A contributory role of oxidative stress and protection by antioxidant nutrients have been suspected in cataract formation. Ganoderic acid A (GAA), an effective lanostane triterpene, is widely reported as an antioxidant. The aim of this study is to investigate the potential effects of GAA on cataract formation. After lens epithelial cells (LECs) were exposed to UVB radiation for different periods, cell viability, apoptosis-related protein levels, malondialdehyde (MDA) and superoxide dismutase (SOD) activities were monitored. We found that cell viability, the Bcl-2/Bax ratio and SOD activity were increased, while Cleaved caspase-3 levels and MDA activity were decreased compared with those in UVB-impaired LECs after GAA treated. Furthermore, GAA activated PI3K/AKT in UVB-impaired LECs and effectively delayed the occurrence of lens opacity in vitro. In conclusion, these findings demonstrated that GAA exhibited protective functions in SRA01/04 cells and rat lenses against UVB-evoked impairment through elevating cell viability and antioxidant activity, inhibiting cell apoptosis, activating the PI3K/AKT pathway and delaying lens opacity.
Animals ; Apoptosis ; Cataract/prevention & control* ; Cell Line ; Cell Survival ; Epithelial Cells/radiation effects* ; Heptanoic Acids/pharmacology* ; Humans ; Lanosterol/pharmacology* ; Lens, Crystalline/radiation effects* ; Malondialdehyde/metabolism* ; Rats ; Superoxide Dismutase/metabolism* ; Ultraviolet Rays/adverse effects*

OBJECTIVETo investigate the effect of ganoderic acid A (GA-A) on the biological behaviors of human osteosarcoma cells in vitro.

METHODSMG63 and HOS cells were treated with 0.1, 0.25, and 0.5 mmol/L GA-A, and the changes in cell proliferation, apoptosis and migration were evaluated using MTT assay, flow cytometry, and Transwell assay, respectively. The expressions of STAT3, p38, and NF-κB1 in the cells were analyzed by Western blotting.

RESULTSGA-A effectively inhibited the proliferation of human osteosarcoma HOS and MG-63 cells in a dose-dependent manner, and induced obvious cell apoptosis in both cells. Treatment with 0.5 mmol/L GA-A also resulted in significant inhibition of the invasion of both cells. The results of Western blotting showed that GA-A down-regulated the expression level of phosphorylated STAT3 and increased the phosphorylation level of p38 and NF-κB1 expression in both cells.

CONCLUSIONGA-A can induce proliferation inhibition, apoptosis and suppression of invasion in human osteosarcoma HOS and MG-63 cells.

Apoptosis ; drug effects ; Bone Neoplasms ; pathology ; Cell Line, Tumor ; drug effects ; Cell Movement ; drug effects ; Cell Proliferation ; drug effects ; Heptanoic Acids ; pharmacology ; Humans ; Lanosterol ; analogs & derivatives ; pharmacology ; NF-kappa B p50 Subunit ; metabolism ; Osteosarcoma ; pathology ; Phosphorylation ; STAT3 Transcription Factor ; metabolism ; p38 Mitogen-Activated Protein Kinases ; metabolism

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 whether atorvastatin inhibits oxidized low-density lipoproteins (Ox-LDL)-stimulated foam cell formation from THP-1 macrophages by regulating the activation of peroxisome proliferator-activated receptor γ (PPARγ) and nuclear factor-κB (NF-κB). Methods THP-1 macrophages were pretreated with 10, 20, or 40 µmol/L atorvastatin for 2 h, and after washing with PBS twice, the cells were incubated with 60 µg/ml of Ox-LDL for 48 h. The quantity of intracellular lipid of the cells was detected with Oil red O staining and enzymatic fluorometric method. The expression of the scavenger receptors of CD36 and SRA were analyzed with Western blotting. We also examined the effect of atorvastatin on adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) expression and the activation of PPARγ and p-iκB, and further assessed the capacity of the macrophages to bind to Dil-oxLDL.

RESULTSAtorvastatin potently inhibited ox-LDL-induced macrophage-derived foam cell formation, down-regulated the expression of CD36 and SRA, and up-regulated the expression of ABCA1. Atorvastatin markedly suppressed the activation of PPARγ and p-iκB in ox-LDL-stimulated THP-1 macrophages (P<0.05) and significantly decreased the Dil-oxLDL-binding capacity of the macrophages (P<0.05).

CONCLUSIONAtorvastatin as an effective anti-atherosclerosis agent can suppress the activation of PPARγ and p-iκB to reduce lipid accumulation in macrophages.

ATP Binding Cassette Transporter 1 ; metabolism ; Atorvastatin Calcium ; Cell Line ; Foam Cells ; cytology ; drug effects ; Heptanoic Acids ; pharmacology ; Humans ; I-kappa B Proteins ; metabolism ; Lipoproteins, LDL ; metabolism ; Macrophages ; cytology ; drug effects ; NF-kappa B ; metabolism ; PPAR gamma ; metabolism ; Pyrroles ; pharmacology ; Signal Transduction ; drug effects ; Transcriptional Activation ; Up-Regulation

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 effect of atorvastatin on exercise tolerance in patients with diastolic dysfunction and exercise-induced hypertension.

METHODSA randomized, double-blind, placebo-controlled prospective study was performed. Sixty patients with diastolic dysfunction (mitral flow velocity E/A <1) and exercise-induced hypertension (SBP>200 mm Hg) treated with atorvastatin (20 mg q.d) or placebo for 1 year. Cardiopulmonary exercise test and exercise blood pressure measurement were performed. Plasma B-natriuretic peptide (BNP) concentration at rest and at peak exercise, plasma high sensitive-C reaction protein (hs-CRP) and endothelin (ET) concentration were determined at baseline and after treatment.

RESULTSAfter treatment by atorvastatin, the resting SBP, pulse pressure, the peak exercise SBP and BNP were significantly decreased; and the exercise time, metabolic equivalent, maximal oxygen uptake and anaerobic threshold were increased. All of these parameters had significant differences with baseline levels (P<0.05) and the rest pulse pressure, the peak exercise SBP and BNP, and the exercise time had significant differences compared with placebo treatment (P<0.05). Plasma concentrations of hs-CRP and ET were markedly reduced by atorvastatin treatment compared with baseline and placebo (P<0.05). No difference in above parameters was found before and after placebo treatment (P>0.05).

CONCLUSIONIn patients with diastolic dysfunction at rest and exercise-induced hypertension, atorvastatin can effectively reduce plasma hs-CRP and ET level, lower blood pressure and peak exercise SBP, decrease peak exercise plasma BNP concentration, and ultimately improve exercise tolerance.

Aged ; Atorvastatin Calcium ; C-Reactive Protein ; metabolism ; Double-Blind Method ; Endothelins ; blood ; Exercise Tolerance ; drug effects ; Female ; Heart Failure ; complications ; drug therapy ; physiopathology ; Heptanoic Acids ; pharmacology ; Humans ; Hypertension ; complications ; drug therapy ; physiopathology ; Male ; Middle Aged ; Natriuretic Peptide, Brain ; blood ; Prospective Studies ; Pyrroles ; pharmacology

BACKGROUNDThe survival ratio of implanted mesenchymal stem cells (MSCs) in the infarcted myocardium is low. Autophagy is a complex "self-eating" process and can be utilized for cell survival. We have found that atorvastatin (ATV) can effectively activate autophagy to enhance MSCs survival during hypoxia and serum deprivation (H/SD). The mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathway is a non-canonical autophagy pathway. We hypothesized that the MEK/ERK pathway mediated ATV-induced autophagy of MSCs under H/SD.

METHODSMSCs were pretreated with ATV (0.01-10 µmol/L) under H/SD for three hours. For inhibitor studies, the cells were pre-incubated with the MEK1/2 inhibitor U0126. Cell autophagy was assessed by acidic vesicular organelles (AVO)-positive cells using flow cytometry, autophagy related protein using Western blotting and autophagosome using transmission electron microscopy.

RESULTSAutophagy was elevated in the H/SD group compared with the normal group. ATV further enhanced the autophagic activity as well as the phosphorylation of ERK1/2 evidenced by more AVO-positive cells ((8.63 ± 0.63)% vs. (5.77 ± 0.44)%, P < 0.05), higher LC3-II/LC3-I ratio (4.36 ± 0.31 vs. 2.52 ± 0.18, P < 0.05) and more autophagosomes. And treatment with U0126 downregulated the phosphorylation of ERK1/2 and attenuated ATV-induced autophagy.

CONCLUSIONThe MEK/ERK pathway participates in ATV-induced autophagy in MSCs under H/SD, and modulation of the pathway could be a novel strategy to improve MSCs survival.

Animals ; Atorvastatin Calcium ; Autophagy ; drug effects ; Cell Hypoxia ; physiology ; Cells, Cultured ; Flow Cytometry ; Heptanoic Acids ; pharmacology ; MAP Kinase Signaling System ; drug effects ; Male ; Mesenchymal Stromal Cells ; cytology ; drug effects ; ultrastructure ; Microscopy, Electron, Transmission ; Pyrroles ; pharmacology ; Rats

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 investigate the effect of atorvastatin on platelet aggregation and activation in the acute phase following balloon-induced carotid artery injury in rabbits fed cholesterol-enriched diet.

METHODSThirty rabbits were randomly divided into 5 equal groups, namely control group, high-cholesterol group, model group, low-dose (5 mg/kg daily) atorvastatin group, and high-dose (10 mg/kg daily) atorvastatin group. Platelet aggregation rate was measured in the rabbits by turbidimetric platelet aggregometry, and the changes of serum P-selectin and thromboxane B2 (TXB2) levels were detected with enzyme-linked immunosorbent assay (ELISA).

RESULTSCompared with those in the control group, serum P-selectin level increased significantly (P<0.01) but platelet aggregation rate and TXB2 level exhibited no obvious changes in high-cholesterol group. After carotid artery balloon injury, P-selectin and TXB2 levels and platelet aggregation significantly increased in cholesterol-fed rabbits, reaching the peak level at 24 h after the injury (P<0.01). Compared with the model group, low-dose atorvastatin treatment significantly decreased P-selectin and TXB2 levels and inhibited platelet aggregation in cholesterol-fed rabbits following carotid artery balloon injury (P<0.01), and such effects of atorvastatin were more prominent at a higher daily dose of 10 mg/kg (P<0.05).

CONCLUSIONSCarotid artery balloon injury in rabbits fed cholesterol-enriched diet can induce platelet activation and aggregation, which reaches the peak level at 24 h after balloon injury and can be dose-dependently inhibited by atorvastatin in the acute phase following the injury.

Animals ; Atorvastatin Calcium ; Blood Platelets ; Carotid Artery Injuries ; drug therapy ; Cholesterol ; Enzyme-Linked Immunosorbent Assay ; Heptanoic Acids ; pharmacology ; P-Selectin ; metabolism ; Platelet Activation ; Platelet Aggregation ; Pyrroles ; pharmacology ; Rabbits ; Thromboxane B2 ; metabolism

BACKGROUNDThe cholesterol-lowering statin drugs have some non-lipid-lowering effects, such as inhibiting myocardial remodeling. However, the underlying mechanism is still unclear.

METHODSThe left anterior descending coronary artery was ligated to establish a rat model of heart failure, and the rats were divided into a sham operation (SO) group, myocardial infarction model (MI) group, and MI-atorvastatin group. Changes in hemodynamic parameters were recorded after the final drug administration. Histological diagnosis was made by reviewing hematoxylin and eosin (HE) stained tissue. Real-time quantitative polymerase chain reaction (PCR) was performed to determine the expressions of type I and type III collagen, matrix metalloproteinase-2 (MMP-2), and tissue matrix metalloproteinase inhibitor-2 (TIMP-2). Further, primary rat cardiac fibroblasts were cultured and the MTT assay was performed to determine the effect of atorvastatin on cardiac fibroblast proliferation.

RESULTSThe model of heart failure was established and the results of HE staining and Masson's trichrome staining revealed that the rats in the heart failure group showed obvious hyperplasia of fibrotic tissue, which was significantly reduced in the atorvastatin group. Real-time quantitative PCR showed that the MI group showed a significantly increased expression of type I and type III collagen, MMP-2, and TIMP-2, but a significantly reduced MMP-2/TIMP-2 ratio. Compared with the MI group, the atorvastatin group showed significantly reduced expression of type I and III collagen, unchanged expression of MMP-2, significantly reduced expression of TIMP-2, and an increased MMP-2/TIMP-2 ratio. We further found that atorvastatin significantly inhibited the Ang II-induced fibroblast proliferation and the expression of type I and type III collagen in cardiac fibroblasts while increasing the MMP-2/TIMP-2 ratio.

CONCLUSIONSThese data suggest that atorvastatin can inhibit cardiac fibroblast proliferation and enhance collagen degradation by increasing the MMP-2/TIMP-2 ratio, thereby inhibiting the formation of myocardial fibrosis in rats with heart failure after myocardial infarction.

Animals ; Atorvastatin Calcium ; Collagen ; biosynthesis ; Disease Models, Animal ; Female ; Fibrosis ; Heart Failure ; drug therapy ; pathology ; Heptanoic Acids ; pharmacology ; therapeutic use ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; pharmacology ; Matrix Metalloproteinase 2 ; genetics ; Myocardial Infarction ; complications ; Myocardium ; pathology ; Pyrroles ; pharmacology ; therapeutic use ; Rats ; Rats, Wistar ; Tissue Inhibitor of Metalloproteinase-2 ; genetics ; Ventricular Remodeling ; drug effects