Identification of key genes as predictive biomarkers for osteosarcoma metastasis using translational bioinformatics.

BACKGROUND: Osteosarcoma (OS) metastasis is the most common cause of cancer-related mortality, however, no sufficient clinical biomarkers have been identified. In this study, we identified five genes to help predict metastasis at diagnosis. METHODS: We performed weighted gene co-expression network analysis (WGCNA) to identify the most relevant gene modules associated with OS metastasis. An important machine learning algorithm, the support vector machine (SVM), was employed to predict key genes for classifying the OS metastasis phenotype. Finally, we investigated the clinical significance of key genes and their enriched pathways. RESULTS: Eighteen modules were identified in WGCNA, among which the pink, red, brown, blue, and turquoise modules demonstrated good preservation. In the five modules, the brown and red modules were highly correlated with OS metastasis. Genes in the two modules closely interacted in protein-protein interaction networks and were therefore chosen for further analysis. Genes in the two modules were primarily enriched in the biological processes associated with tumorigenesis and development. Furthermore, 65 differentially expressed genes were identified as common hub genes in both WGCNA and protein-protein interaction networks. SVM classifiers with the maximum area under the curve were based on 30 and 15 genes in the brown and red modules, respectively. The clinical significance of the 45 hub genes was analyzed. Of the 45 genes, 17 were found to be significantly correlated with survival time. Finally, 5/17 genes, including ADAP2 (P = 0.0094), LCP2 (P = 0.013), ARHGAP25 (P = 0.0049), CD53 (P = 0.016), and TLR7 (P = 0.04) were significantly correlated with the metastatic phenotype. In vitro verification, western blotting, wound healing analyses, transwell invasion assays, proliferation assays, and colony formation assays indicated that ARHGAP25 promoted OS cell migration, invasion, proliferation, and epithelial-mesenchymal transition. CONCLUSION: We identified five genes, namely ADAP2, LCP2, ARHGAP25, CD53, and TLR7, as candidate biomarkers for the prediction of OS metastasis; ARHGAP25 inhibits MG63 OS cell growth, migration, and invasion in vitro, indicating that ARHGAP25 can serve as a promising specific and prognostic biomarker for OS metastasis.

Caffeine-induced nuclear translocation of FoxO1 triggers Bim-mediated apoptosis in human glioblastoma cells.

Caffeine is one of the most commonly ingested neuroactive compounds and exhibits anticancer effects through induction of apoptosis and suppression of cell proliferation. However, the mechanisms underlying these effects are currently unknown. In this study, we investigated the mechanisms of caffeine-induced apoptosis in U251 cells (human glioma cell line). We analyzed the inhibitory effects of caffeine on cell proliferation by performing WST-8 and colony formation assays; in addition, cell survival was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and flow cytometric analysis. Western blotting was used to investigate the role played by FoxO1 in the proapoptotic effects of caffeine on glioma cells. Results showed that caffeine inhibited proliferation and survival of human glioma cells, induced apoptosis, and increased the expression of FoxO1 and its proapoptotic target Bim. In addition, we found that FoxO1 enhanced the transcription of its proapoptotic target Bim. In summary, our data indicates that FoxO1-Bim mediates caffeine-induced regression of glioma growth by activating cell apoptosis, thereby providing new mechanistic insight into the possible use of caffeine in treating human cancer.

Fenofibrate induces G0/G1 phase arrest by modulating the PPARα/FoxO1/p27 kip pathway in human glioblastoma cells.

Fenofibrate, a fibric acid derivative, is known to possess lipid-lowering effects. Although fenofibrate-induced peroxisome proliferator-activated receptor alpha (PPARα) transcriptional activity has been reported to exhibit anticancer effects, the underlying mechanisms are poorly understood. In this study, we investigated the mechanisms behind the antiproliferative effects of fenofibrate in U87MG cells (human glioma cell line) using the WST-8 Cell Proliferation Assay Kit. Furthermore, we examined genome-wide gene expression profiles and molecular networks using the DAVID online software. Fenofibrate reduced the expression of 405 genes and increased the expression of 2280 genes. DAVID analysis suggested that fenofibrate significantly affected cell cycle progression and pathways involved in cancer, including the mTOR signaling pathway and insulin signaling pathway. Results of flow cytometry analysis indicated that fenofibrate induced cell cycle G0/G1 arrest in U87MG cells. Furthermore, we identified the FoxO1-p27(kip) signaling axis to be involved in fenofibrate-induced cell cycle arrest. Our findings suggest that in addition to its known lipid-lowering effects, fenofibrate may be used as an antitumor agent in glioma therapy.

Can kissing cause paraquat poisoning: A case report and review of literature.

BACKGROUND: Paraquat is an effective, broad-spectrum, highly toxic quaternary ammonium herbicide. Paraquat poisoning has been reported frequently in recent years. It has severe lung, kidney, liver, and nervous system toxicity, and there is currently no specific antidote. Paraquat poisoning may follow ingestion, inhalation, and skin contact. There have been no previous reports of paraquat poisoning that resulted from kissing. This rare case provides a new reference for the prevention of paraquat poisoning. CASE SUMMARY: A 27-year-old man came to the emergency department complaining that he had come into contact with paraquat by kissing his girlfriend, who had taken 80-120 mL 20% paraquat. After admission, his lung computed tomography (CT) showed increased lung markings. Redness and a burning sensation developed on his tongue, which progressed to painful erosions and coalescent ulcers. The final diagnosis was mild paraquat poisoning. Anti-inflammatory, antioxidant, and symptomatic treatment were initiated and continued for 7 d. Dyspnea did not occur, subsequent lung CT showed no significant changes, and the tongue pain was slightly improved. One month after discharge, the tongue injury was resolved. CONCLUSION: This case indicated that the tongue and lung tissues are particularly vulnerable to paraquat toxicity, even after a limited exposure.

Protrusion of a ceramic femoral head through the acetabular metallic cup in total-hip arthroplasty: A case report.

RATIONALE: Dislocation, wear, metallosis, and implant loosening are well-known complications of a failed total-hip arthroplasty (THA), and acetabular liner dissociation is an uncommon but catastrophic complication. To our knowledge, this is the first description of metallosis due to acetabular liner dissociation, but not presenting as a result of wear of a metal-on-metal articulation and a polyethylene liner of other articulation. PATIENT CONCERNS: We described a 61-year-old man who had a 2-year history of pain in the right groin region after THA. Postoperative period of primary THA was uneventful. However, he did not undergo postoperative follow-up, and often participated in strenuous sports activities including mountain climbing and long-distance running. DIAGNOSIS: Radiographs demonstrated superior subluxation of the femoral head and direct articulation and abrasion wear of the ceramic femoral head on the cup. Preoperative laboratory data revealed no signs of infection. INTERVENTIONS: We performed revision THA using a direct lateral approach with ceramic-on-ceramic hip prosthesis. OUTCOMES: Postoperatively, the patient wore a hip orthosis for 6 weeks to prevent dislocation but was allowed full weight bearing. At 1-year follow-up, there was no recurrence of hip pain. LESSONS: Wear of THA components can result in catastrophic failure of the implants and significant soft-tissue metallosis. Therefore, regular postoperative follow-up is necessary for early intervention, even in those with asymptomatic hips.

An Update on the Emerging Role of Visfatin in the Pathogenesis of Osteoarthritis and Pharmacological Intervention.

Osteoarthritis (OA) is one of the most common degenerative joint diseases that affects millions of people worldwide, mainly the aging population. Despite numerous published reports, little is known about the pathology of this disease, and no feasible treatment plan exists to stop OA progression. Recently, extensive basic and clinical studies have shown that adipokines play a key role in OA development. Moreover, some drugs associated with adipokines have shown chondroprotective and anti-inflammatory effects on OA. Visfatin has been shown to play a detrimental role in the progression of OA. It increases the production of matrix metalloproteinases and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), induces the production of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α, affects the differentiation of mesenchymal stem cells to adipocytes, and induces osteophyte formation by inhibiting osteoclastogenesis. Although some side effects of chemical visfatin inhibitors have been reported, they were shown to be successful in the treatment of diabetes, cancer, and other diseases that can utilize Chinese herbs, further suggesting that similar therapeutic strategies could be used in OA prevention and treatment. Here, we describe the pathophysiological mechanism of visfatin in OA and discuss some potential pharmacological interventions using Chinese herbs.

Protective Effects and Mechanisms of Action of Ulinastatin against Cerebral Ischemia-Reperfusion Injury.

BACKGROUND: Cerebral ischemia-reperfusion injury is an extremely complicated pathological process that is clinically characterized by high rates of disability and mortality. It is imperative to explore some effective neuroprotective agents for its treatment. Ulinastatin is a protease inhibitor with anti-inflammatory and antioxidant activity. For the past few years, new studies of ulinastatin for the treatment of ischemic brain injury have emerged. OBJECTIVE: We conducted a review to summarize the mechanisms of ulinastatin and analyze its neuroprotective action against cerebral ischemia-reperfusion injury. METHODS: We reviewed and summarized pertinent reports published between 1993 and 2019 from PubMed, Web of Science, and Embaseby searching for the scientific terms ulinastatin, cerebral ischemia-reperfusion injury, neuroprotective, stroke, cardiac arrest, and brain edema. RESULTS: The protective mechanisms of ulinastatin in the key steps of cerebral ischemia-reperfusion injury include inhibition of inflammatory response, oxidative stress, neuronal apoptosis, neuronal autophagy, and aquaporin- 4 expression as well as improvement in blood-brain barrier permeability. In addition, we provide a perspective on potential research directions and clinical safety. CONCLUSION: Ulinastatin seems to have the potential to alleviate cerebral ischemia-reperfusion injury. These findings may be valuable to further promote the research and development of drug candidates and provide novel and reliable references for rational drug use.

A Mini Review: Stem Cell Therapy for Osteonecrosis of the Femoral Head and Pharmacological Aspects.

Osteonecrosis of the femoral head (ONFH) is a common disease that occurs frequently. Due to various etiologies, the blood supply directed to the femoral head is interrupted in patients with ONFH. This disease can result in degeneration and necrosis of the subchondral bone of the femoral head, which ultimately cause a collapse of the femoral head. Of note, ONFH can extremely affect the quality of living of patients with a high disability rate. Also, this disease often includes middle-aged and younger people. However, effective treatments of ONFH are still challenging in clinics. In recent years, stem cells have been profoundly studied and a relevant new technology has been developed rapidly and applied for regenerative medicine. A number of reports have demonstrated successful results of the treatment of ONFH by using stem cell transplantation. By the combination of minimally invasive hip decompression and injection of mesenchymal stem cells into the necrotic lesion, the retrospective analysis of patients treated revealed that significant pain relief was observed in 86% patients and they had no major complications after treatment. Thus, stem cell transplantation is anticipated to be applied as an innovative approach in the treatment of ONFH. This review will summarize results obtained from recent human and animal studies, which include the pathophysiological process of ONFH, current techniques and effects of using stem cells on the treatment of ONFH together with pharmacological aspects. Overall, the current evidence reveals the treatment of ONFH using stem cell technology as promising. Nonetheless, additional in-depth studies are necessary to better explore the application of this technology and seek more ideal approaches to minimize difficulties related to stem cells.

Neuronal NMDAR Currents of the Hippocampus and Learning Performance in Autoimmune Anti-NMDAR Encephalitis and Involvement of TNF-α and IL-6.

Among autoimmune encephalitis, patients with anti-N-methyl D- aspartate receptor (NMDAR) encephalitis typically present epileptic seizures, memory deficits and psychiatric symptoms. However, the signal mechanisms leading to the functional disorders of autoantibodies are largely unclear. In this study, anti-NMDAR antibody was administered into dentate gyri against the NR1 subunit of the NMDAR. The purpose of the study examined the effects of pro-inflammatory tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) on neuronal NMDAR currents of the hippocampus in rats with anti-NMDAR encephalitis and we further determined the role played by TNF-α and IL-6 in modulating learning performance. In results, we observed a decrease in amplitude of the NMDAR-mediated excitatory postsynaptic currents (NMDAR-EPSCs) in the hippocampal neurons of animals treated with anti-NMDAR. In those rats with anti-NMDAR, we also observed impaired learning performance in the Morris water maze and spatial working memory test. Of note, cerebral infusion of TNF-α and IL-6 worsened NMDAR-EPSCs and this was accompanied with exaggeration of impaired learning performance. In conclusion, our findings suggest that the role played by neuroinflammation in exacerbating the memory impairment found in animals treated with anti-NMDAR. Anti-inflammation is a potential target in improving the memory impairment induced by anti-NMDA encephalitis.

A Combination of Ulinastatin and Xuebijing Amplifies Neuroprotection after Transient Cerebral Ischemia via Attenuating Apoptosis Signal Pathways in Hippocampus.

BACKGROUND: Ulinastatin (UTI) plays the beneficial roles in modifying cerebral ischemic injury evoked by cardiac arrest (CA). XueBiJing (XBJ), comprised of extracts from Chinese herbals, has been used for the treatment of sepsis and ischemic disorders linked to multiple organ dysfunction syndromes. The current study was to find interventions that can enhance effectiveness of these drugs and further to provide a fundamental for their rational application in clinical practice. Thus, we examined how apoptosis signal in the hippocampus is engaged in a facilitating role of UTI and XBJ in improving neural injury and neurological functions after transient cerebral ischemia. METHODS: CA was induced by asphyxia followed by cardiopulmonary resuscitation in rats. Western Blot analysis and ELISA were employed to determine the protein expression of Caspase-3 and Caspase-9 in the hippocampus; and representative apoptosis pathways. The modified neurological severity score (mNSS) and spatial working memory performance were used to assess neurological deficiencies in CA rats. RESULTS: CA increased Caspase-3 and Caspase-9 in the hippocampus CA1 region. A lower dose of UTI did not attenuate upregulation of apoptosis signal pathways evoked by CA. However, a systemic administration of XBJ significantly amplified the inhibitory effects of the lower dose of UTI on apoptosis signal of the hippocampus. In addition, a combination of UTI and XBJ improved mNSS and spatial working memory performance to a greater degree. CONCLUSIONS: Our data indicate that a combination of XBJ and UTI plays a facilitating role in improving neuronal injury and neurological deficits observed in transient cerebral ischemia; and an inhibition of apoptosis signal pathways is involved in neuroprotective effects of united XBJ and UTI.