BMC BIOLOGY
·
2025
·Vol. 23
·期 1
·1-23
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IF 4.5
Chen Jiangping,Ren Chengyan,Mao Chuanqing,Lai Yongzhen,Lu Meng,Jiang Yuanjing,Chen Weihui
Background The cranial base develops from multipotent mesenchymal cells through endochondral ossification. Genetic ablation of Sonic hedgehog (Shh) or Smoothened (Smo) leads to early apoptosis of cranial base cells, thus limiting the study of their role in the early development of cranial base. Our previous studies have shown that administration of 150 mg/kg Vismodegib (a Smo-specific small molecule antagonist) in E9.5- or E10.5-mice leads to premature mineralization of the skull base synchondroses. In the current study, we further investigated the molecular mechanisms underlying this model.Results Mice exposed to Vismodegib exhibit premature hypertrophic differentiation and osteogenesis of the cranial base synchondroses after E14.5. However, the expression of Patched1 (Ptch1), Gli1, parathyroid hormone-related protein (PTHrP), and Phh3 was not downregulated in exposure mice. We demonstrate that Shh and Wnt signaling pathways were activated in the cranial base region at E10.5. Administration of Vismodegib at E10.5 transiently inhibited Shh signaling in the cranial base area and caused upregulation of β-catenin expression along with ectopic expression of lymphoid enhancer-binding factor 1 (Lef1) and Runx2 in the ventral mesenchymal cells of the cranial base primordium at E12.5. Diverse degrees of cranial base craniosynostosis induced by various doses of Vismodegib suggest a dose-dependent effect of Shh in early basicranium development.Conclusion sThe present experiment suggests that early activation of Shh standardizes normal embryonic development of cranial base after initial morphogenesis, which may be mediated through the “antagonistic” effect of Shh signaling on Wnt signaling. Our study provides new insights into the role of signal-crosstalk in early morphogenesis of the cranial base.
研究领域:
发育生物学
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分子生物学
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遗传学
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细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2025
·
IF 5.4
Lili Lu,Yuchen Ma,Qing Tao,Jing Xie,Xiao Liu,Yongkang Wu,Yang Zhang,Xiuli Xie,Mingming Liu,Yong Jin
Liver fibrosis is a passive and irreversible wound healing process caused by chronic liver injury. Research has shown that the upregulation of hypoxia inducible factor-1 alpha (HIF-1α) is closely related to the occurrence and development of liver fibrosis and HIF-1 α may be a promising target for the treatment of liver fibrosis. AMSP-30 m is a newly developed novel HIF-1α inhibitor by our group, which has strong anti-tumor and anti-inflammatory effects. In this study, we described the therapeutic effect and specific mechanism of AMSP-30 m on carbon tetrachloride (CCl 4 ) induced liver fibrosis in mice. Liver fibrosis induced by CCl 4 in mice and liver fibrosis induced by cobalt dichloride (CoCl 2 ) in LX-2 cells (human hepatic stellate cell (HSC) line) were studied. Hematoxylin & eosin (H&E)and Masson's trichrome staining were used to observe pathological conditions. Western Blot, immunofluorescence and immunohistochemistry were used to detect protein expression and localization in cells, and quantitative real-time PCR analysis (qRT-PCR) was used to detect mRNA expression. Biochemical detection kits were used to detect alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. The results demonstrated that AMSP-30 m significantly alleviated pathological symptoms, reduced ALT and AST levels, and inhibited the expression of alpha-smooth muscle actin (α-SMA) and collagen type I (COL1α1) in CCl 4 -induced liver fibrosis in mice. AMSP-30 m could significantly reduce the expression of HIF-1α and sonic hedgehog (Shh) pathway related proteins (Smoothened (Smo), Shh, and glioma-associated oncogene-1 (Gli-1)) in CCl 4 induced liver fibrosis mice. AMSP-30 m also played a similar role in the CoCl 2 -induced anoxic liver fibrosis model of LX-2 cells . Further experiments showed that Cyclopamine (a Shh inhibitor) could significantly inhibit the increase of α-SMA and COL1α1 resulting from HIF-1α but not significantly inhibit HIF-1α induced by CoCl 2 in LX-2 cells. And the combination of Cyclopamine and AMSP-30 m further reduced the expression of α-SMA and COL1α1 induced by HIF-1α. In summary, this study demonstrates that the HIF-1α inhibitor AMSP-30 m exerts a robust anti-fibrotic effect by inhibiting the Shh pathway, which is identified as a critical underlying mechanism. These findings suggest a promising therapeutic strategy for the treatment of liver fibrosis.
研究领域:
分子生物学
·
药理学
·
肝病学
·
细胞生物学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2023
·
IF 7.5
Zhenzhen Zhang,Lingling Yang,Ya Li,Di Sun,Rong Chen,Shengqian Dou,Ting Liu,Sai Zhang,Qingjun Zhou,Lixin Xie
Diabetic keratopathy (DK), the diabetic complication in the cornea, is characterized by the delayed epithelial regeneration and sensory nerve degeneration. The involvement of limbal stem/progenitor cells (LSPCs) dysfunction has been reported, however the pathogenic mechanisms remain unclear. Here, we confirmed the dysfunction of LSPCs in diabetic mouse and human corneas. The sympathetic nerve in the cornea was adjacent to LSPCs, and the sympathetic overactivation was found in diabetic mice. Surgical and pharmacological ablation of sympathetic nerves rescued the LSPCs function and promoted corneal epithelial regeneration in diabetic mice. In contrast, both topical norepinephrine (NE) application and chemogenetic sympathetic overactivation directly impaired the stemness and proliferation characteristics of LSPCs, as well as the normal epithelial regeneration. Moreover, we identified that β2-adrenoceptor ( Adrb2 ) was the predominant adrenergic receptor expressed in LSPCs by corneal limbal single-cell sequencing and real time PCR (RT-PCR) analysis of sorted LSPCs. The Adrb2 knockout mice exhibited the enhancement of epithelial regeneration and LSPCs function, compared with the wild-type mice. Similarly, topical application of the Adrb2 specific antagonist ICI 118, 551 effectively accelerated diabetic corneal epithelial regeneration with the restored LSPCs function. Mechanistically, sonic hedgehog (Shh) activity mediated the downstream effects of NE-Adrb2 signaling pathway in regulating LSPCs and epithelial regeneration. Taken together, our data revealed the involvement of sympathetic overactivation in the impairment of diabetic LSPCs function and corneal epithelial regeneration through the NE-Adrb2-Shh signaling pathway. The interference of sympathetic overactivation may provide novel treatment strategies for diabetic keratopathy.
研究领域:
眼科学
·
干细胞生物学
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糖尿病研究
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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