Senescent renal tubular epithelial cells activate fibroblasts by secreting Shh to promote the progression of diabetic kidney disease

IntroductionDiabetic kidney disease (DKD) is one of the complications of diabetes; however, the pathogenesis is not yet clear. A recent study has shown that senescence is associated with the course of DKD. In the present study, we explored whether senescent renal tubular cells promote renal tubulointerstitial fibrosis by secreting Sonic hedgehog (Shh) which mediates fibroblast activation and proliferation in DKD.MethodsA 36-week-old db/db mice model and the renal tubular epithelial cells were cultured in high glucose (HG, 60 mmol/L) medium for in vivo and in vitro experiments.ResultsCompared to db/m mice, blood glucose, microalbuminuria, serum creatinine, urea nitrogen, and UACR (microalbuminuria/urine creatinine) were markedly increased in db/db mice. Collagen III, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α) were also increased in db/db mice kidneys, suggesting fibrosis and inflammation in the organ. Moreover, the detection of SA-β-galactosidase (SA-β-Gal) showed that the activity of SA-β-Gal in the cytoplasm of renal tubular epithelial cells increased, and the cell cycle inhibition of the expression of senescence-related gene cell cycle inhibitor p16INK4A protein and p21 protein increased, indicating that renal fibrosis in db/db mice was accompanied by cell senescence. Furthermore, Shh is highly expressed in the injured renal tubules and in the kidney tissue of db/db mice, as detected by enzyme-linked immunosorbent assay (ELISA). The results of immunofluorescence staining showed increased positive staining for Shh in renal tubular epithelial cells of db/db mice and decreased positive staining for Lamin B1, but increased positive staining for γH2A.X in cells with high Shh expression; similar results were obtained in vitro. In addition, HG stimulated renal tubular epithelial cells to secrete Shh in the supernatant of the medium. D-gal treatment of renal tubular epithelial cells increased the protein levels of Shh and p21. We also found enhanced activation and proliferation of fibroblasts cultured with the supernatant of renal tubular epithelial cells stimulated by HG medium but the proliferative effect was significantly diminished when co-cultured with cyclopamine (CPN), an inhibitor of the Shh pathway.DiscussionIn conclusion, HG induces renal tubular epithelial cell senescence, and the secretion of senescence-associated proteins and Shh mediates inflammatory responses and fibroblast activation and proliferation, ultimately leading to renal fibrosis

Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup

The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer

Rural Renewal of China in the Context of Rural-Urban Integration: Governance Fit and Performance Differences

In recent years, rural-urban integrated development has become a vital national strategy in China. In this context, many regions have implemented rural renewal projects to enhance the vitality and development of rural areas. The objective of this study is to reveal the reasons why different rural renewal modes have emerged in contemporary China and assess their ability to facilitate rural-urban integration. An analytical framework, the Institution of Sustainability (IoS) and a comparative analysis of two cases are used for the rural renewal evaluation. Our findings indicate that the properties of transactions and the characteristics of the actors involved jointly determine the governance structures of rural renewal. Furthermore, different governance structures contribute to performance differences, particularly differences in the physical outcomes, distribution effects and process efficiency. Finally, we suggest relevant policy recommendations

Land-Development Offset Policies in the Quest for Sustainability: What Can China Learn from Germany?

Land-development offset policies consist of measures that require compensation to be made for the negative impact of land development on agricultural production, ecological and environmental conservation, and the sustainability of economic and social development. However, when such policies are inappropriately designed, unexpected problems can result. This paper describes certain land-development offset policies that have recently been implemented in China, with a particular emphasis on three such policies: the Balancing Policy, the Linkage Policy, and the Integrated Policy. These well-intentioned environmental policies have led to unexpected ecological, social, and cultural problems. This paper also describes the core of German land-development policy, which features a distinctive compensation system that has been employed since the 1970s, and compares Chinese and German land-development policies to highlight differences in three main areas: policy purposes, governance structures, and fundamental institutions. The comparisons might help explain the unexpected outcomes in China, and they also lead to land-development offset policy recommendations for China in the near future

Liberalizing rural-to-urban construction land transfers in China : Distribution effects

China's land market is characterized by a dual urban-rural system, with the government in control of rural-urban land transfers. In recent years, different types of pilot projects have been implemented to experiment with liberalizing markets for rural-urban construction land transfers. The objective of this study is to gain insights into the distributional effects of three different types of land liberalization rules by making a comparative analysis of three pilot projects carried out under each of these liberalization rules. We find that transfers facing more liberalized rules result in higher shares of land revenue flowing to the rural sector and thereby reduce the ruralurban income gap. But direct transfers between rural and urban land users also contribute to growing income inequality within the rural sector, as households living in urban fringes benefit relatively more from such transfers. A tradable quota system can reduce the impact of location on the price of land, and thereby contribute to a more equal distribution of the revenues of rural-urban land transfers within the rural sector

Two Types of mafic rocks in southern Tibet: A mark of tectonic setting change from Neo-Tethyan oceanic crust subduction to Indian continental crust subduction

We collated existing data for the Eocene Langshan mafic rocks (Eocene mafic rocks) and the Miocene potassic c-ultrapotassic mafic rocks (Miocene mafic rocks) in southern Tibet to investigate the tectonic transition from Neo-Tethyan oceanic crust subduction to Indian continental crust subduction. The Eocene mafic rocks have high Na2O contents (K2O/Na2O = 0.03-0.2) and show OIB-like trace element patterns (e.g., positive Nb and Ta anomalies) and depleted radiogenic Sr-Nd isotope compositions (Sr-87/Sr-86 of apatite = 0.7031, epsilon Nd-(t) = +5.1 to +6.1). In contrast, the Miocene mafic rocks have high K2O contents (K2O/Na2O = 1.9-8.5) and exhibit arc like trace element patterns (enrichment in LILEs and depletion in HFSEs) and enriched radiogenic Sr-Nd isotope compositions (Sr-87/Sr-86 = 0.7115-0.7362, epsilon Nd-(t) = -16 to -12.4). The mantle source for the Eocene mafic rocks was generated by reactions between asthenospheric mantle wedge and felsic melts from subducted Neo-Tethyan oceanic crust (outside the field of rutile stability). In contrast, the mantle source of the Miocene mafic rocks was generated by reactions between asthenospheric (or lithospheric) mantle wedge and felsic melts from subducted Indian continental crust. Taking into account the regional tectonic evolution, we propose that break-off of the Neo-Tethyan oceanic slab and roll-back and/or break-off of the Indian continental slab were the most likely geodynamic mechanisms that led to the production of the Eocene and Miocene mafic rocks, respectively. Therefore, the transition from the Eocene to Miocene mafic rocks in southern Tibet provides an opportunity to understand the tectonic transition from Neo-Tethyan oceanic to Indian continental crust subduction

Petrogenesis of the ca. 80Ma felsic-intermediate magmatism in the Zhongdian arc terrane and western Yangtze block: Implications for post-collisional metallogenesis

The Relin Mo-Cu deposit and Tongchanggou Mo polymetallic deposit located in the Zhongdian arc which is the southern part of the Yidun arc of Sanjiang Tethys Region. Mineralization is closely associated with the Relin monzonitic granites and Tongchanggou granodiorite-porphyry, which were formed at 79. 0 +/- 1. 4Ma and 81. 3 +/- 1. 1Ma, respectively, according to LA-ICPMS zircon U-Pb dating. Geochemically, the Relin and Tongchanggou rocks have high SiO2 ( > 65%) and Al2O3 ( 13. 74% similar to 14. 91%) , low MgO (0. 86%similar to 1. 49% ) and Mg-#( 36. 3 similar to 47. 3) , and affinity of adakitic rocks given their high Sr (326 x 10(-6) similar to 1174 x 10(-6)) , Sr/Y (22 similar to 86) and La/Yb (30 similar to 70) ratios, and low Y (10. 2 x 10(-6) similar to 15. 6 x 10(-6)) and Yb (1. 00 x 10(-6) similar to 1. 51 x 10(-6)). These geochemical characters indicate that the Relin and Tongchanggou rocks were derived from partial melting of the thickened lower continental crust within garnet as residual minerals. Additionally, our zircon U-Pb dating reveals that the Dali granites in the western Yangtze block were formed at 76. 4 +/- 2. 3Ma, indicating that the Late Cretaceous magmatism are also developed in the western Yangtze block. We suggest that the western Yangtze block probably have the similar tectonic environment with the Zhongdian arc in the Late Cretaceous

Slab Breakoff of the Neo-Tethys Ocean in the Lhasa Terrane Inferred From Contemporaneous Melting of the Mantle and Crust

Oceanic slab breakoff significantly affects the thermal regime of the lithosphere during continental collision. This often triggers extension-related mafic magmatism and crustal melting. It is generally accepted that the Neo-Tethyan lithosphere subducted beneath the southern Lhasa Subterrane, resulting in the formation of the Gangdese magmatic arc. However, the timing of slab breakoff is still disputed, due to a lack of evidence for extension-related mafic magmatism. In this study, we provide comprehensive age, element and Sr-Nd-Hf isotopic data of mafic dikes, felsic intrusions, and enclaves from the Daju area, southern Lhasa Subterrane. The timing of mafic dikes and granitoids are contemporaneous at circa 57 Ma. The mafic dikes are characterized by high Th/U, and Zr/Y ratios, their geochemistry indicates an intraplate affinity rather than arc magmas. Furthermore, the mafic dikes show strongly variable igneous zircon (Hf)(t), and lower whole-rock (Nd)(t) than granitoids. This evidence suggests that the mafic dikes represent asthenosphere-derived melts contaminated by various degrees of ancient lithosphere. However, the granitoids were directly derived from the juvenile lower crust. Given the abrupt decrease in the convergence rate between India and Asia, and the surface uplift and sedimentation cessation in the southern Lhasa Subterrane in the early Cenozoic, the occurrence of synchronous mafic dikes and granitoids is best explained by a slab breakoff model. The occurrence of intraplate-type magmas likely corresponds to the magmatic expression of the initial stage of Neo-Tethyan slab breakoff. The slab breakoff concept also explains the onset of the magmatic flare-up and crustal growth after 57 Ma