Thalidomide is a powerful treatment for inflammatory and cancer-based diseases. However, its clinical use remains limited due to its teratogenic properties, which primarily affect limb development. A prerequisite for overcoming these limitations is to understand the cellular and molecular mechanisms underlying thalidomide teratogenicity, which involve induction of oxidative stress, suppression of ubiquitin-mediated protein degradation and disruption of angiogenesis. Here, we discuss the hypothesis that thalidomide-induced limb teratogenicity is primarily based on the generation of nuclear oxidative stress with subsequent induction of transient apoptosis in the outgrowing limb bud. To this end, we establish a model of the signaling network regulating cell proliferation, survival and endogenous apoptosis-induction required for correct limb outgrowth and patterning. We then summarize data showing how thalidomide interferes with this signaling network: thalidomide inhibits the activity of the redox-sensitive transcription factor NF-κB, shifts the balance of fibroblast growth factors and bone morphogenetic proteins (Bmps) towards pro-apoptotic Bmps, and suppresses Wnt/β-catenin- and Akt-dependent survival signaling in the limb bud. Consequently, prechondrogenic precursor cells that determine skeletal elements are eliminated leading to the development of truncated limbs. We further discuss the involvement of thalidomide effects on ubiquitin-mediated protein degradation and angiogenesis in the induction of apoptosis in the limb bud. Finally, we discuss the paradox that the embryonic molecular pathology induced by thalidomide suggests this drug as a candidate for therapeutic application in idiopathic pulmonary fibrosis (IPF), a chronic and fatal lung disease characterized by downregulation of Bmp signaling, increased Wnt and Akt activity, and apoptosis resistance.
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http://dx.doi.org/10.2174/1874467211104010026 | DOI Listing |
Dev Biol
January 2025
Department of Biology, Faculty of Science, Kyushu University, Fukuoka, 819-0395, Japan.
Cell type-specific reporter transgenic chicken lines are invaluable tools in developmental biology, allowing the visualization of dynamics and differentiation states of target cell types in living embryos. Here, we report the establishment of a new transgenic chicken line in which limb mesenchyme and apical ectodermal ridge (AER) cells are labeled with different fluorescent proteins in the embryos. The processes for generating the reporter line involved using tissue-specific promoters, the Tol2 transposon-mediated genomic integration, and clonal culture system of primordial germ cells.
View Article and Find Full Text PDFDev Growth Differ
January 2025
Graduate School of Medical Sciences, Tottori University Yonago, Tottori, Japan.
5'Hox genes regulate pattern formation along the axes of the limb. Previously, we showed that Hoxa13/Hoxd13 double-mutant newts lacked all digits of the forelimbs during development and regeneration, showing that newt Hox13 is necessary for digit formation in development and regeneration. In addition, we found another unique phenotype.
View Article and Find Full Text PDFGene
February 2025
Zhejiang Provincial Key Laboratory of Germplasm Innovation and Utilization for Garden Plants, College of Landscape Architecture, Zhejiang Agriculture & Forestry University, Hangzhou 311300, Zhejiang, China. Electronic address:
The basic helix-loop-helix (bHLH) family, a prominent group of transcription factors, is involved in plant growth, development, and secondary metabolic processes. Petunia (Petunia hybrida), a beloved and widely cultivated garden flower, boasts a diverse array of varieties, some of which exude a captivating fragrance that has garnered immense popularity. The aromatic allure of petunias primarily stems from the presence of volatile benzenoids/phenylpropanoids, the principal floral scent compounds.
View Article and Find Full Text PDFDifferentiation
December 2024
University of California, Los Angeles, Department of Molecular, Cell and Developmental Biology, Los Angeles, CA, USA. Electronic address:
During the discovery of the Fibroblast Growth Factor superfamily, scientists were determined to uncover all the genes that encoded FGF proteins. In 1998, FGF16 was discovered with classical cloning techniques in human and rat heart samples. FGF16 loss- and gain-of-function experiments in several organisms demonstrated a conserved function in vertebrates, and as a component of the FGF9 subfamily of ligands (FGF-E/-9/-20), is functionally conserved and sufficient to rescue loss-of-function phenotypes in invertebrates, like C.
View Article and Find Full Text PDFInt J Surg Case Rep
January 2025
Department of Plastic Surgery, Omdurman Teaching Hospital, Khartoum, Sudan.
Introduction And Importance: Polymelia is a rare congenital deformity characterized by an extra limb connected to a different part of the body. The Incidence of this condition in humans is scant but relatively higher in animals. Hereditary and genetic factors are linked to the pathogenesis of this condition, but the relationship is not clearly understood.
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