ABSTRACT
Telbivudine (LdT), a widely prescribed anti-hepatitis B virus (HBV) drug for the treatment of chronic Hepatitis B (CHB), causes adverse reactions ranging from creatine kinase (CK) elevation to myopathy. The purpose of this study was to explore the mechanism(s) of LdT induced CK elevation. The effects of LdT on mitochondrial morphology and proteins (TK2 and ß-actin), oxidative stress, intracellular Ca2+ levels, Ca2+-related signaling pathway (CaMKK2/AMPK), and Ca2+-related biomarkers such as superoxide dismutase (SOD) and malondialdehyde (MDA) were assessed in human skeletal muscle cells (HSKMCs). The results showed that LdT induced a dose-dependent increase in CK activity in HSKMCs, without affecting mitochondrial morphology, and TK2 and ß-actin protein levels, following 72â¯h of treatment. In addition, LdT increased Ca2+ production, ROS generation, MDA and lipid peroxide (LPO) levels, and activated the CaMKK2/AMPK signaling pathway. Moreover, these effects were attenuated by the BAPIA-AM (the calcium chelator). We also confirmed the presence of relevant markers (MDA, LPO, and SOD) in serum from CHB patients after LdT treatment, and found that CK was positively correlated with MDA and LPO, and negatively associated with SOD. These findings indicate that LdT induces CK elevation and oxidative stress associated with imbalance of intracellular Ca2+ in HSKMCs, suggesting that Ca2+/CaMKK2 axis imbalance may underlie human LdT-induced CK elevation. The present findings provide a solid basis for assessing the mechanism of drug-induced CK elevation, which can help develop new tools for the prevention and treatment of diseases associated with drug-induced CK elevation.
Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism , Calcium/metabolism , Creatine Kinase/metabolism , Thymidine/analogs & derivatives , Adult , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Calcium-Calmodulin-Dependent Protein Kinase Kinase/genetics , Female , Gene Expression Regulation, Enzymologic/drug effects , Hepatitis B, Chronic/drug therapy , Humans , Liver/enzymology , Male , Middle Aged , Muscle Fibers, Skeletal/drug effects , Muscle Fibers, Skeletal/enzymology , Telbivudine , Thymidine/adverse effects , Thymidine/pharmacology , Up-Regulation , Young AdultABSTRACT
<p><b>OBJECTIVE</b>To investigate the effect of astragaloside IV (As IV) on the activation of rennin-angiotensin system in rats with pressure-overload induced cardiac hypertrophy.</p><p><b>METHOD</b>Left ventricle hypertrophy was induced by abdominal aorta banding between bilateral renal aortas for 12 weeks. Rats were given astragaloside IV 1.0 mg x kg(-1) and 3.3 mg x kg(-1) for 12 weeks, respectively. After treatment, the left ventricular mass index (LVMI)was calculated by morphometry methods. Plasma and cardiac tissue angiotensin II, and plasma aldosterone were measured by ELISA method. Gene expressions of ACE, AT1 and AT2 in cardiac tissue were detected by real time PCR. Protein expressions of AT1 and AT2 in cardiac tissue were detected by Western blot.</p><p><b>RESULT</b>Compared with model rats, LVMI was decreased by astragaloside IV treatment. Biochemical results indicated that the contents of angiotensin II in plasma and cardiac tissue as well as aldosterone in plasma were all increased in abdominal aorta banding rats comparing with sham-operated rats, then, decreased by astragaloside IV treatment. Gene expressions of cardiac ACE was downregulated by astragaloside IV, however, gene and protein expressions of cardiac AT2 were upregulated by astragaloside IV. Both elevated gene and protein expressions of AT1 were not attenuated by astragaloside IV.</p><p><b>CONCLUSION</b>Excessive activated rennin-angiotensin system in rats with pressure-overload induced cardiac hypertrophy is inhibited by astragaloside IV treatment.</p>
