Erratum to "PGAM5-Mediated PHB2 Dephosphorylation Contributes to Diabetic Cardiomyopathy by Disrupting Mitochondrial Quality Surveillance".

[This corrects the article DOI: 10.34133/research.0001.].

Thymidine Phosphorylase Promotes the Formation of Abdominal Aortic Aneurysm in Mice Fed a Western Diet.

Aims: The precise molecular drivers of abdominal aortic aneurysm (AAA) remain unclear. Thymidine phosphorylase (TYMP) contributes to increased platelet activation, thrombosis, and inflammation, all of which are key factors in AAA development. Additionally, TYMP suppresses the proliferation of vascular smooth muscle cells (VSMCs), which are central to the development and progression of AAA. We hypothesize that TYMP plays a key role in AAA development. Methods and Results: We conducted a histological study using human AAA samples and normal abdominal aortas, revealing heightened levels of TYMP in human AAA vessel walls. To validate this observation, we utilized an Ang II perfusion-induced AAA model in wild-type C57BL/6J (WT) and Tymp-/- mice, feeding them a Western diet (TD.88137) starting from 4 weeks of age. We found that Tymp-/- mice were protected from Ang II perfusion-induced AAA formation. Furthermore, by using TYMP-expressing VSMCs as well as primarily cultured VSMCs from WT and Tymp-/- mice, we elucidated the essential role of TYMP in regulating MMP2 expression and activation. TYMP deficiency or inhibition by tipiracil, a selective TYMP inhibitor, led to reduced MMP2 production, release, and activation in VSMCs. Additionally, TYMP was found to promote pro-inflammatory cytokine expression systemically, and its absence attenuates TNF-α-stimulated activation of MMP2 and AKT. By co-culturing VSMCs and platelets, we observed that TYMP-deficient platelets had a reduced inhibitory effect on VSMC proliferation compared to WT platelets. Moreover, TYMP appeared to enhance the expression of activated TGFß1 in cultured VSMCs in vitro and in human AAA vessel walls in vivo. TYMP also boosted the activation of thrombospondin-1 type 1 repeat domain-enhanced TGFß1 signaling, resulting in increased connective tissue growth factor production. Conclusion: Our findings collectively demonstrated that TYMP serves as a novel regulatory force in vascular biology, exerting influence over VSMC functionality and inflammatory responses that promote the development of AAA.

Albumin and C-reactive protein as diagnostic markers for neonatal sepsis: a retrospective study.

OBJECTIVE: To assess the applicability of albumin (ALB) and C-reactive protein (CRP) concentrations in the diagnosis of sepsis in neonates on the day of admission, and to help with early identification and intervention in the development of sepsis. METHODS: This retrospective study included all neonates who were admitted to the neonatal intensive care unit from January 2020 to June 2023. We studied 160 full-term neonates, including 80 with sepsis and 80 healthy controls. A multivariate analysis was conducted to evaluate the associations between ALB, CRP, and sepsis. RESULTS: CRP concentrations were significantly higher in neonates with sepsis than in controls (26.5 ± 8.6 vs. 3.6 ± 1.2 ng/L). At a cut-off point of 10.8 ng/L, CRP showed a sensitivity of 74.3% and a specificity of 80%. Moreover, ALB concentrations were significantly lower in neonates with sepsis than in controls (25.4 ± 2.5 g/L vs. 29.2 ± 2.6 g/L). At a cut-off point of 26.8, ALB showed a sensitivity of 75.6% and a specificity of 84.2%. CONCLUSIONS: Our findings suggest that ALB and CRP concentrations on the first day of admission are different between neonates who do and those who do not develop sepsis. Higher CRP concentrations and lower ALB concentrations may indicate an increased risk of sepsis.

The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation.

Rationale: The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) promotes pathological mitochondrial fission during septic acute kidney injury. The mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) is a mitochondria-derived peptide that exhibits anti-inflammatory properties during cardiovascular illnesses. We explored whether endotoxemia-induced myocardial microvascular injury involved DNA-PKcs and MOTS-c dysregulation. Methods: To induce endotoxemia in vivo, endothelial cell-specific DNA-PKcs-knockout mice were injected intraperitoneally with a single dose of lipopolysaccharide (10 mg/kg) and evaluated after 72 h. Results: Lipopolysaccharide exposure increased DNA-PKcs activity in cardiac microvascular endothelial cells, while pharmacological inhibition or endothelial cell-specific genetic ablation of DNA-PKcs reduced lipopolysaccharide-induced myocardial microvascular dysfunction. Proteomic analyses showed that endothelial DNA-PKcs ablation primarily altered mitochondrial protein expression. Verification assays confirmed that DNA-PKcs drastically repressed MOTS-c transcription by inducing mtDNA breaks via pathological mitochondrial fission. Inhibiting MOTS-c neutralized the endothelial protective effects of DNA-PKcs ablation, whereas MOTS-c supplementation enhanced endothelial barrier function and myocardial microvascular homeostasis under lipopolysaccharide stress. In molecular studies, MOTS-c downregulation disinhibited c-Jun N-terminal kinase (JNK), allowing JNK to phosphorylate profilin-S173. Inhibiting JNK or transfecting cells with a profilin phosphorylation-defective mutant improved endothelial barrier function by preventing F-actin depolymerization and lamellipodial degradation following lipopolysaccharide treatment. Conclusions: DNA-PKcs inactivation during endotoxemia could be a worthwhile therapeutic strategy to restore MOTS-c expression, prevent JNK-induced profilin phosphorylation, improve F-actin polymerization, and enhance lamellipodial integrity, ultimately ameliorating endothelial barrier function and reducing myocardial microvascular injury.

Amphiregulin in lung diseases: A review.

Amphiregulin is a member of the EGFR family, which is involved in many physiological and pathological processes through its binding with EGFR. Studies have found that amphiregulin plays an important role in the occurrence and development of lung diseases. This paper mainly reviews the structure and function of amphiregulin and focuses on the important role of amphiregulin in lung diseases.

Cardiomyocyte-specific deletion of endothelin receptor A (ETA) obliterates cardiac aging through regulation of mitophagy and ferroptosis.

Advanced aging evokes unfavorable changes in the heart including cardiac remodeling and contractile dysfunction although the underlying mechanism remains elusive. This study was conducted to evaluate the role of endothelin-1 (ET-1) in the pathogenesis of cardiac aging and mechanism involved. Echocardiographic and cardiomyocyte mechanical properties were determined in young (5-6 mo) and aged (26-28 mo) wild-type (WT) and cardiomyocyte-specific ETA receptor knockout (ETAKO) mice. GSEA enrichment identified differentially expressed genes associated with mitochondrial respiration, mitochondrial protein processing and mitochondrial depolarization in cardiac aging. Aging elevated plasma levels of ET-1, Ang II and suppressed serum Fe2+, evoked cardiac remodeling (hypertrophy and interstitial fibrosis), contractile defects (fractional shortening, ejection fraction, cardiomyocyte peak shortening, maximal velocity of shortening/relengthening and prolonged relengthening) and intracellular Ca2+ mishandling (dampened intracellular Ca2+ release and prolonged decay), the effects with the exception of plasma AngII, ET-1 and Fe2+ were mitigated by ETAKO. Advanced age facilitated O2- production, carbonyl protein damage, cardiac hypertrophy (GATA4, ANP, NFATc3), ER stress, ferroptosis, compromised autophagy (LC3B, Beclin-1, Atg7, Atg5 and p62) and mitophagy (parkin and FUNDC1), and deranged intracellular Ca2+ proteins (SERCA2a and phospholamban), the effects of which were reversed by ETA ablation. ET-1 provoked ferroptosis in vitro, the response was nullified by the ETA receptor antagonist BQ123 and mitophagy inducer CsA. ETA but not ETB receptor antagonism reconciled cardiac aging, which was abrogated by inhibition of mitophagy and ferroptosis. These findings collectively denote promises of targeting ETA, mitophagy and ferroptosis in the management of aging-associated cardiac remodeling and contractile defect.

Risk factors associated with surgical site infections in patients undergoing cardiothoracic surgery: A systematic review and meta-analysis.

Surgical site infections (SSIs) following cardiothoracic surgery can pose significant challenges to patient recovery and outcome. This systematic review and meta-analysis aim to identify and quantify the risk factors associated with SSIs in patients undergoing cardiothoracic surgery. A comprehensive literature search adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and based on the PICO paradigm was conducted across four databases: PubMed, Embase, Web of Science and the Cochrane Library, without any temporal restrictions. The meta-analysis incorporated studies detailing the risk factors for post-operative sternal infections, especially those reporting odds ratios (OR) or relative risks with 95% confidence intervals (CI). Quality assessment of the studies was done using the Newcastle-Ottawa Scale. Statistical analysis was executed using the chi-square tests for inter-study heterogeneity, with further analyses depending on I2 values. Sensitivity analyses were performed, and potential publication bias was also assessed. An initial dataset of 2442 articles was refined to 21 articles after thorough evaluations based on inclusion and exclusion criteria. Patients with diabetes mellitus have an OR of 1.80 (95% CI: 1.40-2.20) for the incidence of SSIs, while obese patients demonstrate an OR of 1.63 (95% CI: 1.40-1.87). Individuals who undergo intraoperative blood transfusion present an OR of 1.13 (95% CI: 1.07-1.18), and smokers manifest an OR of 1.32 (95% CI: 1.03-1.60). These findings unequivocally indicate a pronounced association between these factors and an elevated risk of SSIs post-operatively. This meta-analysis confirms that diabetes, obesity, intraoperative transfusion and smoking heighten the risk of SSIs post-cardiac surgery. Clinicians should be alert to these factors to optimise patient outcomes.

Single-cell transcriptomics reveals zinc and copper ions homeostasis in epicardial adipose tissue of heart failure.

Epicardial adipose tissue (EAT) is a unique visceral fat reservoir that shares an immune microenvironment without a distinct boundary with myocardium. Increasingly, visceral fat has been studied as a secondary immune organ, and EAT is no exception in this regard. Cellular subsets of EAT are associated with disease development. In heart failure (HF) patients, however, the immune characteristics of EAT have rarely been studied, especially those non-immune cells related to the immune microenvironment. Herein, an analysis of seven EAT samples by single-cell RNA sequencing (scRNA-Seq) is presented here, including 1 neonate, 1 infant, 1 child, 2 adults with heart failure (Adults-HF) and 2 adult heart transplant donors as non-heart failure control (Adults-Non HF). Analysis of 51730 high-quality cells revealed eleven major cell types in EAT. For the first time, the pseudo-temporal reconstruction technique was employed to plot the cell trajectories of various major cell types (such as T lymphocytes, fibroblasts, endothelial cells, monocytes, and smooth muscle cells) in EAT across different developmental stages, achieving a single-cell resolution. The dynamic gene expression patterns of major cell types presented the immune characteristics of metabolism disorder of zinc and copper ions, and downregulated immune-related pathways in EAT of adult patients with HF. These data provide insights regarding HF immune dysregulation at the cellular level.

Mitochondrial aldehyde dehydrogenase rescues against diabetic cardiomyopathy through GSK3ß-mediated preservation of Mitochondrial integrity and parkin-mediated mitophagy.

Mitochondrial aldehyde dehydrogenase (ALDH2) offers proven cardiovascular benefit although its impact in diabetes remains elusive. This study examined the effect of ALDH2 overexpression (OE) and knockout (KO) on diabetic cardiomyopathy and mechanism involved with a focus on mitochondrial integrity. ALDH2 OE and KO mice were challenged with streptozotocin (STZ, 200 mg/kg. i.p.) to establish diabetes. Diabetic patients displayed reduced plasma ALDH2 activity, cardiac remodeling and diastolic dysfunction. STZ challenge prompted reduced respiratory exchange ratio (RER), dampened fractional shortening, ejection fraction, increased LV end systolic and diastolic diameters, cardiac remodeling, cardiomyocyte contractile and intracellular Ca2+ defects (depressed peak shortening and maximal velocity of shortening/relengthening, prolonged relengthening, dampened intracellular Ca2+ rise and clearance), myocardial ultrastructural injury, oxidative stress, apoptosis and mitochondrial damage, the effects of which were overtly attenuated and accentuated by ALDH2 OE and KO, respectively. Immunoblotting revealed downregulated mitochondrial proteins PPARγ coactivator 1α (PGC-1α) and UCP-2, Ca2+ regulatory proteins including SERCA and Na+-Ca2+ exchanger, elevated phospholamban, dampened autophagy and mitophagy (LC3B ratio, TOM20, Parkin, FUNDC1 and BNIP3), disrupted phosphorylation of Akt, GSK3ß and Foxo3a, and elevated PTEN phosphorylation, the effect of which was reversed and worsened by ALDH2 OE and KO, respectively (except FUNDC1 and BNIP3). In vivo and in vitro data revealed that novel ALDH2 activator torezolid/Alda-1 protected against STZ or high glucose-induced cardiac anomalies, the effect was nullified by inhibition of Akt, GSK3ß, Parkin and mitochondrial coupling. Our data discerned a vital role for ALDH2 in diabetic cardiomyopathy possibly through regulation of Akt, GSK3ß activation, parkin mitophagy and mitochondrial function.

MitraClip used for severe mitral regurgitation after surgery for type A aortic dissection combined with Marfan syndrome.

Mitral regurgitation is a rare but catastrophic condition in patients after surgery for type A aortic dissection. The second thoracotomy to complete the mitral valve operation could be fatal. Here, we report a case of severe mitral regurgitation treated with MitraClip in a 53-year-old woman after surgery for type A aortic dissection combined with Marfan syndrome. She was discharged uneventfully, and a significant reduction of regurgitation of mitral valve and tricuspid valve was observed at the 6-month follow-up. MitraClip could be an alternative device for such high-risk patients.

Effect of Low Tube Voltage (100 kV) Combined with ASIR-V on the Visualization and Image Quality of the Adamkiewicz Artery: A Comparison with 120 kV Protocol.

OBJECTIVE: To evaluate the effect of low tube voltage (100 kV) combined with adaptive statistical iterative reconstruction-V (ASIR-V) on the visualization and image quality of the Adamkiewicz artery (AKA). METHODS: One hundred patients were prospectively enrolled and randomly assigned into two groups (both n = 50). Group A (100 kV) was reconstructed with filtered back projection (FBP) and ASIR-V from 10% to 100% with 10% intervals. Group B (120 kV) was only reconstructed with FBP. The objective image quality was evaluated by using CT values of the aorta (CTAorta), background noise, signal-to-noise ratio of the descending aorta (SNRAorta), and contrast-to-noise ratio of the spinal cord (CNRSpinal cord). The subjective image quality and visualization scores of the AKA were assessed on a 5-point scale. RESULTS: CTAorta was significantly higher in Group A than in Group B (p < 0.001). When ASIR-V weights were ≥60%, significant differences were found in the background noise, SNRAorta, and CNRSpinal cord between the two groups (all p < 0.05). In Group A, compared with FBP, the subjective score gradually increased as ASIR-V increased to 80%, which decreased when ASIR-V exceeded 80%. The visualization scores of the AKA (≥60%) and the ability to detect vessel continuity (≥80%) gradually increased as the ASIR-V weights increased (p < 0.05). The effective radiation dose was reduced by about 40.36% in Group A compared to Group B. CONCLUSIONS: compared with conventional scanning protocol, using a combination of low tube voltage (100 kV) and 80% ASIR-V protocol could not only increase the visualization of the AKA, but also improve image quality and reduce the radiation doses.

Impairments to the multisensory integration brain regions during migraine chronification: correlation with the vestibular dysfunction.

Objectives: Migraine is often combined with vestibular dysfunction, particularly in patients with chronic migraine (CM). However, the pathogenesis of migraine chronification leading to vestibular dysfunction is not fully understood. The current study investigated whether structural or functional impairments to the brain during migraine chronification could be associated with vestibular dysfunction development. Methods: The eligible participants underwent clinical assessment and magnetic resonance imaging (MRI) scans. Voxel-based morphometry (VBM) determined structural impairment by evaluating alterations in gray matter volume (GMV). Functional impairment was assessed by the mean amplitude of low-frequency fluctuation (mALFF). Furthermore, the resting-state functional connectivity (rsFC) of regions possessing impairment was examined with a seed-based approach. We also analyzed the correlations between altered neuroimaging features with clinical variables and performed multiple linear regression. Results: Eighteen CM patients, 18 episodic migraine (EM) patients, and 18 healthy controls (HCs) were included in this study. A one-way ANOVA indicated the group differences in mALFF. These were located within right supramarginal gyrus (SMG), left angular gyrus (AG), middle frontal gyrus (MFG), left middle occipital gyrus (MOG), right rolandic operculum (Rol) and left superior parietal gyrus (SPG). During rsFC analysis, the CM group had more enhanced rsFC of left SPG with left MOG than the EM and HC groups. The EM group revealed enhanced rsFC of left SPG with left AG than the CM and HC groups. In multiple linear regression, after controlling for age, body mass index (BMI) and disease duration, the rsFC of left SPG with left MOG (ß = 48.896, p = 0.021) was found to predict the total Dizziness Handicap Inventory (DHI) score with an explained variance of 25.1%. Moreover, the rsFC of left SPG with left MOG (ß = 1.253, p = 0.003) and right SMG (ß = -1.571, p = 0.049) were significant predictors of migraine frequency, accounting for a total explained variance of 73.8%. Conclusion: The functional impairments due to migraine chronification are primarily concentrated in the multisensory integration-related brain regions. Additionally, the rsFC of SPG with MOG can predict the frequency of migraine and the degree of vestibular dysfunction. Therefore, these neuroimaging features could be potential mechanisms and therapeutic targets for developing vestibular dysfunction in migraine.

Epigenetic regulation of temozolomide resistance in human cancers with an emphasis on brain tumors: Function of non-coding RNAs.

Brain tumors, which are highly malignant, pose a significant threat to health and often result in substantial rates of mortality and morbidity worldwide. The brain cancer therapy has been challenging due to obstacles such as the BBB, which hinders effective delivery of therapeutic agents. Additionally, the emergence of drug resistance further complicates the management of brain tumors. TMZ is utilized in brain cancer removal, but resistance is a drawback. ncRNAs are implicated in various diseases, and their involvement in the cancer is particularly noteworthy. The focus of the current manuscript is to explore the involvement of ncRNAs in controlling drug resistance, specifically in the context of resistance to the chemotherapy drug TMZ. The review emphasizes the function of ncRNAs, particularly miRNAs, in modulating the growth and invasion of brain tumors, which significantly influences their response to TMZ treatment. Through their interactions with various molecular pathways, miRNAs are modulators of TMZ response. Similarly, lncRNAs also associate with molecular pathways and miRNAs, affecting the efficacy of TMZ chemotherapy. Given their functional properties, lncRNAs can either induce or suppress TMZ resistance in brain tumors. Furthermore, circRNAs, which are cancer controllers, regulate miRNAs by acting as sponges, thereby impacting the response to TMZ chemotherapy. The review explores the correlation between ncRNAs and TMZ chemotherapy, shedding light on the underlying molecular pathways involved in this process.

Circulating metabolites and depression: a bidirectional Mendelian randomization.

Background: Studies have shown an association between depression and circulating metabolites, but the causal relationship between them has not been elucidated. The purpose of this study was to elucidate the causal relationship between circulating metabolites and depression and to explore the role of circulating metabolites in depression. Methods: In this study, the top single-nucleotide polymorphisms (SNPs) associated with circulating metabolites (n = 24,925) and depression (n = 322,580) were obtained based on the publicly available genome-wide association study using two-sample Mendelian randomization (MR). SNP estimates were summarized through inverse variance weighted, MR Egger, weighted median, MR pleiotropy residual sum and outlier, and "leave-one-out" methods. Results: Apolipoprotein A-I (OR 0.990, 95% CI 981-0.999) and glutamine (OR 0.985, 95% CI 0.972-0.997) had protective causal effects on depression, whereas acetoacetate (OR 1.021, 95% CI 1.009-1.034), glycoproteins (OR 1.005, 95% CI 1.000-1.009), isoleucine (OR 1.013, 95% CI 1.002-1.024), and urea (OR 1.020, 95% CI 1.000-1.039) had an anti-protective effect on depression. Reversed MR showed no effect of depression on the seven circulating metabolites. Conclusion: In this study, MR analysis showed that apolipoprotein A-I and glutamine had a protective effect on depression, and acetoacetate, glycoprotein, isoleucine, glucose, and urea may be risk factors for depression. Therefore, further research must be conducted to translate the findings into practice.

Bestrophin3 Deficiency in Vascular Smooth Muscle Cells Activates MEKK2/3-MAPK Signaling to Trigger Spontaneous Aortic Dissection.

BACKGROUND: Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, the contribution of Best3 to vascular diseases remains elusive. METHODS: Smooth muscle cell-specific and endothelial cell-specific Best3 knockout mice (Best3SMKO and Best3ECKO, respectively) were engineered to investigate the role of Best3 in vascular pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, and coimmunoprecipitation coupled with mass spectrometry were performed to evaluate the function of Best3 in vessels. RESULTS: Best3 expression in aortas of human AD samples and mouse AD models was decreased. Best3SMKO but not Best3ECKO mice spontaneously developed AD with age, and the incidence reached 48% at 72 weeks of age. Reanalysis of single-cell transcriptome data revealed that reduction of fibromyocytes, a fibroblast-like smooth muscle cell cluster, was a typical feature of human ascending AD and aneurysm. Consistently, Best3 deficiency in smooth muscle cells decreased the number of fibromyocytes. Mechanistically, Best3 interacted with both MEKK2 and MEKK3, and this interaction inhibited phosphorylation of MEKK2 at serine153 and MEKK3 at serine61. Best3 deficiency induced phosphorylation-dependent inhibition of ubiquitination and protein turnover of MEKK2/3, thereby activating the downstream mitogen-activated protein kinase signaling cascade. Furthermore, restoration of Best3 or inhibition of MEKK2/3 prevented AD progression in angiotensin II-infused Best3SMKO and ApoE-/- mice. CONCLUSIONS: These findings unveil a critical role of Best3 in regulating smooth muscle cell phenotypic switch and aortic structural integrity through controlling MEKK2/3 degradation. Best3-MEKK2/3 signaling represents a novel therapeutic target for AD.