ABSTRACT
Intestinal epithelial cells line the luminal surface to establish the intestinal barrier, where the cells play essential roles in the digestion of food, absorption of nutrients and water, protection from microbial infections, and maintaining symbiotic interactions with the commensal microbial populations. Maintaining and coordinating all these functions requires tight regulatory signaling, which is essential for intestinal homeostasis and organismal health. Dysfunction of intestinal epithelial cells, indeed, is linked to gastrointestinal disorders such as irritable bowel syndrome, inflammatory bowel disease, and gluten-related enteropathies. Emerging evidence suggests that peroxisome metabolic functions are crucial in maintaining intestinal epithelial cell functions and intestinal epithelium regeneration and, therefore, homeostasis. Here, we investigated the molecular mechanisms by which peroxisome metabolism impacts enteric health using the fruit fly Drosophila melanogaster and murine model organisms and clinical samples. We show that peroxisomes control cellular cholesterol, which in turn regulates the conserved yes-associated protein-signaling and contributes to intestinal epithelial structure and epithelial barrier function. Moreover, analysis of intestinal organoid cultures derived from biopsies of patients affected by Crohn's Disease revealed that the dysregulation of peroxisome number, excessive cellular cholesterol, and inhibition of Yap-signaling are markers of disease and could be novel diagnostic and/or therapeutic targets for treating Crohn's Disease. Our studies provided mechanistic insights on peroxisomal signaling in intestinal epithelial cell functions and identified cholesterol as a novel metabolic regulator of yes-associated protein-signaling in tissue homeostasis.
Subject(s)
Cholesterol , Crohn Disease , Drosophila melanogaster , Intestinal Mucosa , Peroxisomes , Signal Transduction , YAP-Signaling Proteins , Crohn Disease/metabolism , Crohn Disease/pathology , Animals , Humans , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Drosophila melanogaster/metabolism , Cholesterol/metabolism , Mice , Peroxisomes/metabolism , YAP-Signaling Proteins/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Epithelial Cells/metabolism , Epithelial Cells/pathology , Transcription Factors/metabolismABSTRACT
A highly efficient method for the direct construction of amide bonds via a selective cleavage of C-H and C[double bond, length as m-dash]C bonds in indole structures using an iodine-promoted approach was developed. Mechanistic studies indicated the formation of superoxide radicals obtained from molecular oxygen activation as a key intermediate step, which provided a precursor for subsequent oxidative ring-opening and intermolecular cyclization. A broad range of quinazolin-4(3H)-ones and tryptanthrins were synthesized in moderate to good yields under mild and environmentally benign conditions.
ABSTRACT
The healthy gut is achieved and maintained through a balanced relationship between the mucosal immune system, microbial communities resident in the lumen, and the intestinal epithelium. The intestinal epithelium plays an exceptionally important role in harmonizing the interaction between the host immunity and the luminal residents, as this selectively permeable barrier separates but also allows interchange between the 2 environments. Interleukin (IL)-10 has been well established to play an important role in maintaining gut homeostasis by imparting diverse effects on a variety of cell types in this relationship. In the intestine, the source and the target of IL-10 include leukocytes and epithelial cells. Given that both the epithelium and IL-10 are essential players in supporting homeostasis, we discuss the relationship between these 2 factors, focusing on epithelial sources of IL-10 and the effects of IL-10 on the intestinal epithelium. Insight into this relationship reveals an important aspect of the innate immune function of intestinal epithelial cells.
Subject(s)
Homeostasis , Interleukin-10/genetics , Interleukin-10/metabolism , Intestinal Mucosa/metabolism , Animals , Apoptosis , Biomarkers , Disease Management , Disease Susceptibility , Gene Expression Regulation , Humans , Immunomodulation , Inflammatory Bowel Diseases/etiology , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/pathology , Intestinal Mucosa/microbiology , Proteome , Receptors, Interleukin-10/genetics , Receptors, Interleukin-10/metabolism , Signal TransductionSubject(s)
Brain Neoplasms/complications , Brain Neoplasms/diagnosis , Diabetes Insipidus, Neurogenic/etiology , Germinoma/complications , Germinoma/diagnosis , Hypopituitarism/etiology , Adult , Diagnosis, Differential , Humans , Magnetic Resonance Imaging , Male , Pinealoma/diagnosis , Pinealoma/physiopathologyABSTRACT
BACKGROUND: A thyrotropin (TSH)-secreting pituitary adenoma coexisting with differentiated thyroid carcinoma is rare. There have been only four previously reported cases; three were treated with thyroidectomy followed by pituitary resection and one was treated with thyroidectomy alone. METHODS: We hereby report the fifth case, in which a patient presented with a TSH/growth-hormone-secreting pituitary macroadenoma coexisting with papillary thyroid carcinoma (PTC). RESULTS: She underwent biochemical testing, ophthalmologic examination, thyroid ultrasonography, Tc-99m-pertechnetate thyroid scan, whole-body positron emission tomography, (111)In-octreotide scan, thyroid fine-needle aspiration biopsy, octreotide treatment, total thyroidectomy, recombinant human TSH radioactive iodine remnant ablation, and continued treatment with octreotide and levothyroxine after thyroidectomy. She has remained asymptomatic for 24 months without biochemical or radiological evidence of pituitary hormone oversecretion, pituitary adenoma enlargement, and PTC recurrence. CONCLUSION: To our knowledge, this is the first case of a TSH/growth-hormone-secreting pituitary macroadenoma coexisting with PTC being successfully treated with octreotide and levothyroxine after thyroidectomy and recombinant human TSH-stimulated radioactive iodine remnant ablation.