Ciclopirox olamine sensitizes leukemia cells to natural killer cell-mediated cytolysis by upregulating NKG2DLs via the Akt signaling pathway.

The activating receptor natural killer group 2D (NKG2D) expressed by Natural killer (NK) cells functions as a "master-switch" in governing the awakening status of NK cells. The NKG2D-mediated cytotoxicity has been declared to be related with the expression levels of NKG2D ligands (NKG2DLs) expressed on tumor cells. Therefore, selective induction of NKG2DLs could be a reliable approach to enhance the efficacy of NK cell-mediated immunotherapy. Our existing study demonstrated that Ciclopirox Olamine (CPX), an off-patent antifungal agent, effectively elevated the expression of NKG2DLs on leukemia cells and sensitized leukemia cells to NK-cell mediated cytolysis. Induction of ROS production and AKT phosphorylation by CPX is essential for the up-regulation of NKG2DLs expressions. Inhibition of AKT by using AKT inhibitor MK2206 decreased both NKG2DLs expressions and NK cell cytotoxicity. These data indicated that increased sensitivity of CPX-treated leukemia cells to NK cell cytolysis was attributed to higher NKG2DLs expressions, resulting from activated AKT signaling pathway. Our findings support the ongoing development of CPX as an anti-tumor agent and suggest its promising immunotherapeutic value in the medication of leukemia.

Dynamic simulation and assessment of the coupling coordination degree of the economy-resource-environment system: Case of Wuhan City in China.

The environmental and resource issues that accompany rapid economic growth have attracted the attention of the government and the public. Multiple non-linear and complicated interactions exist between the economy, resource and environment subsystem. Accordingly, understanding the operating mechanism of the economy-resource-environment (ERE) system and evaluating its coordination level are of immense significance for sustainable urban development. This study uses system dynamics (SD) to build a dynamic model of the ERE system. Furthermore, a coupling coordination degree model (CCDM) that focuses on the coordination of the ERE system is established using data from 2000 to 2015 for Wuhan City, China. Four typical scenarios (i.e., current, economy, resource and environment scenarios) are designed and simulated by the constructed SD model. Coordination assessment results based on the CCDM show that the coordination of the economy scenario performs the worst, the environment scenario performs best in the short term and the resource scenario is considerably effective for the coordinated development of the urban ERE system in the long term. We suggest that improvements in the energy structure and the natural environment are prior choices for sustainable urban development.

Beyond disasters: Long-run effect of earthquakes on energy poverty in China.

While earthquakes are considered one of the most prevalent natural disasters in China, there is limited empirical evidence regarding the long-term effects of earthquakes on energy poverty. Using data from China Family Panel Studies and China's historical earthquake catalog, this study investigates the long-term effects of earthquake intensity on energy poverty among households in China, and analyzes the long-term effects over different time spans. Our findings indicate that, higher earthquake intensities have an overall worsening long-term impact on energy poverty. When segmented into different time spans, households in regions with higher earthquake intensities are less likely to fall into energy poverty over the past 20 years and the past 20 to 50 years, whereas more likely to be energy poor over the longer time span. Moreover, we uncover that public infrastructure, government assistance, and mental well-being serve as channels through which earthquakes affect household energy poverty, with divergent effects over different time spans. In addition, we observe nonlinear evidence of earthquake intensity's long-term impact on energy poverty, and the long-term impacts are heterogeneous across different regions, as well as households with different registration statuses and household fuel types. These insights can inform policy interventions aimed at alleviating long-term energy poverty in areas affected by natural disasters.

Novel PORCN inhibitor WHN-88 targets Wnt/ß-catenin pathway and prevents the growth of Wnt-driven cancers.

Wnt/ß-catenin signaling pathway is a classical and crucial oncogenic pathway in many carcinomas, and Porcupine (PORCN) is an O-acyltransferase, which is indispensable and highly specific for catalyzing palmitoylation of Wnt ligands and facilitating their secretion and biofunction. Targeting PORCN provides a promising approach to specifically cure Wnt-driven cancers from the root. In this study, we designed series of pyridonyl acetamide compounds, and discovered a novel PORCN inhibitor WHN-88 with a unique di-iodinated pyridone structural fragment, which is significantly different from the reported inhibitors. We demonstrated that WHN-88 effectively abolished palmitoylation of Wnt ligands and prevented their secretion and the subsequent Wnt/ß-catenin signaling transduction. Further experiments showed that, at well-tolerated doses, WHN-88 remarkably suppressed the spontaneous occurrence and growth of MMTV-Wnt1 murine breast tumors. Consistently, WHN-88 also notably restrained the progress of xenografted Wnt-driven human tumors, including PA-1 teratocarcinoma with high autocrine Wnt signaling and Aspc-1 pancreatic carcinoma with Wnt-sensitizing RNF43 mutation. Additionally, we disclosed that WHN-88 inhibited cancer cell stemness obviously. Together, we verified WHN-88 is a novel PORCN inhibitor with potent efficacy against the Wnt-driven cancers. Our findings enriched the structural types of PORCN inhibitors, and facilitated the development and application of PORCN inhibiting therapy in clinic.

Synthesis and anticancer activity of podophyllotoxin derivatives with nitrogen-containing heterocycles.

Three series of podophyllotoxin derivatives with various nitrogen-containing heterocycles were designed and synthesized. The antitumor activity of these podophyllotoxin derivatives was evaluated in vitro against a panel of human tumor cell lines. The results showed that podophyllotoxin-imidazolium salts and podophyllotoxin-1,2,4-triazolium salts a1-a20 exhibited excellent cytotoxic activity. Among them, a6 was the most potent cytotoxic compound with IC50 values of 0.04-0.29 µM. Podophyllotoxin-1,2,3-triazole derivatives b1-b5 displayed medium cytotoxic activity, and podophyllotoxin-amine compounds c1-c3 has good cytotoxic activity with IC50 value of 0.04-0.58 µM. Furthermore, cell cycle and apoptosis experiments of compound a6 were carried out and the results exhibited that a6 could induce G2/M cell cycle arrest and apoptosis in HCT-116 cells.

Discovery of potential novel CRBN modulators by virtual screening and bioassay.

The incidence of malignant tumor with high mortality is increasing yearly. CRBN E3 ubiquitin ligase was proved to be an antitumor target. It was found that thalidomide and its analogs could bind to CRBN E3 ubiquitin ligase and modulate CRBN. CRBN modulators could promote the binding of CRBN to specific target proteins or block the binding of CRBN to some endogenous proteins. In this way, CRBN modulators suppress various tumor cells by modulating the interactions between CRBN and various antitumor target proteins. However, almost all CRBN modulators reported include glutarimide scaffold. Therefore, the aim of this study is to developed novel CRBN modulators. Virtual screening methods and bioassay methods, including structural similarity search, molecular docking, substructure search, antitumor evaluation and apoptosis assay were used to search novel potential CRBN modulators in Specs database. Finally, 15 compounds exhibited strong inhibition activity against A549 cells. Among these active compounds, The IC50 value against A549 of AG6033 was 0.853 ± 0.030 µM. Apoptosis assay demonstrated that AG6033 could promote apoptosis of A549 cells. Further mechanism studies suggested that AG6033 caused remarkable decrease of GSPT1 and IKZF1, the substrates of CRBN, and AG6033 induced cytotoxic effects was CRBN-dependent.

Do carbon emissions impact the health of residents? Considering China's industrialization and urbanization.

Industrialization and urbanization have aggravated the contradiction between environmental protection and economic growth, leading to health issues. While there are considerable interests in understanding the health effects of carbon emissions in the context of climate change, little is observed at regional scale and by econometric methods. Applying regression analysis on 2002-2017 Chinese provincial-level panel data, this study explores the intermediary mechanisms and regional differences of carbon emissions on residents' health. The results indicate that: (1) Carbon emissions have a long-term adverse impact on residents' health-a 1% rise in carbon emission adds 0.298% more outpatients and 0.162% more inpatients; (2) The rise in carbon emissions impairs residents' health mainly by raising the temperature; (3) In areas with high levels of industrialization and urbanization, increased carbon emissions bring greater health risks; and (4) In terms of China's unique "leading industrialization and lagging urbanization" situation, only by upgrading industrial structure, improving urbanization quality, and promoting coordinated industrialization and urbanization can the harm of carbon emissions to residents' health be reduced. Therefore, the "one-size-fits-all" policy model is not suitable for China's current situation. To address global "climate change" issues, China must act according to local conditions by applying mitigating (adaptive) measures in economically developed (less developed) regions. Simultaneously, the authorities must focus on the interaction and synergy between industrialization and urbanization.