Glial cell line-derived neurotrophic factor protects against high-fat diet-induced obesity.

Obesity is a growing epidemic with limited effective treatments. The neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) was recently shown to enhance ß-cell mass and improve glucose control in rodents. Its role in obesity is, however, not well characterized. In this study, we investigated the ability of GDNF to protect against high-fat diet (HFD)-induced obesity. GDNF transgenic (Tg) mice that overexpress GDNF under the control of the glial fibrillary acidic protein promoter and wild-type (WT) littermates were maintained on a HFD or regular rodent diet for 11 wk, and weight gain, energy expenditure, and insulin sensitivity were monitored. Differentiated mouse brown adipocytes and 3T3-L1 white adipocytes were used to study the effects of GDNF in vitro. Tg mice resisted the HFD-induced weight gain, insulin resistance, dyslipidemia, hyperleptinemia, and hepatic steatosis seen in WT mice despite similar food intake and activity levels. They exhibited significantly (P<0.001) higher energy expenditure than WT mice and increased expression in skeletal muscle and brown adipose tissue of peroxisome proliferator activated receptor-α and ß1- and ß3-adrenergic receptor genes, which are associated with increased lipolysis and enhanced lipid ß-oxidation. In vitro, GDNF enhanced ß-adrenergic-mediated cAMP release in brown adipocytes and suppressed lipid accumulation in differentiated 3T3L-1 cells through a p38MAPK signaling pathway. Our studies demonstrate a novel role for GDNF in the regulation of high-fat diet-induced obesity through increased energy expenditure. They show that GDNF and its receptor agonists may be potential targets for the treatment or prevention of obesity.

Tumor necrosis factor-neuropeptide Y cross talk regulates inflammation, epithelial barrier functions, and colonic motility.

BACKGROUND: Neuro-immune interactions play a significant role in regulating the severity of inflammation. Our previous work demonstrated that neuropeptide Y (NPY) is upregulated in the enteric nervous system during murine colitis and that NPY knockout mice exhibit reduced inflammation. Here, we investigated if NPY expression during inflammation is induced by tumor necrosis factor (TNF), the main proinflammatory cytokine. METHODS: Using primary enteric neurons and colon explant cultures from wild type and NPY knockout (NPY(-/-)) mice, we determined if NPY knockdown modulates TNF release and epithelial permeability. Further, we assessed if NPY expression is inducible by TNF in enteric neuronal cells and mouse model of experimental colitis, using the TNF inhibitors-etanercept (blocks transmembrane and soluble TNF) and XPro1595 (blocks soluble TNF only). RESULTS: We found that enteric neurons express TNF receptors (TNFR1 and R2). Primary enteric neurons from NPY(-/-) mice produced less TNF compared with wild type. Further, TNF activated NPY promoter in enteric neurons through phospho-c-Jun. NPY(-/-) mice had decreased intestinal permeability. In vitro, NPY increased epithelial permeability through phosphatidyl inositol-3-kinase (PI3-K)-induced pore-forming claudin-2. TNF inhibitors attenuated NPY expression in vitro and in vivo. TNF inhibitor-treated colitic mice exhibited reduced NPY expression and inflammation, reduced oxidative stress, enhanced neuronal survival, and improved colonic motility. XPro1595 had more protective effects on neuronal survival and motility compared with etanercept. CONCLUSIONS: We demonstrate a novel TNF-NPY cross talk that modulates inflammation, barrier functions, and colonic motility during inflammation. It is also suggested that selective blocking of soluble TNF may be a better therapeutic option than using anti-TNF antibodies.

Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc.

Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic inflammatory disease associated with an increased risk for colon cancer. Matrix metalloproteinases (MMPs) are the predominant proteinases expressed in the gut mucosa during active IBD. Our laboratory has previously demonstrated that epithelial-derived MMP9 is absent in normal colonic tissue but is upregulated during IBD. In this study MMP9 transgenic mice (Tg-villin-MMP9) are generated specifically to overexpress MMP9 in intestinal epithelium to examine the role and underlying mechanism by which it modulates the pathogenesis of acute colitis. Dextran sodium sulfate (3% DSS)- and Salmonella typhimurium (S.T.)-induced colitis models were used to study gut inflammation in Tg-villin-MMP9 and wild-type littermates (WT). Colonic tissue was analyzed via Western blot, histology, myeloperoxidase (MPO) assay, and quantitative PCR. Tg-villin-MMP9 mice expressed significantly increased MMP9 mRNA and protein expression at basal level. There was a significant decrease in the goblet cells, but a significant increase in proliferation and apoptosis were observed among Tg-villin-MMP9 mice compared with WT mice. There was also a significant increase in the proinflammatory chemokine Kc among Tg-villin-MMP9 compared with WT mice. Tg-villin-MMP9 exhibited a severe inflammatory response than WT mice in both DSS- and S.T.-induced colitis models as evident by greater weight loss and higher clinical score, histological score, and MPO activity, which correlated with relative levels of Kc mRNA. MMP9 expressed by intestinal epithelial cells mediates inflammation in colitis with simultaneous increase in proinflammatory cytokine Kc.

A(2B)AR expression in non-immune cells plays an important role in the development of murine colitis.

BACKGROUND: Adenosine, an endogenous purine nucleoside, is involved in several physiological functions. We have previously shown that A(2B)AR plays a pro-inflammatory role during colitis. AIMS: Our goals were to determine if A(2B)AR expression was necessary on immune cells/non-immune cells during colitis and if A(2B)AR was a suitable target for treating intestinal inflammation. METHODS: Wild-type and A(2B)AR knockout mice were utilized in bone marrow transplants to explore the importance of immune/non-immune A(2B)AR expression during the development of colitis. Additionally, a T-cell transfer model of colitis was used in Rag1 knockout or A(2B)AR/RAG1 double knockout recipients. Finally, A(2B)AR small interfering RNA nanoparticles were administered to dextran sodium sulphate-treated mice. RESULTS: Wild-type mice receiving wild-type or knockout bone marrow developed severe colitis after dextran sodium sulphate treatment, whereas colitis was significantly attenuated in knockout mice receiving wild-type or knockout bone marrow. Colitis induced in Rag1 knockout animals was attenuated in A(2B)AR/RAG1 double knockout recipients. Animals receiving nanoparticles exhibited attenuated parameters of colitis severity compared to mice receiving control nanoparticles. CONCLUSIONS: Our results suggest that A(2B)AR on non-immune cells plays an important role for the induction of colitis and targeting A(2B)AR expression during colitis may be useful for alleviating symptoms of intestinal inflammation.

Gut microbial products regulate murine gastrointestinal motility via Toll-like receptor 4 signaling.

BACKGROUND & AIMS: Altered gastrointestinal motility is associated with significant morbidity and health care costs. Toll-like receptors (TLR) regulate intestinal homeostasis. We examined the roles of TLR4 signaling in survival of enteric neurons and gastrointestinal motility. METHODS: We assessed changes in intestinal motility by assessing stool frequency, bead expulsion, and isometric muscle recordings of colonic longitudinal muscle strips from mice that do not express TLR4 (Tlr4(Lps-d) or TLR4(-/-)) or Myd88 (Myd88(-/-)), in wild-type germ-free mice or wild-type mice depleted of the microbiota, and in mice with neural crest-specific deletion of Myd88 (Wnt1Cre(+/-)/Myd88(fl/fl)). We studied the effects of the TLR4 agonist lipopolysaccharide (LPS) on survival of cultured, immortalized fetal enteric neurons and enteric neuronal cells isolated from wild-type and Tlr4(Lps-d) mice at embryonic day 13.5. RESULTS: There was a significant delay in gastrointestinal motility and reduced numbers of nitrergic neurons in TLR4(Lps-d), TLR4(-/-), and Myd88(-/-) mice compared with wild-type mice. A similar phenotype was observed in germ-free mice, mice depleted of intestinal microbiota, and Wnt1Cre(+/-)/Myd88(fl/fl) mice. Incubation of enteric neuronal cells with LPS led to activation of the transcription factor nuclear factor (NF)-κB and increased cell survival. CONCLUSIONS: Interactions between enteric neurons and microbes increases neuron survival and gastrointestinal motility in mice. LPS activation of TLR4 and NF-κB appears to promote survival of enteric neurons. Factors that regulate TLR4 signaling in neurons might be developed to alter gastrointestinal motility.

Gastrointestinal delivery of anti-inflammatory nanoparticles.

The concept of nanomedicine has risen to be the future of medicine. Advantages of using nanoobjects as vectors for drug delivery systems are numerous, such as fewer side effects due to a low drug dose, and high specificity between drug and target. Unlike systemic therapy, targeting a specific target is more efficient and less costly. In inflammatory bowel disease, including ulcerative colitis and Crohn disease, the colon represents the targeted organ. A large number of drugs are candidates for loading into nanoparticles (NPs). Small molecules, such as tripeptides and siRNA, or larger molecules, such as proteins (hormones, antibodies (Ab), etc.), can be encapsulated alone or in a complex form inside the NPs. In our studies, once NPs are synthesized and loaded with anti-inflammatory compounds, they are delivered to the colon. An efficient technique has been developed for specific NP targeting to digestive tract regions, including the colon, using a hydrogel based on electrostatic interactions between positive ions and negative polysaccharides. An in situ double cross-linking process, mediated by Ca²âº and SO4²â», of chitosan and alginate administered to the mouse gastrointestinal (GI) tract by double gavage, is used for gel formation. When the drug is given in NPs, NPs are targeted to the colon, and NP degradation by aggressive environmental conditions in the GI tract is significantly reduced. Using a biomaterial (hydrogel) associated with nanotechnology, lower doses of drug can be loaded efficiently and delivered to the colon to reduce colonic inflammation.

Intestinal epithelial CD98 synthesis specifically modulates expression of colonic microRNAs during colitis.

The transmembrane glycoprotein CD98 is known to be involved in intestinal inflammation. In the present study, we found that CD98 overexpression in intestinal epithelial cells does not normally affect the expression of colonic (epithelial and immune cell) microRNAs (miRNAs), small noncoding RNAs that posttranscriptionally regulate a wide variety of biological processes. However, upon dextran sulfate sodium (DSS) treatment, the expression of several colonic miRNAs, but not miRNAs from other tissues such as liver and spleen, were differentially regulated in mice overexpressing CD98 in epithelial cells compared with wild-type (WT) animals. For example, the level of colonic miRNA 132 was not affected by DSS treatment in WT animals but was upregulated in mice overexpressing CD98 in intestinal epithelial cells. Other colonic miRNAs, including colonic miRNA 23a and 23b, were downregulated in WT animals after DSS treatment but not in colonic epithelial cell CD98-overexpressing mice. Interestingly, the expression of potential miRNA target genes affected intestinal epithelial cells that overexpress CD98 and cell types that did not overexpress CD98 but were in close proximity to CD98-overexpressing intestinal epithelial cells. Taken together, these observations show that the combination of an inflammatory context and intestinal epithelial cell expression of CD98 affects the regulation of miRNA expression in colonic epithelial and immune cells. This is new evidence that protein expression modulates miRNA expression and suggests the existence of regulatory crosstalk between proteins and miRNAs in diseases such as colitis.

Dextran sodium sulfate (DSS) induces colitis in mice by forming nano-lipocomplexes with medium-chain-length fatty acids in the colon.

Inflammatory bowel diseases (IBDs), primarily ulcerative colitis and Crohn's disease, are inflammatory disorders caused by multiple factors. Research on IBD has often used the dextran sodium sulfate (DSS)-induced colitis mouse model. DSS induces in vivo but not in vitro intestinal inflammation. In addition, no DSS-associated molecule (free glucose, sodium sulfate solution, free dextran) induces in vitro or in vivo intestinal inflammation. We find that DSS but not dextran associated molecules established linkages with medium-chain-length fatty acids (MCFAs), such as dodecanoate, that are present in the colonic lumen. DSS complexed to MCFAs forms nanometer-sized vesicles ~200 nm in diameter that can fuse with colonocyte membranes. The arrival of nanometer-sized DSS/MCFA vesicles in the cytoplasm may activate intestinal inflammatory signaling pathways. We also show that the inflammatory activity of DSS is mediated by the dextran moieties. The deleterious effect of DSS is localized principally in the distal colon, therefore it will be important to chemically modify DSS to develop materials beneficial to the colon without affecting colon-targeting specificity.

Is ulcerative colitis associated with survival among older persons with colorectal cancer in the US? A population-based case-control study.

BACKGROUND: While ulcerative colitis (UC) is a risk factor for colorectal cancer, the association of UC with survival after colorectal cancer has not been studied in an older population. AIMS: The objective of our study was to compare the survival of colorectal cancer between persons with and without UC. METHODS: All cases of colorectal cancer (CRC) in persons 67 and older residing in a SEER catchment area and enrolled in the Medicare between 1993 and 1999 were assessed. We identified diagnosis of UC using ICD-9 codes on Medicare outpatient, office, and inpatient claims in the 2 years prior to the date of diagnosis. We used Cox proportional hazards model and Kaplan-Meier curves to compare survival between individuals with UC and CRC (UC-CRC) and sporadic CRC RESULTS: We identified 47,543 cases of colorectal cancer. Cases with UC-CRC tend to be diagnosed at earlier stages compared to sporadic CRC (42 vs. 37% local (TNM stage 1 and 2) and 11 vs. 17% distant spread (TNM stage 4), respectively; P value = 0.04). Controlling for age, gender, race and stage, diagnosis of UC did not affect the 3-year survival for CRC. CONCLUSIONS: Colorectal cancers tend to be diagnosed at earlier stages among persons with UC, but there is no difference in 3-year survival rates for colorectal cancer among individuals with and without UC.

Glial cell line-derived neurotrophic factor enhances human islet posttransplantation survival.

BACKGROUND: Development of pretransplantation islet culture strategies that preserve or enhance ß-cell viability would eliminate the requirement for the large numbers of islets needed to restore insulin independence in type 1 diabetes patients. We investigated whether glial cell line-derived neurotrophic factor (GDNF) could improve human islet survival and posttransplantation function in diabetic mice. METHODS: Human islets were cultured in medium supplemented with or without GDNF (100 ng/mL) and in vitro islet survival and function assessed by analyzing ß-cell apoptosis and glucose stimulated insulin release. In vivo effects of GDNF were assessed in streptozotocin-induced diabetic nude mice transplanted under the kidney capsule with 2000 islet equivalents of human islets precultured in medium supplemented with or without GDNF. RESULTS: In vitro, human islets cultured for 2 to 10 days in medium supplemented with GDNF showed lower ß-cell death, increased Akt phosphorylation, and higher glucose-induced insulin secretion than islets cultured in vehicle. Human islets precultured in medium supplemented with GDNF restored more diabetic mice to normoglycemia and for a longer period after transplantation than islets cultured in vehicle. CONCLUSIONS: Our study shows that GDNF has beneficial effects on human islet survival and could be used to improve islet posttransplantation survival.

L-Ala-γ-D-Glu-meso-diaminopimelic acid (DAP) interacts directly with leucine-rich region domain of nucleotide-binding oligomerization domain 1, increasing phosphorylation activity of receptor-interacting serine/threonine-protein kinase 2 and its interaction with nucleotide-binding oligomerization domain 1.

The oligopeptide transporter PepT1 expressed in inflamed colonic epithelial cells transports small bacterial peptides, such as muramyl dipeptide (MDP) and l-Ala-γ-D-Glu-meso-diaminopimelic acid (Tri-DAP) into cells. The innate immune system uses various proteins to sense pathogen-associated molecular patterns. Nucleotide-binding oligomerization domain (NOD)-like receptors of which there are more than 20 related family members are present in the cytosol and recognize intracellular ligands. NOD proteins mediate NF-κB activation via receptor-interacting serine/threonine-protein kinase 2 (RICK or RIPK). The specific ligands for some NOD-like receptors have been identified. NOD type 1 (NOD1) is activated by peptides that contain a diaminophilic acid, such as the PepT1 substrate Tri-DAP. In other words, PepT1 transport activity plays an important role in controlling intracellular loading of ligands for NOD1 in turn determining the activation level of downstream inflammatory pathways. However, no direct interaction between Tri-DAP and NOD1 has been identified. In the present work, surface plasmon resonance and atomic force microscopy experiments showed direct binding between NOD1 and Tri-DAP with a K(d) value of 34.5 µM. In contrast, no significant binding was evident between muramyl dipeptide and NOD1. Furthermore, leucine-rich region (LRR)-truncated NOD1 did not interact with Tri-DAP, indicating that Tri-DAP interacts with the LRR domain of NOD1. Next, we examined binding between RICK and NOD1 proteins and found that such binding was significant with a K(d) value of 4.13 µM. However, NOD1/RICK binding was of higher affinity (K(d) of 3.26 µM) when NOD1 was prebound to Tri-DAP. Furthermore, RICK phosphorylation activity was increased when NOD was prebound to Tri-DAP. In conclusion, we have shown that Tri-DAP interacts directly with the LRR domain of NOD1 and consequently increases RICK/NOD1 association and RICK phosphorylation activity.

The PepT1-NOD2 signaling pathway aggravates induced colitis in mice.

BACKGROUND & AIMS: The human di/tripeptide transporter human intestinal H-coupled oligonucleotide transporter (hPepT1) is abnormally expressed in colons of patients with inflammatory bowel disease, although its exact role in pathogenesis is unclear. We investigated the contribution of PepT1 to intestinal inflammation in mouse models of colitis and the involvement of the nucleotide-binding oligomerization domain 2 (NOD2) signaling pathway in the pathogenic activity of colonic epithelial hPepT1. METHODS: Transgenic mice were generated in which hPepT1 expression was regulated by the ß-actin or villin promoters; colitis was induced using 2,4,6-trinitrobenzene sulfonic acid (TNBS) or dextran sodium sulfate (DSS) and the inflammatory responses were assessed. The effects of NOD2 deletion in the hPepT1 transgenic mice also was studied to determine the involvement of the PepT1-NOD2 signaling pathway. RESULTS: TNBS and DSS induced more severe levels of inflammation in ß-actin-hPepT1 transgenic mice than wild-type littermates. Intestinal epithelial cell-specific hPepT1 overexpression in villin-hPepT1 transgenic mice increased the severity of inflammation induced by DSS, but not TNBS. Bone marrow transplantation studies showed that hPepT1 expression in intestinal epithelial cells and immune cells has an important role in the proinflammatory response. Antibiotics abolished the effect of hPepT1 overexpression on the inflammatory response in DSS-induced colitis in ß-actin-hPepT1 and villin-hPepT1 transgenic mice, indicating that commensal bacteria are required to aggravate intestinal inflammation. Nod2-/-, ß-actin-hPepT1 transgenic/Nod2-/-, and villin-hPepT1 transgenic/Nod2-/- littermates had similar levels of susceptibility to DSS-induced colitis, indicating that hPepT1 overexpression increased intestinal inflammation in a NOD2-dependent manner. CONCLUSIONS: The PepT1-NOD2 signaling pathway is involved in aggravation of DSS-induced colitis in mice.

Notch1 regulates the effects of matrix metalloproteinase-9 on colitis-associated cancer in mice.

BACKGROUND & AIMS: Inflammatory bowel disease increases the risks of colon cancer and colitis-associated cancer (CAC). Epithelial cell-derived matrix metalloproteinase (MMP)-9 mediates inflammation during acute colitis and the cleavage and activation of the transcription factor Notch1, which prevents differentiation of progenitor cells into goblet cells. However, MMP-9 also protects against the development of CAC and acts as a tumor suppressor. We investigated the mechanisms by which MMP-9 protects against CAC in mice. METHODS: C57/B6 wild-type mice were given a single dose of azoxymethane and 2 cycles of dextran sulfate sodium (DSS). Mice were also given the γ-secretase inhibitor difluorophenacetyl-l-alanyl-S-phenylglycine t-butyl ester (DAPT) or dimethyl sulfoxide (control) during each DSS cycle; they were killed on day 56. We analyzed embryonic fibroblasts isolated from wild-type and MMP-9-/- mice and HCT116 cells that were stably transfected with MMP-9. RESULTS: Wild-type mice were more susceptible to CAC following inhibition of Notch1 by DAPT, shown by increased numbers of tumors and level of dysplasia compared with controls. Inhibition of Notch1 signaling significantly reduced protein levels of active Notch1, p53, p21WAF1/Cip1, Bax-1, active caspase-3, as well as apoptosis, compared with controls. Similar results were observed in transgenic HCT116 cells and embryonic fibroblasts from MMP-9-/- mice on γ-radiation-induced damage of DNA. CONCLUSIONS: MMP-9 mediates Notch1 signaling via p53 to regulate apoptosis, cell cycle arrest, and inflammation. By these mechanisms, it might prevent CAC.

Overexpression of Ste20-related proline/alanine-rich kinase exacerbates experimental colitis in mice.

Inflammatory bowel disease, mainly Crohn's disease and ulcerative colitis, are characterized by epithelial barrier disruption and altered immune regulation. Colonic Ste20-like proline/alanine-rich kinase (SPAK) plays a role in intestinal inflammation, but its underlying mechanisms need to be defined. Both SPAK-transfected Caco2-BBE cells and villin-SPAK transgenic (TG) FVB/6 mice exhibited loss of intestinal barrier function. Further studies demonstrated that SPAK significantly increased paracellular intestinal permeability to FITC-dextran. In vivo studies using the mouse models of colitis induced by dextran sulfate sodium (DSS) and trinitrobenzene sulfonic acid showed that TG FVB/6 mice were more susceptible to DSS and trinitrobenzene sulfonic acid treatment than wild-type FVB/6 mice, as demonstrated by clinical and histological characteristics and enzymatic activities. Consistent with this notion, we found that SPAK increased intestinal epithelial permeability, which likely facilitated the production of inflammatory cytokines in vitro and in vivo, aggravated bacterial translocation in TG mice under DSS treatment, and consequently established a context favorable for the triggering of intestinal inflammation cascades. In conclusion, overexpression of SPAK inhibits maintenance of intestinal mucosal innate immune homeostasis, which makes regulation of SPAK important to attenuate pathological responses in inflammatory bowel disease.

Microbiota modulate host gene expression via microRNAs.

Microbiota are known to modulate host gene expression, yet the underlying molecular mechanisms remain elusive. MicroRNAs (miRNAs) are importantly implicated in many cellular functions by post-transcriptionally regulating gene expression via binding to the 3'-untranslated regions (3'-UTRs) of the target mRNAs. However, a role for miRNAs in microbiota-host interactions remains unknown. Here we investigated if miRNAs are involved in microbiota-mediated regulation of host gene expression. Germ-free mice were colonized with the microbiota from pathogen-free mice. Comparative profiling of miRNA expression using miRNA arrays revealed one and eight miRNAs that were differently expressed in the ileum and the colon, respectively, of colonized mice relative to germ-free mice. A computational approach was then employed to predict genes that were potentially targeted by the dysregulated miRNAs during colonization. Overlapping the miRNA potential targets with the microbiota-induced dysregulated genes detected by a DNA microarray performed in parallel revealed several host genes that were regulated by miRNAs in response to colonization. Among them, Abcc3 was identified as a highly potential miRNA target during colonization. Using the murine macrophage RAW 264.7 cell line, we demonstrated that mmu-miR-665, which was dysregulated during colonization, down-regulated Abcc3 expression by directly targeting the Abcc3 3'-UTR. In conclusion, our study demonstrates that microbiota modulate host microRNA expression, which could in turn regulate host gene expression.

CD98 expression modulates intestinal homeostasis, inflammation, and colitis-associated cancer in mice.

Expression of the transmembrane glycoprotein CD98 (encoded by SLC3A2) is increased in intestinal inflammatory conditions, such as inflammatory bowel disease (IBD), and in various carcinomas, yet its pathogenetic role remains unknown. By generating gain- and loss-of-function mouse models with genetically manipulated CD98 expression specifically in intestinal epithelial cells (IECs), we explored the role of CD98 in intestinal homeostasis, inflammation, and colitis-associated tumorigenesis. IEC-specific CD98 overexpression induced gut homeostatic defects and increased inflammatory responses to DSS-induced colitis, promoting colitis-associated tumorigenesis in mice. Further analysis indicated that the ability of IEC-specific CD98 overexpression to induce tumorigenesis was linked to its capacity to induce barrier dysfunction and to stimulate cell proliferation and production of proinflammatory mediators. To validate these results, we constructed mice carrying conditional floxed Slc3a2 alleles and crossed them with Villin-Cre mice such that CD98 was downregulated only in IECs. These mice exhibited attenuated inflammatory responses and resistance to both DSS-induced colitis and colitis-associated tumorigenesis. Together, our data show that intestinal CD98 expression has a crucial role in controlling homeostatic and innate immune responses in the gut. Modulation of CD98 expression in IECs therefore represents a promising therapeutic strategy for the treatment and prevention of inflammatory intestinal diseases, such as IBD and colitis-associated cancer.

Crohn's disease and small bowel adenocarcinoma: a population-based case-control study.

BACKGROUND: Although Crohn's disease (CD) is thought to predispose to adenocarcinomas of the small bowel, the association has not been well studied in an older population. AIMS: The objective of our study was to evaluate the association of CD with small bowel cancer in a population-based case-control study. METHODS: All cases of small bowel cancer in persons 67 and older in the Surveillance, Epidemiology and End Results catchment area and in the Medicare claims data base were compared with cancer-free controls residing in the same geographic area. We used multivariable logistic regression models adjusted for demographic and other factors. RESULTS: We identified 923 cases of small bowel cancer and 142,273 controls. Although we found a strong association between CD and small bowel cancer (OR = 12.07; 95% CI: 6.07-20.80; P < 0.001), the prevalence of CD in patients with small bowel cancer was low (1.6%). CONCLUSIONS: Although CD is a significant risk factor for small bowel cancers among individuals older than 67, the absolute risk is small. IMPACT: Older individuals with CD can be reassured that although there is an association between CD and small bowel cancer, the absolute risk remains small.

Is inflammatory bowel disease an important risk factor among older persons with colorectal cancer in the United States? A population-based case-control study.

BACKGROUND: While ulcerative colitis (UC) and Crohn's disease (CD) are thought to predispose to colorectal cancer (CRC), the association has not been well studied in an older population. AIMS: The objective of our study was to evaluate the association of ulcerative colitis and Crohn's disease and colorectal cancer in a population-based, case-control study. We also wished to estimate the incidence rates of colorectal cancer among older individuals with UC/CD. METHODS: All cases of colorectal cancer in persons 67 and older in the SEER catchment area and in the Medicare claims database were compared with cancer-free controls residing in the same geographic area. We used multivariable logistic regression models adjusted for demographic and other factors. RESULTS: We identified 47,543 cases of CRC and 142,273 controls. We found a modest association between UC and CRC (OR 1.93; 95% CI 1.54-2.49; P-value<0.001) and a significant, albeit modest, association between CD and CRC (OR 1.45; 95% CI 1.08-1.91; P-value 0.01). We found the incidence of CRC to be 8.2 per 10,000 person-years (95% CI 6.5-10.1/10,000 person-years) among those with UC/CD, and 6.1 per 10,000 person-years (95% CI 4.6-7.8/10,000 person-years) among those without UC/CD, resulting in an incidence rate ratio of 1.34. CONCLUSIONS: Among older persons ulcerative colitis and Crohn's disease are modest risk factors for CRC, and the incidence rate ratio for CRC is modest, suggesting that risk of CRC in patients with IBD may be lower than previously thought.

The role and therapeutic potential of prohibitin in disease.

Prohibitin 1 (PHB1), a pleiotropic protein in the cell, has been implicated in the regulation of proliferation, apoptosis, transcription, mitochondrial protein folding, and as a cell-surface receptor. This diverse array of functions of PHB1 is attributed to the cell type studied and its subcellular localization. This review discusses recent data that indicate a diverse role of PHB1 in disease pathogenesis and suggest that targeting PHB1 may be a potential therapeutic option for treatment of diseases including cancer, inflammatory bowel disease, insulin resistance/type 2 diabetes, and obesity. These diseases are associated with increased oxidative stress and mitochondrial dysfunction and therefore, the role of PHB1 in both responses will also be discussed.

Nanoparticle-based therapeutic delivery of prohibitin to the colonic epithelial cells ameliorates acute murine colitis.

BACKGROUND: Intestinal epithelial expression of antioxidants and nuclear factor kappa B (NF-κB) contribute to mucosal barrier integrity and epithelial homeostasis, two key events in the pathogenesis of inflammatory bowel disease (IBD). Genetic restoration of intestinal epithelial prohibitin 1 (PHB) levels during experimental colitis reduces the severity of disease through sustained epithelial antioxidant expression and reduced NF-κB activation. To determine the therapeutic potential of restoring epithelial PHB during experimental colitis in mice, we assessed two methods of PHB colonic mucosal delivery: adenovirus-directed administration by enema and poly(lactic acid) nanoparticle (NPs) delivery by gavage. METHODS: As a proof-of-principle to demonstrate the therapeutic efficacy of PHB, we utilized adenovirus-directed administration by enema. Second, we used NPs-based colonic delivery of biologically active PHB to demonstrate therapeutic use for human IBD. Colitis was induced by oral administration of dextran sodium sulfate (DSS) in water for 6-7 days. Wildtype mice receiving normal tap water served as controls. RESULTS: Both methods of delivery resulted in increased levels of PHB in the surface epithelial cells of the colon and reduced severity of DSS-induced colitis in mice as measured by body weight loss, clinical score, myeloperoxidase activity, proinflammatory cytokine expression, histological score, and protein carbonyl content. CONCLUSIONS: This is the first study to show oral delivery of a biologically active protein by NPs encapsulated in hydrogel to the colon. Here we show that therapeutic delivery of PHB to the colon reduces the severity of DSS-induced colitis in mice. PHB may represent a novel therapeutic target in IBD.