Preclinical effects of highly potent MEK1/2 inhibitors on rat cerebral vasculature after organ culture and subarachnoid haemorrhage
Conclusion: The PD0325901 treatment did not improve the neurological score after SAH, nor showed any beneficial therapeutic effect on the contractility, contrasting with the reduction in neurological deficits seen after trametinib treatment. These data show that trametinib might be a potential candidate for treatment of SAH. (Source: Clinical Science)
Source: Clinical Science - August 5, 2019 Category: Biomedical Science Authors: Christensen, S. T., Haanes, K. A., Spray, S., Grell, A.-S., Warfvinge, K., Edvinsson, L., Johansson, S. E. Tags: PublishAheadOfPrint Source Type: research
Mitochondrial ROS-induced lysosomal dysfunction impairs autophagic flux and contributes to M1 macrophage polarization in a diabetic condition
Macrophage polarization towards the M1 phenotype and its subsequent inflammatory response have been implicated in the progression of diabetic complications. Despite adverse consequences of autophagy impairment on macrophage inflammation, the regulation of macrophage autophagy under hyperglycemic conditions is incompletely understood. Here, we report that the autophagy-lysosome system and mitochondrial function are impaired in streptozotocin (STZ)-induced diabetic mice and high glucose (HG)-stimulated RAW 264.7 cells. Mitochondrial dysfunction promotes reactive oxygen species (ROS) production and blocks autophagic flux by i...
Source: Clinical Science - August 4, 2019 Category: Biomedical Science Authors: Yuan, Y., Chen, Y., Peng, T., Li, L., Zhu, W., Liu, F., Liu, S., An, X., Luo, R., Cheng, J., Liu, J., Lu, Y. Tags: PublishAheadOfPrint Source Type: research
Fatty acid oxidation inhibitor etomoxir suppresses tumor progression and induces cell cycle arrest via PPAR{gamma}-mediated pathway in bladder cancer
Tumor cells rely on aerobic glycolysis as their main energy resource (Warburg effect). Recent researches highlighted the importance of lipid metabolism in tumor progression and certain cancers even turn to fatty acids as main fuel. Related studies have identified alterations of fatty acid metabolism in human bladder cancer (BCa). Our microarray analysis showed that fatty acid metabolism was activated in BCa compared with normal bladder. And the free fatty acid (FFA) level was increased in BCa compared with paracancerous tissues. Inhibition of FAO with etomoxir caused lipid accumulation, decreased adenosine triphosphate (AT...
Source: Clinical Science - July 28, 2019 Category: Biomedical Science Authors: Cheng, S., Wang, G., Wang, Y., Cai, L., Qian, K., Ju, L., Liu, X., Xiao, Y., Wang, X. Tags: PublishAheadOfPrint Source Type: research
Effect of Mycophenolate and Rapamycin on Renal Fibrosis in Lupus Nephritis
Lupus nephritis (LN) leads to chronic kidney disease through progressive fibrosis. Mycophenolate inhibits inosine monophosphate dehydrogenase and is a standard treatment for LN. The mammalian or mechanistic target of rapamycin (mTOR) pathway is activated in LN. Rapamycin inhibits mTOR and is effective in preventing kidney transplant rejection, with the additional merits of reduced incidence of malignancies and viral infections. The effect of mycophenolate or rapamycin on kidney fibrosis in LN has not been investigated. We investigated the effects of mycophenolate and rapamycin in NZB/W F1 murine LN and human mesangial cell...
Source: Clinical Science - July 28, 2019 Category: Biomedical Science Authors: Zhang, C., Chan, C. C., Cheung, K. F., Chau, M. K., Yap, D. Y., Ma, M. K., Chan, K. W., Yung, S., Chan, T. M. Tags: PublishAheadOfPrint Source Type: research
Empagliflozin prevents cardiomyopathy via sGC-cGMP-PKG pathway in type 2 diabetes mice
Cardiovascular complications contribute to the major mortality and morbidity in type 2 diabetes. Diabetic cardiomyopathy (DCM) is increasingly recognized as an important cause of heart failure. EMPA-REG OUTCOME trial has reported that empagliflozin, the sodium-glucose cotransporter 2 inhibitor, exerts cardiovascular benefits on diabetic population. However, the mechanism by which empagliflozin alleviates DCM still remains unclear. In the current study, we investigated the cardiac protective effects of empagliflozin on spontaneous type 2 diabetes db/db mice and its potential mechanism. 8 weeks of empagliflozin treatment (10...
Source: Clinical Science - July 22, 2019 Category: Biomedical Science Authors: Xue, M., Li, T., Wang, Y., Chang, Y., Cheng, Y., Lu, Y., Liu, X., Xu, L., Li, X., Yu, X., Sun, B., Chen, L. Tags: PublishAheadOfPrint Source Type: research
Endothelial progenitor cell-derived exosomes facilitate vascular endothelial cell repair through shuttling miR-21-5p to modulate Thrombospondin-1 expression
CONCLUSIONS: The present work highlights a critical event for the regulation of EC behavior by EPC-exosomes, which EPC-exosomes may deliver miR-21-5p and inhibit THBS1 expression to promote endothelial cell repair. (Source: Clinical Science)
Source: Clinical Science - July 16, 2019 Category: Biomedical Science Authors: Hu, H., Wang, B., Jiang, C., Li, R., Zhao, J. Tags: PublishAheadOfPrint Source Type: research
RIPK1 inhibitor Cpd-71 attenuates renal dysfunction in cisplatin-treated mice via attenuating necroptosis, inflammation and oxidative stress
In this study, we evaluated the treatment effects of Cpd-71, a novel RIPK1 inhibitor, by comparing with Necrostatin-1 (Nec-1), a classic RIPK1 inhibitor, which has several drawbacks like the narrow structure activity relationship (SAR) profile, moderate potency and non-ideal pharmacokinetic properties, in vivo and in vitro . Our results showed that pretreatment of Cpd-71 attenuated cisplatin-induced renal injury, restored renal function, and suppressed renal inflammation, oxidative stress and cell necroptosis. In addition, Cpd-71 inhibited renal damage while reducing the upregulated serum creatinine and BUN levels in es...
Source: Clinical Science - July 16, 2019 Category: Biomedical Science Authors: Wang, J.-n., Liu, M.-m., Wang, F., Wei, B., Yang, Q., Cai, Y.-t., Chen, X., Liu, X.-q., Jiang, L., Li, C., Hu, X.-w., Yu, J.-t., Ma, T.-t., Jin, J., Wu, Y.-g., Li, J., Meng, X.-M. Tags: PublishAheadOfPrint Source Type: research
PBI-4050 via GPR40 activation improves adenine-induced kidney injury in mice
PBI-4050, a novel first-in-class orally active compound that has completed clinical phases Ib and II in subjects with CKD and metabolic syndrome respectively, exerts antifibrotic effects in several organs via a novel mechanism of action, partly through activation of the GPR40 receptor. Here we evaluate the effects of PBI-4050 in both WT and Gpr40-/- mice on adenine-induced tubulointerstitial injury, anemia and activation of the unfolded protein response pathway. Adenine-induced CKD was achieved in eight-week old C57BL/6 mice fed a diet supplemented with 0.25% adenine. After 1 week, PBI-4050 or vehicle was administered da...
Source: Clinical Science - July 14, 2019 Category: Biomedical Science Authors: Thibodeau, J.-F., Simard, J.-C., Holterman, C. E., Blais, A., Cloutier, M.-P., Medeiros, T., Leduc, M., Grouix, B., Leblond, F. A., Burger, D., Hebert, R. L., Kennedy, C. R. J., Gagnon, L. Tags: PublishAheadOfPrint Source Type: research
Downregulation of LncRNA XIST Inhibits Cell Proliferation via Regulating miR-744/RING1 Axis in Non-small Cell Lung Cancer
Conclusion:Taken together, it was confirmed here that XIST overexpression is associated with tumor progression phenotype and the newly discovered XIST/miR-744/RING1 axis, which could serve as a potential biomarker and therapeutic target for NSCLC. (Source: Clinical Science)
Source: Clinical Science - July 9, 2019 Category: Biomedical Science Authors: Wang, J., Cai, H., Dai, Z., Wang, G. Tags: PublishAheadOfPrint Source Type: research
Soluble ST2 promotes oxidative stress and inflammation in cardiac fibroblasts: An in vitro and in vivo study in aortic stenosis
Conclusions: sST2 affected mitochondrial fusion in human cardiac fibroblasts, increasing oxidative stress production and inflammatory markers secretion. The blockade of NFkB or mitochondrial reactive oxygen species restored MFN-1 expression, improving oxidative stress status and reducing inflammatory markers secretion. In human AS, cardiac sST2 levels associated with oxidative stress and inflammation. The present study reveals a new pathogenic pathway by which sST2 promotes oxidative stress and inflammation contributing to cardiac damage. (Source: Clinical Science)
Source: Clinical Science - July 7, 2019 Category: Biomedical Science Authors: Matilla, L., Ibarrola, J., Arrieta, V., Garcia-Pena, A., Martinez-Martinez, E., Sadaba, R., Alvarez, V., Navarro, A., Fernandez-Celis, A., Gainza, A., Santamaria, E., Fernandez-Irigoyen, J., Bayes-Genis, A., Rossignol, P., Lopez-Andres, N. Tags: PublishAheadOfPrint Source Type: research
HEG1 indicates poor prognosis and promotes hepatocellular carcinoma invasion, metastasis, and EMT by activating Wnt/{beta}-catenin signaling
In conclusion, HEG1 indicates poor prognosis; plays important roles in HCC invasion, metastasis, and EMT by activating Wnt/β-catenin signaling; and can serve as a potentially valuable prognostic biomarker and therapeutic target for HCC. (Source: Clinical Science)
Source: Clinical Science - July 4, 2019 Category: Biomedical Science Authors: Zhao, Y.-r., Wang, J.-l., Xu, C., Li, Y.-m., Sun, B., Yang, L.-y. Tags: PublishAheadOfPrint Source Type: research
CircRNA-104718 acts as competing endogenous RNA and promotes hepatocellular carcinoma progression through microRNA-218-5p/TXNDC5 signaling pathway
This study aims at investigating the role of circRNA-104718 in HCC progression, which has been observed to be significantly up-regulated in HCC tissues. We found that, higher expression of circRNA-104718 also led to a poor prognosis in HCC patients. Using luciferase binding assays and RNA immunoprecipitation studies, we identified circRNA-104718 is physically associated and co-expressed with microRNA-218-5p in HCC. Mechanistically, we demonstrated that circRNA-104718 functions as a competing endogenous RNAs (ceRNAs) and competes with thioredoxin domain-containing protein 5 (TXNDC5) mRNA and directly binds to miR-218-5p. Fu...
Source: Clinical Science - July 4, 2019 Category: Biomedical Science Authors: Yu, J., Yang, M., Zhou, B., Luo, J., Zhang, Z., Zhang, W., Yan, Z. Tags: PublishAheadOfPrint Source Type: research
Impact of ET-1 and sex in glomerular hyperfiltration in humanized sickle cell mice
Hyperfiltration, highly prevalent early in sickle cell disease (SCD), is in part driven by an increase in ultrafiltration coefficient (Kf). The increases in Kf may be due to enlarged filtration surface area and/or increased glomerular permeability (Palb). Previous studies have demonstrated that endothelin-1 (ET-1) contributes to Palb changes in models of diabetes and SCD. Thus, we performed longitudinal studies of renal function to determine the relationship between ET-1 and glomerular size and Palb that may contribute to hyperfiltration in humanized sickle cell (HbSS) and control (HbAA) mice 8 to 32 weeks of age. Hb...
Source: Clinical Science - July 3, 2019 Category: Biomedical Science Authors: Kasztan, M., Pollock, D. M. Tags: PublishAheadOfPrint Source Type: research
Ergosterol attenuates cigarette smoke extract-induced COPD by modulating inflammation, oxidative stress and apoptosis in vitro and in vivo
The objective of this work was to investigate the effects of ergosterol on anti- inflammatory and anti-oxidative stress as well as anti-apoptosis in a cigarette smoke extract (CSE)-induced COPD model both in vitro and in vivo . Our results demonstrate that CSE induced inflammatory and oxidative stress and apoptosis with the involvement of the Bcl-2 family proteins via the NF-B/p65 pathway in both 16HBE cells and Balb/c mice. CSE induced epithelial cell death and increased the expression of NO, IL-6, TNF-α, MDA, and the apoptosis-related proteins cleaved caspase 3/7/9 and cleaved-PARP both in vitro and in vivo ,...
Source: Clinical Science - July 2, 2019 Category: Biomedical Science Authors: Sun, X., Feng, X., Zheng, D., Li, A., Li, C., Li, S., Zhao, Z. Tags: PublishAheadOfPrint Source Type: research
Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity
This study investigated whether nicotinamide riboside, a precursor of NAD+, prevents doxorubicin cardiotoxicity by improving autophagic flux. We report that administration of nicotinamide riboside elevated NAD+ levels, and reduced cardiac injury and myocardial dysfunction in doxorubicin-injected mice. These protective effects of nicotinamide riboside were recapitulated in cultured cardiomyocytes upon doxorubicin treatment. Mechanistically, nicotinamide riboside prevented the blockage of autophagic flux, accumulation of autolysosomes and oxidative stress in doxorubicin-treated cardiomyocytes, the effects of which were assoc...
Source: Clinical Science - July 1, 2019 Category: Biomedical Science Authors: Zheng, D., Zhang, Y., Zheng, M., Cao, T., Wang, G., Zhang, L., Ni, R., Brockman, J., Zhong, H., Fan, G.-C., Peng, T. Tags: PublishAheadOfPrint Source Type: research
