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Glial ion transporters are important in regulation of ionic homeostasis, cell volume, and cellular signal transduction under physiological conditions of the central nervous system (CNS). In response to acute or chronic brain injuries, these ion transporters can be activated and differentially regulate glial functions, which has subsequent impact on brain injury or tissue repair and functional recovery. In this review, we summarized the current knowledge about major glial ion transporters, including Na+/H+ exchangers (NHE), Na+/Ca2+ exchangers (NCX), Na+–K+–Cl− cotransporters (NKCC), and Na+–HCO3− cotransporters (NBC). In acute neurological diseases, such as ischemic stroke and traumatic brain injury (TBI), these ion transporters are rapidly activated and play significant roles in regulation of the intra‐ and extracellular pH, Na+, K+, and Ca2+ homeostasis, synaptic plasticity, and myelin formation. However, overstimulation of these ion transporters can contribute to glial apoptosis, demyelination, inflammation, and excitotoxicity. In chronic brain diseases, such as glioma, Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), glial ion transporters are involved in the glioma Warburg effect, glial activation, neuroinflammation, and neuronal damages. These findings suggest that glial ion transporters are involved in tissue structural and functional restoration, or brain injury and neurological disease development and progression. A better understanding of these ion transporters in acute and chronic neurological diseases will provide insights for their potential as therapeutic targets.

BackgroundSodium/hydrogen exchanger 1 (NHE1), encoded by the SLC9A1 gene (SoLute Carrier family 9A1) in humans, is the main H+ efflux mechanism in maintaining alkaline intracellular pH (pHi) and Warburg effects in glioma. However, to date, there are no clinical studies exploring pharmacological inhibition of NHE1 protein in cancer treatment. In this study, we investigated NHE1 expression in gliomas and its relationship with glioma clinical outcome.MethodsThe Chinese Glioma Genome Atlas (CGGA) dataset containing transcriptome sequencing data of 325 glioma samples and the Cancer Genome Atlas (TCGA) with 698 glioma mRNAseq data were analyzed in this study. Mouse SB28 and GL26 intracranial syngeneic glioma models in C57BL/6 J mice were established to investigate NHE1 expression and impact of NHE1 protein inhibition with its inhibitor HOE642 on tumorigenesis and anti-PD1 therapy. Tumor angiogenesis, immunogenicity, and progression were assessed by immunofluorescence staining and flow cytometric profiling.ResultsAnalysis of SLC9A1 mRNA expression in two data sets, CGGA and TCGA, reveals significantly higher SLC9A1 mRNA levels in higher grade gliomas. The SLC9A1 mRNA expression was especially enriched in isocitrate dehydrogenase (IDH)1/2 wild-type glioblastoma (GBM) and in mesenchymal glioma subtypes. Worsened survival probabilities were correlated with the elevated SLC9A1 mRNA levels in gliomas. The underlying mechanisms include promoting angiogenesis, and extracellular matrix remodeling. Increased SLC9A1 mRNA expression was also associated with tumor-associated macrophage accumulation. NHE1 inhibitor HOE642 reduced glioma volume, invasion, and prolonged overall survival in mouse glioma models. Blockade of NHE1 protein also stimulated immunogenic tumor microenvironment via activating CD8 T-cell accumulation, increasing expression of interferon-gamma (Ifng), and sensitized animals to anti-PD-1 therapy.ConclusionOur findings strongly suggest that NHE1 protein emerges as a marker for tumorigenesis and prognosis in glioma. Blocking NHE1 protein is a novel strategy for adjuvant anti-cancer therapies.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0923-z) contains supplementary material, which is available to authorized users.

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The thousand-grain weight and spikelets per panicle directly contribute to rice yield. Heading date and plant height also greatly influence the yield. Dissection of genetic bases of yield-related traits would provide tools for yield improvement. In this study, quantitative trait loci (QTL) mapping for spikelets per panicle, thousand-grain weight, heading date and plant height was performed using recombinant inbred lines derived from a cross between two diverse cultivars, Nanyangzhan and Chuan7. In total, 20 QTLs were identified for four traits. They were located to 11 chromosomes except on chromosome 4. Seven and five QTLs were detected for thousand-grain weight and spikelets per panicle, respectively. Four QTLs were identified for both heading date and plant height. About half the QTLs were commonly detected in both years, 2006 and 2007. Six QTLs are being reported for the first time. Two QTL clusters were identified in regions flanked by RM22065 and RM5720 on chromosome 7 and by RM502 and RM264 on chromosome 8, respectively. The parent, Nanyangzhan with heavy thousand-grain weight, carried alleles with increased effects on all seven thousand-grain weight QTL, which explained why there was no transgressive segregation for thousand-grain weight in the population. In contrast, Chuan7 with more spikelets per panicle carried positive alleles at all five spikelets per panicle QTL except qspp5. Further work on distinction between pleiotropic QTL and linked QTL is needed in two yield-related QTL clusters.

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This work evaluated the protective effect of procyanidins against oxidative stress in PC-12 neuroblastoma cells and established their activity-structure relationships, which provides useful cellular evidence for the further investigating the structure-optimizing and function-exploiting of procyanidins.