Substituted indole derivatives as UNC-51-like kinase 1 inhibitors: Design, synthesis and anti-hepatocellular carcinoma activity.

The five-year survival rate for patients with hepatocellular carcinoma (HCC) is only 20 %, highlighting the urgent need to identify new therapeutic targets and develop potential therapeutic options to improve patient prognosis. One promising approach is inhibiting autophagy as a strategy for HCC treatment. In this study, we established a virtual docking conformation of the autophagy promoter ULK1 binding XST-14 derivatives. Based on this conformation, we designed and synthesized four series of derivatives. By evaluating their affinity and anti-HCC effects, we confirmed that these compounds exert anti-HCC activity by inhibiting ULK1. The structure-activity relationship was summarized, with derivative A4 showing 10 times higher activity than XST-14 and superior efficacy to sorafenib against HCC. A4 has excellent effect on reducing tumor growth and enhancing sorafenib activity in HepG2 and HCCLM3 cells. Moreover, we verified the therapeutic effect of A4 in sorafenib-resistant HCC cells both in vivo and in vitro. These results suggest that inhibiting ULK1 to regulate autophagy may become a new treatment method for HCC and that A4 will be used as a lead drug for HCC in further research. Overall, A4 shows good drug safety and efficacy, offering hope for prolonging the survival of HCC patients.

Multi-Omics Research Accelerates the Clarification of the Formation Mechanism and the Influence of Leaf Color Variation in Tea (Camellia sinensis) Plants.

Tea is a popular beverage with characteristic functional and flavor qualities, known to be rich in bioactive metabolites such as tea polyphenols and theanine. Recently, tea varieties with variations in leaf color have been widely used in agriculture production due to their potential advantages in terms of tea quality. Numerous studies have used genome, transcriptome, metabolome, proteome, and lipidome methods to uncover the causes of leaf color variations and investigate their impacts on the accumulation of crucial bioactive metabolites in tea plants. Through a comprehensive review of various omics investigations, we note that decreased expression levels of critical genes in the biosynthesis of chlorophyll and carotenoids, activated chlorophyll degradation, and an impaired photosynthetic chain function are related to the chlorina phenotype in tea plants. For purple-leaf tea, increased expression levels of late biosynthetic genes in the flavonoid synthesis pathway and anthocyanin transport genes are the major and common causes of purple coloration. We have also summarized the influence of leaf color variation on amino acid, polyphenol, and lipid contents and put forward possible causes of these metabolic changes. Finally, this review further proposes the research demands in this field in the future.

Design and synthesis of dabigatran etexilate derivatives with inhibiting thrombin activity for hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) is one of the most fatal solid malignancies worldwide. Evidence suggests that thrombin stimulates tumor progression via fibrin formation and platelet activation. Meanwhile, we also found a correlation between thrombin and HCC through bioinformatics analysis. Dabigatran is a selective, direct thrombin inhibitor that reversibly binds to thrombin. Dabigatran was used as the lead agent in this study, and 19 dabigatran derivatives were designed and synthesized based on docking mode. The thrombin-inhibitory activity of the derivative AX-2 was slightly better than that of dabigatran. BX-2, a prodrug of AX-2, showed a fairly strong inhibitory effect on thrombin-induced platelet aggregation, and effectively antagonized proliferation of HCC tumor cells induced by thrombin at the cellular level. Furthermore, BX-2 reduced tumor volume, weight, lung metastasis, and secondary tumor occurrence in nude mouse models. BX-2 combined with sorafenib increased sorafenib efficacy. This study lays the foundation for discovering new anti-HCC mechanism based on thrombin. BX-2 can be used as an anti-HCC drug lead for further research.

Efficacy, Mechanism, and Structure-Activity Relationship of 6-Methoxy Benzofuran Derivatives as a Useful Tool for Senile Osteoporosis.

Most patients with senile osteoporosis (SOP) are severely deficient in bone mass, and treatments using bone resorption inhibitors, such as bisphosphonates, have shown limited efficacy. Small-molecule osteogenesis-promoting drugs are required to improve the treatment for this disease. Previously, we demonstrated that a compound with a benzofuran-like structure promoted bone formation by upregulating BMP-2, and it exhibited a therapeutic effect in SAMP-6 mice, glucocorticoid-induced osteoporosis rats, and ovariectomized rats. In this study, aged C57 and SAMP-6 mice models were used to investigate the therapeutic and preventive effects of compound 125 on SOP. scRNA-seq analysis showed that BMP-2 upregulation is the mechanism through which 125 accelerates bone turnover and increases the proportion of osteoblasts. We evaluated the structure-activity relationship of the candidate drugs and found that the derivative I-9 showed significantly higher efficacy than 125 and teriparatide in the zebrafish osteoporosis model. This study provides a foundation for the development of SOP drugs.

Structure-based virtual screening identified novel FOXM1 inhibitors as the lead compounds for ovarian cancer.

Ovarian cancer (OC) is a gynecological tumor with possibly the worst prognosis, its 5-year survival rate being only 47.4%. The first line of therapy prescribed is chemotherapy consisting of platinum and paclitaxel. The primary reason for treatment failure is drug resistance. FOXM1 protein has been found to be closely associated with drug resistance, and inhibition of FOXM1 expression sensitizes cisplatin-resistant ovarian cancer cells. Combining existing first-line chemotherapy drugs with FOXM1 prolongs the overall survival of patients, therefore, FOXM1 is considered a potential therapeutic target in ovarian cancer. Previous research conducted by our team revealed a highly credible conformation of FOXM1 which enables binding by small molecules. Based on this conformation, the current study conducted virtual screening to determine a new structural skeleton for FOXM1 inhibitors which would enhance their medicinal properties. DZY-4 showed the highest affinity towards FOXM1, and its inhibitory effect on proliferation and migration of ovarian cancer at the cellular level was better than or equal to that of cisplatin, while its efficacy was equivalent to that of cisplatin in a nude mouse model. In this study, the anti-tumor effect of DZY-4 is reported for the first time. DZY-4 shows potential as a drug that can be used for ovarian cancer treatment, as well as a drug lead for future research.

Self-adhesive PMIA membranes with chitosan porous beads immobilized pullulanase for efficient biological aging of beer.

A novel pulluanase@chitosan porous beads/Poly (m-phthaloyl-m-phenylenediamine) (PULL@CPB/PMIA) membrane with good separation and biocatalysis properties was prepared by a self-adhesive method by introducing an immobilized enzyme (PULL@CPB) onto the PMIA membrane. The combination of PULL@CPB and PMIA could increase the one-step refining of protoplasmic beer as well as the ability of biocatalysis to lower the alcohol-to-ester ratio. The experimental results showed that the addition of PULL@CPB and the increase in the ratio of EtOH/water in the coagulation bath both increased the load of pullulanase on the membrane surface, while excessive addition decreased the activity of pullulanase. Under the amount of PULL@CPB is 0.5 g·L-1 and the ratio of EtOH/water is 60%, the relative activity of pullulanase in PULL@CPB modified PMIA membrane was the highest, which was 91.7% of the initial activity. The interception rates of protein and macromolecular ß-glucan were 92.2% and 87.3%, respectively, under the condition of beer flux (162.3 L·m-2·h-1). At the same time, the PULL@CPB/PMIA membrane has strong antibacterial performance and thus plays a role in extending the shelf life of beer. Compared with free pullulanase, the thermal stability, pH stability, organic solvent stability, and storing stability of immobilized pullulanase were significantly improved. The effects of PULL@CPB dosage and operating temperature on biocatalysis efficiency were discussed. The immobilized pullulanase activity on the membrane remained at 70.8% after 10 continuous uses. Therefore, the PMIA membrane is an excellent carrier of pullulanase, so its bioactive membrane has a wide range of prospects in food, medicine, and other fields.

Crystal structure and pale-yellow emitting properties of K3Gd1-xDyxB6O12 solid solutions.

A new potassium dysprosium polyborate, K3DyB6O12, has been prepared via the high-temperature molten salt method and structurally characterized by single-crystal X-ray diffraction analysis. The structure can be described as a three-dimensional framework composed of isolated bicyclic [B5O10]5- groups and Dy3+ and K+ ions. The Fourier transform IR (FT-IR) and ultraviolet-visible (UV-Vis) spectra were investigated. A series of K3Gd1-xDyxB6O12 phosphors was prepared and their photoluminescence properties were studied. The K3Gd1-xDyxB6O12 phosphors exhibit a strong yellow emission band at 577 nm (the 4F9/2→6H13/2 transition of Dy3+) under UV excitation of 275 nm (the 8S7/2→6IJ transition of Gd3+), suggesting the occurrence of the energy transfer Gd3+→Dy3+. The optimized doping concentration of the Dy3+ ion was 8 mol%. We may expect that K3Gd1-xDyxB6O12 is a promising pale-yellow emission phosphor for visual displays or solid-state lighting.

Novel Metabolites from the Endophytic Fungus Chaetomium subaffine L01.

One natural p-terphenyl glycoside, gliocladinin C, and two furano-polyene derivatives, chaetominins A and B, were isolated from potato endophytic fungus Chaetomium subaffine. The absolute configurations of these compounds were elucidated by HR-ESI-MS, NMR, the DP4+ probabilities and electronic circular dichroism (ECD) spectra. Furthermore, gliocladinin C and chaetominin A showed cytotoxic activity against two selected human tumor cell lines (Hep-2 and HepG-2).

K3Eu5(PO4)6: hydrothermal synthesis, crystal structure and photoluminescence properties.

An anhydrous orthophosphate, K3Eu5(PO4)6 (tripotassium pentaeuropium hexaphosphate), has been prepared by a high-temperature solid-state reaction combined with hydrothermal synthesis, and its crystal structure was determined by single-crystal X-ray diffraction analysis (SC-XRD). The results show that the compound crystallizes in the monoclinic space group C2/c and the structure features a three-dimensional framework of [Eu5(PO4)6]∞, with the tunnel filled by K+ ions. The IR spectrum, UV-Vis spectrum and luminescence properties of polycrystalline samples of K3Eu5(PO4)6, annealed at temperatures of 650, 700, 750, 800 and 850 °C, were investigated. Although with a full Eu3+ concentration (9.96 × 1021 ions cm-3), the self-activated phosphor K3Eu5(PO4)6 shows s strong luminescence emission intensity with a quantum yield of 37%. Under near-UV light excitation (393 nm), the series of samples shows the characteristic emissions of Eu3+ ions in the visible region from 575 to 715 nm. The sample sintered at 800 °C gives the strongest emission and its lifetime sintered at 800 °C (1.88 ms) is also the longest of all.

[Vertical distribution characteristics and temporal stability of soil water in deep profile on the Loess Tableland, Northwest China.] / é»„åœŸå¡¬åŒºæ·±å‰–é¢åœŸå£¤æ°´åˆ†åž‚ç›´åˆ†å¸ƒç‰¹å¾åŠå ¶æ—¶é—´ç¨³å®šæ€§.

Study of impacts of land uses on spatiotemporal dynamics of soil water content (SWC) is of great significance for understanding the performance characteristics of regional water cycling under changing environment. Based on long-term located field observations, this paper explored the temporal dynamics of soil water in 0-15 m soil profile under four land use types on the Loess Tableland from September 2012 to December 2015. Results showed that the annually averaged SWCs over the 0-15 m soil profile for alfalfa field, fallow field, fertilized cropland and unfertilized cropland were 15.1%, 22.0%, 19.6% and 21.1%, respectively. Soil water contents along the shallow soil profile exhibited seasonal and annual wetting and drying cycle from March to June and July to October, and the profile depths were 0-2, 0-4.6, 0-3 and 0-4.2 m, respectively. Soil water contents along the deep soil profiles had better temporal stability and were influenced by land-use types. Du-ring the observation years, the yield and water consumption in alfalfa field increased, which caused the increase of deep soil desiccation, the 2-10 m soil profile had become stable dry layer, blocking the way of precipitation recharge.As for the soil water balance in other three land use types, it was negative in cropland and fallow field during winter wheat growing season, however, during spring maize growing season, it was negative in fertilized cropland but positive in unfertilized cropland and fallow field. During the fallow period, it was positive in the three land use types. The crop water use efficiency in the fertilized cropland was increased by more than 3 times than the unfertilized cropland.

Protective effect of heme oxygenase-1 on Wistar rats with heart failure through the inhibition of inflammation and amelioration of intestinal microcirculation.

BACKGROUND: Myocardial infarction (MI) has likely contributed to the increased prevalence of heart failure (HF). As a result of reduced cardiac function, splanchnic blood flow decreases, causing ischemia in villi and damage to the intestinal barrier. The induction of heme oxygenase-1 (HO-1) could prevent, or lessen the effects of stress and inflammation. Thus, the effect and mechanism thereof of HO-1 on the intestines of rats with HF was investigated. METHODS: Male Wistar rats with heart failure through ligation of the left coronary artery were identified with an left ventricular ejection fraction of < 45% through echocardiography and then divided into various experimental groups based on the type of peritoneal injection they received [MI: saline; MI + Cobalt protoporphyrin (CoPP): CoPP solution; and MI + Tin mesoporphyrin IX dichloride (SnMP): SnMP solution]. The control group was comprised of rats without coronary ligation. Echocardiography was performed before ligation for a baseline and eight weeks after ligation in order to evaluate the cardiac function of the rats. The bacterial translocation (BT) incidence, mesenteric microcirculation, amount of endotoxins in the vein serum, ileum levels of HO-1, carbon oxide (CO), nitric oxide (NO), interleukin (IL)-10, tumour necrosis factor-α (TNF-α), and the ileum morphology were determined eight weeks after the operation. RESULTS: The rats receiving MI + CoPP injections exhibited a recovery in cardiac function, an amelioration of mesenteric microcirculation and change in morphology, a lower BT incidence, a reduction in serum and ileac NO and TNF-α levels, and an elevation in ileac HO-1, CO, and interleukin-10 (IL-10) levels compared to the MI group (P < 0.05). The rats that received the MI + SnMP injections exhibited results inverse to the MI (P < 0.05) group. CONCLUSIONS: HO-1 exerted a protective effect on the intestines of rats with HF by inhibiting the inflammation and amelioration of microcirculation through the CO pathway. This protective effect could be independent from the recovery of cardiac function.