1.Depressive effect on proliferation of vascular smooth muscle cells by tetrandrine in hypertensive rats
Qingping LI ; Zean LU ; Manren RAO
Chinese Journal of Pharmacology and Toxicology 2001;15(2):145-149
To analyse the effect of tetrandrine(Tet) on proliferation of aortic vascular smooth muscle cells ( AVSMC), AVSMC were isolated and cultured from sham-operated rats(Sham), renovascular hypertensive rats〔RHR, 18 weeks after two kidney one clip(2K1C) operation〕, and Tet (50 mg*kg-1*d-1 po for 9 weeks from week 9 after 2K1C operation)treated RHR. The proliferation of AVSMC was detected by MTT method, and the DNA synthesis was evaluated by [3H]-thymidine incorporation. The results showed that ①The ultrastructure of aorta suggested that AVSMC in RHR had transferred from contractile phenotype to synthetic phenotype; ②Compared to Sham, AVSMC from RHR showed a higher proliferative property with a higher cell number and an increased growth rate stimulated by norepinephrine(NE) or angiotensinⅡ(AngⅡ); ③Compared to untreated RHR, AVSMC from Tet treated RHR showed a reduced reactivity to NE- or AngⅡ-stimulated proliferation and growth rate; ④Tet(0.1-10 μmol*L-1) treated in vitro induced a concentration-dependent depression in [3H] thymidine-incorporation stimulated by NE or AngⅡ in AVSMC from either RHR or Sham. This study provides an evidence of increased reactivity to NE or AngⅡ in AVSMC of RHR. Tet inhibits the proliferation and DNA synthesis in AVSMC, depresses the susceptibility of AVSMC to AngⅡ and NE, both contribute to the regression effect on hypertensive vascular remodeling.
2.Antidiabetic and insulin-sensitizing effects of neoglitazone in different animal models of type 2 diabetes
Xianghui HAN ; Zean LU ; Wei ZHOU
Chinese Journal of New Drugs and Clinical Remedies 2008;27(9):652-659
AIM To assess antidiabetic and insulin sensitizing effect of a novel thiazolidinedione,neoglitazone, in different animal models of type 2 diabetes. METHODS Neoglitazone combined with low-dose insulin(0.2U·d-1 per mouse,sc)were given in streptozotiocin (STZ)-induced diabetic mice for 7 d to inspect its insulin-sensitive improvement. The antidiabetic effect of chronic oral treatment (8 wk) with neoglitazone on spontaneous diabetes mice (DB/DB mice) was examined. The levels of blood glucose were measured by a One-Touch blood glucose meter and pathology of heart, kidney, and pancreas tissues were observed under a light microscope. The hyperinsulinaemic-euglycaemic clamp technique was applied to measure the increase of glucose infusion rate (GIR) of neoglitazone on the immune insulin-resistant rats induced by Bacillus Calmette-Guerin therapy decreased ( 14±s4)%, (55±24)%,and (28±7)% of blood glucose levels compared with CMC-Na+insulin group, respectively (P < 0.01) . In DB/DB mice, neoglitazone showed better reduction in blood glucose levels than those of model animals (P < 0.01) , and pathological studies indicated that neoglitazone attenuated the diabetic kidney and pancreas lesions. During a hyperinsulinaemic-euglycaemic clamp,neoglitaxone(10,30,and 100mg·kg-1·d-1,ig for 2 wk )-treated groups required significantly higher GIR to maintain basal glucose concentrations than model group (P < 0.01 ). CONCLUSION Neoglitazone could directly enhance insulin sensitivity and ameliorate insulin resistance in different diabetic animal models.
3.Effects of tetrandrine on hydroxyproline content and myosin ATPase activity of hypertrophied myocardium in renovascular hypertensive rats
Zean LU ; Qingping LI ; Manren RAO ; Xiyong YU ; Shuguang LIN
Chinese Journal of Pharmacology and Toxicology 2001;15(2):121-124
To study the effects of tetrandrine (Tet) on hypertrophied myocardial hydroxyproline content and myosin ATPase activity, left ventricular hypertrophy(LVH) was induced by renovascular hypertension (two-kidney, one-clip) in rats. Eight weeks after operation Tet 50 mg*kg-1*d-1 and enalapril(Ena) 6 mg*kg-1*d-1 were given by gavage for 8 weeks. The results showed that hydroxyproline content in LVH group was much higher than that of sham-operated one 〔(5.9±0.3) vs (3.6±0.4) mg*g-1 dry weight〕, and was decreased by 28.2% and 39.0% in Tet and Ena groups, respectively. Myosin ATPase activity in LVH group was much lower than that of sham-operated group 〔(0.43±0.09) vs (0.97±0.06) mmol Pi*min-1*g-1 protein, P<0.01〕. In Tet and Ena groups they were 60.5% and 118.6% higher than that of LVH group, respectively. The results suggest that Tet or Ena partially reduce the hydroxyproline content and elevate myosin ATPase activity of hypertrophied myocardium in renovascular hypertensive rats.
4.Tubeimoside-1 induces TFEB-dependent lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting mTOR.
Xiaojia LIU ; Mingxiao YIN ; Jingwen DONG ; Genxiang MAO ; Wenjian MIN ; Zean KUANG ; Peng YANG ; Lu LIU ; Na ZHANG ; Hongbin DENG
Acta Pharmaceutica Sinica B 2021;11(10):3134-3149
Programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) cascade is an effective therapeutic target for immune checkpoint blockade (ICB) therapy. Targeting PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor immunity. Using flow cytometry-based assay, we identify tubeimoside-1 (TBM-1) as a promising antitumor immune modulator that negatively regulates PD-L1 level. TBM-1 disrupts PD-1/PD-L1 interaction and enhances the cytotoxicity of T cells toward cancer cells through decreasing the abundance of PD-L1. Furthermore, TBM-1 exerts its antitumor effect in mice bearing Lewis lung carcinoma (LLC) and B16 melanoma tumor xenograft