Aucubin prevents interleukin-1 beta induced inflammation and cartilage matrix degradation via inhibition of NF-κB signaling pathway in rat articular chondrocytes.

Proinflammatory cytokine interleukin-1ß (IL-1ß) plays a crucial role in the pathogenesis of Osteoarthritis (OA) by stimulating several mediators contributed to cartilage degradation. Aucubin, a natural compound derived from plants which has been shown to possess diverse biological activities including anti-inflammatory property, may benefit the IL-1ß stimulated chondrocytes. The present study was aimed to investigate the effects of Aucubin on IL-1ß stimulated rat chondrocytes. Rat chondrocytes were cultured and pretreated with Aucubin (1, 10, 20, 50µM), and then stimulated with or without IL-1ß (10ng/ml). Gene and protein expression of MMP-3, MMP-9, MMP-13, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) was determined by real-time PCR and Western blotting respectively. Nitric oxide (NO) production was quantified by Griess reagent. Phosphorylation and nuclear translocation of p65 were detected by western blotting and immunofluorescence, respectively. We found that Aucubin significantly reversed the elevated gene and protein expression of MMP-3, MMP-9, MMP-13, iNOS, COX-2 and the production of NO induced by IL-1ß challenge in rat chondrocytes. Furthermore, Aucubin was able to suppress the IL-1ß-mediated phosphorylation and nuclear translocation of p65, indicating Aucubin may possibly act via the NF-κB signaling pathway. The present study proposes that Aucubin may be a potential therapeutic choice in the treatment of OA due to its anti-inflammatory and chondroprotective features.

[Detection of the mRNA expression of human angiotensin-converting enzyme 2 as a SARS coronavirus functional receptor in human femoral head].

OBJECTIVE: To investigate the mRNA expression of severe acute respiratory syndrome-associated coronavirus (SARS-COV) functional receptor, angiotensin-converting enzyme 2 (ACE2), in human femoral head and conjunctiva, and explore the possible entry route of SARS-COV in human femoral head. METHODS: ACE2 mRNA in human femoral head was detected by nested RT-PCR with human beta actin gene as the positive control. RESULTS: The mRNA of human beta actin gene could be amplified efficiently in all the tissue samples. The mRNA of human ACE2 was expressed efficiently in the normal lung tissue, but not in the cartilage and cancellous bone under the weight-bearing area of the femoral head. CONCLUSION: SARS-COV can not infect the femoral head tissue and lead to avascular necrosis of the femoral head directly by the spike glycoprotein, and mechanism of the virus for causing avascular necrosis needs further investigation.

Deferoxamine prevents cardiac hypertrophy and failure in the gerbil model of iron-induced cardiomyopathy.

To evaluate the effects of the iron chelator deferoxamine on the functional and structural manifestations of iron-induced cardiac dysfunction, we measured cardiac power, left ventricular systolic, and diastolic function as (dP/dt)max and (dP/dt)min, respectively, and left ventricular and septal wall thickness in isolated heart preparations derived from the Mongolian gerbil model of iron overload. We induced iron overload with weekly subcutaneous injections of iron dextran (800 mg/kg/wk); deferoxamine (DFO; 100 mg/kg) was administered twice daily by subcutaneous injection, 5 of 7 days each week; and control animals received weekly subcutaneous injections of dextran alone. Animals administered iron alone initially exhibited, at 5 weeks, increased cardiac power but by 12 to 20 weeks, cardiac power was severely diminished, with impairment of both systolic and diastolic function of the left ventricle and marked cardiac hypertrophy (P<.001 for all vs control animals). Administration of DFO with iron did not interfere with the initial augmentation of cardiac power at 5 weeks but prevented the subsequent deterioration in cardiac performance. After 12 to 20 weeks, gerbils given DFO with iron had mean values of cardiac power indistinguishable from those of control animals; both systolic and diastolic function were significantly enhanced not only in comparison with those of animals treated with iron alone but also with respect to controls. In addition, DFO prevented cardiac hypertrophy; mean ventricular and septal wall thickness in gerbils given DFO and iron were not significantly different from those in controls. In the gerbil model of iron overload, concurrent administration of DFO with iron prevents both the development of cardiac hypertrophy and the progressive deterioration in cardiac performance that are produced by chronic iron accumulation.

Optical mapping reveals conduction slowing and impulse block in iron-overload cardiomyopathy.

Cardiac disease with arrhythmia or heart failure is the leading cause of death in patients with thalassemia major and a major complication of other forms of iron overload. Current antiarrhythmic treatment does not appear to alter the clinical course. Using a gerbil model of iron-overload cardiomyopathy, we previously observed a reduction in the fast inward sodium current in isolated cardiomyocytes. Electrocardiograms (ECGs) in the same gerbil model indicate PR-interval prolongation, QRS-interval widening, and arrhythmias. We hypothesize that such changes in the ECG in this model are the result of abnormal action-potential conduction at the level of the whole heart. To test this hypothesis, we took ECGs and recorded action potentials using high-resolution optical mapping from the anterior surface of 9 iron-overloaded and 9 age-matched control ventricular-paced, Langendorff-perfused gerbil hearts. The iron-overloaded gerbils received weekly iron-dextran injections of 800 mg/kg for 14 to 18 weeks. ECGs showed QRS- and PR-interval prolongation in iron-treated gerbils compared with that in controls. In addition, atrioventricular block was observed in 2 of 6 iron-treated gerbils but not in controls. Conduction velocity was significantly slower in iron-treated gerbils than in controls. At normal pacing rates, abnormal activation patterns caused by stable regions of conduction block were observed in iron-overloaded gerbils (33%) but not in controls. Such abnormal impulse conduction may be a mechanism of increased arrhythmia vulnerability in iron-overload cardiomyopathy.

Deferoxamine promotes survival and prevents electrocardiographic abnormalities in the gerbil model of iron-overload cardiomyopathy.

We investigated the time course of electrocardiographic (ECG) changes in the Mongolian gerbil model of iron overload and the effects of the iron chelator deferoxamine (DFO) on these changes. Iron overload was produced with weekly subcutaneous injections of low doses (200 mg/kg/wk) or high doses (800 mg/kg/wk) of iron-dextran. DFO was administered subcutaneously at a dose of 200 mg/kg/day to high-dose animals. Our results show that (1) survival of iron-overloaded gerbils is dose-dependent, with median survival times of 68 and 14 weeks for low- and high-dose animals, respectively; (2) both low and high doses produce prolongation of the PR interval and bradycardia in early stages and prolongation of the QT interval, premature ventricular contractions, variable degrees of atrioventricular block, changes in the ST segment, and T-wave inversion at later stages coinciding with the development of heart failure; (3) DFO prevented death during 20 weeks of high-dose iron-dextran; (4) DFO prevented ECG changes, although delayed prolongation of PR intervals and QRS complexes occurred; and (5) despite marked prolongation of survival and prevention of ECG changes, DFO had modest effects on total cardiac iron content. We speculate that DFO chelates a small iron pool located within the cytoplasm of iron-overloaded cardiomyocytes.

Bimodal cardiac dysfunction in an animal model of iron overload.

Iron-overload cardiomyopathy is the most common cause of death in patients with thalassemia major, yet the associated changes in cardiac function have not been quantified. We studied the effects of iron overload on cardiac function in Mongolian gerbils, a species that responds to iron overload in the same manner as human beings. We injected iron-dextran or dextran alone at low subcutaneous doses (200 mg/kg/wk) for 20 to 60 weeks and at high doses (800 mg/kg/wk) for 6 to 20 weeks. At shorter durations for either dose, the mean values of cardiac work, coronary flow, left ventricular (dP/dt)(max) and left ventricular (dP/dt)(min) in isolated perfused hearts were significantly greater than control values; at longer durations, these values were significantly less than control values. Echocardiography in intact animals showed eccentric cardiac hypertrophy, increased cardiac output, and normal exercise tolerance at shorter durations of dosage. At longer durations, concentric cardiac hypertrophy developed, and cardiac output and exercise capacity were impaired. The response to iron overload in Mongolian gerbils progresses from an initial state of high cardiac output to a subsequent state of low-output failure similar to the course of cardiomyopathy that has been inferred in patients with transfusional iron overload.