The Magic and Mystery of TRIM65 in Diseases.

Tripartite-motif protein family member 65 (TRIM65) belongs to the tripartite motif (TRIM) protein family. Its typical structure consists of the RING, B-Box motif, and coiled-coil domains, which are highly conserved at the N-terminus and the variable SPRY domain at the C-terminus. TRIM65 is an E3 ubiquitin ligase that participates in physiological and pathological processes through the ubiquitination pathway, including intracellular signal transduction, protein degradation, cell proliferation, apoptosis, carcinogenesis, autophagy, and phenotypic transformation. Evidence shows that TRIM65 plays a remarkable and obscure role in diseases, including multisystem tumours, neurodegenerative diseases, immune system diseases, and inflammatory diseases. This review is devoted to elaborating on the relationship between TRIM65 and diseases and its pathogenic mechanism, providing a theoretical basis for TRIM65 as a possible pathogenic target of diseases and exploring the possible future research direction of TRIM65 and the challenges it may face.

Bilirubin Elevation During Hospitalization Post Radiofrequency Catheter Ablation of Persistent Atrial Fibrillation: Variation Trend, Related Factors, and Relevance to 1-Year Recurrence.

Background: The role of total bilirubin (TBIL) in cardiovascular disease has been increasingly recognized in recent decades. Studies have shown a correlation between total bilirubin levels and the prognosis of patients after heart surgery. This study aimed to investigate the clinical significance of bilirubin elevation in persistent atrial fibrillation (PAF) patients who received radiofrequency catheter ablation (RFCA). Methods and Results: A total of 184 patients with PAF who received RFCA were retrospectively studied. Laboratory examinations and demographic data were analyzed to identify independent predictors of TBIL elevation. The relationship between TBIL and prognosis was further investigated. Our results indicated that TBIL increased significantly after RFCA. Multiple linear regression analysis showed that TBIL elevation owned a negative correlation with the percentile of low voltage areas (LVAs) in left atria (ß=-0.490, P<0.001). In contrast, a positive correlation was observed with the white blood cell (WBC) ratio (ß=0.153, P=0.042) and left atrial diameter (LAD) (ß=0.232, P=0.025). It was found that postoperative TBIL levels increased and then gradually decreased to baseline within 5 days without intervention. The bilirubin ratio <1.211 indicated the possibility of 1-year AF recurrence after ablation with a predictive value of 0.743 (specificity = 75.00%, sensitivity = 66.67%). Conclusion: Bilirubin elevation post PAF RFCA was a common phenomenon and was associated with 1-year recurrence of AF in PAF patients after RFCA.

Potential drug targets for gastroesophageal reflux disease and Barrett's esophagus identified through Mendelian randomization analysis.

Gastroesophageal reflux disease (GERD) is a prevalent chronic ailment, and present therapeutic approaches are not always effective. This study aimed to find new drug targets for GERD and Barrett's esophagus (BE). We obtained genetic instruments for GERD, BE, and 2004 plasma proteins from recently published genome-wide association studies (GWAS), and Mendelian randomization (MR) was employed to explore potential drug targets. We further winnowed down MR-prioritized proteins through replication, reverse causality testing, colocalization analysis, phenotype scanning, and Phenome-wide MR. Furthermore, we constructed a protein-protein interaction network, unveiling potential associations among candidate proteins. Simultaneously, we acquired mRNA expression quantitative trait loci (eQTL) data from another GWAS encompassing four different tissues to identify additional drug targets. Meanwhile, we searched drug databases to evaluate these targets. Under Bonferroni correction (P < 4.8 × 10-5), we identified 11 plasma proteins significantly associated with GERD. Among these, 7 are protective proteins (MSP, GPX1, ERBB3, BT3A3, ANTR2, CCM2, and DECR2), while 4 are detrimental proteins (TMEM106B, DUSP13, C1-INH, and LINGO1). Ultimately, C1-INH and DECR2 successfully passed the screening process and exhibited similar directional causal effects on BE. Further analysis of eQTLs highlighted 4 potential drug targets, including EDEM3, PBX3, MEIS1-AS3, and NME7. The search of drug databases further supported our conclusions. Our study indicated that the plasma proteins C1-INH and DECR2, along with 4 genes (EDEM3, PBX3, MEIS1-AS3, and NME7), may represent potential drug targets for GERD and BE, warranting further investigation.

Multifaceted Nature of HuR in Atherosclerosis Development.

HuR (Human antigen R) is an RNA binding protein (RBP) that specifically binds to certain RNA sequences, influencing post-transcriptional regulation. HuR is primarily involved in tumor regulation, as well as cell growth, proliferation, inflammation, and angiogenesis. HuR is implicated in endothelial activation, smooth muscle proliferation, inflammatory response, macrophage apoptosis, lipid regulation, and autophagy, playing a crucial regulatory role in atherosclerosis. Accumulating evidence suggests that HuR has dual roles in AS. On the one hand, HuR expedites the development of AS by facilitating endothelial activation, smooth muscle proliferation, and inflammation. On the contrary, it exerts beneficial effects by reducing macrophage apoptosis, regulating lipid efflux, and increasing autophagy. In this review, we aim to provide a comprehensive summary of the role of HuR in the development of AS by examining its involvement in cellular mechanisms, inflammation, autophagy, and apoptosis. Additionally, we discuss the mechanisms of drugs that target HuR, with the goal of offering new perspectives for the treatment of AS.

TRIM65 promotes vascular smooth muscle cell phenotypic transformation by activating PI3K/Akt/mTOR signaling during atherogenesis.

BACKGROUND AND AIMS: Tripartite motif (TRIM65) is an important member of the TRIM protein family, which is a newly discovered E3 ligase that interacts with and ubiquitinates various substrates and is involved in diverse pathological processes. However, the function of TRIM65 in atherosclerosis remains unarticulated. In this study, we investigated the role of TRIM65 in the pathogenesis of atherosclerosis, specifically in vascular smooth muscle cells (VSMCs) phenotype transformation, which plays a crucial role in formation of atherosclerotic lesions. METHODS AND RESULTS: Both non-atherosclerotic and atherosclerotic lesions during autopsy were collected singly or pairwise from each individual (n = 16) to investigate the relationship between TRIM65 and the development of atherosclerosis. In vivo, Western diet-fed ApoE-/- mice overexpressing or lacking TRIM65 were used to assess the physiological function of TRIM65 on VSMCs phenotype, proliferation and atherosclerotic lesion formation. In vitro, VSMCs phenotypic transformation was induced by platelet-derived growth factor-BB (PDGF-BB). TRIM65-overexpressing or TRIM65-abrogated primary mouse aortic smooth muscle cells (MOASMCs) and human aortic smooth muscle cells (HASMCs) were used to investigate the mechanisms underlying the progression of VSMCs phenotypic transformation, proliferation and migration. Increased TRIM65 expression was detected in α-SMA-positive cells in the medial and atherosclerotic lesions of autopsy specimens. TRIM65 overexpression increased, whereas genetic knockdown of TRIM65 remarkably inhibited, atherosclerotic plaque development. Mechanistically, TRIM65 overexpression activated PI3K/Akt/mTOR signaling, resulting in the loss of the VSMCs contractile phenotype, including calponin, α-SMA, and SM22α, as well as cell proliferation and migration. However, opposite phenomena were observed when TRIM65 was deficient in vivo or in vitro. Moreover, in cultured PDGF-BB-induced TRIM65-overexpressing VSMCs, inhibition of PI3K by treatment with the inhibitor LY-294002 for 24 h markedly attenuated PI3K/Akt/mTOR activation, regained the VSMCs contractile phenotype, and blocked the progression of cell proliferation and migration. CONCLUSIONS: TRIM65 overexpression enhances atherosclerosis development by promoting phenotypic transformation of VSMCs from contractile to synthetic state through activation of the PI3K/Akt/mTOR signal pathway.

Mapping and ablation of ventricular arrhythmias arising from the left ventricular summit.

The left ventricular summit (LVS) refers to the highest portion of the left ventricular outflow tract (LVOT). It is an epicardially delimited triangular area by the left coronary arteries and the coronary venous circulation. Its deep myocardium correlates closely with the left coronary cusp, aortic-mitral continuity, and right ventricular outflow tract (RVOT), complicating the anatomical relationship. Ventricular arrhythmias (VAs) originating from this area are common, accounting for 14.5% of all VAs origin from left ventricle. Specific electrocardiogram (ECG) characteristics may assist in locating LVS-VAs pre-procedure and facilitate procedure planning. However, catheter ablation of LVS-VAs remains challenging because of anatomical constraints. This paper reviews the recent understanding of LVS anatomy, concludes ECG characteristics, and summarizes current mapping and ablation methods for LVS-VAs.

Intracellular Protein Adsorption Behavior and Biological Effects of Polystyrene Nanoplastics in THP-1 Cells.

Micro(nano)plastics (MNPs) are emerging pollutants that can adsorb pollutants in the environment and biological molecules and ultimately affect human health. However, the aspects of adsorption of intracellular proteins onto MNPs and its biological effects in cells have not been investigated to date. The present study revealed that 100 nm polystyrene nanoplastics (NPs) could be internalized by THP-1 cells and specifically adsorbed intracellular proteins. In total, 773 proteins adsorbed onto NPs with high reliability were identified using the proteomics approach and analyzed via bioinformatics to predict the route and distribution of NPs following cellular internalization. The representative proteins identified via the Kyoto Encyclopedia of Genes and Genomes pathway analysis were further investigated to characterize protein adsorption onto NPs and its biological effects. The analysis revealed that NPs affect glycolysis through pyruvate kinase M (PKM) adsorption, trigger the unfolded protein response through the adsorption of ribophorin 1 (RPN1) and heat shock 70 protein 8 (HSPA8), and are chiefly internalized into cells through clathrin-mediated endocytosis with concomitant clathrin heavy chain (CLTC) adsorption. Therefore, this work provides new insights and research strategies for the study of the biological effects caused by NPs.

LncRNA-mediated Modulation of Endothelial Cells: Novel Progress in the Pathogenesis of Coronary Atherosclerotic Disease.

Coronary atherosclerotic disease (CAD) is a common cardiovascular disease and an important cause of death. Moreover, endothelial cells (ECs) injury is an early pathophysiological feature of CAD, and long noncoding RNAs (lncRNAs) can modulate gene expression. Recent studies have shown that lncRNAs are involved in the pathogenesis of CAD, especially by regulating ECs. In this review, we summarize the novel progress of lncRNA-modulated ECs in the pathogenesis of CAD, including ECs proliferation, migration, adhesion, angiogenesis, inflammation, apoptosis, autophagy, and pyroptosis. Thus, as lncRNAs regulate ECs in CAD, lncRNAs will provide ideal and novel targets for the diagnosis and drug therapy of CAD.

Determination of Enantiomeric Excess by Optofluidic Microlaser near Exceptional Point.

Enantiomeric excess (ee) is an essential indicator of chiral drug purification in the pharmaceutical industry. However, to date the ee determination of unknown concentration enantiomers generally involves two separate techniques for chirality and concentration measurement. Here, a whispering-gallery mode (WGM) based optofluidic microlaser near exceptional point to achieve the ee determination under unknown concentration with a single technique is proposed. Exceptional point induces the unidirectional WGM lasing, providing the optofluidic microlaser with the novel capability to measure chirality by polarization, in addition to wavelength-based concentration detection. The dual-parameters detection of optofluidic microlaser empowers it to achieve ee determination of various unknown enantiomers without additional concentration measurements, a feat that is challenging to accomplish with other methods. Featuring the sensitivity enhancement and miniature structure of the WGM sensors, the obtained chiroptical response of the present approach is ≈30-fold higher than that of the conventional optical rotation-based polarimeter, and the reagent consumption is reduced by three orders of magnitude.

Spatiotemporal evolution trend and decoupling type identification of transport carbon emissions from economic development in China.

Carbon emissions are a major concern in China, and transportation is an important part of it. In this paper, data on China's 30 provinces' transport carbon emissions from 2005 to 2019 were selected to construct a spatial autocorrelation model and identified the decoupling types, which revealed the relationship between transport carbon emissions and economic development. This study suggests a regulation strategy for provincial transport carbon emissions in China based on the contribution rates of transport carbon emission variables. According to the findings, transport carbon emissions of China indicated a slow rise from 2005 to 2019, the annual growth rate has fluctuated downward, and petroleum products have been the most major source. The geographical correlation of transport carbon emissions has gradually improved, and the transport carbon emission intensity has become more significant. Differences in the transport carbon emission intensity slightly increased, which were significantly regionally correlated. There were seven forms of decoupling between yearly provincial transport carbon emissions and economic development, with weak decoupling accounting for the largest proportion, 45.24%. Decoupling was achieved in 83.33% of the provinces in the period of 2005-2019. As a consequence of factor decomposition, the energy intensity, transport intensity, and economic structure played an overall inhibitory role, while the carbon emission intensity, economic scale, and population played promoting roles. The economic scale was the most important influencing factor.

Transcriptomic Analysis of THP-1 Cells Exposed by Monosodium Urate Reveals Key Genes Involved in Gout.

BACKGROUND: Gout is a common inflammatory arthritis, which is mainly caused by the deposition of monosodium urate (MSU) in tissues. Transcriptomics was used to explore the pathogenesis and treatment of gout in our work. OBJECTIVE: The objective of the study was to analyze and validate potential therapeutic targets and biomarkers in THP-1 cells that were exposed to MSU. METHODS: THP-1 cells were exposed to MSU. The inflammatory effect was characterized, and RNA-Seq analysis was then carried out. The differential genes obtained by RNA-Seq were analyzed with gene expression omnibus (GEO) series 160170 (GSE160170) gout-related clinical samples in the GEO database and gout-related genes in the GeneCards database. From the three analysis approaches, the genes with significant differences were verified by the differential genes' transcription levels. The interaction relationship of long non-coding RNA (lncRNA) was proposed by ceRNA network analysis. RESULTS: MSU significantly promoted the release of IL-1ß and IL-18 in THP-1 cells, which aggravated their inflammatory effect. Through RNA-Seq, 698 differential genes were obtained, including 606 differential mRNA and 92 differential `LncRNA. Cross-analysis of the RNA-Seq differential genes, the GSE160170 differential genes, and the gout-related genes in GeneCards revealed a total of 17 genes coexisting in the tripartite data. Furthermore, seven differential genes-C-X-C motif chemokine ligand 8 (CXCL8), C-X-C motif chemokine ligand 2 (CXCL2), tumor necrosis factor (TNF), C-C motif chemokine ligand 3 (CCL3), suppressor of cytokine signaling 3 (SOCS3), oncostatin M (OSM), and MIR22 host gene (MIR22HG)-were verified as key genes that analyzed the weight of genes in pathways, the enrichment of inflammationrelated pathways, and protein-protein interaction (PPI)nodes combined with the expression of genes in RNA-Seq and GSE160170. It is suggested that MIR22HG may regulate OSM and SOCS3 through microRNA 4271 (miR-4271), OSM, and SOCS3m; CCL3 through microRNA 149-3p (miR-149-3p); and CXCL2 through microRNA 4652-3p (miR-4652-3p). CONCLUSION: The potential of CXCL8, CXCL2, TNF, CCL3, SOCS3, and OSM as gout biomarkers and MIR22HG as a therapeutic target for gout are proposed, which provide new insights into the mechanisms of gout biomarkers and therapeutic methods.

TRIM65 Suppresses oxLDL-induced Endothelial Inflammation by Interaction with VCAM-1 in Atherogenesis.

BACKGROUND AND OBJECTIVE: Endothelial cell activation, characterized by increased levels of vascular cell adhesion molecule 1 (VCAM-1), plays a crucial role in the development of atherosclerosis (AS). Therefore, inhibition of VCAM-1-mediated inflammatory response is of great significance in the prevention and treatment of AS. The tripartite motif (TRIM) protein-TRIM65 is involved in the regulation of cancer development, antivirals and inflammation. We aimed to study the functions of TRIM65 in regulating endothelial inflammation by interacting with VCAM-1 in atherogenesis. METHODS AND RESULTS: In vitro, we report that human umbilical vein endothelial cells (HUVECs) treated with oxidized low-density lipoprotein (oxLDL) significantly upregulate the expression of TRIM65 in a time- and dose-dependent manner. Overexpression of TRIM65 reduces oxLDL-triggered VCAM-1 protein expression, decreases monocyte adhesion to HUVECs and inhibits the production of the inflammatory cytokines IL-1ß, IL-6, IL-8, and TNF-α as well as endothelial oxLDL transcytosis. In contrast, siRNA-mediated knockdown of TRIM65 promotes the expression of VCAM-1, resulting in increased adhesion of monocytes and the release of the inflammatory cytokines IL-1ß, IL-6, IL-8, and TNF-α and enhances endothelial oxLDL transcytosis. In vivo, we measured the high expression of TRIM65 in ApoE-/- mouse aortic plaques compared to C57BL/6J mouse aortic plaques. Then, we examined whether the blood levels of VCAM-1 were higher in TRIM65 knockout ApoE-/- mice than in control mice induced by a Western diet. Furthermore, Western blot results showed that the protein expression of VCAM-1 was markedly enhanced in TRIM65 knockout ApoE-/- mouse aortic tissues compared to that of the controls. Immunofluorescence staining revealed that the expression of VCAM-1 was significantly increased in atherosclerotic plaques of TRIM65-/-/ApoE-/- aortic vessels compared to ApoE-/- controls. Mechanistically, TRIM65 specifically interacts with VCAM-1 and targets it for K48-linked ubiquitination. CONCLUSION: Our studies indicate that TRIM65 attenuates the endothelial inflammatory response by targeting VCAM-1 for ubiquitination and provides a potential therapeutic target for the inhibition of endothelial inflammation in AS.

Shear Performance of Epoxy Joints in a Precast Bridge Deck Considering Constraint Effects.

The joint form plays a vital role in the rapid assembly of precast bridge decks for steel-concrete composite bridges. Existing research primarily focuses on studying the shear performance of joints through direct shear tests, which is insufficient to fully reflect the mechanical behavior of joints under the constraint of prefabricated bridge deck panels during actual vehicular traffic. Considering situations such as vehicle loads and external forces acting on precast bridge decks, this study investigates the shear performance of epoxy joints under constraint through an improved shear test. The influence of constraint force, shear key details and interface defects on the shear performance of epoxy joints is investigated. The results reveal that the shear test method employed in this study can realistically reflect the shear performance of epoxy joints in precast bridge decks. Both active and passive constrained epoxy joint specimens exhibited no interface cracks, and their failure modes were identified as shear failure between mid-span supports. Compared with passive constraint, the shear-bearing capacity of epoxy joint specimens under active constraint was increased by 86.1~130.6%. Among the epoxy joint specimens with depth-height ratios of 15/110, 25/110, 35/110 and 45/110, the joint with a depth of 35 mm demonstrated the highest shear strength. Furthermore, the shear performance of epoxy joints significantly deteriorated when the interface defects exceeded 30%, resulting in the failure mode transforming from shear failure to interface failure.

HPV18 E6 inhibits α-ketoglutarate-induced pyroptosis of esophageal squamous cell carcinoma cells via the P53/MDH1/ROS/GSDMC pathway.

Oncogene E6 plays a critical role in the development and progression of esophageal cancer caused by human papillomavirus (HPV) infection. Alpha-ketoglutarate (AKG) is a key metabolite in the tricarboxylic acid cycle and has been widely used as a dietary and anti-ageing supplement. In this study, we found that treating esophageal squamous carcinoma cells with a high dose of AKG can induce cell pyroptosis. Furthermore, our research confirms that HPV18 E6 inhibits AKG-induced pyroptosis of esophageal squamous carcinoma cells by lowering P53 expression. P53 downregulates malate dehydrogenase 1 (MDH1) expression; however, MDH1 downregulates L-2-hydroxyglutarate (L-2HG) expression, which inhibits a rise in reactive oxygen species (ROS) levels-as L-2HG is responsible for excessive ROS. This study reveals the actuating mechanism behind cell pyroptosis of esophageal squamous carcinoma cells induced by high concentrations of AKG, and we posit the molecular pathway via which the HPV E6 oncoprotein inhibits cell pyroptosis.

Enhanced electrochemical CO2 reduction performance of cobalt phthalocyanine with precise regulation of electronic states.

Herein, we report a facile strategy for constructing hybrid coordination configurations by combining functionalized graphene quantum dots (GQDs) with CoPc (CoPc/R-GQDs, with R being -NH2 or -OH) for electrochemical CO2 reduction. Benefiting from the high density of functional groups that can be provided by GQDs and the strong electron-donating property of -NH2, the examined CoPc/NH2-GQDs achieved a 100% faradaic efficiency for CO formation (FECO) at -0.8 to -0.9 V vs. RHE, and high FECO (over 90%) over a wide potential range of 500 mV. This work has presented a novel approach for catalyst design, specifically involving molecular engineering of quantum dots, which can also be applied to other essential electrochemical reactions.

Tuning the Hydroxyl Density of MXene to Regulate the Electrochemical Performance of Anchored Cobalt Phthalocyanine for CO2 Reduction.

Precise electronic state regulation through coordination environment optimization by metal-support interaction is a promising strategy to facilitate catalysis reaction, while the limited density of functional groups in the bulk substrate restricts the regulation degree. Herein, different sizes of Ti3C2Tx MXene with hydroxyl (-OH) terminal including the MXene layer (ML-OH, 3 µm), the MXene nanosheet (MNS-OH, 600 nm), and the MXene quantum dot (MQD-OH, 8 nm) were prepared to anchor CoPc, and the effect of -OH density on the performance of electrochemical CO2 reduction was systematically investigated. Notably, a linear relationship was established by plotting reactivity vs hydroxyl density. With the highest -OH density, CoPc/MQD-OH exhibits a superior Faradaic efficiency for CO formation (FECO) of ∼100% at -0.9 to -1.0 V vs RHE and a high FECO of >90% over a wide potential window from -0.8 to -1.4 V. The mechanism exploration shows that the axial coordination interaction of the -OH terminal with Co increases the electron density of the Co site, thus promoting the adsorption and activation of CO2. This work provides a new insight into designing of molecular catalysts with high efficiency and tunable structure for other electrochemical conversions.

1-Methyl-4-R-1,2,4-triazolium (R = -CH2CH2OCH3, -CH2COOCH2CH3)-Based Ionic Liquids as Plasticizers for Solid Propellants.

In this paper, a series of energetic ionic liquid plasticizers of 1-methyl-4-methoxyethyl-1,2,4-triazolium chloride (1), 1-methyl-4-methoxyethyl-1,2,4-triazolium bis(trifluoromethylsulfonyl)imide (1a), 1-methyl-4-methoxyethyl-1,2,4-triazolium nitrate (1b), 1-methyl-4-ethyl acetate-1,2,4-triazolium chloride (2), 1-methyl-4-ethyl acetate-1,2,4-triazolium bis(trifluoromethylsulfonyl)imide (2a), and 1-methyl-4-ethyl acetate-1,2,4-triazolium nitrate (2b) were synthesized and characterized. The results show that compounds 1a, 1b, 2a, and 2b have lower melting points (Tm, -72.60 to -32.67 °C) and good thermal stability (Td, 161-348 °C) and are suitable as plasticizers for hydroxyl-terminated polybutadiene (HTPB) curing systems. Among these four ionic liquids, ester-functionalized cations can help to improve the tensile strength (2a, 0.943 MPa; 2b, 1.113 MPa) of the cured system, while ether-functionalized cations are more beneficial to improve elongation at break (1a, 522.90%; 1b, 484.45%). Ester-functionalized ionic liquids are more beneficial to reduce the glass transition temperature of HTPB elastomers. The storage modulus of HTPB elastomers containing NO3- is higher, while that of HTPB elastomers containing NTf2- is lower. The crosslink densities of HTPB/TDI/2a and HTPB/TDI/2b plasticized by ester-functionalized ionic liquids are larger, which are 9369 and 9616 mol/m3, respectively. There are hydrogen bond interactions between the ionic liquid and the HTPB elastomer, and these interactions changed the distribution of the hard and soft segments in the polymer molecules.

Bioinformatics Analysis and Verification of Metabolic Abnormalities in Esophageal Squamous Carcinoma.

BACKGROUND: Although esophageal carcinoma (EC) is one of the most common cancers in the world, details of its pathogenesis remain unclear. Metabolic reprogramming is a main feature of EC. Mitochondrial dysfunction, especially the decrease in mitochondrial complex I (MTCI), plays an important role in the occurrence and development of EC. OBJECTIVE: The objective of the study was to analyze and validate the metabolic abnormalities and the role of MTCI in esophageal squamous cell carcinoma. METHODS: In this work, we collected transcriptomic data from 160 esophageal squamous carcinoma samples and 11 normal tissue samples from The Cancer Genome Atlas (TCGA). The OmicsBean and GEPIA2 were used to conduct an analysis of differential gene expression and survival in clinical samples. Rotenone was used to inhibit the MTCI activity. Subsequently, we detected lactate production, glucose uptake, and ATP production. RESULTS: A total of 1710 genes were identified as being significantly differentially expressed. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis suggested that these differentially expressed genes (DEGs) were significantly enriched in various pathways related to carcinoma tumorigenesis and progression. Moreover, we further identified abnormalities in metabolic pathways, in particular, the significantly low expression of multiple subunits of MTCI genes (ND1, ND2, ND3, ND4, ND4L, ND5, and ND6). Rotenone was used to inhibit the MTCI activity of EC109 cells, and it was found that the decrease in MTCI activity promoted HIF1A expression, glucose consumption, lactate production, ATP production, and cell migration. CONCLUSION: Our results indicated the occurrence of abnormal metabolism involving decreased mitochondrial complex I activity and increased glycolysis in esophageal squamous cell carcinoma (ESCC), which might be related to its development and degree of malignancy.

Trim65 attenuates isoproterenol-induced cardiac hypertrophy by promoting autophagy and ameliorating mitochondrial dysfunction via the Jak1/Stat1 signaling pathway.

Pathological cardiac hypertrophy is a major cause of heart failure, and there is no effective approach for its prevention or treatment. The Trim family is a recently identified family of E3 ubiquitin ligases that regulate cardiac hypertrophy. Trim65, which is a member of the Trim family, previous studies have not determined whether Trim65 affects cardiac hypertrophy. In this study, the effects of Trim65 on isoproterenol (ISO)-induced cardiac hypertrophy and the underlying mechanisms were investigated. In contrast to C57BL/6 mice, Trim65-knockout (Trim65-KO) mice developed more severe myocardial hypertrophy, fibrosis and cardiac dysfunction after being intraperitoneally injected with ISO for 2 weeks. Transmission electron microscopy (TEM) revealed that the autophagic flux was inhibited, mitochondria were swollen, and mitochondrial cristae were lost or decreased in the myocardium of Trim65-KO mice. In vitro studies demonstrated that overexpression of Trim65 inhibited ISO-induced cardiomyocyte hypertrophy by increasing mitochondrial density and membrane potential, and the Stat1 inhibitor fludarabine attenuated the effect of Trim65 knockdown on ISO-induced cardiomyocyte hypertrophy by reducing Reactive oxygen species (ROS) production and increasing the mitochondrial density and membrane potential. Our findings provide the first link between Trim65 and mitochondria, and we found for the first time that Trim65 inhibits mitochondria-dependent apoptosis and autophagy via the Jak1/Stat1 signalling pathway, ultimately attenuating ISO-induced cardiac hypertrophy; this effect of Trim65 might be mediated via the regulation of Jak1 ubiquitination. Taking these findings together, we suggest that genes that are related to mitochondria-dependent apoptosis and that are associated with Trim65 could be promising therapeutic targets for cardiac hypertrophy.

Biological functions of CRTC2 and its role in metabolism-related diseases.

CREB-regulated transcription coactivator2 (CRTC2 or TORC2) is a transcriptional coactivator of CREB(cAMP response element binding protein), which affects human energy metabolism through cyclic adenosine phosphate pathway, Mammalian target of rapamycin (mTOR) pathway, Sterol regulatory element binding protein 1(SREBP1), Sterol regulatory element binding protein 2 (SREBP2) and other substances Current studies on CRTC2 mainly focus on glucose and lipid metabolism, relevant studies show that CRTC2 can participate in the occurrence and development of related diseases by affecting metabolic homeostasis. It has been found that Crtc2 acts as a signaling regulator for cAMP and Ca2 + signaling pathways in many cell types, and phosphorylation at ser171 and ser275 can regulate downstream biological functions by controlling CRTC2 shuttling between cytoplasm and nucleus.