Transient ischemic attack (TIA) induces ischemic tolerance that can reduce the subsequent ischemic damage and improve prognosis of patients with stroke. However, the underlying mechanisms remain elusive. Recent advances in plasma metabolomics analysis have made it a powerful tool to investigate human pathophysiological phenotypes and mechanisms of diseases. In this study, we aimed to identify the bioactive metabolites from the plasma of patients with TIA for determination of their prophylactic and therapeutic effects on protection against cerebral ischemic stroke, and the mechanism of TIA-induced ischemic tolerance against subsequent stroke.Metabolomic profiling using liquid chromatography-mass spectrometry was performed to identify the TIA-induced differential bioactive metabolites in the plasma samples of 20 patients at day 1 (time for basal metabolites) and day 7 (time for established chronic ischemic tolerance-associated metabolites) after onset of TIA. Mouse middle cerebral artery occlusion (MCAO)-induced stroke model was used to verify their prophylactic and therapeutic potentials. Transcriptomics changes in circulating neutrophils of patients with TIA were determined by RNA-sequencing. Multivariate statistics and integrative analysis of metabolomics and transcriptomics were performed to elucidate the potential mechanism of TIA-induced ischemic tolerance.Plasma metabolomics analysis identified five differentially upregulated metabolites associated with potentially TIA-induced ischemic tolerance, namely all-trans 13,14 dihydroretinol (atDR), 20-carboxyleukotriene B4, prostaglandin B2, cortisol and 9-KODE. They were associated with the metabolic pathways of retinol, arachidonic acid, and neuroactive ligand-receptor interaction. Prophylactic treatment of MCAO mice with these five metabolites significantly improved neurological functions. Additionally, post-stroke treatment with atDR or 9-KODE significantly reduced the cerebral infarct size and enhanced sensorimotor functions, demonstrating the therapeutic potential of these bioactive metabolites. Mechanistically, we found in patients with TIA that these metabolites were positively correlated with circulating neutrophil counts. Integrative analysis of plasma metabolomics and neutrophil transcriptomics further revealed that TIA-induced metabolites are significantly correlated with specific gene expression in circulating neutrophils which showed prominent enrichment in FoxO signaling pathway and upregulation of the anti-inflammatory cytokine IL-10. Finally, we demonstrated that the protective effect of atDR-pretreatment on MCAO mice was abolished when circulating neutrophils were depleted.TIA-induced potential ischemic tolerance is associated with upregulation of plasma bioactive metabolites which can protect against cerebral ischemic damage and improve neurological functions through a positive role of circulating neutrophils.National Natural Science Foundation of China (81974210), Science and Technology Planning Project of Guangdong Province, China (2020A0505100045), Natural Science Foundation of Guangdong Province (2019A1515010671), Science and Technology Program of Guangzhou, China (2023A03J0577), and Natural Science Foundation of Jiangxi, China（20224BAB216043).
Hantaviruses (HVs) are rodent transmitted viruses that can cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardio-pulmonary syndrome (HCPS)in the Americas. Together, these viruses cause approximately 200,000humaninfections annually worldwide in recent years, with case fatality rate of 5-15%for HFRS and up to 40% for HCPS. There are currently no effective treatment available for either HFRS or HCPS. The only vaccines licensed for use in Republic of Korea and China are based on inactivated whole Seoul virus (SEOV) and Hantaan virus(HTNV), but the protective efficacy of these vaccines are uncertain. To a large extent, the immune correlates of protection against Hantavirus are not known. In this review, we summarized the epidemiology, virology, and pathogenesis of four HFRS causing viruses, HTNV, SEOV, PUUV (Puumala virus), and DOBV (Dobrava-Belgrade virus); and two HCPS causing viruses, ANDV (Andes virus) and SNV (Sin Nombre virus); and then discussed the existing knowledge on vaccine and therapeutics against these diseases. We think these information will shed lights on the rational development of new vaccines and treatment.
Abstract Objectives. Deletion of Fscn2 gene in mice has been linked to progressive hearing loss and degeneration of cochlear cells. Cisplatin, an antitumor drug, can cause various side effects, including ototoxicity. The aim of this study was to investigate the effects of Fscn2 on cisplatin-induced hearing impairment in mice and to explore the possible mechanism. Methods. Two-week-old Fscn2 +/+ mice and Fscn2 -/- mice were treated with two doses of cisplatin, with a 3-day recovery period in between. ABR (auditory evoked brain stem response) thresholds were measured and cochlear pathology was observed at 3 weeks of age. Results. Both Fscn2 +/+ and Fscn2 -/- mice showed hearing loss under the effect of cisplatin, but the impairment was more severe in Fscn2 -/- mice. Further experiments showed that the percentages of outer hair cell (OHC) and spiral ganglion neuron (SGN) loss were significantly higher in cisplatin-treated Fscn2 -/- mice compared to Fscn2 +/+ mice. Additionally, knockdown of Fscn2 in HEI-OC1 cells worsened cisplatin-induced cell apoptosis. Conclusion. FSCN2 mediates reduction of CDDP induced ototoxicity by inhibiting cell apoptosis
Abstract COX7A1, a subunit of cytochrome c oxidase, holds an important position in the super-assembly which integrates into multi-unit heteromeric complexes peripherally in the mitochondrial electron transport chain (ETC). Recently, some studies indicated the significant potential of COX7A1 in cancer metabolism and therapy. However, the underlying metabolic process and therapy mechanism remain unclear. In this study, COX7A1-overexpressed cell line was established via lentivirus transduction. The relationship between COX7A1 and ferroptosis, a novel form of cell death driven by iron-dependent lipid peroxidation, was further analyzed in different human non-small-cell lung carcinoma (NSCLC) cells respectively. Our results showed that COX7A1 increased the sensitivity of NSCLC cells to the ferroptosis induced by cysteine deprivation via enhancing the tricarboxylic acid (TCA) cycle and the activity of complex IV in mitochondrial ETC. Meanwhile, COX7A1 suppressed mitochondrial dynamics as well as mitochondrial biogenesis and mitophagy through blocking autophagic flux. The autophagy activator, rapamycin, relieved the autophagic blockage and further strengthened the sensitivity to cysteine deprivation-induced ferroptosis of NSCLC cells in vitro and in vivo. Taken together, our data indicate the close association of COX7A1 with cysteine deprivation-induced ferroptosis, and provide a novel insight into the therapy mode against human NSCLC.
Introduction Glioblastoma(GBM) is a highly malignant primary brain tumor. Even after undergoing surgery and chemotherapy, patients with this affliction still have little to no chance of survival. Current research on immunotherapy treatment for GBM shows that immune-checkpoint inhibitors (ICIs) may be a promising new treatment method. However, at present, the relationship between the fatty acid metabolic process and the prognosis of GBM patients who are receiving immunotherapy is not clear. Methods First, we downloaded a GBM cohort that had been treated with immunotherapy, which included the mutation and prognosis data, and the TCGA-GBM and Jonsson-GBM queues. CIBERSORT and single sample gene set enrichment analysis(ssGSEA) were used to evaluate immune cell scores. Gene set enrichment analysis (GSEA) was used to evaluate the patient’s accessment score. The pRRophetic algorithm was used to evaluate the drug sensitivity of each patient. Univariable and multivariate cox regression analyses, as well as the Kaplan-Meier (KM) method, were used to evaluate the relationship between the fatty acid metabolic process and the prognosis of GBM patients. Results The univariate and multivariate cox regression models showed that the fatty acid metabolic process mutant-type (MT) can be used as an independent predictor of the efficacy of immunotherapy for GBM patients. In addition, fatty acid metabolic process MT is related with significantly longer overall survival (OS) time than the wild-type(WT) variant. However, the mutation status of the fatty acid metabolic process has nothing to do with the prognosis of GBM patients who are receiving conventional treatment. Our analysis showed that fatty acid metabolic process MT correlated with significantly increased natural killer T (NKT) cells and significantly decreased CD8+T cells. At the same time, GSEA analysis revealed that fatty acid metabolic process MT was associated with significantly increased immune activation pathways and an enriched fraction of cytokine secretion compared with WT. Conclusions We found that fatty acid metabolic process MT may be used as an independent predictor of the efficacy of ICI treatment in GBM patients. Use of the fatty acid metabolic process MT will result in higher immunogenicity rates, a significant increase in the proportion of activated immune cells, and improvement of the immune microenvironment.
// Qikang Ying 1, * , Tiejun Ma 1, * , Linfeng Cheng 1, * , Xiaoxiao Zhang 1 , Agnieszka D. Truax 2 , Ruixue Ma 1 , Ziyu Liu 1 , Yingfeng Lei 1 , Liang Zhang 1 , Wei Ye 1 , Fanglin Zhang 1 , Zhikai Xu 1 , Lei Shang 3 , Rongrong Liu 1 , Fang Wang 1 , Xingan Wu 1 1 Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China 2 The Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA 3 Department of Statistics, Fourth Military Medical University, Xi'an, 710032, China * These authors have contributed equally to this work Correspondence to: Xingan Wu, email: wuxingan@fmmu.edu.cn Fang Wang, email: wangf07@fmmu.edu.cn Rongrong Liu, email: rong4713@163.com Keywords: Hantaan virus, virus like particle, virus vaccine, CD40 ligand, granulocyte macrophage colony-stimulating factor Received: March 28, 2016 Accepted: July 10, 2016 Published: August 17, 2016 ABSTRACT Infection of Hantaan virus (HTNV) usually causes hemorrhagic fever with renal syndrome (HFRS). China has the worst epidemic incidence of HFRS as well as high fatality. Inactivated whole virus has been used for HFRS vaccination, however there are still problems such as safety concerns. CD40 ligand (CD40L) and granulocyte macrophage colony-stimulating factor (GM-CSF) are well-known immune stimulating molecules that can enhance antigen presenting, lymphocytes activation and maturation, incorporation of CD40L and GM-CSF to the surface of virus like particles (VLPs) can greatly improve the vaccination effect. We constructed eukaryotic vectors expressing HTNV M segment and S segment, as well as vectors expressing HTNV M segment with CD40L or GM-CSF, our results showed successful production of CD40L or GM-CSF incorporated HTNV VLPs. In vitro stimulation with CD40L or GM-CSF anchored HTNV VLP showed enhanced activation of macrophages and DCs. CD40L/GM-CSF incorporated VLP can induce higher level of HTNV specific antibody and neutralizing antibody in mice. Immunized mice splenocytes showed higher ability of secreting IFN-γ and IL-2, as well as enhancing CTL activity. These results suggest CD40L/GM-CSF incorporated VLP can serve as prospective vaccine candidate.
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