Selenium (Se) is an essential micronutrient that exerts its functions via selenoproteins. Little is known about the role of Se in inflammatory bowel disease (IBD). Epidemiological studies have ...inversely correlated nutritional Se status with IBD severity and colon cancer risk. Moreover, molecular studies have revealed that Se deficiency activates WNT signaling, a pathway essential to intestinal stem cell programs and pivotal to injury recovery processes in IBD that is also activated in inflammatory neoplastic transformation. In order to better understand the role of Se in epithelial injury and tumorigenesis resulting from inflammatory stimuli, we examined colonic phenotypes in Se-deficient or -sufficient mice in response to dextran sodium sulfate (DSS)-induced colitis, and azoxymethane (AOM) followed by cyclical administration of DSS, respectively. In response to DSS alone, Se-deficient mice demonstrated increased morbidity, weight loss, stool scores, and colonic injury with a concomitant increase in DNA damage and increases in inflammation-related cytokines. As there was an increase in DNA damage as well as expression of several EGF and TGF-β pathway genes in response to inflammatory injury, we sought to determine if tumorigenesis was altered in the setting of inflammatory carcinogenesis. Se-deficient mice subjected to AOM/DSS treatment to model colitis-associated cancer (CAC) had increased tumor number, though not size, as well as increased incidence of high grade dysplasia. This increase in tumor initiation was likely due to a general increase in colonic DNA damage, as increased 8-OHdG staining was seen in Se-deficient tumors and adjacent, non-tumor mucosa. Taken together, our results indicate that Se deficiency worsens experimental colitis and promotes tumor development and progression in inflammatory carcinogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of ...nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and promotion of a protumorigenic microenvironment. Reduced SEPP1 function markedly increased M2-polarized macrophages, indicating a role for SEPP1 in macrophage polarization and immune function. Furthermore, compared with partial loss, complete loss of SEPP1 substantially reduced tumor burden, in part due to increased apoptosis. Using intestinal organoid cultures, we found that, compared with those from WT animals, Sepp1-null cultures display increased stem cell characteristics that are coupled with increased ROS production, DNA damage, proliferation, decreased cell survival, and modulation of WNT signaling in response to H2O2-mediated oxidative stress. Together, these data demonstrate that SEPP1 influences inflammatory tumorigenesis by affecting genomic stability, the inflammatory microenvironment, and epithelial stem cell functions.
The myeloid translocation gene family member MTG16 is a transcriptional corepressor that relies on the DNA-binding ability of other proteins to determine specificity. One such protein is the ZBTB ...family member Kaiso, and the MTG16:Kaiso interaction is necessary for repression of Kaiso target genes, such as matrix metalloproteinase-7. Using the azoxymethane and dextran sodium sulfate (AOM/DSS) murine model of colitis-associated carcinoma, we previously determined that MTG16 loss accelerates tumorigenesis and inflammation. However, it was unknown whether this effect was modified by Kaiso-dependent transcriptional repression. To test for a genetic interaction between MTG16 and Kaiso in inflammatory carcinogenesis, we subjected single and double knockout (DKO) mice to the AOM/DSS protocol. Mtg16
mice demonstrated increased colitis and tumor burden; in contrast, disease severity in Kaiso
mice was equivalent to wild-type controls. Surprisingly, Kaiso deficiency in the context of MTG16 loss reversed injury and pro-tumorigenic responses in the intestinal epithelium following AOM/DSS treatment, and tumor numbers were returned to near to wild-type levels. Transcriptomic analysis of non-tumor colon tissue demonstrated that changes induced by MTG16 loss were widely mitigated by concurrent Kaiso loss, and DKO mice demonstrated downregulation of metabolism and cytokine-associated gene sets with concurrent activation of DNA damage checkpoint pathways as compared with Mtg16
. Further, Kaiso knockdown in intestinal enteroids reduced stem- and WNT-associated phenotypes, thus abrogating the induction of these pathways observed in Mtg16
samples. Together, these data suggest that Kaiso modifies MTG16-driven inflammation and tumorigenesis and suggests that Kaiso deregulation contributes to MTG16-dependent colitis and CAC phenotypes.
Vitamin D deficiency (VDD), defined as 25(OH)D<30 mg/mL, is highly prevalent (as high as 98%) in patients with sickle cell disease (1, 2). It is hypothesized that patients with SCD are predisposed to ...VDD due to decreased cutaneous vitamin D synthesis, compromised intestinal absorption, inadequate dietary intake, and possibly spending less time outdoors (1). Two defining phenotypes of SCD are chronic pain and endothelial dysfunction, both of which may be impacted by vitamin D (3-6). Many centers are active in treating VDD in SCD patients and recently patients in acute pain have been found to have improvement with replacement of their vitamin D. Thus, the purpose of the present study is to evaluate how vitamin D repletion effects inflammation, pain and endothelial function with SCD patients with VDD.
Patients in the adult sickle cell clinic at Georgia Regents University were screened for vitamin D (serum 25-hydroxycholecaciferol levels). Once the inclusion criteria were met, patients were given 8 weeks of high-dose vitamin D repletion (100,000 units oral ergocalciferol weekly) and vitamin D levels (serum 25-hydroxycholecalciferol levels), endothelial function (pulse wave velocity (PWV), flow-mediated dilation (FMD), and endothelial-independent dilation), inflammatory markers (IL6, IL10, TNF-α, ROS, and SVCAM), bone health (bone mineral density using DXA scan), and pain (pain algometer at mandible, neck, and forearm and pain diaries) were evaluated at baseline, week 4 and week 8. All outcomes were again evaluated at week 16 to determine the impact of 8 weeks without treatment.
Thus far, out of 127 SCD patients screened, as expected, we found 95.2% of patients to be VDD. To date, nine patients with SCD who are VDD (<24 mg/ml) have been enrolled. Within the pilot study, 8 patients have completed 16 weeks with the mean vitamin D levels at 14.0mg/ml, 30.3 mg/ml, 67.7 mg/ml, and 52.0mg/ml mg/ml at week 0, week 4, week 8 and week 16, respectively. Pre-liminary we have found that FMD improved from a baseline mean of (8.4% + 4.3) to 4 weeks (11.0% + 4.4; p=0.004) and 8 weeks (11.1% + 4.5) following treatment and began to decrease at week 16 (10.1% + 4.6). The pain algometer readings at week 4, week 8 and 16 are generally lower than the baseline readings. However, this is a general trend, and only one comparison (week 4 vs. baseline at Neck) reaches statistical significance (p=0.010). Most of the comparisons do not reach statistical significance, which could be due to the limited sample size. Our data shows a slight negative relationship between mandibular pain, neck and forearm pain and vitamin D level, all of which were not statistically significant (p=0.88), (p=0.72), and (p=0.52), respectively.
This study has resulted in a sustained significant 5 fold increase in patient vitamin D levels from baseline at only week 4. We see a slight negative relationship between pain and vitamin D level. In addition, an improvement in endothelial function is observed following 8 weeks of Vitamin D supplementation. A reflection of benefit of high dose vitamin D repletion in improving endothelial function in sickle cell patients is noted. More longitudinal and comprehensive studies are needed to further investigate the extensive role vitamin D may play in the overall health in sickle cell disease.
No relevant conflicts of interest to declare.
Prenatal genetic screens, including carrier screening (CS) and aneuploidy screening (AS), comprise an important component of reproductive healthcare delivery. Clinical practice guidelines emphasize ...the importance of informed decision-making and patient's preferences regarding the use of these screens. Yet, it is unclear how to achieve this ideal as prenatal genetic screening options rapidly become more complex and increasingly available to patients. With increased complexity and availability of reproductive testing options, decision-support strategies are critical to prepare patients to consider AS and/or CS.
A self-administered survey evaluated knowledge and decision-making preferences for expanded carrier (CS) and aneuploidy (AS) prenatal screening. The survey was administered to participants before their first prenatal visit to assess baseline decision-making needs and preference at the initiation of prenatal care. Analysis was approached as a descriptive process.
Participants had similar familiarity with the concepts associated with AS compared to CS; mean knowledge scores for CS was 0.59 possible range 0.00 to 1.00 and 0.55 for AS. Participants reported preferences to learn about a range of conditions, including those with severe or mild impact, childhood-onset, and adult-onset. Decision-making preference with respect to learning about the associated disease phenotypes for the contained on AS and CS panel shifted with the complexity of the panel, with a greater preference to learn about conditions post-test compared pre-test education as panels increased from 5 to 100 conditions.
Patients' baseline knowledge of prenatal genetic screens coupled with evolving decision-making preferences presents challenges for the delivery of prenatal genetic screens. This calls for the development and implementation of innovative approaches to support pregnant patients' decision-making commensurate with advances in prenatal genomics.
PDF
