The Oxysterol Synthesising Enzyme CH25H Contributes to the Development of Intestinal Fibrosis

Abstract Intestinal fibrosis and stenosis are common complications of Crohn’s disease [CD], frequently requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, anti-fibrotic therapies remain an unmet clinical need. Oxysterols are oxidised cholesterol derivatives with important roles in various biological processes. The enzyme cholesterol 25-hydroxylase [CH25H] converts cholesterol to 25-hydroxycholesterol [25-HC], which modulates immune responses and oxidative stress. In human intestinal samples from CD patients, we found a strong correlation of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced intestinal fibrosis in mice deficient for the CH25H enzyme, using the sodium dextran sulphate [DSS]-induced chronic colitis model. Additionally, using a heterotopic transplantation model of intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the pathogenesis of intestinal fibrosis.

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The oxysterol synthesizing enzyme CH25H contributes to the development of intestinal fibrosis

10.1101/424820 ◽

2018 ◽

Cited By ~ 1

Author(s):

T. Raselli ◽

A. Wyss ◽

M.N. Gonzalez Alvarado ◽

B. Weder ◽

C. Mamie ◽

...

Keyword(s):

Immune Responses ◽

Dextran Sulfate ◽

Biological Processes ◽

Intestinal Fibrosis ◽

Oxidized Cholesterol ◽

Sodium Dextran Sulfate ◽

Transplant Model ◽

And Oxidative Stress ◽

Colitis Model ◽

Transplantation Model

AbstractIntestinal fibrosis and stenosis are common complications of Crohn’s disease (CD), frequently requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, anti-fibrotic therapies remain an unmet clinical need. Oxysterols are oxidized cholesterol derivatives, with important roles in various biological processes. The enzyme cholesterol 25-hydroxylase (CH25H) converts cholesterol to 25-hydroxycholesterol (25-HC), which modulates immune responses and oxidative stress. In human intestinal samples from CD patients we found a strong correlation of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced intestinal fibrosis in mice deficient for the CH25H enzyme using the sodium dextran sulfate (DSS)-induced chronic colitis model. Additionally, using a heterotopic transplantation model of intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the pathogenesis of intestinal fibrosis.

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Ovarian Cancer G-Protein-Coupled Receptor 1 Deficiency Protects from Fibrogenesis in the Heterotopic Transplantation Model of Intestinal Fibrosis

Gastroenterology ◽

10.1016/s0016-5085(17)33372-3 ◽

2017 ◽

Vol 152 (5) ◽

pp. S995

Author(s):

Senta L. Hutter ◽

Pedro Ruiz ◽

Bruce Weder ◽

Jesus Cosin Roger ◽

Céline Mamie ◽

...

Keyword(s):

Ovarian Cancer ◽

G Protein ◽

Heterotopic Transplantation ◽

G Protein Coupled Receptor ◽

Intestinal Fibrosis ◽

G Protein Coupled ◽

Transplantation Model

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Tu1256 - Optimization of a Chronic Colitis Model in Mice Induced by Dextran Sulphate Sodium (DSS) and Effects of Drugs Thereon

Gastroenterology ◽

10.1016/s0016-5085(18)33082-8 ◽

2018 ◽

Vol 154 (6) ◽

pp. S-916-S-917

Author(s):

Harunor Rashid ◽

Rana Samadfam

Keyword(s):

Dextran Sulphate ◽

Chronic Colitis ◽

Dextran Sulphate Sodium ◽

Colitis Model

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Non-volume-loaded heart provides a more relevant heterotopic transplantation model

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0029-1247061 ◽

2010 ◽

Vol 58 (S 01) ◽

Author(s):

T Deuse ◽

M Kolk ◽

D Meyberg ◽

C Pahrmann ◽

H Reichenspurner ◽

...

Keyword(s):

Heterotopic Transplantation ◽

Transplantation Model

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Emerging Roles of Protein Deamidation in Innate Immune Signaling

Journal of Virology ◽

10.1128/jvi.01980-15 ◽

2016 ◽

Vol 90 (9) ◽

pp. 4262-4268 ◽

Cited By ~ 20

Author(s):

Jun Zhao ◽

Junhua Li ◽

Simin Xu ◽

Pinghui Feng

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Microbial Pathogens ◽

Biological Processes ◽

Innate Immune Responses ◽

Immune Signaling ◽

Host Immune Responses ◽

Innate Immune Signaling ◽

Enzyme Deficient ◽

Signaling Components

Protein deamidation has been considered a nonenzymatic process associated with protein functional decay or “aging.” Recent studies implicate protein deamidation in regulating signal transduction in fundamental biological processes, such as innate immune responses. Work investigating gammaherpesviruses and bacterial pathogens indicates that microbial pathogens deploy deamidases or enzyme-deficient homologues (pseudoenzymes) to induce deamidation of key signaling components and evade host immune responses. Here, we review studies on protein deamidation in innate immune signaling and present several imminent questions concerning the roles of protein deamidation in infection and immunity.

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The RhoA-ROCK pathway in the regulation of T and B cell responses

F1000Research ◽

10.12688/f1000research.7522.1 ◽

2016 ◽

Vol 5 ◽

pp. 2295 ◽

Cited By ~ 14

Author(s):

Edd Ricker ◽

Luvana Chowdhury ◽

Woelsung Yi ◽

Alessandra B. Pernis

Keyword(s):

Immune Responses ◽

Biological Processes ◽

Dynamic Interactions ◽

Cell Responses ◽

Important Mediator ◽

Downstream Effectors ◽

Wide Range ◽

Response To Stress ◽

The Impact ◽

Rho Kinases

Effective immune responses require the precise regulation of dynamic interactions between hematopoietic and non-hematopoietic cells. The Rho subfamily of GTPases, which includes RhoA, is rapidly activated downstream of a diverse array of biochemical and biomechanical signals, and is emerging as an important mediator of this cross-talk. Key downstream effectors of RhoA are the Rho kinases, or ROCKs. The ROCKs are two serine-threonine kinases that can act as global coordinators of a tissue’s response to stress and injury because of their ability to regulate a wide range of biological processes. Although the RhoA-ROCK pathway has been extensively investigated in the non-hematopoietic compartment, its role in the immune system is just now becoming appreciated. In this commentary, we provide a brief overview of recent findings that highlight the contribution of this pathway to lymphocyte development and activation, and the impact that dysregulation in the activation of RhoA and/or the ROCKs may exert on a growing list of autoimmune and lymphoproliferative disorders.

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Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

International Journal of Molecular Sciences ◽

10.3390/ijms21093100 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3100 ◽

Cited By ~ 1

Author(s):

Alia Ghoneum ◽

Ammar Yasser Abdulfattah ◽

Bailey Olivia Warren ◽

Junjun Shu ◽

Neveen Said

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Metabolic Pathways ◽

Redox Homeostasis ◽

Ros Production ◽

Biological Processes ◽

Survival Pathways ◽

Oncogenic Mutations ◽

And Oxidative Stress ◽

Shed Light

Reactive Oxygen Species or “ROS” encompass several molecules derived from oxygen that can oxidize other molecules and subsequently transition rapidly between species. The key roles of ROS in biological processes are cell signaling, biosynthetic processes, and host defense. In cancer cells, increased ROS production and oxidative stress are instigated by carcinogens, oncogenic mutations, and importantly, metabolic reprograming of the rapidly proliferating cancer cells. Increased ROS production activates myriad downstream survival pathways that further cancer progression and metastasis. In this review, we highlight the relation between ROS, the metabolic programing of cancer, and stromal and immune cells with emphasis on and the transcription machinery involved in redox homeostasis, metabolic programing and malignant phenotype. We also shed light on the therapeutic targeting of metabolic pathways generating ROS as we investigate: Orlistat, Biguandes, AICAR, 2 Deoxyglucose, CPI-613, and Etomoxir.

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