TIAM Rac1-associated GEF 2 short form (TIAM2S) as an oncoprotein alters the immunity of peripheral immune cells to construct an inflammatory tumor microenvironment. However, its role in the activation of microglia, the primary innate immune cells of the brain, and neuroinflammation remains unknown. This study investigated the mechanism underlying TIAM2S shapes immune properties of microglia to facilitate neuron damage. Human microglial clone 3 cell line (HMC3) and human brain samples were applied to determine the presence of TIAM2S in microglia by western blots and double immunostaining. Furthermore, TIAM2S transgenic mice combined with multiple reconstituted primary neuron-glial culture systems and a cytokine array were performed to explore how TIAM2S shaped immune priming of microglia and participated in lipopolysaccharide (LPS)-induced neuron damage. TIAM2S protein was detectable in HMC3 cells and presented in a small portion (~11.1%) of microglia in human brains referred to as TIAM2S-positive microglia. With the property of secreted soluble factor-mediated immune priming, TIAM2S-positive microglia enhanced LPS-induced neuroinflammation and neural damage in vivo and in vitro. The gain- and loss-of-function experiments showed soluble intercellular adhesion molecule-1 (sICAM-1) participated in neurotoxic immune priming of TIAM2S+ microglia. Together, this study demonstrated a novel TIAM2S-positive microglia subpopulation enhances inflammation and neurotoxicity through sICAM-1-mediated immune priming.
To investigate the pathogenicity of 2 novel KDM5C variations, report the clinical and neuroimaging findings, and review the available literature.Physical examinations, structural neuroimaging studies, and exome sequence analysis were performed. KDM5C constructs were used to study the effect of the variations in transfected cells.We identified 2 novel variations c.2233C>G and c.3392_3393delAG in the KDM5C gene harboring from 2 Chinese families with X-linked intellectual disability (ID). The affected male patients exhibited severe ID, short stature, and facial dysmorphism. The 1 with c.3392_3393delAG additionally had epilepsy and autistic spectrum disorder (ASD). Transiently transfected mutant KDM5C constructs both reduced protein expression and stability and decreased histone demethylase activities in cells. Reviewing the available literature, we found that the associated ASD tended to occur in patients with variations near the C-terminus of KDM5C.We report the clinical, molecular genetic, and pathologic features in patients with novel variations of KDM5C. The variability of the clinical phenotype in addition to an ID may associate with altered particular parts of KDM5C.
Abstract TIAM Rac1-associated GEF 2 short-form protein (TIAM2S) is abundant in specific brain tissues, especially in the hippocampus, a brain region critical for processing and consolidation of spatial memory. However, how TIAM2S plasticizes the microstructure and circuits of the hippocampus to shape spatial memory as a neuroplastic regulator during aging remains to be determined. In this study, transgenic mice overexpressing human TIAM2S protein (TIAM2S-TG mice) were included, and interdisciplinary approaches, such as spatial memory tests and multiparametric magnetic resonance imaging sequences, were conducted to determine the role and the mechanism of TIAM2S in age-related spatial memory deficits. Despite no changes in their neural and glial markers and neuropathological hallmark expression of the hippocampus, behavioral tests showed that the TIAM2S-TG mice, and not wild-type (WT) mice, developed spatial memory impairment at 18 months old. The T2-weighted and diffusion tensor image analyses were performed to further study the possible role of TIAM2S overexpression in altering the hippocampal structure or neuronal circlets of the mice, increasing their vulnerability to developing spatial memory deficits during aging. The results revealed that the 12-month-old TIAM2S-TG mice had hippocampal dysplasticity, with larger volume, increased fiber numbers, and changed mean fractional anisotropy compared to those in the age-matched WT mice. The fiber tractography analysis exhibited significantly attenuated structural connectivity between the hippocampus and medial prefrontal cortex in the TIAM2S-TG mice. In conclusion, overexpression of TIAM2S, a detrimental factor affecting hippocampus plasticity, causes attenuation of the connectivity within hippocampus–mPFC circuits, leading to age-related spatial memory impairment.
A therapeutic approach for promoting neuroprotection and brain functional regeneration after strokes is still lacking. Histone deacetylase 1 (HDAC1), which belongs to the histone deacetylase family, is involved in the transcriptional repression of cell-cycle-modulated genes and DNA damage repair during neurodegeneration. Our previous data showed that the protein level and enzymatic activity of HDAC1 are deregulated in stroke pathogenesis. A novel compound named 5104434 exhibits efficacy to selectively activate HDAC1 enzymatic function in neurodegeneration, but its potential in stroke therapy is still unknown. In this study, we adopted an induced rat model with cerebral ischemia using the vessel dilator endothelin-1 to evaluate the potential of compound 5104434. Our results indicated compound 5104434 selectively restored HDAC1 enzymatic activity after oxygen and glucose deprivation, preserved neurite morphology, and protected neurons from ischemic damage in vitro. In addition, compound 5104434 attenuated the infarct volume, neuronal loss, apoptosis, DNA damage, and DNA breaks in cerebral ischemia rats. It further ameliorated the behavioral outcomes of neuromuscular response, balance, forepaw strength, and functional recovery. Collectively, our data support the efficacy of compound 5104434 in stroke therapy and contend that it can be considered for clinical trial evaluation.
Abstract Background Rice is one of the major crop species in the world helping to sustain approximately half of the global population’s diet especially in Asia. However, due to the impact of extreme climate change and global warming, rice crop production and yields may be adversely affected resulting in a world food crisis. Researchers have been keen to understand the effects of drought, temperature and other environmental stress factors on rice plant growth and development. Gene expression microarray technology represents a key strategy for the identification of genes and their associated expression patterns in response to stress. Here, we report on the development of the rice OneArray® microarray platform which is suitable for two major rice subspecies, japonica and indica . Results The rice OneArray® 60-mer, oligonucleotide microarray consists of a total of 21,179 probes covering 20,806 genes of japonica and 13,683 genes of indica . Through a validation study, total RNA isolated from rice shoots and roots were used for comparison of gene expression profiles via microarray examination. The results were submitted to NCBI’s Gene Expression Omnibus (GEO). Data can be found under the GEO accession number GSE50844 ( http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE50844 ). A list of significantly differentially expressed genes was generated; 438 shoot-specific genes were identified among 3,138 up-regulated genes, and 463 root-specific genes were found among 3,845 down-regulated genes. GO enrichment analysis demonstrates these results are in agreement with the known physiological processes of the different organs/tissues. Furthermore, qRT-PCR validation was performed on 66 genes, and found to significantly correlate with the microarray results (R = 0.95, p < 0.001***). Conclusion The rice OneArray® 22 K microarray, the first rice microarray, covering both japonica and indica subspecies was designed and validated in a comprehensive study of gene expression in rice tissues. The rice OneArray® microarray platform revealed high specificity and sensitivity. Additional information for the rice OneArray® microarray can be found at http://www.phalanx.com.tw/index.php .
Stroke is a common cause of death worldwide and leads to disability and cognitive dysfunction. Ischemic stroke and hemorrhagic stroke are major categories of stroke, accounting for 68% and 32% of strokes, respectively. Each year, 15 million people experience stroke worldwide, and the stroke incidence is rising. Epigenetic modifications regulate gene transcription and play a major role in stroke. Accordingly, histone deacetylase 1 (HDAC1) participates in DNA damage repair and cell survival. However, the mechanisms underlying the role of HDAC1 in stroke pathogenesis are still controversial. Therefore, we investigated the role of HDAC1 in stroke by using a rat model of endothelin-1-induced brain ischemia. Our results revealed that HDAC1 was deregulated following stroke, and its expressional level and enzymatic activity were decreased. We also used MS-275 to inhibit HDAC1 function in rats exposed to ischemic insult. We found that HDAC1 inhibition promoted the infarct volume, neuronal loss, DNA damage, neuronal apoptosis after stroke, and levels of reactive oxygen species and inflammation cytokines. Additionally, HDAC1 inhibition deteriorated the behavioral outcomes of rats with ischemic insult. Overall, our findings demonstrate that HDAC1 participates in ischemic pathogenesis in the brain and possesses potential for use as a therapeutic target.
The anticancer effects of (−)-anonaine were investigated in this current study. (−)-Anonaine at concentration ranges of 50−200 μM exhibited significant inhibition to cell growth and migration activities on human lung cancer H1299 cells at 24 h, albeit cell cycle analyses showed that (−)-anonaine at the above concentration ranges did not cause any significant changes in cell-cycle distributions. Significant nuclear damages of H1299 cells were observed with 10−200 μM (−)-anonaine treatment in a comet assay, whereas higher concentrations (6 and 30 mM) of (−)-anonaine concentrations were required to cause DNA damages in an in vitro plasmid cleavage assay. In summary, our results demonstrated that (−)-anonaine exhibited dose-dependent antiproliferatory, antimigratory, and DNA-damaging effects on H1299 cells. We inferred that (−)-anonaine can cause cell-cycle arrest and DNA damage to hamper the physiological behavior of cancer cells at 72 h, and therefore, it can be useful as one of the potential herbal supplements for chemoprevention of human lung cancer.
Abstract T‐cell lymphoma invasion and metastasis 2 ( TIAM 2 ) is a neuron‐specific protein that has been found ectopically expressed in hepatocellular carcinoma ( HCC ). Results from clinical specimens and cellular and animal models have shown that the short form of TIAM 2 ( TIAM 2S ) functions as an oncogene in the tumorigenesis of liver cancer. However, the regulation of TIAM 2S ectopic expression in HCC cells remains largely unknown. This study aimed to identify the mechanism underlying the ectopic expression of TIAM 2S in liver cancer cells. In this report, we provide evidence illustrating that Sp1 binds directly to the GC box located in the TIAM 2S core promoter. We further demonstrated that overexpression of Sp1 in Hepa RG cells promotes endogenous TIAM 2S mRNA and protein expressions, and knockdown of Sp1 in 2 HCC cell lines, HepG2 and PLC / PRF /5, led to a substantial reduction in TIAM 2S mRNA and protein in these cells. Of 60 paired HCC samples, 70% showed a significant increase (from 1.1‐ to 3.6‐fold) in Sp1 protein expression in the tumor cells. The elevated Sp1 expression was highly correlated with both TIAM 2S mRNA and protein expressions in these samples. Together, these results illustrate that Sp1 positively controls TIAM 2S transcription and that Sp1‐mediated transcriptional activation is essential for TIAM 2S ectopic expression in liver cancer cells.
We evaluated the possible anticancer performance of a natural compound, goniothalamin (GTN), against human lung cancer using as a non-small cell lung cancer (NSCLC) cell line, H1299, as the model system. Cellular proliferation was significantly inhibited by GTN. Using an improved alkaline comet−nuclear extract (comet−NE) assay, GTN was found to induce a significant increase in the tail DNA. Wound healing and zymography assays showed that GTN attenuated cell migration and caused a reduction in the activity level of two major migration-associated matrix metalloproteinases, MMP-2 and MMP-9. It can be concluded that the DNA-damaging effect of GTN against lung cancer cells leads to growth inhibition as well as a depression in migration ability. Therefore, GTN has potential as a chemotherapeutic agent against lung cancer.
Abstract T-Cell Lymphoma Invasion and Metastasis 2 (TIAM2) gene was identified as the homolog for human TIAM1 gene, a Rac-specific guanine nucleotide exchange factor (GEF), and classified as a member of TIAM GEF subfamily. Although functions of TIAM family proteins have been extensively studied, the characteristics of human TIAM2 remain largely unknown. In this study we systematically investigate the cellular function of TIAM2. Two mRNA isoforms of TIAM2, TIAM2S and TIAM2L, were detected and showed distinct expression patterns in various human tissues. Although both mRNAs are highly expressed in many human tissues, no TIAM2L protein can be detected in any of the examined human tissues and cell lines. In addition, TIAM2S protein only expressed in neuron of restricted regions in the human brain. Overexpression of TIAM2S-GFP fusion protein revealed a cytosolic distribution in both HeLa and NIH3T3 cells. Using LC/MS/MS and enzymatic analysis, TIAM2S was shown to be an O-linked glycoprotein. As transiently transfected TIAM2S-fusion protein neither translocate onto the cell membrane, nor exhibit GEF activity to RhoGTPases in vivo, these data suggested human TIAM2S is not a classical GEF and its functional role in normal brain may differ from other TIAM members. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3852. doi:10.1158/1538-7445.AM2011-3852
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