gdc-0449 and Inflammation

Asthmatics exhibit clinical fluctuations between manageable and treatment-resistant phenotypes as a worldwide socioeconomic health burden. Sonic Hedgehog (Shh) genes mediate regulatory pulmonary cell renewal in adults and contribute to the pathogenesis of high phenotypic asthma which depends mainly on T helper-2 (Th-2) cells and related cytokines. However, the exact pathophysiological roles of Shh molecular signalling in the Th-17-dependent low phenotypic allergic airway inflammation and asthma are not evidenced previously.. Ovalbumin (OVA) and OVA/lipopolysaccharide (LPS)-sensitized and challenged BALB/c mice were enrolled currently to assess the Shh signalling proteins. Furthermore, the effects of vismodegib, a Smo inhibitor, on the modulation of Shh signalling were compared to dexamethasone. The asthma phenotypes were confirmed by serum total immunoglobulin-E (IgE), bronchoalveolar lavage (BAL) fluid white blood cell counts, lung interleukins, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1, and histopathological changes, and scoring.. Mice challenged with OVA or OVA/LPS showed upregulated lung Shh, patched (Ptch1), smoothened (Smo), and Gli1 proteins. Vismodegib in the two experimental phenotypes of asthma showed reduced airway inflammation and remodelling. Additionally, vismodegib reduced the eosinophilia and neutrophilia reported in high and low asthma types, respectively. Moreover, vismodegib and dexamethasone exhibited negative feedback control throughout the enhanced Shh signalling cascades, including Shh, Ptch1, and Gli1 in several asthma models.. In conclusion, Shh signalling partially elucidates the OVA/LPS-challenged mice with severe asthma, which proposes a new promising molecular therapeutic target. Furthermore, Smo inhibition by vismodegib has therapeutic potential in both experimental eosinophilic and neutrophilic allergic airway diseases.

Topics: Anilides; Animals; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Dexamethasone; Disease Models, Animal; Hedgehog Proteins; Inflammation; Lipopolysaccharides; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Pyridines; Zinc Finger Protein GLI1

Histone demethylase JMJD2D can promote gene expression by specifically demethylating H3K9me2/3. The role of JMJD2D in colitis and colitis-associated colorectal cancer (CRC) progression remains unclear. Here, we show that colonic JMJD2D is induced by TNFα during dextran sulfate sodium-induced colitis. JMJD2D-deficient mice exhibit more severe colon damage and defective colon regeneration due to impaired Hedgehog signaling activation after colitis. JMJD2D knockdown in CRC cells suppresses Hedgehog signaling, resulting in reduced CRC growth and metastasis. Mechanistically, JMJD2D promotes Hedgehog target gene expression through interacting with Gli2 to reduce H3K9me3 levels at the promoter. Clinically, JMJD2D expression is upregulated and positively correlated with Gli2 expression in human inflammatory bowel disease specimens and CRC specimens. The JMJD2D inhibitor 5-c-8HQ or aspirin synergizes with Hedgehog inhibitor vismodegib to inhibit CRC cell proliferation and tumorigenesis. Collectively, our findings unveil an essential role of JMJD2D in activating the processes of colonic protection, regeneration, and tumorigenesis.

Topics: Anilides; Animals; Aspirin; Carcinogenesis; Cell Proliferation; Colitis; Colorectal Neoplasms; Disease Models, Animal; Drug Synergism; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Hedgehog Proteins; Humans; Inflammation; Jumonji Domain-Containing Histone Demethylases; Mice; Pyridines; Signal Transduction

Hedgehog (Hh) signaling plays a critical role in liver development, regeneration, injury repair, and carcinogenesis. Activation of Hh signaling has been observed in patients with nonalcoholic fatty liver diseases (NAFLD); however, the pathobiological function and regulatory mechanism of hepatic Hh signaling in the pathogenesis of NAFLD remain to be further defined. This study was designed to examine the effect and mechanism of hepatic Hh signaling in high-fat diet-induced NAFLD by using pharmacological Smoothened (Smo) inhibitors (GDC-0449 and LED225) and liver-specific Smo knockout mice. Administration of Smo inhibitors to high-fat diet-fed wild-type mice significantly reduced the numbers of activated macrophages and decreased the expression of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, monocyte chemoattractant protein 1, and interleukin-6) as assessed by F4/80 immunohistochemistry and quantitative reverse-transcription polymerase chain reaction, respectively. The Smo inhibitors were noted to have variable effects on hepatic fat accumulation. Liver-specific deletion of Smo also reduced macrophage activation and inhibited proinflammatory cytokine expression, while it did not significantly alter fat accumulation in the liver. Mechanistically, we found that activation of glioma-associated oncogene 1 by Hh signaling in primary hepatocytes increased the production of osteopontin, which subsequently enhanced the macrophage-mediated proinflammatory response through paracrine signaling.. Hepatocyte Hh signaling can promote liver inflammation through osteopontin-mediated macrophage activation; this mechanism importantly contributes to the progression of NAFLD.

Topics: Anilides; Animals; Biopsy, Needle; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Hedgehog Proteins; Immunohistochemistry; Inflammation; Macrophages; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Pyridines; Random Allocation; Sensitivity and Specificity; Signal Transduction

The hedgehog (Hh) signalling pathway regulates normal development and cell proliferation in metazoan organisms, but its aberrant activation can promote tumorigenesis and progression of a variety of aggressive human cancers including skin cancer. Despite its importance, little is known about its role in photoageing, a type of UV-induced skin lesions. In this study, we investigated the involvement of Hh signalling in the photoageing process as well as the use of an Hh-regulating alkaloid compound as a novel therapeutic drug to regulate photoageing in keratinocytes. We found that UVB induced Hh signalling by the expression of Hh ligands and Hh-mediated transcription factors, respectively. Moreover, UVB-induced Hh activation relied on mitogen-activated protein kinase (p38, ERK and JNK) activity and inflammatory responses (upregulation of COX-2, IL-1β, IL-6 and TNF-α), resulting in premature senescence and photoageing in vitro and in vivo. Notably, a selected Hh inhibitor, evodiamine, mediated photoageing blockade in a mouse skin model. Taken together, our findings demonstrated that Hh signalling is associated with UVB-induced photoageing, while pharmacological inhibition of Hh signalling significantly reduced experimental photoageing, indicating its potential for use as a therapeutic target for this disease.

Topics: Aging; Anilides; Animals; Cell Line; Cyclooxygenase 2; Cytokines; Drug Evaluation, Preclinical; Flavonoids; Gene Expression Regulation; Hedgehog Proteins; Humans; Inflammation; MAP Kinase Signaling System; Mice; Pyridines; Quinazolines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Skin Aging; Tissue Inhibitor of Metalloproteinase-1; Ultraviolet Rays