Background:The interplay between dyslipidemia-induced inflammation and angiogenesis remains poorly understood. Results: Inhibition of caspase-1 improves VEGFR-2 signaling, tube formation, and blood perfusion in ischemic tissues. Conclusion:The suppression of caspase-1 improves angiogenesis and ischemia prognosis. Significance: Caspase-1 suppression is a novel therapeutic target for improvement of angiogenesis and ischemia under inflammatory environments.

Type III phosphatidylinositol-4-kinase beta (PI4KIII␤) was previously implicated in hepatitis C virus (HCV) replication by small interfering RNA (siRNA) depletion and was therefore proposed as a novel cellular target for the treatment of hepatitis C. Medicinal chemistry efforts identified highly selective PI4KIII␤ inhibitors that potently inhibited the replication of genotype 1a and 1b HCV replicons and genotype 2a virus in vitro. Replicon cells required more than 5 weeks to reach low levels of 3-to 5-fold resistance, suggesting a high resistance barrier to these cellular targets. Extensive in vitro profiling of the compounds revealed a role of PI4KIII␤ in lymphocyte proliferation. Previously proposed functions of PI4KIII␤ in insulin secretion and the regulation of several ion channels were not perturbed with these inhibitors. Moreover, PI4KIII␤ inhibitors were not generally cytotoxic as demonstrated across hundreds of cell lines and primary cells. However, an unexpected antiproliferative effect in lymphocytes precluded their further development for the treatment of hepatitis C. C hronic hepatitis C virus (HCV) infection, a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma, afflicts approximately 3% of the world's population (24). The current standard of care for treating hepatitis C is pegylated interferon and ribavirin, which shows poor tolerability and is capable of achieving a sustained viral response in only half of genotype 1 patients (7). Two NS3 protease inhibitors, telaprevir and boceprevir, have been approved recently, and additional direct-acting antivirals are in clinical development. While triple therapy with interferon, ribavirin, and a protease inhibitor increases the percentage of patients showing a sustained viral response to 75% and can shorten the treatment time, it still has limitations: only genotype 1 patients are responsive, side effects (such as anemia) prevent the use in transplant patients, and the inconvenient dosing schedule (three times a day) might cause noncompliance. Development of viruses resistant to direct antivirals occurs very rapidly and leads to relapse and viral breakthrough. A possible exception might be nucleoside inhibitors, since viruses with resistance mutations are not viable. We therefore executed high-throughput small interfering RNA (siRNA) screens in order to identify novel cellular targets for the treatment of HCV. Type III phosphatidylinositol-4-kinases (PI4KIIIs) were identified from these studies and in screens performed in other laboratories (3,4,(20)(21)(22).Mammalian cells express a large number of lipid kinases, including four enzymes that phosphorylate phosphatidylinositol at position four of the inositol ring, the phosphatidylinositol-4-kinases (PI4Ks). Lipid kinases are involved in multiple functions of the cell, of which phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) signaling is the most thoroughly investigated process. The four PI4Ks (type II ␣ and ␤ and type III ␣ and ␤) are localized to different sites in the cell by pro...

Eukaryotic cell membrane dynamics change in curvature during physiological and pathological processes. In the past ten years, a novel protein family, Fes/CIP4 homology-Bin/Amphiphysin/Rvs (F-BAR) domain proteins, has been identified to be the most important coordinators in membrane curvature regulation. The F-BAR domain family is a member of the Bin/Amphiphysin/Rvs (BAR) domain superfamily that is associated with dynamic changes in cell membrane. However, the molecular basis in membrane structure regulation and the biological functions of F-BAR protein are unclear. The pathophysiological role of F-BAR protein is unknown. This review summarizes the current understanding of structure and function in the BAR domain superfamily, classifies F-BAR family proteins into nine subfamilies based on domain structure, and characterizes F-BAR protein structure, domain interaction, and functional relevance. In general, F-BAR protein binds to cell membrane via F-BAR domain association with membrane phospholipids and initiates membrane curvature and scission via Src homology-3 (SH3) domain interaction with its partner proteins. This process causes membrane dynamic changes and leads to seven important cellular biological functions, which include endocytosis, phagocytosis, filopodium, lamellipodium, cytokinesis, adhesion, and podosome formation, via distinct signaling pathways determined by specific domain-binding partners. These cellular functions play important roles in many physiological and pathophysiological processes. We further summarize F-BAR protein expression and mutation changes observed in various diseases and developmental disorders. Considering the structure feature and functional implication of F-BAR proteins, we anticipate that F-BAR proteins modulate physiological and pathophysiological processes via transferring extracellular materials, regulating cell trafficking and mobility, presenting antigens, mediating extracellular matrix degradation, and transmitting signaling for cell proliferation.

Lakes have played a critical role in providing water and ecosystem services for people and other organisms in China for millennia. However, accelerating climate change and economic boom have resulted in unprecedented changes in these valuable lakes. Using Landsat images covering the entity of the country, we explored the changes in China’s lakes and the associated driving forces over the last 30 years (i.e., mid-1980s to 2015). We discovered that China’s lakes have changed with divergent regional trends: in the sparsely populated Tibetan Plateau, lakes are abundant, and the lake area has increased dramatically from 38,596 km2 to 46,831 km2 (i.e., increased by 8235 km2, or 21.3%), whereas in the densely populated northern and eastern regions, lakes are relatively scarce, and the lake area has decreased from 36,659 km2 to 33,657 km2 (i.e., decreased by 3002 km2, or 8.2%). In particular, severe lake decreases occurred in the Mongolia-Xinjiang Plateau and the Eastern Plain (–2151 km2). Statistical analyses indicated that climate was the most important factor controlling lake changes in the Tibetan Plateau, the Yun-Gui Plateau and the Northeast Plain. However, the strength of climatic control on lake changes was low in the Eastern Plain and the Mongolia-Xinjiang Plateau, where human activities, e.g., impoldering, irrigation, and mining, have caused serious impacts on lakes. Further lake changes will exacerbate regional imbalances between lake resources and population distribution and thus may increase the risk of water resource crises in China.

Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are common drug targets and canonically couple to specific Gα protein subtypes and β-arrestin adaptor proteins. G protein- and β-arrestin-mediated signaling have been considered separable. We show GPCRs promote a direct interaction between Gαi protein subtype family members and β-arrestins, regardless of their canonical Gαi protein subtype coupling. Gαi:β-arrestin complexes bound extracellular signal-regulated kinase (ERK) and their disruption impaired both ERK activation and cell migration, consistent with β-arrestins requiring a functional interaction with Gαi for certain signaling events. These results introduce a GPCR signaling mechanism distinct from canonical G protein activation in which GPCRs cause the formation of Gαi:β-arrestin signaling complexes.