CDGSH iron sulfur domain 2 mitigates apoptosis, oxidative stress and inflammatory response caused by oxygen-glucose deprivation/reoxygenation in HT22 hippocampal neurons by Akt-Nrf2-activated pathway.

CDGSH iron sulfur domain 2 (Cisd2) is known as a key determinant factor in maintaining cellular homeostasis. However, whether Cisd2 contributes to the mediation of neuronal injury during ischemic stroke has not been well stressed. This work focuses on investigating the role of Cisd2 in regulating neuronal injury caused by oxygen-glucose deprivation/reoxygenation (OGD/R). The dramatic down-regulation of Cisd2 was observed in hippocampal neurons suffering from OGD/R injury. In Cisd2-overexpressed neurons, OGD/R-induced neuronal apoptosis, oxidative stress and inflammation were prominently mitigated. Further investigation uncovered that the forced expression of Cisd2 reinforced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in OGD/R-exposed neurons. Moreover, the overexpression of Cisd2 enhanced Akt activation, and the restraint of Akt abolished Cisd2-induced Nrf2 activation. Importantly, restraint of Nrf2 reversed Cisd2-conferred neuroprotective effects in OGD/R-exposed neurons. Taken together, our findings indicate that Cisd2 is able to protect neurons from OGD/R-induced injuries by strengthening Nrf2 activation via Akt. Our work identifies Cisd2 as a potential determinant factor for neuronal injury during cerebral ischemia/reperfusion injury.

Efficacy and safety of current therapeutic options for COVID-19 - lessons to be learnt from SARS and MERS epidemic: A systematic review and meta-analysis.

The rapidly progressing of coronavirus disease 2019 (COVID-19) pandemic has become a global concern. This meta-analysis aimed at evaluating the efficacy and safety of current option of therapies for severe acute respiratory syndrome (SARS), Middle Eastern respiratory syndrome (MERS) besides COVID-19, in an attempt to identify promising therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients. We searched PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and WANFANG DATA for randomized controlled trials (RCTs), prospective cohort, and retrospective cohort studies that evaluated therapies (hydroxychloroquine, lopinavir/ritonavir-based therapy, and ribavirin-based therapy, etc.) for SARS, MERS, and COVID-19. The primary outcomes were mortality, virological eradication and clinical improvement, and secondary outcomes were improvement of symptoms and chest radiography results, incidence of acute respiratory disease syndrome (ARDS), utilization of mechanical ventilation, and adverse events (AEs). Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models, and the quality of evidence was appraised using GRADEpro. Eighteen articles (5 RCTs, 2 prospective cohort studies, and 11 retrospective cohort studies) involving 4,941 patients were included. Compared with control treatment, anti-coronary virus interventions significantly reduced mortality (RR 0.65, 95% CI 0.44-0.96; I2 = 81.3%), remarkably ameliorate clinical improvement (RR 1.52, 95% CI 1.05-2.19) and radiographical improvement (RR 1.62, 95% CI 1.11-2.36, I2 = 11.0 %), without manifesting clear effect on virological eradication, incidence of ARDS, intubation, and AEs. Subgroup analyses demonstrated that the combination of ribavirin and corticosteroids remarkably decreased mortality (RR 0.43, 95% CI 0.27-0.68). The lopinavir/ritonavir-based combination showed superior virological eradication and radiographical improvement with reduced rate of ARDS. Likewise, hydroxychloroquine improved radiographical result. For safety, ribavirin could induce more bradycardia, anemia and transaminitis. Meanwhile, hydroxychloroquine could increase AEs rate especially diarrhea. Overall, the quality of evidence on most outcomes were very low. In conclusion, although we could not draw a clear conclusion for the recommendation of potential therapies for COVID-19 considering the very low quality of evidence and wide heterogeneity of interventions and indications, our results may help clinicians to comprehensively understand the advantages and drawbacks of each anti-coronavirus agents on efficacy and safety profiles. Lopinavir/ritonavir combinations might observe better virological eradication capability than other anti-coronavirus agents. Conversely, ribavirin might cause more safety concerns especially bradycardia. Thus, large RCTs objectively assessing the efficacy of antiviral therapies for SARS-CoV-2 infections should be conducted with high priority.

Effectiveness of tigecycline in the treatment of infections caused by carbapenem-resistant gram-negative bacteria in pediatric liver transplant recipients: A retrospective study.

INTRODUCTION: Tigecycline (TGC) is effective for the infections caused by carbapenem-resistant gram-negative bacteria (CRGNB) in adults, but it is not investigated systematically in children because of concern about adverse effects. This study aimed to analyze the effectiveness of TGC in treating CRGNB infections in children after receiving liver transplant. METHODS: The subjects in this retrospective study were pediatric liver transplant recipients treated with TGC for at least 3 days to fight microbiologically verified CRGNB infection after initial antibiotic failure during the period from January 2014 to May 2018. Clinical and microbiological outcomes were reviewed to evaluate the efficacy and safety of TGC. RESULTS: Of the 1177 pediatric liver transplant recipients, 13 patients were eligible for inclusion in this analysis. All the patients received TGC at dose of 2 mg/kg every 12 hours for a duration of 10.1 ± 5.1 days on average to treat CRGNB infections, including complicated intra-abdominal infection, ventilator-associated pneumonia, and bloodstream infection. The isolates included Klebsiella pneumoniae (69.2%, 9/13) and Acinetobacter baumannii (30.8%, 4/13). Clinical efficacy was achieved in 84.6% (11/13) and pathogen eradicated in 69.2% (9/13) of the patients. The overall mortality rate was 15.4% (2/13). No TGC-related serious adverse event was reported. CONCLUSION: Tigecycline can be considered in combination antimicrobial regimen for treating CRGNB-related infections in pediatric liver transplant recipients.

Wiskott-Aldrich syndrome protein may be critical for CD8+ T cell function following MCMV infection.

Wiskott-Aldrich syndrome (WAS) patients are characterized by immunodeficiency and viral infections. T cells derived from WAS patients and WAS protein (WASP)-deficient mice have various defects. However, whether WASP plays a role in immune control of cytomegalovirus (CMV) infection remains unclear. We analyzed the distribution of CD8+ T subsets and the pathological damage to various organs and tissues in MCMV infected Was knockout (KO) mice. A relatively high number of MCMV-specific cytotoxic T cells (CTLs) were observed in the spleen of Was KO mice. In MCMV infected Was KO mice, the late differentiated CD8+ T subset (CD27-CD28-) decreased in lungs, compared with those in the spleen and peripheral blood. Additionally, we found that the most severe pathological lesions occurred in the lungs, the main target organ of MCMV infection. By stimulating the spleen-derived CD8+ T lymphocytes of Was KO mice, we found that IL-2 and granzyme B production declined compared with that in wild- type mice. Moreover, the number of apoptotic CD8+ T cells increased in Was KO mice compared with the number in wild-type mice. Therefore, our results demonstrate that WASP may be involved in regulating cytotoxic function and apoptosis in CD8+ T cells following MCMV infection, which is supported by the distribution and memory compartment of MCMV-specific T cells in MCMV infected WAS mice.

MiR-187-3p mimic alleviates ischemia-reperfusion-induced pain hypersensitivity through inhibiting spinal P2X7R and subsequent mature IL-1ß release in mice.

BACKGROUND: Ischemia-reperfusion (IR)-induced pain hypersensitivity shares features of neuroinflammation and neuropathic pain, accompanied by overproduction of interleukin (IL)-1ß. Multiple microRNAs (miRs) are dysregulated during IR; among these miRs, miR-187-3p was recently reported to drive IL-1ß release in retinal disease by activating members of the purinergic receptor family. However, the roles of miR-187-3p in the spinal cord are unclear. Thus, we investigated whether miR-187-3p is involved in the pathogenesis of IR-induced pain hypersensitivity by regulating the P2X7R signal and subsequent IL-1ß release. METHODS: A mouse model was established by 5-min occlusion of the aortic arch. Pain hypersensitivity was assessed by the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). MiR-187-3p, P2X7R, cleaved caspase-1 and mature IL-1ß expression levels were measured by RT-PCR and Western blotting. The in vivo roles of miR-187-3p, P2X7R and IL-1ß were explored by intrathecal treatment with synthetic miRs, selective agonists and antagonists in separate experiments. Double immunofluorescence staining was performed to delineate the cellular distribution of P2X7R and IL-1ß. RESULTS: IR-induced progressively decreased PWT and PWL values were closely related to decreases in miR-187-3p and increases in P2X7R expression levels over time. The functional miR-187-3p/P2X7R pair was preliminarily predicted by a bioinformatic database and confirmed in vivo by quantitative analysis, as mimic-187 greatly increased miR-187-3p but decreased P2X7R expression levels, whereas inhibitor-187 reversed these changes. In contrast, downregulating P2X7R by mimic-187 or A-438079 treatment comparably increased PWT and PWL values in IR-injured mice, while upregulating P2X7R by inhibitor-187 or BzATP treatment decreased PWT and PWL values in sham-operated mice. Moreover, P2X7R and IL-1ß immunoreactivities in each group were changed in the same patterns. This finding was further supported by results showing that downregulating IL-1ß by A-438079 and IL-1ß-neutralizing antibody similarly decreased P2X7R, cleaved caspase-1 and mature IL-1ß expression levels, whereas BzATP treatment increased these levels. Expectedly, mimic-187 treatment preserved PWT and PWL values, with decreased cleaved caspase-1 and mature IL-1ß expression levels, whereas inhibitor-187 reversed these effects. CONCLUSIONS: The spinal miR-187-3p/P2X7R pair functioned in a mouse IR model. Increasing miR-187-3p protected against pain hypersensitivity and mature IL-1ß overproduction, partially through inhibiting P2X7R activation.

Inhibiting aberrant p53-PUMA feedback loop activation attenuates ischaemia reperfusion-induced neuroapoptosis and neuroinflammation in rats by downregulating caspase 3 and the NF-κB cytokine pathway.

BACKGROUND: Ischaemia reperfusion (IR) induces multiple pathophysiological changes. In addition to its classical role in regulating tumourigenesis, the feedback loop formed by p53 and its driven target p53-upregulated modulator of apoptosis (PUMA) was recently demonstrated to be the common node tightly controlling various cellular responses during myocardial IR. However, the roles of the p53-PUMA feedback loop in the spinal cord remain unclear. This study aimed to elucidate the roles of p53-PUMA feedback interactions in the spinal cord after IR, specifically investigating their regulation of caspase 3-mediated apoptosis and nuclear factor (NF)-κB-mediated cytokine release. METHODS: SD rats subjected to 12 min of aortic arch occlusion served as IR models. Neurological assessment as well as p53 and PUMA mRNA and protein expression analyses were performed at 12-h intervals during a 48-h reperfusion period. The cellular distributions of p53 and PUMA were determined via double immunofluorescence staining. The effects of the p53-PUMA feedback loop on modulating hind-limb function; the number of TUNEL-positive cells; and protein levels of caspase 3, NF-κB and cytokines interleukin (IL)-1ß and tumour necrosis factor (TNF)-α, were evaluated by intrathecal treatment with PUMA-specific or scramble siRNA and pifithrin (PFT)-α. Blood-spinal cord barrier (BSCB) breakdown was examined by Evans blue (EB) extravasation and water content analyses. RESULTS: IR induced significant behavioural deficits as demonstrated by deceased Tarlov scores, which displayed trends opposite those of PUMA and p53 protein and mRNA expression. Upregulated PUMA and p53 fluorescent labels were widely distributed in neurons, astrocytes and microglia. Injecting si-PUMA and PFT-α exerted significant anti-apoptosis effects as shown by the reduced number of TUNEL-positive cells, nuclear abnormalities and cleaved caspase 3 levels at 48 h post-IR. Additionally, p53 colocalized with NF-κB within the cell. Similarly, injecting si-PUMA and PFT-α exerted anti-inflammatory effects as shown by the decreased NF-κB translocation and release of IL-1ß and TNF-α. Additionally, injecting si-PUMA and PFT-α preserved the BSCB integrity as determined by decreased EB extravasation and spinal water content. However, injecting si-Con did not induce any of the abovementioned effects. CONCLUSIONS: Inhibition of aberrant p53-PUMA feedback loop activation by intrathecal treatment with si-PUMA and PFT-α prevented IR-induced neuroapoptosis, inflammatory responses and BSCB breakdown by inactivating caspase 3-mediated apoptosis and NF-κB-mediated cytokine release.

MicroRNA-125b mimic inhibits ischemia reperfusion-induced neuroinflammation and aberrant p53 apoptotic signalling activation through targeting TP53INP1.

BACKGROUND: Ischemia reperfusion (IR) injury affects neuronal function through multiple pathogeneses that induce neuroinflammation and cellular apoptosis. The important roles of microRNAs (miRs) in the regulation of spinal cord IR have been recently reported. Among these roles, we investigated whether miR-125b and its downstream targets regulated the p53 signalling network and participated in both inflammation and apoptosis. METHODS: An IR model was established via 12-min occlusion of the aortic arch. The direct interaction between miR-125b and TP53INP1 was demonstrated by Western blotting and luciferase assays. The cellular distributions of TP53INP1 were visualised by double immunofluorescence labelling. The effects of miR-125b on the expression of TP53INP1, p53 and release of proinflammatory cytokines were evaluated by synthetic miRs. Additionally, the detection of hind-limb motor function in vivo and motor neuronal apoptosis in vitro were evaluated to explore the potential mechanisms. RESULTS: IR-induced alterations in hind-limb motor function were closely related to the temporal changes in miR-125b and TP53INP1 expression. The miR-125b/TP53INP1 gene pair was confirmed by luciferase assay. Compared with Sham controls, IR treatment resulted in increased TP53INP1 immunoreactivity that was primarily distributed in neurons. Treatment with miR-125b mimic markedly decreased the protein levels of TP53INP1, p53 and cytokines interleukin (IL)-1ß and tumour necrosis factor (TNF)-α, whereas miR-125b control or inhibitor did not have the above-mentioned effects. Moreover, miR-125b mimic improved motor function in vivo and attenuated neuronal apoptosis in vitro, as demonstrated by the increased average Tarlov scores in lower limbs and lower percentages of neurons in the A4 and A2 quadrants of flow cytometry. Fluorescent staining and quantification further indicated that miR-125b mimic decreased the immunoreactivities of p53 and cleaved caspase 3 in neurons and simultaneously reduced the number of double-labelled cells with TP53INP1. CONCLUSIONS: miR-125b mimic partially protected neurons against neuroinflammation and aberrant p53 network activation-induced apoptosis during IR injury through downregulation of TP53INP1.

Elevated microRNA-129-5p level ameliorates neuroinflammation and blood-spinal cord barrier damage after ischemia-reperfusion by inhibiting HMGB1 and the TLR3-cytokine pathway.

BACKGROUND: Ischemia-reperfusion (IR) affects microRNA (miR) expression and causes substantial inflammation. Multiple roles of the tumor suppressor miR-129-5p in cerebral IR have recently been reported, but its functions in the spinal cord are unclear. Here, we investigated the role of miR-129-5p after spinal cord IR, particularly in regulating high-mobility group box-1 (HMGB1) and the Toll-like receptor (TLR)-3 pathway. METHODS: Ischemia was induced via 5-min occlusion of the aortic arch. The relationship between miR-129-5p and HMGB1 was elucidated via RT-PCR, western blotting, and luciferase assays. The cellular distribution of HMGB1 was determined via double immunofluorescence. The effect of miR-129-5p on the expression of HMGB1, TLR3, and downstream cytokines was evaluated using synthetic miRs, rHMGB1, and the TLR3 agonist Poly(I:C). Blood-spinal cord barrier (BSCB) permeability was examined by measuring Evans blue (EB) dye extravasation and the water content. RESULTS: The temporal miR-129-5p and HMGB1 expression profiles and luciferase assay results indicated that miR-129-5p targeted HMGB1. Compared with the Sham group, the IR group had higher HMGB1 immunoreactivity, which was primarily distributed in neurons and microglia. Intrathecal injection of the miR-129-5p mimic significantly decreased the HMGB1, TLR3, interleukin (IL)-1ß and tumor necrosis factor (TNF)-α levels and the double-labeled cell count 48 h post-surgery, whereas rHMGB1 and Poly(I:C) reversed these effects. Injection of miR-129-5p mimic preserved motor function and prevented BSCB leakage based on increased Basso Mouse Scale scores and decreased EB extravasation and water content, whereas injection rHMGB1 and Poly(I:C) aggravated these injuries. CONCLUSIONS: Increasing miR-129-5p levels protect against IR by ameliorating inflammation-induced neuronal and BCSB damage by inhibiting HMGB1 and TLR3-associated cytokines.

miR-320a affects spinal cord edema through negatively regulating aquaporin-1 of blood-spinal cord barrier during bimodal stage after ischemia reperfusion injury in rats.

BACKGROUND: Spinal cord edema is a serious complication and pathophysiological change after ischemia reperfusion (IR) injury. It has been demonstrated closely associated with bimodal disruption of blood-spinal cord barrier (BSCB) in our previous work. Aquaporin (AQP)1 plays important but contradictory roles in water homeostasis. Recently, microRNAs (miRs) effectively regulate numerous target mRNAs during ischemia. However, whether miRs are able to protect against dimodal disruption of BSCB by regulating perivascular AQP1 remains to be elucidated. RESULTS: Spinal water content and EB extravasation were suggested as a bimodal distribution in directly proportion to AQP1, since all maximal changes were detected at 12 and 48 h after reperfusion. Further TEM and double immunofluorescence showed that former disruption of BSCB at 12 h was attributed to cytotoxic edema by up-regulated AQP1 expressions in astrocytes, whereas the latter at 48 h was mixed with vasogenic edema with both endothelial cells and astrocytes involvement. Microarray analysis revealed that at 12 h post-injury, ten miRs were upregulated (>2.0 fold) and seven miRs were downregulated (<0.5 fold) and at 48 h, ten miRs were upregulated and eleven were downregulated compared to Sham-operated controls. Genomic screening and luciferase assays identified that miR-320a was a potential modulator of AQP1 in spinal cord after IR in vitro. In vivo, compared to rats in IR and negative control group, intrathecal infusion of miR-320a mimic attenuated IR-induced lower limb motor function deficits and BSCB dysfunction as decreased EB extravasation and spinal water content through down-regulating AQP1 expressions, whereas pretreated with miR-320a AMO reversed above effects. CONCLUSION: These findings indicate miR-320a directly and functionally affects spinal cord edema through negatively regulating AQP1 of BSCB after IR.

Elevated microRNA-214-3p level ameliorates neuroinflammation after spinal cord ischemia-reperfusion injury by inhibiting Nmb/Cav3.2 pathway.

BACKGROUND: Neuromedin B (Nmb) plays a pivotal role in the transmission of neuroinflammation, particularly during spinal cord ischemia-reperfusion injury (SCII). However, the detailed molecular mechanisms underlying this process remain elusive. METHODS: The SCII model was established by clamping the abdominal aorta of male Sprague-Dawley (SD) rats for 60 min. The protein expression levels of Nmb, Cav3.2, and IL-1ß were detected by Western blotting, while miR-214-3p expression was quantified by qRT-PCR. The targeted regulation between miR-214-3p and Nmb was investigated using a dual-luciferase reporter gene assay. The cellular localization of Nmb and Cav3.2 with cell-specific markers was visualized by immunofluorescence staining. The specific roles of miR-214-3p on the Nmb/Cav3.2 interactions in SCII-injured rats were explored by intrathecal injection of Cav3.2-siRNA, PD168368 (a specific NmbR inhibitor) and synthetic miR-214-3p agomir and antagomir in separate experiments. Additionally, hind-limb motor function was evaluated using the modified Tarlov scores. RESULTS: Compared to the Sham group, the protein expression levels of Nmb, Cav3.2, and the proinflammatory factor Interleukin(IL)-1ß were significantly elevated at 24 h post-SCII. Intrathecal injection of PD168368 and Cav3.2-siRNA significantly suppressed the expression of Cav3.2 and IL-1ß compared to the SCII group. The miRDB database and dual-luciferase reporter gene assay identified Nmb as a direct target of miR-214-3p. As expected, in vivo overexpression of miR-214-3p by agomir-214-3p pretreatment significantly inhibited the increases in Nmb, Cav3.2 and IL-1ß expression and improved lower limb motor function in SCII-injured rats, while antagomiR-214-3p pretreatment reversed these effects. CONCLUSIONS: Nmb protein levels positively correlated with Cav3.2 expression in SCII rats. Upregulating miR-214-3p ameliorated hind-limb motor function and protected against neuroinflammation via inhibiting the aberrant Nmb/Cav3.2 interactions and downstream IL-1ß release. These findings provide novel therapeutic targets for clinical prevention and treatment of SCII.

A graphene-based electrochemical sensor for rapid determination of phenols in water.

A glassy carbon electrode (GCE) coated with a graphene/polymer film was fabricated for rapid determination of phenols in aqueous solutions. The electrochemical behavior of different phenols at the graphene/polymer-coated GCE was also investigated. In PBS buffer solution with a pH of 6.5, hydroquinone exhibits a well-defined reduction peak at the modified GCE. Based on this, an electrochemical method for the direct determination of phenols is proposed. Investigating different parameters revealed the optimized detection conditions for the electrode are a scan rate of 50 mV/s, dosage of graphene-polyaniline of 8 µL, dosage of tyrosinase of 3 µL, and pH of 6.5. Under the optimal conditions, the reduction peak current varies linearly with the concentration of phenols, with a linear regression equation of I (10(-6)A) = -4.887 × 10(-4)C (mol/L)-5.331 × 10(-6) with a correlation coefficient of 0.9963 and limit of detection (S/N = 3) of 2.00 × 10(-4) mol/L. The electrochemical sensor is also used to detect phenols in actual samples, where it shows great promise for rapid, simple and quantitative detection of phenols.

Eph receptor A4 regulates motor neuron ferroptosis in spinal cord ischemia/reperfusion injury in rats.

Previous studies have shown that the receptor tyrosine kinase Eph receptor A4 (EphA4) is abundantly expressed in the nervous system. The EphA4 signaling pathway plays an important role in regulating motor neuron ferroptosis in motor neuron disease. To investigate whether EphA4 signaling is involved in ferroptosis in spinal cord ischemia/reperfusion injury, in this study we established a rat model of spinal cord ischemia/reperfusion injury by clamping the left carotid artery and the left subclavian artery. We found that spinal cord ischemia/reperfusion injury increased EphA4 expression in the neurons of anterior horn, markedly worsened ferroptosis-related indicators, substantially increased the number of mitochondria exhibiting features consistent with ferroptosis, promoted deterioration of motor nerve function, increased the permeability of the blood-spinal cord barrier, and increased the rate of motor neuron death. Inhibition of EphA4 largely rescued these effects. However, intrathecal administration of the ferroptosis inducer Erastin counteracted the beneficial effects conferred by treatment with the EphA4 inhibitor. Mass spectrometry and a PubMed search were performed to identify proteins that interact with EphA4, with the most notable being Beclin1 and Erk1/2. Our results showed that inhibition of EphA4 expression reduced binding to Beclin1, markedly reduced p-Beclin1, and reduced Beclin1-XCT complex formation. Inhibition of EphA4 also reduced binding to p-Erk1/2 and markedly decreased the expression of c-Myc, transferrin receptor 1, and p-Erk1/2. Additionally, we observed co-localization of EphA4 and p-Beclin1 and of EphA4 and p-ERK1/2 in neurons in the anterior horn. In conclusion, EphA4 participates in regulating ferroptosis of spinal motor neurons in the anterior horn in spinal cord ischemia/reperfusion injury by promoting formation of the Beclin1-XCT complex and activating the Erk1/2/c-Myc/transferrin receptor 1 axis.

Fra-1 induces apoptosis and neuroinflammation by targeting S100A8 to modulate TLR4 pathways in spinal cord ischemia/reperfusion injury.

Spinal cord ischemia/reperfusion injury (SCII) is a severe complication driven by apoptosis and neuroinflammation. An increase in the expression of c-Fos, a member of the AP-1 family, is known as a neuronal activation marker in SCII. The AP-1 family is composed of Jun, Fos, and is associated with the regulation of cytokines expression and apoptosis. Fra-1 is a member of the Fos family, however, the contribution of Fra-1 to SCII is still unclear. In our study, Fra-1 was highly upregulated especially in neurons and microglia and promoted apoptosis by changing the expression of Bax/Bcl-2 after SCII. Furthermore, we found that Fra-1 directly regulated the transcription expression of S100A8. We demonstrated that knockdown of Fra-1 alleviated S100A8 mediated neuronal apoptosis and inflammatory factor release, thus improved motor function after SCII. Interestingly, we showed that administration of TAK-242, the TLR4 inhibitor, to the ischemia/reperfusion (I/R) injury induced rats suppressed the activation of the ERK and NF-κB pathways, and further reduced Fra-1 expression. In conclusion, we found that Fra-1-targeted S100A8 was expressed the upstream of Fra-1, and the Fra-1/S100A8 interaction formed a feedback loop in the signaling pathways activated by SCII.

MicroRNA-101a-3p mimic ameliorates spinal cord ischemia/reperfusion injury.

miR-101a-3p is expressed in a variety of organs and tissues and plays a regulatory role in many diseases, but its role in spinal cord ischemia/reperfusion injury remains unclear. In this study, we established a rat model of spinal cord ischemia/reperfusion injury by clamping the aortic arch for 14 minutes followed by reperfusion for 24 hours. Results showed that miR-101a-3p expression in L4-L6 spinal cord was greatly decreased, whereas MYCN expression was greatly increased. Dual-luciferase reporter assay results showed that miR-101a-3p targeted MYCN. MYCN immunoreactivity, which was primarily colocalized with neurons in L4-L6 spinal tissue, greatly increased after spinal cord ischemia/reperfusion injury. However, intrathecal injection of an miR-101a-3p mimic within 24 hours before injury decreased MYCN, p53, caspase-9 and interleukin-1ß expression, reduced p53 immunoreactivity, reduced the number of MYCN/NeuN-positive cells and the number of necrotic cells in L4-L6 spinal tissue, and increased Tarlov scores. These findings suggest that the miR-101a-3p mimic improved spinal ischemia/reperfusion injury-induced nerve cell apoptosis and inflammation by inhibiting MYCN and the p53 signaling pathway. Therefore, miR-101a-3p mimic therapy may be a potential treatment option for spinal ischemia/reperfusion injury.

Case report: Reducing the duration of positive-pressure ventilation for large mediastinal masses.

Large mediastinal masses (MMs) are rare and present some challenges in hemodynamic and airway management under general anesthesia. Multiple studies have reported cardiopulmonary collapse during general anesthesia. Maintenance of spontaneous ventilation, avoidance of muscle relaxants, and awake-intubation were usually recommended during general anesthesia for high-risk patients with large MMs. However, the recent notion challenged the classic teaching that maintaining spontaneous ventilation is superior to positive-pressure ventilation (PPV). In our case reports, we present two patients with large MMs during general anesthesia. In the first case, a 21-year-old male was administered a muscle relaxant during induction, followed by PPV, but his blood oxygen saturation decreased to 40% after 20 min. Finally, his oxygen saturation was restored by a sternotomy rather than by cardiopulmonary bypass (CPB) by femoral vascular intubation. In the second case, a 33-year-old male was also administered a muscle relaxant during induction followed by PPV, but for him, sternotomy was immediately performed, with stable blood oxygen saturation. Both patients recovered well and were discharged from hospital a week after surgery. Therefore, we present a recommendation that patients with large MMs could undergo PPV after the administration of a muscle relaxant during induction, but the cardiothoracic surgeon should immediately cleave the sternum.

Delayed aortoesophageal and tracheoesophageal fistulas secondary to foreign body ingestion: a case report.

Ingestion of a foreign body (FB) is a common condition with a few potentially life-threatening complications, including esophageal perforation (EP), aortoesophageal fistula (AEF), mediastinal infection, and tracheoesophageal fistula (TEF). In this case, a patient who accidentally ingested a duck bone gradually experienced all of the above complications. To resolve the symptom of difficulty swallowing, the patient underwent emergency treatment for removal of the esophageal FB via endoscopic surgery. Under endoscopy, esophageal mucosal injuries were present, but no other abnormalities, such as active bleeding, were observed. However, the patient returned to our hospital a week later with symptoms of vomiting and black stool and received the diagnosis of EP, AEF and mediastinal infection. Two days later, he vomited 1,000-2,000 mL of blood after experiencing sudden severe chest pain. Then, thoracic endovascular aortic repair (TEVAR) and mediastinal drainage with video-assisted thoracoscopic surgery (VATS) were performed under emergency general anesthesia. Additionally, the patient underwent esophageal stent implantation when TEF was confirmed by tracheal computed tomography (CT). The patient was treated with anti-infective therapy throughout the treatment process. Finally, he recovered and was able to tolerate a liquid diet. Comprehensive evaluation and multidisciplinary cooperation are all very important for the treatment of esophageal foreign bodies and complications.

Inhibiting the aberrant PACT-p53 axis activation ameliorates spinal cord ischaemia-reperfusion injury in rats.

Spinal cord ischaemia-reperfusion injury (SCII) induces multiple molecular and cellular changes, resulting in dyskinesia. Recently, it is reported that the p53 network plays a vital role in SCII. However, the roles of the PACT/PRKRA (interferon-inducible double-stranded RNA-dependent protein kinase activator A)-p53 axis in SCII are still unclear. The aim of this study was to elucidate the roles of the PACT-p53 axis in SCII. A Sprague-Dawley rat model of SCII was established by subjecting rats to a 14-min occlusion of the aortic arch. The Tarlov criteria, Western blotting, double immunofluorescence staining, haematoxylin and eosin (HE) staining, and transferase dUTP nick end labelling (TUNEL) assay were performed after SCII. Here, spinal cord ischaemia-reperfusion (SCI) caused hindlimb motor functional deficits as assessed by the Tarlov criteria. The protein expression of PACT was substantially upregulated at 48 h after SCII. Increased PACT fluorescence was mainly localized to neurons. Si-PACT pretreatment improved hindlimb motor function, ameliorated histological changes, and attenuated cell apoptosis after SCII. Si-PACT pretreatment reduced the protein expression of PACT, p53, Caspase-8 and IL-1ß and the number of double-labelled PACT and p53. Taken together, inhibiting the aberrant PACT-p53 axis activation by si-PACT pretreatment ameliorates SCI-induced neuroapoptosis and neuroinflammation in rats. Silencing PACT expression is promising new therapeutic strategy for SCII.