Sphingosine-1-Phosphate Protects Against the Development of Cardiac Remodeling via Sphingosine Kinase 2 and the S1PR2/ERK Pathway.

OBJECTIVE: Cardiac remodeling is a common pathological change in various cardiovascular diseases and can ultimately result in heart failure. Thus, there is an urgent need for more effective strategies to aid in cardiac protection. Our previous work found that sphingosine-1-phosphate (S1P) could ameliorate cardiac hypertrophy. In this study, we aimed to investigate whether S1P could prevent cardiac fibrosis and the associated mechanisms in cardiac remodeling. METHODS: Eight-week-old male C57BL/6 mice were randomly divided into a sham, transverse aortic constriction (TAC) or a TAC+S1P treatment group. RESULTS: We found that S1P treatment improved cardiac function in TAC mice and that the cardiac fibrosis ratio in the TAC+S1P group was significantly lower and was accompanied by a decrease in α-smooth muscle actin (α-SMA) and collagen type I (COL I) expression compared with the TAC group. We also found that one of the key S1P enzymes, sphingosine kinase 2 (SphK2), which was mainly distributed in cytoblasts, was downregulated in the cardiac remodeling case and recovered after S1P treatment in vivo and in vitro. In addition, our in vitro results showed that S1P treatment activated extracellular regulated protein kinases (ERK) phosphorylation mainly through the S1P receptor 2 (S1PR2) and spurred p-ERK transposition from the cytoplasm to cytoblast in H9c2 cells exposed to phenylephrine. CONCLUSION: These findings suggest that SphK2 and the S1PR2/ERK pathway may participate in the anti-remodeling effect of S1P on the heart. This work therefore uncovers a novel potential therapy for the prevention of cardiac remodeling.

Diversity of the Bosmina (Cladocera: Bosminidae) in China, revealed by analysis of two genetic markers (mtDNA 16S and a nuclear ITS).

BACKGROUND: China is an important biogeographical zone in which the genetic legacies of the Tertiary and Quaternary periods are abundant, and the contemporary geography environment plays an important role in species distribution. Therefore, many biogeographical studies have focused on the organisms of the region, especially zooplankton, which is essential in the formation of biogeographical principles. Moreover, the generality of endemism also reinforces the need for detailed regional studies of zooplankton. Bosmina, a group of cosmopolitan zooplankton, is difficult to identify by morphology, and no genetic data are available to date to assess this species complex in China. In this study, 48 waterbodies were sampled covering a large geographical and ecological range in China, the goal of this research is to explore the species distribution of Bosmina across China and to reveal the genetic information of this species complex, based on two genetic markers (a mtDNA 16S and a nuclear ITS). The diversity of taxa in the Bosmina across China was investigated using molecular tools for the first time. RESULTS: Two main species were detected in 35 waterbodies: an endemic east Asia B. fatalis, and the B. longirostris that has a Holarctic distribution. B. fatalis had lower genetic polymorphism and population differentiation than B. longirostris. B. fatalis was preponderant in central and eastern China, whereas B. longirostris was dominated in western China. The third lineage (B. hagmanni) was only detected in a reservoir (CJR) of eastern China (Guangdong province). Bosmina had limited distribution on the Tibetan plateau. CONCLUSIONS: This study revealed that the biogeography of Bosmina appear to be affected by historical events (Pleistocene glaciations) and contemporary environment (such as altitude, eutrophication and isolated habitat).

Microcystin-LR disturbs testicular development of giant freshwater prawn Macrobrachium rosenbergii.

Microcystins (MCs) are produced by cyanobacterial blooms and known for their hepatotoxicity. They could cause serious damage to the reproduction of higher vertebrate mice and fish. However, few studies have focused on the reproductive toxicity of MCs to invertebrates. Giant freshwater prawn Macrobrachium rosenbergii are highly cultivated in China. During their breeding process, M. rosenbergii are often infested by cyanobacteria blooms. In the present study, to investigate the toxic effect of MCs on the testicular development of M. rosenbergii. Male M. rosenbergii were exposed to environmental relevant concentration of MC-LR for 1, 2 and 3 weeks. Results showed that MC-LR entered M. rosenbergii testis, down-regulated hemolymph testosterone (T) levels, and damaged testicular germ cells, mitochondria and cell junctions, and inhibited testicular development. Moreover, MC-LR could significantly induce the expression of gonadal development related genes in testis and eyestalk). The present results indicate that MC-LR can disrupt the testicular development of M. rosenbergii by affecting T levels and gonadal development related genes in the testis and eyestalk.

Excessive use of enrofloxacin leads to growth inhibition of juvenile giant freshwater prawn Macrobrachium rosenbergii.

Giant freshwater prawn Macrobrachium rosenbergii is an economically important species. However, its growth retardant have brought serious economic losses in recent years. Antibiotics abuse is suggested as a reason for M. rosenbergii's growth retardant, while few studies focused on the toxic effect of antibiotics on M. rosenbergii. To investigate the effect of enrofloxacin, a widely used antibiotic, on juvenile M. rosenbergii, a 14 days exposure study was carried out within 0.2, 1 and 5 mg/L enrofloxacin and followed by 7 days decontamination. Results showed that during the test period, enrofloxacin had the largest accumulation in juvenile shrimp at day 3, and gradually decreased at day 7 and 14, and almost all the drugs are cleared after 3 days decontamination. Short-term exposure to low dose enrofloxacin can promote the growth of juveniles. High dose enrofloxacin inhibited the growth of juvenile shrimp, to gill and liver damage, and induced apoptosis of the hepatopancreatic cells. These adverse effects was possibly caused by enrofloxacin-induced oxidative stress. Moreover, we also found the damage caused by high concentrations of enrofloxacin was irreversible in the short term. Collectively, these data indicated that enrofloxacin did affect the juvenile shrimp growth and development, and high level enrofloxacin abuse may contributed to M. rosenbergii's growth retardant.

Pretreatment of rAAV-Mediated Expression of Myostatin Propeptide Lowers Type 2 Diabetes Incidence in C57BL/6 Mice on a High-Fat Diet.

Myostatin, a negative modulator of muscle growth, has been considered as a potential target for the treatment of type 2 diabetes (T2D). In previous work, it was found that myostatin inhibition by adeno-associated virus (AAV)-mediated gene delivery of myostatin propeptide (MPRO) could improve muscle mass and achieve therapeutic effects on glucose regulation and lipid metabolism in db/db mice. This study investigated whether pre-intervention of rAAV-mediated expression of MPRO could lower the incidence of T2D. Three-week-old male C57BL/6 mice were randomly divided into saline control, rAAV-GFP, and rAAV-MPRO groups, all of which were fed on a high-fat diet. It was observed that pre-intervention of rAAV-MPRO prevented high-fat diet-induced hyperglycemia and hyperlipidemia. It also improved glucose tolerance, downregulated serum insulin levels, and facilitated the growth of skeletal muscle and fat redistribution, with no significant difference in serum free fatty acid levels and body weight, which ultimately reduced the incidence of T2D. In addition, pretreatment of rAAV-MPRO in C2C12 cells increased insulin-stimulated glucose uptake, as well as glycogen synthesis under insulin resistance conditions induced by free fatty acids, with no significant difference in insulin-stimulated glucose oxidation. Finally, the study demonstrated that improved glucose metabolism by rAAV-MPRO pretreatment might be due to the activation of the PI3K/Akt/GSK3ß pathway and spurring Glut4 transposition from the cytoplasm to the cytomembrane in C2C12 cells. Based on these findings, MPRO is most likely to be a new method for the prevention of T2D.

Distributed gene clinical decision support system based on cloud computing.

BACKGROUND: The clinical decision support system can effectively break the limitations of doctors' knowledge and reduce the possibility of misdiagnosis to enhance health care. The traditional genetic data storage and analysis methods based on stand-alone environment are hard to meet the computational requirements with the rapid genetic data growth for the limited scalability. METHODS: In this paper, we propose a distributed gene clinical decision support system, which is named GCDSS. And a prototype is implemented based on cloud computing technology. At the same time, we present CloudBWA which is a novel distributed read mapping algorithm leveraging batch processing strategy to map reads on Apache Spark. RESULTS: Experiments show that the distributed gene clinical decision support system GCDSS and the distributed read mapping algorithm CloudBWA have outstanding performance and excellent scalability. Compared with state-of-the-art distributed algorithms, CloudBWA achieves up to 2.63 times speedup over SparkBWA. Compared with stand-alone algorithms, CloudBWA with 16 cores achieves up to 11.59 times speedup over BWA-MEM with 1 core. CONCLUSIONS: GCDSS is a distributed gene clinical decision support system based on cloud computing techniques. In particular, we incorporated a distributed genetic data analysis pipeline framework in the proposed GCDSS system. To boost the data processing of GCDSS, we propose CloudBWA, which is a novel distributed read mapping algorithm to leverage batch processing technique in mapping stage using Apache Spark platform.

Sphingosine-1-phosphate ameliorates the cardiac hypertrophic response through inhibiting the activity of histone deacetylase-2.

Inhibition of histone deacetylase-2 (HDAC2), which is a prohypertrophic factor in the heart, can functionally attenuate cardiac hypertrophy. The present study aimed to investigate whether sphingosine­1­phosphate (S1P), which has recently been reported to suppress HDAC2 activity, could ameliorate the cardiac hypertrophic response and improve cardiac function in mice with transverse aortic constriction (TAC), as well as to determine the underlying mechanisms. Briefly, 8­week­old male C57BL/6 mice were randomly divided into sham, TAC and TAC + S1P groups; the results indicated that S1P treatment attenuated TAC­induced cardiac dysfunction. In addition, heart size and the expression levels of fetal cardiac genes were reduced in the TAC + S1P group compared with in the TAC group. Furthermore, in cultured H9c2 cells exposed to phenylephrine, S1P was revealed to decrease cardiomyocyte size and the exaggerated expression of fetal cardiac genes. The present study also demonstrated that S1P had no effect on HDAC2 expression, but it did suppress its activity and increase acetylation of histone H3 in vivo and in vitro. Krüppel­like factor 4 (KLF4) is an antihypertrophic transcriptional regulator, which mediates HDAC inhibitor­induced prevention of cardiac hypertrophy; in the present study, KLF4 was upregulated by S1P. Finally, the results indicated that S1P receptor 2 (S1PR2) may be involved in the antihypertrophic effects, whereas the suppressive effects of S1P on HDAC2 activity were independent of S1PR2. In conclusion, the present study demonstrated that S1P treatment may ameliorate the cardiac hypertrophic response, which may be partly mediated by the suppression of HDAC2 activity and the upregulation of KLF4; it was suggested that S1PR2 may also be involved. Therefore, S1P may be considered a potential therapy for the treatment of heart diseases caused by cardiac hypertrophy.

Relationship Between ß-Blocker Therapy at Discharge and Clinical Outcomes in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

BACKGROUND: The evidence supporting the use of ß-blockers in patients with acute coronary syndrome after successful percutaneous coronary intervention has been inconsistent and scarce. METHODS AND RESULTS: Between March 1, 2009, and December 30, 2014, a total of 3180 eligible patients with acute coronary syndrome undergoing percutaneous coronary intervention were consecutively enrolled. The primary end point was all-cause death and the secondary end point was a composite of all-cause death, nonfatal myocardial infarction, heart failure readmission, and cardiogenic hospitalization. Patients were compared according to the use of ß-blockers at discharge. Compared with the no ß-blocker group, the risk of all-cause death was significantly lower in the ß-blocker group (hazard ratio [HR], 0.33; 95% CI, 0.17-0.65 [P=0.001]). A consistent result was obtained in multiple adjusted model and propensity score-matched analysis. The use of ß-blockers was also associated with decreased risk of composite of adverse cardiovascular events (HR, 0.47; 95% CI, 0.28-0.81 [P=0.006]), although statistical significance disappeared after multivariable adjustment and propensity score matching. Furthermore, we performed post hoc analysis for the subsets of patients and the results revealed that patients with non-ST-segment elevation myocardial infarction benefited the most from ß-blocker therapy at discharge (HR, 0.04; 95% CI, 0.00-0.27 [P=0.001]), and the use of <50% of target dose was significantly associated with better outcome compared with no ß-blocker use, rather than ≥50% of target dose. CONCLUSIONS: The administration of relatively low ß-blocker dose is associated with improved clinical outcomes among patients with acute coronary syndrome after successful percutaneous coronary intervention, especially for patients with non-ST-segment elevation myocardial infarction.