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Background: Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is an oncogenic regulator of Wnt/β-catenin signaling in colon cancer. Previously we have reported a pentacyclic triterpenoid compound liquidambaric acid (LDA) inhibiting Wnt/β-catenin signaling via targeting TRAF2, however, LDA inhibition of cancer cells was observed only at high doses. It is important to identify small molecules targeting TRAF2 in colon cancer with higher potency . Methods: Microscale thermophoresis (MST) assay was used to screen a panel of pentacyclic triterpenoids. Cellular thermal shift assay (CETSA) was used to confirm target engagment in living cells. Drug affinity responsive target stability (DARTS) coupled with mass spectrometry (MS) was used to identify the potential targets of candidate TRAF2 binder. Wnt signaling inhibition was evaluated by 7TGC reporter assay, TOPFlash assay, reverse transcription and real-time quantitative PCR, as well as zebrafish eyeless assay. Cancer inhibition was assessed by cell viability assay, colony formation assay and xenograft studies. CRISPR/Cas9 knockout HCT116 cells was used to assess the requirement of TRAF2 for liquidambaric lactone (LDL) inhibition of cancer. Results: A LDA analogue LDL selectively targeted TRAF2 with higher binding affinity. Both LDL and LDA targeted the TRAF-C domain of TRAF2 with slightly different binding sites. Of note, LDL showed much stronger inhibition of colon cancer cells than LDA in colony formation assay. LDL inhibition of cancer was also comfirmed in xenograft mice. Depletion of TRAF2 totally blocked LDL inhibition of Wnt signaling, TNF signaling and growth of cancer cells. Conclusions: A natural product LDL is a potent inhibitor of TRAF2 for cancer therapy, and TRAF2 is required for LDL inhibition of cancer.

Unicentric Castleman disease (UCD) is a rare, benign lymphoproliferative disorder. Mediastinal UCD has tumors with no clear boundaries that are highly vascularized. Resection surgery results in bleeding, leading to further challenges. Mixed-type UCD is rare. We report the case of a 38-year-old asymptomatic patient with mixed-type UCD; the tumor measured 7.8 cm in size and had unclear boundaries. The tumor was successfully resected by performing a cardiopulmonary bypass on the beating heart; the patient recovered uneventfully.

In the present study, three series of novel celastrol derivatives were designed and synthesised by modifying the carboxylic acid at the 20th position with amino acid, amine, and triazole derivatives. All the synthesised compounds were screened for their anticancer activities using MTT assay against AGS, MGC-803, SGC-7901, HCT-116, A549, HeLa, BEL-7402, and HepG-2 cell lines. Most of the synthesised compounds exhibited potent antiproliferative effects. The most promising compound 3-Hydroxy-9β,13α-dimethyl-2-oxo-24,25,26-trinoroleana-1(10),3,5,7-tetraen-29-oic amide, N-(R)-methyl-3-(1H-indol-2-yl)propanoate (11) showed considerable high anticancer activity against AGS cell lines, with an IC50 value of 0.44 μM, and considerably higher activities against HCT-116, BEL-7402, and HepG-2 cell lines, with IC50 values of 0.78, 0.63, and 0.76 μM, respectively. The results of apoptosis tests and molecular docking study of compound 11 binding to Caspase-3 revealed that its mechanism of action with antiproliferative was possibly involved in inducing apoptosis by inducing the activation of caspase-3. [ABSTRACT FROM AUTHOR]

Abstract Metastasis is the primary cause of cancer-related mortality in colorectal cancer (CRC) patients. How to improve therapeutic options for patients with metastatic CRC is the core question for CRC treatment. However, the complexity and diversity of stromal context of the tumor microenvironment (TME) in liver metastases of CRC have not been fully understood, and the influence of stromal cells on response to chemotherapy is unclear. Here we performed an in-depth analysis of the transcriptional landscape of primary CRC, matched liver metastases and blood at single-cell resolution, and a systematic examination of transcriptional changes and phenotypic alterations of the TME in response to preoperative chemotherapy (PC). Based on 111,292 single-cell transcriptomes, our study reveals that TME of treatment-naïve tumors is characterized by the higher abundance of less-activated B cells and higher heterogeneity of tumor-associated macrophages (TAMs). By contrast, in tumors treated with PC, we found activation of B cells, lower diversity of TAMs with immature and less activated phenotype, lower abundance of both dysfunctional T cells and ECM-remodeling cancer-associated fibroblasts, and an accumulation of myofibroblasts. Our study provides a foundation for future investigation of the cellular mechanisms underlying liver metastasis of CRC and its response to PC, and opens up new possibilities for the development of therapeutic strategies for CRC.

In this study, four novel series of 4-phenyl-1 H-1,2,4-triazol-5(4 H)-one derivatives containing triazole or piperazine moieties were designed, synthesized, and evaluated for negative inotropic activity by measuring the left atrium stroke volume in isolated rabbit heart preparations. Almost all of the compounds showed an ability to moderate the cardiac workload by decreasing the heart rate and contractility. Among them, 7h was found to be the most potent with a change in stroke volume of −48.22 ± 0.36% at a concentration of 3 × 10−5 mol/L (metoprolol: −9.74 ± 0.14%). The cytotoxicity of these compounds was evaluated using the human cervical cancer cell line HeLa, the liver cancer cell line Hep3B, and the human normal hepatic cell line LO2. A preliminary study of the mechanism of action for the compound 7h on the regulation of atrial dynamics with ATP-sensitive K+ channel and L-type Ca2+ channel blockers glibenclamide and nifedipine was performed in the isolated perfused beating rabbit atria. [ABSTRACT FROM AUTHOR]