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S Qian

Publications and source records attributed to S Qian.

At least 55 records · Page 3Linked to original sources
PubMed2000

[Photoluminescence study of star-like C60(CH3)x(PAN)x copolymer].

Thin film of new synthesized C60(CH3)x(PAN)x copolymer was fabricated by physical jet deposition (PJD) technique. C60 molecule lies in the center of the star-like copolymers. PAN main chain is modified around the C60 molecules. Absorption and photoluminescence spectra show that there are strong interaction between C60 molecule and PAN, which depends on the length of PAN chain. Partly excitation transfer process between C60 molecule and PAN was observed, which leads to the fluorescence quenching of the PAN.

English Abstract↗
PubMed1999

Differential effects of exogenous interleukin-10 on cardiac allograft survival: inhibition of rejection by recipient pretreatment reflects impaired host accessory cell function.

BACKGROUND: There have been conflicting reports of the influence of exogenous mammalian interleukin (IL)-10 on immune reactivity. These findings may reflect the pleiotropic effects of IL-10 on the functions of antigen-presenting cells and immune effector cells. The purpose of this study was to extend observations of the influence of the cytokine on organ allograft survival and to investigate its effects on the function of accessory and immune effector cells in a mouse cardiac transplant model. METHODS: C3H (H2k) recipients of heterotopic vascularized B10 (H-2b) heart allografts were treated with recombinant (r) mouse IL-10 over a wide range of doses (0.2-200 microg/day), either before the transplant (days -3, -2, -1), peri-operatively (days -1, 0, 1), or after the transplant (days 0-6). Anti-donor cytotoxic T lymphocyte activity of host spleen and graft-infiltrating cells, and circulating complement-dependent cytotoxic antibody titers were determined by isotope release assays. Mixed leukocyte reactions were used to determine the influence of IL-10 on the function of antigen-presenting cells and allogeneic responder T cells. RESULTS: Recipient pre-transplant administration of IL-10 (days -3, -2, -1) prolonged graft survival at all doses tested. Donor pretreatment with IL-10 (25 microg/day; days -3, -2, -1) was also effective, but less. A pre-transplant or perioperative course of IL-10, however, did not significantly affect the immunosuppressive action of tacrolimus given on days 0-6. If given only after the transplant, IL-10 either had no effect on graft survival or (at high dosage) accelerated rejection and prevented the immunosuppressive effect of cyclosporine. Pretransplant treatment of graft recipients with IL-10 reduced splenic anti-donor cytotoxic T lymphocyte activity and the incidence of graft-infiltrating CD8+ cells. There was no significant effect on circulating alloantibody titers. MLR assays revealed that preincubation of responder cells, but not stimulator spleen cells with IL-10, inhibited T cell proliferation, whereas addition of IL-10 after the start of culture modestly enhanced proliferation. Preincubation of purified T responders with IL-10 showed no inhibitory effect. CONCLUSION: The modest and opposing effects of exogenous IL-10 on organ allograft survival are dependent on timing and dosage. Recipient pretreatment prolongs graft survival. This finding, together with the MLR results, suggest that IL-10 inhibits the function of host immune accessory cells and that the direct pathway of alloantigen presentation may be less susceptible to inhibition by IL-10.

Animals↗
PubMed1999

Increased apoptosis of immunoreactive host cells and augmented donor leukocyte chimerism, not sustained inhibition of B7 molecule expression are associated with prolonged cardiac allograft survival in mice preconditioned with immature donor dendritic cells plus anti-CD40L mAb.

BACKGROUND: We previously reported the association among donor leukocyte chimerism, apoptosis of presumedly IL-2-deficient graft-infiltrating host cells, and the spontaneous donor-specific tolerance induced by liver but not heart allografts in mice. Survival of the rejection-prone heart allografts in the same strain combination is modestly prolonged by the pretransplant infusion of immature, costimulatory molecule-(CM) deficient donor dendritic cells (DC), an effect that is markedly potentiated by concomitant CM blockade with anti-CD40L (CD154) monoclonal antibody (mAb). We investigated whether the long survival of the heart allografts in the pretreated mice was associated with donor leukocyte chimerism and apoptosis of graft-infiltrating cells, if these end points were similar to those in the spontaneously tolerant liver transplant model, and whether the pretreatment effect was dependent on sustained inhibition of CM expression of the infused immature donor DC. In addition, apoptosis was assessed in the host spleen and lymph nodes, a critical determination not reported in previous studies of either spontaneous or "treatment-aided" organ tolerance models. METHODS: Seven days before transplantation of hearts from B10 (H-2b) donors, 2x10(6) donor-derived immature DC were infused i.v. into C3H (H-2k) recipient mice with or without a concomitant i.p. injection of anti-CD40L mAb. Donor cells were detected posttransplantation by immunohistochemical staining for major histocompatibility complex class II (I-Ab) in the cells of recipient lymphoid tissue. CM expression was determined by two-color labeling. Host responses to donor alloantigen were quantified by mixed leukocyte reaction, and cytotoxic T lymphocyte (CTL) assays. Apoptotic death in graft-infiltrating cells and in areas of T-dependent lymphoid tissue was visualized by terminal deoxynucleotidyltransferase-catalyzed dUTP-digoxigenin nick-end labeling and quantitative spectrofluorometry. Interleukin-2 production and localization were estimated by immunohistochemistry. RESULTS: Compared with control heart transplantation or heart transplantation after only DC administration, concomitant pretreatment with immature donor DC and anti-CD40L mAb caused sustained elevation of donor (I-Ab+) cells (microchimerism) in the spleen including T cell areas. More than 80% of the I-Ab+ cells in combined treatment animals also were CD86+, reflecting failure of the mAb to inhibit CD40/ CD80/CD86 up-regulation on immature DC in vitro after their interaction with host T cells. Donor-specific CTL activity in graft-infiltrating cells and spleen cell populations of these animals was present on day 8, but decreased strikingly to normal control levels by day 14. The decrease was associated with enhanced apoptosis of graft-infiltrating cells and of cells in the spleen where interleukin-2 production was inhibited. The highest levels of splenic microchimerism were found in mice with long surviving grafts (>100 days). In contrast, CTL activity was persistently elevated in control heart graft recipients with comparatively low levels of apoptotic activity and high levels of interleukin-2. CONCLUSION: The donor-specific acceptance of rejection-prone heart allografts by recipients pretreated with immature donor DC and anti-CD40L mAb is not dependent on sustained inhibition of donor DC CM (CD86) expression. Instead, the pretreatment facilitates a tolerogenic cascade similar to that in spontaneously tolerant liver recipients that involves: (1) chimerism-driven immune activation, succeeded by deletion of host immune responder cells by apoptosis in the spleen and allograft that is linked to interleukin-2 deficiency in both locations and (2) persistence of comparatively large numbers of donor-derived leukocytes. These tolerogenic mechanisms are thought to be generic, explaining the tolerance induced by allografts spontaneously, or with the aid of various kinds of immunosuppression.

Animals↗
PubMed1999

Prevention and restoration of second-set liver allograft rejection in presensitized mice: the role of "passenger" leukocytes, donor major histocompatibility complex antigens, and host cytotoxic effector mechanisms.

BACKGROUND: The aim was to determine whether sublethal donor total body irradiation (TBI) might be as effective as lethal TBI in preventing mouse second-set liver allograft rejection, and to evaluate the role of passenger leukocytes, donor major histocompatibility complex (MHC) antigens, and host effector mechanisms in the response to livers from sublethally irradiated donors. METHODS: B10 (H2b) donors received various doses of TBI at different times before their livers were transplanted orthotopically into normal or donor skin-presensitized C3H (H2k) recipients. The influence of irradiation on graft non-parenchymal cells (NPC) was determined by monoclonal antibody staining, and flow cytometric analysis. Hematopoietic cells within the grafts were reconstituted by intravenous infusion of syngeneic or third-party bone marrow cells. Allograft survival was determined in recipients that received no treatment, or that were given spleen cells from either normal B10 donors, or MHC class I - or class II-deficient mice syngeneic with the donors. Cytotoxic activity of graft-infiltrating cells and host spleen cells, and complement-dependent cytotoxic alloantibody titers were determined by isotype release assays. RESULTS: The protective effect of donor TBI was observed both at lethal (9.5 Gy) and sublethal doses (5 and 3 Gy; graft median survival time: >100 days). Extended delay in liver transplantation, allowing hematopoietic recovery and graft reconstitution eliminated the effect. Liver NPC were reduced about 80% within 24 hr of 3 Gy TBI, with a selective reduction in the incidence of B cells. The NPC-depleted livers underwent accelerated rejection when donor (but not third-party) spleen cells (5 x 10(7) were administered systemically to the recipient immediately after graft revascularization. Spleen cells from MHC class I-deficient (but not MHC class II-deficient) mice failed to fully restore accelerated rejection of TBI liver grafts. Freshly isolated graft NPC, or spleen cells from TBI liver recipients, harvested 4 days after transplantation, exhibited lower, donor-specific cytotoxic activity than cells from mice given normal livers. Recipients of TBI livers also showed much lower serum complement-dependent cytotoxic alloantibody titers. CONCLUSIONS: By substantially depleting "passenger leukocytes," sublethal donor TBI undermines anti-donor cell-mediated and humoral immune reactivity and inhibits second-set liver allograft rejection in presensitized recipients. The interval between irradiation and transplantation is important in conferring resistance to rejection. Expression of MHC class I on donor leukocyte infusions is important for overcoming resistance to second-set rejection induced by donor irradiation.

Animals↗
PubMed1999

Evidence for a role of IL-17 in organ allograft rejection: IL-17 promotes the functional differentiation of dendritic cell progenitors.

IL-17 is a T cell-derived cytokine that stimulates stromal cells and macrophages to secrete proinflammatory cytokines. We hypothesized that IL-17 might play a role in alloimmune responses, and that interference with its activity might suppress allograft rejection. IL-17R:Fc or control IgG was added at the start of mouse MLR or was administered i.p. (100-500 microg/day) for different durations post-transplant to murine recipients of MHC-mismatched cardiac allografts. IL-17R:Fc (50-200 microg/ml) markedly inhibited T cell proliferation in vitro and significantly prolonged nonvascularized cardiac allograft median survival time from 13 to 20 days (100 microg/day; days 0 and 1) or to 19 days (100-300 microg/day; days 0-4). Survival of vascularized grafts was also extended significantly from 10.5 to 19 days by IL-17R:Fc (500 microg/day; days 0-6). To address a possible mechanism by which IL-17 may promote alloreactivity, we examined the influence of IL-17 on the differentiation and function of bone marrow-derived cells propagated in granulocyte-macrophage CSF with or without IL-4 to promote dendritic cell (DC) growth. A minor proportion of CD11c+ DC expressed the IL-17R. IL-17 promoted the maturation of DC progenitors, as evidenced by increased cell surface expression of CD11c, costimulatory molecules (CD40, CD80, CD86), and MHC class II Ag, and allostimulatory capacity. IL-17 had a lesser effect on the phenotype and function of more fully differentiated myeloid DC. These findings suggest a role for IL-17 in allogeneic T cell proliferation that may be mediated in part via a maturation-inducing effect on DC. IL-17 appears to be a novel target for therapeutic intervention in allograft rejection.

Adjuvants, Immunologic↗
PubMed1999

Genetic engineering of dendritic cells to express immunosuppressive molecules (viral IL-10, TGF-beta, and CTLA4Ig).

There is growing evidence that, in addition to their role as initiators of immune responses, dendritic cells (DC) can exhibit tolerogenic properties. Immature DC deficient in cell surface costimulatory/accessory molecules can prolong organ and pancreatic islet allograft survival, whereas in vitro manipulation of DC by exposure to a variety of factors (e.g., viral interleukin-10; CTLA4Ig) can confer tolerogenic properties on these cells. Genetic engineering of DC to express immunosuppressive molecules is, in theory, an attractive approach to the therapy of allograft rejection and possibly, autoimmune disorders.

Abatacept↗
PubMed1999

Hepatic dendritic cells: immunobiology and role in liver transplantation.

Traditional investigations of hepatic dendritic cells (DC) have focused on immunohistochemical studies of these cells within normal and pathological liver tissue. The recent availability of reagents for the improved characterization of DC, together with cytokine-based methods for the expansion of liver DC both in vivo and in vitro have begun to provide new insight into the immunobiology of these important antigen-presenting cells. Hepatic DC probably play a key role in the host response to blood-borne pathogens, and in the pathogenesis of infectious and autoimmune liver diseases. They appear to be important in determining the balance between liver transplant tolerance and rejection. Their possible role in oral and portal venous tolerance remains to be defined. In this article, we focus on emerging aspects of hepatic DC immunobiology, with particular reference to liver transplantation.

Animals↗
PubMed1999

Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their in vitro tolerogenicity and survival in allogeneic recipients.

Dendritic cells (DC) are highly specialized antigen-presenting cells (APC) that initiate and modulate immune responses. They are essential for naive T cell activation, but may also play roles both in central and peripheral tolerance. Blockade of costimulatory pathways that provide the crucial second signal for lymphocyte activation is one strategy to augment the potential tolerogenicity of DC. Here, in vitro propagated DC were transduced using an adenoviral (Ad) vector to express the gene encoding cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4lg), which blocks interaction of CD80 and CD86 on DC with CD28 on T cells. Supernatants of AdCTLA4lg-transduced DC strikingly inhibited mixed leukocyte reactions (MLR) induced by non-transduced DC. Whereas transduction of marker genes (LacZ or enhanced green fluorescence protein (EGFP)) did not alter their potent allostimulatory activity, DC transduced with CTLA4lg exhibited striking reductions in cell surface staining for CD86, but not MHC class II, and were poor stimulators of T cell proliferation and cytotoxic T lymphocyte (CTL) responses. In addition, they induced alloantigen-specific T cell hyporesponsiveness. They were detected, following local injection, in significantly increased numbers in the lymphoid tissue of unmodified allogeneic recipients. This is the first report of the functional properties of DC genetically engineered to express CTLA4lg.

Abatacept↗
PubMed1999

[Purification and properties of human lysozyme in engineered bacterium E. coli].

To obtain the SDS-PAGE-pure human lysozyme, the crude enzyme of engineered bacterium E. coli was purified by chromatography on cation ion exchange of Express-Ion S. The optimum reaction temperature and pH of this lysozyme were 45 degrees C and 6.5, respectively. The isoelectric point is pH 8.91, and Km of the enzyme for Micrococcus lysodeikticus is 0.0311 mg/mL. The thermal stability of the engineered enzyme is more sensible than hen egg white lysozyme and human milk lysozyme. The sequence of 5 amino acids in N-end is same as designed, except an Met at the first. The affects of some metal ion on this enzyme were shown. Cu2+ of 0.01 mmol/L could completely inactivate the enzyme.

Amino Acid Sequence↗
PubMed1999

[Preparation, purification and identification of sialic acid from Escherichia coli C-8].

Colominic acid produced from Escherichia coli C-8 was purified by ammonia sulfate precipitation, dialysis and concentration. After hydrolysis of colominic acid at a pH of 2.5, at 70 degrees C for 4 h, sialic acid was obtained, then purified by chromatography on Dowex1-x8. Analysis of thin-layer chromatography and absorption spectrum of sialic acid in the orcinol/Fe3+/HCl and the periodic acid/thiobarbituric acid confirmed that its purity was identical with that of standard sample.

Chromatography, Thin Layer↗
PubMed1999

[Culture conditions of engineered strain of L-asparaginase and the recombinant plasmid stability].

The growth curves of engineered strain JM105(pASN) were different in LB and M-3 media. The expression level and activity of L-asparaginase were affected apparently by both biomass and induction time. Glucose repression of production of L-asparaginase was found. The stability of the recombinant plasmid pASN in different host strains and in LB and M-3 media was determined. After cultivation inLB broth and M-3 media at 30 degrees C for more than 50 generations without antibiotic selection, then induced at 42 degrees C for up to 5 h, the engineered strains were proved to be stable, except for DHA alpha (pASN).

Asparaginase↗
PubMed1999

[Study on application of crosslinked chitosan to the speciation analysis of selenium].

The adsorption of Se(IV)/Se(VI) by crosslinked chitosan was studied and the adsorption mechanism was concerned. The results indicated that the adsorption of Se(VI) was 95% at pH=4, while almost no adsorption for Se(IV). The adsorbed Se(VI) was quantitatively desorbed with 1 mol/L HCl after adsorption of Se(VI). A new method for the determination of trace Se(IV)/Se(VI) and organic selenium in environmental samples with hydride generation and atomic absorption spectphotometry has been developed. The detection limit of this method was 20 ng/L, the recovery was 93%-106% and the coefficient of variation was 2.0%-5.0%.

Adsorption↗
PubMed1998

Systemic administration of anti-interleukin-10 antibody prolongs organ allograft survival in normal and presensitized recipients.

BACKGROUND: Systemic administration of cellular interleukin (IL)-10 at a dose of 100 microg/day for 1 week after transplantation accelerates mouse cardiac allograft rejection across MHC barriers. This effect is associated with enhancement of donor-specific cytotoxic T lymphocyte and alloantibody (alloAb) titers. To further evaluate the in vivo role of IL-10, we tested the influence of a neutralizing anti-IL-10 monoclonal antibody (mAb) in both normal and donor (skin) presensitized mouse organ allograft recipients. METHODS: Heart or liver transplants were performed from B10 (H2b) donors to C3H (H2k) recipients. Anti-IL-10 mAb (SXC.I) was administered intravenously in a single injection or repeated once daily injections. Cytotoxic activity of graft-infiltrating cells was determined by 51Cr-release assay. Circulating alloAb levels were quantified by complement-dependent cytotoxicity and flow cytometry. RESULTS: Survival of vascularized B10 cardiac allografts in normal recipients was prolonged significantly in the mAb-treated groups. A single injection of 1 mg of anti-IL-10 mAb immediately after heart transplantation gave a similar graft median survival time to repeated injections of lower dose mAb (0.5 mg/day for 6 days after transplantation) (Ig isotype control 11 days; single mAb injection 18 days; multiple injection 20 days). In presensitized recipients, anti-IL-10 mAb from days 0 to 6 significantly prolonged survival of both cardiac and orthotopic liver grafts. Graft median survival time was extended from 5 to 10 days and from 4 to 11 days, respectively. Prolongation of liver allograft survival in presensitized recipients was associated with suppression of circulating alloAb levels and with significant reductions in the incidence of B220+ cells in both grafts and recipient spleens. CONCLUSIONS: The data support an adverse role of anti-IL-10 in allograft rejection; it seems that by reducing alloAb responses, anti-IL-10 mAb may have potential for use as a therapeutic immunosuppressant, particularly in presensitized organ allograft recipients.

Animals↗
PubMed1998

Phenotype, function, and in vivo migration and survival of allogeneic dendritic cell progenitors genetically engineered to express TGF-beta.

BACKGROUND: Administration of donor bone marrow (BM)-derived dendritic cell (DC) progenitors (DCp) that are major histocompatibility complex (MHC) class II+ but costimulatory molecule (CD40, CD80, CD86)-deficient can prolong mouse heart allograft survival This is associated with microchimerism and inhibition of antidonor cytotoxic T lymphocyte (CTL) activity. Genetic modification of these donor antigen-presenting cells to express an immunosuppressive molecule(s) may enhance their in vivo survival and potential tolerogenicity. METHODS: The surface phenotype of B10(H-2b) DCp before and after gene transfer using replication-deficient adenoviral (Ad) vectors was determined by monoclonal antibody (mAb) staining and flow cytometry. Transforming growth factor-beta (TGF-beta) production was quantitated by enzyme-linked immunosorbent assay. Allostimulatory activity of the gene-transduced DCp was ascertained by mixed leukocyte reaction (MLR) and CTL induction. To assess their in vivo migratory activity and survival, the transduced cells were injected subcutaneously into one hind footpad of C3H (H-2k) mice. Tissues (draining popliteal lymph nodes [LN], spleens, and thymi) were removed 1, 2, 7, and 14 days later and stained for donor MHC class II using anti-LA(b) mAb in an immunohistochemical procedure. The mean number of IAb+ cells per unit area was determined. RESULTS: Transduction with a control Ad vector (Ad-LacZ) at 50 multiplicity of infection slightly increased CD40 and CD86 expression and up-regulated the poor allostimulatory activity of the DCp assessed by MLR and CTL responses. These effects on function were negated in Ad-TGF-beta1-transduced cells. After their injection into mouse footpads, the gene-transduced IAb+ cells were observed in maximal numbers in the popliteal LN at day 1 and in marginal zones and T-dependent areas of spleens (peak at day 7) but were rare in thymi. Transduction with Ad-LacZ reduced the numbers of IAb+ cells identified in both LN and spleens at all time points postinjection, suggesting that the vector alone affected DC life span in allogeneic recipients. TGF-beta1 transgene expression not only fully prevented the reduction in DC induced by Ad transduction alone, but also increased numbers and prolonged the survival of donor cells in the spleen, as shown by a two-to fivefold increase in IAb+ cells at days 2-14 compared with control (Ad-LacZ-transduced) DC. CONCLUSION: BM-derived DCp can be transduced efficiently to express TGF-beta1 using an Ad vector. They exhibit very poor allostimulatory activity and similar migration characteristics in vivo to unmodified DCp. Survival of TGF-beta gene-transduced DC, however, is enhanced significantly compared with unmodified and (especially) control Ad-LacZ gene-transduced DC. Genetic engineering of donor DC to express the immunosuppressive molecule TGF-beta promotes their survival in allogeneic hosts and may potentiate their previously reported tolerogenicity.

Adenoviridae↗
PubMed1998

Donor pretreatment with Flt-3 ligand augments antidonor cytotoxic T lymphocyte, natural killer, and lymphokine-activated killer cell activities within liver allografts and alters the pattern of intragraft apoptotic activity.

BACKGROUND: Liver allografts are accepted across major histocompatibility complex (MHC) barriers in mice and induce donor-specific tolerance without requirement for immunosuppressive therapy. There is evidence that passenger leukocytes may play a key role in tolerance induction. Flt-3 ligand (FL) is a recently cloned hematopoietic cytokine that strikingly augments functional dendritic cells (DCs) within lymphoid and nonlymphoid tissue. METHODS: The expression of costimulatory molecules and MHC class II antigen on DCs isolated from livers of FL-treated B10 (H2b) mice (10 microg/day; 10 days) was examined by flow cytometric analysis, and their allostimulatory activity assessed in primary mixed leukocyte cultures. B10 livers from FL-treated donors were transplanted orthotopically into naive C3H (H2k) recipients. Donor cells (MHC class II+) in recipient spleens were identified by immunohistochemistry. Antidonor cytotoxic T lymphocyte activity, and both natural killer and lymphokine-activated killer cell activities of graft nonparenchymal cells and host splenocytes were determined using isotope release assays. Apoptotic activity within liver grafts was determined by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling. RESULTS: DCs isolated from livers of FL-treated donor mice exhibited increased cell surface expression of CD40, CD80, CD86, and IAb, and augmented T cell allostimulatory activity compared with controls. Within 24 hr of organ transplantation, the numbers of donor IAb+ cells within recipient spleens was augmented substantially compared with normal liver recipients. Livers from FL-treated donors were rejected acutely (median survival time, 5 days), whereas control B10 liver allografts survived >100 days. Nonparenchymal cells from rejecting grafts 4 days after transplantation exhibited increased antidonor cytotoxic T lymphocyte, natural killer, and lymphokine-activated killer cell activities compared with cells from spontaneously accepted grafts. This augmented cytotoxic reactivity was associated with histologic evidence of injury to bile duct epithelium and vascular endothelium that was not readily evident in controls. CONCLUSION: Thus, although normal livers provide allostimulatory signals sufficient to elicit an antidonor immune response, regulatory mechanisms that may include apoptosis of graft-infiltrating T cells, and that are overcome by augmenting the number of functional donor DCs, may account for inherent liver tolerogenicity.

Animals↗
PubMed1998

Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Abeta1-42/43 expression.

Mutations in presenilin 1 (PS1) are linked to early onset of familial Alzheimer's disease (FAD) and are shown to foster production of Abeta1-42/43 in FAD patients and transgenic mice. PS1 null mice are embryonic lethal and exhibit axial skeleton malformation and CNS defects. We show that transgenic mouse lines expressing either the wild-type human PS1 protein or human PS1 with the A246E FAD mutation can rescue the PS1 knockout mouse from embryonic lethality to similar degrees, indicating that the mutation does not lead to loss of PS1 function during development. Furthermore, a 50% reduction of PS1 activity in PS1(+/-) mice does not lead to Abeta1-42/43 increase, whereas expression of human mutant PS1 on murine PS1 null background is sufficient to elevate Abeta1-42/43, supporting a gain-of-function activity as the result of the PS1 mutation.

Alzheimer Disease↗
PubMed1998

Vanadate elevates lipogenicity of starved rat adipose tissue: mechanism of action.

We have established an experimental system in rats in which the lipogenic capacity of adipose tissue was decreased in vivo by prolonged fasting, and restored in vitro by glucose together with insulin or vanadate. Incubation of fasted adipose explants for 5 h at 37 C with 2 mM glucose alone did not elevate lipogenic capacity. However, glucose with insulin (17 nM) or vanadate (100 microM), led, respectively, to 2.2- and 8- to 10-fold elevation. Actinomycin D (50 microM) completely blocked this increase, while low concentrations (ED50 = 4.0 +/- 0.4 microM) of vanadate potentiated it. Neither insulin nor vanadate elevated fasted adipose explants' lipogenic capacity in the absence of glucose, or in the presence of the nonmetabolizable glucose analog 3-O-methylglucose. Upon replacing glucose with 2-deoxyglucose (1 mM), a glucose analog that undergoes phosphorylation to 2-deoxyglucose-6-phosphate with no further metabolism, vanadate was nearly as potent as with glucose in elevating lipogenic capacity. Vanadate was superior to insulin in increasing glucose-6-phosphate level in fasted-adipose explants. Adipose glucose-6-phosphatase activity was inhibited by vanadate (IC50 = 7.0 +/- 0.4 microM). We have concluded that glucose-6-phosphate is the key metabolite of glucose involved in the transcriptionally regulated elevation of lipogenic capacity of fasted adipose explants. Vanadate has a more profound effect than insulin, as it elevates glucose-6-phosphate to higher levels and the subsequent increase in lipogenic capacity is four to five times greater than that induced by insulin. The mechanism involved is the combined action of vanadate in enhancing glucose entry and in inhibiting dephosphorylation of endogenously formed glucose-6-phosphate. The latter effect is not exerted by insulin.

3-O-Methylglucose↗