A Natural Small Molecule Mitigates Kidney Fibrosis by Targeting Cdc42-mediated GSK-3ß/ß-catenin Signaling.

Kidney fibrosis is a common fate of chronic kidney diseases (CKDs), eventually leading to renal dysfunction. Yet, no effective treatment for this pathological process has been achieved. During the bioassay-guided chemical investigation of the medicinal plant Wikstroemia chamaedaphne, a daphne diterpenoid, daphnepedunin A (DA), is characterized as a promising anti-renal fibrotic lead. DA shows significant anti-kidney fibrosis effects in cultured renal fibroblasts and unilateral ureteral obstructed mice, being more potent than the clinical trial drug pirfenidone. Leveraging the thermal proteome profiling strategy, cell division cycle 42 (Cdc42) is identified as the direct target of DA. Mechanistically, DA targets to reduce Cdc42 activity and down-regulates its downstream phospho-protein kinase Cζ(p-PKCζ)/phospho-glycogen synthase kinase-3ß (p-GSK-3ß), thereby promoting ß-catenin Ser33/37/Thr41 phosphorylation and ubiquitin-dependent proteolysis to block classical pro-fibrotic ß-catenin signaling. These findings suggest that Cdc42 is a promising therapeutic target for kidney fibrosis, and highlight DA as a potent Cdc42 inhibitor for combating CKDs.

A synthesis of nitric oxide emissions across global fertilized croplands from crop-specific emission factors.

Nitrogen (N) fertilizer application to agricultural soils results in substantial emissions of nitric oxide (NO), a key substance in tropospheric chemistry involved in climate forcing and air pollution. However, the estimates of global cropland NO emissions remain uncertain due to a lack of information on direct NO emission factors (EFd s) of applied N for various cropping systems at seasonal or annual scales. Here we quantified the crop-specific seasonal and annual-scale NO EFd s through synthesizing 1094 measurements from 125 field-based studies worldwide. The global mean crop-specific seasonal EFd was 0.53%, with the highest for vegetables (0.75%). Among cereal crops, the EFd of maize (0.45%) or wheat (0.47%) was about three times higher than for rice (0.12%). At annual scale, the mean EFd across all cropping systems was 0.58%, with tea plantations having the highest (1.54%). For other cropping systems, the annual-scale EFd s ranged from 0.02% to 1.07%. Besides crop type, also soil organic carbon, total N, and pH as well as N fertilizer type were the main factors explaining the variations of NO EFd s. Based on obtained specific EFd s for each crop type, we estimated that NO emissions due to the use of synthetic fertilizers from global croplands are about 0.42-0.62 Tg N year-1 . Our budgets are relatively lower if compared to estimates derived by the use of IPCC defaults for NO emissions (0.72-1.66 Tg N year-1 ) or reported elsewhere (0.67-1.04 Tg N year-1 ). In our estimates, cash crops (vegetable, tea and orchard), which cover only 9% of the world cropland area, contributed about 31% to total NO emissions from global fertilized croplands. Overall, our meta-analysis provides improved crop-specific NO EFd s reflecting current stage of knowledge. The work also highlights the relative importance of cash crop production as sources for atmospheric NO, that is, agricultural systems on which mitigation efforts may focus.