The Expression and Function of Circadian Rhythm Genes in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is among the most common and lethal form of cancer worldwide. However, its diagnosis and treatment are still dissatisfactory, due to limitations in the understanding of its pathogenic mechanism. Therefore, it is important to elucidate the molecular mechanisms and identify novel therapeutic targets for HCC. Circadian rhythm-related genes control a variety of biological processes. These genes play pivotal roles in the initiation and progression of HCC and are potential diagnostic markers and therapeutic targets. This review gives an update on the research progress of circadian rhythms, their effects on the initiation, progression, and prognosis of HCC, in a bid to provide new insights for the research and treatment of HCC.

HIV Tat Protein Induces Myocardial Fibrosis Through TGF-ß1-CTGF Signaling Cascade: A Potential Mechanism of HIV Infection-Related Cardiac Manifestations.

Human immunodeficiency virus (HIV) infection is a risk factor of cardiovascular diseases (CVDs). HIV-infected patients exhibit cardiac dysfunction coupled with cardiac fibrosis. However, the reason why HIV could induce cardiac fibrosis remains largely unexplored. HIV-1 trans-activator of transcription (Tat) protein is a regulatory protein, which plays a critical role in the pathogenesis of various HIV-related complications. In the present study, recombinant Tat was administered to mouse myocardium or neonatal mouse cardiac fibroblasts in different doses. Hematoxylin-eosin and Masson's trichrome staining were performed to observe the histological changes of mice myocardial tissues. EdU staining and MTS assay were used to evaluate the proliferation and viability of neonatal mouse cardiac fibroblasts, respectively. Real-time PCR and western blot analysis were used to detect CTGF, TGF-ß1, and collagen I mRNA and protein expression levels, respectively. The results showed that Tat promoted the occurrence of myocardial fibrosis in mice. Also, we found that Tat increased the proliferative ability and the viability of neonatal mouse cardiac fibroblasts. The protein and mRNA expression levels of TGF-ß1 and CTGF were significantly upregulated both in Tat-treated mouse myocardium and neonatal mouse cardiac fibroblasts. However, co-administration of TGF-ß inhibitor abrogated the enhanced expression of collagen I induced by Tat in neonatal mouse cardiac fibroblasts. In conclusion, Tat contributes to HIV-related cardiac fibrosis through enhanced TGF-ß1-CTGF signaling cascade.

Downregulation of miR-200a protects cardiomyocyte against apoptosis.

BACKGROUND/AIMS: Acute myocardial infarction (AMI) is a major clinical manifestation of ischemic heart disease and represents a significant cause of morbidity and mortality. However, key regulators in the pathogenesis of ischemic heart disease remain controversial. The present study was designed to investigate the involvement of miR-200a and its related mechanism in AMI. METHODS: Left coronary artery (LCA) ligation was conducted to induce an AMI mouse model. The infarct size was measured by TTC staining. H2O2 was used to induce an AMI model in vitro. miR-200a mimics, anti-miR-200a antisense oligodeoxyribonucleotides (AMO-200a), as well as corresponding negative controls were transfected into cardiomyocytes to observe the effect of miR-200a. Flow cytometry was used to detect cell apoptosis. Real-time PCR, immunofluorescence and western blot assays were used to evaluate gene expression at RNA or protein levels, respectively. RESULTS: Apoptosis was activated in AMI models. The expression of miR-200a was upregulated both in the peri-infarcted region of mice myocardium and H2O2-treated cardiomyocytes. The co-administration of AMO-200a decreased the number of apoptosis cells and altered the expression of apoptosis related proteins. Interestingly, bioinformatics analysis results revealed that miR-200a could bind to the 3'-untranslated regions (3'-UTR) of Fus mRNA. In addition, the expression of Fus was downregulated in the AMI mouse models and in H2O2-treated cardiomyocytes. The alteration of miR-200a negatively regulated Fus expression in cardiomyocytes. Also, the protective effect of AMO-200a was observed through its regulation of Fus. CONCLUSION: MiR-200a-dependent apoptosis signaling pathway plays an important role in the pathogenesis of AMI injury and could be an exciting potential therapeutic target.

Anthocyanidin attenuates myocardial ischemia induced injury via inhibition of ROS-JNK-Bcl-2 pathway: New mechanism of anthocyanidin action.

Despite treatment options available to date, myocardial ischemia (MI) remains the leading cause of death worldwide. Studies are focused on finding effective therapeutic strategies against MI injury. Growing interest has been developed in natural compounds possessing medicinal properties with scarcer side effects. Here, we have evaluated the cardioprotective potential of anthocyanidin against MI injury and explored its underlying protective mechanism. Left anterior descending coronary artery was ligated to induce MI in mice. Neonatal mice cardiomyocytes were treated with H2 O2 to induce oxidative stress (a major contributor to MI injury) in vitro. Anthocyanidin pretreatment significantly reduced the infarct size, preserved the cell viability, and protected against ischemia-induced cardiac injury in treatment groups compared with the H2 O2 -treated group in vitro. Measurement of reactive oxygen species (ROS) validated the strong antioxidant potential of anthocyanidin, as significant reduction in oxidative stress was observed in anthocyanidin-pretreated groups. Mechanistically, pretreatment with anthocyanidin significantly subdued the activation of JNK (to p-JNK) and elevated Bcl-2 levels. Both in vivo and in vitro findings suggest that anthocyanidin can induce a state of myocardial resistance against ischemic insult. We have provided the experimental evidence for inhibition of ROS/p-JNK/Bcl-2 pathway being the underlying mechanism of action of anthocyanidin. Our results support the use of anthocyanidin as therapeutic strategy against MI injury.

Activation of M3 Muscarinic Acetylcholine Receptors Delayed Cardiac Aging by Inhibiting the Caspase-1/IL-1ß Signaling Pathway.

BACKGROUND/AIMS: Because the prevalence of age-related cardiac impairment increases as the human lifespan increases, it is important to combat the effects of aging. Recently, the cardiac M3 muscarinic acetylcholine receptor (M3-mAChR) has been demonstrated to play important roles in cardiac development and in the pathogenesis of cardiac diseases. However, the role of M3-mAChR in aging remains largely unknown. Therefore, the aim of this study was to investigate the involvement of M3-mAChR in the progression of cardiac aging. METHODS: We established a cardiac aging model in mice through subcutaneous injection with D-galactose at a dose of 100 mg/kg/day for 6 weeks. D-galactose was also used to induce aging in primary cultured neonatal mouse cardiomyocytes. The myocardium from mice was stained with hematoxylin and eosin for histological analysis. The protein expression levels of p53 and p21 were determined using western blotting. The mRNA and protein expression levels of M3-mAChR, caspase-1, and interleukin (IL)-1ß were determined using real-time PCR, immunohistochemical staining, and western blotting. RESULTS: The expression of M3-mAChR was down-regulated in the myocardium from aged mice and D-galactose-treated mice, while the expression levels of caspase-1 and its downstream molecule IL-1ß were significantly increased. The M3-mAChR agonist choline reduced the increase in caspase-1 in cardiomyocytes induced by D-galactose, which was reversed by the M3-mAChR antagonist 4-DAMP. Moreover, 4-DAMP promoted D-galactose-induced cardiomyocyte aging, which was attenuated by a caspase-1 inhibitor. CONCLUSION: Activation of M3-mAChR delayed cardiac aging by inhibiting the caspase-1/IL-1ß signaling pathway.

The role of HIV Tat protein in HIV-related cardiovascular diseases.

The human immunodeficiency virus (HIV) is a major global public health issue. HIV-related cardiovascular disease remains a leading cause of morbidity and mortality in HIV positive patients. HIV Tat is a regulatory protein encoded by tat gene of HIV-1, which not only promotes the transcription of HIV, but it is also involved in the pathogenesis of HIV-related complications. This review is aimed at summarizing the current understanding of Tat in HIV-related cardiovascular diseases.