MicroRNA-595 promotes osteogenic differentiation of bone marrow mesenchymal stem cells by targeting HMGA2

Purpose: To investigate the effect of miR-595 on osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs).Methods: Human BMSCs were osteogenically differentiated, and protein expression of alkaline phosphatase (ALP), osteocalcin (OCN), and Runt-related transcription factor 2 (RUNX2) were evaluated by western blot. Expression of miR-595 was measured by quantitative reverse transcription (qRT-PCR). The effect of miR-595 on viability of BMSCs was determined by MTT assay. Osteogenic differentiation of BMSCs was assessed by ALP and Alizarin red S (ARS) staining. The target gene of miR-595 was predicted by TargetScan analysis and validated by luciferase activity assay.Results: MiR-595 expression was higher in osteogenically differentiated BMSCs than in undifferentiated BMSCs (p < 0.01). Osteogenic ALP, OCN, and RUNX2 were also upregulated (p < 0.01). MiR-595 expression increased the viability of BMSCs, mineralized bone matrix formation, and ALP activity. High mobility group AT-hook 2 (HMGA2) expression was lower in osteogenically differentiated BMSCs and was found to be a target of miR-595. Overexpression of HMGA2 attenuated the miR-595-induced increase in cell viability, ALP activity, mineralized bone matrix formation, and osteogenic gene expression in BMSCs.Conclusion: The miR-595/HMGA2 axis is involved in osteogenic differentiation of BMSCs suggesting that it is a promising therapeutic target for osteoporosis

Cerebrospinal fluid oligoclonal bands in Chinese patients with multiple sclerosis: the prevalence and its association with clinical features

BackgroundCerebrospinal fluid oligoclonal band (CSF-OCB) is an established biomarker in diagnosing multiple sclerosis (MS), however, there are no nationwide data on CSF-OCB prevalence and its diagnostic performance in Chinese MS patients, especially in the virtue of common standard operation procedure (SOP).MethodsWith a consensus SOP and the same isoelectric focusing system, we conducted a nationwide multi-center study on OCB status in consecutively, and recruited 483 MS patients and 880 non-MS patients, including neuro-inflammatory diseases (NID, n = 595) and non-inflammatory neurological diseases (NIND, n=285). Using a standardized case report form (CRF) to collect the clinical, radiological, immunological, and CSF data, we explored the association of CSF-OCB positivity with patient characters and the diagnostic performance of CSF-OCB in Chinese MS patients. Prospective source data collection, and retrospective data acquisition and statistical data analysis were used.Findings369 (76.4%) MS patients were OCB-positive, while 109 NID patients (18.3%) and 6 NIND patients (2.1%) were OCB-positive, respectively. Time from symptom onset to diagnosis was significantly shorter in OCB-positive than that in OCB-negative MS patients (13.2 vs 23.7 months, P=0.020). The prevalence of CSF-OCB in Chinese MS patients was significantly higher in high-latitude regions (41°-50°N)(P=0.016), and at high altitudes (>1000m)(P=0.025). The diagnostic performance of CSF-OCB differentiating MS from non-MS patients yielded a sensitivity of 76%, a specificity of 87%.InterpretationThe nationwide prevalence of CSF-OCB was 76.4% in Chinese MS patients, and demonstrated a good diagnostic performance in differentiating MS from other CNS diseases. The CSF-OCB prevalence showed a correlation with high latitude and altitude in Chinese MS patients

Cyclosporine A Promotes Bone Remodeling in LPS-Related Inflammation via Inhibiting ROS/ERK Signaling: Studies In Vivo and In Vitro

In some inflammatory diseases of bone, osteogenesis and osteoclasis are uncoupled and the balance is usually tipped resulting in bone destruction. The underlying mechanism of osteogenic dysfunction in inflammation still needs further study. This study is aimed at investigating the effects of cyclosporine A (CsA) on bone remodeling in lipopolysaccharide- (LPS-) related inflammation. In vivo, an alveolar bone defect model was established using 10-week-old C57BL/6J mice. The mice were divided into phosphate-buffered saline (PBS), LPS, and LPS+CsA groups. After 3 weeks, micro-CT analysis and histomorphometric evaluation were conducted. In vitro, murine osteoblasts were treated with vehicle medium, LPS, LPS+CsA, LPS+extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor (LPS+PD98059), and LPS+antioxidant (LPS+EUK134). Cell proliferation, osteogenic behaviors, oxidative stress, and ERK signaling were determined. By these approaches, LPS inhibited bone remodeling and promoted oxidative stress accumulation in alveolar bone defects. When animals were treated with CsA, all LPS-induced biochemical changes ameliorated with a marked protective effect. In vitro, the reactive oxygen species (ROS) levels in mitochondria increased in LPS-treated osteoblasts, with decreased expression of osteogenic differentiation genes. The CsA, PD98059, and EUK134 presented remarkable protective effects against LPS treatment. CsA effectively enhanced bone remodeling and attenuated oxidative stress caused by LPS via inhibiting ROS/ERK signaling. Taken together, the protective effect of CsA and the inhibitory effect of ERK signaling on the maintenance of mitochondrial function and reduction of ROS levels hold promise as a potential novel therapeutic strategy for inflammatory diseases in bones

Integrated single-cell and bulk RNA sequencing analysis identifies a neoadjuvant chemotherapy-related gene signature for predicting survival and therapy in breast cancer

Abstract Neoadjuvant chemotherapy (NAC) is a well-established treatment modality for locally advanced breast cancer (BC). However, it can also result in severe toxicities while controlling tumors. Therefore, reliable predictive biomarkers are urgently needed to objectively and accurately predict NAC response. In this study, we integrated single-cell and bulk RNA-seq data to identify nine genes associated with the prognostic response to NAC: NDRG1, CXCL14, HOXB2, NAT1, EVL, FBP1, MAGED2, AR and CIRBP. Furthermore, we constructed a prognostic risk model specifically linked to NAC. The clinical independence and generalizability of this model were effectively demonstrated. Additionally, we explore the underlying cancer hallmarks and microenvironment features of this NAC response-related risk score, and further assess the potential impact of risk score on drug response. In summary, our study constructed and validated a nine-gene signature associated with NAC prognosis, which was accomplished through the integration of single-cell and bulk RNA data. The results of our study are of crucial significance in the prediction of the efficacy of NAC in BC, and may have implications for the clinical management of this disease

HDAC6 Regulates the Chaperone-Mediated Autophagy to Prevent Oxidative Damage in Injured Neurons after Experimental Spinal Cord Injury

Hypoxia-ischemia- (HI-) induced oxidative stress plays a role in secondary pathocellular processes of acute spinal cord injury (SCI) due to HI from many kinds of mechanical trauma. Increasing evidence suggests that the histone deacetylase-6 (HDAC6) plays an important role in cell homeostasis in both physiological and abnormal, stressful, pathological conditions. This paper found that inhibition of HDAC6 accelerated reactive oxygen species (ROS) generation and cell apoptosis in response to the HI. Deficiency of HDAC6 hindered the chaperone-mediated autophagy (CMA) activity to resistance of HI-induced oxidative stress. Furthermore, this study provided the experimental evidence for the potential role of HDAC6 in the regulation of CMA by affecting HSP90 acetylation. Therefore, HDAC6 plays an important role in the function of CMA pathway under the HI stress induced by SCI and it may be a potential therapeutic target in acute SCI model

Removal of Pharmaceuticals and Illicit Drugs from Wastewater Due to Ferric Dosing in Sewers

Ferric (Fe3+) salt dosing is an efficient sulfide control strategy in the sewer network, with potential for multiple benefits including phosphorus removal in the biological reactors and sulfide emission control in the anaerobic digesters of wastewater treatment plant (WWTP). This paper extends the knowledge on the benefit of iron dosing by exploring its impact on the fate of organic micropollutants (MPs) in the wastewater using sewer reactors simulating a rising main sewer pipe. The sulfide produced by the sewer biofilms reacted with Fe3+ forming black colored iron sulfide (FeS). Among the selected MPs, morphine, methadone, and atenolol had \u3e90% initial rapid removal within 5 min of ferric dosing in the sewer reactor. The ultimate removal after 6 h of retention time in the reactor reached 93-97%. Other compounds, ketamine, codeine, carbamazepine, and acesulfame had 30-70% concentration decrease. The ultimate removal varied between 35 and 70% depending on the biodegradability of those MPs. In contrast, paracetamol had no initial removal. The rapid removal of MPs was likely due to adsorption to the FeS surface, which is further confirmed by batch tests with different FeS concentrations. The results showed a direct relationship between the removal of MPs and FeS concentration. The transformation kinetics of these compounds in the reactor without Fe3+ dosing is in good agreement with biodegradation associated with the sewer biofilms in the reactor. This study revealed a significant additional benefit of dosing ferric salts in sewers, that is, the removal of MPs before the sewage enters the WWTP