Enhancing healthy aging with small molecules: A mitochondrial perspective.

The pursuit of enhanced health during aging has prompted the exploration of various strategies focused on reducing the decline associated with the aging process. A key area of this exploration is the management of mitochondrial dysfunction, a notable characteristic of aging. This review sheds light on the crucial role that small molecules play in augmenting healthy aging, particularly through influencing mitochondrial functions. Mitochondrial oxidative damage, a significant aspect of aging, can potentially be lessened through interventions such as coenzyme Q10, alpha-lipoic acid, and a variety of antioxidants. Additionally, this review discusses approaches for enhancing mitochondrial proteostasis, emphasizing the importance of mitochondrial unfolded protein response inducers like doxycycline, and agents that affect mitophagy, such as urolithin A, spermidine, trehalose, and taurine, which are vital for sustaining protein quality control. Of equal importance are methods for modulating mitochondrial energy production, which involve nicotinamide adenine dinucleotide boosters, adenosine 5'-monophosphate-activated protein kinase activators, and compounds like metformin and mitochondria-targeted tamoxifen that enhance metabolic function. Furthermore, the review delves into emerging strategies that encourage mitochondrial biogenesis. Together, these interventions present a promising avenue for addressing age-related mitochondrial degradation, thereby setting the stage for the development of innovative treatment approaches to meet this extensive challenge.

Nrf2-mediated redox balance alleviates LPS-induced vascular endothelial cell inflammation by inhibiting endothelial cell ferroptosis.

Ferroptosis plays an important role in inflammation and oxidative stress. Whether ferroptosis is involved in the inflammation of vascular endothelial cells and its regulation mechanism remains unclear. We estimated the correlation between serum iron ion levels and the inflammation index of 33 patients with arteriosclerosis. In vitro, HUVECs with or without ferrostatin-1 were exposed to Lipopolysaccharide. Corresponding cell models to verify the target signaling pathway. The results showed that serum iron ion levels had a significant positive correlation with N ratio, N/L, LDL level, and LDL/HDL (P < 0.05), and a negative correlation with L ratio (P < 0.05) in the arteriosclerosis patients. In vitro, ferroptosis is involved in HUVECs inflammation. Ferrostatin-1 can rescue LPS-induced HUVECs inflammation by decreasing HMGB1/IL-6/TNF-α expression. Nrf2 high expression could protect HUVECs against ferroptosis by activating the GPX4/GSH system, inhibiting ferritinophagy, and alleviating inflammation in HUVECs by inhibiting HMGB1/IL-6/TNF-α expression. It also found that Nrf2 is a key adaptive regulatory factor in the oxidative damage of HUVECs induced by NOX4 activation. These findings indicated that ferroptosis contributed to the pathogenesis of vascular endothelial cell damage by mediating endothelial cell inflammation. Nrf2-mediated redox balance in vascular inflammation may be a therapeutic strategy in vascular diseases.

A fourteen-lncRNA risk score system for prognostic prediction of patients with non-small cell lung cancer.

Growing evidence has underscored long non-coding RNAs (lncRNAs) serving as potential biomarkers for cancer prognosis. However, systematic tracking of a lncRNA signature for prognosis prediction in non-small cell lung cancer (NSCLC) has not been accomplished yet. Here, comprehensive analysis with differential gene expression analysis, univariate and multivariate Cox regression analysis based on The Cancer Genome Atlas (TCGA) database was performed to identify the lncRNA signature for prediction of the overall survival of NSCLC patients. A risk-score model based on a 14-lncRNA signature was identified, which could classify patients into high-risk and low-risk groups and show poor and improved outcomes, respectively. The receiver operating characteristic (ROC) curve revealed that the risk-score model has good performance with high AUC value. Multivariate Cox's regression model and stratified analysis indicated that the risk-score was independent of other clinicopathological prognostic factors. Furthermore, the risk-score model was competent for the prediction of metastasis-free survival in NSCLC patients. Moreover, the risk-score model was applicable for prediction of the overall survival in the other 30 caner types of TCGA. Our study highlighted the significant implications of lncRNAs as prognostic predictors in NSCLC. We hope the lncRNA signature could contribute to personalized therapy decisions in the future.

Analysis of Effectiveness, Safety, and Bleeding Related to Rivaroxaban in Elderly Patients.

This study explored the efficacy and safety of rivaroxaban in elderly patients, at different doses and age of patients, and analyzed risk factors of bleeding. A retrospective analysis was conducted of 299 patients aged 60 years or older who were admitted to the First Hospital of Jilin University between January 2016 and August 2018. It was found that the rate of bleeding events (but not embolism) significantly increased as the dose of oral rivaroxaban increased (P < .001), and with age, especially in patients aged ≥80 years (P = .001, both). The multivariate logistic regression analysis indicated that age (odds ratio [OR]: 2.963, 95% CI: 1.627-5.396) and the daily dose of rivaroxaban (OR: 2.325, 95% CI: 1.483-3.645) were independent risk factors for bleeding. The study determined that rivaroxaban anticoagulant therapy is effective in the elderly patients, but the risk of bleeding increases with age, and is a concern especially in the most old patients. The recommended daily dose of rivaroxaban is effective, but a lower dose is safer for the elderly patients.

Erratum: Increased cathepsin K levels in human atherosclerotic plaques are associated with plaque instability.

[This corrects the article DOI: 10.3892/etm.2017.4935.].

Age­related differences in serum MFG­E8, TGF­ß1 and correlation to the severity of atherosclerosis determined by ultrasound.

Atherosclerosis (AS) is an age­related inflammatory disease. Globule­epidermal growth factor­8 (MFG­E8) and transforming growth factor-ß1 (TGF­ß1) are involved in the pathogenesis of AS. However, age­related changes in circulating levels of MFG­E8 and TGF­ß1, and their correlation with the severity of AS is not well­characterized. In this study, we investigated age­related changes in serum levels of MFG­E8, TGF­ß1 and examined their association with the severity of AS. Sixty healthy volunteers were divided into young, middle­age and old­age groups. In addition, carotid ultrasound examination was performed to assess the intima­media thickness (IMT) of carotid artery. Sixty­seven patients with carotid AS and 30 age­matched healthy persons were divided into IMT increased group, plaque group and control group. Serum levels of MFG­E8, TGF­ß1, tumor necrosis factor-α (TNF­α) and intercellular adhesion molecule­1 were measured in all subjects. A positive association between serum MFG­E8 levels and age was observed in healthy volunteers, while a significant negative association was observed between TGF­ß1 levels and age. Serum levels of MFG­E8 and TNF­α showed a positive correlation while those of TGF­ß1 showed a negative correlation with Crouse scores for carotid artery IMT (P<0.05 for both). Both MFG­E8 and TGF­ß1 were age­related inflammatory factors. MFG­E8 showed a positive correlation, while TGF­ß1 showed a negative correlation with the severity of AS. Our findings suggest that both MFG­E8 and TGF­ß1 are age­related inflammatory factors and are related to the degree of AS. In conclusion, both MFG­E8 and TGF­ß1 may serve as potential markers of the severity of AS.

Decreased cathepsin K levels in human atherosclerotic plaques are associated with plaque instability.

Investigating the determinants and dynamics of atherosclerotic plaque instability is a key area of current cardiovascular research. Extracellular matrix degradation from excessive proteolysis induced by enzymes such as cathepsin K (Cat K) is implicated in the pathogenesis of unstable plaques. The current study assessed the expression of Cat K in human unstable atherosclerotic plaques. Specimens of popliteal arteries with atherosclerotic plaques were classified as stable (<40% lipid core plaque area; n=6) or unstable (≥40% lipid core plaque area; n=14) based on histopathological examinations of hematoxylin and eosin stained sections. The expression of Cat K and cystatin C (Cys C) were assessed by immunohistochemical examination and levels of Cat K mRNA were detected by semi-quantitative reverse transcriptase polymerase chain reaction. Morphological changes including a larger lipid core, endothelial proliferation with foam cells and destruction of internal elastic lamina were observed in unstable atherosclerotic plaques. In unstable plaques, the expression of Cat K protein and mRNA was upregulated, whereas Cys C protein expression was downregulated. The interplay between Cat K and Cys C may underlie the progression of plaques from stable to unstable and the current study indicated that Cat K and Cys C are potential targets for preventing and treating vulnerable atherosclerotic plaque ruptures.

miR-128 regulates differentiation of hair follicle mesenchymal stem cells into smooth muscle cells by targeting SMAD2.

Human hair follicle mesenchymal stem cells (hHFMSCs) are an important source of cardiovascular tissue engineering for their differentiation potential into smooth muscle cells (SMCs), yet the molecular pathways underlying such fate determination is unclear. MicroRNAs (miRNAs) are non-coding RNAs that play critical roles in cell differentiation. In present study, we found that miR-128 was remarkably decreased during the differentiation of hHFMSCs into SMCs induced by transforming growth factor-ß1 (TGF-ß1). Moreover, overexpression of miR-128 led to decreased expression of SMC cellular marker proteins, such as smooth muscle actin (SMA) and calponin, in TGF-ß1-induced SMC differentiation. Further, we identified that miR-128 targeted the 3'-UTR of SMAD2 transcript for translational inhibition of SMAD2 protein, and knockdown of SMAD2 abrogated the promotional effect of antagomir-128 (miR-128 neutralizer) on SMC differentiation. These results suggest that miR-128 regulates the differentiation of hHFMSCs into SMCs via targeting SMAD2, a main transcription regulator in TGF-ß signaling pathway involving SMC differentiation. The miR-128/SMAD2 axis could therefore be considered as a candidate target in tissue engineering and regenerative medicine for SMCs.

Increased ADRP expression in human atherosclerotic lesions correlates with plaque instability.

UNLABELLED: Adipose differentiation-related protein (ADRP) is intrinsically associated with the surface of lipid droplets implicated in the development of atherosclerosis. We analyzed expression of ADRP in human popliteal artery plaques. Atherosclerotic plaque tissue from the popliteal artery was obtained from 18 patients undergoing lower extremity amputation for arteriosclerosis obliterans, and with either stable (n = 6) or unstable (n = 12) atherosclerotic plaques. Plaques were histologically classified as either unstable (≥ 40% lipid core plaque area) or stable (< 40% lipid core plaque area). Control tissues consisted of sections of mesenteric arteries obtained from 10 patients without a history of atherosclerosis, but undergoing a subtotal gastrectomy. Plaque tissues were analyzed for expression of ADRP and protein kinase C (PKC) protein by immunohistochemical methods, and ADRP mRNA expression was measured using the reverse transcription polymerase chain reaction (RT-PCR). Immunohistochemical analyses showed that ADRP expression was higher in samples of unstable plaque when compared with expression in stable plaque (gray intensities 103.56 ± 1.187 vs 106.95 ± 1.389, respectively, P < 0.05) and that ADRP expression was associated with increased PKC expression (gray intensities 102.32 ± 1.730 vs 104.70 ± 0.959, respectively, P < 0.01). Consistent with ADRP protein expression, expression of ADRP mRNA was also higher in unstable plaque compared to expression in stable plaque (relative expression 1.17 ± 0.15 vs 0.81 ± 0.03, respectively, P < 0.05). IN CONCLUSION: this study demonstrated that increased expression of ADRP in human atherosclerosis was associated with plaque instability.

VEGF induces angiogenesis in a zebrafish embryo glioma model established by transplantation of human glioma cells.

Zebrafish (Danio rerio) is becoming an increasingly popular vertebrate cancer model. In this study, we established a xenotransplanted zebrafish embryo glioma model to further investigate the molecular mechanisms of tumor angiogenesis. We find that the glioma cell line U87 can survive, proliferate and induce additional SIV branches in zebrafish embryos. In addition, by the means of in situ hybridization and quantitive RT-PCR analyses we find that the transplanted U87 cells can induce the ectopic zebrafish vascular endothelial growth factor A (VEGF A) and its receptor VEGFR2/KDR mRNA expression and increase their expression levels, resulting in additional SIV branches.