N6-methyladenosine-modified circPLPP4 sustains cisplatin resistance in ovarian cancer cells via PIK3R1 upregulation.

BACKGROUND: Cisplatin (CDDP) is the first-line chemotherapeutic strategy to treat patients with ovarian cancer (OC). The development of CDDP resistance remains an unsurmountable obstacle in OC treatment and frequently induces tumor recurrence. Circular RNAs (circRNAs) are noncoding RNAs with important functions in cancer progression. Whether circRNAs function in CDDP resistance of OC is unclear. METHODS: Platinum-resistant circRNAs were screened via circRNA deep sequencing and examined using in situ hybridization (ISH) in OC. The role of circPLPP4 in CDDP resistance was assessed by clone formation and Annexin V assays in vitro, and by OC patient-derived xenografts and intraperitoneal tumor models in vivo. The mechanism underlying circPLPP4-mediated activation of miR-136/PIK3R1 signaling was examined by luciferase reporter assay, RNA pull-down, RIP, MeRIP and ISH. RESULTS: circPLPP4 was remarkably upregulated in platinum resistant OC. circPLPP4 overexpression significantly enhanced, whereas circPLPP4 silencing reduced, OC cell chemoresistance. Mechanistically, circPLPP4 acts as a microRNA sponge to sequester miR-136, thus competitively upregulating PIK3R1 expression and conferring CDDP resistance. The increased circPLPP4 level in CDDP-resistant cells was caused by increased RNA stability, mediated by increased N6-methyladenosine (m6A) modification of circPLPP4. In vivo delivery of an antisense oligonucleotide targeting circPLPP4 significantly enhanced CDDP efficacy in a tumor model. CONCLUSIONS: Our study reveals a plausible mechanism by which the m6A -induced circPLPP4/ miR-136/ PIK3R1 axis mediated CDDP resistance in OC, suggesting that circPLPP4 may serve as a promising therapeutic target against CDDP resistant OC. A circPLPP4-targeted drug in combination with CDDP might represent a rational regimen in OC.

The c-MYC-WDR43 signalling axis promotes chemoresistance and tumour growth in colorectal cancer by inhibiting p53 activity.

Oxaliplatin chemoresistance is a major challenge in the clinical treatment of colorectal cancer (CRC), which is one of the most common malignancies worldwide. In this study, we identified the tryptophan-aspartate repeat domain 43 (WDR43) as a potentially critical oncogenic factor in CRC pathogenesis through bioinformatics analysis. It was found that WDR43 is highly expressed in CRC tissues, and WDR43 overexpression is associated with poor prognosis of CRC patients. WDR43 knockdown significantly inhibits cell growth by arresting cell cycle and enhancing the effect of oxaliplatin chemotherapy both in vitro and in vivo. Mechanistically, upon oxaliplatin stimulation, c-MYC promotes the transcriptional regulation and expression of WDR43. WDR43 enhances the ubiquitination of p53 by MDM2 through binding to RPL11, thereby reducing the stability of the p53 protein, which induces proliferation and chemoresistance of CRC cells. Thus, the overexpression of WDR43 promotes CRC progression, and could be a potential therapeutic target of chemoresistance in CRC.

Liquid nitric oxide donor for adjuvant therapy of acute ischemic stroke via nasal administration.

OBJECTIVES: The aim of this study was to synthesize and characterize a novel NO donor, PEI-PO-NONOate, using propylene oxide and to investigate its biosafety and therapeutic efficacy via nasal administration in vitro and vivo. EXPERIMENTAL PROCEDURES: The PEI-PO-NONOate was synthesized based on polyethylenimine (PEI) with different molecular weights and characterized using Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR), and ultraviolet (UV) spectroscopy. Cytotoxicity assays were performed on mouse fibroblast cells L929 and human nasal mucosa epithelial cells (HNEpC), and a rat middle cerebral artery occlusion (MCAO) model was established to evaluate the therapeutic efficacy of PEI-PO-NONOate via nasal administration. RESULTS: The PEI-PO-NONOate was found to be stable under dark, dry, and airproof conditions, and its release was accelerated in an aqueous phase or acidic environment, while it was slowed down in a polyethylene glycol (PEG) mixture system. The NO donor released approximately 0.4, 0.5, and 0.6 µmol of gaseous NO from 1.0 mg of the polymer based on PEI600, PEI1800, and PEI10K, respectively. Cytotoxicity assays showed that the PEI-PO-NONOates had a cryoprotective effect as compared with PEI and PEI-PO. Furthermore, nasal administration of PEI-PO-NONOates resulted in a significant reduction in overall necrotic ratio as compared with the control group (16.4% versus 24.6%, p < 0.05). CONCLUSION: The findings of this study suggest that PEI-PO-NONOates may have potential as an adjuvant therapy for acute ischemic stroke when administered via the nasal route.

Comparison of predictive performance for cage subsidence between CT-based Hounsfield units and MRI-based vertebral bone quality score following oblique lumbar interbody fusion.

OBJECTIVE: To compare the predictive performance between CT-based Hounsfield units (HU) and MRI-based vertebral bone quality (VBQ) for cage subsidence (CS) following oblique lumbar interbody fusion combined with anterolateral single-rod screw fixation (OLIF-AF). METHODS: A retrospective study was performed on consecutive patients who underwent OLIF-AF at our institution from 2018 to 2020. CS was determined by CT according to the change in the midpoint intervertebral space height. The VBQ score and HU value were measured from preoperative MRI and CT, respectively. Then, we evaluated the predictive performance of those two parameters by comparing the receiver operating characteristic (ROC) curves. RESULTS: The mean global and segmental VBQ scores were significantly higher in the CS group, and the mean global and segmental HU values were significantly lower in the CS group. The area under the curve (AUC) of CS prediction was higher in the operative segments' VBQ score and HU value than the measurement in the global lumbar spine. Finally, the combined segmental VBQ score and segmental HU value demonstrated the highest AUC. CONCLUSION: Both MRI-based VBQ score and CT-based HU value can achieve accurate CS prediction. Moreover, the combination of those two measurements indicated the best predictive performance. CLINICAL RELEVANCE STATEMENT: Both MRI-based VBQ score and CT-based HU value can be used for cage subsidence prediction, in order to take preventive measures early enough. KEY POINTS: • Osteoporosis is a risk factor for CS, both MRI-based VBQ score and CT-based HU value are important predictors during vertebral bone quality evaluation. • The VBQ score and HU value measured in the operative segments are better predictors of CS than the measurement in the global lumbar spine. • Combined segmental VBQ score and segmental HU value achieved the best predictive performance for CS.

IgG1 Is the Optimal Subtype for Treating Atherosclerosis by Inducing M2 Macrophage Differentiation, and Is Independent of the FcγRIIA Gene Polymorphism.

In recent years, it has been established that atherosclerosis is an autoimmune disease. However, little is currently known about the role of FcγRIIA in atherosclerosis. Herein, we sought to investigate the relationship between FcγRIIA genotypes and the effectiveness of different IgG subclasses in treating atherosclerosis. We constructed and produced different subtypes of IgG and Fc-engineered antibodies. In vitro, we observed the effect of different subtypes of IgG and Fc-engineered antibodies on the differentiation of CD14+ monocytes from patients or healthy individuals. In vivo, Apoe-/- mice were fed a high-fat diet (HFD) for 20 weeks and administered injections of different CVI-IgG subclasses or Fc-engineered antibodies. Flow cytometry was used to assess the polarization of monocytes and macrophages. Although CVI-IgG4 reduced the release of MCP-1 compared to the other subtypes, IgG4 did not yield an anti-inflammatory effect by induction of human monocyte and macrophage differentiation in vitro. Furthermore, genetic polymorphisms of FcγRIIA were not associated with different CVI-IgG subclasses during the treatment of atherosclerosis. In vivo, CVI-IgG1 decreased Ly6Chigh monocyte differentiation and promoted M2 macrophage polarization. We also found that the secretion of IL-10 was upregulated in the CVI-IgG1-treated group, whereas V11 and GAALIE exerted no significant effect. These findings highlight that IgG1 is the optimal subtype for treating atherosclerosis, and CVI-IgG1 can induce monocyte/macrophage polarization. Overall, these results have important implications for the development of therapeutic antibodies.

High AKAP8L expression predicts poor prognosis in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a severe disease with high mortality, and is associated with poor prognosis and frequent lymphatic metastasis. Therefore, prognostic indicators for ESCC are urgently needed. A-kinase anchor-protein 8-like (AKAP8L) is a member of the A kinase anchor-protein (AKAPs) family and is overexpressed in many cancers. However, the role of AKAP8L in ESCC remains unclear. The aim of this study is to investigate the expression patterns and prognostic value of AKAP8L in ESCC. METHODS: The mRNA expression of AKAP8L was analyzed from the dataset of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Immunohistochemistry was applied to detect the AKAP8L expression in tissue microarray. Pearson's chi-square test was carried out for the correlation analysis of clinicopathological features and AKAP8L expression. The prognostic significance of clinicopathological features and AKAP8L expression was determined by univariate and multivariate Cox hazard models. Kaplan-Meier survival curve was used for survival analysis. RESULTS: We found that the mRNA level of AKAP8L was higher in tumor tissues than in adjacent tissues in TCGA and GEO dataset. High AKAP8L expression was associated with poor overall survival (OS) in ESCC patients (p = 0.0039). Besides, AKAP8L expression was highly expressed in patients with lymph node metastasis detected by ESCC tissue microarray (p = 0.0014). The comparison of the different clinicopathological features of ESCC between high and low AKAP8L expression groups revealed that high AKAP8L expression was related to lymph node stage (p = 0.041). Kaplan-Meier survival analysis revealed that high AKAP8L expression indicates an unfavorable progression-free survival (PFS) and OS in ESCC patients (p < 0.0001). Univariate and multivariate analyses confirmed that AKAP8L was an independent prognostic factor for PFS and OS in ESCC (p = 0.003 and p < 0.0001). CONCLUSIONS: In conclusion, this study demonstrated that high expression of AKAP8L is associated with poor prognosis of ESCC and can be considered an independent risk factor for ESCC.

Computational fluid dynamics simulation of hemodynamic changes in a hemodialysis patient with central venous stenosis treated with stent.

BACKGROUND: It has not been demonstrated that computational fluid dynamics (CFD) can be used to model central venous stenosis (CVS), nor that hemodynamic changes in CVS treated with stent placement can be anticipated. The purpose of this study was to demonstrate the hemodynamic performance of CVS patients treated with stent placement. METHODS: Patient-specific geometric models were constructed using computed tomography images of veins from hemodialysis patients treated with stent placement. CFD simulation based on geometry was performed using ANSYS-15 to compare pressure quantitatively, wall shear stress (WSS), and flow velocity in the brachial vein before and after stent placement. RESULTS: Following a covered stent placement, the swelling of the left upper extremity was relieved. Prior to stent implantation, the maximum and mean brachial vein wall pressures were 465.2 Pa and 224.609 Pa, respectively. It was determined that the maximum WSS value was 8.449 Pa and that the mean WSS value was 0.743 Pa. The maximum and mean flow velocities were 1.16 and 0.173 m/s, respectively. After stent placement, the maximum wall pressure, maximum WSS, and maximum flow velocity dropped by 59.4%, 71.2%, and 57.8%, respectively. The mean wall pressure, mean WSS, and mean flow rate decreased by 43.5%, 52.7%, and 17.6%, respectively. CONCLUSION: Hemodynamics of CVS in hemodialysis patients exhibited turbulent, imbalances and disorders, which can be improved by stent placement.

Spontaneous facet joint fusion in patients following oblique lateral lumbar interbody fusion combined with lateral single screw-rod fixation: prevalence, characteristics and significance.

PURPOSE: To explore the characteristics of spontaneous facet joint fusion (SFJF) in patients after oblique lateral lumbar interbody fusion combined with lateral single screw-rod fixation (OLIF-LSRF). METHODS: We randomly selected 300 patients from 723 patients treated with OLIF-LSRF into a cross-sectional study based on the pilot study results. A novel fusion classification system was designed to evaluate the fusion status of the facet joints at three time points. Ultimately, the prevalence, characteristics, and significance of SFJF were analyzed. RESULTS: A total of 265 (333 levels) qualified cases were included in our study. The novel classification for SFJF has excellent reliability (kappa > 0.75). The rate of SFJF was 15.20% (45/296 levels) at 3 months postoperatively, 31.34% (89/284 levels) at 6 months postoperatively, and 33.63% (112/333 levels) at the last follow-up. The circumferential fusion rate was 31.53% (105/333 levels) at the last follow-up. The location of SFJF was mostly on the right facet joint (P < 0.001), and the rate of SFJF increased significantly from 3 to 6 months after the operation (P < 0.001). The average age of patients with SFJF was older than that of patients without SFJF (P < 0.001). There was no significant difference in Visual Analog Scale or Oswestry Disability Index scores between patients with and without SFJF. CONCLUSION: In the OLIF-LSRF procedure, SFJF occurs mostly at 3-6 months postoperatively, especially in elderly patients and at the right facet joint. OLIF-LSRF has the potential for circumferential fusion.

Stepwise reduction of bone mineral density increases the risk of cage subsidence in oblique lumbar interbody fusion patients biomechanically: an in-silico study.

BACKGROUND: Cage subsidence causes poor prognoses in patients treated by oblique lumbar interbody fusion (OLIF). Deterioration of the biomechanical environment initially triggers cage subsidence, and patients with low bone mineral density (BMD) suffer a higher risk of cage subsidence. However, whether low BMD increases the risk of cage subsidence by deteriorating the local biomechanical environment has not been clearly identified. METHODS: OLIF without additional fixation (stand-alone, S-A) and with different additional fixation devices (AFDs), including anterolateral single rod screws (ALSRs) and bilateral pedicle screws (BPSs) fixation, was simulated in the L4-L5 segment of a well-validated finite element model. The biomechanical effects of different BMDs were investigated by adjusting the material properties of bony structures. Biomechanical indicators related to cage subsidence were computed and recorded under different directional moments. RESULTS: Overall, low BMD triggers stress concentration in surgical segment, the highest equivalent stress can be observed in osteoporosis models under most loading conditions. Compared with the flexion-extension loading condition, this variation tendency was more pronounced under bending and rotation loading conditions. In addition, AFDs obviously reduced the stress concentration on both bony endplates and the OLIF cage, and the maximum stress on ALSRs was evidently higher than that on BPSs under almost all loading conditions. CONCLUSIONS: Stepwise reduction of BMD increases the risk of a poor local biomechanical environment in OLIF patients, and regular anti-osteoporosis therapy should be considered an effective method to biomechanically optimize the prognosis of OLIF patients.

The potential of microRNA-126 in predicting disease risk, mortality of sepsis, and its correlation with inflammation and sepsis severity.

BACKGROUND: MicroRNA-126 (miR-126) has been investigated in autoimmune diseases and organ failures, whereas its implication in sepsis is rarely reported. Our study initially explored the value of miR-126 in diagnosing sepsis and predicting disease severity, degree of inflammation, and mortality. METHODS: Totally, 208 sepsis patients and 210 healthy controls were enrolled; then, their plasma samples were collected for detecting circulating miR-126 by quantitative polymerase chain reaction. For sepsis patients, their cytokine levels in plasma samples were detected by enzyme-linked immunosorbent assay. RESULTS: miR-126 was upregulated in sepsis patients compared with healthy controls, and it was of certain value in distinguishing sepsis patients from healthy controls (AUC: 0.726 (95% CI: 0.678-0.774)). miR-126 expression was positively correlated with acute physiology and chronic health evaluation II score, serum creatinine, and C-reactive protein but not albumin or white blood cell count in sepsis patients. Regarding cytokines, miR-126 was positively correlated with tumor necrosis factor-α, interleukin (IL)-6, and IL-8, but negatively correlated with IL-10 in sepsis patients. As for mortality, miR-126 expression was higher in deaths compared with survivors, and ROC curve displayed that it could predict mortality of sepsis patients to some extent with AUC of 0.619 (95% CI: 0.533-0.705). CONCLUSION: miR-126 potentially serves as an assistant diagnostic and prognostic biomarker for sepsis.

Metal-free one-pot synthesis of 2-substituted and 2,3-disubstituted morpholines from aziridines.

The metal-free synthesis of 2-substituted and 2,3-disubstituted morpholines through a one-pot strategy is described. A simple and inexpensive ammonium persulfate salt enables the reaction of aziridines with halogenated alcohols to proceed via an SN2-type ring opening followed by cyclization of the resulting haloalkoxy amine.

Visible-light-induced bromoetherification of alkenols for the synthesis of ß-bromotetrahydrofurans and -tetrahydropyrans.

A visible-light-induced photoredox-catalyzed bromoetherification of alkenols is described. This approach, with CBr4 as the bromine source through generation of bromine in situ, provides a mild and operationally simple access to the synthesis of ß-bromotetrahydrofurans and -tetrahydropyrans with high efficiency and regioselectivity.

Ultrashort echo time (UTE) imaging of receptor targeted magnetic iron oxide nanoparticles in mouse tumor models.

PURPOSE: The purpose of this study was to investigate an ultrashort echo time (UTE) imaging approach for improving the detection of receptor targeted magnetic nanoparticles in cancer xenograft models using positive contrast. MATERIALS AND METHODS: Iron oxide nanoparticle (IONP) conjugated with tumor targeting ligands were prepared. A 3D UTE gradient echo sequence with the shortest TE of 0.07 msec was evaluated on a 3T magnetic resonance imaging (MRI) scanner using IONP solution, cancer cells bound with targeted IONPs and orthotopic human pancreatic, and breast cancer mouse models administered tumor targeting IONPs. A simulation was performed to analyze contrast-to-noise ratios (CNR) of UTE images and subtraction of the images obtained UTE and longer TE (SubUTE). T2-weighted imaging and T2 relaxometry mapping were applied for comparison and validation. RESULTS: UTE and SubUTE images showed positive contrast in pancreatic tumors accumulated with EGFR targeted ScFvEGFR-IONPs and mammary tumors accumulated with uPAR targeted ATF-IONPs. The positive contrast observed in UTE images was consistent with the negative contrast observed in the T2-weighted images. A flip angle of 10° and a maximal possible TE for the second echo are suitable for SubUTE imaging. CONCLUSION: UTE imaging is capable of detecting tumor targeted IONPs in vivo with positive contrast in molecular MRI applications.

Visible-light photoredox catalysis enabled bromination of phenols and alkenes.

A mild and efficient methodology for the bromination of phenols and alkenes has been developed utilizing visible light-induced photoredox catalysis. The bromine was generated in situ from the oxidation of Br(-) by Ru(bpy)3 (3+), both of which resulted from the oxidative quenching process.

Simultaneous antioxidant and neuroprotective effects of two-dimensional (2D) MXene-loaded isoquercetin for ischemic stroke treatment.

Oxidative stress and reactive oxygen species drive ischemic stroke and its related complications. New antioxidant medications are therefore crucial for treating ischemic stroke. We developed Ti2C@BSA-ISO nanocomposites loaded with the hydrophobic drug isoquercetin (ISO) encapsulated in BSA on Ti2C nano-enzymes as a novel therapeutic nanomedicine for the treatment of ischemic stroke targeting reactive oxygen species (ROS). TEM visually proved the successful preparation of Ti2C@BSA-ISO, and the FTIR, XPS, zeta potential and DLS together demonstrated the acquisition of Ti2C@BSA-ISO. In addition, the enzyme-mimicking activity of Ti2C was evaluated and the antioxidant capacity of Ti2C@BSA-ISO was verified. Ti2C@BSA-ISO was able to reverse the decrease in cellular activity caused by ROS. Experiments in vivo showed that Ti2C@BSA-ISO could promote neuroprotection and scavenging of ROS in the hippocampal CA1 area and cerebral cortex of rats, thereby inhibiting cellular death and alleviating ischaemic stroke. Specifically, Ti2C@BSA-ISO alleviated ischemic stroke by inhibiting NLRP3/caspase-1/GSDMD pathway-mediated pyroptosis. Our study demonstrates the effectiveness of nanomedicines that can be directly used as drugs for the treatment of ischemic stroke in synergy with other drugs, which greatly expands the application of nanomaterials in the treatment of ischemic stroke.

Acupressure: a possible therapeutic strategy for anxiety related to COVID-19: a meta-analysis of randomized controlled trials.

Background: From the end of 2019 to December 2023, the world grappled with the COVID-19 pandemic. The scope and ultimate repercussions of the pandemic on global health and well-being remained uncertain, ushering in a wave of fear, anxiety, and worry. This resulted in many individuals succumbing to fear and despair. Acupoint massage emerged as a safe and effective alternative therapy for anxiety relief. However, its efficacy was yet to be extensively backed by evidence-based medicine. This study aimed to enhance the clinical effectiveness of acupoint massage and extend its benefits to a wider population. It undertakes a systematic review of the existing randomized controlled trials (RCTs) assessing the impact of acupoint massage on anxiety treatment, discussing its potential benefits and implications. This research aims to furnish robust evidence supporting anxiety treatment strategies for patients afflicted with COVID-19 disease and spark new approaches to anxiety management. Objectives: This study evaluates the evidence derived from randomised controlled trials (RCTs), quantifies the impact of acupressure on anxiety manifestations within the general population, and proposes viable supplementary intervention strategies for managing COVID-19 related anxiety. Materials and methods: This review included RCTs published between February 2014 and July 2023, that compared the effects of acupressure with sham control in alleviating anxiety symptomatology as the outcome measure. The studies were sourced from the multiple databases, including CINAHL, EBM Reviews, Embase, Medline, PsycINFO, Scopus and Web of Science. A meta-analysis was performed on the eligible studies, and an overall effect size was computed specifically for the anxiety outcome. The Cochrane Collaboration Bias Risk Assessment Tool (RevMan V5.4) was employed to assess bias risk, data integration, meta-analysis, and subgroup analysis. The mean difference, standard mean deviation, and binary data were used to represent continuous outcomes. Results: Of 1,110 studies of potential relevance, 39 met the criteria for inclusion in the meta-analysis. The majority of the studies reported a positive effect of acupressure in assuaging anticipatory anxiety about treatment. Eighteen studies were evaluated using the STAI scale. The acupressure procedures were thoroughly documented, and studies exhibited a low risk of bias. The cumulative results of the 18 trials showcased a more substantial reduction in anxiety in the acupressure group compared to controls (SMD = -5.39, 95% CI -5.61 to -5.17, p < 0.01). A subsequent subgroup analysis, based on different interventions in the control group, demonstrated improvement in anxiety levels with sham acupressure in improving changes in anxiety levels (SMD -1.61, 95% CI: -2.34 to -0.87, p < 0.0001), and blank controls (SMD -0.92, 95% CI: -2.37 to 0.53, p = 0.22). Conclusion: In the clinical research of traditional Chinese medicine treatment of anxiety, acupressure demonstrated effectiveness in providing instant relief from anxiety related to multiple diseases with a medium effect size. Considering the increasing incidence of anxiety caused by long COVID, the widespread application of acupressure appears feasible. However, the results were inconsistent regarding improvements on physiological indicators, calling for more stringent reporting procedures, including allocation concealment, to solidify the findings.

Endoplasmic reticulum stress-related gene expression causes the progression of dilated cardiomyopathy by inducing apoptosis.

Background: Previous studies have shown that endoplasmic reticulum stress (ERS) -induced apoptosis is involved in the pathogenesis of dilated cardiomyopathy (DCM). However, the molecular mechanism involved has not been fully characterized. Results: In total, eight genes were obtained at the intersection of 1,068 differentially expressed genes (DEGs) from differential expression analysis between DCM and healthy control (HC) samples, 320 module genes from weighted gene co-expression network analysis (WGCNA), and 2,009 endoplasmic reticulum stress (ERGs). These eight genes were found to be associated with immunity and angiogenesis. Four of these genes were related to apoptosis. The upregulation of MX1 may represent an autocompensatory response to DCM caused by a virus that inhibits viral RNA and DNA synthesis, while acting as an autoimmune antigen and inducing apoptosis. The upregulation of TESPA1 would lead to the dysfunction of calcium release from the endoplasmic reticulum. The upregulation of THBS4 would affect macrophage differentiation and apoptosis, consistent with inflammation and fibrosis of cardiomyocytes in DCM. The downregulation of MYH6 would lead to dysfunction of the sarcomere, further explaining cardiac remodeling in DCM. Moreover, the expression of genes affecting the immune micro-environment was significantly altered, including TGF-ß family member. Analysis of the co-expression and competitive endogenous RNA (ceRNA) network identified XIST, which competitively binds seven target microRNAs (miRNAs) and regulates MX1 and THBS4 expression. Finally, bisphenol A and valproic acid were found to target MX1, MYH6, and THBS4. Conclusion: We have identified four ERS-related genes (MX1, MYH6, TESPA1, and THBS4) that are dysregulated in DCM and related to apoptosis. This finding should help deepen understanding of the role of endoplasmic reticulum stress-induced apoptosis in the development of DCM.

Potential molecular and cellular mechanisms of the effects of cuproptosis-related genes in the cardiomyocytes of patients with diabetic heart failure: a bioinformatics analysis.

Background: Diabetes mellitus is an independent risk factor for heart failure, and diabetes-induced heart failure severely affects patients' health and quality of life. Cuproptosis is a newly defined type of programmed cell death that is thought to be involved in the pathogenesis and progression of cardiovascular disease, but the molecular mechanisms involved are not well understood. Therefore, we aimed to identify biomarkers associated with cuproptosis in diabetes mellitus-associated heart failure and the potential pathological mechanisms in cardiomyocytes. Materials: Cuproptosis-associated genes were identified from the previous publication. The GSE26887 dataset was downloaded from the GEO database. Methods: The consistency clustering was performed according to the cuproptosis gene expression. Differentially expressed genes were identified using the limma package, key genes were identified using the weighted gene co-expression network analysis(WGCNA) method, and these were subjected to immune infiltration analysis, enrichment analysis, and prediction of the key associated transcription factors. Consistency clustering identified three cuproptosis clusters. The differentially expressed genes for each were identified using limma and the most critical MEantiquewhite4 module was obtained using WGCNA. We then evaluated the intersection of the MEantiquewhite4 output with the three clusters, and obtained the key genes. Results: There were four key genes: HSDL2, BCO2, CORIN, and SNORA80E. HSDL2, BCO2, and CORIN were negatively associated with multiple immune factors, while SNORA80E was positively associated, and T-cells accounted for a major proportion of this relationship with the immune system. Four enriched pathways were found to be associated: arachidonic acid metabolism, peroxisomes, fatty acid metabolism, and dorsoventral axis formation, which may be regulated by the transcription factor MECOM, through a change in protein structure. Conclusion: HSDL2, BCO2, CORIN, and SNORA80E may regulate cardiomyocyte cuproptosis in patients with diabetes mellitus-associated heart failure through effects on the immune system. The product of the cuproptosis-associated gene LOXL2 is probably involved in myocardial fibrosis in patients with diabetes, which leads to the development of cardiac insufficiency.

Electroacupuncture Enhances the Functional Connectivity of Limbic System to Neocortex in the 5xFAD Mouse Model of Alzheimer's Disease.

Our previous study revealed that acupuncture may exhibit therapeutic effects on Alzheimer's disease (AD) through the activation of metabolism in memory-related brain regions. However, the underlying functional mechanism remains poorly understood and warrants further investigation. In this study, we used resting-state functional magnetic resonance imaging (rsfMRI) to explore the potential effect of electroacupuncture (EA) on the 5xFAD mouse model of AD. We found that the EA group exhibited significant improvements in the number of platforms crossed and the time spent in the target quadrant when compared with the Model group (p < 0.05). The functional connectivity (FC) of left hippocampus (Hip) was enhanced significantly among 12 regions of interest (ROIs) in the EA group (p < 0.05). Based on the left Hip as the seed point, the rsfMRI analysis of the entire brain revealed increased FC between the limbic system and the neocortex in the 5xFAD mice after EA treatment. Additionally, the expression of amyloid-ß(Aß) protein and deposition in the Hip showed a downward trend in the EA group compared to the Model group (p < 0.05). In conclusion, our findings indicate that EA treatment can improve the learning and memory abilities and inhibit the expression of Aß protein and deposition of 5xFAD mice. This improvement may be attributed to the enhancement of the resting-state functional activity and connectivity within the limbic-neocortical neural circuit, which are crucial for cognition, motor function, as well as spatial learning and memory abilities in AD mice.

Single-cell RNA-Seq reveals CVI-mAb-induced Lyve1+ M2-like macrophages reduce atherosclerotic plaque area in Apoe-/- mice.

BACKGROUND: Atherosclerosis is a lipid imbalance-induced autoimmune disease. Macrophages participate in the development and progression of atherosclerosis. Although numerous studies have utilized single-cell RNA sequencing to identify the role of various macrophage phenotypes in atherosclerosis, the macrophage subpopulations that have therapeutic benefits against atherosclerosis are not fully understood. METHODS: In this study, a single-cell RNA sequencing analysis was performed on the F4/80+ macrophages of apolipoprotein E-deficient (Apoe-/-) mice on a normal diet (ND), a high-fat diet (HFD), and a high-fat diet (HFD) with collagen VI monoclonal antibodies (CVI-mAb) treatment. A population of M2-like macrophages expressing the hyaluronan receptor Lyve1 was almost exclusively detectable in Apoe-/- mice on an HFD with CVI-mAb treatment, compared with other groups. Differential gene expression and gene ontology enrichment analyses revealed specific gene expression patterns that distinguished this macrophage subset and uncovered its functions. RESULTS: Lyve1+ M2 macrophages appear to have specialized functions in lipid metabolism. Lyve1+ M2-like macrophages were sorted via fluorescence- activated cell sorting (FACS) and adoptively transferred to Apoe-/- mice fed an HFD. CONCLUSION: Our result showed that Lyve1+ M2 macrophages could reduce the plaque areas in Apoe-/- mice.