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Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase, which plays an essential role in both innate and adaptive immunity. However, the key molecular mechanisms that regulate SYK activity are poorly understood. Here we identified the E3 ligase TRIM31 as a crucial regulator of SYK activation. We found that TRIM31 interacted with SYK and catalyzed K27-linked polyubiquitination at Lys375 and Lys517 of SYK. This K27-linked polyubiquitination of SYK promoted its plasma membrane translocation and binding with the C-type lectin receptors (CLRs), and also prevented the interaction with the phosphatase SHP-1. Therefore, deficiency of Trim31 in bone marrow-derived dendritic cells (BMDCs) and macrophages (BMDMs) dampened SYK-mediated signaling and inhibited the secretion of proinflammatory cytokines and chemokines against the fungal pathogen Candida albicans infection. Trim31−/− mice were also more sensitive to C. albicans systemic infection than Trim31+/+ mice and exhibited reduced Th1 and Th17 responses. Overall, our study uncovered the pivotal role of TRIM31-mediated K27-linked polyubiquitination on SYK activation and highlighted the significance of TRIM31 in anti-C. albicans immunity.

Stringent regulation of the transcription factor NF-κB signaling is essential for the activation of host immune responses and maintaining homeostasis, yet the molecular mechanisms involved in its tight regulation are not completely understood. In this study, we report that IKK-interacting protein (IKIP) negatively regulates NF-κB activation. IKIP interacted with IKKα/β to block its association with NEMO, thereby inhibiting the phosphorylation of IKKα/β and the activation of NF-κB. Upon LPS, TNF-α, and IL-1β stimulation, IKIP-deficient macrophages exhibited more and prolonged IKKα/β phosphorylation, IκB, and p65 phosphorylation and production of NF-κB–responsive genes. Moreover, IKIP-deficient mice were more susceptible to LPS-induced septic shock and dextran sodium sulfate–induced colitis. Our study identifies a previously unrecognized role for IKIP in the negative regulation of NF-κB activation by inhibition of IKKα/β phosphorylation through the disruption of IKK complex formation.

The IκB kinase (IKK) complex plays a vital role in regulating the NF-κB activation. Aberrant NF-κB activation is involved in various inflammatory diseases. Thus, targeting IKK activation is an ideal therapeutic strategy to cure and prevent inflammatory diseases related to NF-κB activation. In a previous study, we demonstrated that IKK-interacting protein (IKIP) inhibits the phosphorylation of IKKα/β and the activation of NF-κB through disruption of the formation of IKK complex. In this study, we identified a 15-aa peptide derived from mouse IKIP (46–60 aa of IKIP), which specifically suppressed IKK activation and NF-κB targeted gene expression via disrupting the association of IKKβ and NEMO. Importantly, administration of the peptide reduced LPS-induced acute inflammation and attenuated Zymosan-induced acute arthritis in mice. These findings suggest that this IKIP peptide may be a promising therapeutic reagent in the prevention and treatment of inflammatory diseases.

Unmanned aerial vehicles (UAVs) have developed rapidly and are widely used in many fields. This phenomenon also causes security problems that urgently need to be addressed by anti-UAV technique. The localization of UAV plays an important role in anti-UAV system. An acoustic source localization scheme based on machine learning (ML) in wireless sensor networks is proposed in this study. Five ML algorithms, namely, artificial neural network (ANN), Naive Bayes, decision tree (DT), K nearest neighbors (KNN) and random forest (RF), are designed to estimate the coordinate of a single UAV. The acoustic energy decay model is constructed to simulate the attenuation and distortion caused by the ambient noise and changing surroundings. We use both received signal strength (RSS) based on acoustic energy and the difference of RSS as the input. Our experiments show that ML algorithms perform well except ANN. For ambient noise case, the ones with the input we propose achieve better localization accuracy than those only using RSS. KNN and RF are more suitable and reliable models for localization.

// Qun Zhang 1 , Song Liu 1 , Tong Li 1 , Lin Yuan 1 , Hansen Liu 2 , Xueer Wang 1 , Fuwu Wang 3 , Shuanglian Wang 1 , Aijun Hao 3 , Dexiang Liu 2 , Zhen Wang 1, 3 1 Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China 2 Department of Medical Psychology, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China 3 Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Histology and Embryology, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China Correspondence to: Dexiang Liu, email: Liudexiang@sdu.edu.cn Zhen Wang, email: wangzhen@sdu.edu.cn Keywords: hydrogen sulfide, bone marrow mesenchymal stem cells, transplants, brain-derived neurotrophic factor, vascular endothelial growth factor Received: February 08, 2016 Accepted: July 27, 2016 Published: August 09, 2016 ABSTRACT Bone marrow mesenchymal stem cells (BMSCs) transplantation has shown great promises for treating various brain diseases. However, poor viability of transplanted BMSCs in injured brain has limited the therapeutic efficiency. Hypoxia-ischemic injury is one of major mechanisms underlying the survival of transplanted BMSCs. We investigated the mechanism of preconditioning of BMSCs with hydrogen sulfide (H2S), which has been proposed as a novel therapeutic strategy for hypoxia-ischemic injury. In this study, we demonstrated that preconditioning of NaHS, a H2S donor, effectively suppressed hypoxia-ischemic-induced apoptosis whereby the rise in Bax/Bcl-2 ratio. Further analyses revealed Akt and ERK1/2 pathways were involved in the protective effects of NaHS. In addition, NaHS preconditioning increased secretion of BDNF and VEGF in BMSCs. Consistent with in vitro data, transplantation of NaHS preconditioned BMSCs in vivo further enhanced the therapeutic effects of BMSCs on neuronal injury and neurological recovery, associated with increased vessel density and upregulation of BDNF and VEGF in the ischemic tissue. These findings suggest that H2S could enhance the therapeutic effects of BMSCs. The underlying mechanisms might be due to enhanced capacity of BMSCs and upregulation of protective cytokines in the hypoxia tissue.

Depression is one of the most common neuropsychiatric disorders and has been associated with oxidative stress and brain protein alterations. Resveratrol is a natural polyphenol enriched in Polygonum cuspidatum and has diverse biological activities including potent antidepressant-like effects. The present study attempts to explore the mechanisms underlying the antidepressant-like action of resveratrol by measuring oxidative stress parameters and phosphorylation of AKT/mTOR pathway in the rat hippocampus and prefrontal cortex (PFC) exposed to the chronic unpredictable mild stress (CUMS). Male Wistar rats were subjected to CUMS protocol for a period of 4 weeks to induce depressive-like behavior. The results showed that resveratrol treatment (80 mg/kg/i.p. 4 weeks) significantly reversed the CUMS-induced behavioral abnormalities (reduced sucrose preference, increased immobility time and decreased locomotor activity) and biochemical changes (increased lipid peroxidation and decreased superoxide dismutase). Additionally, CUMS exposure significantly decreased phosphorylation of Akt and mTOR in the hippocampus and PFC, while resveratrol treatment normalized these parameters. In conclusion, our study showed that resveratrol exerted antidepressant-like effects in CUMS rats, which was mediated in part by its antioxidant action, up-regulation of phosphor-Akt and mTOR levels in the hippocampus and PFC.

Although the neuroprotective effects of hydrogen sulfide (H2 S) have been demonstrated in several studies, whether H2 S protects against early brain injury (EBI) and secondary cognitive dysfunction in subarachnoid hemorrhage (SAH) model remains unknown. This study was undertaken to evaluate the influence of H2 S on both acute brain injury and neurobehavioral changes as well as the underlying mechanisms after SAH. The H2 S donor, NaHS, was administered via an intraperitoneal injection at a dose of 5.6 mg/kg at 2 h, 6 h, 24 h, and 46 h after SAH in rat model. The results showed that NaHS treatment significantly improved brain edema and neurobehavioral function, and attenuated neuronal cell death in the prefrontal cortex, associated with a decrease in Bax/Bcl-2 ratio and suppression of caspase-3 activation at 48 h after SAH. NaHS also promoted phospho-Akt and phospho-ERK levels. Furthermore, NaHS treatment significantly enhanced the levels of brain-derived neurotrophic factor (BDNF) and phospho-CREB. Importantly, NaHS administration improved learning and memory performance in the Morris water maze test at 7 days post-SAH in rats. These results demonstrated that NaHS, as an exogenous H2 S donor, could significantly alleviate the development of EBI and cognitive dysfunction induced by SAH via Akt/ERK-related antiapoptosis pathway, and upregulating BDNF-CREB expression.

Current evidence supports that depression is accompanied by the activation of the inflammatory-response system, and overproduction of pro-inflammatory cytokines may play a role in the pathophysiology of depressive disorders. Resveratrol has anti-inflammatory, antioxidant and anti-depressant-like properties. Using an animal model of depression induced by a single administration of lipopolysaccharide (LPS), the present study investigated the effects of resveratrol on LPS-induced depressive-like behavior and inflammatory-response in adult mice. Our results showed that pretreatment with resveratrol (80mg/kg, i.p.) for 7 consecutive days reversed LPS-increased the immobility time in the forced swimming test and tail suspension test, and LPS-reduced sucrose preference test. Moreover, the antidepressant action of resveratrol was paralleled by significantly reducing the expression levels of pro-inflammatory cytokines, and up-regulating phosphorylated cAMP response-element-binding protein (pCREB)/brain-derived neurotrophic factor (BDNF) expression in prefrontal cortex (PFC) and hippocampus. In addition, resveratrol ameliorated LPS-induced NF-κB activation in the PFC and hippocampus. The results demonstrate that resveratrol may be an effective therapeutic agent for LPS-induced depressive-like behavior, partially due to its anti-inflammatory aptitude and by modulating pCREB and BDNF expression in the brain region of mice.

Chronic stress occurs in everyday life and induces depression-like behaviors, associated with proteins alterations and apoptosis in brain. Resveratrol is a natural polyphenol enriched in polygonum cuspidatum and has diverse biological activities, including potent antidepressant-like effects. The aim of this study was to determine whether resveratrol administration influences chronic restraint stress (CRS) - induced depression-like behaviors and explores underlying mechanisms. Male Wistar rats were subjected to CRS protocol for a period of 3 weeks to induce depressive-like behavior. The results showed that resveratrol (80mg/kg/i.p) administrated for 3 weeks significantly reversed the CRS-induced behavioral abnormalities (reduced sucrose preference and increased immobility time) in stressed rats. CRS exposure significantly decreased BDNF levels and phosphorylation of extracellular signal-regulated kinase (pERK) in hippocampus and prefrontal cortex (PFC), accompanied by decreased Bcl-2 mRNA expression and increased Bax mRNA expression, while resveratrol treatment normalized these levels. All of these effects of resveratrol were essentially identical to that observed with fluoxetine. In conclusion, our studies showed that resveratrol exerted antidepressant-like effects in CRS rats, mediated in part by the apoptotic machinery and up-regulating BDNF and pERK levels in the brain region.