Objective To study the relationship among leptin, neuropeptide Y and plasma lipid in the patients with essential hypertension. Methods In 116 patients with essential hypertension (EH) and 26 healthy subjects, the plasma concentrations of leptin(LE), neuropeptide Y(NPY), total cholesterol(TC), triglyceride(TG) and high density lipoprotein cholesterol(HDL) were determined using RIA. Results The body mass index (BMI), plasma concentrations of TC, TG, NPY and LE were higher in the patients with EH than those in healthy subjects, and the HDL concentration was lower than that in control group (P

Objective To observe the effects of curcumin on hepatic oxidant stress in water arsenic-exposed rats and to study its mechanism,which can offer references for curcumin used in antioxidant therapy of arsenic poisoning.Methods Thirty-two SD rats were divided into 4 groups according to body weight by random number table,half male and half female.Including control group (lavaged 135 days with deionized water),arsenic poisoning group (lavaged 45 days with deionized water after lavaging 90 days with 10 mg/kg sodium arsenite),pure curcumin group (lavaged 135 days with 1 000 mg/kg curcumin solution) and curcumin treatment group (lavaged 45 days with 1 000 mg/kg curcumin solution after lavaging 90 days with 10 mg/kg sodium arsenite),8 rats in each group.The arsenic contents of urine (urine creatinine corrected) and liver were detected by hydride generation inductively coupled plasma optical emission spectrometer (HG-ICP-OES);the activity of Cu/Zn-superoxide dismutase (SOD1) and catalase (CAT),the contents of malondialdehyde (MDA) in serum and liver homogenate by colorimetric method;the protein expression of liver antioxidant enzyme (SOD 1 and CAT) was assayed by Western blotting.Results The arsenic contents of urine and liver in arsenic poisoning group [(5.83 ± 0.29)μg/g Cr,(15.76 ± 1.65)μg/g] and the arsenic contents of urine in curcumin treatment group [(1.07 ± 0.14)μg/g Cr] were obviously higher than those of control group [(0.40 ± 0.14)μg/g Cr,(4.56 ± 1.05)μg/g,all P ＜ 0.05];compared to arsenic poisoning group,the arsenic contents of urine and liver in curcumin treatment group [(1.07 ± 0.14)μg/g Cr,(5.42 ± 1.76)μg/g] were obviously lower (all P ＜ 0.05).The contents of serum and liver SOD1,CAT and MDA in control group respectively were (102.46 ± 5.03),(29.33 ± 8.13)U/ml,(3.11 ± 0.49)μ mol/L and (204.05 ± 18.33),(126.26 ± 13.19)U/mg prot,(1.62 ± 0.42) μmol/g prot.Compared to the control,the activity of serum and liver SOD1 and CAT in arsenic poisoning group [(60.97 ± 7.94),(13.56 ± 5.14)U/ml and (133.66 ± 11.51),(74.01 ± 13.30)U/mg prot] were lower,the contents of MDA [(7.26 ± 0.54)μmol/L and (2.61 ± 0.52)μmol/g prot] were higher (all P ＜ 0.05).Compared to arsenic poisoning group,the activity of serum and liver SOD1 and CAT in curcumin treatment group [(87.39 ± 9.38),(20.45 ± 6.49) U/ml and (178.27 ± 9.32),(93.70 ± 20.35)U/mg prot] were higher,the contents of MDA [(4.34 ± 0.79)μmol/L and (1.92 ± 0.18)μmol/g prot] were lower (all P ＜ 0.05).The protein expressions of SOD1 and CAT in control group respectively were 0.64 ± 0.32 and 0.72 ± 0.31.Compared to the control group,the protein expressions of SOD1 and CAT in pure curcumin group (1.03 ± 0.23,1.02 ± 0.20) were significantly higher (all P ＜ 0.05) and in arsenic poisoning group (0.34 ± 0.12,0.39 ± 0.11) were lower (all P ＜ 0.05);Compared with the arsenic poisoning group,the protein expressions of SOD1 and CAT in curcumin treatment group (0.58 ± 0.09,0.68 ± 0.29) were significantly higher (all P ＜ 0.05).The arsenic content of urine in rats were positively related with arsenic content of liver and the content of MDA [correlation coefficient (r) =0.952,0.732,all P ＜ 0.05],but negativity related with the activity of SOD1 and CAT in liver (r =-0.874,-0.679,all P ＜ 0.05);the activity of SOD1 and CAT and the content of MDA in serum and liver were positively related (r =0.796,0.484,0.607,all P ＜ 0.05),the activity and protein expression of SOD1 and CAT in liver were positively related (r =0.748,0.424,all P ＜ 0.05).Conclusion The curcumin may improve the activity of hepatic antioxidant enzyme in water arsenic-exposed rats and effectively decrease lipid poroxidation damage caused by arsenic via promoting the excretion of arsenic and the protein expression of hepatic antioxidant enzyme.

Aim To investigate the effect of indirubin derivative PHⅡ-7 and TRAIL on proliferation in breast cancer cell MCF-7 and its MDR counterpart MCF-7/ADR and the mechanism.Methods Growth inhibition rate was examined respectively by MTT assay under treatment with TRAIL or PHⅡ-7 or in combination. Cell apoptosis and ROS production were examined by flow cytometry.The change of TRAIL receptors(DR4/DR5 )in mRNA was analysed by realtime PCR.Re-sults IC50 of PHⅡ-7 on MCF-7 and MCF-7/ADR was (4.49 ±1.55 ),(3.44 ±0.90 )μmol · L-1 respec-tively;MDA-MB-231 was TRAIL sensitive cell line, and apparently TRAIL induced apoptosis in MDA-MB-23 1 .Low concentration of PHⅡ-7 in combination with TRAIL could augment TRAIL-induced cytotoxic effect including apoptosis while TRAIL or PHⅡ-7 treatment alone had limited cytotoxity to those cells.Besides, PHⅡ-7 at this concentration had little toxicity to hu-man peripheral blood mononuclear cells even if in com-bination with TRAIL.PHⅡ-7 generated ROS produc-tion inside MCF-7 and MCF-7/ADR cells and up-regu-lated DR4/DR5 expression concentration dependently. Once upon ROS scavenger NAC involved,the effect of TRAIL receptors up-regualtion by expression was abro-gated.Conclusions PHⅡ-7 at low concentration could improve the sensitivities of breast cancer cell MCF-7 and MCF-7/ADR to TRAIL,the mechanism of which may be the ability of ROS production by PHⅡ-7 help up-regulated TRAIL receptor DR4,DR5 .Our re-search set a solid foundation for PHⅡ-7 in combination with TRAIL in future clinical application.

The study was designed to explore the drug-drug interactions mechanisms mediated by OATP1B1 between traditional Chinese medicine Danshensu and rosuvastatin. First, the changes of rosuvastatin pharmacokinetics were investigated in presence of Danshensu in rats. Then, the primary rat hepatocytes model was established to explore the effects of Danshensu on the uptake of rosuvastatin by hepatocytes. Finally, HEK293T cells with overexpression of OATP1B1*a and OATP1B1*5 were established using a lentiviral delivery system to explore the effects of Danshensu on the uptake of rosuvastatin. Rosuvastatin pharmacokinetic parameters of C(max0, AUCO(0-t), AUC(0-∞) were increased about 123%, 194% and 195%, by Danshensu in rats, while the CL z/F value was decreased by 60%. Uptake of rosuvastatin in the primary rat hepatocytes was decreased by 3.13%, 41.15% and 74.62%, respectively in the presence of 20, 40 and 80 μmol x L(-1) Danshensu. The IC50 parameters was (53.04 ± 2.43) μmol x L(-1). The inhibitory effect of Danshensu on OATP1B1 mediated transport of rosuvastatin was related to the OATP1B1 gene type. In OATP1B1*5-HEK293T mutant cells, transport of rosuvastatin were reduced by (39.11 ± 4.94)% and (63.61 ± 3.94)%, respectively, by Danshensu at 1 and 10 μmol x L(-1). While transport of rosuvastatin was reduced by (8.22 ± 2.40)% and (11.56 ± 3.04)% and in OATP1B1*1a cells, respectively. Danshensu significantly altered the pharmacokinetics of rosuvastatin in rats, which was related to competitive inhibition of transport by OATPJBI. Danshensu exhibited a significant activity in the inhibition of rosuvastatin transport by OATP1B1*5-HEK293T, but not by OATP1B1*1a, suggesting a dependence on OATP1B1 sequence.

Sterol-regulatory element binding proteins (SREBPs) are the key transcriptional regulators of lipid metabolism. The activation of SREBP requires translocation of the SREBP precursor from the endoplasmic reticulum to the Golgi, where it is sequentially cleaved by site-1 protease (S1P) and site-2 protease and releases a nuclear form to modulate gene expression. To search for new genes regulating cholesterol metabolism, we perform a genome-wide CRISPR/Cas9 knockout screen and find that partner of site-1 protease (POST1), encoded by C12ORF49, is critically involved in the SREBP signaling. Ablation of POST1 decreases the generation of nuclear SREBP and reduces the expression of SREBP target genes. POST1 binds S1P, which is synthesized as an inactive protease (form A) and becomes fully mature via a two-step autocatalytic process involving forms B'/B and C'/C. POST1 promotes the generation of the functional S1P-C'/C from S1P-B'/B (canonical cleavage) and, notably, from S1P-A directly (non-canonical cleavage) as well. This POST1-mediated S1P activation is also essential for the cleavages of other S1P substrates including ATF6, CREB3 family members and the α/β-subunit precursor of N-acetylglucosamine-1-phosphotransferase. Together, we demonstrate that POST1 is a cofactor controlling S1P maturation and plays important roles in lipid homeostasis, unfolded protein response, lipoprotein metabolism and lysosome biogenesis.

T cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy. Emerging evidence has shown that interferon-gamma (IFNγ) could enhance CXCL9 secretion from macrophages to recruit T cells, but Siglec15 expressed on TAMs can attenuate T cell proliferation. Therefore, targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues. We herein developed reduction-responsive nanoparticles (NPs) made with poly (disulfide amide) (PDSA) and lipid-poly (ethylene glycol) (lipid-PEG) for systemic delivery of Siglec15 siRNA (siSiglec15) and IFNγ for enhanced cancer immunotherapy. After intravenous administration, these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages (TAMs). With the highly concentrated glutathione (GSH) in the cytoplasm to destroy the nanostructure, the loaded IFNγ and siSiglec15 could be rapidly released, which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation, leading to significant inhibition of hepatocellular carcinoma (HCC) growth when combining with the immune checkpoint inhibitor. The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.