Atomically precise copper clusters are highly desirable catalysts for electrocatalytic CO 2 reduction reaction (CO 2 RR) and provide an ideal platform for elaborating structure-activity relationships. However, systematic comparative studies of Cu cluster isomers for electrocatalytic CO 2 RR are lacking because they are challenging to synthesize. A group of structurally precise Cu 8 cluster isomers with different core structures (cubeand ditetrahedron-shaped) were developed and investigated for highly active and selective CO 2 reduction. Electrocatalytic measurements showed that the ditetrahedron-shaped Cu 8 cluster exhibited a higher FE HCOOH ( � 92 %) at À 1.0 V and higher selectivity than the cubeshaped cluster. Theoretical investigations revealed different levels of competitiveness with the hydrogen evolution reaction on the respective core-shaped Cu 8 clusters and decreased free energies for the adsorbed HCOO* intermediates on the ditetrahedron-shaped Cu 8 clusters.

BackgroundThe transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) signaling pathways are both constitutively activated in triple-negative breast cancer (TNBC). We are interested in isolating the naturally-derived small-molecule inhibitor that could simultaneously targeting TGFβ/BMP pathways and further studying its anti-proliferative/−metastatic effects as well as the underlying mechanisms in multiple tumor models.MethodsMultiple in vitro cell-based assays are used to examine the compound’s inhibitory efficacy on TNBC cell growth, stemness, epithelial-mesenchymal transition (EMT), invasion and migration by targeting TGFβ/BMP signaling pathways. Transgenic breast cancer mouse model (MMTV-PyMT), subcutaneous xenograft and bone metastasis models are used to examine ZL170’s effects on TNBC growth and metastasis potentials in vivo.ResultsZL170 dose-dependently inhibits cell proliferation, EMT, stemness, invasion and migration in vitro via specifically targeting canonical TGFβ/BMP-SMADs pathways in TNBC cells. The compound significantly hinders osteolytic bone metastasis and xenograft tumor growth without inflicting toxicity on vital organs of tumor-bearing nude mice. ZL170 strongly inhibits primary tumor growth and lung metastases in MMTV-PyMT transgenic mice. ZL170-treated tumors exhibit impaired TGFβ/BMP signaling pathways in both epithelial and stromal compartments, thereby creating a suppressive tumor microenvironment characterized by reduced extracellular matrix deposition and decreased infiltration of stromal cells.ConclusionsZL170 inhibits tumor EMT, stemness and metastasis and could be further developed as a potent anti-metastatic agent used in combination with cytotoxic drugs for treatment of TNBC and other advanced metastatic cancers.Electronic supplementary materialThe online version of this article (10.1186/s13046-019-1130-2) contains supplementary material, which is available to authorized users.

Accumulating evidence indicates that the zinc-finger transcription factor ZEB1 is predominantly expressed in the stroma of several tumours. However, the role of stromal ZEB1 in tumour progression remains unexplored. In this study, while interrogating human databases, we uncover a remarkable decrease in relapse-free survival of breast cancer patients expressing high ZEB1 levels in the stroma. Using a mouse model of breast cancer, we show that ZEB1 inactivation in stromal fibroblasts suppresses tumour initiation, progression and metastasis. We associate this with reduced extracellular matrix remodeling, immune cell infiltration and decreased angiogenesis. ZEB1 deletion in stromal fibroblasts increases acetylation, expression and recruitment of p53 to FGF2/7 , VEGF and IL6 promoters, thereby reducing their production and secretion into the surrounding stroma. Importantly, p53 ablation in ZEB1 stroma-deleted mammary tumours sufficiently recovers the impaired cancer growth and progression. Our findings identify the ZEB1/p53 axis as a stroma-specific signaling pathway that promotes mammary epithelial tumours.

Juglans mandshurica MAXIM. (Juglandaceae) is widely distributed throughout urban and rural areas in northeast of China. Its fresh rejuvenated fruit, commonly called "Qing Long Yi", has been used as a folk medicine for treatment of cancer and dermatosis and as an anodyne to relieve aches in China. Although phytochemical analyses were extensively carried out on not only the root [1][2][3][4][5] but also the stem bark 6) of J. mandshurica, little chemical work appears to have been done on the chemical composition of its fresh rejuvenated fruit. To our best knowledge, only two naphthalene glucosides, 4-hydroxynaphthalenyl b-D-glucopyranoside and 4,8-dihydroxy-1-naphthalenyl b-D-glucopyranoside have been isolated from the fruit of J. mandshurica.7) The medicinal uses of "Qing Long Yi" prompted us to investigate its chemical constituents, resulting in the isolation of five new atetralonyl glucosides (1-5). This paper deals with the isolation and structural elucidation of the new compounds on the basis of spectroscopic analysis, including two-dimensional NMR spectroscopic data, and the results of hydrolysis. Results and DiscussionThe fresh rejuvenated fruit of J. mandshurica, which was collected in a mountain area of Heilongjiang Province, China, was decocted twice with water and extracted with hexane, EtOAc and n-BuOH, successively. The n-BuOH extract was chromatographed on a Diaion HP-20 column to give water and 40% methanol eluate fraction. The 40% methanol eluate fraction was chromatographed on an ODS column, and subjected to a combination of silica gel, Lobar RP-C 18 column chromatography, and HPLC. Then, five new compounds, named juglanosides A-E (1-5) were isolated, and their structures were characterized as follows.Juglanoside A (1) was isolated as an amorphous powder. Its molecular formula was determined to be C 16 H 20 O 7 by high-resolution (HR)-FAB-MS. On acid hydrolysis, 1 afforded D-glucose as a component sugar, which was identified by GLC analysis of its trimethylsilyl thiazolidine derivative. The 1 H-NMR spectrum of 1 showed a set of proton signals due to two methylenes at d 3.04 (1H, ddd, Jϭ17.8, 9.5, 4.8 Hz) and 2. 60 (1H, ddd, Jϭ17.8, 6.7, 4.8 Hz), and 2. 44 (1H, dddd, Jϭ13.3, 9.5, 4.8, 3.4 Hz) and 2.36 (1H, dddd, Jϭ13.3, 6.7, 6.2, 4.8 Hz), and an oxymethylene at d 5.10 (1H, dd, Jϭ6.2, 3.4 Hz). Moreover, the 13 C-NMR spectrum, in combination with distortionless enhancement by polarization transfer (DEPT) and Five new a a-tetralonyl glucosides, juglanosides A-E (1-5) were isolated from the fresh rejuvenated fruit of Juglans mandshurica. Their structures were elucidated as (4S)-4-hydroxy-a a-tetralone 4-O-b b-D-glucopyranoside (1), (4S)-4,5-dihydroxy-a a-tetralone 4-O-b b-D-glucopyranoside (2), (4S)-4,6-dihydroxy-a a-tetralone 4-O-b b-D-glucopyranoside (3), (4S)-4,5,8-trihydroxy-a a-tetralone 4-O-b b-D-glucopyranoside (4), and (4S)-4,5,8-trihydroxy-a