Drugs targeting TGF-ß/Notch interaction attenuate hypertrophic scar formation by optic atrophy 1-mediated mitochondrial fusion.

Hypertrophic scar (HS) formation is a cutaneous fibroproliferative disease that occurs after skin injuries and results in severe functional and esthetic disability. To date, few drugs have shown satisfactory outcomes for the treatment of HS formation. Transforming growth factor-beta (TGF-ß)/Notch interaction via small mothers against decapentaplegic 3 (Smad3) could facilitate HS formation; therefore, targeting TGF-ß/ Notch interaction via Smad3 is a potential therapeutic strategy to attenuate HS formation. In addition, optic atrophy 1 (OPA1)-mediated mitochondrial fusion contributes to fibroblast proliferation, and TGF-ß/Smad3 axis and the Notch1 pathway facilitate OPA1-mediated mitochondrial fusion. Thus, the aim of this study was to investigate whether drugs targeting TGF-ß/Notch interaction via Smad3 suppressed fibroblast proliferation to attenuate HS formation through OPA1-mediated mitochondrial fusion. We found that the TGF-ß pathway, Notch pathway, and TGF-ß/Notch interaction via Smad3 were inhibited by pirfenidone, the gamma- secretase inhibitor DAPT, and SIS3 in human keloid fibroblasts (HKF) and an HS rat model, respectively. Protein interaction was detected by co-immunoprecipitation, and mitochondrial morphology was determined by electron microscopy. Our results indicated that pirfenidone, DAPT, and SIS3 suppressed the proliferation of HKFs and attenuated HS formation in the HS rat model by inhibiting TGF-ß/Notch interaction via Smad3. Moreover, pirfenidone, DAPT, and SIS3 hindered OPA1-mediated mitochondrial fusion through inhibiting TGF-ß/Notch interaction, thereby suppressing the proliferation of HS fibroblasts and HS formation. In summary, these findings investigating the effects of drugs targeting TGF-ß/Notch interaction on HS formation might lead to novel drugs for the treatment of HS formation.

[Nutrient spatiotemporal distribution and eutrophication process in subsidence waters of Huainan and Huaibei mining areas, China].

A total of eight mining subsidence waters, including five sites in Huainan "Panxie" Mining Areas (PXS-1, PXS-2, PXS-3, PXS-4, and PXS-5) and three sites in Huaibei "Zhu-Yang huang" Mining Areas (HBDH, HBZH, HBNH), were selected to study the nutrient temporal and spatial distribution and trophic states. Among the sites, three sites (PXS-1, PXS-3, and HBDH) showed higher nutrient level and could be classified into moderate eutrophication, whereas the other five were in moderate nutrient level and mild eutrophication. Overall, the nutrient level of Huainan mining subsidence waters was higher than that of Huaibei mining subsidence waters. All the test samples in the two mining areas had a higher ratio of nitrogen to phosphorus (N:P), being 25-117 in Huainan and 17-157 in Huaibei, and with a seasonal variety, the lowest in growth season. The dissolved inorganic phosphorus (DIP) in total phosphorous (TP) occupied a small percentage, being averagely 15.4% and 18.4% in Huainan and Huaibei mining areas, respectively. Nitrate was the main specie of dissolved inorganic nitrogen (DIN), with the ratio of nitrate to DIN being 74% and 89% in Huainan and Huaibei mining areas, respectively. Relative to the waters age, human activities could be one of the main factors responsible for the high nutrient level and the faster eutrophication process of these waters.