The structure-based optimization of 3-substituted indolin-2-one derivatives as potent and isoform-selective c-Jun N-terminal kinase 3 (JNK3) inhibitors and biological evaluation.

An indolin-2-(4-thiazolidinone) scaffold was previously shown to be a novel chemotype for JNK3 inhibition. However, more in vivo applications were limited due to the unconfirmed configuration and poor physicochemical properties. Here, the indolin-2-(4-thiazolidinone) scaffold validated the absolute configuration; substituents on the scaffold were optimized. Extensive structure activity relationship (SAR) studies were performed using kinase activity assays, thus leading to potent and highly selective JNK3 inhibitors with neuroprotective activity and good oral bioavailability. One lead compound, A53, was a potent and selective JNK3 inhibitor (IC50 = 78 nM) that had significant inhibition (>80% at 1 µM) to only JNK3 in a 398-kinase panel. A53 had low inhibition against JNK3 and high stability (t1/2(α) = 0.98 h, t1/2(ß) = 2.74 h) during oral administration. A modeling study of A53 in human JNK3 showed that the indolin-2-(4-thiazolidinone)-based JNK3 inhibitor with a 5-position-substituted hydrophilic group offered improved kinase inhibition.

Microstructures and Properties Investigation on DP980 Dual-Phase Steel CMT + P Welded Joints.

The increasing demand for the lightweight production of advanced high-strength steel puts forward higher requirements for the quality of welded joint forming. The common CMT welding process has certain limitations and is difficult to meet the needs of lightweight manufacturing. In this study, the CMT + P welding technology was used to weld the DP980 dual-phase steel plate with 1.2 mm thickness. The ER120S-G welding wire was used as the filling material to conduct a 70° angle lap welding experiment. The effects of wire feeding speed (3 m/min~5 m/min) and welding speed (350 mm/min~600 mm/min) on the forming, microstructures, and mechanical properties of DP980 dual-phase steel welded joints were analyzed. The results show that the CMT + P welding process can produce lap weldments with good formability and properties. The welded joints can be divided into the weld zone, the HAZ, and the base metal zone, where the HAZ can be divided into the coarse-grained zone and the softened zone. The role of the elements Ni and Si is to promote the production of martensite and to increase the ferrite strength in welded joints. As the wire feeding speed increases, the grain size of the coarse grain zone in the HAZ increases from 31.90 µm to 50.93 µm; while the welding speed increases, the grain size of the coarse grain zone decreases from 45.48 µm to 35.73 µm. The average microhardness of the weld zone is 420 HV. In contrast, the average microhardness of the softening zone in HAZ is reduced to 250 HV. When the wire feeding speed is 4 m/min and the welding speed is 550 mm/min, the tensile properties of the weldment are optimal, its tensile strength can reach 973 MPa, and the tensile fracture is ductile fracture.

Integrated microarray for identifying the hub mRNAs and constructed miRNA-mRNA network in coronary in-stent restenosis.

As a major complication after percutaneous coronary intervention (PCI) in patients who suffer from coronary artery disease, in-stent restenosis (ISR) poses a significant challenge for clinical management. A miRNA-mRNA regulatory network of ISR can be constructed to better reveal the occurrence of ISR. The relevant data set from the Gene Expression Omnibus (GEO) database was downloaded, and 284 differentially expressed miRNAs (DE-miRNAs) and 849 differentially expressed mRNAs (DE-mRNAs) were identified. As predicted by online tools, 65 final functional genes (FmRNAs) were overlapping DE-mRNAs and DE-miRNAs target genes. In the biological process (BP) terms of gene ontology (GO) functional analysis, the FmRNAs were mainly enriched in the cellular response to peptide, epithelial cell proliferation, and response to peptide hormone. In the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the FmRNAs were mainly enriched in breast cancer, endocrine resistance, and Cushing syndrome. Jun proto-oncogene, activator protein-1 (AP-1) transcription factor subunit (JUN), insulin-like growth factor 1 receptor (IGF1R), member RAS oncogene family (RAB14), specificity protein 1 (SP1), protein tyrosine phosphatase nonreceptor type 1 (PTPN1), DDB1 and CUL4 associated factor 10 (DCAF10), retinoblastoma-binding protein 5 (RBBP5), and eukaryotic initiation factor 4A-I (EIF4A1) were hub genes in the protein-protein interaction network (PPI network). The miRNA-mRNA network containing DE-miRNAs and hub genes was built. Hsa-miR-139-5p-JUN, hsa-miR-324-5p-SP1 axis pairs were found in the miRNA-mRNA network, which could promote ISR development. The aforementioned results indicate that the miRNA-mRNA network constructed in ISR has a regulatory role in the development of ISR and may provide new approaches for clinical treatment and experimental development.

Co-Amorphous Formation of Simvastatin-Ezetimibe: Enhanced Physical Stability, Bioavailability and Cholesterol-Lowering Effects in LDLr-/-Mice.

Hypercholesterolemia is one of the independent risk factors for the development of cardiovascular diseases such as atherosclerosis. The treatment of hypercholesterolemia is of great significance to reduce clinical cardiovascular events and patient mortality. Simvastatin (SIM) and ezetimibe (EZE) are commonly used clinically as cholesterol-lowering drugs; however, their treatment efficacy is severely affected by their poor water solubility and low bioavailability. In this study, SIM and EZE were made into a co-amorphous system to improve their dissolution, oral bioavailability, storage stability, and cholesterol-lowering effects. The SIM-EZE co-amorphous solids (CO) were prepared successfully using the melt-quenched technique, and the physicochemical properties of CO were characterized accordingly, which exhibited improved physical stability and faster dissolution release profiles than their physical mixture (PM). In the pharmacokinetic study, the SIM-EZE CO or PM was given once by oral gavage, and mouse blood samples were collected retro-orbitally at multiple time points to determine the plasma drug concentrations. In the pharmacodynamic study, low-density lipoprotein receptor-deficient (LDLr-/-) mice were fed with a high-fat diet (HFD) for two weeks to establish a mouse model of hypercholesterolemia. Using PM as a control, we investigated the regulation of CO on plasma lipid levels in mice. Furthermore, the mice feces were collected to determine the cholesterol contents. Besides, the effect of EZE on the NPC1L1 mRNA expression level in the mouse intestines was also investigated. The pharmacokinetics results showed that the SIM-EZE CO has improved bioavailability compared to the PM. The pharmacodynamic studies showed that SIM-EZE CO significantly increased the cholesterol-lowering effects of the drugs compared to their PM. The total cholesterol excretion in the mouse feces and inhibitory effect on NCP1L1 gene expression in the mouse intestines after being given the SIM-EZE CO were more dramatic than the PM. Our study shows that the SIM-EZE CO prepared by the melt-quenched method can significantly improve the stability, bioavailability, and cholesterol-lowering efficacy with excellent development potential as a new drug formulation.

Inonotus obliquus and its bioactive compounds alleviate non-alcoholic fatty liver disease via regulating FXR/SHP/SREBP-1c axis.

Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide. However, there is still lack of specific drugs for treating NAFLD in clinic. Inonotus obliquus (IO), a folk medicinal fungus, has long been used to prevent against metabolic syndrome related diseases, such as hypertension and diabetes, etc. However, the study of IO anti-NAFLD effect has been reported rarely. This study aimed to investigate whether IO has an inhibitory effect on NAFLD, identify the active compounds in IO and clarify the underlying mechanisms of its anti-NAFLD effects. The results of Oil Red O(ORO) and Hematoxylin-Eosin (HE) staining, lipid extraction and determination showed that IO and its extracts, including inotodiol (Ino), lanosterol (Lan) and trametenolic acid (TA), could remarkably ameliorate lipid accumulation in MCD diet-induced mouse livers or OA-induced LO2 hepatocytes. Moreover, qPCR analysis revealed that IO and its compounds significantly downregulated the mRNA levels of lipogenic genes, such as SREBP-1c, ACC1 and FASN, and upregulated the mRNA levels of FXR and SHP. We found that the administration of guggulsterone (GS), a FXR inhibitor, abolished the inhibitory effect of Ino on lipid deposition in OA-induced LO2 cells. In conclusion, IO and its compounds attenuate hepatic lipid accumulation in NAFLD by inhibiting liver lipogenesis. The anti-NAFLD effects of Ino, a bioactive compound in IO, are through regulating FXR/SHP/SREBP-1c pathway. Our results suggested that IO and its bioactive compound Ino may become promising drugs to treat NAFLD.

Characteristic research of lower extremity injuries in elderly pedestrians during collisions.

PURPOSE: The aim of this research is to study the trend of pedestrian lower extremity injuries during vehicle-pedestrian collisions. METHODS: In this study, pedestrian's age, collision angle and pedestrian's position are considered influencing factors. Nine experiments using a novel lower extremity mechanical model are designed with the orthogonal experiment method. RESULTS: Under the same collision angle, collisions in the left and right positions caused more serious tibia injuries than the middle position. As for the collision angle, the tibial injury at +45° is more significant than the tibial injury at -45°, and the injury of oblique collisions is slightly greater than that at 0°. Moreover, tibial injury is more sensitive to research variables than femoral injury. When the collision angle and position are changed, the difference ratio of tibia stress is by 483.2% higher than that of femur stress. The axial force and bending moment of the quadriceps tendon in the left-position collision reach peak values, which are 3.83 kN and 165.98 Nm, respectively. The peak quadriceps tendon axial force is captured with the collision angle of -45°, and the peak quadriceps tendon bending moment is obtained with a collision angle of +45°. CONCLUSIONS: The effects of differences in impact position and angle on lower extremity injury in the elderly were analyzed, and the results of this study can be used as a reference for research on lower extremity protection.

Long non-coding RNA MIR31HG as a prognostic predictor for malignant cancers: A meta- and bioinformatics analysis.

BACKGROUND: The possible regulatory mechanism of MIR31HG in human cancers remains unclear, and reported results of the prognostic significance of MIR31HG expression are inconsistent. METHODS: The meta-analysis and related bioinformatics analysis were conducted to evaluate the role of MIR31HG in tumor progression. RESULTS: The result showed that high MIR31HG expression was not related to prognosis. However, in the stratified analysis, we found that the overexpression of MIR31HG resulted in worse OS, advanced TNM stage, and tumor differentiation in respiratory system cancers. Moreover, our results also found that MIR31HG overexpression was related to shorter OS in cervical cancer patients and head and neck tumors. In contrast, the MIR31HG was lower in digestive system tumors which contributed to shorter overall survival, advanced TNM stage, and distant metastasis. Furthermore, the bioinformatics analysis showed that MIR31HG was highly expressed in normal urinary bladder, small intestine, esophagus, stomach, and duodenum and low in colon, lung, and ovary. The results obtained from FireBrowse indicated that MIR31HG was highly expressed in LUSC, CESC, HNSC, and LUAD and low in STAD and BLCA. Gene Ontology analysis showed that the co-expressed genes of MIR31HG were most enriched in the biological processes of peptide metabolism and KEGG pathways were most enriched in Ras, Rap1, and PI3K-Akt signaling pathway. CONCLUSION: MIR31HG may serve as a potential biomarker in human cancers.