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Objective: To investigate the value of carbon nanoparticles in identifying sentinel lymph nodes in early-stage cervical cancer. Methods: From January 2014 to January 2016, 40 patients with cervical cancer stage IA2–IIA, based on the International Federation of Gynecology and Obstetrics (FIGO) 2009 criteria, were included in this study. The normal cervix around the tumor was injected with a total of 1 mL of carbon nanoparticles (CNP)at 3 and 9 o'clock. All patients then underwent laparoscopic pelvic lymph node dissection and radical hysterectomy. The black-dyed sentinel lymph nodes were removed for routine pathological examination and immunohistochemical staining. Results: Among the 40 patients, 38 patients had at least one sentinel lymph node (SLN). The detection rate was 95% (38/40). One hundred seventy-three SLNs were detected with an average of 3.9 SLNs per side. 25 positive lymph nodes, which included 21 positive SLNs, were detected in 8 (20%) patients. Sentinel lymph nodes were localized in the obturator (47.97%), internal lilac (13.87%), external lilac (26.59%), parametrial (1.16%), and common iliac (8.67%) regions. The sensitivity of the SLN detection was 100% (5/5), the accuracy was 97.37% (37/38), and the negative predictive value was 100. 0% and the false negative rate was 0%. Conclusions: Sentinel lymph nodes can be used to accurately predict the pathological state of pelvic lymph nodes in early cervical cancer. The detection rates and accuracy of sentinel lymph node were high. Carbon nanoparticles can be used to trace the sentinel lymph node in early cervical cancer. [ABSTRACT FROM AUTHOR]

Background: Viral myocardial disease (VMD) is a common disease inducing heart failure. It has not been clear the roles of mitochondrial damage in the pathological changes of cardiomyocytes in VMD. Methods: Myocardial tissues and lymphocytes were collected from 83 VMD patients. Control groups included 12 cases of healthy accidental death with myocardial autopsy and 23 healthy blood donors. The mouse model of viral myocarditis (VMC) was established by Coxsackie virus B3 infection and myocardial tissues and skeletal muscle were collected. Mitochondrial DNA (mtDNA) deletion rate was quantitatively determined using polymerase chain reaction. Results: There was significantly difference of myocardial mitochondrial DNA deletion rate between VMD or VMC group and control group (P<0.05). Moreover, the loss of mitochondrial membrane phospholipids was significantly different between VMD or VMC group and control group. In VMC mice, there were negative correlations between myocardial mtDNA3867 deletion rate and left ventricular peak systolic pressure (LVPSP) (r = −0.66, P<0.05), and between myocardial mtDNA3867 deletion rate and +dp/dtmax (r = −0.79, P<0.05), while there was positive correlation between myocardial mtDNA3867 deletion rate and −dp/dtmax (r = 0.80, P<0.05). Conclusion: Mitochondrial damage is an important pathophysiological mechanism leading to myocardial injury and cardiac dysfunction. The mitochondrial damage in the skeletal muscle and lymphocytes reflect a “window” of myocardial mitochondrial damage. [ABSTRACT FROM AUTHOR]

Background: The management of limited-disease esophageal small cell carcinoma is not well defined, and the role of surgery is still controversial. We aim to determine the optimal treatment strategy in limited-disease of esophageal small cell carcinoma. Methods and Findings: We conducted a retrospective review of 141 patients with limited-disease esophageal small cell carcinoma from 3 institutions in China who underwent treatment between July 1994 and September 2008, July 1994 and July 2011, and June 2004 and December 2010, respectively. The survival rate was calculated by the Kaplan-Meier method, and the log-rank test was used to assess the survival differences between the groups. Cox proportional hazards model were used to further determine the independent factors impacting overall survival. The median survival time was 16.1 months for the entire cohort of patients, with a 5-year survival rate of 6.7%. The median survival times for surgery alone, surgery combined with chemotherapy, surgery combined with radiotherapy, surgery combined with chemotherapy and radiotherapy, chemotherapy plus radiotherapy, and chemotherapy alone were 18.0 months, 15.0 months, 23.0 months, 25.0 months, 17.1 months, and 6.1 months, respectively; the corresponding 5-year survival rates were 0%, 15.4%, 0%, 38.9%, 0%, and 0%, respectively. For the 105 patients who underwent R0 resection, the median disease-free survival time was 12.0 months, with a 95% confidence interval of 9.5 months to 14.5 months. The multivariate Cox regression analysis demonstrated that advanced pathological staging (p = 0.003), and pure esophageal small cell carcinoma (p = 0.035) were independent factors decreasing overall survival. Conclusions: Our data suggested that multidisciplinary modalities achieved encouraging long-term survival in patients with resectable limited-disease of esophageal small cell carcinoma. [ABSTRACT FROM AUTHOR]

Background: Calreticulin is a Ca2+-binding chaperone of the endoplasmic reticulum which regulates the signal transducer and activator of transcription 3 (STAT3). The effects of the calreticulin-STAT3 signaling pathway on cardiac mitochondria and on the progress of dilated cardiomyopathy (DCM) are still unclear. Methods and Results: The DCM model was generated in rats by the daily oral administration of furazolidone. Echocardiographic and hemodynamic studies demonstrated enlarged LV dimensions and reduced systolic and diastolic functions at thirty weeks after the first furazolidone administration. Morphometric analysis showed significant myocardial degeneration, interstitial fibrosis, and mitochondrial swelling with fractured or dissolved cristae in the model group. Compared with the control group, the mitochondrial membrane potential (MMP) level of the freshly isolated cardiac mitochondria and the enzyme activities of cytochrome c oxidase and succinate dehydrogenase in the model group were significantly decreased (P<0.05). Real-time PCR and western-blot revealed the increased expression of calreticulin associated with decreased activity of STAT3 in the model group. When cultured neonatal rat cardiomyocytes were exposed to furazolidone, a dose-dependent decrease in cell viability and MMP, and the increase of apoptosis rate were observed. The mRNA and protein expression of CRT gradually increased with the increase of furazolidone concentration, associated with a gradual decrease of the STAT3 phosphorylation level both in the whole cell and mitochondrial fraction. When calreticulin was knocked down with siRNA in cardiomyocytes, these changes of cardiomyocytes and mitochondria induced by furazolidone were significantly attenuated. Conclusions: A rat model of DCM induced by furazolidone is successfully established. The calreticulin-STAT3 signaling pathway is involved in cardiac mitochondrial injury and the progress of furazolidone induced DCM. [ABSTRACT FROM AUTHOR]

Background: Via sequencing the genes of apelin/angiotensin receptor-like 1 (apelin/APJ) pathway, we have recently identified and validated four common polymorphisms (rs3761581, rs56204867, rs7119375, and rs10501367) implicated in the development of hypertension. Extending these findings, we, in Chinese hypertensive patients, sought to investigate the association of these four polymorphisms and one additional promising candidate (rs9943582) from this pathway with the risk of developing coronary artery disease (CAD). Methodology/Principal Findings: Genotypes were obtained from 994 sporadic CAD patients and 708 age- and sex-matched controls. All participants were hypertensives and angiographically-confirmed. Data were analyzed by Haplo.Stats and multifactor dimensionality reduction (MDR) softwares. Genotype distributions of five examined polymorphisms satisfied Hardy-Weinberg equilibrium in controls of both genders. Single-locus analyses exhibited no significant differences in the genotype/allele frequencies of examined polymorphisms between CAD patients and controls (P>0.05), even after controlling traditional cardiovascular confounders. In haplotype analyses, low-penetrance haplotype G-A (in order of rs56204867 and rs3761581 from apelin gene) was significantly overrepresented in controls (1.73%) relative to in CAD patients (0.4%) in males (P = 0.047). Further interaction analyses suggested an overall best MDR model including rs3761581 in males (P = 0.0408) and including rs7119375 and rs9943582 in females (P<0.0001), which were further substantiated in the classical logistical regression model. Conclusions: Our findings demonstrated a contributive role of low-penetrance haplotype in apelin gene on CAD in males, and more importantly, interactive effects of genetic defects in apelin/APJ pathway might confer a potential risk in Chinese hypertensive patients. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the most frequently diagnosed cancers among women, and metastasis makes it lethal. Tumorassociated macrophages (TAMs) that acquire an alternatively activated macrophage (M2) phenotype may promote metastasis. However, the underlying mechanisms are still elusive. Here, we examined how TAMs interact with breast cancer cells to promote metastasis. Immunohistochemistry was used to examine the expression of the M2-specific antigen CD163 in paraffin-embedded mammary carcinoma blocks to explore fusion events in breast cancer patients. U937 cells were used as a substitute for human monocytes, and these cells differentiated into M2 macrophages following phorbol 12-myristate 13-acetate (PMA) and M-CSF stimulation. M2 macrophages and the breast cancer cell lines MCF-7 and MDA-MB-231 fused in the presence of 50% polyethylene glycol. Hybrids were isolated by fluorescence-activated cell sorting, and the relevant cell biological properties were compared with their parental counterparts. Breast cancer stem cell (BCSC)-related markers were quantified by immunofluorescence staining, RT-PCR, quantitative RT-PCR and/or western blotting. The tumor-initiating and metastatic capacities of the hybrids and their parental counterparts were assessed in NOD/SCID mice. We found that the CD163 expression rate in breast cancer tissues varied significantly and correlated with estrogen receptor status (p<0.05). The fusion efficiency of either breast cancer cell line with M2 macrophages ranged from 1.81 to 6.47% in the presence of PEG, and no significant difference was observed between the breast cancer cell lines used (p>0.05). Characterization of the fusion hybrids revealed a more aggressive phenotype, including increased migration, invasion and tumorigenicity, but reduced proliferative ability, compared with the parental lines. The hybrids also gained a CD44+CD24-/low phenotype and over-expressed epithelial-mesenchymal transition-associated genes. These results indicate that TAMs may promote breast cancer metastasis through cell fusion, and the hybrids may gain a BCSC phenotype. [ABSTRACT FROM AUTHOR]

The leptin gene has received intensive attention and scientific investigation for its importance in energy homeostasis and reproductive regulation in mammals. Furthermore, study of the leptin gene is of crucial importance for public health, particularly for its role in obesity, as well as for other numerous physiological roles that it plays in mammals. In the present work, we report the identification of novel leptin genes in 4 species of Cetacea, and a comparison with 55 publicly available leptin sequences from mammalian genome assemblies and previous studies. Our study provides evidence for positive selection in the suborder Odontoceti (toothed whales) of the Cetacea and the family Phocidae (earless seals) of the Pinnipedia. We also detected positive selection in several leptin gene residues in these two lineages. To test whether leptin and its receptor evolved in a coordinated manner, we analyzed 24 leptin receptor gene (LPR) sequences from available mammalian genome assemblies and other published data. Unlike the case of leptin, our analyses did not find evidence of positive selection for LPR across the Cetacea and Pinnipedia lineages. In line with this, positively selected sites identified in the leptin genes of these two lineages were located outside of leptin receptor binding sites, which at least partially explains why co-evolution of leptin and its receptor was not observed in the present study. Our study provides interesting insights into current understanding of the evolution of mammalian leptin genes in response to selective pressures from life in an aquatic environment, and leads to a hypothesis that new tissue specificity or novel physiologic functions of leptin genes may have arisen in both odontocetes and phocids. Additional data from other species encompassing varying life histories and functional tests of the adaptive role of the amino acid changes identified in this study will help determine the factors that promote the adaptive evolution of the leptin genes in marine mammals. [ABSTRACT FROM AUTHOR]

Background: Human skeletal system has evolved rapidly since the dispersal of modern humans from Africa, potentially driven by selection and adaptation. Osteogenin (BMP3) plays an important role in skeletal development and bone osteogenesis as an antagonist of the osteogenic bone morphogenetic proteins, and negatively regulates bone mineral density. Methodology/Principal Findings: Here, we resequenced the BMP3 gene from individuals in four geographically separated modern human populations. Features supportive of positive selection in the BMP3 gene were found including the presence of an excess of nonsynonymous mutations in modern humans, and a significantly lower genetic diversity that deviates from neutrality. The prevalent haplotypes of the first exon region in Europeans demonstrated features of long-range haplotype homogeneity. In contrast with findings in European, the derived allele SNP Arg192Gln shows higher extended haplotype homozygosity in East Asian. The worldwide allele frequency distribution of SNP shows not only a high-derived allele frequency in Asians, but also in Americans, which is suggestive of functional adaptation. Conclusions/Significance: In conclusion, we provide evidence for recent positive selection operating upon a crucial gene in skeletal development, which may provide new insight into the evolution of the skeletal system and bone development. [ABSTRACT FROM AUTHOR]

Objective: Increasing evidence suggested that endoplasmic reticulum (ER) stress contributes to insulin resistance, which plays an important role in the development of type 2 diabetes mellitus (T2DM). Accumulation of endogenous nitric oxide synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA), is associated with insulin resistance, T2DM, and diabetic cardiovascular complications, although the mechanisms have not been elucidated. This study was to determine whether elevated endogenous ADMA is involved in hepatic ER stress of type 2 diabetic rats, verify their causal relationship, and elucidate the potential mechanism underlying ADMA induced ER stress in rat hepatocytes. Methods: Immunoglobulin binding protein (Bip) transcription, eukaryotic initiation factor 2α kinase (eIF2α) phosphorylation, X box-binding protein-1 (XBP-1) mRNA splicing and C/EBP homologues protein (CHOP) expression were measured to reflect ER stress. Contents of ADMA and nitrite/nitrate as well as activities or expression of NOS and dimethylarginine dimethylaminohydrolase (DDAH) were detected to show the changes in DDAH/ADMA/NOS/NO pathway. The lipid peroxidation product malondialdehyde content and antioxidant enzyme superoxide dismutase activity were analyzed to evaluate oxidative stress. Results: ER stress was provoked in the liver of type 2 diabetic rats, as expressed by increases of Bip transcription, eIF2α phosphorylation, XBP-1 splicing and CHOP expression, all of which were in parallel with the elevation of serum ADMA, suppression of NO generation, NOS and DDAH activities in the liver. Exposure of hepatocytes to ADMA or hydrogen peroxide also induced ER stress, which was associated with the inhibition of NO production and increase of oxidative stress. Treatment of hepatocytes with antioxidant pyrrolidine dithiocarbamate not only decreased ADMA-induced oxidative stress and inhibition of NO production but also reduced ADMA-triggered ER stress. Conclusions: These results indicate that increased endogenous ADMA contributes to hepatic ER stress in type 2 diabetic rats, and the mechanism underlying ADMA-induced ER stress may relate to oxidative stress via NOS uncoupling. [ABSTRACT FROM AUTHOR]

Background: Contradictory results have been reported regarding the association between Pro12Ala polymorphism of PPARc2 and coronary artery disease (CAD). We sought to estimate the inconsistent results by performing a comprehensive meta-analysis. Methods: Studies in English or Chinese publications were identified by screening MEDLINE, Embase, CNKI, Wanfang and CBM. 22 studies including 8948 cases and 14427 controls were selected. A random-effects model was applied to combine the divergent outcomes of the individual studies, while addressing between-study heterogeneity and publication bias. Results: The Pro12Ala polymorphism of control population followed Hardy-Weinberg equilibrium for all studies (P=0.05). Overall, a marginal increased risk of CAD under the recessive genetic model (AlaAla vs ProAla+ProPro: P = 0.04, OR = 1.31, 95%CI 1.01-1.69, Pheterogeneity = 0.67, I2 = 0%) and the homozygote comparison (AlaAla vs ProPro: P = 0.04,OR = 1.30, 95%CI 1.01-1.68, Pheterogeneity = 0.68, I2 = 0%) was observed. In the subgroup analysis by ethnicity, carriers of AlaAla homozygotes had a significant increased risk for CAD among Caucasians (AlaAla vs ProAla+ProPro: P = 0.01, OR = 1.45, 95%CI 1.08-1.96, Pheterogeneity = 0.48, I2 = 0%; AlaAla vs ProPro: P = 0.02,OR = 1.44, 95%CI 1.07-1.93, Pheterogeneity = 0.46, I2 = 0%). After dividing into population source, the CAD risk magnitude of hospital-based studies was distinctly strengthened under the recessive model (P = 0.03,OR = 1.85,95%CI 1.07-3.19, Pheterogeneity = 0.87,I2 = 0%) and the homozygote comparison (P = 0.03,OR = 1.83, 95%CI 1.06-3.16, Pheterogeneity = 0.88, I2 = 0%). There was no observable publication bias as reflected by funnel plot and Egger's linear regression test (t = -0.12, P = 0.91). Conclusion:: Our results demonstrated that the PPAR γ2 Pro12Ala polymorphism might be risk-conferring locus for the progression of CAD among Caucasians, but not among Asians. [ABSTRACT FROM AUTHOR]

GDF5 is a member of the bone morphogenetic protein (BMP) gene family, and plays an important role in the development of the skeletal system. Variants of the gene are associated with osteoarthritis and height in some human populations. Here, we resequenced the gene in individuals from four geographically separated human populations, and found that the evolution of the promoter region deviated from neutral expectations, with the sequence evolution driven by positive selection in the East Asian population, especially the haplotypes carrying the derived alleles of 59 UTR SNPs rs143384 and rs143383. The derived alleles of rs143384 and rs143383, which are associated with a risk of osteoarthritis and decreased height, have high frequencies in non-Africans and show strong extended haplotype homozygosity and high population differentiation in East Asian. It is concluded that positive selection has driven the rapid evolution of the two osteoarthritis osteoarthritis-risk and decreased height associated variants of the human GDF5 gene, and supports the suggestion that the reduction in body size during the terminal Pleistocene and Holocene period might have been an adaptive process influenced by genetic factors. [ABSTRACT FROM AUTHOR]

The current study examined the effect of a group's potential for improvement and decline in morality and competence on applicants' willingness to join the group. We conducted four experiments with 399 Chinese participants who rated their willingness to join groups with potential for improvement, potential for decline, or stability in terms of morality or competence. The results showed that, compared with groups with stable competence, participants preferred groups with potential for competence improvement and were more averse to groups with potential for competence decline. However, the biases regarding the potential for moral improvement and decline were asymmetric. Specifically, compared with groups with stable morality, participants had no preference for groups with potential for moral improvement, but were more averse to groups with potential for moral decline. Possible explanations for the asymmetric biases regarding the potential for moral improvement and decline and future research directions are discussed. [ABSTRACT FROM AUTHOR]

Previously, VpPR-10.1 was isolated and characterized from a cDNA library of a fungus-resistant accession of Chinese wild grape (Vitis pseudoreticulata). We found that expression of VpPR-10.1 is affected by the fungal pathogen Erysiphe necator. To investigate the biochemical basis of the nuclease activity of VpPR-10.1 and its role in antifungal resistance, we generated recombinant VpPR-10.1 as well as site-directed mutations targeting three conserved amino acid residues among plant PR-10 s: Lys55, Glu149, and Tyr151. We showed that wild-type recombinant VpPR-10.1 exhibits both RNase and DNase activities. Mutant VpPR10.1-Y151H essentially retained all these activities. In contrast, VpPR10.1-K55N, where Lys55 in the P-loop region is mutated to Asn, and VpPR10.1-E149G, where Glu149 is mutated to Gly, lost their nuclease activity, indicating that both residues play a critical role in catalyzing RNA and DNA degradation. Furthermore, VpPR10.1 and VpPR10.1-Y151H inhibited the growth of the cultured fungal pathogen Alternaria alternate. Through transient expression in grapevine, we also demonstrated that VpPR10.1-K55N and VpPR10.1-E149G compromised resistance to E. necator. Finally, we further found that VpPR-10.1 can lead to programmed cell death and DNA degradation when incubated with tobacco BY-2 suspension cells. We show here that Lys55 and Glu149, but not Tyr151, are required for the RNase, DNase and antifungal activities of VpPR-10.1. The strong correlation between the level of VpPR-10.1 nuclease activity and its antifungal property indicates that the former is the biochemical basis for the latter. Taken together, our experiments revealed that VpPR-10.1 is critical in mediating fungal resistance in grape, potentially playing a dual role by degrading pathogen RNA and inducing programmed death of host cells. [ABSTRACT FROM AUTHOR]

Background: The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the progression of heart failure (HF). We investigated whether cyclooxygenase-2 (COX-2) inhibition in the PVN attenuates the activities of sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in rats with adriamycin-induced heart failure. Methodology/Principal Finding: Heart failure was induced by intraperitoneal injection of adriamycin over a period of 2 weeks (cumulative dose of 15 mg/kg). On day 19, rats received intragastric administration daily with either COX-2 inhibitor celecoxib (CLB) or normal saline. Treatment with CLB reduced mortality and attenuated both myocardial atrophy and pulmonary congestion in HF rats. Compared with the HF rats, ventricle to body weight (VW/BW) and lung to body weight (LW/BW) ratios, heart rate (HR), left ventricular end-diastolic pressure (LV±DP), left ventricular peak systolic pressure (LVPSP) and maximum rate of change in left ventricular pressure (LV6dp/dtmax) were improved in HF+CLB rats. Angiotensin II (ANG II), norepinephrine (NE), COX-2 and glutamate (Glu) in the PVN were increased in HF rats. HF rats had higher levels of ANG II and NE in plasma, higher level of ANG II in myocardium, and lower levels of ANP in plasma and myocardium. Treatment with CLB attenuated these HF-induced changes. HF rats had more COX-2-positive neurons and more corticotropin releasing hormone (CRH) positive neurons in the PVN than did control rats. Treatment with CLB decreased COX-2-positive neurons and CRH positive neurons in the PVN of HF rats. Conclusions: These results suggest that PVN COX-2 may be an intermediary step for PVN neuronal activation and excitatory neurotransmitter release, which further contributes to sympathoexcitation and RAS activation in adriamycin-induced heart failure. Treatment with COX-2 inhibitor attenuates sympathoexcitation and RAS activation in adriamycin-induced heart failure. [ABSTRACT FROM AUTHOR]

Vagus nerve stimulation (VNS) has been shown to improve left ventricular function and survival in rats with acute myocardial infarction (AMI), and this maneuver has also been adopted clinically for the treatment of patients with chronic heart failure (CHF). Recent in vitro and in vivo studies have suggested that VNS can modulate the level of pro-inflammatory factors. Despite the beneficial effects of VNS, the stimulation parameters for obtaining favorable outcomes appear highly variable. To optimize VNS parameters, we set up different stimulation protocols with different pulse width (1-2 ms), frequency (1-6 Hz), voltage (1-6 V) and duration (40-240 min) of VNS by uniform design (UD). Rats were divided into seven groups with (Group1-Group6) or without VNS (MI group). Our results demonstrate that (1) the parameter sets in Group1, Group2 and Group3 yield the best post-MI protection by VNS, while the protective role were not observed in Group4, Group5 and Group6; (2) baroreflex sensitivity and the α7 nicotinic acetylcholine receptor level were also increased in Group1, Group2 and Group3. (3) the parameter set in Group1 (G1:1 ms, 2 Hz, 3 V, 240 min) is judged the most optimal parameter in this study as rats in this group not only showed a reduced myocardial injury with better-preserved cardiac function compared with other groups, more important, but also exhibited minimal heart rate (HR) reduction. (4) the duration of VNS plays an important role in determining the protection effect of VNS. In conclusion, VNS displays a beneficial role in Group1, Group2 and Group3. Of note, the parameter set in Group1 provides the most optimal cardioprotective effect. These results may provide insight into development of novel treatment for ischemic heart diseases. [ABSTRACT FROM AUTHOR]

Background: Coronary artery disease (CAD) is the most common heart disease worldwide. Association of CAD with variants in the myocyte enhancer factor 2A (MEF2A) gene, the first identified CAD-causing gene, has attracted special attention but the results are controversial. We aimed to evaluate this genetic association via a case-control study and meta-analysis. Methodology/Principal Findings: We performed a case-control association study to investigate the relationship between variations in exon 11 of MEF2A gene and CAD in 1045 sporadic patients and 1008 controls enrolled angiographically among southern Chinese population, and then the data from this study were compared and discussed in a systematic review and meta-analysis with all available published studies on MEF2A gene and CAD. In total, eight variants were identified (21-bp deletion, CAG repeats, CCG repeats, a CCA deletion and four SNPs). No significant link was observed between the common (CAG)n polymorphism and CAD, whereas the rare 21-bp deletion was detected only in five affected individuals. The metaanalysis of (CAG)n polymorphism and CAD risk, including nine studies with 3801 CAD patients and 4020 controls, also provided no convincing evidence for the genetic association, even upon stratification by race (mainly Whites and Chinese). However, the 21-bp deletion was regarded as a potentially logical, albeit undetermined, candidate for CAD in the following systematic review. Conclusions/Significance: Our findings failed to demonstrate a correlation between (CAG)n polymorphism with CAD, however, we concluded that the rare 21-bp deletion might have a more compelling effect on CAD than the common (CAG)n polymorphism, and MEF2A genetic variant might be a rare but specific cause of CAD/MI. [ABSTRACT FROM AUTHOR]

Anthracycline daunorubicin (DNR) is one of the major antitumor agents widely used in the treatment of myeloid leukemia. Unfortunately, the clinical efficacy of DNR was limited because of its cytotoxity at high dosage. As a novel cytoprotective mechanism for tumor cell to survive under unfavorable conditions, autophagy has been proposed to play a role in drug resistance of tumor cells. Whether DNR can activate to impair the sensitivity of cancer cells remains unknown. Here, we first report that DNR can induce a high level of autophagy, which was associated with the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Moreover, cell death induced by DNR was greatly enhanced after autophagy inhibition by the pharmacological inhibitor chloroquine (CQ) and siRNAs targeting Atg5 and Atg7, the most important components for the formation of autophagosome. In conclusion, we found that DNR can induce cytoprotective autophagy by activation of ERK in myeloid leukemia cells. Autophagy inhibition thus represents a promising approach to improve the efficacy of DNR in the treatment of patients with myeloid leukemia. [ABSTRACT FROM AUTHOR]

Adenosine, a catabolite of ATP, displays a wide variety of effects in the heart including regulation of cardiac response to myocardial ischemia and reperfusion injury. Nonetheless, the precise mechanism of adenosine-induced cardioprotection is still elusive. Isolated Sprague-Dawley rat hearts underwent 30 min global ischemia and 120 min reperfusion using a Langendorff apparatus. Both adenosine and acetylcholine treatment recovered the post-reperfusion cardiac function associated with adenosine and muscarinic receptors activation. Simultaneous administration of adenosine and acetylcholine failed to exert any additive protective effect, suggesting a shared mechanism between the two. Our data further revealed a cross-talk between the adenosine and acetylcholine receptor signaling in reperfused rat hearts. Interestingly, the selective M2 muscarinic acetylcholine receptor antagonist methoctramine significantly attenuated the cardioprotective effect of adenosine. In addition, treatment with adenosine upregulated the expression and the maximal binding capacity of muscarinic acetylcholine receptor, which were inhibited by the selective A1 adenosine receptor antagonist 8-Cyclopentyl- 1,3-dipropylxanthine (DPCPX) and the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME). These data suggested a possible functional coupling between the adenosine and muscarinic receptors behind the observed cardioprotection. Furthermore, nitric oxide was found involved in triggering the response to each of the two receptor agonist. In summary, there may be a cross-talk between the adenosine and muscarinic receptors in ischemic/reperfused myocardium with nitric oxide synthase might serve as the distal converging point. In addition, adenosine contributes to the invigorating effect of adenosine on muscarinic receptor thereby prompting to regulation of cardiac function. These findings argue for a potentially novel mechanism behind the adenosine-mediated cardioprotection. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that mitochondria may play important roles in the Ca2+ homeostasis of cardiac myocytes. However, it is still unclear if mitochondrial Ca2+ flux can regulate the generation of Ca2+ waves (CaWs) and triggered activities in cardiac myocytes. In the present study, intracellular/cytosolic Ca2+ (Cai2+) was imaged in Fluo-4-AM loaded mouse ventricular myocytes. Spontaneous sarcoplasmic reticulum (SR) Ca2+ release and CaWs were induced in the presence of high (4 mM) external Ca2+ (Cao2+). The protonophore carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) reversibly raised basal Cai2+ levels even after depletion of SR Ca2+ in the absence of Cao2+ , suggesting Ca2+ release from mitochondria. FCCP at 0.01 - 0.1 µM partially depolarized the mitochondrial membrane potential (Δψm) and increased the frequency and amplitude of CaWs in a dose-dependent manner. Simultaneous recording of cell membrane potentials showed the augmentation of delayed afterdepolarization amplitudes and frequencies, and induction of triggered action potentials. The effect of FCCP on CaWs was mimicked by antimycin A (an electron transport chain inhibitor disrupting Δψm) or Ru360 (a mitochondrial Ca2+ uniporter inhibitor), but not by oligomycin (an ATP synthase inhibitor) or iodoacetic acid (a glycolytic inhibitor), excluding the contribution of intracellular ATP levels. The effects of FCCP on CaWs were counteracted by the mitochondrial permeability transition pore blocker cyclosporine A, or the mitochondrial Ca2+ uniporter activator kaempferol. Our results suggest that mitochondrial Ca2+ release and uptake exquisitely control the local Ca2+ level in the micro-domain near SR ryanodine receptors and play an important role in regulation of intracellular CaWs and arrhythmogenesis. [ABSTRACT FROM AUTHOR]