Salvianolic acid B alleviates neurological injury by upregulating stanniocalcin 1 expression.

Background: Salvianolic acid B (Sal B) is a representative component of phenolic acids derived from the dried root and rhizome of Salvia miltiorrhiza Bge. (Labiatae), which promotes angiogenesis in myocardial infarction and diabetic cardiomyopathy. However, whether Sal B has a neuroprotective function in ischemic stroke by promoting angiogenesis is still unclear. Methods: In the present study, ischemic stroke models were induced in rats by middle cerebral artery occlusion (MCAO), and Sal B (10 or 20 mg/kg/d) was intraperitoneally injected according to a previous study. Neurological deficits were evaluated by the modified Longa five-point scale, modified Bederson scores and cerebral infarction sizes by triphenyltetrazolium chloride (TTC) staining. Apoptotic cells were tested by cleaved-caspase3 immunofluorescence staining and an in situ cell death (TUNEL) detection kit. Human umbilical vein endothelial cells (HUVECs) exposed to hypoxia were used to investigate the effects of Sal B on angiogenesis and tube formation in vitro. Results: Sal B ameliorated the neurological deficits, decreased the cerebral infarction volumes in rats with ischemic stroke, significantly increased the expression of vascular endothelial growth factor receptor 2 (VEGFR2) and VEGFA and promoted angiogenesis both in vivo and in vitro. Furthermore, Sal B increased stanniocalcin 1 (STC1) expression, induced the phosphorylation of protein kinase B (AKT) and mammalian target of rapamycin (mTOR) activity, enhanced cell migration, and activated VEGFR2/VEGFA signaling in endothelial cells. Conclusions: This study showed that Sal B promoted angiogenesis and alleviated neurological apoptosis in rats with ischemic stroke by promoting STC1.

Miniphocaeibacter halophilus sp. nov., an ammonium-tolerant acetate-producing bacterium isolated from a biogas system.

An anaerobic bacterial strain, designated AMB_01T, recovered from mesophilic propionate enrichment of a high-ammonia biogas digester, was characterised using phenotypic and molecular taxonomic methods. Cells of AMB_01T are coccus-shaped and often occur arranged as diplococci or sarcina. Growth occurred at 20-45 °C, initial pH 5.5-8.5 and with up to 0.7 M NH4Cl, with optimum growth at 37-42 °C and pH 8.0. AMB_01T achieved high cell density and highest acetate production when grown on carbohydrates, including monomers, disaccharides and polysaccharides, such as glucose, maltose, cellobiose and starch. The strain was also able to use amino acids and some organic acids and alcoholic compounds for growth. Acetate was formed as the main product and yeast was not required for growth. The major cellular fatty acids were summed feature 4 (iso-C17 : 1I and/or anteiso-C17 : 1B), C18 : 1ω7, C14 : 0, C16 : 0 and summed feature 3 (C16 : 1ω7 and/or iso-C15 : 0 2OH). The highest 16S rRNA gene sequence similarity found was with Miniphocaeibacter massiliensis (96.6 %), within the family Peptoniphilaceae, phylum Bacillota (Firmicutes). The genomic DNA G+C content was 29.0 mol%. An almost complete set of genes for the acetyl-CoA pathway was found. Genome comparisons between AMB_01T and close relatives showed highest digital DNA-DNA hybridisation to Finegoldia magna (23 %), highest average nucleotide identity with genome nucleotide and amino acid sequences to M. massiliensis (72 and 73 %, respectively) and highest average nucleotide identity (87 %) with Schnuerera ultunensis, indicating that AMB_01T represents a novel species. Analysis of genomic, chemotaxonomic, biochemical and physiological data confirmed that strain AMB_01T represents a novel species, for which the name Miniphocaeibacter halophilus sp. nov. is proposed. The type strain is AMB_01T (=DSM 110247T=JCM 39107 T).

MicroRNA-145-5p inhibits hypoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes by targeting ROCK1.

There is increasing evidence that microRNAs (miRs) play critical roles in the pathological and physiological processes associated with myocardial ischemia reperfusion (I/R). miR-145 has been extensively studied in the cardiovascular system; however, the role of miR-145 in myocardial I/R remains unclear. Therefore, the present study aimed to investigate the role and mechanism of miR-145-5p in myocardial I/R by establishing a hypoxia/reoxygenation (H/R) model using H9c2 cardiomyocytes. The expression of miR-145-5p was regulated by transfection and the potential target of miR-145-5p was identified. In addition, apoptosis of the cardiomyocytes was evaluated using flow cytometry and the detection of cleaved caspase-3 by western blotting. The results revealed that miR-145-5p expression was decreased while cell apoptosis and Rho-associated coiled-coil-containing kinase 1 (ROCK1) expression were increased in H/R-stimulated H9c2 cardiomyocytes. The upregulation of miR-145-5p reduced apoptosis and the expression of ROCK1 in H/R-stimulated H9c2 cardiomyocytes. Furthermore, the overexpression of ROCK1 significantly attenuated the miR-145-5p-induced reduction of apoptosis following H/R. In conclusion, the present study indicates that the overexpression of miR-145-5p inhibits H/R-induced cardiomyocyte apoptosis by targeting ROCK1.

Upregulation of Long Noncoding RNA FGD5-AS1 Ameliorates Myocardial Ischemia/Reperfusion Injury via MicroRNA-106a-5p and MicroRNA-106b-5p.

ABSTRACT: Long noncoding RNAs have been known to play key roles in myocardial ischemia/reperfusion injury. This study was conducted to investigate whether upregulation of FGD5-AS1 can improve hypoxia/reoxygenation (H/R) injury of cardiomyocytes and its underlying mechanisms. Pc-FGD5-AS1 was used to overexpress FGD5-AS1 in cardiomyocytes. Cholecystokinin octapeptide and flow cytometry assays were performed to detect the effect of FGD5-AS1 on myocardial cell H/R injury. Quantitative real-time polymerase chain reaction and luciferase reporter assay were performed to assess the relationship between FGD5-AS1 and microRNA-106a-5p (miR-106a-5p) or miR-106b-5p. In patients with acute myocardial infarction and in H/R cardiomyocytes and ischemia/reperfusion myocardium, the expression levels of FGD5-AS1 were reduced, whereas the expression levels of miR-106a-5p and miR-106b-5p were increased. Overexpression of FGD5-AS1 increased the viability of H/R-treated cardiomyocytes and reduced the levels of apoptosis and creatine kinase-MB. In addition, FGD5-AS1 could bind to miR-106a-5p or miR-106b-5p and showed a mutual inhibitory effect between them. Furthermore, overexpression of miR-106a-5p or miR-106b-5p inhibited the expression of SMAD5. FGD5-AS1 upregulated the expression of SMAD5. In conclusion, FGD5-AS1 may be a potential therapeutic target for myocardial H/R injury, and its cardioprotective effect may be realized by reducing inflammatory response and cell apoptosis.

Inhibition of Rho-kinase is involved in the therapeutic effects of atorvastatin in heart ischemia/reperfusion.

The aim of the present study was to investigate the effects of atorvastatin against heart ischemia/reperfusion (I/R) injury and its potential underlying mechanism. Rats were allocated into the following groups: Sham, I/R, atorvastatin (10 mg/kg daily), fasudil (10 mg/kg daily) and atorvastatin + fasudil in combination. Drugs were administered for 2 weeks prior to I/R injury. I/R was established by ligating the left anterior descending branch (LAD) for 30 min and releasing the ligature for 180 min. The I/R group was found to have increased myocardial infarct size, cardiomyocyte apoptosis, levels of plasma interleukin (IL)-6 and tumor necrosis factor (TNF)-α, superoxide dismutase (SOD) activity, malondialdehyde (MDA) levels and Rho-kinase activity compared with the other treatment groups (P<0.05). Moreover, pretreatment with atorvastatin significantly attenuated Rho-kinase activity, myocardial infarct size, cardiomyocyte apoptosis, levels of plasma IL-6 and TNF-α, SOD activity and MDA levels, and upregulated nitric oxide production. It was also indicated that the specific Rho-kinase inhibitor, fasudil, had the same effects as atorvastatin in I/R. Therefore, the present results suggested atorvastatin may lead to cardiovascular protection, which may be mediated by Rho-kinase inhibition in heart I/R injury.

miR-26a-5p protects against myocardial ischemia/reperfusion injury by regulating the PTEN/PI3K/AKT signaling pathway.

Reperfusion strategies in acute myocardial infarction (AMI) can cause a series of additional clinical damage, defined as myocardial ischemia/reperfusion (I/R) injury, and thus there is a need for effective therapeutic methods to attenuate I/R injury. miR-26a-5p has been proven to be an essential regulator for biological processes in different cell types. Nevertheless, the role of miR-26a-5p in myocardial I/R injury has not yet been reported. We established an I/R injury model in vitro and in vivo. In vitro, we used cardiomyocytes to simulate I/R injury using hypoxia/reoxygenation (H/R) assay. In vivo, we used C57BL/6 mice to construct I/R injury model. The infarct area was examined by TTC staining. The level of miR-26a-5p and PTEN was determined by bioinformatics methods, qRT-PCR, and western blot. In addition, the viability and apoptosis of cardiomyocytes were separately detected by MTT and flow cytometry. The targeting relationship between miR-26a-5p and PTEN was analyzed by the TargetScan website and luciferase reporter assay. I/R and H/R treatment induced myocardial tissue injury and cardiomyocyte apoptosis, respectively. The results showed that miR-26a-5p was down-regulated in myocardial I/R injury. PTEN was found to be a direct target of miR-26a-5p. Furthermore, miR-26a-5p effectively improved viability and inhibited apoptosis in cardiomyocytes upon I/R injury by inhibiting PTEN expression to activate the PI3K/AKT signaling pathway. miR-26a-5p could protect cardiomyocytes against I/R injury by regulating the PTEN/PI3K/AKT pathway, which offers a potential approach for myocardial I/R injury treatment.

Metabolic performance of anaerobic digestion of chicken manure under wet, high solid, and dry conditions.

The anaerobic digestion (AD) of chicken manure as a solo substrate has been challenging due to the ammonium inhibition effects when adopting a high organic loading rate (OLR). In this study, through increasing both the total solid in the feeding materials from 5% to 20%, and the OLR from 1.7 to 7.1 g-volatile solids (VS)/(L·d), the AD of chicken manure under wet, high solid, and dry conditions, with a fixed hydraulic retention time of 20 days, was investigated. The results obtained indicated that the wet AD system could achieve a methane yield of 0.28 L/g-VS and a low volatile fatty acid level. However, the process deteriorated under dry conditions, and methane formed mainly through acetate oxidation and methanogenesis. Methanosarcina and Methanoplasma were found to be more tolerant But, whether the dry AD of chicken manure can survive an ammonia-stressed environment when the OLR is lowered, still needs investigation.

miR-26a-5p protects against myocardial ischemia/reperfusion injury by regulating the PTEN/PI3K/AKT signaling pathway

Reperfusion strategies in acute myocardial infarction (AMI) can cause a series of additional clinical damage, defined as myocardial ischemia/reperfusion (I/R) injury, and thus there is a need for effective therapeutic methods to attenuate I/R injury. miR-26a-5p has been proven to be an essential regulator for biological processes in different cell types. Nevertheless, the role of miR-26a-5p in myocardial I/R injury has not yet been reported. We established an I/R injury model in vitro and in vivo. In vitro, we used cardiomyocytes to simulate I/R injury using hypoxia/reoxygenation (H/R) assay. In vivo, we used C57BL/6 mice to construct I/R injury model. The infarct area was examined by TTC staining. The level of miR-26a-5p and PTEN was determined by bioinformatics methods, qRT-PCR, and western blot. In addition, the viability and apoptosis of cardiomyocytes were separately detected by MTT and flow cytometry. The targeting relationship between miR-26a-5p and PTEN was analyzed by the TargetScan website and luciferase reporter assay. I/R and H/R treatment induced myocardial tissue injury and cardiomyocyte apoptosis, respectively. The results showed that miR-26a-5p was down-regulated in myocardial I/R injury. PTEN was found to be a direct target of miR-26a-5p. Furthermore, miR-26a-5p effectively improved viability and inhibited apoptosis in cardiomyocytes upon I/R injury by inhibiting PTEN expression to activate the PI3K/AKT signaling pathway. miR-26a-5p could protect cardiomyocytes against I/R injury by regulating the PTEN/PI3K/AKT pathway, which offers a potential approach for myocardial I/R injury treatment.

Serum cystatin C levels relate to no-reflow phenomenon in percutaneous coronary interventions in ST-segment elevation myocardial infarction.

BACKGROUND/AIM: No-reflow is a serious and frequent event during primary percutaneous coronary intervention (PPCI) for acute ST segment elevation myocardial infarction (STEMI). The aim of this study was to identify possible predictors for no-reflow. PATIENTS AND METHODS: We investigated 218 patients with acute anterior STEMI who underwent PPCI from December 2016 to December 2018. No-reflow was defined as a coronary TIMI flow grade of ≤ 2. TIMI flow grade 3 was defined as normal reflow. RESULTS: In our study, the no-reflow phenomenon was observed in 39 patients (18%) during angiography. The patients of no-reflow group were found to be more older, diabetics, longer pain-to-balloon time, lower blood pressure, higher platelet counts and higher levels of D-Dimer and Cystatin C (Cys-C). In multivariate logistic regression analysis, only diabetes (OR = 0.371, 95% CI: 0.157-0.872, P = 0.023), longer pain-to-balloon time (OR = 1.147, 95% CI: 1.015-1.297, P = 0.028) and higher Cys-C level (OR = 10.07, 95% CI: 2.340-43.377, P = 0.002) were predictors for no-reflow. CONCLUSION: Cys-C might be a useful predictor for the no-reflow phenomenon after PPCI in STEMI patients. It might help to screen STEMI patients with high risk of no-reflow on admission.

Enhanced methanogenic performance and metabolic pathway of high solid anaerobic digestion of chicken manure by Fe2+ and Ni2+ supplementation.

High solid anaerobic digestion (AD) is a promising technology for the treatment of organic waste in terms of efficient bioenergy production and digestate volume reduction. However, the high solid AD of chicken manure has been a challenge due to the inhibition effects caused by high ammonia levels. In this study, the addition of 280 mg/L Fe2+ and 2 mg/L Ni2+ has been proven to enhance the microbial activity and to overcome inhibition under the stressed environment. The mesophilic digesters feeding with total solid around 150 g/kg operated at an organic loading rate of 4.8 g/(L d) based on volatile solid and a 20-day hydraulic retention time. The total ammonia-nitrogen reached around 6.8 g/L in control and Fe-Ni digesters. The results from the 147-day continuously-fed experiment provided an increment of 34% methane production and a 29% reduction of volatile fatty acids against control. The acetoclastic and hydrogenotrophic methanogenic activity was increased by 89% and 40% respectively. The high throughout sequencing results showed an increased percentage of Methanosarcina sp., which may have contributed to the shifting of the methanogenic pathway towards acetoclastic methanogenesis. The positive effects of Fe2+ and Ni2+ supplementation obtained in this study lay the foundation for its use in AD of nitrogen rich materials.

Response of the microbial community to the methanogenic performance of biologically hydrolyzed sewage sludge with variable hydraulic retention times.

Hyperthermophilic biological hydrolysis of sewage sludge was applied before long-term anaerobic digestion to investigate how shortening hydraulic retention times (HRT, 20-5d) affected methanogenic performances and microbial dynamics. Results indicated that although the three different HRTs provided a stable process with a steady-state of methane production, both methane yield (161 L kg-VSin-1, 25% higher) and volatile solids removal (VS, 50%, 2-fold higher) increased during longer HRTs. Redundancy analysis results indicated that Sporosarcina and Methnosarcina positively correlated to VS removal and methane yield, and negatively correlated to volatile fatty acids (VFAs) accumulation. The relative abundance of Coprothermobacter (>60%), syntrophic acetate oxidation bacteria (SAOB), and Methanospirillum (8-15%), increased during shorter HRTs. A slight shift to two-stage acetate conversion was observed during shorter HRTs. The results demonstrated that HRTs played a key role in shaping microbial structure, leading to a new steady-state of microbial community profiles and process performances at variable HRTs.

Enhancing autophagy protects platelets in immune thrombocytopenia patients.

BACKGROUND: Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder and involves increased apoptosis of platelets. Autophagy is an essential process for platelets to maintain their life and physiological functions. However, the role of autophagy in ITP platelets was previously unclear. METHODS: In the present study, the expression of autophagy-related protein and autophagy flux were detected in platelets from ITP patients and healthy controls by immunofluorescence staining and immunoblotting, and the influence of autophagy on the viability and apoptosis of ITP platelets was further explored. RESULTS: We found that platelet autophagy was diminished in ITP patients. Platelet autophagy in ITP was regulated by the PI3K/AKT/mTOR pathway, with mTOR (mammalian target of rapamycin) as a negative regulator and class III PtdIns3K playing a crucial role in the process. Importantly, the small-molecule compound ABO (6-amino-2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine) enhanced autophagy in ITP platelets. Enhancing platelet autophagy alleviated platelet destruction by inhibiting apoptosis and improving platelet viability. CONCLUSIONS: These results suggest a role for autophagy regulation in the pathogenesis of ITP, and offer a novel treatment for these patients.

Enhancing anaerobic digestion of dairy and swine wastewater by adding trace elements: evaluation in batch and continuous experiments.

Trace elements play a critical role for microbial activity in anaerobic digestion (AD) but their effects were probably overestimated in batch tests and should be comparably evaluated in continuous systems. In this study, Fe2+, Co2+, Ni2+, Cu2+ and Zn2+ were added in different concentrations to manure wastewater, and the effects were compared in both batch and continuous systems. The results were used to demonstrate suitable trace element compositions for AD of dairy and swine wastewater, and to compare the outcomes from batch and continuous systems. Fe2+ and Zn2+ were identified as being the most efficient stimulant of dairy and swine wastewater respectively. The addition of 5 mg/L Fe2+ and 0.4 mg/L Zn2+ increased the batch specific methane yield by 62% and 126% for dairy and swine wastewater, respectively. Nevertheless, a lower increment of 2% and 21%, for dairy and swine wastewater was obtained in the 120-day continuously-fed experiments. The 16S rRNA gene sequencing results indicated a relationship between the methanogens population, specific methanogenic activities, propionate, and dissolved hydrogen. Conclusively, the addition of a low dosage of Fe2+ and Zn2+ is a feasible strategy to enhance the methanogenic metabolism of the AD of dairy and swine wastewater respectively.

Increased Rho kinase activity in patients with heart ischemia/reperfusion.

BACKGROUND/AIM:\: Rho kinase is a downstream effector of Rho GTPase that is known to regulate various pathological processes. The aim of this study was to evaluate the regulation of Rho kinase activity in leukocytes in patients with ischemia/reperfusion (I/R) injury. PATIENTS AND METHODS: We investigated 38 patients with acute ST-segment elevation myocardial infarction (STEMI), 26 patients with atherosclerosis (AS) and 22 normal subjects. All patients underwent coronary angiography (CAG) and all STEMI patients received primary percutaneous coronary intervention (PPCI) of the left anterior descending artery (LAD) within 12 h after chest pain on-set. Blood samples for leukocyte Rho kinase activity were obtained before CAG and 3 and 24 hours after CAG/PCI. RESULTS: Rho kinase activity increased in the I/R and AS groups. Compared with the AS group, Rho kinase activity was significantly higher in peripheral blood leukocytes in STEMI/PPCI. Furthermore, there was no correlation between changes in Rho kinase activity and changes in high-sensitivity troponin I (hs-TnI) and C-reactive protein (CRP). There was a negative correlation between Rho kinase activity and IL-6. CONCLUSION: Rho kinase is involved in the pathogenesis of heart I/R injury in patients. Inhibition of Rho kinase may be an additional therapeutic intervention for the treatment of I/R.

An explanation of the methanogenic pathway for methane production in anaerobic digestion of nitrogen-rich materials under mesophilic and thermophilic conditions.

The impact of temperature on the anaerobic digestion of chicken manure was investigated by studying the process performance and pathway for continuously-fed digesters under mesophilic and thermophilic conditions. The mesophilic digester obtained a 15% higher methane yield compared with the thermophilic digester. Mesophilic and thermophilic digester had free ammonia of 31 and 145 mg/L, respectively. The stable carbon isotope analysis indicated that 41% and 50% of acetate was converted to methane through the syntrophic acetate oxidation and hydrogenotrophic methanogenesis (SAO-HM) pathway under mesophilic and thermophilic conditions, respectively. The genus Pseudomonas represented 10% and 16% under mesophilic and thermophilic conditions, respectively. A high abundance of the methanogens genus Methanoculleus (94% of total methanogens) in mesophilic and the genus Methanothermobacter (96%) in thermophilic digesters indicated they were the main hydrogenotrophic partners in SAO. The present study therefore illustrated that methanogenic pathway shifting, induced by free ammonia, closely correlated to the process performance.

Impact of temperature and substrate concentration on degradation rates of acetate, propionate and hydrogen and their links to microbial community structure.

The present study investigates the conversion of acetate, propionate and hydrogen consumption linked to the microbial community structure and related to temperature and substrate concentration. Biogas reactors were continuously fed with coffee powder (20 g-COD/L) or acetate (20, 40, and 60 g-COD/L) and operated for 193 days at 37 °C or 55 °C conditions. Starting HRT was 23 days which was then reduced to 7 days. The kinetics of acetate and propionate degradation and hydrogen consumption rates were measured in batch assays. At HRT 7 days, the degradation rate of propionate was higher in thermophilic batches, while acetate degradation rate was higher at mesophilic conditions. The gaseous hydrogen consumption in acetate reactors increased proportionally with temperature and substrate concentration, while the dissolved hydrogen was not affected. The relative high abundance of hydrogentrophic methanogens indicated that the methanogenesis was directed towards the syntrophic acetate oxidation pathway at high acetate concentration and high temperature.

LncRNA-MALAT1-mediated Axl promotes cell invasion and migration in human neuroblastoma.

Overexpression of Axl has been noted to correlate with several human cancers. However, the regulatory mechanisms and effects of Axl in human neuroblastoma development remain unclear. Here, we explore the expression of Axl in neurobalstoma and related upstream regulatory mechanisms of invasion and migration. We found that Axl was overexpressed in metastatic neuroblastoma tissues and positively associated with long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1. Meanwhile, our data suggested that metastasis-associated lung adenocarcinoma transcript 1 upregulated Axl expression in neuroblastoma cells, resulting in cell invasion and migration. Furthermore, we found that targeting Axl by inhibitor R428 significantly suppressed the abilities of tumor cell invasion and migration. In summary, these results suggested that Axl, which is regulated by long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1, may exert great influence on invasion and migration of neuroblastoma.

Correlation between serum exosome derived miR-208a and acute coronary syndrome.

OBJECTIVE: To explore the correlation of miRNAs with clinical characteristics of ACS. METHODS: 50 ACS patients and 50 healthy controls were randomly selected. On the basis of miRNA expression levels, ACS patients were classified as low miRNA expression group (fold change: <3) and high miRNA expression group (≥3). RESULTS: miR-208a expression increased markedly in the serum exosomes of ACS patients, and miR-208a expression in the serum of ACS patients was also significantly higher than that in healthy controls. However, the sensitivity of serum miR-208a was inferior to that of exosome miR-208a. Analysis of clinical characteristics showed the mean age of 500 ACS patients was 62.35±9.70 years, and there were 300 patients in low miR-208a expression group and 200 patients in high miR-208a expression group. When compared with low miR-208a expression group, patients with high miR-208a expression were older, and had higher Killip class, higher CK-MB peak, higher cTnT peak and elevated LDL (P<0.05). Within 1-year follow up, 32 patients died including 10 in low miR-208a expression group with the mortality of 3.3% and 22 in high miR-208a expression group with the mortality of 11.0%. Kaplan-Meier survival analysis revealed that the 1-year survival rate reduced significantly in patients with high miR-208a expression. CONCLUSION: miRNA-208a expression is significantly up-regulated in the serum exosomes of ACS patients and is crucial for the diagnosis of ACS.

Inhibition of Mer and Axl receptor tyrosine kinases leads to increased apoptosis and improved chemosensitivity in human neuroblastoma.

Ectopic expression of Mer and Axl receptor tyrosine kinases (RTKs) are frequently found in various cancers as known to promote oncogenesis by activating antiapoptotic signaling pathways. However, the roles of these receptors in neuroblastoma remain unclear. We found Mer and Axl was co-expressed in neuroblastoma patient samples and cell lines. Ligand-dependent Mer or Axl activation led to an increase in phosphorylated ERK1/2, AKT and FAK indicating roles for these RTKs in multiple oncogenic processes. Furthermore, Mer and Axl knockdown led to apoptosis and inhibition of migration as well as a significant increase in chemosensitivity in response to cisplatin and vincristine treatment. Taken together, our results demonstrated that inhibition of Mer and Axl improved apoptotic response and chemosensitivity in neuroblastoma, providing new insights into development of novel therapeutic strategies by targeting these oncogenes.

Atorvastatin up-regulates TRIB3 independent of ATF4-CHOP pathway in atherosclerotic patients.

BACKGROUND: Macrophage apoptosis triggered by endoplasmic reticulum (ER) stress contributes much to atherosclerosis, especially plaque vulnerability. Activating transcription factor 4 (ATF4)-CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP)-Tribbles 3 (TRIB3) pathway is closely related to the ER stress. This study aimed to investigate the effect of atorvastatin on the ATF4-CHOP-TRIB3 pathway. METHODS: Forty-seven patients were randomized into 80-mg and 20-mg atorvastatin group. Follow-up was performed at weeks 6 and 12, and complete blood chemistry, lipid assay and detection of 5 target genes (tumor protein 53, ATF4, C/EBP, CHOP and TRIB3) in monocytes/macrophages were conducted. Furthermore, the interaction between dosage and duration of therapy was evaluated. RESULTS: After 12-week therapy, patients in both groups experienced significant reductions in ATF4 (P=0.038) and C/EBP (P=0.003) expressions. Tumor protein 53 (P=0.015) and TRIB3 (P=0.045) expressions increased markedly in 80-mg atorvastatin group. However, there was no significant difference in CHOP expression at three time-points and between atorvastatin groups. Moreover, there was no interaction between dosage and duration of therapy. CONCLUSIONS: Atorvastatin has an effect on ER stress through ATF4-CHOP pathway. Atorvastatin at a high dose is more likely to increase TRIB3 expression, but this warrants further investigation.