Modulation of ER-mitochondria tethering complex VAPB-PTPIP51: Novel therapeutic targets for aging-associated diseases.

Aging is a gradual and irreversible natural process. With aging, the body experiences a functional decline, and the effects amplify the vulnerability to a range of age-related diseases, including neurodegenerative, cardiovascular, and metabolic diseases. Within the aging process, the morphology and function of mitochondria and the endoplasmic reticulum (ER) undergo alterations, particularly in the structure connecting these organelles known as mitochondria-associated membranes (MAMs). MAMs serve as vital intracellular signaling hubs, facilitating communication between the ER and mitochondria when regulating various cellular events, including calcium homeostasis, lipid metabolism, mitochondrial function, and apoptosis. The formation of MAMs is partly dependent on the interaction between the vesicle-associated membrane protein-associated protein-B (VAPB) and protein tyrosine phosphatase-interacting protein-51 (PTPIP51). Accumulating evidence has begun to elucidate the pivotal role of the VAPB-PTPIP51 tether in the initiation and progression of age-related diseases. In this study, we delineate the intricate structure and multifunctional role of the VAPB-PTPIP51 tether and discuss its profound implications in aging-associated diseases. Moreover, we provide a comprehensive overview of potential therapeutic interventions and pharmacological agents targeting the VAPB-PTPIP51-mediated MAMs, thereby offering a glimmer of hope in mitigating aging processes and treating age-related disorders.

Ferroptosis in age-related vascular diseases: Molecular mechanisms and innovative therapeutic strategies.

Aging, an inevitable aspect of human existence, serves as one of the predominant risk factors for vascular diseases. Delving into the mystery of vascular disease's pathophysiology, the profound involvement of programmed cell death (PCD) has been extensively demonstrated. PCD is a fundamental biological process that plays a crucial role in both normal physiology and pathology, including a recently discovered form, ferroptosis. Ferroptosis is characterized by its reliance on iron and lipid peroxidation, and its significant involvement in vascular disease pathophysiology has been increasingly acknowledged. This phenomenon not only offers a promising therapeutic target but also deepens our understanding of the complex relationship between ferroptosis and age-related vascular diseases. Consequently, this article aims to thoroughly review the mechanisms that enable the effective control and inhibition of ferroptosis. It focuses on genetic and pharmacological interventions, with the goal of developing innovative therapeutic strategies to combat age-related vascular diseases.

Identification and validation of a copper homeostasis-related gene signature for the predicting prognosis of breast cancer patients via integrated bioinformatics analysis.

The prognostic value of copper homeostasis-related genes in breast cancer (BC) remains largely unexplored. We analyzed copper homeostasis-related gene profiles within The Cancer Genome Atlas Program breast cancer cohorts and performed correlation analysis to explore the relationship between copper homeostasis-related mRNAs (chrmRNA) and lncRNAs. Based on these results, we developed a gene signature-based risk assessment model to predict BC patient outcomes using Cox regression analysis and a nomogram, which was further validated in a cohort of 72 BC patients. Using the gene set enrichment analysis, we identified 139 chrmRNAs and 16 core mRNAs via the Protein-Protein Interaction network. Additionally, our copper homeostasis-related lncRNAs (chrlncRNAs) (PINK1.AS, OIP5.AS1, HID.AS1, and MAPT.AS1) were evaluated as gene signatures of the predictive model. Kaplan-Meier survival analysis revealed that patients with a high-risk gene signature had significantly poorer clinical outcomes. Receiver operating characteristic curves showed that the prognostic value of the chrlncRNAs model reached 0.795 after ten years. Principal component analysis demonstrated the capability of the model to distinguish between low- and high-risk BC patients based on the gene signature. Using the pRRophetic package, we screened out 24 anticancer drugs that exhibited a significant relationship with the predictive model. Notably, we observed higher expression levels of the four chrlncRNAs in tumor tissues than in the adjacent normal tissues. The correlation between our model and the clinical characteristics of patients with BC highlights the potential of chrlncRNAs for predicting tumor progression. This novel gene signature not only predicts the prognosis of patients with BC but also suggests that targeting copper homeostasis may be a viable treatment strategy.

Terazosin attenuates abdominal aortic aneurysm formation by downregulating Peg3 expression to inhibit vascular smooth muscle cell apoptosis and senescence.

Abdominal aortic aneurysm (AAA), a vascular degenerative disease, is a potentially life-threatening condition characterised by the loss of vascular smooth muscle cells (VSMCs), degradation of extracellular matrix (ECM), inflammation, and oxidative stress. Despite the severity of AAA, effective drugs for treatment are scarce. At low doses, terazosin (TZ) exerts antiapoptotic and anti-inflammatory effects in several diseases, but its potential to protect against AAA remains unexplored. Herein, we investigated the effects of TZ in two AAA animal models: Angiotensin II (Ang II) infusion in Apoe-/- mice and calcium chloride application in C57BL/6J mice. Mice were orally administered with TZ (100 or 1000 µg/kg/day). The in vivo results indicated that low-dose TZ alleviated AAA formation in both models. Low-dose TZ significantly reduced aortic pulse wave velocity without exerting an apparent antihypertensive effect in the Ang II-induced AAA model. Paternally expressed gene 3 (Peg3) was identified via RNA sequencing as a novel TZ target. PEG3 expression was significantly elevated in both mouse and human AAA tissues. TZ suppressed PEG3 expression and reduced the abundance of matrix metalloproteinases (MMP2/MMP9) in the tunica media. Functional experiments and molecular analyses revealed that TZ (10 nM) treatment and Peg3 knockdown effectively prevented Ang II-induced VSMC senescence and apoptosis in vitro. Thus, Peg3, a novel target of TZ, mediates inflammation-induced VSMC apoptosis and senescence. Low-dose TZ downregulates Peg3 expression to attenuate AAA formation and ECM degradation, suggesting a promising therapeutic strategy for AAA.

Development and Validation of Robust Ferroptosis-Related Genes in Myocardial Ischemia-Reperfusion Injury.

(1) Background: Despite the evidence that ferroptosis is involved in myocardial ischemia-reperfusion (MIR), the critical regulator of ferroptosis in MIR remains unclear. (2) Methods: We included three GEO datasets and a set of ferroptosis-related genes with 259 genes. Following the identification of the differentially expressed ferroptosis-related genes (DEFRGs) and hub genes, we performed the functional annotation, protein-protein interaction network, and immune infiltration analysis. The GSE168610 dataset, a cell model, and an animal model were then used to verify key genes. (3) Results: We identified 17 DEFRGs and 9 hub genes in the MIR samples compared to the control. Heme oxygenase 1 (Hmox1), activating transcription factor 3 (Atf3), epidermal growth factor receptor (Egfr), and X-box binding protein 1 (Xbp1) were significantly upregulated in response to ischemic and hypoxic stimuli. In contrast, glutathione peroxidase 4 (Gpx4) and vascular endothelial growth factor A (Vegfa) were consistently decreased in either the oxygen and glucose deprivation/reoxygenation cell or the MIR mouse model. (4) Conclusions: This study emphasized the relevance of ferroptosis in MIR. It has been successfully demonstrated that nine ferroptosis-related genes (Hmox1, Atf3, Egfr, Gpx4, Cd44, Vegfa, asparagine synthetase (Asns), Xbp1, and bromodomain containing 4 (Brd4)) are involved in the process. Additional studies are needed to explore potential therapeutic targets for MIR.

Close association between lifestyle and circulating FGF21 levels: A systematic review and meta-analysis.

Background: The impact of lifestyle factors on circulating fibroblast growth factor 21 (cFGF21) remains unclear. We conducted this systematic review and meta-analysis to evaluate the association between lifestyle factors and cFGF21 levels. Methods: We included studies that evaluated the effects of different lifestyles on cFGF21 concentration in adults, which included smoking, exercise, diets, alcohol consumption and weight loss. Random effects models or fixed effects models were used for meta-analysis to calculate the standardized mean difference (SMD) and 95% confidence interval according to the heterogeneity among studies. Study quality was assessed using the Newcastle-Ottawa Scale for cohort studies, the Joanna Briggs Institution Checklist for cross-sectional studies, and the PEDro scale for experimental studies. Results: A total of 50 studies with 1438 individuals were included. Overall, smoking, a hypercaloric carbohydrate-rich diet, a hypercaloric fat-rich diet, amino acid or protein restriction, excessive fructose intake and alcohol consumption significantly upregulated cFGF21 levels (p<0.05), whereas fish oil intake and calorie restriction with sufficient protein intake significantly decreased cFGF21 (p<0.05). Compared to the preexercise cFGF21 level, the cFGF21 level significantly increased within 3 hours postexercise (p<0.0001), while it significantly decreased in the blood sampled >6 h postexercise (p=0.01). Moreover, higher exercise intensity resulted in higher upregulation of cFGF21 at 1-hour post exercise (p=0.0006). Conclusion: FGF21 could serve as a potential biomarker for the assessment of different lifestyle interventions. When it is used for this purpose, a standard study protocol needs to be established, especially taking into consideration the intervention types and the sampling time post-intervention. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021254758, identifier CRD42021254758.

FGF21 at physiological concentrations regulates vascular endothelial cell function through multiple pathways.

Cardiovascular diseases are closely associated with dysfunction of vascular endothelial cells (VECs), which can be influenced by various intrinsic and extrinsic factors, including fibroblast growth factor 21 (FGF21), but the effects of serum FGF21 on VECs remain unclear. We performed a cross-sectional study nested within a prospective cohort to assess the range of physiological concentrations of fasting serum FGF21 in 212 healthy individuals. We also treated human umbilical VECs (HUVECs) with recombinant FGF21 at different concentrations. The effects of FGF21 treatment on glycolysis, nitric oxide release and reduction of intracellular reactive oxygen species were assessed. The cells were also collected for RNA transcriptomic sequencing to investigate the potential mechanisms induced by FGF21 treatment. In addition, the roles of SIRT1 in the regulation of FGF21 were evaluated by SIRT1 knockdown. The results showed that the serum FGF21 concentration in healthy individuals ranged from 15.70 to 499.96 pg/mL and was positively correlated with age and pulse wave velocity. FGF21 at 400 pg/mL was sufficient to enhance glycolysis, increase nitric oxide release and protect cells from H2O2-induced oxidative damage. The upregulated genes after FGF21 treatment were mostly enriched in metabolic pathways, whereas the downregulated genes were mostly enriched in inflammation and apoptosis signaling pathways. Moreover, SIRT1 may be involved in the regulation of some genes by FGF21. In conclusion, our data indicate that FGF21 at a level within the physiological concentration range has a beneficial effect on HUVECs and that this effect may partly depend on the regulation of SIRT1.

High-Level Serum Fibroblast Growth Factor 21 Concentration Is Closely Associated With an Increased Risk of Cardiovascular Diseases: A Systematic Review and Meta-Analysis.

Background: The association between fibroblast growth factor 21 (FGF21) and cardiovascular disease (CVD) risk remains unclear. We conducted this systematic review and meta-analysis to evaluate the association between FGF21 and CVDs, and relevant vascular parameters. Methods: PubMed and Web of Science databases were systematically searched to identify relevant studies published before March 2021. The FGF21 concentration was compared between individuals with and without CVDs. The effect of FGF21 on CVD risk was assessed by using hazard ratio (HR) and odds ratio (OR). The association between FGF21 and vascular parameters was assessed by Pearson's r. Study quality was assessed using Newcastle-Ottawa Scale and Joanna Briggs Institution Checklist. Results: A total of 29,156 individuals from 30 studies were included. Overall, the serum FGF21 concentration was significantly higher in CVD patients (p < 0.001), especially for coronary artery disease (CAD) (p < 0.001) and hypertension (p < 0.001). The pooled OR (p = 0.009) and HR (p < 0.001) showed that the risk of CVDs increased with FGF21. The linear association between FGF21 and vascular parameters, including pulse wave velocity (r = 0.32), carotid intima-media thickness (r = 0.21), ankle-brachial index (r = 0.33), systolic blood pressure (r = 0.13), and diastolic blood pressure (r = 0.05), was insignificant. The incidence of overall CVDs (p = 0.03) was significantly higher in individuals with higher FGF21 levels. Conclusion: High-level serum FGF21 concentration is closely associated with an increased risk of CVDs, which may be independent of vascular parameters. A standard FGF21 classification threshold needs to be established before clinical use for CVD risk assessment. Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=241968, identifier: CRD42021241968.