scholarly journals Disruption of water networks is the cause of human/mouse species selectivity in urokinase plasminogen activator (uPA) inhibitors derived from hexamethylene amiloride (HMA)

2021 ◽  
Author(s):  
Nehad El Salamouni ◽  
Benjamin Buckley ◽  
Longguang Jiang ◽  
Mingdong Huang ◽  
Marie Ranson ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Critical Role ◽  
Parent Drug ◽  
Urokinase Plasminogen Activator ◽  
Water Networks ◽  
Invasion And Migration ◽  
Species Selectivity ◽  
And Migration ◽  
Experimental Findings ◽  
Hexamethylene Amiloride

The urokinase plasminogen activator (uPA) plays a critical role in tumor cell invasion and migration and is a promising anti-metastasis target. 6-Substituted analogs of 5-N,N-(hexamethylene)amiloride (HMA) are potent and selective uPA inhibitors that lack the diuretic and anti-kaliuretic properties of the parent drug amiloride. However, the compounds display pronounced selectivity for human over mouse uPA, thus confounding interpretation of data from human xenografted mouse models of cancer. Here, computational and experimental findings reveal that residue 99 is a key contributor to the observed species selectivity, whereby enthalpically unfavorable expulsion of a water molecule by the 5-N,N-hexamethylene ring occurs when residue 99 is Tyr (as in mouse uPA). Analog 7 lacking the 5-N,N-hexamethylene ring maintained similar water networks when bound to human and mouse uPA and displayed reduced selectivity, thus supporting this conclusion. The study will guide further optimization of dual-potent human/mouse uPA inhibitors from the amiloride class as anti-metastasis drugs.

scholarly journals LncRNA MALAT1 Regulating Lung Carcinoma Progression via the miR-491-5p/UBE2C Axis

2021 ◽  
Vol 27 ◽  
Author(s):  
Juanjuan Dai ◽  
Ning Zhou ◽  
Rui Wu ◽  
Jing Du ◽  
Shuang Miao ◽  
...  
Keyword(s):  
Lung Carcinoma ◽  
Critical Role ◽  
Carcinoma Cells ◽  
Migration Ability ◽  
Invasion And Migration ◽  
Lung Carcinoma Cells ◽  
Lncrna Malat1 ◽  
Anti Cancer ◽  
And Migration

Long noncoding RNAs (lncRNAs) play a critical role in the development of lung carcinoma. The mechanism of MALAT1 in lung carcinoma development is not understood very well. This study aimed to investigate the role of MALAT1 in lung carcinoma progression and the mechanism underlying the role of miR-491-5p in the MALAT1 mediated regulation of UBE2C expression. The results indicated that the expression of MALAT1 was often augmented in lung carcinoma cells. Suppression of MALAT1 blocked the proliferation, invasion and migration ability of cancer cells and inhibited the expression of UBE2C. UBE2C restoration attenuated the MALAT1 knockdown-induced anti-cancer effects. Moreover, UBE2C and MALAT1 were indicated as targets of miR-491-5p and inhibition of miR-491-5p restored the MALAT1 knockdown-induced inhibition of the progression of lung carcinoma. Furthermore, MALAT1 sponged miR-491-5p to upregulate UBE2C expression, causing it to act as a competing endogenous RNA. Collectively, MALAT1 downregulation suppressed lung carcinoma progression by regulating the miR-491-5p/UBE2C axis. These results indicate that MALAT1 could be a molecular target for lung carcinoma treatment and prognosis.

scholarly journals MiR-203 Targets to the 3′-UTR of SLUG to Suppress Cerebral Infarction-Induced Endothelial Cell Growth and Motility

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Yunsong Li ◽  
Wei Bi ◽  
Bing Han ◽  
Tao Yuan ◽  
Long Shi ◽  
...  
Keyword(s):  
Cerebral Infarction ◽  
Molecular Mechanisms ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Critical Role ◽  
Ectopic Expression ◽  
Serum Samples ◽  
Invasion And Migration ◽  
And Migration

Cerebral infarction is one of the leading causes of death worldwide, in which angiogenesis plays a critical role. On the other hand, accumulating evidence has demonstrated that microRNAs (miRNAs) function as key modulators in the formation and progression of cerebral infarction. However, the molecular mechanisms of miRNAs underlying cerebral infarction-associated angiogenesis remain unclear. In the present study, we indicated that the expression of miR-203 was significantly downregulated in serum samples derived from patients with cerebral infarction and in mice brain samples following middle cerebral artery occlusion (MCAO) compared with healthy controls. In vitro, the expression of miR-203 was obviously downregulated in hypoxia-induced human umbilical vein vascular endothelial cells (HUVECs). Functionally, ectopic expression of miR-203 drastically suppressed HUVEC proliferation, invasion, and migration. In addition, SLUG, a zinc finger transcriptional repressor, was identified as a direct target of miR-203 and was negatively correlated with miR-203 expression in MCAO mice and in hypoxia-induced HUVECs. Furthermore, overexpression of SLUG reversed the inhibitory effect of miR-203 on proliferation, invasion, and migration abilities of HUVECs. Taken together, our research provides a novel insight of the miR-203-SLUG axis into cerebral infarction-associated endothelial behaviors and may offer a powerful therapeutic target of cerebral ischemia.

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