Recent advances in application of computer-aided drug design in anti-COVID-19 Virials Drug Discovery.

Corona Virus Disease 2019 (COVID-19) is a global pandemic epidemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which poses a serious threat to human health worldwide and results in significant economic losses. With the continuous emergence of new virus strains, small molecule drugs remain the most effective treatment for COVID-19. The traditional drug development process usually requires several years; however, the development of computer-aided drug design (CADD) offers the opportunity to develop innovative drugs quickly and efficiently. The literature review describes the general process of CADD, the viral proteins that play essential roles in the life cycle of SARS-CoV-2 and can serve as therapeutic targets, and examples of drug screening of viral target proteins by applying CADD methods. Finally, the potential of CADD in COVID-19 therapy, the deficiency, and the possible future development direction are discussed.

Temporal and Spatial Evolution of the African Swine Fever Epidemic in Vietnam.

African swine fever (ASF) is a severe infectious disease affecting domestic and wild suids. Spatiotemporal dynamics analysis of the ASF is crucial to understanding its transmission. The ASF broke out in Vietnam in February 2019. The research on the spatiotemporal evolution characteristics of ASF in Vietnam is lacking. Spatiotemporal statistical methods, including direction analysis, spatial autocorrelation analysis, and spatiotemporal scan statistics were used to reveal the dynamics of the spatial diffusion direction and spatiotemporal aggregation characteristics of ASF in Vietnam. According to the cessation of the epidemic, it was divided into three phases: February to August 2019 (phase 1), April to December 2020 (phase 2), and January 2021 to March 2022 (phase 3). The ASF showed a significant spread trend from north to south in phase 1. The occurrence rate of the ASF aggregated spatially in phase 1 and became random in phases 2 and 3. The high-high ASF clusters (the province was a high cluster and both it and its neighbors had a high ASF occurrence rate) were concentrated in the north in phases 1 and 2. Four spatiotemporal high-risk ASF clusters were identified with a mean radius of 121.88 km. In general, there were significant concentrated outbreak areas and directional spread in the early stage and small-scale, high-frequency, and randomly scattered outbreaks in the later stage. The findings could contribute to a deeper understanding of the spatiotemporal spread of the ASF in Vietnam.

Pinocembrin alleviates chronic morphine-induced analgesic tolerance and hyperalgesia by inhibiting microglial activation.

BACKGROUND: Chronic opioid induced analgesic tolerance is a major obstacle in pain management. Microglial activation is involved in morphine tolerance and pinocembrin suppresses microglial activation in several disease models. We aim to investigate whether and how pinocembrin alleviates morphine tolerance. METHODS: We induced chronic morphine tolerance in mice by daily morphine injection, with some mice receiving pinocembrin. Analgesic tolerance and hyperalgesia were determined by behavioral assays. The effects of pinocembrin on morphine induced microglial activation, neuroinflammation, and STAT3 activation were determined by Iba1 immunostaining, Il1b and Tnfa mRNA levels and STAT3 phosphorylation. Finally, the effects of STAT3 inhibition on chronic morphine tolerance were assessed. RESULTS: We show that pinocembrin not only suppressed but also reversed preexisting chronic morphine tolerance and hyperalgesia. We found that chronic administration of morphine lead to microglial activation and neuroinflammation, which were suppressed by pinocembrin. Our results reveal a strong connection of STAT3 with morphine tolerance and pinocembrin suppressed morphine-induced STAT3 activation both in vivo and in BV2 cells. Finally, we show that STAT3 inhibition is sufficient to suppress morphine tolerance and hyperalgesia. CONCLUSION: Our study suggests that pinocembrin effectively prevents and alleviates chronic morphine tolerance through inhibition of STAT3 mediated microglia activation and neuroinflammation.

Impact analysis of environmental and social factors on early-stage COVID-19 transmission in China by machine learning.

As a highly contagious disease, COVID-19 caused a worldwide pandemic and it is still ongoing. However, the infection in China has been successfully controlled although its initial transmission was also nationwide and has caused a serious public health crisis. The analysis on the early-stage COVID-19 transmission in China is worth investigating for its guiding significance on prevention to other countries and regions. In this study, we conducted the experiments from the perspectives of COVID-19 occurrence and intensity. We eliminated unimportant factors from 113 variables and applied four machine learning-based classification and regression models to predict COVID-19 occurrence and intensity, respectively. The influence of each important factor was analysed when applicable. Our optimal model on COVID-19 occurrence prediction presented an accuracy of 91.91% and the best R2 of intensity prediction reached 0.778. Linear regression-based model was identified as unable to fit and predict the intensity, and thus only the variable influence on COVID-19 occurrence can be explained. We found that (1) CO VID-19 was more likely to occur in prosperous cities closer to the epicentre and located on higher altitudes, (2) and the occurrence was higher under extreme weather and high minimum relative humidity. (3) Most air pollutants increased the risk of COVID-19 occurrence except NO2 and O3, and there existed a lag effect of 6-7 days. (4) NPIs (non-pharmaceutical interventions) did not show apparent effect until two weeks after.

Circ-FAT1 Up-Regulates FOSL2 Expression by Sponging miR-619-5p to Facilitate Colorectal Cancer Progression.

Circular RNA FAT atypical cadherin 1 (circ-FAT1) has been reported to play roles in colorectal cancer (CRC) development. Here, the purpose of this study was to investigate the function and mechanism of circ-FAT1 in CRC tumorigenesis and its potential value in the clinic. Levels of genes and proteins were examined by quantitative real-time polymerase chain reaction and Western blot. In vitro assays were conducted using cell counting kit-8 assay, 5-Ethynyl-2'-deoxyuridine assay, flow cytometry, transwell assay, and tube formation assay, respectively. The target relationship between miR-619-5p and circ-FAT1 or FOS-like antigen 2 (FOSL2) was verified by dual-luciferase reporter and RNA immunoprecipitation assays. In vivo assay was performed using a mouse subcutaneous xenograft model. Circ-FAT1 and FOSL2 were highly expressed in CRC tissues and cells. Functionally, knockdown of circ-FAT1 or FOSL2 suppressed CRC cell apoptosis, migration, invasion, and angiogenesis, but induced cell apoptosis in vitro. Mechanistically, circ-FAT1 acted as a sponge for miR-619-5p to up-regulate the expression of FOSL2, which was confirmed to be a target of miR-619-5p. A series of rescue experiments demonstrated that miR-619-5p inhibition or FOSL2 overexpression reversed the inhibitory action of circ-FAT1 silencing on CRC cell malignant phenotypes mentioned above. Pre-clinically, lentivirus-mediated circ-FAT1 knockdown inhibited the tumorigenesis of CRC xenografts in nude mice via regulating miR-619-5p and FOSL2. Circ-FAT1 knockdown repressed FOSL2 expression by sponging miR-619-5p to suppress CRC tumorigenesis, providing a potential approach for CRC therapeutics.

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.

A multiplicity of environmental, economic and social factor analyses to understand COVID-19 diffusion.

Research on the impact of the environment on COVID-19 diffusion lacks a full-comprehensive perspective, and neglecting the multiplicity of the human-environment system can lead to misleading conclusions. We attempted to reveal all pre-existing environmental-to-human and human-to-human determinants that influence the transmission of COVID-19. As such, We estimated the daily case incidence ratios (CIR) of COVID-19 for prefectures across mainland China, and used a mixed-effects mixed-distribution model to study the association between the CIR and 114 factors related to climate, atmospheric environmental quality, terrain, population, economic, human mobility as well as non-pharmaceutical interventions (NPIs). Not only the changes in determinants over time as the pandemic progresses but also their lag and interaction effects were examined. CO, O3, PM10 and PM2.5 were found positively linked with CIR, but the effect of NO2 was negative. The temperature had no significant association with CIR, and the daily minimum humidity was a significant negatively predictor. NPIs' level was negatively associated with CIR until with a lag of 15 days. Higher accumulated destination migration scale flow from the epicenter and lower distance to the epicenter (DisWH) were associated with a higher CIR, however, the interaction between DisWH and the time was positive. The more economically developed and more densely populated cities have a higher probability of CIR occurrence, but they may not have a higher CIR intensity.The COVID-19 diffusion are caused by a multiplicity of environmental, economic, social factors as well as NPIs. First, multiple pollutants carried simultaneously on particulate matter affect COVID-19 transmission. Second, the temperature has a limited impact on the spread of the epidemic. Third, NPIs must last for at least 15 days or longer before the effect has been apparent. Fourth, the impact of population movement from the epicenter on COVID-19 gradually diminished over time and intraregional migration deserves more attention.

Exosomes Derived by SIRT1-Overexpressing Bone Marrow Mesenchymal Stem Cells Improve Pubococcygeus Muscle Injury in Rats.

BACKGROUND AND OBJECTIVES: To evaluate the effect of exosomes (Exos) derived from silent mating type information regulation 2 homolog 1 (SIRT1)-overexpressing human bone marrow mesenchymal stem cells (BMSCs) on the recovery of pubococcygeus muscle Injury. METHODS AND RESULTS: Exos isolated from SIRT1-overexpressing BMSCs (SIRT1/exos) were injected into a vaginal dilation-induced rat model of Stress urinary incontinence (SUI). The efficacy of Exos treatment on SUI was evaluated by determining the values of urodynamic parameters. The proliferation and differentiation of satellite cells (SCs) were examined by CCK-8 assay, Western blotting, and immunofluorescence staining. The mRNA and protein expression of molecules related to SC differentiation were detected by RT-qPCR and Western blotting, respectively. Treatment with SIRT1/exos significantly improved the values of abdominal leak point pressure (ALPP), maximum bladder volume (MBV), and estimated marginal mean in rats of SUI. Exposure of SIRT1/exos enhanced the proliferation, differentiation, and activation of SCs. Moreover, SIRT1/exos exhibited their positive effect on BMSCs by activating the ERK signaling. CONCLUSIONS: Our findings demonstrated that SIRT1/exos meliorated pubococcygeus muscle injury in rats by promoting ERK pathway, which may provide a novel cell-free therapeutic strategy for SUI.

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.

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.

Lethal diquat poisoning manifesting as central pontine myelinolysis and acute kidney injury: A case report and literature review.

Diquat is a nonselective herbicide that is used as a contact and preharvest desiccant to control terrestrial and aquatic vegetation. Increasing numbers of cases of diquat poisoning have recently been reported. Organs commonly affected by diquat poisoning include the kidney, liver, and lung. Neurological involvement of diquat poisoning is relatively rare. A 21-year-old man ingested 100 mL of diquat (20 g/100 mL) 5 hours before admission. Fifteen minutes after ingestion, he developed nausea and vomiting. The patient was sent to the emergency intensive care unit, and gastric lavage was performed. Continuous renal replacement therapy and continuous venovenous hemodiafiltration with hemoperfusion were performed, and methylprednisolone was administered. Five days after admission, the patient developed disturbance of consciousness and positive bilateral Babinski signs. Head computed tomography demonstrated hypodensity in the pons. At 11 days after admission, brain magnetic resonance imaging showed acute pontine demyelination. At 15 days after admission, the patient died of multiple organ dysfunction syndrome. We encountered a case of diquat poisoning with central pontine myelinolysis and acute kidney injury. This case highlights the clinical value of neuroimaging examination for early diagnosis of central pontine myelinolysis.

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.

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.

Elevated frequencies of total and MAIT cell subsets in patients with knee osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is characterized by the degeneration of joint cartilage, with concomitant changes in the synovium and subchondral bone. Recently, the inflammatory response and involvement of several types of T-cells has been implicated in the development of OA. This study investigated the frequency of MR1-restricted mucosal-associated invariant T (MAIT) cells in patients with knee OA. METHODS: Forty-five patients recently diagnosed with knee OA and 21 age- and gender-matched healthy controls were recruited for this study. Percentages of circulating MAIT cells were assessed by flow cytometry. Plasma cytokine levels were measured using cytometric bead arrays. Associations between the percentages of MAIT cells, plasma cytokine levels, and clinical parameters of OA (erythrocyte sedimentation rate [ESR] and the Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) were analyzed using the Spearman correlation test. RESULTS: The percentages of total, CD8αα, and CD8αß MAIT cells were higher in patients with OA compared to healthy controls. The percentages of total and CD8αα MAIT cells were higher in patients with multi-joint OA (MOA) compared to patients with knee-only OA (KOA). Plasma IFN-γ and TNF-α levels were elevated in patients with OA compared to healthy controls, and there was a positive correlation between plasma IFN-γ levels and the percentages of total, CD8αα, and CD8αß MAIT cells. Plasma IFN-γ and IL-17 levels were higher in patients with MOA compared to healthy controls or patients with KOA. There were positive correlations between the percentages of total and CD8αα MAIT cells and clinical parameters (ESR and WOMAC scores) in patients with OA or MOA. Binary logistic regression analysis shown the frequency of MAIT cells was associated with the risk of OA. CONCLUSIONS: MAIT cells and their subpopulations were significantly increased in patients with OA and have potential as biological markers of OA disease severity, especially in patients with MOA.

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.

Napabucasin, a novel STAT3 inhibitor suppresses proliferation, invasion and stemness of glioblastoma cells.

BACKGROUND: Glioblastoma (GBM) cells with stem cell-like properties are called glioma stem cells (GSCs). GSCs display highly treatment resistance and are responsible for tumor recurrence. Napabucasin (BBI608), a novel small molecule inhibitor of STAT3, has been identified to eliminate stemness-like tumor cells in some cancers. However, the influence of Napabucasin on GBM cells, especially on GSCs, is currently unclear. In this study, we explored the influence and underlying mechanisms of Napabucasin on GBM cells. METHODS: STAT3 expression and its correlation with the glioma grade and patient survival were analyzed using CGGA and TCGA glioma databases. The influence of Napabucasin on proliferation, stemness, the cell cycle, apoptosis, and invasion of human GBM cell lines U87MG and LN229 was tested by CCK8, EdU incorporation, colony formation, Transwell invasion, and three-dimensional spheroid assays as well as flow cytometry, qPCR, and western blot analysis. The ability of Napabucasin to inhibit cell proliferation of U87MG tumor xenografts in mice was assessed using a live animal bioluminescence imaging system and immunohistochemistry. RESULTS: Napabucasin suppressed the proliferation, colony formation, and invasion of U87MG and LN229 cells. Furthermore, Napabucasin induced cell cycle arrest and apoptosis. More importantly, Napabucasin treatment obviously inhibited expression of stemness-associated genes including STAT3 and suppressed the spheroid formation of glioma cells in vitro. Napabucasin also disrupted the NF-κB signaling pathway via downregulation of RelA (p65). Finally, glioma growth was effectively impaired by Napabucasin in nude mice bearing intracranial glioma xenografts. CONCLUSIONS: Napabucasin treatment may be a novel approach for the treatment of GBM, particularly GSCs.

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.

LncRNA HIF2PUT inhibited osteosarcoma stem cells proliferation, migration and invasion by regulating HIF2 expression.

PURPOSE: The function of lncRNAs in cancer stem cells (CSCs) remains to be elucidated. The present study aimed to investigate the regulating role of a novel lncRNA, hypoxia-inducible factor-2α (HIF-2α) promoter upstream transcript (HIF2PUT), in osteosarcoma stem cells. METHODS: The expression of lncRNA HIF2PUT and HIF-2α in osteosarcoma stem cell lines and tissues was monitored by real-time PCR and western blot. The proliferation ability was examined by MTT assay when HIF2PUT overexpression or knockdown. The self-renewing capabilities of the cells were assessed by spheroid formation assay. The migration and invasion of cells were monitored by wound-healing assay and transwell cell assay, respectively. The correlation of HIF2PUT and HIF-2α expression was determined in osteosarcoma cancer tissues. RESULTS: LncRNA HIF2PUT and HIF-2α were downregulated in osteosarcoma cell lines. HIF2PUT exhibited a significant decline in proliferation capacity. Wound healing and transwell assays showed that lncRNA overexpression inhibited osteosarcoma stem cell migration and invasion. HIF2PUT inhibited sphere formation in osteosarcoma stem cells. Increased HIF2PUT expression inhibited the enrichment of CD133 in osteosarcoma stem cells. There was a strong positive correlation between relative HIF2PUT level and relative HIF-2α level in the 30 paired osteosarcoma cancer tissues. CONCLUSIONS: Overexpression of lncRNA HIF2PUT significantly attenuated the proliferation, migration and invasion of osteosarcoma stem cells. Furthermore, we demonstrated that lncRNA overexpression inhibited the sphere-formation of osteosarcoma stem cells by downregulating HIF-2α. These findings suggest that lncRNA HIF2PUT may act as a tumour suppressor in osteosarcoma. LncRNA HIF2PUT/HIF-2α may be a novel therapeutic target in the treatment of osteosarcoma.

CREB Protects against Temporal Lobe Epilepsy Associated with Cognitive Impairment by Controlling Oxidative Neuronal Damage.

BACKGROUND: Cognitive dysfunction as a common comorbidity of epilepsy often manifests as learning and memory impairments in patients with temporal lobe epilepsy (TLE). The pathogenetic molecular mechanisms underlying epilepsy-associated cognitive dysfunction are incompletely understood. We investigated the role of cAMP response element binding protein (CREB) and its downstream signaling pathways in the pathogenesis of cognitive impairment in mice with TLE. METHODS: Plasmid vectors of CREB-specific short-hairpin RNAs and CREB cDNA were prepared and transfected into primary neurons. Neuronal apoptosis and mitochondrial oxidative stress were assessed by flow cytometry. For in vivo studies, TLE in mice was induced by pilocarpine injection, and TLE-associated memory decline was evaluated using the Morris water maze after treatment with the CREB inhibitor 666-15, with or without the mitochondria-specific antioxidant MitoQ. CREB and its downstream mediators were examined by Western blotting analysis and quantitative reverse transcription polymerase chain reaction. RESULTS: CREB knockdown induced mitochondrial reactive oxygen species production and apoptosis in primary neurons whereas CREB overexpression brought the opposite effects. The TLE mice exhibited elevated oxidative stress and neuronal apoptosis with decreased expression of CREB and its downstream mediators including PKA, CaMKIV, arc, and c-fos. CREB inhibition exacerbated TLE-associated oxidative neuronal apoptosis and memory decline. MitoQ treatment restored the expression of CREB and its downstream mediators, and prevented TLE-associated oxidative neuronal damage and memory deficits aggravated by CREB inhibition. CONCLUSION: CREB plays a significant role in TLE-associated oxidative neuronal damage and memory impairment. This novel finding provides the evidence of the relationship between CREB and mitochondrial oxidative stress and cognitive dysfunction in epilepsy. Mitochondria-specific antioxidants such as MitoQ may alleviate TLE-associated cognitive dysfunction through activation of CREB and its downstream signaling pathways.