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Bicyclol, an innovative hepatoprotective drug, was approved by the Chinese National Medical Products Administration (NMPA) in 2001 to treat Hepatitis B and drug-induced liver injury. Two active metabolites of bicyclol have been identified as M2 and M3. To evaluate the impact on drug safety and efficacy of possible drug-drug interactions (DDIs) associated with these metabolites, a sufficient quantity of these metabolites is required. Herein, we report a concise novel route for the synthesis of M2 and M3 using the Suzuki-Miyaura coupling as the key step. Furthermore, we complete the gram-scale syntheses of M2 and M3. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) is the most predominant RNA epigenetic regulation in eukaryotic cells. Numerous evidence revealed that m6A modification exerts a crucial role in the regulation of tumor microenvironment (TME) cell infiltration in several tumors. Nevertheless, the potential role and mechanism of m6A modification in nasopharyngeal carcinoma (NPC) remains unknown. mRNA expression data and clinical information from GSE102349, and GSE53819 datasets obtained from Gene Expression Omnibus (GEO) was used for differential gene expression and subsequent analysis. Consensus clustering was used to identify m6A-related molecular patterns of 88 NPC samples based on prognostic m6A regulators using Univariate Cox analysis. The TME cell-infiltrating characteristics of each m6A-related subclass were explored using single-sample gene set enrichment (ssGSEA) algorithm and CIBERSORT algotithm. DEGs between two m6A-related subclasses were screened using edgeR package. The prognostic signature and predicated nomogram were constructed based on the m6A-related DEGs. The cell infiltration and expression of prognostic signature in NPC was determined using immunohistochemistry (IHC) analysis. Chi-square test was used to analysis the significance of difference of the categorical variables. And survival analysis was performed using Kaplan-Meier plots and log-rank tests. The NPC samples were divided into two m6A-related subclasses. The TME cell-infiltrating characteristics analyses indicated that cluster 1 is characterized by immune-related and metabolism pathways activation, better response to anit-PD1 and anti-CTLA4 treatment and chemotherapy. And cluster 2 is characterized by stromal activation, low expression of HLA family and immune checkpoints, and a worse response to antiPD1 and anti-CTLA4 treatment and chemotherapy. Furthermore, we identified 1558 DEGs between two m6A-related subclasses and constructed prognostic signatures to predicate the progression-free survival (PFS) for NPC patients. Compared to non-tumor samples, REEP2, TMSB15A, DSEL, and ID4 were upregulated in NPC samples. High expression of REEP2 and TMSB15A showed poor survival in NPC patients. The interaction between REEP2, TMSB15A, DSEL, ID4, and m6A regulators was detected. Our finding indicated that m6A modification plays an important role in the regulation of TME heterogeneity and complexity. [ABSTRACT FROM AUTHOR]

The proliferation and myogenic differentiation of muscle stem cells (MuSCs) are important factors affecting muscle development and beef quality. There is increasing evidence that circRNAs can regulate myogenesis. We found a novel circRNA, named circRRAS2 that is significantly upregulated in the differentiation phase of bovine MuSCs. Here, we aimed to determine its roles in the proliferation and myogenic differentiation of these cells. The results showed that circRRAS2 was expressed in several bovine tissues. CircRRAS2 inhibited MuSCs proliferation and promoted myoblast differentiation. In addition, chromatin isolation by using RNA purification and mass spectrometry in differentiated muscle cells identified 52 RNA-binding proteins that could potentially bind to circRRAS2, in order to regulate their differentiation. The results suggest that circRRAS2 could be a specific regulator of myogenesis in bovine muscle. CircRRAS2 expression is higher in DM cells than in GM cells. CircRRAS2 could significantly inhibit the proliferation and apoptosis of bovine MuSCs. CircRRAS2 promotes the differentiation of bovine MuSCs into myotubes. CircRRAS2 may exert regulatory effects through multiple RNA binding proteins. [ABSTRACT FROM AUTHOR]

Objective: Toll-like receptor 4 (TLR4) is crucial in induction of innate immune response through recognition of invading pathogens or endogenous alarming molecules. Ligand-triggered dimerization of TLR4 is essential for the activation of NF-κB and IRF3 through MyD88- or TRIF-dependent pathways. Saquinavir (SQV), an FDA-approved HIV protease inhibitor, has been shown to attenuate the activation of NF-κB induced by HMGB1 by blocking TLR4-MyD88 association in proteasome independent pathway. This study aims to define whether SQV is an HMGB1-specific and MyD88-dependent TLR4 signaling inhibitor and which precise signaling element of TLR4 is targeted by SQV. Materials and Methods: PMA differentiated human THP-1 macrophages or reconstituted HEK293 cells were pretreated with SQV before stimulated by different TLR agonists. TNF-a level was evaluated through ELISA assay. NF-κB activation was analyzed using NF-κB SEAP reporting system. The levels of MyD88/TRIF pathways-related factors were examined by immunoblot. TLR4 endocytosis was assessed by immunocytochemistry. TLR4 dimerization was determined using immunoprecipitation between different tagged TLR4 and an in silico molecular docking experiment was performed to explore the possible binding site of SQV on its target. Results: Our data showed that SQV suppresses both MyD88- and TRIF-dependent pathways in response to lipopolysaccharide (LPS), a critical sepsis inducer and TLR4 agonist, leading to downregulation of NF-κB and IRF3. SQV did not suppress MyD88-dependent pathway triggered by TLR1/2 agonist Pam3csk4. In the only TRIF-dependent pathway, SQV did not alleviate IRF3 phosphorylation induced by TLR3 agonist Poly(I:C). Furthermore, dimerization of TLR4 following LPS or HMGB1 stimulation was decreased by SQV. Conclusion: We concluded that TLR4 receptor complex is one of the mammalian targets of SQV, and TLR4-mediated immune responses and consequent risk for uncontrolled inflammation could be modulated by FDA-approved drug SQV. [ABSTRACT FROM AUTHOR]

While the detailed mechanisms for how particulate matter (PM) causes adverse health effects in the lungs remain largely unknown, endoplasmic reticulum (ER) stress has been implicated in PM-induced lung injury. The present study was undertaken to examine how/if ER stress might regulate PM-induced inflammation, and to begin to define potential underlying molecular mechanisms. Here, ER stress hallmarks were examined in human bronchial epithelial (HBE) cells exposed to PM. To confirm roles of certain pathways, siRNA targeting ER stress genes and an ER stress inhibitor were employed. Expression of select inflammatory cytokines and related signaling pathway components by the cells were assessed as well. The results showed that PM exposure induced elevations in two ER stress hallmarks, i.e. GRP78 and IRE1a, in time-and/or dose-related manners in the HBE cells. Inhibition of ER stress by siRNA for GRP78 or IRE1a significantly alleviated the PM-induced effects. Further, ER stress appeared to regulate PM-induced inflammation -- likely through downstream autophagy and NF-jB pathways -- as implied by studies showing that inhibition of ER stress by siRNA of GRP78 or IRE1a caused significant amelioration of PM-induced autophagy and subsequent activation of NF-jB pathways. Moreover, the ER stress inhibitor 4-PBA were used to confirm the protective effects against PM-induced outcomes. Together, the results suggest ER stress plays a deleterious role in PM-induced airway inflammation, possibly through activation of autophagy and NF-jB signaling. Accordingly, protocols/treatments that could lead to inhibited ER stress could potentially be effective for treatment of PM-related airway disorders. [ABSTRACT FROM AUTHOR]

High entropy alloys (HEAs), consisting of five or more elements with nearly equal atomic composition with one another (5–35%), are new-generation alloys that have attracted signifi)cant interest since their advent in 2004 because of their unique structural and mechanical properties and thermodynamic and chemical stability. Some characteristics, including high mechanical strength at elevated temperatures, high ductility and fracture toughness at cryo)genic temperatures and high corrosion, erosion and wear resistance, have been demonstrated for HEAs that outperform traditional alloys and superalloys. Laser-cladding (LC) is an additive manufacturing technique that has good feasibility in designing and processing HEAs for advanced structural components and protective coatings. This overview provides a glimpse of recent advances in LC of HEAs in terms of design fundamentals, metallurgical phase and microstructure, specific properties for advanced coating applications and the effect of ceramic particles reinforcement in LC deposition of HEA coatings. [ABSTRACT FROM AUTHOR]

Osteosarcoma, originating from primitive bone-forming mesenchymal cells, is the most common malignant bone tumour among children and adolescents. N6-methyladenosine (m6A), the most ubiquitous type of posttranscriptional modification, is a methylation that occurs in the N6-position of adenosine. m6A dramatically affects the splicing, export, translation, and stability of various RNAs, including mRNA and noncoding RNAs (ncRNAs). Increasing evidence suggests that ncRNAs, especially microRNAs (miRNA), long noncoding RNAs (lncRNA), and circular RNAs (circRNAs), regulate the m6A modification process by affecting the expression of m6A-associated enzymes. m6A modification interactions with ncRNAs provide new perspectives for exploring the underlying mechanisms of tumorigenesis and progression. In the current review, we summarized the expression and biological functions of m6A regulators in osteosarcoma. At the same time, the present review systematically elucidated the functional and mechanical interactions between m6A modification and ncRNAs in osteosarcoma. In addition, we discussed the effect of m6A and ncRNAs in the tumour microenvironment and potential clinical applications of osteosarcoma. [ABSTRACT FROM AUTHOR]

Context: Lily bulb and Rehmannia decoction (LBRD), consisting of Lilium henryi Baker (Liliaceae) and Rehmannia glutinosa (Gaertn) DC (Plantaginaceae), is a specialized traditional Chinese medicine formula for treating depression. However, the underlying mechanisms, especially the relationship between LBRD efficacy and metabolomics, remains unclear. Objective: This study was aimed to investigate the metabolic mechanism of LBRD in treating depression. Materials and methods: Network pharmacology was conducted using SwissTargetPrediction, DisGeNET, DrugBank, Metascape, etc., to construct component-target-pathway networks. The depression-like model was induced by intraperitoneal injection with lipopolysaccharide (LPS) (0.3 mg/kg) for 14 consecutive days. After the administration of LBRD (90 g/kg) and fluoxetine (2 mg/kg) for 14 days, we assessed behaviour and the levels of neurotransmitter, inflammatory cytokine and circulating stress hormone. Prefrontal metabolites of rats were detected by using liquid chromatography-mass spectrometry metabolomics method. Results: The results of network pharmacology showed that LBRD mainly acted on neurotransmitter and second messenger pathways. Compared to the model group, LBRD significantly ameliorated depressive phenotypes and increased the level of 5-HT (13.4%) and GABA (24.8%), as well as decreased IL-1β (30.7%), IL-6 (32.8%) and TNF-α (26.6%). Followed by LBRD treatment, the main metabolites in prefrontal tissue were contributed to retrograde endocannabinoid signalling, glycerophospholipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, autophagy signal pathway, etc. Discussion and conclusions: LBRD were effective at increasing neurotransmitter, attenuating proinflammatory cytokine and regulating glycerophospholipid metabolism and glutamatergic synapse, thereby ameliorating depressive phenotypes. This research will offer reference for elucidating the metabolomic mechanism underlying novel antidepressant agents contained LBRD formula. [ABSTRACT FROM AUTHOR]

This study develops two multi-label chain machine learning predictive models to anticipate patient punctuality and turnaround time. The first model uses an integrated model of clustering and classification where the check-in, service, and checkout times are clustered into three categories using the K-means algorithm. Then, patient punctuality and established clusters are used to develop a multi-label chain predictive model that utilizes Logistic Regression, Multi-Layer Perceptron, and tree-based classifiers. The second model predicts patient punctuality and turnaround time using a multi-label chain regression model that utilizes Linear Regression, Huber Regressor, ADR Regression, Multi-Layer Perceptron, and tree-based regressors. It was found that a patient’s age is a key driver for both patient punctuality and turnaround time. Also, there is a significant association between patient punctuality and turnaround time. The first proposed model predicted the punctuality and turnaround time with an average best F1-score of about 70.4% and 71.9%, respectively. The second model produced acceptable results with the best average R-squared of 0.67 for punctuality and 0.68 for turnaround time. The models can reduce the complexity and time of predicting several numerical outputs, enhance the interpretation of the results, and improve the understanding of the results by non-technical staff. [ABSTRACT FROM AUTHOR]

In this study, a novel intelligent nanoplatform to integrate multiple imaging and therapeutic functions for targeted cancer theranostics. The nanoplatform, DOX@Gd-MFe3O4 NPs, was constructed Gd-doped mesoporous Fe3O4 nanoparticles following with the doxorubicin (DOX) loading in the mesopores of the NPs. The DOX@Gd-MFe3O4 NPs exhibited good properties in colloidal dispersity, photothermal conversion, NIR triggered drug release, and high T1/T2 relaxicity rate (r1=9.64mM-1s-1, r2= 177.71mM-1s-1). Benefiting from the high MR contrast, DOX@Gd-MFe3O4 NPs enabled simultaneous T1/T2 dual-modal MR imagining on 4T1 bearing mice in vivo and the MR contrast effect was further strengthened by external magnetic field. In addition, the DOX@Gd-MFe3O4 NPs revealed the strongest inhibition to the growth of 4T1 in vitro and in vivo under NIR irradiation and guidance of external magnetic field. Moreover, biosafety was also validated by in vitro and in vivo tests. Thus, the prepared DOX@Gd-MFe3O4 NPs would provide a promising intelligent nanoplatform for dual-modal MR imagining guided synergistic therapy in cancer theranostics. [ABSTRACT FROM AUTHOR]