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The aim of the present study was to investigate the effect of black sesame seeds ethanol extract (BSSEE) against nonalcoholic fatty liver disease (NAFLD) in fructose-fed mice. Mice were fed a standard diet without or with 30% fructose in drinking water for 8 consecutive weeks, while mice in three BSSEE tested groups received different doses of BSSEE (0.5, 1, and 2 mL/kg) once a day from the fifth week to the eighth week. Administration of BSSEE dose-dependently exerted antiobesity and protective effect against metabolism disorder in fructose-fed mice. Histological examinations indicated that administration of BSSEE obviously reduced hepatic lipid accumulation. Insulin tolerance test (ITT) and glucose tolerance test (GTT) along with decreases of serum insulin and glucose levels by BSSEE treatment suggested the improvement of body insulin resistance, and administration of 1 and 2 mL/kg BSSEE mitigated liver insulin resistance as the evidence of downregulated expression of phospho-JNK1/2/3, phospho-NF-κB p65, phospho-IRS1, and phospho-IKK alpha/beta, up-regulated XBP1 expression, and reductions of TNF-α and IL-6 levels. In addition, BSSEE treatment ameliorated hepatic oxidative stress through increasing GSH, vitamin C, and Nrf2 levels, decreasing MDA and NO levels, and enhancing SOD, CAT, and GSH-Px activities. These results demonstrated that BSSEE showed protective effects against NAFLD-related metabolic diseases in fructose-fed mice. Therefore, BSSEE may be a potent dietary supplement to ameliorate the diseases.

We introduce a number of computationally inexpensive modifications to the MM/PBSA and MM/GBSA estimators for binding free energies, which are based on average receptor–ligand interaction energies in simulations of a noncovalent complex, to improve the treatment of entropy: second- and higher-order terms in a cumulant expansion and a confining potential on ligand external degrees of freedom. We also consider a filter for snapshots where ligands have drifted from the initial binding pose. The variations were tested on six sets of systems for which binding modes and free energies have previously been experimentally determined. For some data sets, none of the tested estimators led to results significantly correlated with measured free energies. In data sets with nontrivial correlation, a ligand RMSD cutoff of 3 Å and a second-order truncation of the cumulant expansion was found to be comparable or better than the average interaction energy by several statistical metrics.

Short selective CD28 blockade combined with prolonged anti-CD154-treatement in heart transplanted primates decreased severity of acute rejection and of cardiac allograft vasculopathy as well as maintained levels of CD4+Treg. Although it did not prolong survival over anti-CD154 treatment, these results warrant more prolonged treatments with selective CD28 blockade. Supplemental digital content is available in the text.

Treatment with 2 αCD40L (IDEC-131, 5C8H1) or 1 αCD40 (2C10R4) MAbs in a cynomolgus monkey cardiac allograft recipients prolong graft survival, but grafts from 5C8H1 or 2C10R4-treated recipients show longer prolongation vs IDEC-131. Attenuation of alloAb was more efficient in 5C8H1 or 2C10R4 recipients, but all grafts show Ab-mediated rejection. Supplemental digital content is available in the text.

Gentiopicroside is a secoiridoid compound isolated from Gentiana lutea which is called Qin Jiao in Chinese. It is one of the most common herbal medicines used in China. In this article, we review the pharmacological and biological activity (antiviral, anti-inflammatory, analgesia, antihepatotoxic and choleretic), as well as biotransformation of the gentiopicroside. In addition, attempt towards the total synthesis of gentiopicroside is also presented.

Gentiopicroside (GE), a naturally occurring iridoid glycoside, has been developed into a Novel Traditional Chinese Drug named gentiopicroside injection, and it was approved for the treatment of acute jaundice and chronic active hepatitis by SFDA. However, the inhibitory and inducible effects of GE on the activity of cytochrome P450 (CYP450) are unclear. The purpose of this study was to evaluate the ability of GE to inhibit and induce human cytochrome P450 enzymes in vitro.In human liver microsomes, GE inhibited CYP2A6 and CYP2E1 in a concentration-dependent manner, with IC50values of 21.8μg/ml and 594μg/ml, respectively, and the IC50of CYP2A6 was close to the Cmaxvalue observed clinically. GE was a non-competitive inhibitor of CYP2A6 at lower concentrations and a competitive inhibitor at higher concentrations. GE did not produce inhibition of CYP2C9, CYP2D6, CYP1A2 or CYP3A4 activities. However, a significant increase of CYP1A2 and CYP3A4 activity was observed at high concentrations. In cultured human hepatocytes no significant induction of CYP1A2, CYP3A4 or CYP2B6 was observed. Given these results, the in vivopotential inhibition of GE on CYP2A6 deserves further investigation, and it seems that the hepatoprotective effect of GE is irrelevant to its effect on P450s.

Immature dendritic cells (DCs) have the tolerogenic potential to induce alloantigen-specific immune tolerance. Cytotoxic T lymphocyte antigen 4 immunoglobulin (CTLA4Ig) gene-modified immature DCs have been shown to maintain their tolerogenicity and prolong allograft survival to some extent. We investigated whether blockade of CD40 pathway by anti-CD40 ligand (L) monoclonal antibody (mAb) could enhance the immune tolerance induction by immature DCs genetically modified to express CTLA4Ig (DC-CTLA4Ig).

A new steroidal saponin containing six monosaccharides was obtained from the total plant of Tribulus terrestris and elucidated based on chemical spectroscopic analysis, especially on 2D-NMR technology as 26- O - g - d -glucopyranosyl-22-methoxy-furostane-3- O -{ g - d -xylopyranosyl(1 M 3)-[ g - d -xylopyranosyl(1 M 2)- g - d -glucopyranosyl(1 M 4)]}-[ f - l -rhamnopyranosy(1 M 2)]- g - d -galactopyranoside.

A new steroidal saponin containing six monosaccharides was obtained from the total plant of Tribulus terrestris and elucidated based on chemical spectroscopic analysis, especially on 2D-NMR technology as 26- O - g - d -glucopyranosyl-22-methoxy-furostane-3- O -{ g - d -xylopyranosyl(1 M 3)-[ g - d -xylopyranosyl(1 M 2)- g - d -glucopyranosyl(1 M 4)]}-[ f - l -rhamnopyranosy(1 M 2)]- g - d -galactopyranoside.

A novel amide, qinjiaoamide and a novel iridoid, erythrocentaurin acid, together with seven known compounds [erythrocentaurin (3), roburic acid (4), oleanolic acid (5), gentiopicroside (6), swertiamarine (7), sweroside (8), and 6′-O-β-D-glucosylgentiopicroside (9)], were isolated from the root of Gentiana macrophylla Pall. from Shaanxi Province, China. The novel compounds were identified as N-pentacosyl-2-carboxy-benzoyl amide (1) and 5-carboxyl-3,4-dihydrogen-1H-2-benzopyran-1-one (2), on the basis of spectroscopic (UV, IR, 1D- and 2D-NMR) and mass spectrometric data. Among the known compounds, erythrocentaurin (3) was isolated from the genus Gentiana for the first time.

To control graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell (HSC) transplantation while maintaining the graft antileukemic effects of donor T cells, a suicide gene encoding the herpes simplex virus thymidine kinase (HSV-TK) enzyme was introduced ex vivo via a retroviral vector into donor T cells. Although previous clinical trials showed that it was an efficient tool for controlling GVHD, the gene transduction process of donor T lymphocytes may influence the immunocompetence of the T cells. In the current study, we investigated the impact that the gene manipulation in vitro had on the phenotype and functionality of human donor T lymphocytes. We engineered human T lymphocytes with HSV-TK and puromycin resistance gene with a retrovirus vector and analyzed the phenotype change of gene modified cells with flowcytometry. The secretion of gamma-interferon and interleukin-4 of T lymphocyte were detected with enzyme-linked immunospot(ELIPOT)assays. We also analyzed the lytic activity of T cells against allogeneic targets. The result showed that the number of TK gene transduced T lymphocyte was sufficient for clinical use. There was an inversion of the CD4+/CD8+ ratio in the gene modified T cell (GMC) compared with the fresh peripheral blood lymphocytes (PBLs). In addition, the GMCs showed a higher expression of HLA-DR and had more antigen-experienced cells than did the PBLs. In ELIPOT assays, significantly less gamma-interferon secretion by GMCs was observed compared to PBLs (50 vs. 115 spots/well-3×104cells, p<0.05). The results also showed that IL-4-secreting cell frequencies was similar in GMCs and in PBLs (19.3 vs. 20.3 spots/well-3×104cells, p>0.05). After stimulated by allogeneic PBMCs, the GMCs effectors showed a significant reduction in lytic activity against allogeneic targets in contrast with PBL. In conclusion, HSV-TK gene transduction and selection procedure can change the phenotype and functions of human T lymphocyte. The gene modified T lymphocytes still showed biological activities although lower than those of PBLs.

To control graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell (HSC) transplantation while maintaining the graft antileukemic effects of donor T cells, a suicide gene encoding the herpes simplex virus thymidine kinase (HSV-TK) enzyme was introduced ex vivo via a retroviral vector into donor T cells. Although previous clinical trials showed that it was an efficient tool for controlling GVHD, the gene transduction process of donor T lymphocytes may influence the immunocompetence of the T cells. In the current study, we investigated the impact that the gene manipulation in vitro had on the phenotype and functionality of human donor T lymphocytes. We engineered human T lymphocytes with HSV-TK and puromycin resistance gene with a retrovirus vector and analyzed the phenotype change of gene modified cells with flowcytometry. The secretion of gamma-interferon and interleukin-4 of T lymphocyte were detected with enzyme-linked immunospot(ELIPOT)assays. We also analyzed the lytic activity of T cells against allogeneic targets. The result showed that the number of TK gene transduced T lymphocyte was sufficient for clinical use. There was an inversion of the CD4+/CD8+ratio in the gene modified T cell (GMC) compared with the fresh peripheral blood lymphocytes (PBLs). In addition, the GMCs showed a higher expression of HLA-DR and had more antigen-experienced cells than did the PBLs. In ELIPOT assays, significantly less gamma-interferon secretion by GMCs was observed compared to PBLs (50 vs. 115 spots/well-3×104cells, p<0.05). The results also showed that IL-4-secreting cell frequencies was similar in GMCs and in PBLs (19.3 vs. 20.3 spots/well-3×104cells, p>0.05). After stimulated by allogeneic PBMCs, the GMCs effectors showed a significant reduction in lytic activity against allogeneic targets in contrast with PBL. In conclusion, HSV-TK gene transduction and selection procedure can change the phenotype and functions of human T lymphocyte. The gene modified T lymphocytes still showed biological activities although lower than those of PBLs.

Mycophenolate mofetil (MMF) is a newly developed immunosuppressor, currently widely used in allogeneic bone marrow transplantation. Its active metabolite, mycophenolic acid (MPA) is a noncompetitive, reversible inhibitor of the enzyme inosine 59-monophosphate dehydrogenase, which plays a major role in the de novo synthesis of guanosine nucleotides. Unlike other cells that also use the salvage pathway for purine biosynthesis, proliferating B and T cells are dependent on the de novo pathway generate guanosine. Thus, MMF exerts its immunosuppressive effects of lymphocyte proliferation. Recently, some studies found that MPA could inhibit the immun immune function of antigen presenting cells. Dendritic cells (DCs), the most potent antigen presenting cells with the unique ability to prime naive T cells, play a central role in antigen processing and presentation to induce T cell response in vitro and in vivo. This study is to evaluate the effects of MPA, the in vivo active metabolite of MMF, on the maturation and immune function of murine bone marrow-derived dendritic cells, and to explore the underlying mechanisms of MMF in graft versus host disease. Bone marrow-derived dendritic cells (DC) were cultured with GM-CSF and IL-4 in the presence of MPA at doses of 0.01 and 0.1μmol/L. The ability of the allostimulatory activities of the DCs on allogeneic T cells was assessed by MLR. IL-12 production in culture supernatant and the Th1/Th2 cytokines such as IL-2, IFN-g, IL-4 and IL-10 levels in mixed lymphocyte reaction (MLR) supernatant were examined by ELISA assays. The activity of NF-κB in DCs was measured with Western blot assays. Our results showed that DCs cultured in the presence of MPA expressed lower levels of CD40, CD80 and CD86, exhibited weaker activity of stimulating the allogeneic T cell proliferation and weaker in antigen presenting function with a concurrent reduction of IL-12 production. MPA-treated DCs stimulated allogeneic T cells to secrete higher levels of Th2 cytokines IL-4 and IL-10 but lower levels of Th1 cytokines IL-2 and IFN-g than did DCs not treated with MPA. The activity of NF-κB was decreased in DCs treated with MPA in a dose-dependent manner. We conclude that MPA, and hence MMF, exerts a negative effect on the maturation and immune function of in vitro cultured DCs, and drives a shift of Th1 cytokines to Th2 cytokines in MLR. This negative effect is associated with a decrease in NF-κB activity. Say something about the significance of this finding regarding GVHD.

Mycophenolate mofetil (MMF) is a newly developed immunosuppressor, currently widely used in allogeneic bone marrow transplantation. Its active metabolite, mycophenolic acid (MPA) is a noncompetitive, reversible inhibitor of the enzyme inosine 59-monophosphate dehydrogenase, which plays a major role in the de novo synthesis of guanosine nucleotides. Unlike other cells that also use the salvage pathway for purine biosynthesis, proliferating B and T cells are dependent on the de novo pathway generate guanosine. Thus, MMF exerts its immunosuppressive effects of lymphocyte proliferation. Recently, some studies found that MPA could inhibit the immun immune function of antigen presenting cells. Dendritic cells (DCs), the most potent antigen presenting cells with the unique ability to prime naive T cells, play a central role in antigen processing and presentation to induce T cell response in vitro and in vivo. This study is to evaluate the effects of MPA, the in vivo active metabolite of MMF, on the maturation and immune function of murine bone marrow-derived dendritic cells, and to explore the underlying mechanisms of MMF in graft versus host disease. Bone marrow-derived dendritic cells (DC) were cultured with GM-CSF and IL-4 in the presence of MPA at doses of 0.01 and 0.1μmol/L. The ability of the allostimulatory activities of the DCs on allogeneic T cells was assessed by MLR. IL-12 production in culture supernatant and the Th1/Th2 cytokines such as IL-2, IFN-g, IL-4 and IL-10 levels in mixed lymphocyte reaction (MLR) supernatant were examined by ELISA assays. The activity of NF-κB in DCs was measured with Western blot assays. Our results showed that DCs cultured in the presence of MPA expressed lower levels of CD40, CD80 and CD86, exhibited weaker activity of stimulating the allogeneic T cell proliferation and weaker in antigen presenting function with a concurrent reduction of IL-12 production. MPA-treated DCs stimulated allogeneic T cells to secrete higher levels of Th2 cytokines IL-4 and IL-10 but lower levels of Th1 cytokines IL-2 and IFN-g than did DCs not treated with MPA. The activity of NF-κB was decreased in DCs treated with MPA in a dose-dependent manner. We conclude that MPA, and hence MMF, exerts a negative effect on the maturation and immune function of in vitro cultured DCs, and drives a shift of Th1 cytokines to Th2 cytokines in MLR. This negative effect is associated with a decrease in NF-κB activity. Say something about the significance of this finding regarding GVHD.