PUM2 promoted osteoarthritis progression through PTEN-mediated chondrocyte ferroptosis by facilitating NEDD4 mRNA degradation.

Osteoarthritis (OA) is a prevalent degenerative joint disease with a lack of effective therapeutic. Chondrocyte ferroptosis contributes to the progression of OA. PUM2 is shown to exacerbate ischemia-reperfusion-induced neuroinflammation by promoting ferroptosis, but its role in OA remains unexplored. Here, primary mouse chondrocytes were stimulated with IL-1ß to mimic OA chondrocyte injury in vitro. And PUM2 was upregulated in OA cartilage tissues and IL-1ß-induced chondrocytes. Silencing PUM2 alleviated IL-1ß-induced chondrocyte inflammation and ECM degradation. Mechanistically, PUM2 facilitated the degradation of NEDD4 mRNA by binding to the 3'UTR of NEDD4 mRNA, which in turn inhibited NEDD4 induced PTEN ubiquitination and degradation. Consistently, NEDD4 silencing reversed the ameliorative effect of PUM2 knockdown on chondrocyte injury, and overexpression of PTEN abolished the improved role of NEDD4 in chondrocyte injury. Moreover, PTEN aggravated IL-1ß-induced ferroptosis in chondrocytes through the Nrf2/HO-1 pathway by increasing the levels of Fe2+, ROS, MDA, and ACSL4 protein, decreasing the activity of SOD and the levels of GSH and GPX4 protein, and aggravating mitochondrial damage. Additionally, destabilized medial meniscus (DMM) were conducted to establish the OA mouse model, and adenovirus-mediated PUM2 shRNA was administered intra-articularly. Silencing PUM2 attenuated OA-induced cartilage damage in vivo. In conclusion, PUM2 promoted OA progression through PTEN-mediated chondrocyte ferroptosis by facilitating NEDD4 mRNA degradation.

PPARγ inhibition promotes osteogenic differentiation of bone marrow mesenchymal stem cells and fracture healing.

This study aimed to explore the effects of peroxisome proliferator-activated receptor γ (PPARγ) inhibition on fracture healing of nonunion and the underlying mechanisms. Bone marrow mesenchymal stem cells (BMSCs) were treated with PPARγ antagonist GW9662 (5 µM, 10 µM). Alkaline phosphatase (ALP) staining and Alizarin Red S was used to assess early stage of osteogenesis and osteogenic differentiation. GW9662 (1 mg/kg/day) were administered intraperitoneally into the rats with bone fracture. Bone healing processes in the rat femur fracture model were recorded and assessed by radiographic methods on Weeks 8, 14, and 20 postoperation. Osteogenesis and angiogenesis at the fracture sites were evaluated by radiographic and histological methods on postoperative Week 20. GW9662 treatment increased ALP activity and Alp mRNA expression in rat BMSCs. Moreover, GW9662 administration increased matrix mineralization and mRNA and protein levels of Bmp2 and Runx2 in the BMSCs. In addition, GW9662 treatment improved radiographic score in the fracture rats and increased osteogenesis-related proteins, including type I collagen, osteopontin, and osteoglycin, in the bone tissues of the fracture sites. In conclusion, PPARγ inhibition promotes osteogenic differentiation of rat BMSCs, as well as improves the fracture healing of rats through Bmp2/Runx2 signaling pathway in the rat model of bone fracture.

Identification of prognostic alternative splicing events in sarcoma.

Sarcoma is a rare malignancy with unfavorable prognoses. Accumulating evidence indicates that aberrant alternative splicing (AS) events are generally involved in cancer pathogenesis. The aim of this study was to identify the prognostic value of AS-related survival genes as potential biomarkers, and highlight the functional roles of AS events in sarcoma. RNA-sequencing and AS-event datasets were downloaded from The Cancer Genome Atlas (TCGA) sarcoma cohort and TCGA SpliceSeq, respectively. Survival-related AS events were further assessed using a univariate analysis. A multivariate Cox regression analysis was also performed to establish a survival-gene signature to predict patient survival, and the area-under-the-curve method was used to evaluate prognostic reliability. KOBAS 3.0 and Cytoscape were used to functionally annotate AS-related genes and to assess their network interactions. We detected 9674 AS events in 40,184 genes from 236 sarcoma samples, and the 15 most significant genes were then used to construct a survival regression model. We further validated the involvement of ten potential survival-related genes (TUBB3, TRIM69, ZNFX1, VAV1, KCNN2, VGLL3, AK7, ARMC4, LRRC1, and CRIP1) in the occurrence and development of sarcoma. Multivariate survival model analyses were also performed, and validated that a model using these ten genes provided good classifications for predicting patient outcomes. The present study has increased our understanding of AS events in sarcoma, and the gene-based model using AS-related events may serve as a potential predictor to determine the survival of sarcoma patients.

MicroRNA-181a/b-1-encapsulated PEG/PLGA nanofibrous scaffold promotes osteogenesis of human mesenchymal stem cells.

Bioactive nanofibres play a useful role in increasing the efficiency of tissue engineering scaffolds. MicroRNAs (miRs) alone, and in combination with tissue engineering scaffolds, can be effective in treating bone fractures and osteoporosis by regulating many post-transcriptional cellular pathways. Herein, miR-181a/b-1 was incorporated in the electrospun poly (lactic-co-glycolic acid) (PLGA) nanofibres (PLGA-miR). After characterization scaffolds, the osteoinductive capacity of the nanofibres was investigated when adipose-derived mesenchymal stem cells (AT-MSCs) were cultured on the PLGA and PLGA-miR nanofibres. miR incorporating in the nanofibres has not any significant effect on the size and morphology of the nanofibres, but its biocompatibility was increased significantly compared to the empty nanofibres. Alkaline phosphatase (ALP) activity and calcium measures were evaluated as two important osteogenic markers, and the results revealed that the highest measures were observed in the AT-MSCs cultured on PLGA-miR nanofibres. Detected ALP activity and calcium measures in miR-transduced AT-MSCs cultured on TCPS were also significantly higher than AT-MSCs cultured on PLGA and TCPS groups. The highest expression levels of bone-related genes were observed in the AT-MSCs cultured on PLGA-miR nanofibres. This improvement in the osteogenic differentiation potential of the AT-MSCs was also confirmed by evaluating osteopontin protein in the cells cultured on PLGA-miR. It can be concluded that miR-181a/b-1 has a significant impact on the AT-MSC osteogenic differentiation, and this impact synergistically increased when incorporated in the PLGA nanofibres.

Quercetin Nanoparticle Ameliorates Lipopolysaccharide-Triggered Renal Inflammatory Impairment by Regulation of Sirt1/NF-KB Pathway.

As a conventional complication of sepsis, acute kidney injury (AKI) is characterized by high incidence and mortality. Effective management methods are still lacking. Quercetin belongs to a kind of flavonoids that exerts many functions, for example anti-inflammation and anti-fibrosis. However, its function in sepsis AKI is uncertain. Our study therefore set out to assess the function of quercetin in AKI mice model induced by lipopolysaccharide (LPS) and human proximal tubular cells (HK-2), including the potential mechanisms. Quercetin was loaded onto a biodegradable polymer carrier (nanoparticle) to enhance its bioavailability. The data showed that quercetin administration strikingly improved renal dysfunction and ameliorated tubular injury caused by LPS in mice. In mice model and in cultured cells, quercetin pretreatment obviously restrained LPS-triggered cell apoptosis and inflammation, including generation of various cytokines. Moreover, the results from mice model and cell model showed that quercetin could diminish IκBα and p65 phosphorylation after LPS treatment. The most significant observation of this study was that quercetin elevated the expression of Sirt1. Transfection of Sirt1 specific shRNA mitigated the suppression of quercetin on cell apoptosis, inflammation and of NF-κB activation triggered by LPS. Therefore, these sequels indicate that quercetin protects against sepsis-associated AKI by upregulation Sirt1 expression through quenching NF-κB activation and may be an encouraging therapeutic agent for patients with sepsis-associated AKI.

Sex-based differences in outcomes after severe injury: an analysis of blunt trauma patients in China.

BACKGROUND: Experimental research suggests that females have a higher survival rate after trauma, although this claim is controversial. This study sought to determine the role of sex on mortality among trauma patients in China. METHODS: The study enrolled 1789 trauma patients who visited the Emergency Intensive Care Unit of the First Affiliated Hospital of Zhengzhou University during 2015 and 2016. A retrospective data analysis was performed to determine sex-based differences after blunt trauma. Patients were stratified by age and injury severity (using the Injury Severity Score). Multiple logistic regression was used to analyze the association between sex and post-injury complications and mortality. RESULTS: Female trauma patients experienced a significantly lower risk of mortality than males (odds ratio, 0.931; 95% confidence interval, 0.883-0.982). This survival advantage of females was particularly notable in the 'younger than 45 years' age group. Sex-based differences were also found in the occurrence of life-threatening complications after trauma. CONCLUSION: This study demonstrated that females are more likely to survival after severe blunt trauma and also have less inpatient complications than men, suggesting an important role for sex hormones after severe traumatic injury.

Sleep disorders in patients with multiple sclerosis in China.

BACKGROUND: Poor sleep is common in patients with multiple sclerosis (MS). This study assessed the prevalence of poor sleep and investigated the potential impact factors that influence sleep quality of patients with MS. METHODS: A cross-sectional self-report survey of 231 patients with MS and 265 sex- and age-matched controls was conducted. Good sleepers and poor sleepers were separated by their global score on the Pittsburgh Sleep Quality Index (PSQI). Sociodemographic parameters, such as age, gender, and marital status, and clinical-demographic parameters, such as excessive daytime sleepiness (measured by the Epworth Sleepiness Scale), snoring, insomnia, obstructive sleep apnea, drugs, pain, depression, fatigue, and quality of life, were registered. Clinical and sociodemographic parameters were compared between patients with MS and controls and between good and poor sleepers among patients with MS. RESULTS: The prevalence of poor sleep in patients with MS was 64.9. Univariate analysis found that gender (p < 0.001), antidepressant drugs (p < 0.001), insomnia (p < 0.001), fatigue (p < 0.001), Epworth Sleepiness Scale (ESS) (p < 0.001), pain (p < 0.001), and depression (p < 0.001) were associated with sleep disorders. Multivariate analysis revealed that female gender, antidepressant drug treatment, and a high psychological burden of MS may be risk factors for poor sleep among patients with MS. CONCLUSIONS: Poor sleep is more common in patients with MS than in the general population. Sleep disorders should routinely be evaluated in patients with MS to improve the quality of sleep among them.