ASIC1/RIP1 accelerates atherosclerosis via disrupting lipophagy.

INTRODUCTION: Atherosclerosis, a major contributor to cardiovascular disease, remains a significant health concern worldwide. While previous research has shown that acid-sensing ion channel 1 (ASIC1) impedes macrophage cholesterol efflux, its precise role in atherogenesis and the underlying mechanisms have remained elusive. OBJECTIVES: This study aimed to investigate the role of ASIC1 in atherosclerosis and its underlying mechanisms. METHODS: First, data from a single-cell RNA sequencing (scRNA-seq) database were used to explore the relationships between ASIC1 differential expression and lipophagy in human atherosclerotic lesions. Finally, we validated the role of ASIC1/RIP1 signaling in lipophagy in vivo (human and mice) and in vitro (RAW264.7 and HTP-1 cells). RESULT: Our results demonstrated a significant increase in ASIC1 protein levels within CD68+ macrophages in both human aortic lesions and AopE-/- mouse lesion areas compared to nonlesion regions. Concurrently, there was a notable decrease in lipophagy, a crucial process for lipid metabolism. In vitro assays further elucidated that ASIC1 interaction with RIP1 (receptor-interacting protein 1) promoted the phosphorylation of RIP1 at serine 166 and transcription factor EB (TFEB) at serine 142, leading to disrupted lipophagy and increased lipid accumulation. Intriguingly, all these events were reversed upon ASIC1 deficiency and RIP1 inhibition. Furthermore, in ApoE-/- mouse models of atherosclerosis, silencing ASIC1 expression or inhibiting RIP1 activation not only significantly attenuated atherogenesis but also restored TFEB-mediated lipophagy in aortic tissues. This was evidenced by reduced TFEB Ser-142 phosphorylation, decreased LC3II and LAMP1 protein expression, increased numbers of lipophagosomes, and a decrease in lipid droplets. CONCLUSION: Our findings unveil the critical role of macrophage ASIC1 in interacting with RIP1 to inhibit lipophagy, thereby promoting atherogenesis. Targeting ASIC1 represents a promising therapeutic avenue for the treatment of atherosclerosis.

Efficient Electrochemical Water Oxidation Mediated by Pyridylpyrrole-Carboxylate Ruthenium Complexes.

Spurred by the rapid growth of Ru-based complexes as molecular water oxidation catalysts (WOCs), we propose novel ruthenium(II) complexes bearing pyridylpyrrole-carboxylate (H2ppc) ligands as members of the WOC family. The structure of these complexes has 4-picoline (pic)/dimethyl sulfoxide (DMSO) in [Ru(ppc)(pic)2(dmso)] and pic/pic in [Ru(ppc)(pic)3] as axial ligands. Another ppc2- ligand and one pic ligand are located at the equatorial positions. [Ru(ppc)(pic)2(dmso)] behaves as a WOC as determined by electrochemical measurement and has an ultrahigh electrocatalytic current density of 8.17 mA cm-2 at 1.55 V (vs NHE) with a low onset potential of 0.352 V (vs NHE), a turnover number of 241, a turnover frequency of 203.39 s-1, and kcat of 16.34 s-1 under neutral conditions. The H2O/pic exchange of the complexes accompanied by oxidation of a ruthenium center is the initial step in the catalytic cycle. The cyclic voltametric measurements of [Ru(ppc)(pic)2(dmso)] at various scan rates, Pourbaix diagrams (plots of E vs pH), and kinetic studies suggested a water nucleophilic attack mechanism. HPO42- in a phosphate buffer solution is invoked in water oxidation as the proton acceptor.

GADD45α alleviates the CDDP resistance of SK-OV3/cddp cells via redox-mediated DNA damage.

Epithelial ovarian cancer has the highest mortality rate of all malignant ovarian cancer types. Great progress has been made in the treatment of ovarian cancer in recent years. However, drug resistance has led to a low level of 5-year survival rate of epithelial ovarian cancer, and the molecular mechanism of which remains unknown. The aim of the present study was to identify the role of redox status in the cisplatin (CDDP) resistance of ovarian cancer. CDDP-resistant SK-OV3 (SK-OV3/cddp) cells were prepared and their reactive oxygen species and glutathione levels were investigated. The effects of hydrogen peroxide on the CDDP sensitivity of the SK-OV3/cddp cells and their expression levels of the redox-associated protein growth arrest and DNA damage 45a (GADD45α) were also investigated. In addition, the impact of GADD45α overexpression on cell viability was evaluated in vitro and in vivo, and the levels of Ser-139 phosphorylated H2A histone family member X (γ-H2AX), which is associated with DNA damage, were detected. The results suggested that redox status affected the drug resistance of the ovarian cancer cells by increasing the expression of GADD45α. The overexpression of GADD45α reversed the CDDP resistance of the SK-OV3/cddp cells and increased the level of γ-H2AX. In conclusion, GADD45α alleviated the CDDP resistance of SK-OV3/cddp cells via the induction of redox-mediated DNA damage.

Critical role of dysfunctional mitochondria and defective mitophagy in autism spectrum disorders.

Autism spectrum disorders (ASDs) are a group of complex neurodevelopmental disorders, including autistic disorder, Asperger's syndrome, pervasive developmental disorder and childhood disintegrative disorder. Mitochondria not only provide neurons with energy in the form of ATP to sustain neuron growth, proliferation and neurodevelopment, but also regulate neuron apoptosis, intracellular calcium ion (Ca2+) homeostasis, and reactive oxygen species (ROS) clearance. Due to their postmitotic state and high energy-demanded feature, neurons are particularly prone to mitophagy and mitochondrial disfunction. Mitophagy, a selective autophagy, is critical for sustaining mitochondrial turnover and quality control via eliminating unwanted and dysfunctional mitochondria in neurons. Dysfunctional mitochondria and dysregulated mitophagy have been closely associated with the onset of ASDs. In this review, we summarize the mechanism of mitophagy and its role in neurons, and the consequence of mitophagy dysfunction in ASDs. Deeper appreciation of the role of mitophagy in ASDs pathology is required for developing new therapeutic approaches.

Acid-Sensing Ion Channel 1/Calpain1 Activation Impedes Macrophage ATP-Binding Cassette Protein A1-Mediated Cholesterol Efflux Induced by Extracellular Acidification.

BACKGROUND: Extracellular acidification is a common feature of atherosclerotic lesions, and such an acidic microenvironment impedes ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux and promotes atherogenesis. However, the underlying mechanism is still unclear. Acid-sensing ion channel 1 (ASIC1) is a critical H+ receptor, which is responsible for the perception and transduction of extracellular acidification signals. AIM: In this study, we explored whether or how ASIC1 influences extracellular acidification-induced ABCA1-mediated cholesterol efflux from macrophage-derived foam cells. METHODS: RAW 264.7 macrophages were cultured in an acidic medium (pH 6.5) to generate foam cells. Then the intracellular lipid deposition, cholesterol efflux, and ASIC1/calpain1/ABCA1 expressions were evaluated. RESULTS: We showed that extracellular acidification enhanced ASIC1 expression and translocation, promoted calpain1 expression and lipid accumulation, and decreased ABCA1 protein expression as well as ABCA1-mediated cholesterol efflux. Of note, inhibiting ASIC1 activation with amiloride or Psalmotoxin 1 (PcTx-1) not only lowered calpain1 protein level and lipid accumulation but also enhanced ABCA1 protein levels and ABCA1-mediated cholesterol efflux of macrophages under extracellular acidification conditions. Furthermore, similar results were observed in macrophages treated with calpain1 inhibitor PD150606. CONCLUSION: Extracellular acidification declines cholesterol efflux via activating ASIC1 to promote calpain1-mediated ABCA1 degradation. Thus, ASIC1 may be a novel therapeutic target for atherosclerosis.

Lipophagy in atherosclerosis.

Atherosclerosis results from the excessive accumulation of lipids within the arterial wall. Lipophagy, referred to as the autophagic degradation of lipids, is a critical mechanism that regulates lipid metabolism in numerous cell types. The contribution of lipophagy to intracellular lipid turnover makes it a major player in the development and progression of atherosclerosis. This review addresses recent advances in lipid metabolism via lipophagy. The relationship between lipophagy and atherosclerosis is discussed focusing on the roles of lipophagy in vascular endothelial cell injury, vascular smooth muscle cells phenoypic shift, and macrophage lipid accumulation. A further understanding of lipophagy in these processes may provide promising new therapeutic options for atherosclerotic diseases.

Effect of coherence of nonthermal reservoirs on heat transport in a microscopic collision model.

We investigate the heat transport between two nonthermal reservoirs based on a microscopic collision model. We consider a bipartite system consisting of two identical subsystems, and each subsystem interacts with its own local reservoir, which consists of a large collection of initially uncorrelated ancillas. Then a heat transport is formed between two reservoirs by a sequence of pairwise collisions (intersubsystem and subsystem-local reservoir). In this paper we consider two kinds of the reservoir's initial states: the thermal state and the state with coherence whose diagonal elements are the same as that of the thermal state and the off-diagonal elements are nonzero. In this way, we define the effective temperature of the reservoir with coherence according to its diagonal elements. We find that for two reservoirs having coherence the direction of the steady current of heat is different for different phase differences between the two initial states of two reservoirs, especially the heat can transfer from the "cold reservoir" to the "hot reservoir" in the steady regime for particular phase difference. In the limit of the effective temperature difference between the two reservoirs ΔT→0, for most of the phase differences, the steady heat current increases with the increase of effective temperature until it reaches the high effective temperature limit, while for the thermal state or particular phase difference the steady heat current decreases with the increase of temperature at high temperatures, and in this case the conductance can be obtained.

Genome-wide discovery of novel and conserved microRNAs in white shrimp (Litopenaeus vannamei).

Of late years, a large amount of conserved and species-specific microRNAs (miRNAs) have been performed on identification from species which are economically important but lack a full genome sequence. In this study, Solexa deep sequencing and cross-species miRNA microarray were used to detect miRNAs in white shrimp. We identified 239 conserved miRNAs, 14 miRNA* sequences and 20 novel miRNAs by bioinformatics analysis from 7,561,406 high-quality reads representing 325,370 distinct sequences. The all 20 novel miRNAs were species-specific in white shrimp and not homologous in other species. Using the conserved miRNAs from the miRBase database as a query set to search for homologs from shrimp expressed sequence tags (ESTs), 32 conserved computationally predicted miRNAs were discovered in shrimp. In addition, using microarray analysis in the shrimp fed with Panax ginseng polysaccharide complex, 151 conserved miRNAs were identified, 18 of which were significant up-expression, while 49 miRNAs were significant down-expression. In particular, qRT-PCR analysis was also performed for nine miRNAs in three shrimp tissues such as muscle, gill and hepatopancreas. Results showed that these miRNAs expression are tissue specific. Combining results of the three methods, we detected 20 novel and 394 conserved miRNAs. Verification with quantitative reverse transcription (qRT-PCR) and Northern blot showed a high confidentiality of data. The study provides the first comprehensive specific miRNA profile of white shrimp, which includes useful information for future investigations into the function of miRNAs in regulation of shrimp development and immunology.

[Analysis of risk factors for epithelial ovarian cancer recurrence].

BACKGROUND & OBJECTIVE: Advanced ovarian cancer shows a high recurrence and poor survival rate. It is important to identify the risk factors for the recurrence of ovarian cancer, due to the lack of reliable methods for the detection of early disease. This study was designed to explore the risk factors for the recurrence of epithelial ovarian cancer. METHODS: Factors that might be related to the recurrence of 109 epithelial ovarian cancer patients including age, pathological type, FIGO stage, operation type, chemotherapy regimen, neoadjuvant chemotherapy, postoperative chemotherapy cycles, first operation status, and size of residual tumor were analyzed by logistic regression model using SPSS 10.0 statistical software. RESULTS: Of 109 patients with ovarian cancer, 36 (33%) relapsed after a combination of surgery and chemotherapy, and the median recurrence-free interval was 19 months. The 5-year survival rates were 62.7% and 43.3% for the 109 patients and the recurrent patients, respectively. The survival rates of pelvic recurrence (50.1%) and extra-pelvic recurrence (36.1%) were not statistically different. Univariate analysis showed that the risk of recurrence in mucous adenocarcinoma or FIGO stage I patients were lower than that of other pathology type or FIGO stage (beta=-1.565 and -1.799,P=0.0120 and 0.026 ) while it was higher in the patients given above 8 cycles chemotherapy than those given 1-4 or 6-8 cycles(beta=-3.591 and -1.500,P< 0.001 and =0.038). Multivariate analysis showed that histological type, FIGO stage and postoperative chemotherapy cycles had remarkable influence on the relapse of epithelial ovarian cancer independently(RR=3.473, 4.713, and 6.140, respectively, P< 0.05). CONCLUSION: Histological type, FIGO stage, and postoperative chemotherapy cycles influence the recurrence of epithelial ovarian cancer. Since FIGO stage is a remarkable risk factor for the recurrence, early diagnosis should be the key point to decrease it. Reasonable chemotherapy plan is essential for the therapy of ovarian cancer, but excessive chemotherapy is not good for effectiveness.