Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis

Ferroptosis is an iron-dependent novel cell death pathway. Deferoxamine, a ferroptosis inhibitor, has been reported to promote spinal cord injury repair. It has yet to be clarified whether ferroptosis inhibition represents the mechanism of action of Deferoxamine on spinal cord injury recovery. A rat model of Deferoxamine at thoracic 10 segment was established using a modified Allen's method. Ninety 8-week-old female Wistar rats were used. Rats in the Deferoxamine group were intraperitoneally injected with 100 mg/kg Deferoxamine 30 minutes before injury. Simultaneously, the Sham and Deferoxamine groups served as controls. Drug administration was conducted for 7 consecutive days. The results were as follows:(1) Electron microscopy revealed shrunken mitochondria in the spinal cord injury group.(2) The Basso, Beattie and Bresnahan locomotor rating score showed that recovery of the hindlimb was remarkably better in the Deferoxamine group than in the spinal cord injury group.(3) The iron concentration was lower in the Deferoxamine group than in the spinal cord injury group after injury.(4) Western blot assay revealed that, compared with the spinal cord injury group, GPX4, xCT, and glutathione expression was markedly increased in the Deferoxamine group.(5) Real-time polymerase chain reaction revealed that, compared with the Deferoxamine group, mRNA levels of ferroptosis-related genes Acyl-CoA synthetase family member 2(ACSF2) and iron-responsive element-binding protein 2(IREB2) were up-regulated in the Deferoxamine group.(6) Deferoxamine increased survival of neurons and inhibited gliosis. These findings confirm that Deferoxamine can repair spinal cord injury by inhibiting ferroptosis. Targeting ferroptosis is therefore a promising therapeutic approach for spinal cord injury.     

Liproxstatin-1 is an effective inhibitor of oligodendrocyte ferroptosis induced by inhibition of glutathione peroxidase 4

Our previous studies showed that ferroptosis plays an important role in the acute and subacute stages of spinal cord injury.High intracellular iron levels and low glutathione levels make oligodendrocytes vulnerable to cell death after central nervous system trauma.In this study,we established an oligodendrocyte(OLN-93 cell line) model of ferroptosis induced by RSL-3,an inhibitor of glutathione peroxidase 4(GPX4).RSL-3 significantly increased intracellular concentrations of reactive oxygen species and malondialdehyde.RSL-3 also inhibited the main antiferroptosis pathway,i.e.,SLC7A11/glutathione/glutathione peroxidase 4(xCT/GSH/GPX4),and downregulated acyl-coenzyme A synthetase long chain family member 4.Furthermore,we evaluated the ability of several compounds to rescue oligodendrocytes from ferroptosis.Liproxstatin-1 was more potent than edaravone or deferoxamine.Liproxstatin-1 not only inhibited mitochondrial lipid peroxidation,but also restored the expression of GSH,GPX4 and ferroptosis suppressor protein 1.These findings suggest that GPX4 inhibition induces ferroptosis in oligodendrocytes,and that liproxstatin-1 is a potent inhibitor of ferroptosis.Therefore,liproxstatin-1 may be a promising drug for the treatment of central nervous system diseases.     

Therapeutic effect of regulating autophagy in spinal cord injury: a network meta-analysis of direct and indirect comparisons

Objective:An increasing number of studies indicate that autophagy plays an important role in the pathogenesis of spinal cord injury,and that regulating autophagy can enhance recovery from spinal cord injury.However,the effect of regulating autophagy and whether autophagy is detrimental or beneficial after spinal cord injury remain unclear.Therefore,in this study we evaluated the effects of autophagy regulation on spinal cord injury in rats by direct and indirect comparison,in an effort to provide a basis for further research.Data source:Relevant literature published from inception to February 1,2018 were included by searching Wanfang,CNKI,Web of Science,MEDLINE(OvidSP),PubMed and Google Scholar in English and Chinese.The keywords included"autophagy","spinal cord injury",and"rat".Data selection:The literature included in vivo experimental studies on autophagy regulation in the treatment of spinal cord injury(including intervention pre-and post-spinal cord injury).Meta-analyses were conducted at different time points to compare the therapeutic effects of promoting or inhibiting autophagy,and subgroup analyses were also conducted.Outcome measure:Basso,Beattie,and Bresnahan scores.Results:Of the 622 studies,33 studies of median quality were included in the analyses.Basso,Beattie,and Bresnahan scores were higher at 1 day(MD=1.80,95%CI:0.81-2.79,P=0.0004),3 days(MD=0.92,95%CI:0.72-1.13,P<0.00001),1 week(MD=2.39,95%CI:1.85-2.92,P<0.00001),2 weeks(MD=3.26,95%CI:2.40-4.13,P<0.00001),3 weeks(MD=3.13,95%CI:2.51-3.75,P<0.00001)and 4 weeks(MD=3.18,95%CI:2.43-3.92,P<0.00001)after spinal cord injury with upregulation of autophagy compared with the control group(drug solvent control,such as saline group).Basso,Beattie,and Bresnahan scores were higher at 1 day(MD=6.48,95%CI:5.83-7.13,P<0.00001),2 weeks(MD=2.43,95%CI:0.79-4.07,P=0.004),3 weeks(MD=2.96,95%CI:0.09-5.84,P=0.04)and 4 weeks(MD=4.41,95%CI:1.08-7.75,P=0.01)after spinal cord injury with downregulation of autophagy compared with the control group.Indirect comparison of upregulation and downregulation of autophagy showed no differences in Basso,Beattie,and Bresnahan scores at 1 day(MD=-4.68,95%CI:-5.840 to-3.496,P=0.94644),3 days(MD=-0.28,95%CI:-2.231-1.671,P=0.99448),1 week(MD=1.83,95%CI:0.0076-3.584,P=0.94588),2 weeks(MD=0.81,95%CI:-0.850-2.470,P=0.93055),3 weeks(MD=0.17,95%Cl:-2.771-3.111,P=0.99546)or 4 weeks(MD=-1.23,95%Cl:-4.647-2.187,P=0.98264)compared with the control group.Conclusion:Regulation of autophagy improves neurological function,whether it is upregulated or downregulated.There was no difference between upregulation and downregulation of autophagy in the treatment of spinal cord injury.The variability in results among the studies may be associated with differences in research methods,the lack of clearly defined autophagy characteristics after spinal cord injury,and the limited autophagy monitoring techniques.Thus,methods should be standardized,and the dynamic regulation of autophagy should be examined in future studies.     

Comparison of acute pneumonia caused by SARS-CoV-2 and other respiratory viruses in children:a retrospective multi-center cohort study during COVID-19 outbreak

Background:Until January 18,2021,coronavirus disease-2019 (COVID-19) has infected more than 93 million individuals and has caused a certain degree of panic.Vira...     

P38 MAPK信号传导通路与胃癌关系的研究现状

丝裂原活化蛋白激酶(mitogen-activated proteinkinases,MAPKs)级联反应是细胞内重要的信号传导系统之一,参与细胞生长、发育、分化和凋亡等一系列生理、病理过程.P38 MAPK信号传导通路是MAPK通路的分支之一,介导了应激、炎性细胞因子、细菌产物等多种刺激引起的细胞反应,对细胞周期调控具有重要作用.但对不同的胃癌细胞系,或者不同的刺激,P38通路的作用不完全相同,甚至可能相反.提示对P38通路的功能仍需进一步的研究,他可能是肿瘤治疗的新靶点.     

Interacting with HBsAg compromises resistance of jumping translocation breakpoint protein to ultraviolet radiation-induced apoptosis in 293FT cells

Jumping translocation breakpoint protein (JTB) is suppressed in many cancers, implying it plays a role in the neoplastic transformation of cells. In order to explore the role of JTB in the carcinogenesis of liver, we used mammalian two-hybrid, co-immunoprecipitation, GST pull-down and laser scanning confocal to verify the interaction between HBs and JTB. According to the results, HBs interacts with JTB. In addition, we further determined that S region within HBs is sufficient for binding JTB. Overexpression of JTB conferred resistance to apoptosis induced by ultraviolet radiation, whereas this effect was compromised by the co-overexpression of HBs.     

Involvement of Ca~(2+) activated K~+channels in receptor regulated sperm motility in rats

Involvement of Ca~(2+) activated K~+channels in receptor regulated sperm motility in rats     

Candidate colorectal cancer predisposing gene variants in Chinese early-onset and familial cases

AIM: To investigate whether whole-exome sequencing may serve as an efficient method to identify known or novel colorectal cancer(CRC) predisposing genes in early-onset or familial CRC cases.METHODS: We performed whole-exome sequencing in 23 Chinese patients from 21 families with nonpolyposis CRC diagnosed at ≤ 40 years of age, or from multiple affected CRC families with at least 1 firstdegree relative diagnosed with CRC at ≤ 55 years of age.Genomic DNA from blood was enriched for exome sequences using the Sure Select Human All Exon Kit, version 2(Agilent Technologies) and sequencing was performed on an Illumina Hi Seq 2000 platform.Data were processed through an analytical pipeline to search for rare germline variants in known or novel CRC predisposing genes.RESULTS: In total, 32 germline variants in 23 genes were identified and confirmed by Sanger sequencing.In 6 of the 21 families(29%), we identified 7 mutations in 3 known CRC predisposing genes including MLH1(5 patients), MSH2(1 patient), and MUTYH(biallelic, 1 patient), five of which were reported as pathogenic.Inthe remaining 15 families, we identified 20 rare and novel potentially deleterious variants in 19 genes, six of which were truncating mutations.One previously unreported variant identified in a conserved region of EIF2AK4(p.Glu738_Asp739insA rgA rg) was found to represent a local Chinese variant, which was significantly enriched in our early-onset CRC patient cohort compared to a control cohort of 100 healthy Chinese individuals scored negative by colonoscopy(33.3% vs 7%, P 0.001).CONCLUSION: Whole-exome sequencing of early-onset or familial CRC cases serves as an efficient method to identify known and potential pathogenic variants in established and novel candidate CRC predisposing genes.     

What is the Potential Interplay between Microbiome and Tumor Microenvironment in Oral Squamous Cell Carcinomas?

Oral cancer, with an around 50% mortality rate, is one of the most common malignancies world-wide. It is often detected in advanced or terminal stage and has a poor prognosis, although substantial progress in cancer management. Microbiome has become an increasingly recognized factor that may contribute to the cancerous development. Oral microbiological population comprising more than 700 bacterial species, varies since saliva and different habitats of oral cavity. A shift of composition of oral microbiome from usual condition to functional inflammation to pathological state has been discovered amongst patients with premalignant disorders and oral carcinoma, with evidence suggesting the tumor microenvironment (TME) could strongly exacerbate the influence of oral microorganisms. The complex interactions taking place in either cancer formation or progression have been evaluated in several publications, however given their results’ heterogeneity, a review is needed to correctly untangle the potential correlation in this group of pro-carcinogenesis. In this review, we briefly summarize our current knowledge of the role of oral microbiome, focusing on its potential crosstalk with TME in oral squamous cell carcinomas (OSCC) more precisely, and pave the way for manipulating oral microbiome to deal with OSCC in the future.     

Development and validation of a deep learning model to screen hypokalemia from electrocardiogram in emergency patients

Background:A deep learning model (DLM) that enables non-invasive hypokalemia screening from an electrocardiogram (ECG) may improve the detection of this life-threatening condition. This study aimed to develop and evaluate the performance of a DLM for the detection of hypokalemia from the ECGs of emergency patients.Methods:We used a total of 9908 ECG data from emergency patients who were admitted at the Second Affiliated Hospital of Nanchang University, Jiangxi, China, from September 2017 to October 2020. The DLM was trained using 12 ECG leads (lead I, II, III, aVR, aVL, aVF, and V₁–₆) to detect patients with serum potassium concentrations <3.5 mmol/L and was validated using retrospective data from the Jiangling branch of the Second Affiliated Hospital of Nanchang University. The blood draw was completed within 10 min before and after the ECG examination, and there was no new or ongoing infusion during this period.Results:We used 6904 ECGs and 1726 ECGs as development and internal validation data sets, respectively. In addition, 1278 ECGs from the Jiangling branch of the Second Affiliated Hospital of Nanchang University were used as external validation data sets. Using 12 ECG leads (leads I, II, III, aVR, aVL, aVF, and V₁–₆), the area under the receiver operating characteristic curve (AUC) of the DLM was 0.80 (95% confidence interval [CI]: 0.77–0.82) for the internal validation data set. Using an optimal operating point yielded a sensitivity of 71.4% and a specificity of 77.1%. Using the same 12 ECG leads, the external validation data set resulted in an AUC for the DLM of 0.77 (95% CI: 0.75–0.79). Using an optimal operating point yielded a sensitivity of 70.0% and a specificity of 69.1%.Conclusions:In this study, using 12 ECG leads, a DLM detected hypokalemia in emergency patients with an AUC of 0.77 to 0.80. Artificial intelligence could be used to analyze an ECG to quickly screen for hypokalemia.