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Emerging evidence suggests that transforming growth factor β1 (TGFβ1) can inhibit angiogenesis, contradicting the coexistence of active angiogenesis and high abundance of TGFβ1 in the tumor microenvironment. Here, we investigated how tumors overcome the anti-angiogenic effect of TGFβ1. TGFβ1 treatment suppressed physiological angiogenesis in chick chorioallantoic membrane and zebrafish models but did not affect angiogenesis in mouse hepatoma xenografts. The suppressive effect of TGFβ1 on angiogenesis was recovered in mouse xenografts by a hypoxia-inducible factor 1α (HIF1α) inhibitor. In contrast, a HIF1α stabilizer abrogated angiogenesis in zebrafish, indicating that hypoxia may attenuate the anti-angiogenic role of TGFβ1. Under normoxic conditions, TGFβ1 inhibited angiogenesis by upregulating anti-angiogenic factor thrombospondin 1 (TSP1) in endothelial cells (ECs) via TGFβ type I receptor (TGFβR1)-SMAD2/3 signaling. In a hypoxic microenvironment, HIF1α induced microRNA-145 (miR145) expression; miR145 abolished the inhibitory effect of TGFβ1 on angiogenesis by binding and repressing SMAD2/3 expression and subsequently reducing TSP1 levels in ECs. Primary ECs isolated from human hepatocellular carcinoma (HCC) displayed increased miR145 and decreased SMAD3 and TSP1 compared to ECs from adjacent non-tumor livers. The reduced SMAD3 or TSP1 in ECs was associated with increased angiogenesis in HCC tissues. Collectively, this study identified that TGFβ1-TGFβR1-SMAD2/3-TSP1 signaling in ECs inhibits angiogenesis. This inhibition can be circumvented by a hypoxia-HIF1α-miR145 axis, elucidating a mechanism by which hypoxia promotes angiogenesis.

Three hitherto unknown eight-electron rhodium/silver alloy nanoclusters, [RhAg 21 {S 2 P(O n Pr) 2 } 12 ] ( 1 ), [RhHAg 20 {S 2 P(O n Pr) 2 } 12 ] ( 2 ), and [RhH 2 Ag 19 {S 2 P(O n Pr) 2 } 12 ] ( 3 ), have been isolated and fully characterized. Cluster 1 contains a regular Rh@Ag 12 icosahedral core, whereas 2 and 3 exhibit distorted RhH@Ag 12 and RhH 2 @Ag 12 icosahedral cores. The single-crystal neutron structure of 2 located the encapsulated hydride at the center of an enlarged RhAg 3 tetrahedron. A similar position was found by neutron diffraction for one of the hydrides in 3 , whereas the other hydride is trigonally coordinated to Rh and an elongated Ag-Ag edge. The solid-state structures of 1 - 3 possess C 1 symmetry due to the asymmetric arrangement of the surrounding capping Ag atoms. Our investigation shows that the insertion of one hydride dopant provokes the elimination of one capping silver atom on the cluster surface, resulting in the general formula [RhH x @Ag 21- x {S 2 P(O n Pr) 2 } 12 ] ( x = 0-2), which maintains the same number of cluster electrons as well as neutral charge. Clusters 1 - 3 exhibit an intense emission band in the NIR region. Contrarily to their PdAg 21 and PdHAg 20 relatives, the 4d orbitals of the encapsulated heterometal are somewhat involved in the optical processes.

Kinds of antibiotics are used to prevent and control bacteria infections, unfortunately, the overuse and misuse of antibiotic have promoted the emergence and spread of antibiotic-resistant bacteria. Therefore, understanding the mechanism of antibiotic resistance is very important. This study explores the combined effection of metal ions and antibiotic to the drug resistance of Escherichia coli. Our results found that the minimum inhibitory concentration (MIC) increased as the ammonium ferric citrate concentration increased, especially for gentamicin antibiotic. When the Fe 3+ concentration reached 300 μM, the survival of E. coli was stably restored with the increased gentamicin concentration. Exogenous Fe 3+ could decrease intracellular gentamicin concentration. On the other hand, Fe 3+ treatment together with gentamicin could reduce reactive oxygen species (ROS) production, characterized by decreased levels of NADH and ATP. Furthermore, ROS-scavenging enzymes of superoxide dismutase (SOD) and catalase (CAT) were up-regulated and H 2 O 2 plus gentamicin-mediated killing was restored by Fe 3+ . These results may have significant implications in understanding bacterial antibiotic-resistant mechanisms based on the external Fe 3+ concentration., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment of non-small cell lung cancer (NSCLC) patients., Methods: Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios (ORs) for objective response rate (ORR) and hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were calculated., Results: Mutation in K-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval (CI), 0.13-0.35], shorter PFS (HR =1.56; 95% CI, 1.27-1.92), and shorter OS (HR =1.59; 95% CI, 1.33-1.91) in NSCLC patients treated with EGFR-TKIs. Mutant PIK3CA significantly predicted shorter OS (HR =1.83; 95% CI, 1.05-3.20), showed poor ORR (OR =0.70; 95% CI, 0.22-2.18), and shorter PFS (HR =1.79; 95% CI, 0.91-3.53) in NSCLC patients treated with EGFR-TKIs., Conclusion: K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFR-TKIs. PIK3CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will benefit from EGFR-TKI treatment.