Mitochondrial function and gastrointestinal diseases.

Mitochondria are dynamic organelles that function in cellular energy metabolism, intracellular and extracellular signalling, cellular fate and stress responses. Mitochondria of the intestinal epithelium, the cellular interface between self and enteric microbiota, have emerged as crucial in intestinal health. Mitochondrial dysfunction occurs in gastrointestinal diseases, including inflammatory bowel diseases and colorectal cancer.

Effectiveness of Upadacitinib for Patients With Acute Severe Ulcerative Colitis: A Multicenter Experience.

Introduction: A significant proportion of patients with acute severe ulcerative colitis (ASUC) require colectomy.

Methods: Patients with ASUC treated with upadacitinib and intravenous corticosteroids at 5 hospitals are presented. The primary outcome was 90-day colectomy rate.

Study Transportation of Drugs within Newly Established Murine Colon Organoid Systems.

The development of 3D organoids of the small intestine is a tremendous breakthrough in drug development and biological research. However, the development of colonic organoids (i.e.

Inflammatory Bowel Disease in Appalachian Kentucky: An Investigation of Outcomes and Health Care Utilization.

Background: Rural residence has been associated with a lower incidence of inflammatory bowel disease (IBD) but higher health care utilization and worse outcomes. Socioeconomic status is intrinsically tied to both IBD incidence and outcomes. Inflammatory bowel disease outcomes have not been investigated in Appalachia: a rural, economically distressed region rife with risk factors for both increased incidence and unfavorable outcomes.

Chronic opioid use is associated with early biologic discontinuation in inflammatory bowel disease.

Background: Chronic opioid use is associated with poorer clinical outcomes in inflammatory bowel disease.

Aims: To investigate an association between chronic opioid use and persistence with biologic agents in management of inflammatory bowel disease.

Methods: A total of 16 624 patients diagnosed with inflammatory bowel disease and receiving a first-time biologic prescription from 2011 to 2016 were identified retrospectively from the Truven MarketScan Database.

Ustekinumab dose escalation improves clinical responses in refractory Crohn's disease.

Background: Clinicians often utilize off-label dose escalation of ustekinumab (UST) in Crohn's disease (CD) patients with disease refractory to standard dosing. Previous studies report mixed results with dose escalation of UST.

Methods: A retrospective observational study of 143 adult patients with CD receiving UST over a 33-month time period was conducted.

Vedolizumab Dose Escalation Improves Therapeutic Response in a Subset of Patients with Ulcerative Colitis.

Background: The Gemini trial failed to detect a significant difference in response rate for patients with ulcerative colitis (UC) randomized to standard (every 8 week) vedolizumab dosing vs escalated (every 4 week) dosing. Subsequent real-world data imply the Gemini trial design may have obscured a benefit of escalated dosing.

Aims: We investigated outcomes after vedolizumab dose escalation for patients with UC.

Doublecortin-like kinase 1 promotes hepatocyte clonogenicity and oncogenic programming via non-canonical β-catenin-dependent mechanism.

Chronic liver injury is a risk factor for cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms that regulate the decision between normal injury repair and neoplastic initiation are unclear. Doublecortin-like kinase 1 (DCLK1), a tumor stem cell marker, is induced during cirrhosis and HCC.

Double Biologic Therapy for Refractory Stricturing Crohn's Disease: A Successful Case of Deep Remission with Ustekinumab and Vedolizumab.

Stricturing Crohn's disease (CD) is a severe phenotype that presents unique challenges to therapeutic management. Emerging literature suggests that anti-TNF monoclonal antibody (mAb) therapies are inadequate for preventing progression to stricture. We hereby present a case of a patient with refractory CD who required multiple surgical resections despite several anti-TNF treatment regimens.

SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and Differentiation.

Background And Aims: Intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD). We investigated the role of Sirtuin 2 (SIRT2), a NAD-dependent protein deacetylase, in intestinal epithelial cell (IEC) proliferation and differentiation and the mechanism by which SIRT2 contributes to maintenance of intestinal cell homeostasis.

Vitamin C and B as new biomaterials to alter intestinal stem cells.

Vitamin C (ascorbic acid) and vitamin B (niacin) have been extensively studied since the 20th century. In the area of stem cell biology, vitamin C has shown its direct impact toward homeostasis and epigenetic changes (D'Aniello et al., Stem Cells International, 2017, 1-16).

The mitochondrial retrograde signaling regulates Wnt signaling to promote tumorigenesis in colon cancer.

Cancer cells are known to upregulate aerobic glycolysis to promote growth, proliferation, and survival. However, the role of mitochondrial respiration in tumorigenesis remains elusive. Here we report that inhibition of mitochondrial function by silencing TFAM, a key transcription factor essential for mitochondrial DNA (mtDNA) replication and the transcription of mtDNA-encoded genes, markedly reduced tumor-initiating potential of colon cancer cells.

Correction: Validation of near infrared fluorescence (NIRF) probes in vivo with dual laser NIRF endoscope.

[This corrects the article DOI: 10.1371/journal.pone.

Blocking NF-κB Activation in Ly6c Monocytes Attenuates Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is a devastating disease affecting premature infants with intestinal inflammation and necrosis. The neonatal intestinal inflammatory response is rich in macrophages, and blood monocyte count is low in human NEC. We previously found that NF-κB mediates the intestinal injury in experimental NEC.

Effects of six common dietary nutrients on murine intestinal organoid growth.

The intestinal epithelium of the gastrointestinal (GI) tract constantly renews itself to absorb nutrients and provide protection for the body from the outside world. Since the intestinal epithelium is constantly exposed to various chemicals and dietary components, it is critical to determine which constituents promote or inhibit intestinal epithelium health and growth rate. Intestinal organoids, three-dimensional miniature models of the intestines, represent an ex vivo tool to investigate intestinal physiology and growth patterns.

Beta-catenin cleavage enhances transcriptional activation.

Nuclear activation of Wnt/β-catenin signaling is required for cell proliferation in inflammation and cancer. Studies from our group indicate that β-catenin activation in colitis and colorectal cancer (CRC) correlates with increased nuclear levels of β-catenin phosphorylated at serine 552 (pβ-Cat). Biochemical analysis of nuclear extracts from cancer biopsies revealed the existence of low molecular weight (LMW) pβ-Cat, increased to the exclusion of full size (FS) forms of β-catenin.

Intestinal organoids containing poly(lactic-co-glycolic acid) nanoparticles for the treatment of inflammatory bowel diseases.

Inflammatory bowel disease (IBD) causes inflammation to the gastrointestinal tract. Local administration of anti-inflammatory drugs such as 5-aminosalicylic acid (5-ASA) can alleviate the symptoms of IBD. The application of nanoparticles for IBD treatment in direct rectal administration showed high drug availability and treatment efficacy.

Myo-inositol reduces β-catenin activation in colitis.

Aim: To assess dietary myo-inositol in reducing stem cell activation in colitis, and validate pβ-catenin as a biomarker of recurrent dysplasia.

Methods: We examined the effects of dietary myo-inositol treatment on inflammation, pβ-catenin and pAkt levels by histology and western blot in IL-10 and dextran sodium sulfate-treated colitic mice. Additionally, we assessed nuclear pβ-catenin in patients treated with myo-inositol in a clinical trial, and in patients with and without a history of colitis-induced dysplasia.

Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease.

TNF plays an integral role in inflammatory bowel disease (IBD), as evidenced by the dramatic therapeutic responses in Crohn's disease (CD) patients induced by chimeric anti-TNF mAbs. However, treatment of CD patients with etanercept, a decoy receptor that binds soluble TNF, fails to improve disease. To explore this discrepancy, we investigated the role of TNF signaling in Wnt/β-catenin-mediated intestinal stem cell and progenitor cell expansion in CD patients, human cells, and preclinical mouse models.

Interdependency of EGF and GLP-2 Signaling in Attenuating Mucosal Atrophy in a Mouse Model of Parenteral Nutrition.

Background & Aims: Total parenteral nutrition (TPN), a crucial treatment for patients who cannot receive enteral nutrition, is associated with mucosal atrophy, barrier dysfunction, and infectious complications. Glucagon-like peptide-2 (GLP-2) and epidermal growth factor (EGF) improve intestinal epithelial cell (IEC) responses and attenuate mucosal atrophy in several TPN models. However, it remains unclear whether these 2 factors use distinct or overlapping signaling pathways to improve IEC responses.

Predictors of Chronic Opioid Use in Newly Diagnosed Crohn's Disease.

Background And Aims: Patients with Crohn's disease (CD) are often prescribed opioids chronically to manage pain associated with their disease. However, little evidence exists to support this practice. Here, we examine newly diagnosed patients with CD with and without chronic opioid use (COU) and sought to identify predictors and consequences of COU.

Near-Infrared Fluorescence Endoscopy to Detect Dysplastic Lesions in the Mouse Colon.

Near-infrared fluorescence (NIRF) endoscopy has a great potential for efficient early detection of dysplastic lesions in the colon. For preclinical studies, we developed a small animal NIRF endoscope and successfully used this device to identify dysplastic lesions in a murine model of chronic colitis. In this chapter, we present a step-by-step protocol for using NIRF endoscopy to examine the location, the size, and the borders of the dysplastic lesions developed in murine colitis.