor carbon quantum dots (CQDs) have been widely used in metal ion sensing and bioimaging. Here, we used the renewable resource Curcuma zedoaria as a carbon source and prepared green carbon quantum dots with good water solubility by a hydrothermal method without any chemical reagent. At different pH values (4-6) and high NaCl concentrations, the photoluminescence of the CQDs was very stable, which indicated that they were suitable for a wide range of applications even under harsh conditions. The CQDs exhibited fluorescence quenching in the presence of Fe3+ ions, indicating their application potential as fluorescence probes for the sensitive and selective detection of Fe3+ ions. The CQDs showed high photostability, low cytotoxicity, and good hemolytic activity, and were successfully applied to bioimaging experiments, i.e. multicolor cell imaging in L-02 (human normal hepatocytes) and CHL (Chinese hamster lung) cells with and without Fe3+, as well as wash-free labeling imaging of Staphylococcus aureus and Escherichia coli. The CQDs also showed good free radical scavenging activity and demonstrated a protective effect against photooxidative damage to L-02 cells. These results indicate that CQDs obtained from medicinal herb sources have multiple potential applications in the fields of sensing, bioimaging, and even disease diagnosis.

HNRNPA2B1-mediated m6A modification of TLR4 mRNA promotes progression of multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a malignancy of plasma cells that remains incurable. Toll-like receptor 4 (TLR4) acts as a stress-responsive signal, protecting mitochondria during proteasome inhibitor (PI) exposure, maintaining mitochondrial metabolism and increasing drug resistance in MM. However, the mechanism of TLR4 regulation remains elusive. AIMS: The purpose of this study was to investigate the methylation pattern of multiple myeloma and its effect on the expression of HNRNPA2B1 and downstream targets. METHODS: The methylation level in MM and normal bone marrow specimens was detected using a colorimetric assay. HNRNPA2B1 gene knockdown was achieved in RPMI 8226 MM cells via adenovirus transfection. CCK8 and flow cytometric assays were used to detect proliferation and apoptosis, respectively. Transcriptome sequencing and m6A methylation MeRIP sequencing were applied, and differentially expressed genes (DEGs) were detected. Three independent NCBI GEO datasets were applied to examine the effects of HNRNPA2B1 and TLR4 expression on MM patient survival. RESULTS: HNRNPA2B1 promoted MM progression. Clinical data from database revealed that HNRNPA2B1 was adverse prognostic factor for survival among MM patients. Furthermore, transcriptome sequencing and methylation sequencing showed that HNRNPA2B1 recognized and was enriched at the m6A sites of TLR4 and TLR4 was down-regulated of both the m6A level and transcription level in HNRNPA2B1-knockdown MM cells. Moreover, TLR4 was an adverse survival prognostic factor based on database analysis. CONCLUSION: Overall, our study implies that the RNA-binding protein HNRNPA2B1 increases cell proliferation and deregulates cell apoptosis in MM through TLR4 signaling. Our study suggests HNRNPA2B1 as a potential therapeutic target for MM.

Incorporation of Urinary Neutrophil Gelatinase-Associated Lipocalin and Computed Tomography Quantification to Predict Acute Kidney Injury and In-Hospital Death in COVID-19 Patients.

BACKGROUND: The prevalence of acute kidney injury (AKI) in COVID-19 patients is high, with poor prognosis. Early identification of COVID-19 patients who are at risk for AKI and may develop critical illness and death is of great importance. OBJECTIVE: The aim of this study was to develop and validate a prognostic model of AKI and in-hospital death in patients with COVID-19, incorporating the new tubular injury biomarker urinary neutrophil gelatinase-associated lipocalin (u-NGAL) and artificial intelligence (AI)-based chest computed tomography (CT) analysis. METHODS: A single-center cohort of patients with COVID-19 from Wuhan Leishenshan Hospital were included in this study. Demographic characteristics, laboratory findings, and AI-assisted chest CT imaging variables identified on hospital admission were screened using least absolute shrinkage and selection operator (LASSO) and logistic regression to develop a model for predicting the AKI risk. The accuracy of the AKI prediction model was measured using the concordance index (C-index), and the internal validity of the model was assessed by bootstrap resampling. A multivariate Cox regression model and Kaplan-Meier curves were analyzed for survival analysis in COVID-19 patients. RESULTS: One hundred seventy-four patients were included. The median (±SD) age of the patients was 63.59 ± 13.79 years, and 83 (47.7%) were men.u-NGAL, serum creatinine, serum uric acid, and CT ground-glass opacity (GGO) volume were independent predictors of AKI, and all were selected in the nomogram. The prediction model was validated by internal bootstrapping resampling, showing results similar to those obtained from the original samples (i.e., 0.958; 95% CI 0.9097-0.9864). The C-index for predicting AKI was 0.955 (95% CI 0.916-0.995). Multivariate Cox proportional hazards regression confirmed that a high u-NGAL level, an increased GGO volume, and lymphopenia are strong predictors of a poor prognosis and a high risk of in-hospital death. CONCLUSIONS: This model provides a useful individualized risk estimate of AKI in patients with COVID-19. Measurement of u-NGAL and AI-based chest CT quantification are worthy of application and may help clinicians to identify patients with a poor prognosis in COVID-19 at an early stage.