Possible Biomarkers in Blood for Crohn’s Disease: Oxidative Stress and MicroRNAs—Current Evidences and Further Aspects to Unravel

Crohn’s disease (CD) is an inflammatory disorder characterised by a transmural inflammation of the intestinal wall. Although the physiopathology of the disease is not yet fully understood, it is clear that the immune response plays an important role in it. This hyperreactive immune system is accompanied by the presence of unregulated reactive oxygen species (ROS). These elements are modulated in normal conditions by different elements, including enzymes that function as antioxidant defences preventing the harmful effects of ROS. However, in CD there is an imbalance between ROS production and these antioxidant elements, resulting in oxidative stress (OxS) phenomena. In fact, now OxS is being considered more a potential etiological factor for Crohn’s disease rather than a concomitant effect in the disease. The persistence of the OxS can also be influencing the evolution of the disease. Furthermore, the epigenetic mechanisms, above all microRNAs, are being considered key elements in the pathogenesis of CD. These elements and the presence of OxS have also been linked to several diseases. We, therefore, describe in this review the most significant findings related to oxidative stress and microRNAs profiles in the peripheral blood of CD patients.

Download Full-text

New Possibilities for the Treatment of Crohn’s Disease

Russian Journal of Gastroenterology Hepatology Coloproctology ◽

10.22416/1382-4376-2019-29-5-13-20 ◽

2019 ◽

Vol 29 (5) ◽

pp. 13-20

Author(s):

Z. A. Mamieva ◽

E. A. Poluektova ◽

O. S. Shifrin

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Clinical Remission ◽

Human Monoclonal Antibody ◽

Intestinal Wall ◽

Tnf Α ◽

Favourable Safety ◽

Favourable Safety Profile ◽

Transmural Inflammation ◽

Maintenance Of Remission

Aim. To review data on the efficiency and safety of using Ustekinumab in patients with Crohn’s disease.Key findings. Ustekinumab is a fully human monoclonal antibody of the IgG1k class to the p40 subunit of IL-12 and IL-23. The drug interrupts the cascade of humoral and cellular reactions leading to transmural inflammation of the intestinal wall by blocking the interaction of the p40 subunit with the IL-12Rβ1 chain on the surface of T-lymphocytes and NK cells. A number of placebo-controlled studies have demonstrated the effectiveness of Ustekinumab in the induction and the maintenance of remission in those patients with Crohn’s disease who showed no response to conventional therapy (glucocorticosteroids and immunosuppressants) and therapy with TNF-α antagonists. In addition, the efficiency of Ustekinumab in maintaining a clinical response and clinical remission over two years of therapy has been shown. The drug has a favourable safety profile and a low immunogenicity.Conclusion. The reviewed studies show Ustekinumab to be an effective and safe drug for the induction and the maintenance of clinical remission in patients with Crohn’s disease.

Download Full-text

Relevance of monitoring transmural disease activity in patients with Crohn’s disease: current status and future perspectives

Therapeutic Advances in Gastroenterology ◽

10.1177/17562848211006672 ◽

2021 ◽

Vol 14 ◽

pp. 175628482110066

Author(s):

Rune Wilkens ◽

Kerri L. Novak ◽

Christian Maaser ◽

Remo Panaccione ◽

Torsten Kucharzik

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Disease Activity ◽

Symptom Control ◽

Current Status ◽

Clinical Relapse ◽

Cross Sectional ◽

Treatment Targets ◽

Endoscopic Remission ◽

Transmural Inflammation

Treatment targets of inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s disease (CD) have evolved over the last decade. Goals of therapy consisting of symptom control and steroid sparing have shifted to control of disease activity with endoscopic remission being an important endpoint. Unfortunately, this requires ileocolonoscopy, an invasive procedure. Biomarkers [C-reactive protein (CRP) and fecal calprotectin (FCP)] have emerged as surrogates for endoscopic remission and disease activity, but also have limitations. Despite this evolution, we must not lose sight that CD involves transmural inflammation, not fully appreciated with ileocolonoscopy. Therefore, transmural assessment of disease activity by cross-sectional imaging, in particular with magnetic resonance enterography (MRE) and intestinal ultrasonography (IUS), is vital to fully understand disease control. Bowel-wall thickness (BWT) is the cornerstone in assessment of transmural inflammation and BWT normalization, with or without bloodflow normalization, the key element demonstrating resolution of transmural inflammation, namely transmural healing (TH) or transmural remission (TR). In small studies, achievement of TR has been associated with improved long-term clinical outcomes, including reduced hospitalization, surgery, escalation of treatment, and a decrease in clinical relapse over endoscopic remission alone. This review will focus on the existing literature investigating the concept of TR or residual transmural disease and its relation to other existing treatment targets. Current data suggest that TR may be the next logical step in the evolution of treatment targets.

Download Full-text

Intracellular Sources of ROS/H2O2 in Health and Neurodegeneration: Spotlight on Endoplasmic Reticulum

Cells ◽

10.3390/cells10020233 ◽

2021 ◽

Vol 10 (2) ◽

pp. 233

Author(s):

Tasuku Konno ◽

Eduardo Pinho Melo ◽

Joseph E. Chambers ◽

Edward Avezov

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Hydrogen Peroxide ◽

Endoplasmic Reticulum ◽

Neurodegenerative Diseases ◽

Antioxidative Enzymes ◽

Redox Reactions ◽

Ros Production ◽

Oxygen Species ◽

Specific Target

Reactive oxygen species (ROS) are produced continuously throughout the cell as products of various redox reactions. Yet these products function as important signal messengers, acting through oxidation of specific target factors. Whilst excess ROS production has the potential to induce oxidative stress, physiological roles of ROS are supported by a spatiotemporal equilibrium between ROS producers and scavengers such as antioxidative enzymes. In the endoplasmic reticulum (ER), hydrogen peroxide (H2O2), a non-radical ROS, is produced through the process of oxidative folding. Utilisation and dysregulation of H2O2, in particular that generated in the ER, affects not only cellular homeostasis but also the longevity of organisms. ROS dysregulation has been implicated in various pathologies including dementia and other neurodegenerative diseases, sanctioning a field of research that strives to better understand cell-intrinsic ROS production. Here we review the organelle-specific ROS-generating and consuming pathways, providing evidence that the ER is a major contributing source of potentially pathologic ROS.

Download Full-text

Vitamin E-Coated Dialyzer Inhibits Oxidative Stress

Blood Purification ◽

10.1159/000478971 ◽

2017 ◽

Vol 44 (4) ◽

pp. 288-293 ◽

Cited By ~ 4

Author(s):

Shiho Yamadera ◽

Yuya Nakamura ◽

Masahiro Inagaki ◽

Isao Ohsawa ◽

Hiromichi Gotoh ◽

...

Keyword(s):

Oxidative Stress ◽

Vitamin E ◽

Synthetic Polymer ◽

Intracellular Reactive Oxygen Species ◽

Ros Production ◽

Oxygen Species ◽

In Vitro Methods ◽

Stress Effects ◽

Intracellular Ros

Aim: To examine the effects of vitamin E-coated dialyzer on oxidative stress in vitro. Methods: A dialyzer with a synthetic polymer membrane (APS-11SA) and vitamin E-coated dialyzer (VPS-11SA) were connected to a blood tubing line, and U937 cells were circulated in the device. The circulating fluid was collected at 1, 2, 5, 10, 25, and 50 cycles, which are estimated numbers of passes through the dialyzer. Intracellular reactive oxygen species (ROS) production, malondialdehyde (MDA), and Cu/Zn-superoxide dismutase (SOD) were quantified. Results: Intracellular ROS production was increased in the first cycle by APS-11SA and was decreased throughout the experiment by VPS-11SA. Intracellular ROS production in the VPS-11SA device was lower, and MDA levels were decreased. MDA levels were lower during VPS-11SA processing than during APS-11SA processing. Cu/Zn-SOD levels remained unchanged. Conclusion: Our results highlight anti-oxidative-stress effects of a vitamin E-coated dialyzer.

Download Full-text

Use of Thiols in the Treatment of COVID-19: Current Evidence

Lung ◽

10.1007/s00408-021-00465-3 ◽

2021 ◽

Author(s):

Mario Cazzola ◽

Paola Rogliani ◽

Sundeep Santosh Salvi ◽

Josuel Ora ◽

Maria Gabriella Matera

Keyword(s):

Oxidative Stress ◽

Influenza Virus Infection ◽

Current Evidence ◽

Low Molecular Weight ◽

Oxygen Species ◽

Cytokine Storm ◽

Antioxidant Defences ◽

Antioxidant Molecule ◽

Novel Therapeutic

AbstractThere is a possible role for oxidative stress, a state characterized by an altered balance between the production of free radicals or reactive oxygen species (ROS) and antioxidant defences, in coronavirus disease 2019 (COVID-19), the genesis of which is quite complex. Excessive oxidative stress could be responsible for the alveolar damage, thrombosis, and red blood cell dysregulation observed in COVID-19. Apparently, deficiency of glutathione (GSH), a low-molecular-weight thiol that is the most important non-enzymatic antioxidant molecule and has the potential to keep the cytokine storm in check, is a plausible explanation for the severe manifestations and death in COVID-19 patients. Thiol drugs, which are considered mucolytic, also possess potent antioxidant and anti-inflammatory properties. They exhibit antibacterial activity against a variety of medically important bacteria and may be an effective strategy against influenza virus infection. The importance of oxidative stress during COVID-19 and the various pharmacological characteristics of thiol-based drugs suggest a possible role of thiols in the treatment of COVID-19. Oral and intravenous GSH, as well as GSH precursors such as N-acetylcysteine (NAC), or drugs containing the thiol moiety (erdosteine) may represent a novel therapeutic approach to block NF-kB and address the cytokine storm syndrome and respiratory distress observed in COVID-19 pneumonia patients

Download Full-text

Hyperglycemia Induces Generation of Reactive Oxygen Species and Accelerates Apoptotic Cell Death in Salivary Gland Cells

Pathobiology ◽

10.1159/000512639 ◽

2021 ◽

pp. 1-8

Author(s):

Naoyuki Matsumoto ◽

Daisuke Omagari ◽

Ryoko Ushikoshi-Nakayama ◽

Tomoe Yamazaki ◽

Hiroko Inoue ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Salivary Gland ◽

Tissue Injury ◽

Ros Production ◽

Oxygen Species ◽

Saliva Secretion ◽

Salivary Gland Tissue ◽

Gland Tissue

Introduction: Type-2 diabetes mellitus (T2DM) is associated with several systemic vascular symptoms and xerostomia. It is considered that hyperglycemia-induced polyuria and dehydration cause decreased body-water volume, leading to decreased saliva secretion and, ultimately, xerostomia. In T2DM, increased production of reactive oxygen species (ROS) causes tissue damage to vascular endothelial cells as well as epithelial tissue, including pancreas and cornea. Hence, a similar phenomenon may occur in other tissues and glands in a hyperglycemic environment. Methods: Salivary gland tissue injury was examined, using T2DM model mouse (db/db). Transferase‐mediated dUTP nick‐end labeling (TUNEL) was conducted to evaluate tissue injury. The levels of malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine, Bax/Bcl-2 ratio were measured as indicator of oxidative stress. Moreover, in vitro ROS production and cell injury was evaluated by mouse salivary gland-derived normal cells under high-glucose condition culture. Results: In vivo and in vitro analysis showed a higher percentage of TUNEL-positive cells and higher levels of MDA and 8-hydroxy-2′-deoxyguanosine in salivary gland tissue of db/db mice. This suggests damage of saliva secretion-associated lipids and DNA by hyperglycemic-induced oxidative stress. To analyze the mechanism by which hyperglycemia promotes ROS production, mouse salivary gland-derived cells were isolated. The cell culture with high-glucose medium enhanced ROS production and promotes apoptotic and necrotic cell death. Conclusion: These findings suggest a novel mechanism whereby hyperglycemic-induced ROS production promotes salivary gland injury, resulting in hyposalivation.

Download Full-text

Pulmonary Crohn's Disease in Down Syndrome: A Link or Linkage Problem

Case Reports in Gastroenterology ◽

10.1159/000445975 ◽

2016 ◽

Vol 10 (2) ◽

pp. 206-211

Author(s):

Danyal Thaver ◽

Mirza Beg

Keyword(s):

Down Syndrome ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Pediatric Population ◽

Pulmonary Nodules ◽

Pulmonary Involvement ◽

Lung Nodules ◽

Inflammatory Disorder ◽

Ct Guided ◽

History Of

Crohn’s disease (CD) is an autoimmune inflammatory disorder that primarily affects the gastrointestinal tract. It may have pulmonary involvement, which has been rarely reported in pediatric patients. Down syndrome (DS) has been associated with increased frequency of autoimmune diseases. However, associations between CD and DS have been rarely reported. We present the case of a 5-year-old girl with known DS and a history of chronic intermittent abdominal pain who presented with persistent pneumonia. Her workup included a chest computed tomography (CT) scan that showed multiple noncalcified pulmonary nodules. An extensive infectious workup was done that was negative. CT-guided needle biopsy of the lung nodules showed necrotizing granulomas. This raised concern for primary CD with extraintestinal pulmonary manifestation. An esophagogastroduodenoscopy and colonoscopy were performed, and colon biopsies showed scattered epithelioid granulomas. Based on this information, there was consensus that her lung nodules were secondary to CD. She was started on standard therapy for CD, and her abdominal and respiratory symptoms gradually improved. However, she continues to have mild residual lung calcification and fibrosis. To our knowledge, this is the first reported case of pulmonary CD in a child with DS. The natural history of pulmonary CD in the pediatric population is not very well studied. Furthermore, since DS has been well known to be associated with increased frequency of malignancies and autoimmune conditions due to immune dysregulation, it is difficult to predict the severity and possible complications in this patient.

Download Full-text

Riboflavin Supplementation in Patients with Crohn’s Disease [the RISE-UP study]

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz208 ◽

2019 ◽

Vol 14 (5) ◽

pp. 595-607 ◽

Cited By ~ 3

Author(s):

Julius Z H von Martels ◽

Arno R Bourgonje ◽

Marjolein A Y Klaassen ◽

Hassan A A Alkhalifah ◽

Mehdi Sadaghian Sadabad ◽

...

Keyword(s):

Oxidative Stress ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Disease Activity ◽

Clinical Symptoms ◽

Fish Analysis ◽

Markers Of Inflammation ◽

Anti Inflammatory ◽

Faecal Microbiome ◽

Chronic Intestinal Inflammation

Abstract Background and Aims Crohn’s disease [CD] is characterised by chronic intestinal inflammation and dysbiosis in the gut. Riboflavin [vitamin B2] has anti-inflammatory, antioxidant and microbiome-modulatory properties. Here, we analysed the effect of riboflavin on oxidative stress, markers of inflammation, clinical symptoms, and faecal microbiome in patients with CD. Methods In this prospective clinical intervention study, patients received 100 mg riboflavin [DSM, Nutritional Products Ltd] daily for 3 weeks. Clinical disease activity [Harvey-Bradshaw Index: HBI], serum biomarkers of inflammation and redox status [plasma free thiols], and faecal microbiome taxonomical composition and functionality [fluorescent in situ hybridisation: FISH; and metagenomic shotgun sequencing: MGS], were analysed before and after riboflavin intervention. Results In total, 70 patients with CD with varying disease activity were included. Riboflavin supplementation significantly decreased serum levels of inflammatory markers. In patients with low faecal calprotectin [FC] levels, IL-2 decreased, and in patients with high FC levels, C-reactive protein [CRP] was reduced and free thiols significantly increased after supplementation. Moreover, HBI was significantly decreased by riboflavin supplementation. Riboflavin supplementation led to decreased Enterobacteriaceae in patients with low FC levels as determined by FISH; however, MGS analysis showed no effects on diversity, taxonomy, or metabolic pathways of the faecal microbiome. Conclusions Three weeks of riboflavin supplementation resulted in a reduction in systemic oxidative stress, mixed anti-inflammatory effects, and a reduction in clinical symptoms [HBI]. FISH analysis showed decreased Enterobacteriaceae in patients with CD with low FC levels, though this was not observed in MGS analysis. Our data demonstrate that riboflavin supplementation has a number of anti-inflammatory and anti-oxidant effects in CD.

Download Full-text