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With the rapid development of the economy, China’s environmental problems remain prominent, and ecological environmental protection has far to go. Many factors work together to affect environmental pollution. In this study, based on the spatial correlation of environmental situation between adjacent regions, spatial autoregressive models are constructed to examine the impacts of foreign direct investment (FDI) on environmental pollution in China. We find an inverted U-shaped relationship between FDI and environmental situation. The study further investigates the mediating effect of economic scale, technology, and industrial structure between FDI and environmental situation. The results show that regions with a larger economic scale and better industrial structure experience a greater FDI impact on environmental situation, but technological level does not serve as a moderator in this study. Our findings have important implications for environmental pollution control and provide important insights for China into a new stage of high-quality development.

Background The cytoskeletal architecture of osteoclasts (OCs) and bone resorption activity must be appropriately controlled for proper bone remodeling, which is associated with osteoporosis. The RhoA protein of GTPase plays a regulatory role in cytoskeletal components and contributes to osteoclast adhesion, podosome positioning, and differentiation. Although osteoclast investigations have traditionally been performed by in vitro analysis, however, the results have been inconsistent, and the significance of RhoA in bone physiology and pathology is still unknown. Methods We generated RhoA knockout mice by specifically deleting RhoA in the osteoclast lineage to understand more about RhoA’s involvement in bone remodeling. The function of RhoA in osteoclast differentiation and bone resorption and the mechanisms were assessed using bone marrow macrophages (BMMs) in vitro. The ovariectomized (OVX) mouse model was adopted to examine the pathological effect of RhoA in bone loss. Results Conditional deletion of RhoA in the osteoclast lineage causes a severe osteopetrosis phenotype, which is attributable to a bone resorption suppression. Further mechanistic studies suggest that RhoA deficiency suppresses Akt-mTOR-NFATc1 signaling during osteoclast differentiation. Additionally, RhoA activation is consistently related to the significant enhancement the osteoclast activity, which culminates in the development of an osteoporotic bone phenotype. Furthermore, in mice, the absence of RhoA in osteoclast precursors prevented occurring OVX-induced bone loss. Conclusion RhoA promoted osteoclast development via the Akt-mTOR-NFATc1 signaling pathway, resulting a osteoporosis phenotype, and that manipulating RhoA activity might be a therapeutic strategy for osteoporotic bone loss.

The proliferation of glomerular mesangial cells is a fundamental pathological change in immunoglobulin A nephropathy (IgAN). This study aims to elucidate the mechanisms that affect the proliferation of glomerular mesangial cells. Bioinformatics analysis combined with clinical detection identified the key molecule glycine decarboxylase (GLDC). In vitro experiments revealed that GLDC knockdown reduces the proliferative effect of pIgA on mesangial cells. Pyrimidine metabolism is involved in the proliferation regulation of mesangial cells by GLDC. Additionally, GLDC’s regulation of glycolysis in mesangial cells was discovered, which further affects the progression of renal fibrosis and the proliferation of glomerular mesangial cells. Upon knockdown of the key rate-limiting enzymes of pyrimidine metabolism, CAD and DHODH, the overexpression of GLDC lost its regulatory effect on glycolysis. The regulatory mechanisms described above were confirmed by inhibiting GLDC expression in the kidneys in vivo. In conclusion, GLDC upregulates pyrimidine metabolic flux, which subsequently fuels glycolysis to promote mesangial cell proliferation, promoting IgAN progression. Synopsis This study reveals that glycine decarboxylase (GLDC) promotes IgA nephropathy (IgAN) progression by enhancing mesangial cell proliferation through the pyrimidine pathway. GLDC’s inhibition of pyrimidine metabolism and glycolysis could offer a new therapeutic approach for IgAN. GLDC expression was significantly elevated in IgAN glomeruli correlating with disease severity. Knockdown of GLDC reduced mesangial cell proliferation and inhibited pyrimidine metabolism. GLDC regulated glycolysis, influencing the progression of renal fibrosis in IgAN. In vivo silencing of GLDC alleviated IgAN progression by reducing glomerular damage and inflammation. Targeting GLDC or its metabolic pathways may provide a novel therapeutic strategy for IgAN. This study reveals that glycine decarboxylase (GLDC) promotes IgA nephropathy (IgAN) progression by enhancing mesangial cell proliferation through the pyrimidine pathway. GLDC’s inhibition of pyrimidine metabolism and glycolysis could offer a new therapeutic approach for IgAN.

Coronary artery calcification (CAC) is common in dialysis patients and is associated with a higher risk of future cardiovascular events. Sodium thiosulfate (STS) is effective for calciphylaxis in dialysis patients; however, the influence of STS on CAC in dialysis patients remains unclear. This systematic review and meta-analysis were conducted to evaluate the effects of STS on CAC in patients undergoing dialysis. PubMed, Embase, Cochrane Library, CNKI, and Wanfang databases were searched from inception to 22 March 2023 for controlled studies comparing the influence of STS versus usual care without STS on CAC scores in dialysis patients. A random effects model incorporating the potential influence of heterogeneity was used to pool the results. Nine studies, including two non-randomized studies and seven randomized controlled trials, were included in the meta-analysis. Among these, 365 patients on dialysis were included in the study. Compared with usual care without STS, intravenous STS for 3-6 months was associated with significantly reduced CAC scores (mean difference [MD] = -180.17, 95% confidence interval [CI]: -276.64 to -83.70,  < 0.001, I = 0%). Sensitivity analysis limited to studies of patients on hemodialysis showed similar results (MD: -167.33, 95% CI: -266.57 to -68.09,  = 0.001; I = 0%). Subgroup analyses according to study design, sample size, mean age, sex, dialysis vintage of the patients, and treatment duration of STS also showed consistent results (p for subgroup differences all > 0.05). In conclusion, intravenous STS may be effective in attenuating CAC in dialysis patients.

Aberrant activation of sonic hedgehog (SHH) signaling and its effector transcriptional factor GLI1 are essential for oncogenesis of SHH-dependent medulloblastoma (MB SHH ) and basal cell carcinoma (BCC). Here, we show that SHH inactivates p38α (MAPK14) in a smoothened-dependent manner, conversely, p38α directly phosphorylates GLI1 on Ser937/Ser941 (human/mouse) to induce GLI1’s proteasomal degradation and negates the transcription of SHH signaling. As a result, Gli1 S941E loss-of-function knock-in significantly reduces the incidence and severity of smoothened-M2 transgene-induced spontaneous MB SHH , whereas Gli1 S941A gain-of-function knock-in phenocopies Gli1 transgene in causing BCC-like proliferation in skin. Correspondingly, phospho-Ser937-GLI1, a destabilized form of GLI1, positively correlates to the overall survival rate of children with MB SHH . Together, these findings indicate that SHH-induced p38α inactivation and subsequent GLI1 dephosphorylation and stabilization in controlling SHH signaling and may provide avenues for future interventions of MB SHH and BCC. Upregulation of GLI1 of has previously been reported in sonic hedgehog (SHH) driven medulloblastoma and basal cell carcinoma (BCC). Here, the authors find that SHH-inactivation of p38 results in stabilization of the transcription factor GLI1 via dephosphorylation at Ser937, resulting in expression of SHH genes and presenting a potential therapy strategy for medulloblastoma and BCC.

Allergic asthma is characterized by goblet cell metaplasia and subsequent mucus hypersecretion that contribute to the morbidity and mortality of this disease. Here, we explore the potential role and underlying mechanism of protein SUMOylation-mediated goblet cell metaplasia. The components of SUMOylaion machinery are specifically expressed in healthy human bronchial epithelia and robustly upregulated in bronchial epithelia of patients or mouse models with allergic asthma. Intratracheal suppression of SUMOylation by 2-D08 robustly attenuates not only allergen-induced airway inflammation, goblet cell metaplasia, and hyperreactivity, but IL-13-induced goblet cell metaplasia. Phosphoproteomics and biochemical analyses reveal SUMOylation on K1007 activates ROCK2, a master regulator of goblet cell metaplasia, by facilitating its binding to and activation by RhoA, and an E3 ligase PIAS1 is responsible for SUMOylation on K1007. As a result, knockdown of PIAS1 in bronchial epithelia inactivates ROCK2 to attenuate IL-13-induced goblet cell metaplasia, and bronchial epithelial knock-in of ROCK2(K1007R) consistently inactivates ROCK2 to alleviate not only allergen-induced airway inflammation, goblet cell metaplasia, and hyperreactivity, but IL-13-induced goblet cell metaplasia. Together, SUMOylation-mediated ROCK2 activation is an integral component of Rho/ROCK signaling in regulating the pathological conditions of asthma and thus SUMOylation is an additional target for the therapeutic intervention of this disease. Allergic asthma is characterized by goblet cell metaplasia. Here, the authors show protein SUMOylation contributes to goblet cell metaplasia and SUMOylation-mediated ROCK2 activation is an integral component of Rho/ROCK signalling pathway in controlling the airway goblet cell metaplasia.

Large tumour suppressor (LATS) 1/2, the core kinases of Hippo signalling, are critical for maintaining tissue homeostasis. Here, we investigate the role of SUMOylation in the regulation of LATS activation. High cell density induces the expression of components of the SUMOylation machinery and enhances the SUMOylation and activation of Lats1 but not Lats2, whereas genetic deletion of the SUMOylation E2 ligase, Ubc9 , abolishes this Lats1 activation. Moreover, SUMOylation occurs at the K830 (mouse K829) residue to activate LATS1 and depends on the PIAS1/2 E3 ligase. Whereas the K830 deSUMOylation mutation of LATS1 found in the human metastatic prostate cancers eliminates the kinase activity by attenuating the formation of the phospho-MOB1/phospho-LATS1 complex. As a result, the LATS1(K830R) transgene phenocopies Yap transgene to cause the oversized livers in mice, whereas Lats1(K829R) knock-in phenocopies the deletion of Lats1 in causing the reproductive and endocrine defects and ovary tumours in mice. Thus, SUMOylation-mediated LATS1 activation is an integral component of Hippo signalling in the regulation of tissues homeostasis.

Endochondral ossification consists of successive steps of chondrocyte differentiation, including mesenchymal condensation, differentiation of chondrocytes, and hypertrophy followed by mineralization and ossification. Loss-of-function studies have revealed that abnormal growth plate cartilage of the Cdc42 mutant contributes to the defects in endochondral bone formation. Here, we have investigated the roles of Cdc42 in osteogenesis and signaling cascades governing Cdc42-mediated chondrogenic differentiation. Though deletion of Cdc42 in limb mesenchymal progenitors led to severe defects in endochondral ossification, either ablation of Cdc42 in limb preosteoblasts or knockdown of Cdc42 in vitro had no obvious effects on bone formation and osteoblast differentiation. However, in Cdc42 mutant limb buds, loss of Cdc42 in mesenchymal progenitors led to marked inactivation of p38 and Smad1/5, and in micromass cultures, Cdc42 lay on the upstream of p38 to activate Smad1/5 in bone morphogenetic protein-2-induced mesenchymal condensation. Finally, Cdc42 also lay on the upstream of protein kinase B to transactivate Sox9 and subsequently induced the expression of chondrocyte differential marker in transforming growth factor-β1-induced chondrogenesis. Taken together, by using biochemical and genetic approaches, we have demonstrated that Cdc42 is involved not in osteogenesis but in chondrogenesis in which the BMP2/Cdc42/Pak/p38/Smad signaling module promotes mesenchymal condensation and the TGF-β/Cdc42/Pak/Akt/Sox9 signaling module facilitates chondrogenic differentiation.

Background Vascular endothelial growth factor D (VEGFD), a member of the VEGF family, is implicated in angiogenesis and lymphangiogenesis, and is deemed to be expressed at a low level in cancers. S-nitrosylation, a NO (nitric oxide)-mediated post-translational modification has a critical role in angiogenesis. Here, we attempt to dissect the role and underlying mechanism of S-nitrosylation-mediated VEGFD suppression in lung adenocarcinoma (LUAD). Methods Messenger RNA and protein expression of VEGFD in LUAD were analyzed by TCGA and CPTAC database, respectively, and Assistant for Clinical Bioinformatics was performed for complex analysis. Mouse models with urethane (Ure)–induced LUAD or LUAD xenograft were established to investigate the role of S-nitrosylation in VEGFD expression and of VEGFD mutants in the oncogenesis of LUAD. Molecular, cellular, and biochemical approaches were applied to explore the underlying mechanism of S-nitrosylation-mediated VEGFD suppression. Tube formation and wound healing assays were used to examine the role of VEGFD on the angiogenesis and migration of LUAD cells, and the molecular modeling was applied to predict the protein stability of VEGFD mutant. Results VEGFD mRNA and protein levels were decreased to a different extent in multiple primary malignancies, especially in LUAD. Low VEGFD protein expression was closely related to the oncogenesis of LUAD and resultant from excessive NO-induced VEGFD S-nitrosylation at Cys277. Moreover, inhibition of S-nitrosoglutathione reductase consistently decreased the VEGFD denitrosylation at Cys277 and consequently promoted angiogenesis of LUAD. Finally, the VEGFD C277S mutant decreased the secretion of mature VEGFD by attenuating the PC7-dependent proteolysis and VEGFD C277S mutant thus reversed the effect of VEGFD on angiogenesis of LUAD. Conclusion Low-expression of VEGFD positively correlates with LUAD development. Aberrant S-nitrosylation of VEGFD negates itself to induce the tumorigenesis of LUAD, whereas normal S-nitrosylation of VEGFD is indispensable for its secretion and repression of angiogenesis of LUAD.