The present study aimed at identifying cell cycle inhibitors from the fermentation broth of Streptomyces pseudoverticillus YN17707. Activity-guided isolation was performed on tsFT210 cells. Compounds were isolated through various chromatographic methods and elucidated by spectroscopic analyses. Flow cytometry was used to evaluate the cell cycle inhibitory activities of the fractions and compounds. Two compounds were obtained and identified as pteridic acid hydrate (1) and pteridic acid C (2), which arrested the tsFT210 cells at the G0/G1 phase with the MIC values being 32.8 and 68.9 μmol·L(-1), respectively. These results provide a basis for future development of Compounds 1 and 2 as novel cell cycle inhibitors for cancer therapy.
Cell Cycle Checkpoints ; drug effects ; Cell Line ; Heptanoic Acids ; chemistry ; isolation & purification ; pharmacology ; Humans ; Molecular Structure ; Spiro Compounds ; chemistry ; isolation & purification ; pharmacology ; Streptomyces ; chemistry

OBJECTIVETo evaluate the time course of granulocyte-colony-stimulating-factor (G-CSF), estrogen and various doses of atorvastatin on endothelial progenitor cells (EPCs) mobilization.

METHODA total of 48 male New Zealand White rabbits were treated with placebo, estrogen (0.25 mg.k(-1).d(-1)), Atorvastatin (2.5, 5, or 10 mg) and G-CSF (50 microg/rabbit/d), respectively. Peripheral EPCs number was surveyed weekly for 4 weeks by FACS analysis (double-positive for PE-CD34/FITC-CD133) and under fluorescent microscope (double-positive for FITC-UEA-1/Dil-acLDL). Serum nitric oxide (NO) and lipids were also measured at the third week.

RESULTSPeripheral EPCs was significantly increased in G-CSF treated animals and remained constant for 4 weeks compared to placebo treated animals. Atorvastatin increased peripheral EPCs dose-dependently from 2.5 to 5 mg and peaked at the third week while peripheral EPCs number was not affected by 10 mg.k(-1).d(-1) atorvastatin during the first 3 weeks and was significantly higher only in the fourth week compared to placebo group. Estrogen also significantly increased peripheral EPCs at the third and fourth week compared to placebo group. At the third week, serum NO was similar in G-CSF group, significantly higher in atorvastatin 5 mg.k(-1).d(-1) and estrogen groups while significantly lower in atorvastatin 10 mg.k(-1).d(-1) group compared to placebo group. Serum lipids were similar among various groups.

CONCLUSIONAtorvastatin, estrogen and G-CSF could mobilize EPCs. The mobilization efficacy is as follows: G-CSF > atorvastatin 5 mg.k(-1).d(-1) > estrogen > atorvastatin 2.5 mg.k(-1).d(-1) > atorvastatin 10 mg.k(-1).d(-1). NO might partly contribute to the mobilizing effect of estrogen and atorvastatin.

Animals ; Atorvastatin Calcium ; Endothelial Cells ; cytology ; drug effects ; Estrogens ; pharmacology ; Granulocyte Colony-Stimulating Factor ; pharmacology ; Heptanoic Acids ; pharmacology ; Hypolipidemic Agents ; pharmacology ; Lipids ; blood ; Male ; Nitric Oxide ; blood ; Pyrroles ; pharmacology ; Rabbits ; Recombinant Proteins ; Stem Cells ; drug effects

OBJECTIVETo assess the effect of atorvastatin on lipopolysaccharide (LPS)-induced TNF-α production in RAW264.7 macrophages.

METHODSRAW264.7 macrophages were treated in different LPS concentrations or at different time points with or without atorvastatin. TNF-α level in supernatant was measured. Expressions of TNF-α mRNA and protein and heme oxygenase-1 (HO-1) were detected by ELISA, PCR, and Western blot, respectively. HO activity was assayed.

RESULTSLPS significantly increased the TNF-α expression and secretion in a dose- and time-dependent manner. The HO-1 activity and HO-1 expression level were significantly higher after atorvastatin treatment than before atorvastatin treatment and attenuated by SB203580 and PD98059 but not by SP600125, suggesting that the ERK and p38 mitogen-activated protein kinase (MAPK) pathways participate in regulating the above-mentioned effects of atorvastatin. Moreover, the HO-1 activity suppressed by SnPP or the HO-1 expression inhibited by siRNA significantly attenuated the effect of atorvastatin on TNF-α expression and production in LPS-stimulated macrophages.

CONCLUSIONAtorvastatin can attenuate LPS-induced TNF-α expression and production by activating HO-1 via the ERK and p38 MAPK pathways, suggesting that atorvastatin can be used in treatment of inflammatory diseases such as sepsis, especially in those with atherosclerotic diseases.

Adjuvants, Immunologic ; pharmacology ; Animals ; Atorvastatin Calcium ; Enzyme Activation ; drug effects ; Heme Oxygenase-1 ; genetics ; metabolism ; Heptanoic Acids ; pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; pharmacology ; Lipopolysaccharides ; pharmacology ; Macrophages ; drug effects ; Membrane Proteins ; genetics ; metabolism ; Mice ; Pyrroles ; pharmacology ; Tumor Necrosis Factor-alpha ; metabolism

OBJECTIVETo investigate the correlation between atorvastatin inhibiting the expression level of matrix metalloproteinase 9 (MMP-9) and peroxisome proliferator activated receptor alpha (PPARalpha) signal channel in myocyte of aging rat.

METHODSPrimary cultures of myocyte were got ten from aging rats. Myocyte were divided into control group, DMSO group, atorvastatin group, atorvastatin plus GW6471 group, which treated respectively by cell culture medium, DMSO, atorvastatin, atorvastatin plus GW6471. The expression of MMP-9 mRNA was evaluated by RT-PCR, and content of MMP-9 protein was detected by Western blot.

RESULTS(1) There was no difference between control group and DMSO group in level of MMP-9 mRNA and protein expression (P > 0.05); (2) The level of MMP-9 mRNA and MMP-9 protein expression in atorvastatin group were significantly lower than those in control group (P < 0.01); (3) Both level of MMP-9 mRNA and protein expression in atorvastatin plus GW6471 group were significantly higher than those in atorvastatin group (P < 0.05), but were still lower than those in control group (P < 0.05).

CONCLUSIONAtorvastatin inhibit MMP-9 expression of aging myocytes by PPARalpha signal channel.

Aging ; Animals ; Atorvastatin Calcium ; Cells, Cultured ; Heptanoic Acids ; pharmacology ; Matrix Metalloproteinase 9 ; metabolism ; Muscle Cells ; drug effects ; metabolism ; Oxazoles ; pharmacology ; PPAR alpha ; metabolism ; Pyrroles ; pharmacology ; Rats ; Rats, Wistar ; Signal Transduction ; Tyrosine ; analogs & derivatives ; pharmacology

The effect of atorvastatin on warfarin-induced aortic medial calcification and systolic blood pressure (SBP) of rats induced by warfarin was studied. Thirty healthy and adult rats were randomly divided into Warfarin group (n=10), Atorvastatin group (n=10) and normal control group (n=10). Caudal arterial pressure of rats was measured once a week, and 4 weeks later, aorta was obtained. Elastic fiber, collagen fiber and calcium accumulation in tunica media of cells were measured by Von Kossa staining. The results showed that warfarin treatment led to elevation of systolic blood pressure and aortic medial calcification. The chronic treatment also increased collagen, but decreased elastin in the aorta. However, the atorvastatin treatment had adverse effects. It was concluded that treatment with atorvastatin presented evidence of blood pressure lowing and calcification reducing. These data demonstrate that atorvastatin protected aortic media from warfarin-induced calcification and elevation of systolic blood pressure.
Aortic Diseases/chemically induced ; Aortic Diseases/drug therapy ; Aortic Diseases/*pathology ; Blood Pressure/*drug effects ; Calcinosis/chemically induced ; Calcinosis/*drug therapy ; Calcinosis/pathology ; Heptanoic Acids/*pharmacology ; Heptanoic Acids/therapeutic use ; Hypertension/chemically induced ; Hypertension/*drug therapy ; Pyrroles/*pharmacology ; Pyrroles/therapeutic use ; Random Allocation ; Rats, Wistar ; Warfarin

OBJECTIVE: To investigate the effect of atorvastatin on the expression of angiotensin converting enzyme 2 (ACE2) mRNA and its protein in hypertrophic myocardium in rats. METHODS: Suprarenal abdominal aortic coarctation was performed to create the pressure overload induced left ventricular hypertrophy model in rats. RESULTS: Rats were randomly divided into 5 groups: (1) normal control group (Group A); (2) normal control group treated with atorvastatin [(5 mg/(kg.dd), Group B]; (3) sham group (Group C); (4) atorvastatin given orally by gastric gavage for 4 weeks [5 mg/(kg.dd),Group D]; (5) vehicle group (Group E). Stained pathological section was observed under light microscope to measure cardiomyocyte diameter transversa and collagen volume fraction. ACE2 mRNA and its protein expression were detected by real-time RT-PCR and Western blot. Compared with Group A,B, and C, the left ventricular mass index, cardiomyocyte diameter transversa and collagen volume fraction in Group E increased statistically (P< 0.01), ACE2 mRNA and its protein expression also elevated remarkably (P< 0.01). Compared with Group E, the above mentioned indexes in Group D reduced significantly (P< 0.01). CONCLUSION ACE2 mRNA and its protein expression increase significantly in hypertrophic myocardium in rats; atorvastatin can attenuate cardiac hypertrophy due to pressure overload in rats effectively, and part of this anti-hypertrophy effect may be attributed to decrease ACE2 mRNA and protein expression.
Animals ; Aorta ; Atorvastatin ; Heptanoic Acids ; pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; pharmacology ; Hypertrophy, Left Ventricular ; etiology ; metabolism ; Ligation ; Male ; Peptidyl-Dipeptidase A ; biosynthesis ; genetics ; Pyrroles ; pharmacology ; RNA, Messenger ; biosynthesis ; genetics ; Random Allocation ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo study the effect of compound Danshen dripping pills and atorvastatin on restenosis after abdominal aorta angioplasty in rabbits.

METHODSRabbit models of abdominal aorta restenosis after angioplasty were established and treated with saline (group A), compound Danshen dripping pills (group B), atorvastatin (group C), or compound Danshen dripping pills plus atorvastatin (group D). HE staining was used to determine the thickness of arterial intimal hyperplasia and assess the morphological changes of the narrowed artery. Immunohistochemistry was employed to detect the expression of nuclear factor-κB (NF-κB) and monocyte chemoattractant protein-1 (MCP-1).

RESULTSCompared with group A, the 3 treatment groups showed significant increased vascular cavity area and reduced intimal area and percentage of intimal hyperplasia (P<0.05). The vascular cavity area, intimal area and percentage of intimal hyperplasia levels differed significantly between group D and groups B and C (P<0.05). Immunohistochemistry showed a significant reduction of the expression rate of NF-κB and MCP-1 in the 3 treatment groups compared with group A (P<0.05), and the reduction was especially obvious in group D (P<0.05).

CONCLUTIONSCompound danshen dripping pills combined with atorvastatin produces better effects than the drugs used alone in inhibiting vascular smooth muscle cell proliferation in rabbits after abdominal aorta angioplasty possibly due to a decreased expression of MCP-1 as a result of NF-κB inhibition.

Angioplasty ; Animals ; Aorta ; pathology ; Atorvastatin Calcium ; Cell Proliferation ; Chemokine CCL2 ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; Heptanoic Acids ; pharmacology ; Hyperplasia ; Myocytes, Smooth Muscle ; drug effects ; NF-kappa B ; metabolism ; Phenanthrolines ; Pyrroles ; pharmacology ; Rabbits ; Salvia miltiorrhiza ; chemistry ; Tunica Intima

OBJECTIVETo evaluate whether taking atorvastatin for long time has positive effects on age-related renal impairment.

METHODS20-month-age normal female Wistar rats were divided into three groups (n = 9). First group were fed atorvastatin 10 mg/(kg x d). Second group were fed atorvastatin 1 mg/(kg x d). Third group were fed the same volume normal saline served as control. All the rats were sacrificed after four months. 3-month-age normal female Wistar rats (n = 9) also served as normal control. Kidney weight, serum creatinine (Scr) and blood-lipoids were measured. Paraffin sections of renal tissues were stained with PAS and Sirius red. Sclerosis index of glomerulus was calculated.

RESULTSRenal mass diminution was found in all the groups of aging rats. Scr was decreased in the group of aging rats with atorvastatin 1 mg/(kg x d). The level of blood-lipoids of aging rats was higher than that of young rats. The level of serum cholesterol and low-density lipoprotein (LDL) were decreased in first group (both P < 0.05) and only LDL decreased in second group (P < 0.05). Morphological changes of aging kidney were focal segmental glomerulosclerosis, widen of mesangial region, infiltration of inflammatory cells and sclerosis of arteriole. The treatment of atorvastatin improved the pathologic changes in the aging rats significantly, especially in the first group.

CONCLUSIONTaking atorvastatin for long time can notably improve the pathological changes of aging kidney. All these effects may be induced by lowing of blood-lipoids, relieving the sclerosis of renal arteriole and reducing the infiltration of inflammatory cells.

Aging ; physiology ; Animals ; Anticholesteremic Agents ; administration & dosage ; pharmacology ; Arteriosclerosis ; pathology ; prevention & control ; Atorvastatin Calcium ; Female ; Heptanoic Acids ; administration & dosage ; pharmacology ; Kidney ; pathology ; Kidney Diseases ; prevention & control ; Pyrroles ; administration & dosage ; pharmacology ; Rats ; Rats, Wistar ; Renal Artery ; pathology

OBJECTIVE: To determine the effect of atorvastatin on lipopolysaccharide-induced expression of C-reactive protein in cultured A549 cells. METHODS: A549 cells were incubated in DMEM medium containing lipopolysaccharide in the absence or presence of various concentrations of atorvastatin. After the incubation, the medium was collected and the level of C-reactive protein was measured by enzyme-linked immunosorbent assay. The cells were harvested and C-reactive protein mRNA was analyzed by reverse transcription polymerase chain reaction. RESULTS: Incubation with lipopolysaccharide significantly induced a time and dose dependent increase in the mRNA expression and the production of C-reactive protein in A549 cells (P<0.05). Atorvastatin significantly decreased the lipopolysaccharide induced the mRNA expression and the production of C-reactive protein in a dose dependent manner in A549 cells (P<0.05). CONCLUSION Atorvastatin downregulates lipopolysaccharide-induced expression of C-reactive protein in cultured A549 cells, which may be its mechanism of anti-inflammation.
Atorvastatin ; C-Reactive Protein ; genetics ; metabolism ; Cell Line ; Down-Regulation ; drug effects ; Epithelial Cells ; metabolism ; pathology ; Heptanoic Acids ; pharmacology ; Humans ; Lipopolysaccharides ; antagonists & inhibitors ; Lung ; metabolism ; pathology ; Pyrroles ; pharmacology ; RNA, Messenger ; genetics ; metabolism

OBJECTIVETo investigate the effects of atorvastatin on matrix metalloproteinase-9 (MMP-9) and the tissue inhibitor-1 of matrix metalloproteinase (TIMP-1) levels in bronchoalveolar lavage fluid (BALF) and serum of rats with experimental pulmonary fibrosis.

METHODSPulmonary fibrosis was induced by intratracheal administration of bleomycin in 30 female rats, which were further divided into two groups: Group M (without treatment) and Group A (treated with atorvastatin 10 mg/kg); control group (n = 5, Group C) was intratracheally administrated with same volume of saline. Five animals were sacrificed at 2 weeks (M2 and A2), 4 weeks (M4 and A4) and 6 weeks (M6 and A6) after model establishment, respectively. Lung tissue samples were harvested and prepared for HE and Masson's trichrome staining. Concentrations of MMP-9 and TIMP-1 in BALF and serum were measured by ELISA.

RESULTThe severity of inflammation and pulmonary fibrosis was significantly reduced in Group A than that in Group M, especially at week 6. No significant difference was noted in the serum concentrations of MMP-9 and TIMP-1 among the Group M, A and Group C. The BALF concentrations of MMP-9 in Group M2 and M6 were significantly higher than those in Group C (P < 0.01 and 0.05), whereas those in the atorvastatin groups (A2, A4 and A6) were lower than those in M2, M4 and M6. Although the MMP-9 was still higher in Groups A2 and A4 than in the Group C, there was no significant difference in MMP-9 between Group A6 and Group C. TIMP-1 levels in BALF were significantly higher in M4 and M6 than Group C (P < 0.01 and 0.05), there were no significant differences between Group M2 and Group C. The TIMP-1 levels in BALF of atorvastatin groups were significantly lower than those of model groups and control group (P < 0.01 and 0.05), which resulted in a significantly increased ratio of MMP-9 to TIMP-1 in the atorvastatin groups.

CONCLUSIONAtorvastatin inhibits the synthesis and release of MMP-9 and TIMP-1 in the lung tissue of rats with bleomycin-induced pulmonary fibrosis, and has no significant effect on circulating MMP-9 and TIMP-1, which may be associated with the attenuation of experimental pulmonary fibrosis in rats.

Animals ; Atorvastatin Calcium ; Bleomycin ; toxicity ; Bronchoalveolar Lavage Fluid ; chemistry ; Disease Models, Animal ; Female ; Heptanoic Acids ; pharmacology ; Matrix Metalloproteinase 9 ; metabolism ; Pulmonary Fibrosis ; chemically induced ; metabolism ; Pyrroles ; pharmacology ; Rats ; Rats, Wistar ; Tissue Inhibitor of Metalloproteinase-1 ; metabolism