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Objectives Hypoxia conditions promote the adaptation and progression of non-small-cell lung cancer (NSCLC) via hypoxia-inducible factors (HIF). HIF-1α may regulate estrogen receptor β (ERβ) and promote the progression of NSCLC. The phytochemical homoharringtonine (HHT) exerts strong inhibitory potency on NSCLC, with molecular mechanism under hypoxia being elusive. Methods The effects of HHT on NSCLC growth were determined by cell viability assay, colony formation, flow cytometry, and H460 xenograft models. Western blotting, molecular docking program, site-directed mutagenesis assay, immunohistochemical assay, and immunofluorescence assay were performed to explore the underlying mechanisms of HHT-induced growth inhibition in NSCLC. Key findings HIF-1α/ERβ signaling-related E2F1 is highly expressed and contributes to unfavorable survival and tumor growth. The findings in hypoxic cells, HIF-1α overexpressing cells, as well as ERβ- or E2F1-overexpressed and knockdown cells suggest that the HIF-1α/ERβ/E2F1 feedforward loop promotes NSCLC cell growth. HHT suppresses HIF-1α/ERβ/E2F1 signaling via the ubiquitin-proteasome pathway, which is dependent on the inhibition of the protein expression of HIF-1α and ERβ. Molecular docking and site-directed mutagenesis revealed that HHT binds to the GLU305 site of ERβ. HHT inhibits cell proliferation and colony formation and promotes apoptosis in both NSCLC cells and xenograft models. Conclusion The formation of the HIF-1α/ERβ/E2F1 feedforward loop promotes NSCLC growth and reveals a novel molecular mechanism by which HHT induces cell death in NSCLC. [ABSTRACT FROM AUTHOR]

Heatwave events over Guangdong have attracted recent attention under changing climate conditions. It is desired to explore the future changes of heatwave due to its associated consequences on society economy and environment. In this study, a stepwise‐clustered heatwave downscaling approach (i.e., SCHW) was developed for the projection of HWs in Guangdong. The heatwave indicators (occurrence, duration, magnitude, intensity, frequency, and accumulated intensity) were investigated from both the absolute and relative definitions of heatwave events (i.e., AHWs and RHWs) based on the multi‐model ensemble of 13 coupled model intercomparison projected phase 5 (CMIP5) global climate models (GCMs) under two representative concentration pathways (RCPs). The trends (i.e., 0.18–0.29°C per decade under RCP4.5 and 0.30–0.58°C per decade under RCP8.5) of the projected daily maximum temperature indicate that Guangdong would experience continuous warming in the future. The occurrence, frequency, and accumulated intensity of heatwave would increase by 198%, 272%, and 346% in the 2080s (i.e., 2066–2095) under RCP8.5 compared to the historical period (i.e., 1976–2005), respectively. Moreover, the three indicators of HWs are projected to have more substantial increases over inland Guangdong than its costal parts. The spatial variation of occurrence of absolute and relative heatwave under RCP8.5 (2.80 and 2.78) is larger than these under RCP4.5 (2.50 and 2.32) during 2080s (i.e., 2066–2095). The projections of future HWs can help provide valuable information for assessing extreme climate change and identifying desired adaptation strategies. [ABSTRACT FROM AUTHOR]

Dopaminergic neurons in the substantia nigra pars compacta (SNpc) demonstrate regionally selective susceptibility in Parkinson's disease (PD) compared to those in the ventral tegmental area (VTA). However, the molecular mechanism for this distinct vulnerability remains unclear. Here, it is shown that Legumain, also known as asparagine endopeptidase (AEP), is activated in a subgroup of SRY-box transcription factor 6 /Aldehyde dehydrogenase 1 family member A1, (Sox6 + /ALDH1A1 + ) neurons in the ventral tier of the SNpc and cleaves Sox6 and ALDH1A1, leading to repression of Special AT-rich sequence binding protein 1 (Satb1) that is a dimeric/tetrameric transcription factor specifically binding to AT-rich DNA sequences, and toxic dopamine metabolite accumulation. AEP cuts Sox6 and ALDH1A1 in dopaminergic neurons that project to the locus coeruleus (LC), abolishing Sox6's transcriptive and ALDH1A1's enzymatic activities. Co-expressing AEP-truncated Sox6 and ALDH1A1 fragments in 3-month-old A53T SNCA transgenic mice accelerates dopamine degeneration, whereas expressing AEP-resistant Sox6 N336A/N446A and ALDH1A1 N220A mutants alleviates rotenone-induced PD pathologies. Hence, different circuitries and intrinsic properties of dopaminergic neurons in the SNpc and VTA render differential predispositions in PD., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)