Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence.

Senescence of vascular smooth muscle cells (VSMCs) contributes to aging-related cardiovascular diseases by promoting arterial remodelling and stiffness. Ferroptosis is a novel type of regulated cell death associated with lipid oxidation. Here, we show that pro-ferroptosis signaling drives VSMCs senescence to accelerate vascular NAD+ loss, remodelling and aging. Pro-ferroptotic signaling is triggered in senescent VSMCs and arteries of aged mice. Furthermore, the activation of pro-ferroptotic signaling in VSMCs not only induces NAD+ loss and senescence but also promotes the release of a pro-senescent secretome. Pharmacological or genetic inhibition of pro-ferroptosis signaling, ameliorates VSMCs senescence, reduces vascular stiffness and retards the progression of abdominal aortic aneurysm in mice. Mechanistically, we revealed that inhibition of pro-ferroptotic signaling facilitates the nuclear-cytoplasmic shuttling of proliferator-activated receptor-γ and, thereby impeding nuclear receptor coactivator 4-ferrtin complex-centric ferritinophagy. Finally, the activated pro-ferroptotic signaling correlates with arterial stiffness in a human proof-of-concept study. These findings have significant implications for future therapeutic strategies aiming to eliminate vascular ferroptosis in senescence- or aging-associated cardiovascular diseases.

Knockdown of galectin-1 suppresses the growth and invasion of osteosarcoma cells through inhibition of the MAPK/ERK pathway.

Galectin-1 (GAL1), a widely expressed ß­galacto-side-binding protein, exerts pleiotropic biological functions. GAL1 has been found to be upregulated in many malignancies; yet the role of GAL1 in the pathophysiology of human osteosarcoma (OS) remains uncertain. The present study was carried out to investigate the expression of GAL1 in human OS tissues and to explore its effects on the growth and invasion of OS cells. OS and corresponding adjacent non-cancerous tissues (ANCT) were collected from 30 consecutive cases. The expression of GAL1 was detected by immunohistochemical assay through tissue microarray procedure. Using small hairpin RNA (shRNA)-mediated GAL1 knockdown (Lv-shGAL1) in OS (MG-63 and U-2 OS) cells, we observed the changes in the malignant phenotype in OS cells in vitro and in vivo. As a consequence, the positive expression of GAL1 was significantly higher in OS tissues than that in the ANCT (63.3 vs. 36.7%, P=0.029), and was positively correlated with distant metastasis in the OS patients (P=0.022). Knockdown of GAL1 suppressed cell proliferative activities and invasive potential and induced apoptosis in OS cells with decreased expression of p38MAPK, p-ERK, Ki-67 and matrix metallopeptidase-9 (MMP-9) and increased expression of caspase-3. In addition, the tumor volume in the MG-63 subcutaneous tumor models treated with Lv-shGAL1 was significantly smaller than that in the negative control (NC) group (P<0.01). Altogether, our findings indicate that high expression of GAL1 is associated with distant metastasis of OS patients, and knockdown of GAL1 inhibits growth and invasion of OS cells possibly through inhibition of the MAPK/ERK pathway, suggesting that GAL1 may represent a potential target for the treatment of cancer.

Liver X receptor α inhibits osteosarcoma cell proliferation through up-regulation of FoxO1.

BACKGROUND: Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. METHODS: We analyzed liver X receptor α (LXRα) mRNA expression in 16 pairs of human osteosarcoma tissues and adjacent noncancerous tissues. Moreover, we investigated LXRα's potential role in regulating cell proliferation in Saos-2 and U2OS cells. RESULTS: We found that activation of LXRα, a member of nuclear receptor, was able to inhibit cell proliferation in Saos-2 and U2OS cells. At the molecular level, our results further revealed that expression of tumor suppressor gene, FoxO1, was up-regulated by LXRα activation. LXRα activates FoxO1 transcription through a direct binding on its promoter region. CONCLUSION: LXRα acts as a tumor suppressor for osteosarcoma, which may offer a new way in molecular targeting cancer treatment.

Single-stage combined decompression for patients with tandem ossification in the cervical and thoracic spine.

STUDY DESIGN: Retrospective study of clinical outcomes of single-staged combined cervical and thoracic decompression for patients with tandem ossification (TO). OBJECTIVE: To describe primary clinical outcomes of this procedure. TO is introduced to described a double ossification lesion of the posterior longitudinal ligament (OPLL) or the ligament flavum (OLF) at the cervical, thoracic and lumbar spine. In clinical practice, cervical OPLL combined with thoracic OPLL or/and OLF are the most common types of TO. However, little is known about the clinical outcomes of surgical treatment and there is no consensus on the optimal treatment to this combined disorder. METHODS: Between January 2005 and December 2008, 15 patients of this complicated phenomenon were treated by single-staged combined cervical and thoracic decompression in conditions where patients' general condition allowed and individuals agreed on. Surgical intervention, perioperative complications, and clinical outcomes were reviewed in these 15 TO patients who were followed up for more than 2 years (range 2-5 years). Clinical symptoms were evaluated using the JOA scoring system and activity of daily life was evaluated by Nurick classification before surgery, at 6 months postoperatively, and at final follow-up. Patient satisfaction was determined at final follow-up. RESULTS: The mean blood loss was 1,553.3 ± 735.7 ml (range 700-2,900 ml) and the mean operation time was 280.7 ± 53.6 min (range 220-370 min). The important intraoperative and postoperative complications recorded in medical documents included CSF leakage, hematoma, C5 palsy and neurological deterioration. The JOA score was significantly higher 6 months after surgery (8.1 ± 1.8 points vs. 11.0 ± 1.6 points, p < 0.0001), and there was no significant change between 6 months after surgery and final follow-up (11.0 ± 1.6 points vs. 11.3 ± 2.1, p = 0.5894). The mean Nurick classification significantly improved from grade 3.6 ± 0.7 before surgery to grade 2.5 ± 0.9 at 6 months after surgery (p < 0.001), and well maintained as grade 2.3 ± 1.0 at final follow-up (p = 0.3343). Three patients had satisfaction scores of 3 points, 5 had scores of 2 or 1 point, and 2 had score of 0 point. Pearson correlation analysis showed a significant positive correlation between satisfaction score and JOA score (r = 0.6493, p = 0.0093), and a significant negative correlation between satisfaction score and Nurick classification (r = -0.5941, p = 0.0195). Besides, perioperative complications and progression of tandem ossification which needed revision surgery had significant adverse effect on patients' satisfaction. CONCLUSIONS: The results showed that single-staged combined decompression could provide comparable clinical outcomes, and patients' satisfaction was significantly related with postoperative neurological function. In addition, satisfaction score could be decreased by perioperative complications and progression of tandem ossification. Thus, this aggressive surgical strategy should be used more carefully with emphasis on preoperative communication with patients.