Biomedical subjects

Yingnian Shen

Publications and source records attributed to Yingnian Shen.

4 recordsLinked to original sources

PubMed2006

Limited role for SREBP-1c in defective glucose-induced insulin secretion from Zucker diabetic fatty rat islets: a functional and gene profiling analysis.

Accumulation of intracellular lipid may contribute to defective insulin secretion in type 2 diabetes. Although Zucker diabetic fatty (ZDF; fa/fa) rat islets are fat-laden and overexpress the lipogenic master gene, sterol regulatory element binding protein 1c (SREBP-1c), the contribution of SREBP-1c to the secretory defects observed in this model remains unclear. Here we compare the gene expression profile of lean control (fa/+) and ZDF rat islets in the absence or presence of dominant-negative SREBP-1c (SREBP-1c DN). ZDF islets displayed elevated basal insulin secretion at 3 mmol/l glucose but a severely depressed response to 17 mmol/l glucose. While SREBP-1c DN reduced basal insulin secretion from ZDF islets, glucose-stimulated insulin secretion was not improved. Of 57 genes differentially regulated in ZDF islets and implicated in glucose metabolism, vesicle trafficking, ion fluxes, and/or exocytosis, 21 were upregulated and 5 were suppressed by SREBP-1c DN. Genes underrepresented in ZDF islets were either unaffected (Glut-2, Kir6.2, Rab3), stimulated (voltage-dependent Ca(2+) channel subunit alpha1D, CPT2, SUR2, rab9, syt13), or inhibited (syntaxin 7, secretogranin-2) by SREBP-1c inhibition. Correspondingly, SREBP-1c DN largely corrected decreases in the expression of the transcription factors Pdx-1 and MafA but did not affect the abnormalities in Pax6, Arx, hepatic nuclear factor-1alpha (HNF1alpha), HNF3beta/Forkhead box-a2 (Foxa2), inducible cyclic AMP early repressor (ICER), or transcription factor 7-like 2 (TCF7L2) expression observed in ZDF islets. We conclude that upregulation of SREBP-1c and mild increases in triglyceride content do not explain defective glucose-stimulated insulin secretion from ZDF rats. However, overexpression of SREBP-1c may contribute to enhanced basal insulin secretion in this model.

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PubMed2006

Suppression of the cell-mediated immune response by a Fas-immunoglobulin fusion protein.

INTRODUCTION: Immunosuppressive agents must not only be effective in impairing the host's allo-immune response, but should also be selective in targeting only those elements of the immune system activated by the allograft. The fact that allo-activated T cells express surface protein molecules that are not typically present on resting T cells can be exploited to specifically target this population. Fas ligand is one such molecule whose cell surface expression on T cells is dramatically up-regulated upon activation. METHODS: We constructed a murine fusion protein by linking the extracellular domain of Fas to the Fc region of IgG2a. The rationale being to selectively target activated T cells via binding of its Fas moiety to cell surface Fas ligand, and then to allow the Fc moiety to invoke its usual effector mechanisms resulting in the destruction of the allo-activated T cell. Here, we describe the design and expression of Fas-IgG2a and characterize several key in vitro and in vivo properties of this fusion protein including its ability to impact on both cell-mediated immune responses and cellular apoptotic activity using a murine model of delayed-type hypersensitivity. RESULTS: In vitro, our Fas-IgG2a construct bound activated T cells via FasL and invoked cytotoxicity. In vivo, it demonstrated a prolonged half-life characteristic of an immunoglobulin-like molecule. Most significantly, it suppressed the cell-mediated immune response and diminished cellular apoptotic activity in lymphoid tissue in our murine model. CONCLUSION: Fas-IgG2a is a novel agent for delivering target-specific immunosuppression with potential applicability in the transplant setting.

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PubMed2005

Decrease in brain POMC mRNA expression and onset of obesity in guinea pigs exposed to 2-chloroethyl ethyl sulfide, a mustard analogue.

The full spectrum of physiological effects resulting from exposure to sulfur mustard and its analogs is currently unknown. In a guinea pig model, initially selected to study the role of an inflammatory cytokine cascade in mustard gas induced lung injury, we observed significant body weight gain in guinea pigs exposed to an intratracheally injected single dose of 2-chloroethyl ethyl sulfide, a mustard analog. The body weight gain was not associated with any apparent change in appetite. To further elucidate a molecular basis for the observed weight gain, we evaluated candidate genes for the obese phenotype by quantitative RT-PCR. We observed a time- and dose-dependent decrease in guinea pig pro-opiomelanocortin (POMC) message following treatment with mustard gas. This reduction in POMC message is consistent with the onset of obesity in the animals. We hypothesize that the POMC melanocortin pathway provides a mechanistic basis for the observed effects of sulfur mustard on body weight.

Animals↗

PubMed2004

Quantification of donor microchimerism in sex-mismatched porcine allotransplantation by competitive PCR.

The persistence of donor cells in recipient circulation and peripheral tissues post-transplantation has been demonstrated in solid organ allotransplantation and xenotransplantation models. Although this state of microchimerism has been postulated as the basis for graft acceptance, chimerism has not been directly linked to the maintenance of peripheral tolerance or prevention of rejection. Studies have demonstrated that the qualitative presence or absence of donor microchimerism bears no association with graft acceptance. Our preliminary work suggests that there is a threshold chimerism necessary for the induction of donor-specific hyporesponsiveness. Because the kinetics of donor cell accumulation and distribution in allograft recipients are largely unknown, quantitative analyses are needed to evaluate chimerism's significance to donor-specific tolerance. We developed a quantitative, competitive PCR assay to precisely measure the amount of chimerism in male to female transplant pairs by targeting the sex-determining region of the Y chromosome (SRY gene). Traditionally, this technique requires that serial known amounts of an SRY-specific competitive template (CT) be coamplified with a constant amount of sample DNA to determine the equivalence point of the relative band intensities of the PCR products. However running a panel of PCRs with CT amounts above and below the equivalence point to generate a standard curve for ever' sample is laborious. Here we describe the generation of a single standard curve that permits the rapid and reliable quantification of microchimerism after coamplification of sample DNA with a single amount of CT.

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