Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer

The aberrant activation of STAT3 is associated with the etiology and progression in a variety of malignant epithelial-derived tumors, including head and neck squamous cell carcinoma (HNSCC) and colorectal cancer (CRC). Due to the lack of an enzymatic catalytic site or a ligand-binding pocket, there are no small-molecule inhibitors directly targeting STAT3 that have been approved for clinical translation. Emerging proteolysis targeting chimeric (PROTAC) technology-based approach represents a potential strategy to overcome the limitations of conventional inhibitors and inhibit activation of STAT3 and downstream genes. In this study, the heterobifunctional small-molecule-based PROTACs are successfully prepared from toosendanin (TSN), with 1 portion binding to STAT3 and the other portion binding to an E3 ubiquitin ligase. The optimized lead PROTAC (TSM-1) exhibits superior selectivity, potency, and robust antitumor effects in STAT3-dependent HNSCC and CRC - especially in clinically relevant patient-derived xenografts (PDX) and patient-derived organoids (PDO). The following mechanistic investigation identifies the reduced expression of critical downstream STAT3 effectors, through which TSM-1 promotes cell cycle arrest and apoptosis in tumor cells. These findings provide the first demonstration to our knowledge of a successful PROTAC-targeting strategy in STAT3-dependent epithelial cancer

Anti-inflammatory effects, nuclear magnetic resonance identification, and high-performance liquid chromatography isolation of the total flavonoids from Artemisia frigida

AbstractThe aerial parts of Artemisia frigida Willd. are used to treat joint swelling, renal heat, abnormal menstruation, and sore carbuncle. The anti-inflammatory effects of A. frigida have been well-known in folk medicine, suggesting that components extracted from A. frigida could potentially treat inflammatory disease. With the aim of discovering bioactive compounds, in this study, we extracted total flavonoids from the aerial parts of A. frigida and investigated their anti-inflammatory effects against inflammation induced by carrageenan and egg albumin in rats. At the doses studied, total flavonoids (100 mg/kg, 200 mg/kg, and 400 mg/kg) and some isolated compounds (30 mg/kg) showed significant and dose-dependent anti-inflammatory effects. According to the high-performance liquid chromatography analysis of the total flavonoids from A. frigida, there are five major compounds, namely, 5-hydroxy-3′,4′-dimethoxy-7-O-β-d-glucuronide (F1), 5-hydroxy-3′,4′,5′-trimethoxy-7-O-β-d-glucuronide (F2), 5,7,3′-trihydroxy-6,4′-dimethoxyflavone (F3), 5,3′-dihydroxy-6,7,4′-trimethoxyflavone (F4), and 5,3′-dihydroxy-3,6,7,4′-tetramethoxyflavone (F5), which may explain the anti-inflammatory activity

Highlights of the 2nd International Symposium on Tribbles and Diseases: Tribbles tremble in therapeutics for immunity, metabolism, fundamental cell biology and cancer

The Tribbles (TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2nd International Symposium on Tribbles and Diseases held on May 7‒9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases

Functions of Snake Sloughs in Bird Nests Vary with Habitats: A Test of the Anti-Predation Hypothesis

Snake sloughs in bird nests can reduce nest predation and serve as an anti-predator strategy. However, the anti-predator function of snake sloughs in nests has only been tested twice, and it is difficult to speculate around the origin of the differences, which may well include habitat, as predator species and predation risk vary in different habitat types. Habitat would be a good place to speculate as to how differences in habitats could explain differences in responses by nest predators. Thus, we selected three different habitats, namely, the Diaoluoshan National Nature Reserve in Hainan (DLS, tropical forest), the Hainan Normal University campus (HNU, urban area), and Qingchuifeng National Forest Park in Hebei (QCF, suburban area), to verify the anti-predator function of snake sloughs in bird nests. The experimental results showed that snake sloughs in the nests reduced the predation rate of the experimental nests in HNU, whereas no such effect occurred in DLS and QCF. This suggests that the anti-predatory function of snake sloughs may not be the same over some environmental gradients and could be dependent on the species of nest predators and food resources in the habitat, which does not apply to all types of habitats

The quality control and hypoglycemic effect of Cinnamomi Cortex aqueous extract

ABSTRACT: Cinnamomi Cortex was a material as medicinal and edible resources and it has been demonstrated that Cinnamomi Cortex aqueous extract (CCAE) possess hypoglycemic effect, but there were no active compounds identified as quality standard of CCAE to be used in the investigate of hypoglycemic activity. Hence, in this study, the quality standard and the hypoglycemic effect of CCAE were investigated. Cinnamaldehyde and coumarin as the quality control in CCAE were analyzed by high performance liquid chromatography (HPLC) method. The results showed that the average yield of extraction was 10.06%. The concentration of coumarin was linear with peak area ranging from 0.02–1.00 μg/mL (r = 0.999 6, n = 6) and that of cinnamaldehyde also demonstrated a good linear relationship with peak area in the range of 1.05–52.50 μg/mL (r = 0.999 7, n = 6). The average recovery rate of coumarin and cinnamaldehyde was 99.42% and 100.11%, respectively. The investigation of hypoglycemic effect revealed that CCAE could improve weight loss, lower liver and pancreas indices, improve organ damage caused by diabetes, and lower fasting blood glucose, glycosylated serum protein (GSP) and total cholesterol (TC) levels. The results showed that CCAE can reduce fasting blood glucose and blood lipid levels in diabetic mice

Integrative Multi-Omics Analysis Identifies Transmembrane p24 Trafficking Protein 1 (TMED1) as a Potential Prognostic Marker in Colorectal Cancer

Several TMED protein family members are overexpressed in malignant tumors and associated with tumor progression. TMED1 belongs to the TMED protein family and is involved in protein vesicular trafficking. However, the expression level and biological role of TMED1 in colorectal cancer (CRC) have yet to be fully elucidated. In this study, the integration of patient survival and multi-omics data (immunohistochemical staining, transcriptomics, and proteomics) revealed that the highly expressed TMED1 was related to the poor prognosis in CRC. Crystal violet staining indicated the cell growth was reduced after knocking down TMED1. Moreover, the flow cytometry results showed that TMED1 knockdown could increase cell apoptosis. The expression of TMED1 was positively correlated with other TMED family members (TMED2, TMED4, TMED9, and TMED10) in CRC, and the protein–protein interaction network suggested its potential impact on immune regulation. Furthermore, TMED1 expression was positively associated with the infiltration levels of regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), and endothelial cells and negatively correlated with the infiltration levels of CD4+ T cells, CD8+ T cells, and B cells. At last, the CTRP and GDSC datasets on the GSCA platform were used to analyze the relationship between TMED1 expression and drug sensitivity (IC50). The result found that the elevation of TMED1 was positively correlated with IC50 and implied it could increase the drug resistance of cancer cells. This research revealed that TMED1 is a novel prognostic biomarker in CRC and provided a valuable strategy for analyzing potential therapeutic targets of malignant tumors