Biomedical subjects

Li Wang

Publications and source records attributed to Li Wang.

At least 73 records · Page 4Linked to original sources

PubMed2006

[Bile salts induce differentiation in cultured human normal esophageal mucosal epithelial cells].

OBJECTIVE: To investigate the effects of bile salts on the proliferation and differentiation of human normal esophageal mucosal epithelial cells on cultured. METHODS: Normal human esophageal mucosa was obtained during operation. The esophageal epithelial cells were isolated, cultured, and treated with 6 different conjugated bile salts [glycocholate (GC), glycochenodeoxycholate (GCDC), glycodeoxycholate (GDC), taurochenodeoxycholate (TCDC), and taurodeoxycholate (TDC), all of the concentration of 50 micromol/L, and taurocholate (TC) of the concentration of 20 micromol/L], and their mixtures the concentration of 50 micromol/L respectively. One, three, and five days later MTT assay was applied to detect the cell proliferation. The cell cycle was assayed by flow cytometry with propidium iodide staining 1 and 3 d after treating with the bile salts. The cytokeratin 13 (CK13) in the differentiated cells and cytokeratin 14 (CK14) in the proliferating cells were detected by immunocytochemical assay. The concentration of intercellular calcium ([Ca(2+)]i) was analyzed by Laser Scanning Confocal Microscope (LSCM) in cells with TC, mixed bile salts and GC. RESULTS: The cultured esophageal epithelial cells treated by the bile salts, except those treated by GC for 1 - 3 days, became larger and shuttle-like, with the cell proliferation inhibited, the percentages of cells in G(0)-G(1) phase increased and percentages of cells in S phase decreased. The percentages of CK14 positive cells were increased, but the percentages of CK13 positive cells were decreased time-dependently in cells treated for 1 - 5 days. The most obvious effects were seen in those cells treated with TC. The percentage of CK13 positive cells reached 74% +/- 8% in those cells treated with TC for 5 days, higher significantly than the percentage in the control cell (22% +/- 7%), (P < 0.01). The [Ca(2+)]i increased significantly only several minutes after treatment of TC and mixed bile salts, however, GC failed to cause the increase of [Ca(2+)]i. CONCLUSION: GCDC, GDC, TC, TCDC, TDC and their mixture all induce differentiation of cultured human normal esophageal mucosal epithelial cells, but nor does GC. Increased [Ca(2+)]i is related to the TC-induced differentiation in those esophageal mucosal epithelial cells.

Bile Acids and Salts↗

PubMed2006

Immunogenicity of a plant-derived edible rotavirus subunit vaccine transformed over fifty generations.

Major efforts have been put forth for the development of effective rotavirus vaccines including transgenic plant vaccines. Previous studies have reported that rotavirus VP7 maintains its neutralizing immunity when it is transformed into the potato genome. The present study was aimed at investigating the hereditary stability of VP7-transformed potatoes over fifty generations. The VP7 gene was stably transcribed and expressed in potato cells as detected by RT-PCR and Western blotting. Humeral and mucosal responses were successfully induced in BALB/c mice fed with the fiftieth generation transformed potato tubers. There were no significant differences in serum IgG and fecal IgA between the mice fed with the first and fiftieth generation potatoes (P>0.05). Profiles of cytokines such as IFN-gamma, IL-2, IL-4, IL-5 and TGF-beta in immunized mice showed a naive T-cells bias to Th1 and Th3 polarization. Moreover, specific CTL responses were also detected in C57BL/6 mice fed with transformed potatoes. This research represents a significant step towards the development of rotavirus vaccines derived from a transgenic plant that can be obtained by long-term and large-scale vegetative reproduction. To our knowledge, this is the first finding regarding vaccines derived from plants that can be propagated for many generations.

Animals↗

PubMed2006

Coordinated control of bile acids and lipogenesis through FXR-dependent regulation of fatty acid synthase.

We discovered a nuclear receptor element in the FAS promoter consisting of an inverted repeat spaced by one nucleotide (IR-1) and located 21 bases downstream of a direct repeat sequenced by 4 nucleotides (DR-4) oxysterol liver X receptor response element. An IR-1 is present in promoters of several genes of bile acid and lipid homeostasis and binds farnesoid X receptor/retinoid X receptor (FXR/RXR) heterodimers to mediate bile acid-dependent transcription. We show that FXR/RXRalpha specifically binds to the FAS IR-1 and that the FAS promoter is activated approximately 10-fold by the addition of a synthetic FXR agonist in transient transfection assays. We also demonstrate that endogenous FXR binds directly to the murine FAS promoter in the hepatic genome using a tissue-based chromatin immunoprecipitation procedure. Furthermore, we show that feeding wild-type mice a chow diet supplemented with the natural FXR agonist chenodeoxycholic acid results in a significant induction of FAS mRNA expression. Thus, we have identified a novel IR-1 in the FAS promoter and demonstrate that it mediates FXR/bile acid regulation of the FAS gene. These findings provide the first evidence for direct regulation of lipogenesis by bile acids and also provide a mechanistic rationale for previously unexplained observations regarding bile acid control of FAS expression.

Animals↗

PubMed2006

Investigation of the acid-base properties of mononitro-calix[4]arene with chemometric methods.

The acid-base properties of mononitro-calix[4]arene was studied with chemometric methods by measurement of its UV absorbance under different pH. The chemometric method-iterative target transformation factor (ITTFA) was employed to resolve the acid-base fraction curves. Combining with other chemometric methods-principal component analysis (PCA) and evolving factor analysis (EFA), the proton dissociation behavior of the derivative was investigated in detail. The pK(a) values of the derivative were determined and the fraction curves and pure absorbing spectra of each absorbing component were obtained.

Acids↗

PubMed2006

Eliminating established tumor in nu/nu nude mice by a tumor necrosis factor-alpha-related apoptosis-inducing ligand-armed oncolytic adenovirus.

PURPOSE: The tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) and oncolytic viruses have recently been investigated extensively for cancer therapy. However, preclinical and clinical studies have revealed that their clinical application is hampered by either weak anticancer activity or systemic toxicity. We examined whether the weaknesses of the two strategies can be overcome by integrating the TRAIL gene into an oncolytic vector. EXPERIMENTAL DESIGN: We constructed a TRAIL-expressing oncolytic adenovector designated as Ad/TRAIL-E1. The expression of both the TRAIL and viral E1A genes is under the control of a synthetic promoter consisting of sequences from the human telomerase reverse transcriptase promoter and a minimal cytomegalovirus early promoter. The transgene expression, apoptosis induction, viral replication, antitumor activity, and toxicity of Ad/TRAIL-E1 were determined in vitro and in vivo in comparison with control vectors. RESULTS: Ad/TRAIL-E1 elicited enhanced viral replication and/or stronger oncolytic effect in vitro in various human cancer cell lines than a TRAIL-expressing, replication-defective adenovector or an oncolytic adenovector-expressing green fluorescent protein. Intralesional administration of Ad/TRAIL-E1 eliminated all s.c. xenograft tumors established from a human non-small cell lung cancer cell line, H1299, on nu/nu nude mice, resulting in long-term, tumor-free survival. Furthermore, we found no treatment-related toxicity. CONCLUSIONS: Viral replication and antitumor activity of oncolytic adenovirus can be enhanced by the TRAIL gene and Ad/TRAIL-E1 could become a potent therapeutic agent for cancer therapy.

Animals↗

PubMed2006

Transfection activity of binary mixtures of cationic o-substituted phosphatidylcholine derivatives: the hydrophobic core strongly modulates physical properties and DNA delivery efficacy.

A combination of two cationic lipid derivatives having the same headgroup but tails of different chain lengths has been shown to have considerably different transfection activity than do the separate molecules. Such findings point to the importance of investigating the hydrophobic portions of cationic amphiphiles. Hence, we have synthesized a variety of cationic phosphatidylcholines with unusual hydrophobic moieties and have evaluated their transfection activity and that of their mixtures with the original molecule of this class, dioleoyl-O-ethylphosphatidylcholine (EDOPC). Four distinct relationships between transfection activity and composition of the mixture (plotted as percent of the new compound added to EDOPC) were found, namely: with a maximum or minimum; with a proportional change; or with essentially no change. Relevant physical properties of the lipoplexes were also examined; specifically, membrane fusion (by fluorescence resonance energy transfer between cationic and anionic lipids) and DNA unbinding (measured as accessibility of DNA to ethidium bromide by electrophoresis and by fluorescence resonance energy transfer between DNA and cationic lipid), both after the addition of negatively charged membrane lipids. Fusibility increased with increasing content of second cationic lipid, regardless of the transfection pattern. However, the extent of DNA unbinding after addition of negatively charged membrane lipids did correlate with extent of transfection. The phase behavior of cationic lipids per se as well as that of their mixtures with membrane lipids revealed structural differences that may account for and support the hypothesis that a membrane lipid-triggered, lamellar-->nonlamellar phase transition that facilitates DNA release is critical to efficient transfection by cationic lipids.

Cations↗

PubMed2006

Molecular cloning and expression of the porcine high-affinity immunoglobulin G Fc receptor (FcgammaRI).

Receptors for the Fc region (FcgammaRs) of immunoglobulin G (IgG) play a crucial role in the immune system and host protection against infection. In this study, we describe the cloning, sequencing, and expression of the high-affinity IgG receptor from pig. By screening a translated Expressed Sequence Tags database with the human FcgammaRI (CD64) protein sequence, we identified a putative porcine homologue. Subsequent polymerase chain reaction amplification confirmed that the identified full-length cDNA was expressed in porcine cells. Rosetting analysis shows that COS-7 cells transfected with a plasmid containing the cloned cDNA were able to bind chicken erythrocytes sensitized with porcine IgG. Scatchard analysis indicated that monomeric IgG bound to transiently transfected cells with an affinity of approximately 4x10(7) M(-1). The porcine FcgammaRI cDNA is 1,038 nucleotides long and is predicted to encode a 346-amino-acid transmembrane glycoprotein composed of three Ig-like domains, a transmembrane region, and a short cytoplasmic tail. The overall identity of the porcine FcgammaRI to its human and mouse counterparts at the level of the amino acid sequence was 75% and 57%, respectively. Identification of porcine FcgammaRI will aid in the understanding of the molecular basis of the porcine immune system and further studies of the receptor function.

Amino Acid Sequence↗

PubMed2006

Theoretical dynamic studies on the reaction of CH3C(O)CH3-nFn with the hydroxyl radical and the chlorine atom.

The mechanisms of the reactions: CH(3)C(O)CH(2)F+OH/Cl-->products (R1/R2) and CH(3)C(O)CF(3)+OH/Cl-->products (R3/R4) are studied over a wide temperature range (200-2000 K) by means of the dual-level direct dynamics method. The optimized geometries and frequencies of the stationary points are calculated at the MP2/cc-pVDZ and B3LYP/6-311G(d,p) levels. The energy profiles of the reactions are then refined with the interpolated single-point-energy method (ISPE) at the BMC-CCSD level. The canonical variational transition-state theory (CVT) with the small-curvature-tunneling (SCT) correction method is used to calculate the rate constants. Using group-balanced isodesmic reactions as working chemical reactions, the standard enthalpies of formation for CH(3)C(O)CH(2)F, CH(3)C(O)CF(3), CH(3)C(O)CHF, CH(2)C(O)CH(2)F, and CH(2)C(O)CF(3) are evaluated at the CCSD(T)/6-311+G(2d,p)//MP2/cc-pVDZ level of theory. The results indicate that the hydrogen abstraction is dominated by removal from the fluoromethyl position rather than from the methyl position.

Journal Article↗

PubMed2006

Mutation breeding of chitosanase-producing strain Bacillus sp. S65 by low-energy ion implantation.

In order to obtain an industrial strain with higher chitosanase yield, the wild strain Bacillus sp. S65 cells were mutated by a novel mutagen, nitrogen ion beam, with energy of 15 keV and dose ranging from 2.6 x 10(14 )to 5.2 x 10(15) ions/cm(2). One mutant, s65F5 with high yield of chitosanase was isolated. Results showed that the production of chitosanase of s65F5 was dramatically increased from 4.1 U/ml in s65 to 25 U/ml by ion beam implantation, while the fermentation time was shortened from 72 to 56 h, both of which greatly increased efficiency and reduced the cost of industrial production. Besides, the mutagenic effects of low-energy ion beam on survival rate showed characteristic down-up-down pattern, which was different from the traditional mutagens such as UV and gamma-ray and the possible mutation mechanism was discussed.

Bacillus↗

PubMed2006

Functional magnetic resonance imaging study of writer's cramp.

BACKGROUND: Writer's cramp is a type of task specific idiopathic focal dystonia and has an incompletely understood pathophysiology. The present study utilized functional magnetic resonance imaging (fMRI) to investigate what type of brain activity correlates with writer's cramp and its physiological mechanism. METHODS: Ten patients with writer's cramp were age and gender matched with ten healthy control subjects in a block design. Subjects were scanned by fMRI while performing three consecutive, visually instructive, tasks with MR Vision 2000: (1) suppositional writing, (2) writing with finger and (3) writing with a pencil. Data was analysed using AFNI software for groups of patients and controls. RESULTS: The patients with writer's cramp showed significant activations of contralateral basal ganglion (especially the putamen), motor cortex (primary sensorimotor cortex, supplementary motor cortex, premotor cortex) and ipsilateral cerebellar hemisphere in writing with a pencil compared with controls; whereas there was no obvious difference between patients and controls during writing with finger. Furthermore, these differences exist in the subtractive activated maps for "writing with a pencil" minus "writing with finger" of patients, when the activation of subcortical area and insula in controls disappeared. CONCLUSIONS: Abnormal activations of contralateral basal ganglion, motor cortex and ipsilateral cerebellar hemisphere of the patients with writer's cramp suggest dysfunction of basal ganglion and subcortical-cortical loop might play a pathophysiological role in writer's cramp.

Adult↗

PubMed2006

Solution structure of Urm1 and its implications for the origin of protein modifiers.

Protein modifiers are involved in diverse biological processes and regulate the activity or function of target proteins by covalently conjugating to them. Although ubiquitin and a number of ubiquitin-like protein modifiers (Ubls) in eukaryotes have been identified, no protein modifier has been found in prokaryotes; thus, their evolutionary origin remains a puzzle. To infer the evolutionary relationships between the protein modifiers and sulfur carrier proteins, we solved the solution NMR structure of the Urm1 (ubiquitin-related modifier-1) protein from Saccharomyces cerevisiae. Both structural comparison and phylogenetic analysis of the ubiquitin superfamily, with emphasis on the Urm1 family, indicate that Urm1 is the unique "molecular fossil" that has the most conserved structural and sequence features of the common ancestor of the entire superfamily. The similarities of 3D structure and hydrophobic and electrostatic surface features between Urm1 and MoaD (molybdopterin synthase small subunit) suggest that they may interact with partners in a similar manner, and similarities between Urm1-Uba4 and MoaD-MoeB establish an evolutionary link between ATP-dependent protein conjugation in eukaryotes and ATP-dependent cofactor sulfuration.

Models, Molecular↗

PubMed2006

An integrative approach for causal gene identification and gene regulatory pathway inference.

MOTIVATION: Gene expression variation can often be linked to certain chromosomal regions and are tightly associated with phenotypic variation such as disease conditions. Inferring the causal genes for the expression variation is of great importance but rather challenging as the linked region generally contains multiple genes. Even when a single candidate gene is proposed, the underlying biological mechanism by which the regulation is enforced remains unknown. Novel approaches are needed to both infer the causal genes and generate hypothesis on the underlying regulatory mechanisms. RESULTS: We propose a new approach which aims at achieving the above objectives by integrating genotype information, gene expression, protein-protein interaction, protein phosphorylation, and transcription factor (TF)-DNA binding information. A network based stochastic algorithm is designed to infer the causal genes and identify the underlying regulatory pathways. We first quantitatively verified our method by a test using data generated by yeast knock-out experiments. Over 40% of inferred causal genes are correct, which is significantly better than 10% by random guess. We then applied our method to a recent genome-wide expression variation study in yeast. We show that our method can correctly identify the causal genes and effectively output experimentally verified pathways. New potential gene regulatory pathways are generated and presented as a global network. AVAILABILITY: Source code is available upon request.

Chromosome Mapping↗

PubMed2006

Disordered beta-catenin expression and E-cadherin/CDH1 promoter methylation in gastric carcinoma.

AIM: To investigate the distribution of beta-catenin in nuclei or membrane/cytoplasm of gastric carcinoma cells, the relationship between E-cadherin gene methylation and its expression, and the role of beta-catenin and E-cadherin as potential molecular markers in predicting tumor infiltration. METHODS: Twenty-nine cases of gastric carcinoma, classified as diffuse and intestinal variants, were selected for study. Nuclear and cytoplasmic proteins were purified and beta-catenin content was detected by ELISA. DNA methylation of E-cadherin/CDH1 gene promoter was studied by methylation-specific PCR and compaired with E-cadherin expression detected by immunohistochemistry. RESULTS: In 27 cases of gastric carcinoma, the ratio of beta-catenin content between nuclei and membrane/cytoplasm was correlated with the T-classification (r = 0.392, P = 0.043). The significance was present between T2 and T3 groups. No correlation was detected between diffuse and intestinal variants in terms of their beta-catenin distribution. In 21 cases of diffuse variants of gastric carcinoma, there was a difference in E-cadherin expression between CDH1 gene-methylated group and non-methylated group (29 % vs 71 %, P = 0.027). No correlation between CDH1 gene methylation and T-classification was found, neither was the significance between E-cadherin expression and tumor infiltration grade. CONCLUSION: Comparative analysis of nuclear and membrane/cytoplasmic beta-catenin can predict local tumor infiltration. E-cadherin/CDH1 gene methylation is an important cause for its gene silence in diffuse variant gastric carcinoma. Methylation of CDH1 gene in the absence of E-cadherin is an early event in gastric carcinogenesis.

Antigens, CD↗

PubMed2006

[Expression of exogenous Smad7 gene in lung: in vivo study with mice].

OBJECTIVE: To investigate the regular pattern of expression, and expression localization in lung of Smad7 gene mediated by adenovirus and regulated by irradiation via early growth response (Egr) factor-1 promoter and the safe dose of the recombinant adenovirus. METHODS: The radio-inducible element of Egr-1 gene promoter and cDNA encoding Smad7 were enclosed into the replication-defective adenovirus, thus establishing the recombinant adenovirus AD.Egr-Smad7. 720 C57BL/6J mice were randomly divided into 6 different groups: Group C (blank control group, receiving normal saline only), Group R (receiving radiation with the dose of 8 Gy at the whole chest only), Group AR (undergoing intratracheal instillation of AD.Egr-Smad7 without radiation), Group RAR (undergoing intratracheal instillation of AD.Egr-Smad7 and then radiation 24 hours later), Group AV (receiving the replication-defective adenovirus without radiation), and Group AVR (receiving both the replication-defective adenovirus and radiation). The following studies were conducted. (1) Tolerance to the adenovirus. Sixty mice were divided into 11 equal subgroups: Subgroups C, and Subgroups RA and AV receiving AD.Egr-Smad7 at 5 different concentrations: 10(8), 5 x 10(8), 10(9), 5 x 10(9), and 10(10) pfu/0.1 ml respectively. The mice were observed for the symptoms of dyspnea and cyanosis and death within 72 hours. (2) Localization of the expression of exogenous Smad7 in the lungs. 36 mice were divided into 6 equal Subgroups: C, R, RA, RAR, AV, and AVR, the adenovirus titre being 10(9) pfu/0.1 ml. Five hours after the irradiation all mice were killed to take out their lungs. (3) Relationship between the titre of AD.Egr-Smad7 and expression of Smad7 in lung. 168 mice were divided into 28 Subgroups: C, R, RA, RAR, AV, and AVR, the titre of virus being 10(8), 5 x 10(8), or 10(9) respectively, and the time after irradiation being 6 hours or 9 hours. The mice were killed at specific time points and their lungs were taken out. (4) Time-effect on Smad7 expression in lung. 134 mice were divided into 54 equal Subgroups: R, RA, RAR, AV, and AVR. The mice were killed 0, 1, 2, 3, 5, 7, 9, 12, and 15 hours after irradiation and their lungs were taken out. (5) Dose-effect of irradiation on the Smad7 expression in lung. 126 mice were divided into 21 Subgroups: C, R, RA, RAR, AV, and AVR, the irradiation dose being 5, 8, 10, 12, 15, or 20 Gy. Five hours after the irradiation the mice were killed and their lungs were taken out. Western blotting was used to detect the mRNA expression of Smad7 in lung and the protein expression of Smad7 in lung was examined by immunohistochemistry. RESULTS: (1) The concentration of 10(9) pfu and lower was safe, no matter the adenovirus contained Egf-Smad7 or not. (2) mRNA expression of exogenous SmaD7 was found in the cytoplasm of bronchial epithelium cells, alveolar epithelial cells, and blood vessel endothelial cells in Subgroup RAR but not in the other subgroups. (3) Western blotting showed that the protein expression of Smad7 was obvious in the lung tissues of Subgroup RAR, being more obvious 6 hours after irradiation than 9 hours later (P < 0.01), AD.Egr-Smad7 dose-dependently increased the protein expression of exogenous Smad7 in Subgroup RAR (P < 0.01), and that the protein expression of Smad7 was very weak in the other subgroups in comparison with Subgroup RAR (all P < 0.01). (4) The protein expression of Smad7 in the lung tissues of Subgroup RAR began to increase 1 hour after irradiation, peaked 5 hours later, then gradually decreased, returned to the level 1 hour later by the 12 th hour after irradiation, and almost disappeared 15 hours later. (5) The protein expression of Smad7 in Subgroup RAR increased after irradiation in a dose-dependent manner (P < 0.01), with a peak when the dose was 12 Gy. CONCLUSION: Gamma irradiation markedly induces the expression of exogenous Smad7 gene mediated by recombinant adenovirus in the cells of lung tissues dose-dependently that is correlated with time interval as well. It is important to look for a safe titre of the recombinant adenovirus. Blocking the signal transduction of transforming growth factor-beta may become a novel strategy for gene therapy aiming at preventing irradiation-induced lung fibrosis.

Adenoviridae↗

PubMed2006

Preparation of nanosheet polyethylene with heterogeneous metallocene catalyst and formation mechanism of nanosheet polyethylene.

Silica with small and regular pore sizes was synthesized by hydrothermal crystallization and investigated with thermogravimetric analysis, X-ray diffraction, Fourier transform infrared spectroscopy, N2 adsorption-desorption, and scanning electron microscopy (SEM). The ethylene polymerization was carried out with the silica-supported metallocene catalyst, and the morphology of the resultant polyethylene was investigated with SEM. It was found that the silica could break up into sheet fragments instantaneously during polymerization and the polyethylene could replicate it to obtain nanosheet polyethylene. A possible formation mechanism of the nanosheet polyethylene is proposed.

Catalysis↗

PubMed2006

An eco-friendly and sustainable process for enzymatic hydrolysis of penicillin G in cloud point system.

Enzymatic hydrolysis of penicillin G by immobilized penicillin acylase in a nonionic surfactant mediated cloud point system was presented. The effect of the operation parameters on equilibrium pH of this enzymatic hydrolysis process without pH control was examined. A relatively high equilibrium pH in cloud point system without pH control can be obtained. The feasibility of recycling utilization of the nonionic surfactant, a novel green solvent, was also investigated experimentally. Enzymatic hydrolysis of penicillin G in a discrete semi-batch mode, which simulates a semi-continuous process, envisages a completely eco-friendly, sustainable and efficient process for production of 6-aminopenicillanic acid.

Conservation of Natural Resources↗

PubMed2006

Lithium regulates glycogen synthase kinase-3beta in human peripheral blood mononuclear cells: implication in the treatment of bipolar disorder.

BACKGROUND: Bipolar disorder has been linked to alterations in the multifunctional enzyme glycogen synthase kinase-3beta (GSK3beta). The mood stabilizer lithium inhibits GSK3beta in vitro and in mouse brain, and this is currently the strongest known potential therapeutic target of lithium. We tested whether lithium modified GSK3beta in vivo or in vitro in peripheral blood mononuclear cells (PBMCs) from healthy control and bipolar disorder subjects. METHODS: The PBMCs were obtained from 23 healthy control subjects, 9 bipolar subjects currently treated with lithium, and 13 lithium-free bipolar subjects. Immunoblot analyses were used to measure the inhibited, serine9-phosphorylated GSK3beta. RESULTS: The level of phospho-Ser9-GSK3beta in PBMCs was regulated by agents that modified kinases and phosphatases acting on GSK3beta and was increased by in vitro lithium treatment. More important, phospho-Ser9-GSK3beta levels were eightfold higher in PBMCs from lithium-treated bipolar than healthy control subjects. CONCLUSIONS: Signaling pathways regulating serine9-phosphorylation of GSK3beta can be studied in human PBMCs. Both in vitro and in vivo therapeutic lithium treatment is associated with a large increase in phospho-Ser9-GSK3beta in PBMCs. Therefore, the inhibitory serine9-phosphorylation of GSK3beta in human PBMCs may provide a biochemical marker to evaluate the association between GSK3beta inhibition and therapeutic responses to lithium treatment.

Adult↗

PubMed2006

Orphan receptor small heterodimer partner is an important mediator of glucose homeostasis.

The orphan receptor small heterodimer partner (SHP; NROB2) is a transcriptional repressor that inhibits nuclear receptor signaling in diverse metabolic pathways. Here, we report that SHP(-/-) mice exhibited hypoinsulinemia with age, which was associated with increased peripheral insulin sensitivity and increased response of isolated islets to glucose stimulation, yet maintain normal levels of blood glucose. Deficiency in SHP function resulted in up-regulation of glucose transporter 4 mRNA and glucose uptake in muscles, and overexpression of SHP in C2C12 cells inhibited both basal and peroxisomal proliferator-activated receptor gamma (PPARgamma) coactivator-1alpha-stimulated glucose transporter 4 expression and glucose uptake. SHP(-/-) hepatocytes showed markedly decreased basal glucose production in cultures, and SHP(-/-) livers had increased glycogen stores and were more sensitive to insulin inhibition of glucose output, which were concomitant with decreased expression for PPARgamma1, fatty acid translocase, glucose-6-phosphatase, and phosphoenol/pyruvate carboxykinase, and increased mRNAs for glucokinase and pyruvate kinase. In white fat, SHP deficiency resulted in up-regulation of genes involved in insulin sensitizing, including PPARgamma2 and adiponectin. We show that, at the transcriptional level, SHP directly represses adiponectin promoter activity by PPARgamma/liver receptor homolog-1. The results suggest that the increases in insulin sensitivity through multiple signaling pathways in muscle, liver, and fat, with an increase in islet secretory function, represent the complex mechanism whereby SHP deficiency leads to improvement in insulin sensitivity, secretion, and diabetes.

Adipose Tissue, White↗