A new selenium-containing curcumin polymer was synthesized by polycondensation of curcumin with dihydride, polyethylene glycol, and selenium amino acid monomers. The polymer was stable, water soluble, and injectable with a molecular weight of 6.1 x 10(4) Da. The in vivo anti-liver fibrosis efficacy of the polymer was investigated with Sprague Dawley rats. The results showed the curcumin polymer had strong anti-hepafibrosis activity.

Oleanolic Acid (OA) is a nature product extracted from Chinese Herb Medicine which is traditionally used as treatment of diabetes and ischemic heart diseases. Mounting evidence showed that AMP-activated protein kinase (AMPK) has cardioprotective effect against ischemic injury and the forkhead transcription factor 3 (FOXO3) was recently identified as a downstream target of AMPK. We hypothesize that OA may protect against ischemic dysfunction of cardiomyocytes via activation of AMPK signaling pathway. Male C57BL/6 mice which were subjected to in vivo regional cardiac ischemia stimulated AMPK Thr(172) phosphorylation, as well as phosphorylation of downstream FOXO3 (Ser(413)) and acetyl CoA carboxylase (ACC). The natural product, OA, significantly stimulated cardiac AMPK activation in cardiomyocyes in time- and dose-dependent manners. The mechanism of AMPK activation by OA may be due to the loss mitochondrial membrane potential (ΔΨm) as shown by JC-1 fluorescence assay. Intriguingly, OA as an AMPK activator also triggered FOXO3 (Ser(413)) phosphorylation in cardiomyocytes. Furthermore, OA treatment can protect cardiomyocytes from contractile dysfunction induced by hypoxia. Taken together, the results indicated that both ischemia and OA stimulated cardiac AMPK phosphorylation, as well downstream FOXO3 phosphorylation. The cardioprotective effect of OA maybe associated with activation of AMPK signaling pathways.[This corrects the article on p. 116 in vol. 1, PMID: 20445824.].

Toll-like receptor 4 (TLR4), a proximal signalling receptor in innate immune responses to lipopolysaccharide of gram-negative pathogens, is expressed in the heart. Accumulating evidence have consolidated the notion that TLR4 plays an essential role in the pathogenesis of cardiac dysfunction. However, the molecular mechanisms of TLR4 responsible for ischemia-induced cardiac dysfunction remain unclear. To address the signalling mechanisms of TLR4-deficiency cardioprotection against ischemic injury, in vivo regional ischemia was induced by occlusion of the left anterior descending coronary artery in wild-type (WT) C3H/HeN and TLR4-mutated C3H/HeJ mice. The results demonstrated that blunted ischemic activation of p38 mitogen-activated protein kinase and JNK signalling occurred in C3H/HeJ hearts versus C3H/HeN hearts, while ERK and AMP-activated protein kinase (AMPK) signalling pathways were augmented during ischemia in C3H/HeJ hearts versus C3H/HeN hearts. Intriguingly, ischemia-stimulated endoplasmic reticulum stress was higher in C3H/HeN hearts than that in C3H/HeJ as demonstrated by up-regulation of Grp78/BiP, Gadd153/CHOP and IRE-1 alpha. Myocardial infarct, caspase-3 activity and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining demonstrated that C3H/HeN hearts suffered more damage than those of C3H/HeJ hearts during ischemia. Moreover, isolated cardiomyocytes from C3H/HeJ hearts showed resistance to hypoxia-induced contractile dysfunction compared to those from C3H/HeN hearts, which are associated with greater hypoxic activation of AMPK and ERK signalling, better intracellular Ca2+ handling in C3H/HeJ versus C3H/HeN cardiomyocytes. These findings suggest that the cardioprotective effects against ischemic injury of hearts with deficiency in TLR4 signalling may be mediated through modulating AMPK and ERK signalling pathway during ischemia.

Myocardial ischemia/reperfusion injury involves a robust inflammatory response especially activation of toll-like receptor 4 (TLR4), a proximal signaling receptor in innate immune responses to lipopolysaccharide of Gram-negative pathogens. TLR4 is expressed in the heart and vasculature, the deficiency of which was shown to protect the heart against ischemia/reperfusion injury. However, the molecular mechanisms behind TLR4 deficiency-induced cardioprotection against ischemic damage remain unclear. The AMP-activated protein kinase (AMPK), an intracellular energy gauge, plays an important role in limiting cardiac damage following by ischemia, thus we hypothesized that AMPK maybe a mediator of TLR4-deficiency cardioprotection against ischemic injury. To test this hypothesis, In vivo regional ischemia was induced by occlusion of the left anterior descending (LAD) coronary artery in wild type (WT) C3H/HeN and TLR4-deficient C3H/HeJ mice, which carry a natural mutation of TLR4. Immunoblotting analysis was performed to assess the activation of AMPK and TLR4 downstream signal, the mitogen-activated protein kinase (MAPK). The endoplasmic reticulum (ER) chaperons, Grp78/BiP and Gadd153/CHOP, and ER integral membrane protein IRE1α were also monitored. The results demonstrated that C3H/HeJ hearts had impaired ischemic MAPK and AMPK activation compared to WT C3H/HeN hearts, i.e. activation of p38 MAPK and JNK was blunted, while ERK and AMPK signaling pathways were augmented during ischemia in C3H/HeJ hearts. Intriguingly, ischemia-stimulated ER stress was higher in WT C3H/HeN hearts than that in C3H/HeJ as demonstrated by up-regulation of Grp78/BiP, Gadd153/CHOP and IRE1α. Caspase-3 activity and TUNEL staining results showed that WT C3H/HeN hearts have more damages than those of C3H/HeJ hearts. Moreover, isolated cardiomyocytes from C3H/HeJ hearts showed resistance to ischemia-induced contractile dysfunction compared to WT C3H/HeN hearts. These findings suggest that the cardioprotective effects against ischemic injury of TLR4-deficient hearts may mediated through augmentation of AMPK and ERK while alleviation of p38 MAPK and JNK inflammatory signaling pathways. This research has received full or partial funding support from the American Heart Association, AHA National Center.

Cellular hypertrophy is regulated by coordinated pro- and antigrowth machineries. Foxo transcription factors initiate an atrophy-related gene program to counter hypertrophic growth. This study was designed to evaluate the role of Akt, the forkhead transcription factor Foxo3a, and atrophy genes muscle-specific RING finger (MuRF)-1 and atrogin-1 in cardiac hypertrophy and contractile dysfunction associated with high-fat diet-induced obesity. Mice were fed a low- or high-fat diet for 6 mo along with a food-restricted high-fat weight control group. Echocardiography revealed decreased fractional shortening and increased end-systolic diameter and cardiac hypertrophy in high-fat obese but not in weight control mice. Cardiomyocytes from high-fat obese but not from weight control mice displayed contractile and intracellular Ca2+ defects including depressed maximal velocity of shortening/relengthening, prolonged duration of shortening/relengthening, and reduced intracellular Ca2+ rise and clearance. Caspase activities were greater in high-fat obese but not in weight control mouse hearts. Western blot analysis revealed enhanced basal Akt and Foxo3a phosphorylation and reduced insulin-stimulated phosphorylation of Akt and Foxo3a without changes in total protein expression of Akt and Foxo3a in high-fat obese hearts. RT-PCR and immunoblotting results displayed reduced levels of the atrogens atrogin-1 and MuRF-1, the upregulated hypertrophic markers GATA4 and ciliary neurotrophic factor receptor-alpha, as well as the unchanged calcineurin and proteasome ubiquitin in high-fat obese mouse hearts. Transfection of H9C2 myoblast cells with dominant-negative Foxo3a adenovirus mimicked palmitic acid (0.8 mM for 24 h)-induced GATA4 upregulation without an additive effect. Dominant-negative Foxo3a-induced upregulation of pAkt and repression of phosphatase and tensin homologue were abrogated by palmitic acid. These results suggest a cardiac hypertrophic response in high-fat diet-associated obesity at least in part through inactivation of Foxo3a by the Akt pathway.