Chemical constituents from the seeds of Cullen corylifolium and their inhibitory activity on diacylglycerol acyltransferase.

A large number of extracts of medicinal plants or natural products shows beneficial to combat obesity. In the present work, a new flavonoid named (2S,1″R,2″R)-4'-hydroxy-7-methoxy-6-(1,2,3-trihydroxy-3-methyl-butyl)-flavanone (1), along with seven known compounds (2-8) were isolated from the seeds of Cullen corylifolium. Their structures, including the absolute configurations, were determined by the analysis of comprehensive spectroscopic data and computational calculation methods. All isolates were evaluated for their diacylglycerol acyltransferase (DGAT) inhibitory activity. Compounds 1-4 exhibited different level of DGAT1 inhibitory activity with IC50 values ranging from 28.2 ± 1.1 to 127.3 ± 1.9 µM. In addition, 45 flavonoids which be evaluated for DGAT inhibitory activity were summarised and potential structure-activity relationships were discussed.

[Effects of Arsenic Disulfide Combined with Itraconazole on Proli- feration and Apoptosis and Hedgehog Pathway of Diffuse Large B-Cell Lymphoma Cells].

OBJECTIVE: To investigate the effect of arsenic disulfide (AS2S2) combined with itraconazole on the proliferation, apoptosis and hedgehog pathway of diffuse large B-cell lymphoma (DLBCL) cells. METHODS: The human DLBCL cell OCI-LY3 was treated with different concentrations of AS2S2 and itraconazole. Cell proliferation inhibition was detected by CCK-8, cell apoptosis rate was determined by flow cytometry. The expression levels of BCL-2, BAX, SMO and GLi1 were detected by Western blot. RESULTS: The DLBCL cell viability was decreased significantly at 24, 48 or 72 h as cultured with itraconazole. Along with the increasing of itraconazole concentration, the DLBCL cell viability was significantly reduced as compared with that in control group, and the results showed statistically significant(r=-0.690，r=-0.639, r=-0.833, r=-0.808, r=-0.578). The inhibitory and apoptosis rates of the cells were significantly increased as compared with those of the single drug-treated group after treated by the combination of itraconazole and AS2S2(P<0.05). The protein levels of SMO and Glil were significantly down-regulated after treated by arsenic disulfide and itraconazole alone(P<0.01). The protein expression levels of SMO and Glil was down-regulated in the combined-treatment group(P<0.01). CONCLUSION: Itraconazole can inhibit proliferation of DLBCL cells in a concentration-and time-dependent manner. In addition, the combination of AS2S2 and itraconazole show a synergistic effects, which may be related with the down-regulated protein expression of SMO and Glil of Hedgehog signaling pathway.

[The Effect of γ-secretase Inhibitor Combined with BMSC on the aGVHD in Mice Model].

OBJECTIVE: To establish the aGVHD mouse model，and investigate the regulatory effect and its mechanism of low-dose GSI combined with BMSC on aGVHD mice. METHODS: C57BL/6 (H-2b) and BALB/c (H-2d) were selected as donor and recipient of allogeneic transplantation to establish the aGVHD mouse model. BALB/c mice were randomly divided into 6 groups, which were the bone marrow cell infusion after irradiation (BM) group; the bone marrow cells + spleen cells after irradiation (BM+SC) group; the bone marrow cells + spleen cells + DMSO (BM+SC+DMSO) (transplant control) group; bone marrow cells + splenocytes +GSI after irradiation (BM+SC+GSI) group; bone marrow cells + spleen cells + bone marrow mesenchymal stromal infusion after irradiation cell (BM+SC+BMSC) group; bone marrow cells + spleen cells + bone marrow mesenchymal stromal cells +GSI infused after irradiation (BM+SC+BMSC+GSI) group. The mice in the two groups containing GSI were intraperitoneally injected with GSI at 5 µmol/kg on day 1, 2, and 3 after transplantation with DMSO as a control. The general conditions, survival time and hematopoietic recovery of mice were observed, cytokines were detected by ELISA, and histopathological changes were detected by immunohistochemistry. The effects of low-dose GSI combined with BMSC on hematopoietic reconstruction and aGVHD development after allo-BMT were investigated. RESULTS: The survival rate of the mice in BM+SC+BMSC+GSI combination group was 80% during the observation period, which was significantly higher than that in the other groups; the incidence of aGVHD was reduced in the BMSC GSI or their combination groups after 21 days of transplantation. GSI could partly promote the recovery of leukocytes, and show no significant delayed effect on the recovery platelets. Moreover, the level of Th1 cytokines (IFN-γ) in BM+SC+BMSC+GSI combined group was lower than that in BM+SC+GSI group (P<0.01), the level of Th2 cytokines (IL-4) in the combination group was higher than that in BM+SC+GSI group (P<0.01), also the level of IL-17 was significantly lower than that in the corresponding control group (P<0.001). CONCLUSION: Low dose GSI combined with BMSC can promote hematopoietic reconstruction and regulate cytokines secretion including IFN-γ, IL-4 and IL-17. GSI combined with BMSC achieve the goal of synergistically inhibiting the occurrence and progression of aGVHD.

Co-Inhibition of the Immunoproteasome Subunits LMP2 and LMP7 Ameliorates Immune Thrombocytopenia.

The immunoproteasome, a special isoform of the 20S proteasome, is expressed when the cells receive an inflammatory signal. Immunoproteasome inhibition proved efficacy in the treatment of autoimmune diseases. However, the role of the immunoproteasome in the pathogenesis of immune thrombocytopenia (ITP) remains unknown. We found that the expression of the immunoproteasome catalytic subunit, large multifunctional protease 2 (LMP2), was significantly upregulated in peripheral blood mononuclear cells of active ITP patients compared to those of healthy controls. No significant differences in LMP7 expression were observed between patients and controls. ML604440, an specific LMP2 inhibitor, had no significant impact on the platelet count of ITP mice, while ONX-0914 (an inhibitor of both LMP2 and LMP7) increased the number of platelets. In vitro assays revealed that ONX-0914 decreased the expression of FcγRI in ITP mice and decreased that of FcγRIII in ITP patients, inhibited the activation of CD4+ T cells, and affected the differentiation of Th1 cells in patients with ITP. These results suggest that the inhibition of immunoproteasome is a potential therapeutic approach for ITP patients.

New polyacetylenes glycoside from Eclipta prostrate with DGAT inhibitory activity.

One new polyacetylene glycoside eprostrata Ⅰ (1), together with seven known compounds (2-8), were isolated from Eclipta prostrata. Their structures were elucidated on the basis of spectroscopic and physico-chemical analyses. All the isolates were evaluated inhibitory activity on DGAT in an in vitro assay. Compounds 1-8 were found to exhibit inhibitory activity of DGAT1 with IC50 values ranging from 74.4 ± 1.3 to 101.1 ± 1.1 µM.

Four new compounds isolated from Psoralea corylifolia and their diacylglycerol acyltransferase (DGAT) inhibitory activity.

A new bakuchiol compound Δ11-12-hydroxy-12-dimethyl bakuchiol (1), a new flavanone compound 2(S)-6-methoxy-7- hydroxymethylene-4'-hydroxyl-flavanone (8), and two new isoflavanone compounds 4',7-dihydroxy-3'-(6"ß-hydroxy-3″,7″-dimethyl-,2″,7″-dibutenyl)-geranylisoflavone (9) and 4',7-dihydroxy-3'-(7″-hydroxy-7″-methyl-2″,5″-dibutenyl)-geranylisoflavone (10) together with eight known compounds (2-7, 11, 12) were isolated from the P. corylifolia. Their structures were elucidated on the basis of spectroscopic and physico-chemical analyses. All the isolates were evaluated for in vitro inhibitory activity against DGAT1/2. Among them, compounds 3, 9 and 10 were found to exhibit selective inhibitory activity on DGAT1 with IC50 values ranging from 93.7 ±â€¯1.3 to 96.2 ±â€¯1.1 µM. Compound 1 showed inhibition activity on DGAT1 with IC50 values 73.4 ±â€¯1.3 µM and inhibition of DGAT2 with IC50 value 121.1 ±â€¯1.3 µM.

Four new neolignans isolated from Eleutherococcus senticosus and their protein tyrosine phosphatase 1B inhibitory activity (PTP1B).

Four new compounds, erythro-7'E-4-hydroxy-3,3'-dimethoxy-8,5'-oxyneoligna-7'-ene-7,9-diol-9'-al (1), (7S,8S)-4-hydroxy-3,1',3'-trimethoxy-4',7-epoxy-8,5'-neolign-9-ol (5), (7S,8S,7'E)-5-hydroxy-3,3'-dimethoxy-4',7-epoxy-8,5'-neolign-7'-ene-9,9'-diol (6) and (7S,8S,7'E)-5-hydroxy-3,3',9'-trimethoxy-4'-7-epoxy-8,5'-neolign-7'-ene-9-ol (7). Along with four known compounds (2-4, 8) were isolated from the EtOAc-soluble extract of Eleutherococcus senticosus. Their structures were elucidated on the basis of spectroscopic and physicochemical analyses. All the compounds were evaluated for in vitro inhibitory activity against PTP1B, VHR and PP1. Among them, compounds 1-4 and 6-8 were found to exhibit selective inhibitory activity on PTP1B with IC50 values ranging from 17.2±1.6 to 32.7±1.2µM.

[Research Progress on Notch Signal Pathway in Acute Graft-Versus-Host Disease -Review].

The Notch signaling pathway is a highly conserved cell signaling system that plays an essential role in many biological processes. Notch signaling regulates multiple aspects of hematopoiesis, especially during T cell develop-ment. Recent data suggest that Notch also regulates mature T cell differentiation and function. The latest data show that Notch also plays an essential role in alloreactive T cells mediating acute graft-versus-host disease (aGVHD), the most severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Notch inhibition in donor-derived T cells or blockade of individual Notch ligands and receptors after transplantation can reduce GVHD severity and mortality in mouse models of allo-HSCT, without causing global immunosuppression. These findings indicate Notch in T cells as an attractive therapeutic target to control aGVHD. In this article, the pathophysiology of aGVHD, the Notch signal pathway and aGVHD are reviewed.

New neo-lignan from Acanthopanax senticosus with protein tyrosine phosphatase 1B inhibitory activity.

New neo-lignan, (7S, 8R)-3-hydroxyl-4-methoxyl-balanophonin (1), together with seven known compounds (2-8) were isolated from the EtOAc-soluble extract of Acanthopanax senticosus. The structure of the new neo-lignan was elucidated with spectroscopic and physico-chemical analyses. All the isolates were evaluated for in vitro inhibitory activity against PTP1B, VHR and PP1. Among them, the new compound (1) was found to exhibit selective inhibitory activity on PTP1B with IC50 value 15.2 ± 1.4 µM.

Diacylglycerol acyltransferase 1 (DGAT1) inhibition by furofuran lignans from stems of Acanthopanax senticosus.

Two new furofuran lignans were isolated from the stems of Acanthopanax senticosus, along with seven known compounds. Their structures were all determined by spectroscopic analyses and chemical methods. All the isolates were evaluated for in vitro inhibitory activity against DGAT1 and DGAT2. Compounds 1 and 2 were found to exhibit selective inhibitory activity on DGAT1 with IC50 values 89.5 ± 1.5 and 57.5 ± 1.3 µM, respectively.

Four new sesqui-lignans isolated from Acanthopanax senticosus and their diacylglycerol acyltransferase (DGAT) inhibitory activity.

Four new sesqui-lignans, (7R, 7'R, 7″S, 8S, 8'S, 8″S)-4',5″-dihydroxy-3,5,3',4″-tetramethoxy-7,9':7',9-diepoxy-4,8″-oxy-8,8'-sesquineo-lignan-7″,9″-diol (1), (7R, 7'R, 7″S, 8S, 8'S, 8″S)-4',3″-dihydroxy-3,5,3',5',4″-pentamethoxy-7,9':7',9-diepoxy-4,8″-oxy-8,8'-sesquineo-lignan-7″,9″-diol (2), (7R, 7'R, 7″S, 8S, 8'S, 8″S)-3',4″-dihydroxy-3,5,4',5″-tetramethoxy-7,9':7',9-diepoxy-4,8″-oxy-8,8'-sesquineo-lignan-7″,9″-diol (3) and acanthopanax A (7) together with three known compounds (4-6) were isolated from the EtOAc-soluble extract of Acanthopanax senticosus. Their structures were elucidated on the basis of spectroscopic and physicochemical analyses. All the isolates were evaluated for in vitro inhibitory activity against DGAT1 and DGAT2. Among them, compounds 1-6 were found to exhibit selective inhibitory activity on DGAT1 with IC50 values ranging from 61.1 ± 1.3 to 97.7 ± 1.1 µM and compound 7 showed selective inhibition of DGAT2 with IC50 value 93.2 ± 1.2.

Effects of Morus root bark extract and active constituents on blood lipids in hyperlipidemia rats.

OBJECTIVE: Chinese crude drug Mori Cortex Radicis (the root cortex of Morus species) has been used as a folk medicine to treat hypertension, diabetes, as well as in expectorant, diuretic agents. This investigation aims to study the anti-hyperlipidemia effects of Mori Cortex Radicis (MCR) extracts in hyperlipidemic rat models and the potential therapeutic activities of compounds isolated from the extracts. MATERIALS AND METHODS: The effects of MCR on hypolipidemic parameters were investigated using Wistar rats induced by high-lipid emulsion. Sixty healthy Wistar rats were randomly divided into 6 groups: normal group, hyperlipidaemia model group, simvastatin, and high-, medium- and low-dose MCR extracts. After four weeks, body weight, total cholesterol (TC), triglycerides (TG), high and low-density lipoproteins (HDL, LDL), as well as aspartate aminotransferase (AST), alanine aminotransferase (ALT) were measured. To further investigation, four major active compounds were isolated from extracts through high performance liquid chromatography (HPLC) and their diacylglycerol acyltransferase 1 (DGAT1) inhibitory activity was evaluated. RESULTS: MCR dose-dependently reduced serum TC, TG, LDL-C, inhibited the activity of ALT, AST, and increased HDL-C. Furthermore, in vitro biochemistry tests revealed that four active isolates showed moderate inhibitory activity against DGAT1 with IC50 values ranging from 62.1 ± 1.2 to 99.3 ± 2.3 µM. CONCLUSIONS: The results demonstrated that MCR could effectively ameliorate hyperlipidaemia and inhibit DGAT1 that a key enzyme closely related to hyperlipidaemia and type 2 diabetes. It may provide a new pharmacological basis for treating hyperlipidaemia and related diseases using MCR.