DNA topoisomerases play a key role in tumor proliferation. Chemotherapeutics targeting topoisomerases have been widely used in clinical oncology, but resistance and side effects, particularly cardiotoxicity, usually limit their application. Clinical data show that a decrease in topoisomerase (top) levels is the primary factor responsible for resistance, but in cells there is compensatory effect between the levels of top1 and top2α. Here, we validated cyclizing-berberine A35, which is a dual top inhibitor and preferentially targets top2α. The impact on the top2α catalytic cycle indicated that A35 could intercalate into DNA but did not interfere with DNA-top binding and top2α ATPase activity. A35 could facilitate DNA-top2α cleavage complex formation by enhancing pre-strand and post-strand cleavage and inhibiting religation, suggesting this compound can be a topoisomerase poison and had a district mechanism from other topoisomerase inhibitors. TARDIS and comet assays showed that A35 could induce cell DNA breakage and DNA-top complexes but had no effect on the cardiac toxicity inducer top2β. Silencing top1 augmented DNA break and silencing top2α decreased DNA break. Further validation in H9c2 cardiac cells showed A35 did not disturb cell proliferation and mitochondrial membrane potency. Additionally, an assay with nude mice further demonstrated A35 did not damage the heart. Our work identifies A35 as a novel skeleton compound dually inhibits topoisomerases, and predominantly and specially targets top2α by interfering with all cleavage steps and its no cardiac toxicity was verified by cardiac cells and mice heart. A35 could be a novel and effective targeting topoisomerase agent.

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Humans benefit from ecosystem services (ES) and profoundly influence the ecosystem in rapid urbanisation and large-scale urban sprawl contexts, especially at the landscape level. However, the impacts of landscape pattern, the driving mechanism of sub-ES and the spatially explicit regional optimisation, have been largely ignored. In response, to the present paper explores two primary aspects: the relationship among ES, landscape pattern, urban income and agricultural output, and the regional governance of optimised ES values (ESV), using the Wuhan urban agglomeration as a case study area. The survey method is employed in obtaining the adjusted magnitude matrix of land use and ecosystem services. Spatial regression analyses are conducted on each ES, including food provision, climate regulation and soil maintenance, with socio-economic indicators and landscape pattern index as explanatory variables. Finally, geographically weighted regression and scenario analyses are conducted on each sub-ESV to generate adjusted coefficients in each county for ESV regulation. The results show that urban per capita disposable income and agricultural output significantly contribute to ESV change, with the former being negative and the latter being positive. A highly aggregated landscape also produces reduced ESV, particularly in soil maintenance and gas and climate regulation. We summarise the ESV in 2020 and in the period after adjustment in different administrative counties. Provision, regulation and culture ecosystem benefits substantially increase when attempts are made to lower the landscape aggregation pattern by 1%. In general, counties and county-level cities have the largest ESV, with food provision as the optimum ecosystem benefit. Districts in the capital city show an immense growth in provision and regulation, and county-level cities show the highest growth rate in cultural service. Integrating the landscape pattern into characterising and optimising ES, provides references for regional governance on land-use planning and socio-economic development, which is vital to sustainable regional development.