MicroRNA-547-5p-mediated interleukin-33/suppressor of tumorigenicity 2 signaling underlies the genesis and maintenance of neuropathic pain and is targeted by the therapy with bone marrow stromal cells.

Interleukin-33 (IL-33)/suppressor of tumorigenicity 2 (ST2) signaling is known to promote inflammation and the genesis and maintenance of neuropathic pain. However, it remained mostly unknown how IL-33/ST2 signaling can be enhanced by neuropathic stimulations. Here, we report that the chronic constriction nerve injury (CCI)-induced increases in the expression of IL-33 and ST2 and a decrease in microRNA (miRNA)-547-5p not only in the dorsal root ganglia (DRG) but also in spinal dorsal horn (SDH) ipsilateral to the CCI.

Regulation of the firing activity by PKA-PKC-Src family kinases in cultured neurons of hypothalamic arcuate nucleus.

The cAMP-dependent protein kinase A family (PKAs), protein kinase C family (PKCs), and Src family kinases (SFKs) are found to play important roles in pain hypersensitivity. However, more detailed investigations are still needed in order to understand the mechanisms underlying the actions of PKAs, PKCs, and SFKs. Neurons in the hypothalamic arcuate nucleus (ARC) are found to be involved in the regulation of pain hypersensitivity.

Src activation in the hypothalamic arcuate nucleus may play an important role in pain hypersensitivity.

Src family of kinases (SFKs) has been found to play an important role in the regulation of nociception. However, how each member of this family acts in the central nervous system (CNS) structures involved in the relay and/or modulation of nociceptive signals, and thereby contributes to the formation and maintenance of pain hypersensitivity, is still a challenge. In this work, a combined study using biochemical, genetic and behavioral approaches was conducted.

Hippocampal protein kinase D1 is necessary for DHPG-induced learning and memory impairments in rats.

Background: Understanding molecular mechanisms underlying the induction of learning and memory impairments remains a challenge. Recent investigations have shown that the activation of group I mGluRs (mGluR1 and mGluR5) in cultured hippocampal neurons by application of (S)-3,5-Dihydroxyphenylglycine (DHPG) causes the regulated internalization of N-methyl-D-aspartate receptors (NMDARs), which subsequently activates protein kinase D1 (PKD1). Through phosphorylating the C-terminals of the NMDAR GluN2 subunits, PKD1 down-regulates the activity of remaining (non-internalized) surface NMDARs.

Development of regional specificity of spinal and medullary dorsal horn neurons.

Extensive studies have focused on the development and regionalization of neurons in the central nervous system (CNS). Many genes, which play crucial roles in the development of CNS neurons, have been identified. By using the technique "direct reprogramming", neurons can be produced from multiple cell sources such as fibroblasts.

Regulated internalization of NMDA receptors drives PKD1-mediated suppression of the activity of residual cell-surface NMDA receptors.

Background: Constitutive and regulated internalization of cell surface proteins has been extensively investigated. The regulated internalization has been characterized as a principal mechanism for removing cell-surface receptors from the plasma membrane, and signaling to downstream targets of receptors. However, so far it is still not known whether the functional properties of remaining (non-internalized) receptor/channels may be regulated by internalization of the same class of receptor/channels.

Locally released small (non-protein) ninhydrin-reacting molecules underlie developmental differences of cultured medullary versus spinal dorsal horn neurons.

Neurons located in the trigeminal subnucleus caudalis (Vc) play crucial roles in pain and sensorimotor functions in the orofacial region. Because of many anatomical and functional similarities with the spinal dorsal horn (SDH), Vc has been termed the medullary dorsal horn--analogous to the SDH. Here, we report that when compared with embryonic SDH neurons in culture, neurons isolated from the Vc region showed significantly slower growth, lower glutamate receptor activity, and more cells undergoing cell death.

Regulation of voltage-gated sodium current by endogenous Src family kinases in cochlear spiral ganglion neurons in culture.

Voltage-gated sodium (Na+) and potassium (K+)channels have been found to be regulated by Src family kinases(SFKs).However, how these channels are regulated by SFKs in cochlear spiral ganglion neurons (SGNs) remains unknown.Here, we report that altering the activity of endogenous SFKs modulated voltage-gated Na+, but not K+, currents recorded in embryonic SGNs in culture.

Src family kinases in the nervous system.

Src family kinases (SFKs) are key factors in the process of coupling signals from the cell surface to intracellular machinery and critically involved in the regulation of many neural functions mediated through growth factors, G-protein-coupled receptors or ligand-gated ion channels. The three minireviews here focus on recent findings dealing with the regulation of N-methyl-d-aspartate (NMDA) receptors by SFKs.

The regulation of N-methyl-D-aspartate receptors by Src kinase.

Src family kinases (SFKs) play critical roles in the regulation of many cellular functions by growth factors, G-protein-coupled receptors and ligand-gated ion channels. Recent data have shown that SFKs serve as a convergent point of multiple signaling pathways regulating N-methyl-d-aspartate (NMDA) receptors in the central nervous system. Multiple SFK molecules, such as Src and Fyn, closely associate with their substrate, NMDA receptors, via indirect and direct binding mechanisms.

Lack of association of SULT1A1 R213H polymorphism with colorectal cancer: a meta-analysis.

Background: A number of case-control studies were conducted to investigate the association of SULT1A1 R213H polymorphisms with colorectal cancer (CRC) in humans. But the results were not always consistent. We performed a meta-analysis to examine the association between the SULT1A1 R213H polymorphism and CRC.

Enhanced NMDA receptor NR1 phosphorylation and neuronal activity in the arcuate nucleus of hypothalamus following peripheral inflammation.

Unlabelled: AbstractAim:To investigate the role of glutamate and N-methyl-D-aspartate (NMDA) receptors in central sensitization following peripheral inflammation in the arcuate nucleus (ARC) of the mediobasal hypothalamus.

Methods: Mediobasal hypothalamic slices were prepared from rats undergoing peripheral inflammation, which was induced by a unilateral injection of complete Freund's adjuvant (CFA) into hind paw. Neuronal activation levels in the ARC were monitored by recording extracellular unit discharges.

THE ROLE OF INTRACELLULAR SODIUM (Na) IN THE REGULATION OF CALCIUM (Ca)-MEDIATED SIGNALING AND TOXICITY.

It is known that activated N-methyl-D-aspartate receptors (NMDARs) are a major route of excessive calcium ion (Ca(2+)) entry in central neurons, which may activate degradative processes and thereby cause cell death. Therefore, NMDARs are now recognized to play a key role in the development of many diseases associated with injuries to the central nervous system (CNS). However, it remains a mystery how NMDAR activity is recruited in the cellular processes leading to excitotoxicity and how NMDAR activity can be controlled at a physiological level.

Roles of the SH2 and SH3 domains in the regulation of neuronal Src kinase functions.

Previous studies demonstrated that intra-domain interactions between Src family kinases (SFKs), stabilized by binding of the phosphorylated C-terminus to the SH2 domain and/or binding of the SH2 kinase linker to the SH3 domain, lock the molecules in a closed conformation, disrupt the kinase active site, and inactivate SFKs. Here we report that the up-regulation of N-methyl-D-aspartate receptors (NMDARs) induced by expression of constitutively active neuronal Src (n-Src), in which the C-terminus tyrosine is mutated to phenylalanine (n-Src/Y535F), is significantly reduced by dysfunctions of the SH2 and/or SH3 domains of the protein. Furthermore, we found that dysfunctions of SH2 and/or SH3 domains reduce auto-phosphorylation of the kinase activation loop, depress kinase activity, and decrease NMDAR phosphorylation.

The NMDA receptor NR1 subunit is critically involved in the regulation of NMDA receptor activity by C-terminal Src kinase (Csk).

Previous studies have shown that Csk plays critical roles in the regulation of neural development, differentiation and glutamate-mediated synaptic plasticity. It has been found that Csk associates with the NR2A and 2B subunits of N-methyl-D-aspartate receptors (NMDARs) in a Src activity-dependent manner and serves as an intrinsic mechanism to provide a "brake" on the induction of long-term synaptic potentiation (LTP) mediated by NMDARs. In contrast to the NR2A and 2B subunits, no apparent tyrosine phosphorylation is found in the NR1 subunit of NMDARs.

Characterization of neuronal Src kinase purified from a bacterial expression system.

Neuronal Src (n-Src) is an alternative isoform of Src kinase containing a 6-amino acid insert in the SH3 domain that is highly expressed in neurons of the central nervous system (CNS). To investigate the function of n-Src, wild-type n-Src, constitutively active n-Src in which the C-tail tyrosine 535 was mutated to phenylalanine (n-Src/Y535F) and inactive n-Src in which the lysine 303 was mutated to arginine in addition to the mutation of Y535F (n-Src/K303R/Y535F), were expressed and purified from Escherichia coli BL21(DE3) cells. We found that all three types of n-Src constructs expressed at very high yields (∼500 mg/L) at 37°C, but formed inclusion bodies.

Central sensitization induced in trigeminal and upper cervical dorsal horn neurons by noxious stimulation of deep cervical paraspinal tissues in rats with minimal surgical trauma.

Objective: This study investigated if central sensitization is induced in the trigeminal subnucleus caudalis (also termed the medullary dorsal horn) and C1 and C2 dorsal horns by noxious stimulation of deep upper cervical paraspinal tissues in a preparation relatively free of surgical trauma.

Methods: Adult male Sprague-Dawley rats (275-450 g) were anesthetized intraperitoneally. Animals were then placed in a stereotaxic frame; a small cutaneous incision was made 3 to 4 mm near the bregma in the midline, and an opening into the skull was prepared by a 1/32-inch drill, 1 mm to the left from the midline.

Control of excitatory synaptic transmission by C-terminal Src kinase.

The induction of long-term potentiation at CA3-CA1 synapses is caused by an N-methyl-d-aspartate (NMDA) receptordependent accumulation of intracellular Ca(2+), followed by Src family kinase activation and a positive feedback enhancement of NMDA receptors (NMDARs). Nevertheless, the amplitude of baseline transmission remains remarkably constant even though low frequency stimulation is also associated with an NMDAR-dependent influx of Ca(2+) into dendritic spines. We show here that an interaction between C-terminal Src kinase (Csk) and NMDARs controls the Src-dependent regulation of NMDAR activity.

[Systematic assessment of acupuncture for treatment of herpes zoster in domestic clinical studies].

Objective: To assess the effectiveness of acupuncture for treatment of herpes zoster.

Methods: According to the requirement of evidence-based medicine, acupuncture, body acupuncture, electroacupuncture, head acupuncture, three edged needle, plum-blossom needle, fire needle, elongated needle, encircling needling, herpes zoster, etc. were selected as subject words to retrieve the relative medical database at home, and clinically randomized controlled trials were used as enrolled criteria, the treatment group were treated with acupuncture or acupuncture plus other therapies, and the control group with medicine, the cured rate and the time of killing pain for herpes zoster were used as assessment indexes.

[Effects of electroacupuncture treatment on nitrergic neurotransmitter in bladder neck and detrusor of rats with unstable bladder].

Objective: To observe the effects of electroacupuncture treatment on nitrergic neurotransmitter in bladder neck and detrusor of rats with unstable bladder.

Methods: Rat models of unstable bladder were established by operation to induce urethral obstruction. Electroacupuncture treatment was given by acupuncturing Huiyang and Zhonglushu points for a week.

The Role of Intracellular Sodium in the Regulation of NMDA-Receptor-Mediated Channel Activity and Toxicity.

Sodium (Na+) is the major cation in extracellular space and, with its entry into cells, may act as a critical intracellular second messenger that regulates many cellular functions. Through our investigations of mechanisms underlying the activity-dependent regulation of N-methyl-D-aspartate (NMDA) receptors, we recently characterized intracellular Na+ as a possible signaling factor common to processes underlying the upregulation of NMDA receptors by non-NMDA glutamate channels, voltage-gated Na+ channels, and remote NMDA receptors. Furthermore, although Ca2+ influx during the activation of NMDA receptors acts as a negative feedback mechanism that downregulates NMDA receptor activity, Na+ influx provides an essential positive feedback mechanism to overcome Ca2+ -induced inhibition, thereby potentiating both NMDA receptor activity and inward Ca2+ flow.

The removal of extracellular calcium: a novel mechanism underlying the recruitment of N-methyl-D-aspartate (NMDA) receptors in neurotoxicity.

The involvement of NMDA-type glutamate receptor in neuronal injury established in experimental stroke and neurotrauma models has been recently challenged by failures in treatment of stroke/neurotrauma patients with NMDA receptor antagonists. NMDA receptor activity is known to be essential for mediating a multitude of physiological functions. However, how NMDA receptors are recruited to cause neuronal injury remains unclear.

A functional interaction of sodium and calcium in the regulation of NMDA receptor activity by remote NMDA receptors.

The NMDA receptor is an important subtype glutamate receptor that acts as a nonselective cation channel highly permeable to both calcium (Ca2+) and sodium (Na+). The activation of NMDA receptors produces prolonged increases of intracellular Ca2+ concentration ([Ca2+]i) and thereby triggers downstream signaling pathways involved in the regulation of many physiological and pathophysiological processes. Previous studies have focused on how Ca2+ or Na+ affects NMDA receptor activity in isolation.

Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor.

Dopamine D1-like receptors, composed of D1 and D5 receptors, have been documented to modulate glutamate-mediated fast excitatory synaptic neurotransmission. Here, we report that dopamine D1 receptors modulate NMDA glutamate receptor-mediated functions through direct protein-protein interactions. Two regions in the D1 receptor carboxyl tail can directly and selectively couple to NMDA glutamate receptor subunits NR1-1a and NR2A.