Combined knockout of collecting duct endothelin A and B receptors causes hypertension and sodium retention

The collecting duct (CD) endothelin (ET) system regulates blood pressure (BP) and Na excretion. CD-specific knockout (KO) of ET-1 causes hypertension, CD-specific KO of the ETA receptor does not alter BP, while CD-specific KO of the ETB receptor increases BP to a lesser extent than CD ET-1 KO. These findings suggest a paracrine role for CD-derived ET-1; however, they do not exclude compensation for the loss of one ET receptor by the other. To examine this, mice with CD-specific KO of both ETA and ETB receptors were generated (CD ETA/B KO). CD ETA/B KO mice excreted less urinary Na than controls during acute or chronic Na loading. Urinary aldosterone excretion and plasma renin concentration were similar during Na intake and both fell comparably during Na loading. On a normal sodium diet, CD ETA/B KO mice had increased BP, which increased further with high salt intake. The degree of BP elevation during normal Na intake was similar to CD ET-1 KO mice and higher than CD ETB KO animals. During 1 wk of Na loading, CD ETA/B KO mice had higher BPs than CD ETB KO, while BP was less than CD ET-1 KOs until the latter days of Na loading. These studies suggest that 1) CD ETA/B deficiency causes salt-sensitive hypertension, 2) CD ETA/B KO-associated Na retention is associated with failure to suppress the renin-angiotensin-aldosterone system, and 3) CD ETA and ETB receptors exerts a combined hypotensive effect that exceeds that of either receptor alone

Cytoskeletal and Cytoskeleton-Associated Proteins: Key Regulators of Cancer Stem Cell Properties

Cancer stem cells (CSCs) are a subpopulation of cancer cells possessing stemness characteristics that are closely associated with tumor proliferation, recurrence and resistance to therapy. Recent studies have shown that different cytoskeletal components and remodeling processes have a profound impact on the behavior of CSCs. In this review, we outline the different cytoskeletal components regulating the properties of CSCs and discuss current and ongoing therapeutic strategies targeting the cytoskeleton. Given the many challenges currently faced in targeted cancer therapy, a deeper comprehension of the molecular events involved in the interaction of the cytoskeleton and CSCs will help us identify more effective therapeutic strategies to eliminate CSCs and ultimately improve patient survival

KDM5 family of demethylases promotes CD44-mediated chemoresistance in pancreatic adenocarcinomas

Abstract A growing body of evidence suggests that the histone demethylase-lysine demethylase 5 (KDM5) family is associated with drug resistance in cancer cells. However, it is still not clear whether KDM5 family members promote chemotherapy resistance in pancreatic ductal adenocarcinomas (PDAC). Comprehensive bioinformatics analysis was performed to investigate the prognostic value, and functional mechanisms of KDM5 family members in PDAC. The effects of KDM5 family members on drug resistance in PDAC cells and the relationship with CD44, as a stem cell marker, were explored by gene knockout and overexpression strategies. Finally, our findings were validated by functional experiments such as cell viability, colony formation and invasion assays. We found that the expression of KDM5A/C was significantly higher in gemcitabine-resistant cells than in sensitive cells, consistent with the analysis of the GSCALite database. The knockdown of KDM5A/C in PDAC cells resulted in diminished drug resistance, less cell colonies and reduced invasiveness, while KDM5A/C overexpression showed the opposite effect. Of note, the expression of KDM5A/C changed accordingly with the knockdown of CD44. In addition, members of the KDM5 family function in a variety of oncogenic pathways, including PI3K/AKT and Epithelial-Mesenchymal Transition. In conclusion, KDM5 family members play an important role in drug resistance and may serve as new biomarkers or potential therapeutic targets in PDAC patients

Transition Metal-Free Direct C–H Functionalization of Quinones and Naphthoquinones with Diaryliodonium Salts: Synthesis of Aryl Naphthoquinones as β‑Secretase Inhibitors

A novel ligand-free, transition metal-free direct C–H functionalization of quinones with diaryliodonium salts has been developed for the first time. The transformation was promoted only through the use of a base and gave aryl quinone derivatives in moderate to good yields. This methodology provided an effective and easy way to synthesize β-secretase inhibitors. The radical trapping experiments showed that this progress was the radical mechanism

A new reflowing strategy based on lithiophilic substrates towards smooth and stable lithium metal anodes

In this work, we propose a facile, efficient and novel reflowing strategy to smooth the surface and decrease the interfacial resistance of lithium metal pre-deposited on a lithiophilic substrate, leading to a stable lithium metal anode with high electrochemical performance. First, on the basis of lithiophilic modification of a Cu substrate with a Au sputtering layer, the Li metal nucleation overpotential on the substrate is decreased, thus favoring uniform Li nucleation and growth. Second, owing to morphology reshaping by the reflowing treatment, the surface of the lithium metal anode could be further smoothed, and the interfacial resistance could also be reduced due to the modified solid electrolyte interface (SEI) film after the reflowing treatment. Therefore, a novel reflowing-treated Li/Au/Cu (RF-Li/Au/Cu) anode exhibits excellent electrochemical performance. Through galvanostatic measurements, stable cycling of the symmetric cells with the RF-Li/Au/Cu electrode for more than 1600 h and nearly 900 h is achieved at 0.5 mA cm-2 and 1 mA cm-2 with a capacity of 1 mA h cm-2, respectively. In addition, LiFePO4 cells with the RF-Li/Au/Cu anode show better rate performance and longer cycling life compared with those with an untreated Li/Au/Cu anode. This work provides a new concept and facile approach for developing stable Li metal anodes with high electrochemical performance