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Interleukin-15 is a pleiotropic cytokine type I four alpha-helical bundle cytokine that along with IL-2, IL-4, IL-7, IL-9, and IL-21 shares the common cytokine receptor γ chain, γc. IL-15 is vital for the development, survival, and expansion of natural killer cells and for the development of CD8+ memory T cells. Whereas other family γc cytokines signal by directly binding to their target cells, IL-15 is distinctive in that it binds to IL-15Rα, a sushi domain containing binding protein that is expressed on a number of cell types, including monocytes and dendritic cells as well as T cells, and then is trans-presented to responding cells that express IL-2Rβ and γc. This distinctive mechanism for IL-15 relates to its role in signaling in the context of cell-cell interactions and signaling synapses. The actions of IL-15 and ways of manipulating its actions to potential therapeutic benefit are discussed. [ABSTRACT FROM AUTHOR]

Grain quality has become one of the foci in rice breeding worldwide since it is crucial for farmers, millers and consumers. Previous studies have revealed that rice gain quality is mainly determined with several major characteristics including milling, physical appearance, eating and cooking, sensory and nutritional value. In genetics, rice grain quality is a complex trait controlled by polygene/QTL. Better understanding the mechanism underlying the grain quality is fundamental for developing new breeding strategies. Therefore, abundant studies had been conducted to discover the factors that control the quality traits, and led to dozens of QTL identified and several major genes cloned. This has enabled development of the functional markers to facilitate selection of the complex traits. But breeding for rice varieties with desired grain quality needs to pyramid multiple and beneficial loci or alleles, some of which are still untapped. In this chapter, we first summarize the literatures on rice grain quality traits and the relevant phenotyping approaches, and then review the progress in genetic dissection of these traits. This review also presented the breeding attempts using marker-assisted selection, genomics-assisted breeding approaches, as well as genome editing technologies, and finally provided innovative insights into the future of rice grain quality breeding by using the modern technology with integration of machine learning and genomic selection. [ABSTRACT FROM AUTHOR]

Gastric cancer metastasis is a major cause of poor prognosis. Our previous research showed that methionine restriction (MR) lowers the invasiveness and motility of gastric carcinoma. In this study, we investigated the particular mechanisms of MR on gastric carcinoma metastasis. In vitro, gastric carcinoma cells (AGS, SNU-5, MKN7, KATO III, SNU-1, and MKN45) were grown in an MR medium for 24 h. In vivo, BALB/c mice were given a methionine-free (Met−) diet. Transwell assays were used to investigate cell invasion and migration. The amounts of Krüppel like factor 10 (KLF10) and cystathionine β-synthase (CBS) were determined using quantitative real-time PCR and Western blot. To determine the relationship between KLF10 and CBS, chromatin immunoprecipitation and a dual-luciferase reporter experiment were used. Hematoxylin–eosin staining was used to detect lung metastasis. Liquid chromatography–mass spectrometry was used to determine cystathionine content. MR therapy had varying effects on the invasion and migration of gastric carcinoma cells AGS, SNU-5, MKN7, KATO III, SNU-1, and MKN45. KLF10 was highly expressed in AGS cells but poorly expressed in KATO III cells. KLF10 improved MR's ability to prevent gastric carcinoma cell invasion and migration. In addition, KLF10 may interact with CBS, facilitating transcription. Further detection revealed that inhibiting the KLF10/CBS-mediated trans -sulfur pathway lowered Met−'s inhibitory effect on lung metastasis development. KLF10 transcription activated CBS, accelerated the trans -sulfur pathway, and increased gastric carcinoma cells' susceptibility to MR. [Display omitted] [ABSTRACT FROM AUTHOR]

• A rapid discovery and functional characterization platform of diterpene synthases from basidiomycete fungi was developed. • 25 putative diterpene synthases from 220 genome sequenced basidiomycete fungi were mined as potential diterpene synthases by genome mining. • The structure of products of four active diterpene synthases were determined via extensive NMR and MS spectroscopic analyses as (−)-(R)-nephthenol, ent-kauran-16α-ol, and (−)-cyatha-3, 12-diene. Basidiomycete fungi are a rich source of bioactive diterpenoid secondary metabolites. However, compared with the large number of diterpene synthases (di-TPSs) identified in plants and ascomycete fungi, only three di-TPSs have been described from basidiomycete fungi. Large scale genome sequencing projects combined with the development of synthetic biology techniques now has enabled the rapidly discovery and characterization of di-TPSs from basidiomycete fungi. In this study, we discovered and functionally characterized four di-TPSs from 220 genome sequenced basidiomycete fungi by a combined strategy of genomic data mining, phylogenetic analysis and fast products characterization with synthetic biology techniques. Among them, SteTC1 of Stereum histurum was characterized as the first fungal cembrane diterpene synthase; PunTC of Punctularia strigosozonata and SerTC of Serpula lacrymans were characterized as ent-kauran-16α-ol synthase and DenTC3 of Dentipellis sp was characterized as a cyathane synthase. Our results provide opportunities for the discovery of new diterpenoids from basidiomycete fungi by genome mining. [ABSTRACT FROM AUTHOR]

Peripheral painful neuropathy is one of the most common complications in diabetes and necessitates improved treatment. Fisetin, a naturally occurring flavonoid, has been reported to exert antidepressant-like effect in previous studies. As antidepressant drugs are employed clinically to treat neuropathic pain, this work aimed to investigate whether fisetin posses beneficial effect on diabetic neuropathic pain and explore the mechanism(s). We subjected mice to diabetes by a single intraperitoneal (i.p.) injection of streptozotocin (200 mg/kg), and von Frey test or Hargreaves test was used to assess mechanical allodynia or thermal hyperalgesia, respectively. Chronic treatment of diabetic mice with fisetin not only ameliorated the established symptoms of thermal hyperalgesia and mechanical allodynia, but also arrested the development of neuropathic pain when given at low doses. Although chronic fisetin administration did not impact on the symptom of hyperglycemia in diabetic mice, it reduced exacerbated oxidative stress in tissues of spinal cord, dorsal root ganglion (DRG) and sciatic verve. Furthermore, the analgesic actions of fisetin were abolished by repetitive co-treatment with the reactive oxygen species (ROS) donor tert -butyl hydroperoxide ( t -BOOH), but potentiated by the ROS scavenger phenyl- N - tert -butylnitrone (PBN). Finally, acute blockade of spinal GABA A receptors by bicuculline totally counteracted such fisetin analgesia. These findings indicate that chronic fisetin treatment can delay or correct neuropathic hyperalgesia and allodynia in mice with type 1 diabetes. Mechanistically, the present fisetin analgesia may be associated with its antioxidant activity, and spinal GABA A receptors are likely rendered as downstream targets. [ABSTRACT FROM AUTHOR]

The concept of a glycolytic cancer cell was introduced by Warburg over 70 years ago. This perception has since become the rationale that drives a considerable proportion of basic research on cancer, and it influences the current strategies for the diagnosis, monitoring, and treatment of cancer. Here we review the data from the last 40 years on this issue. We conclude that there is no evidence that cancer cells are inherently glycolytic, but that some tumours might indeed be glycolytic in vivo as a result of their hypoxic environment. [Copyright &y& Elsevier]

Emerging evidence has linked chronic temporal lobe epilepsy to dramatically reduced neurogenesis in the dentate gyrus. However, the profile of different components of neurogenesis in the chronically epileptic hippocampus is still unclear, especially the incorporation of newly generated cells. To address the issue, newly generated cells in the sub-granular zone of the dentate gyrus were labeled by the proliferation marker bromodeoxyuridine (BrdU) or retroviral vector expressing green fluorescent protein 2 months after pilocarpine-induced status epilepticus. The newly generated neurons that extended axons to CA3 area or integrated into memory circuits were visualized by cholera toxin B subunit retrograde tracing, and detecting activation of BrdU + cells following a recall of spatial memory test at the chronic stage of TLE. We found that the microenvironment was still able to sustain significant neuronal differentiation of newly generated cells at 2 months post-status epilepticus time-point, and newly added neurons into granular cell layer were still able to integrate into neuronal circuitry, both anatomically and functionally. Quantified analyses of BrdU + or Ki-67 + cells demonstrated that there was a reduced proliferation of progenitor cells and diminished survival of newly generated cells in the epileptic hippocampus. Both decreased levels of neurotrophic factors in the surrounding milieu and cell loss in the CA3 area might contribute the decreased production of new cells and their survival following chronic epilepsy. These results suggest that decreased neurogenesis in the chronically epileptic hippocampus 2 months post status epilepticus is not associated with altered integration of newly generated neurons, and that developing strategies to augment hippocampal neurogenesis in chronic epilepsy might be protective. [ABSTRACT FROM AUTHOR]

KDM2A is a histone demethylase, which primarily catalyzes the demethylation of H3K36me2. Abnormal expression of KDM2A is observed in many types of cancers; however, the molecular events connected to KDM2A expression remain unclear. We report that KDM2A performs an oncogenic function in esophageal squamous cell carcinoma (ESCC) and is robustly expressed in ESCC cells. ShRNA-mediated knockdown of KDM2A resulted in a significant inhibition of the malignant phenotype of ESCC cell lines, whereas ectopic expression of KDM2A showed the opposite effect. We also analyzed the function of KDM2A using a CRISPR-CAS9 depletion system and subsequent rescue experiment, which also indicated a cancerous role of KDM2A. Interestingly, analysis of the gene expression network controlled by KDM2A using RNA-seq revealed an unexpected feature: KDM2A could induce expression of a set of well-documented oncogenic genes, including IL6 and LAT2, while simultaneously suppressing another set of oncogenes, including MAT2A and HMGCS1. Targeted inhibition of the upregulated oncogene in the KDM2A-depleted cells led to a synergistic suppressive effect on the malignant phenotype of ESCC cells. Our results revealed the dual role of KDM2A in ESCC cells, which may have therapeutic implications. • Ablation of KDM2A attenuates the malignant phenotype of ESCC cell lines. • Augmented expression of KDM2A promotes the malignant phenotype of ESCC cells. • KDM2A activates one set of oncogenic genes and represses another set of cancerous genes simultaneously. • Inhibition of activated oncogenes generates a synergistic antitumor effect in KDM2A-deficient ESCC cells. • The dual role of KDM2A may be used to develop a combination treatment for ESCC. [ABSTRACT FROM AUTHOR]

Transcription factors (TFs) play an important role in tumors. We integrated and analyzed 13 GPL570 platform gastric cancer (GC) microarrays, identified 10 independent prognostic TFs, and constructed a GC prognostic model. Using GSE26942 as the verification set, the Kaplan-Meier curve showed that the signature distinguish the survival rate of GC patients (P < 0.01), and the AUC values are 0.746 and 0.630, respectively. Compared with the clinicopathological characteristics, the signature is an independent prognostic factor (P < 0.05). A nomogram was established based on the model, and the five-year calibration curve verified that the prediction of the nomogram was almost consistent with the actual survival rate, C-index of 0.747 indicated a moderate prognostic ability. The analysis of target genes of 10 TFs showed that they are closely related to the progression of GC. External database and rt-PCR showed that the RNA and protein expression of TFs are consistent with our analysis. • Integrating the GPL570 platform 13 gastric cancer micro-arrays to get 1027 samples. • Transcription factors differentially expressed in gastric cancer were identified. • The prognostic-related TFs were identified and a prognostic model was constructed. • The target genes of hub TFs were predicted and the molecular mechanism was analyzed. • The critical TFs have been verified by external databases and experiments. [ABSTRACT FROM AUTHOR]

Our previous study has shown heme oxygenase-1 (HO-1) protects human lens epithelial cells (LECs) against H 2 O 2 -induced oxidative stress and apoptosis. Nrf2, the major regulator of HO-1, is triggered during the mutual induction of oxidative stress and ER stress. In response to ER stress, unfolded protein response (UPR) serves as a program of transcriptional and translational regulation mechanism with PERK involved. Both Nrf2 and ATF4 are activated as the downstream effect of PERK signaling coordinating the convergence of dual stresses. However, the ways in which Nrf2 interacting with ATF4 regulates deteriorated redox state have not yet been fully explored. Here, the transfected LECs with Nrf2 overexpression illustrated enhanced resistance in morphology and viability upon H 2 O 2 treatment condition. Intracellular ROS accumulation arouses ER stress, initiating PERK dependent UPR and inducing the downstream signal Nrf2 and ATF4 auto-phosphorylation. Further, converging at target promoters, ATF4 facilitates Nrf2 with the expression of ARE-dependent phase II antioxidant and detoxification enzymes. According to either Nrf2 or ATF4 gene modification, our data suggests a novel interaction between Nrf2 and ATF4 under oxidative and ER stress, thus drives specific enzymatic and non-enzymatic reactions of antioxidant mechanisms maintaining redox homeostasis. Therapies that restoring Nrf2 or ATF4 expression might help to postpone LECs aging and age-related cataract formation. [ABSTRACT FROM AUTHOR]

Purpose To conduct a systematic review and meta-analysis of studies testing exercise in animal models of pilocarpine induced status epilepticus (SE) and to compare the efficacy of different training strategies used in those studies. Methods We searched 2 online databases (Pubmed and Web of Science) for studies analyzing the efficacy of different trainings in pilocarpine-induced SE models. Training was categorized into forced physical training (PT), voluntary PT and resistance PT. Two reviewers independently extracted data on study quality, behavioral seizures, and histological, chemical and cognitive outcomes. Data were pooled by means of a meta-analysis. Results Among 17 selected studies; 174 animals from 8 studies with 10 comparison groups showed that exercise intervention after induction of SE significantly decreased spontaneous recurrent seizures with [mean difference (MD) = − 1.80, 95% confidence interval (CI): − 3.22, − 0.37, p = 0.02] and 60 animals showed statistically significant decrease in latency in Morris water maze (standardized mean difference (SMD) = − 2.57, 95% CI: − 4.06, − 1.08, p = 0.0007). Although not statistically significant, still a remarkable increase in number of CA1 neurons and hippocampal BDNF level (MD = 2.27, [95% CI: − 1.20, 5.73], p = 0.19, SMD = 1.07, [95% CI: − 0.36, 2.51], p = 0.14 respectively) and a decrease in mossy fibers sprouting (SMD = − 1.03, [95% CI: − 3.06, 1.00], p = 0.32) were observed. PT interventions in 72 animals before induction of SE showed favorable increase in latency to develop SE (MD = 8.34, [95% CI: − 3.10, 19.78], p = 0.15) but no remarkable improvements in latency for the first motor sign and motor signs intensity. Conclusions PT after SE reduces the recurrent seizures and improves the morphological, biochemical and cognitive profiles of pilocarpine epileptic models. Resistance PT was identified as particularly effective in reducing behavioral seizures. The efficacy of training was also dependent upon duration. [ABSTRACT FROM AUTHOR]

Enteric neural crest-derived cells (ENCCs) can migrate into endogenous ganglia and differentiate into progeny cells, and have even partially rescued bowel function; however, poor reliability and limited functional recovery after ENCC transplantation have yet to be addressed. Here, we investigated the induction of endogenous ENCCs by combining exogenous ENCC transplantation with a 5-HT 4 receptor agonist mosapride in a rat model of hypoganglionosis, established by benzalkonium chloride treatment. ENCCs, isolated from the gut of newborn rats, were labeled with a lentiviral eGFP reporter. ENCCs and rats were treated with the 5-HT 4 receptor agonist/antagonist. The labeled ENCCs were then transplanted into the muscular layer of benzalkonium chloride-treated colons. At given days post-intervention, colonic tissue samples were removed for histological analysis. ENCCs and neurons were detected by eGFP expression and immunoreactivity to p75 NTR and peripherin, respectively. eGFP-positive ENCCs and neurons could survive and maintain levels of fluorescence after transplantation. With longer times post-intervention, the number of peripherin-positive cells gradually increased in all groups. Significantly more peripherin-positive cells were found following ENCCs plus mosapride treatment, compared with the other groups. These results show that exogenous ENCCs combined with the 5-HT 4 receptor agonist effectively induced endogenous ENCCs proliferation and differentiation in a rat hypoganglionosis model. [ABSTRACT FROM AUTHOR]

A growing body of evidence supports the potential use of enteric neural crest-derived cells (ENCCs) as a cell replacement therapy for Hirschsprung's disease. Based on previous observations of robust propagation of primary ENCCs, as opposed to their progeny, it is suggested that their therapeutic potential after in vitro expansion may be restricted. We therefore examined the growth and differentiation activities and phenotypic characteristics of continuous ENCC cultures. ENCCs were isolated from the intestines of postnatal rats and were identified using an immunocytochemical approach. During continuous ENCC culture expansion, proliferation, migration, apoptosis, and differentiation potentials were monitored. The Cell Counting Kit-8 was used for assessment of ENCC vitality, Transwell inserts for cell migration, immunocytochemistry for cell counts and identification, and flow cytometry for apoptosis. Over six continuous generations, ENCC proliferation potency was reduced and with prolonged culture, the ratio of migratory ENCCs was decreased. The percentage of apoptosis showed an upward trend with prolonged intragenerational culture, but showed a downward trend with prolonged culture of combined generations. Furthermore, the percentage of peripherin + cells decreased whilst the percentage of GFAP + cells increased with age. The results demonstrated that alterations in ENCC growth characteristics occur with increased culture time, which may partially account for the poor results of proposed cell therapies. [ABSTRACT FROM AUTHOR]

Abstract: Associations between five polymorphisms of vascular endothelial growth factor (i.e., VEGF +936C/T, −1154A/G, −2578C/A, −634G/C and −460T/C) and risk of breast cancer have been extensively studied, and the currently available results are inconclusive. Therefore, we performed this meta-analysis to further study the associations. The databases of Pubmed, Embase and CNKI were retrieved up to April 1st, 2010. The pooled ORs and 95% CIs were used to assess the strength of the associations. A total of 10 case–control studies with 8175 cases and 8528 controls were included in this study. The overall results of combined analyses showed that five polymorphisms of VEGF were not associated with risk of breast cancer [ORs (95% CIs): 1.03 (0.84–1.27) for CC vs. TT for +936C/T, 0.95 (0.81–1.12) for AA vs. GG for −1154A/G, 1.01 (0.90–1.14) for CC vs. AA for −2578C/A, 1.02 (0.90–1.16) for GG vs. CC for −634G/C and 0.86 (0.68–1.09) for TT vs. CC for −460T/C]. When subgroup analyses by ethnicity for VEGF +936C/T and −634G/C, the results suggested that +936C/T was not associated with the risk of breast cancer for either Asians [1.40 (0.92–2.13) for CC vs. TT and CC+CT vs. TT: 1.38 (0.91–2.10) for CC+CT vs. TT] or Caucasians [0.93 (0.73–1.19) for CC vs. TT and 0.91 (0.72–1.16) for CC+CT vs. TT], and −634G/C was not associated with the breast cancer for Caucasians [1.07 (0.92–1.24) for GG vs. CC and 1.05 (0.91–1.21) for GG+GC vs. CC]. In addition, when excluding one study, which was out of Hardy–Weinberg equilibrium for VEGF +963C/T and whose controls were from both patients and healthy people, the negative results were also persistent, and ORs (95% CIs) were 1.04 (0.84–1.29) for CC vs. TT, 1.03 (0.83–1.27) for (CC+CT) vs. TT. This meta-analysis suggests that the VEGF +936C/T, −1154A/G, −2578C/A, −634G/C and −460T/C may be not associated with risk of breast cancer development based on the currently available studies, especially for Caucasians. More well designed studies with larger sample size on different ethnicities are needed to further assess the associations. [Copyright &y& Elsevier]

• The best human STING agonist 12b displayed similar activities with 2′3′-cGAMP. • Compound 2g, 9g, and 12b can directly bind to the human STING protein. • The Structure-Activity Relationships of synthetic compounds were discussed. • Compound 12b is better than 2′3′-cGAMP in the induction of assorted cytokines. STING (Stimulator of Interferon Genes) has become a focal point in immunology research and a target in drug discovery. The discovery of a potent human-STING agonist is expected to revolutionize current anti-virus or cancer immunotherapy. Inspired by the structure and function of murine STING-specific agonists (DMXAA and CMA), we rationally designed and synthesized four series of novel compounds for the enhancement of human sensitivity. In the cell-based assay, we identified six compounds from all the synthetic small molecules: 2g, 9g, and 12b are STING agonists that are efficacious across species, and all have the skeleton of acridone; 1b, 1c, and 12c just function in the murine STING pathway. Notably, 12b exhibits the best activity among the six agonists, and its inductions of both human and murine STING-dependent signalling are similar to that of 2′3′-cGAMP, which is a well-known STING inducer. While a protein assay indicated that 2 g, 9 g, and 12b could activate the pathway by directly binding human STING, 12b also displayed the strongest binding affinity. Additionally, our studies show that 12b can induce faster, more powerful, and more durable responses of assorted cytokines in a native system than 2′3′-cGAMP. Consequently, our team is the first to successfully modify murine STING agonists to obtain human sensitivity, and these results suggest that 12b is a potent direct-human-STING agonist. Additionally, the acridone analogues demonstrate tremendous potential in the treatment of tumours or viral infections. [ABSTRACT FROM AUTHOR]