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Biomedical subjects

Joseph H Sellin

Publications and source records attributed to Joseph H Sellin.

12 recordsLinked to original sources
PubMed2006

Dual alterations in casein kinase I-epsilon and GSK-3beta modulate beta-catenin stability in hyperproliferating colonic epithelia.

Casein kinase I (CKI)-epsilon and GSK-3beta phosphorylate beta-catenin at Ser(45) (beta-cat(45)) and Thr(41)/Ser(37,33) (beta-cat(33,37,41)) residues, thereby facilitating its ubiquitination and proteasomal degradation. We used a Citrobacter rodentium-induced transmissible murine colonic hyperplasia (TMCH) model to determine Ser/Thr phosphorylation and biological function of beta-catenin during crypt hyperproliferation. TMCH was associated with 3-fold and 3.3-fold increases in CKI-epsilon cellular abundance and 2-fold and 1.8-fold increase in its activity at 6 and 12 days after infection, respectively. beta-Catenin coimmunoprecipitated with both cellular and nuclear CKI-epsilon and cellular axin at these time points. Cellular beta-catenin was constitutively phosphorylated at Ser(45) and underwent subcellular redistribution to cytoskeletal and nuclear fractions at days 6 and 12 of TMCH, respectively. beta-cat(33,37,41), however, exhibited only subtle changes in either phosphorylation status or subcellular distribution even after blocking proteasomal degradation in vivo. Interestingly, GSK-3beta underwent increased phosphorylation at Ser(9), leading to 40% and 70% decreases in its activity at these time points, respectively. Coimmunoprecipitation studies exhibited strong association of GSK-3beta with PKC-zeta at either time point. Cellular beta-cat(45) stabilized and, along with unphosphorylated beta-catenin, underwent nuclear translocation, associated with nuclear accumulated Tcf-4 and cAMP response element binding protein binding protein, and was significantly acetylated, leading to increases in DNA binding. Priming of beta-catenin at Ser(45) exists in vivo. However, beta-cat(45) does not necessarily enter the degradation pathway. Impairment in linking beta-cat(45) to subsequent GSK-3beta-mediated phosphorylation and degradation may account for increased steady-state levels of both unphosphorylated as well as Ser(45)-phosphorylated beta-catenin, which may be causally linked to increases in cell census during TMCH.

Animals↗
PubMed2006

Chronic PKC-beta activation in HT-29 Cl.19a colonocytes prevents cAMP-mediated ion secretion by inhibiting apical membrane current generation.

We investigated the effects of PKC-stimulating 12-deoxyphorbol 13-phenylacetate 20-acetate (DOPPA) and phorbol 12-myristate 13-acetate (PMA) phorbol esters on cAMP-dependent, forskolin (FSK)-stimulated, short-circuit Cl- current (ISC-cAMP) generation by colonocyte monolayers. These agonists elicited different actions depending on their dose and incubation time; PMA effects at the onset (<5 min) were independent of cAMP agonist and were characterized by transient anion-dependent transcellular and apical membrane ISC generation. DOPPA failed to elicit similar responses. Whereas chronic (24 h) exposure to both agents inhibited FSK-stimulated transcellular and apical membrane ISC-cAMP, the effects of DOPPA were more complex: this conventional PKC-beta-specific agonist also stimulated Ba2+-sensitive basolateral membrane-dependent facilitation of transcellular ISC-cAMP. PMA did not elicit a similar phenomenon. Prolonged exposure to high-dose PMA but not DOPPA led to apical membrane ISC-cAMP recovery. Changes in PKC alpha-, beta1-, gamma-, and epsilon-isoform membrane partitioning and expression correlated with these findings. PMA-induced transcellular ISC correlated with PKC-alpha membrane association, whereas low doses of both agents inhibited transcellular and apical membrane ISC-cAMP, increased PKC-beta1, decreased PKC-beta2 membrane association, and caused reciprocal changes in isoform mass. During the apical membrane ISC-cAMP recovery after prolonged high-dose PMA exposure, an almost-complete depletion of cellular PKC-beta1 and a significant reduction in PKC-epsilon mass occurred. Thus activated PKC-beta1 and/or PKC-epsilon prevented, whereas activated PKC-alpha facilitated, apical membrane ISC-cAMP. PKC-beta-dependent augmentation of transcellular ISC-cAMP at the level of the basolateral membrane demonstrated that transport events with geographically distinct subcellular membranes can be independently regulated by the PKC beta-isoform.

Colon↗
PubMed2006

Chronic PKC-beta2 activation in HT-29 Cl.19a colonocytes prevents cAMP-mediated ion secretion by inhibiting apical membrane CFTR targeting.

We investigated the effects of chronically applied PKC-stimulating phorbol esters on subcellular CFTR expression and localization in polarized HT-29 Cl.19A monolayers. Modulation of PKC activity with the PKC-beta-specific agonist 12-deoxyphorbol 13-phenylacetate 20-acetate (DOPPA) or nonisoform-selective PMA altered monolayer CFTR immunofluorescence. A decrease in the CFTR signal within the luminal cellular pole was noted with both phorbol esters. Volumetric analysis of the intracellular CFTR signal revealed that both compounds promoted CFTR accumulation into punctate vesicle-like structures found adjacent to the cellular tight junction [labeled with zona occludens (ZO)-1 antibody], extending basally (DOPPA) into the cell. Puncta were more frequent with DOPPA and larger in size with PMA. DOPPA also promoted ZO-1 accumulation at tricellular corners associated with enhanced CFTR puncta number. The observed loss of CFTR immunofluorescence signal induced by low-dose PMA was related to CFTR sequestration into fewer cytoplasmic puncta and correlated with larger increases in PKC substrate phosphorylation. Both phorbol esters downregulated steady-state cellular CFTR mRNA levels by 70%. However, the effects of DOPPA and PMA were largely independent of CFTR biosynthesis: expression levels were 80-85% of control, and the glycosylation status of immunoprecipitated protein remained largely unchanged. Thus changes in cellular CFTR localization correlated with our companion study showing that PMA-induced inhibition of transcellular cAMP-dependent short-circuit current (ISC) was accompanied by cytoplasmic PKC-beta2 accumulation and modest activation of PKC-beta1 and PKC-epsilon. The inhibitory effect of DOPPA on ISC was related solely to increased cytoplasmic PKC-beta2 levels. Thus PKC-beta2 is hypothesized to participate in the regulation of CFTR apical plasma membrane targeting within the constitutive cellular biosynthetic pathway.

Colon↗
PubMed2006

Ileostomy diarrhea.

Ileostomy diarrhea is not an uncommon problem and can lead to considerable loss of quality of life. Unfortunately, well-designed therapeutic trials are lacking, and thus, treatment of patients with ileostomy diarrhea remains largely empiric. The majority of individuals will have "idiopathic" ileostomy diarrhea, or increased output due to proctocolectomy with limited ileal resection alone. Once other, less common causes are excluded, empiric treatment should be initiated with the safest, least costly option. In general, this consists of a dietary evaluation and symptomatic treatment with loperamide and advancing as needed to other, more expensive options, frequently with an increase in side effect profile. Other more recently evaluated treatment options include budesonide and oleic acid; however, efficacy has only been demonstrated in preliminary studies; further evaluation is needed. Limited data exist regarding success of surgical therapy such as reversed peristaltic ileal segments. It remains to be seen if surgery, other than ileostomy revision, has a role in the treatment of ileostomy diarrhea.

Journal Article↗
PubMed2006

Effect of race and ethnicity on perceptions of inflammatory bowel disease.

BACKGROUND AND AIMS: Historically, inflammatory bowel disease (IBD) was thought to predominantly affect whites. However, IBD is now increasingly recognized in diverse ethnic populations. There is a paucity of studies of IBD in nonwhite populations, especially in Mexican Americans. The aims of this study were to compare the impact of IBD on the quality of life of whites, African Americans, and Mexican Americans and to evaluate differing patient understanding and beliefs regarding IBD. MATERIALS AND METHODS: A questionnaire was administered to 148 patients between June 1999 and November 2003 at a university gastroenterology practice in Houston, Tex. RESULTS: Caucasians (W) comprised 40%, African Americans (AA) 37%, and Mexican Americans (MA) 20% of the respondents. AA and W had predominantly Crohn's disease (CD), whereas MA had predominantly ulcerative colitis (UC; P<0.05). We therefore compared W and AA with CD and W and MA with UC. W were more likely to tell their employers (57% vs 27.5%, P=0.02), fellow employees (68% vs 43.8%, P=0.02) and friends (100% vs 79%, P=0.034) that they had CD. W and AA were equally as likely to have regular checkups by a physician, and there was no difference in the access to gastroenterologists or surveillance colonoscopy. There were fewer differences between MA and W with UC. MA were more likely to believe that UC was caused by stress (70% vs 37%, p=0.044) and cigarette smoking. CONCLUSIONS: Significant differences appear among racial and ethnic groups with IBD regarding attitudes toward disease and impact on daily life. Appreciation of varying ethnic and racial perceptions, attitudes, and beliefs among patients with IBD may be critical to more effective management.

Black or African American↗
PubMed2005

Epithelial proliferation induces novel changes in APC expression.

The role of wild-type adenomatous polyposis coli (APC) protein in native epithelia is poorly understood. The present study examined the relationships between wild-type APC and beta-catenin expression in an established model of hyperproliferation, transmissible murine colonic hyperplasia (TMCH). Distal colonic crypts isolated from normal or TMCH mice were: (i) fractionated into cytosolic and nuclear components for Western blotting and immunoprecipitation (IP), (ii) extracted for total RNA isolation for Northern blotting and, (iii) analysed immunohistochemically by confocal microscopy. Western blots performed sequentially through day 12 TMCH with N-terminal APC antibodies revealed increased abundance of approximately 312 kDa (p312) protein by day 6 (4.0 +/- 0.75-fold, n = 6) that peaked by day 9, before declining by day 12. A approximately 130 kDa (p130) band appeared at day 9 and increased by day 12 (1.5 +/- 0.11-fold, n = 6). A C-terminal antibody detected only p312. APC mRNA level did not change during TMCH and appearance of p130 was not due to alternative splicing. Co-IP with N-terminal anti-APC antibodies, revealed APC's association with beta-catenin both at day 6 and day 12. p130, but not p312, associated predominantly with beta-catenin at day 12 during co-IP with anti-beta-catenin. p130 also selectively accumulated in the nucleus, bound to nuclear beta-catenin at day 12. Immunocytochemistry with N-terminal antibodies revealed an increasing crypt base : surface gradient of APC within the apical pole/apical-lateral membranes at day 6. At day 12, intense apical/cytoplasmic and occasional nuclear staining along the longitudinal crypt axis was observed. Full-length APC increases during epithelial hyperproliferation and may represent a homoeostatic response. The dramatic increase in cytoplasmic and sporadic nuclear APC staining at day 12 with N-terminal antibodies may represent p130. The nuclear accumulation of p130 may be a novel mechanism regulating nuclear beta-catenin function during TMCH.

Animals↗
PubMed2005

Impact of race and ethnicity on inflammatory bowel disease.

INTRODUCTION: Inflammatory bowel disease (IBD) is now increasingly recognized in diverse ethnic populations. In the United States, IBD among the minority populations, especially Mexican Americans, has not been extensively studied. Apart from the known genetic influences that differ among the IBD subtypes [ulcerative colitis (UC) vs. Crohn's disease (CD)], serologic markers may differentiate UC and CD, including perinuclear antineutrophilic cytoplasmic antibody (p-ANCA) and anti-Saccharomyces cerevisiae antibody (ASCA) in UC and CD. METHODS: One hundred forty-eight patients with IBD seen in a university gastroenterology practice in Houston, Texas, between June 1999 and November 2003 were analyzed to determine whether there were significant differences among racial/ethnic groups. Whites comprised 40%, African Americans 37%, Mexican Americans 20%, and Asians 3% of the total IBD patients. RESULTS: We found that African Americans and whites predominantly had CD, whereas Mexican Americans predominantly had UC. There was no difference between African Americans and Mexican Americans when separately compared to whites in terms of intestinal manifestations of CD and UC, respectively. However, African Americans with CD had a significantly higher incidence of IBD-associated arthritis (p= 0.004) and ophthalmological manifestations, notably uveitis (p= 0.028), compared to whites with CD. Among UC patients, in comparison to the Mexican Americans, whites had significantly higher incidences of joint symptoms (p < 0.0001) and osteoporosis (p= 0.001). Whites had a stronger family history of IBD and colorectal carcinoma compared to the other ethnic groups. p-ANCA served as a sensitive marker for UC among Mexican Americans. All the Mexican Americans with UC tested had positive p-ANCA compared to only 40% of whites (p= 0.033). CONCLUSION: There are significant differences in IBD subtypes and serologic markers among racial/ ethnic groups with IBD in the United States.

Adolescent↗
PubMed2004

Common variable immunodeficiency and the gastrointestinal tract.

Common variable immunodeficiency (CVID) is the second most prevalent primary immunodeficiency disorder but clinically the most important. It causes a wide spectrum of symptoms and signs affecting many systems of the body. CVID is a combination of humoral and cell-mediated deficiency, which explains not only why so many systems are affected but also why standard therapy in the form of intravenous immunoglobulin is not always effective. The gastrointestinal tract is the largest immune organ in the body, and it is therefore expected that this immunodeficiency will affect it in some way. The gastrointestinal manifestations of CVID are variable and tend to mimic known diseases, such as celiac sprue, pernicious anemia, and inflammatory bowel disease, but show significant differences on the microscopic level. Many studies continue to confirm a high prevalence of inflammatory, malignant, and infectious gastrointestinal disorders in patients with CVID. The T-cell-mediated defects of this immunodeficiency disorder are thought to be the cause of the majority of the gastrointestinal disorders in CVID and not the antibody deficiency. Therefore, intravenous immunoglobulin alone may be ineffective. Combination therapy with immunomodulators, such as azathioprine and 6-mercaptopurine, may be needed to treat these gastrointestinal manifestations of CVID.

Common Variable Immunodeficiency↗
PubMed2003

Video, part two.

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Endoscopes, Gastrointestinal↗
PubMed2003

Video, part three.

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Crohn Disease↗