Disruption of the Hedgehog signaling pathway in inflammatory bowel disease fosters chronic intestinal inflammation

Buongusto, Fernanda; Bernardazzi, Cláudio; Yoshimoto, Agnes N.; Nanini, Hayandra F.; Coutinho, Raquel; Carneiro, Antonio José V.; Castelo-Branco, Morgana T.; Souza, Heitor Siffert Pereira de

doi:10.1007/s10238-016-0434-1

Cited by 12 publications

(10 citation statements)

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“…When body tissues or cells are invaded by infectious or neoplastic factors, the inflammatory response and immune regulation of the body are activated by external stimulation and environmental stresses. The development-related Hedgehog signaling pathway is involved in the regulation of immune and inflammatory responses [35][36][37]. In the current study, LPS/D-GalN-induced liver tissues showed increased activity of the Hedgehog signaling pathway, increased expression of Ptch, Smo, and Gli genes and proteins, increased inflammation in the liver, and aggravated liver injury.…”

Section: Discussionsupporting

confidence: 48%

RETRACTED ARTICLE: Sedum sarmentosum Bunge extract ameliorates lipopolysaccharide- and D-galactosamine-induced acute liver injury by attenuating the hedgehog signaling pathway via regulation of miR-124 expression

Hao

Liu

et al. 2020

BMC Complement Med Ther

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Background: Sedum sarmentosum is traditionally used to treat various inflammatory diseases in China. It has protective effects against acute liver injury, but the exact mechanism of such effects remains unclear. This study investigated the protective effects of S. sarmentosum extract on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)induced acute liver injury in mice and the mechanism of such effects.Methods: Mice were randomly divided into control, treatment, model, and model treatment groups. Acute liver injury was induced in model mice via intraperitoneal injection of LPS and D-GalN with doses of 10 μg/kg of LPS and 500 mg/kg, respectively. The mRNA expression levels of miR-124, Hedgehog, Patched (Ptch), Smoothened (Smo), and glioma-associated oncogene homolog (Gli) in liver tissues were determined through RT-PCR, and the protein levels of Hedgehog, Ptch, Smo, Gli, P13k, Akt, HMGB1, TLR4, IkB-α, p-IkB-α, and NF-kB65 were evaluated via Western blot analysis. The serum levels of IL-6, TNF-α, CRP, IL-12, and ICAM-1 were determined via ELISA. TLR4 and NF-κBp65 activity and the levels of DNA-bound NF-KB65 and TLR4 in LPS/D-GalN-induced liver tissues were also determined. We recorded the time of death, plotted the survival curve, and calculated the liver index. We then observed the pathological changes in liver tissue and detected the levels of liver enzymes (alanine aminotransferase [ALT] and aspartate transaminase [AST]) in the serum and myeloperoxidase (MPO) and plasma inflammatory factors in the liver homogenate. Afterward, we evaluated the protective effects of S. sarmentosum extracts on acute liver injury in mice.Results: Results showed that after S. sarmentosum extract was administered, the expression level of miR-124 increased in liver tissues. However, the protein expression levels of Hedgehog, Ptch, Smo, Gli, P13k, p-Akt, HMGB1, TLR4, p-IκB-α, and NF-κB65 and the mRNA expression levels of Hedgehog, Ptch, Smo, and Gli decreased. The MPO level in the liver, the IL-6, TNF-α, CRP, IL-12, and MMP-9 levels in the plasma, and the serum ALT and AST levels also decreased, thereby reducing LPS/D-GalN-induced liver injury and improving the survival rate of liver-damaged animals within 24 h.Conclusions: S. sarmentosum extract can alleviate LPS/D-GalN-induced acute liver injury in mice and improve the survival rate of mice. The mechanism may be related to the increase in miR-124 expression, decrease in Hedgehog and HMGB1 signaling pathway activities, and reduction in inflammatory responses in the liver. Hedgehog is a regulatory target for miR-124.

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Section: Discussionsupporting

confidence: 48%

RETRACTED ARTICLE: Sedum sarmentosum Bunge extract ameliorates lipopolysaccharide- and D-galactosamine-induced acute liver injury by attenuating the hedgehog signaling pathway via regulation of miR-124 expression

Hao

Liu

et al. 2020

BMC Complement Med Ther

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“…As for HH/GLI signaling, recent studies have linked HH/GLI pathway activation with concomitant anti-inflammatory signals [45, 46] and revealed a significant downregulation of the pathway in a set of chronic inflammatory diseases such as inflammatory bowel disease [47], colitis [48, 49] and Helicobacter pylori associated gastric inflammation [21, 50]. Notably, there is also increasing evidence, showing that oncogenic HH/GLI signaling regulates immunosuppressive mechanisms such as enhanced regulatory T-cell (Treg) formation and production of immunosuppressive cytokines, which can open new avenues for combination treatments and immunotherapy [49, 51–56].…”

Section: Introductionmentioning

confidence: 99%

Hedgehog/GLI signaling in tumor immunity - new therapeutic opportunities and clinical implications

2019

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Uncontrolled activation of the Hedgehog/Glioma-associated oncogene (HH/GLI) pathway is a potent oncogenic driver signal promoting numerous cancer hallmarks such as proliferation, survival, angiogenesis, metastasis and metabolic rewiring. Several HH pathway inhibitors have already been approved for medical therapy of advanced and metastatic basal cell carcinoma and acute myeloid leukemia with partially impressive therapeutic activity. However, de novo and acquired resistance as well as severe side effects and unexplained lack of therapeutic efficacy are major challenges that urgently call for improved treatment options with more durable responses. The recent breakthroughs in cancer immunotherapy have changed our current understanding of targeted therapy and opened up promising therapeutic opportunities including combinations of selective cancer pathway and immune checkpoint inhibitors. Although HH/GLI signaling has been intensely studied with respect to the classical hallmarks of cancer, its role in the modulation of the anti-tumoral immune response has only become evident in recent studies. These have uncovered HH/GLI regulated immunosuppressive mechanisms such as enhanced regulatory T-cell formation and production of immunosuppressive cytokines. In light of these exciting novel data on oncogenic HH/GLI signaling in immune cross-talk and modulation, we summarize and connect in this review the existing knowledge from different HH-related cancers and chronic inflammatory diseases. This is to provide a basis for the investigation and evaluation of novel treatments combining immunotherapeutic strategies with approved as well as next-generation HH/GLI inhibitors. Further, we also critically discuss recent studies demonstrating a possible negative impact of current HH/GLI pathway inhibitors on the anti-tumoral immune response, which may explain some of the disappointing results of several oncological trials with anti-HH drugs.

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“…Associated mechanisms included downregulating inflammatory cytokines, and repressing monocyte chemo-attraction and fibroblast proliferation. Hh blockade increased the abundance of TNF-α, IL-17, and TGF-β [23]. However, Hh signaling was found to promote the induction and progression of inflammation and neoplastic transformation in infection with the pathogen Helicobacter pylori [24].…”

Section: Foxp3mentioning

confidence: 99%

Gli2 Mediated Activation of Hedgehog Signaling Attenuates Acute Pancreatitis via Balancing Inflammatory Cytokines in Mice

Liu

Lai

Xie

et al. 2018

Cell Physiol Biochem

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Background/Aims: Inflammatory response is a determinant in the pathological progression of acute pancreatitis (AP). Previous studies have shown that the activation of hedgehog (Hh) signaling is a remarkable change in caerulein-induced AP. However, the relationship between Hh signaling and inflammation is largely ambiguous. Methods: The AP mouse model was induced by injection of cerulein, and histological staining and serum enzymology assays were used to evaluate the establishment of AP. Western blot assay was used to determine the protein levels, cleavage of apoptotic proteins, and activation of the NF-κB signaling pathway. Cytokine array was used to screen inflammatory cytokines, and target cytokines’ transcriptional expression and serum levels were examined by real-time PCR and enzyme-linked immunosorbent assay, respectively. Results: The key transcriptional factor in Hh signaling, Gli2, was upregulated in the pancreas and other tissues during the process of AP, and it seems to be a characteristic feature of local inflammation in pancreatic tissue and systemic inflammatory response in multiple organs. The inflammatory NF-κB pathway is required for the activation of Hh signaling, as blockade of the NF-κB pathway by pyrrolidine dithiocarbamate impaired the Gli2 upregulation. Manipulation of Gli2 expression altered the activation of the NF-κB pathway correspondingly, as well as the cell apoptosis in cerulein-induced AP. Moreover, Gli2 upregulation changed the cytokine expression profile in mouse pancreatic acinar cells, mainly decreasing the pro-inflammatory cytokines interleukin (IL)-6, interferon-γ, and FasL. The anti-inflammatory cytokine IL-10 was upregulated by Gli2 overexpression. Interdiction of Gli2 by the Gli-specific inhibitor GANT61 exacerbated AP in mice and altered the balance of inflammatory cytokines. Conclusions: This study indicates that Hh activation during AP development is a negative feedback of the inflammatory response, restricting inflammatory injury to the pancreas and other tissues. Thus, manipulation of Hh signaling should shed light on limiting inflammation and alleviating AP damage.

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Disruption of the Hedgehog signaling pathway in inflammatory bowel disease fosters chronic intestinal inflammation

Cited by 12 publications

References 79 publications

RETRACTED ARTICLE: Sedum sarmentosum Bunge extract ameliorates lipopolysaccharide- and D-galactosamine-induced acute liver injury by attenuating the hedgehog signaling pathway via regulation of miR-124 expression

RETRACTED ARTICLE: Sedum sarmentosum Bunge extract ameliorates lipopolysaccharide- and D-galactosamine-induced acute liver injury by attenuating the hedgehog signaling pathway via regulation of miR-124 expression

Hedgehog/GLI signaling in tumor immunity - new therapeutic opportunities and clinical implications

Gli2 Mediated Activation of Hedgehog Signaling Attenuates Acute Pancreatitis via Balancing Inflammatory Cytokines in Mice

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