Truncated GPNMB, a microglial transmembrane protein, serves as a scavenger receptor for oligomeric β-amyloid peptide in primary type 1 microglia.

Glycoprotein non-metastatic melanoma protein B (GPNMB) is up-regulated in one subtype of microglia (MG) surrounding senile plaque depositions of amyloid-beta (Aβ) peptides. However, whether the microglial GPNMB can recognize the fibrous Aβ peptides as ligands remains unknown. In this study, we report that the truncated form of GPNMB, the antigen for 9F5, serves as a scavenger receptor for oligomeric Aβ (o-Aβ) in rat primary type 1 MG.

Synthesis and evaluation of radioiodinated 1-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}piperidin-4-amine derivatives for platelet-derived growth factor receptor β (PDGFRβ) imaging.

Platelet-derived growth factor receptor β (PDGFRβ) is a transmembrane tyrosine kinase receptor and it is upregulated in various malignant tumors. Radiolabeled PDGFRβ inhibitors can be a convenient tool for the imaging of tumors overexpressing PDGFRβ. In this study, [I]-1-{5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinoline-8-yl}piperidin-4-amine ([I]IIQP) and [I]-N-3-iodobenzoyl-1-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}-piperidin-4-amine ([I]IB-IQP) were designed and synthesized, and their potential as PDGFRβ imaging agents was evaluated.

Autocrine Semaphorin3A signaling is essential for the maintenance of stem-like cells in lung cancer.

Cancer stem-like cells (CSCs) exist in tumor tissues composed of heterogeneous cell population and are characterized by their self-renewal capacity and tumorigenicity. Many studies demonstrate that eradication of CSCs prevents development and recurrences of tumor; yet, molecules critical for the maintenance of CSCs have not been completely understood. We previously reported that Semaphorin3A (Sema3a) knockdown suppressed the tumorigenicity and proliferative capacity of Lewis lung carcinoma (LLC) cells.

Plexin A1 signaling confers malignant phenotypes in lung cancer cells.

Aberrant changes to several signaling pathways because of genetic mutations or increased cytokine production are critical for tumor cells to become malignant. Semaphorin 3A (SEMA3A) acts as a bivalent factor that suppresses or promotes tumor development in different pathological backgrounds. Previously, we showed that SEMA3A positively regulated the proliferative and glycolytic activities of mouse-derived Lewis lung carcinoma (LLC) cells.

Cancer pain relief achieved by disrupting tumor-driven semaphorin 3A signaling in mice.

Cancer-induced bone pain (CIBP) is the most common pain arising from cancer and is inadequately managed with current standard therapeutics. While the etiology of CIBP remains to be fully elucidated, increasing evidence suggests that CIBP is uniquely complex. We tested whether semaphorin 3A (Sema3A) signals were involved in the development of CIBP in mice.

The novel monoclonal antibody 9F5 reveals expression of a fragment of GPNMB/osteoactivin processed by furin-like protease(s) in a subpopulation of microglia in neonatal rat brain.

To differentiate subtypes of microglia (MG), we developed a novel monoclonal antibody, 9F5, against one subtype (type 1) of rat primary MG. The 9F5 showed high selectivity for this cell type in Western blot and immunocytochemical analyses and no cross-reaction with rat peritoneal macrophages (Mφ). We identified the antigen molecule for 9F5: the 50- to 70-kDa fragments of rat glycoprotein nonmetastatic melanoma protein B (GPNMB)/osteoactivin, which started at Lys(170) .

mTORC1 is a critical mediator of oncogenic Semaphorin3A signaling.

Aberration of signaling pathways by genetic mutations or alterations in the surrounding tissue environments can result in tumor development or metastasis. However, signaling molecules responsible for these processes have not been completely elucidated. Here, we used mouse Lewis lung carcinoma cells (LLC) to explore the mechanism by which the oncogenic activity of Semaphorin3A (Sema3A) signaling is regulated.

Tumor cell-derived secretory factor downregulates Semaphorin-3a in osteoblasts by activating mammalian target of rapamycin pathway.

We found that conditioned medium derived from Lewis Lung Carcinoma cells down-regulated Semaphorin3a (Sema3a) mRNA expression and increased the activity of mammalian target of rapamycin complex 1 (mTORC1) in osteoblast-like MC3T3-E1 cells. Furthermore, mTORC1 inhibition with rapamycin counteracted the effect of conditioned media on Sema3a mRNA expression. These results suggest that tumor cells decrease Sema3a mRNA expression in osteoblast in an mTORC1-dependent manner.

Macrophage-T cell interactions mediate neuropathic pain through the glucocorticoid-induced tumor necrosis factor ligand system.

Peripheral neuroinflammation caused by activated immune cells can provoke neuropathic pain. Herein, we investigate the actions of macrophages and T cells through glucocorticoid-induced tumor neurosis factor receptor ligand (GITRL) and its receptor (GITR) in neuropathic pain. After partial sciatic nerve ligation (PSL) in enhanced green fluorescent protein (eGFP) chimeric mice generated by the transplantation of eGFP(+) bone marrow cells, eGFP(+) macrophages, and T cells markedly migrated to the injured site after PSL.

Peripheral interleukin-4 ameliorates inflammatory macrophage-dependent neuropathic pain.

There is increasing evidence that inflammatory (M1-polarized) macrophages drive the nonresolving neuroinflammation that causes neuropathic pain after nerve injury. As interleukin-4 (IL-4) promotes the suppressive (M2-polarized) state in macrophages, we examined whether exploiting an IL-4-mediated pathway could ameliorate M1 macrophage-dependent neuropathic pain. The mRNA and protein expression of IL-4 receptor α chain (IL-4Rα) were upregulated in accumulating F4/80 macrophages in injured sciatic nerve (SCN).

[Study on novel mechanism underlying analgesia targeting TRPV1].

Transient receptor potential protein (TRP) channels are distributed in pain pathways including primary afferent neurons and function as transduction of various noxious stimuli to innocuous stimuli. TRP channels are considered as molecular basis of chronic pain. Targeting TRPs may lead to novel class of analgesics, and so drug-discovery efforts are focused on TRP agonists and its antagonists.

Possible involvement of endogenous opioid system located downstream of α7 nicotinic acetylcholine receptor in mice with physical dependence on nicotine.

We previously reported that nicotine (NIC)-induced analgesia was elicited in part by activation of the endogenous opioid system. Moreover, it is well known that NIC has physical-dependence liability, but its mechanism is unclear. Therefore, we examined whether physical dependence on NIC was mediated by activation of the endogenous opioid system in ICR mice.

HMGB1 as a potential therapeutic target for neuropathic pain.

Neuropathic pain, which is intolerable and persistent, arises as a direct consequence of a lesion or disease affecting the somatosensory system and can be debilitating for the affected patients. Accumulating evidence from animal studies has revealed the potential molecular basis for neuropathic pain, resulting in many promising therapeutic targets. While efforts at drug discovery have been made, conventional pharmacotherapy, including the use of opioid analgesics, is still insufficient for the relief of neuropathic pain.

Activation of nicotinic acetylcholine receptors on bone marrow-derived cells relieves neuropathic pain accompanied by peripheral neuroinflammation.

Emerging evidence indicates that chronic neuroinflammation plays a pivotal role in neuropathic pain. We explored whether activation of the nicotinic acetylcholine receptor (nAChRs) pathway on peripheral immune cells improves neuropathic pain. Mice were subjected to partial sciatic nerve ligation (PSL).

The critical role of spinal ceramide in the development of partial sciatic nerve ligation-induced neuropathic pain in mice.

Recent observations indicate that peripheral nerve injury induces central sensitization through microglial activation and the release of inflammatory cytokines, resulting in the development of neuropathic pain. However, the underlying mechanisms of this phenomenon remain to be fully elucidated. In this study, we examined the involvement of spinal ceramide, a bioactive lipid, in the development of neuropathic pain induced by partial sciatic nerve ligation (PSL).

Epigenetic augmentation of the macrophage inflammatory protein 2/C-X-C chemokine receptor type 2 axis through histone H3 acetylation in injured peripheral nerves elicits neuropathic pain.

Although there is growing evidence showing that the involvement of chemokines in the pathogenesis of neuropathic pain is associated with neuroinflammation, the details are unclear. We investigated the C-X-C chemokine ligand type 2 [macrophage inflammatory protein 2 (MIP-2)]/C-X-C chemokine receptor type 2 (CXCR2) axis and epigenetic regulation of these molecules in neuropathic pain after peripheral nerve injury. Expression of MIP-2 and CXCR2 were up-regulated and localized on accumulated neutrophils and macrophages in the injured sciatic nerve (SCN) after partial sciatic nerve ligation (PSL).

Pharmacological relationship between nicotinic and opioid systems in analgesia and corticosterone elevation.

Aims: Although a pharmacological relationship is known to exist between nicotine and morphine, the exact mechanisms are unclear. Here, we investigated crosstalk between the endogenous opioid system and nicotinic acetylcholine receptors (nAChRs), specifically in nicotine-induced analgesia and activation of the hypothalamic-pituitary-adrenal (HPA) axis.

Main Methods: Nicotine and morphine were administered subcutaneously to mice and the effects of these drugs on analgesia and serum corticosterone (SCS) levels were evaluated by the tail-pinch method and fluorometric assay, respectively.

CC-chemokine MIP-1α in the spinal cord contributes to nerve injury-induced neuropathic pain.

We investigated the involvement of spinal macrophage inflammatory protein-1α (MIP-1α), an inflammatory chemokine, in partial sciatic nerve ligation (PSL)-induced neuropathic pain in mice. PSL increased MIP-1α mRNA levels as well as levels of the MIP-1α receptor, CCR1, but not CCR5 in the spinal dorsal horn. PSL-induced tactile allodynia and thermal hyperalgesia were prevented by intrathecal (i.

Increment of activated serine/threonine protein phosphatase in brain membrane fraction synchronized with antinociceptive effect of morphine in mice.

We have examined the involvement of serine/threonine protein phosphatase (PP) sensitive to okadaic acid (OA) in the antinociceptive effect of morphine in mice. The present study was performed to elucidate subcellular distribution and activity of OA-sensitive PPs in the brain when mice exposed to morphine. Subcutaneous administration of morphine (5 mg/kg) produced the antinociceptive effect with the maximum 30 min after its administration, evaluated by tail-pinch test.

Macrophage inflammatory protein-1alpha mediates the development of neuropathic pain following peripheral nerve injury through interleukin-1beta up-regulation.

In the present study, we investigated the role of the macrophage inflammatory protein-1alpha (MIP-1alpha) in the pathogenesis of neuropathic pain following partial sciatic nerve ligation (PSL) in mice. MIP-1alpha mRNA and its protein were dramatically up-regulated after PSL, and MIP-1alpha was localized on macrophages and Schwann cells in the injured sciatic nerve (SCN). PSL-induced long-lasting tactile allodynia and thermal hyperalgesia were prevented by the perineural injection of anti-MIP-1alpha (2ng).

Activation of extracellular signal-regulated kinase in sciatic nerve contributes to neuropathic pain after partial sciatic nerve ligation in mice.

Background: The mitogen-activated protein kinase family plays an important role in several types of pain. However, the detailed role of phosphorylated extracellular signal-regulated kinase (pERK) in the region of injured peripheral nerve is poorly understood. In this study, we investigated whether pERK in injured sciatic nerve contributes to neuropathic pain induced by partial sciatic nerve ligation (PSL) in mice.

Leptin derived from adipocytes in injured peripheral nerves facilitates development of neuropathic pain via macrophage stimulation.

Nerve injury may result in neuropathic pain, characterized by allodynia and hyperalgesia. Accumulating evidence suggests the existence of a molecular substrate for neuropathic pain produced by neurons, glia, and immune cells. Here, we show that leptin, an adipokine exclusively produced by adipocytes, is critical for the development of tactile allodynia through macrophage activation in mice with partial sciatic nerve ligation (PSL).

Involvement of inflammatory mediators in neuropathic pain caused by vincristine.

Elucidation of the mechanism of neuropathic pain caused by vincristine is required because long-term treatment with this anticancer agent often causes neuropathic pain. We refer to the involvement of inflammatory mediators in vincristine-induced neuropathic pain in this review. Several reports using rodents have shown that long-lasting neuropathic pain (mechanical allodynia) is caused by repeated systemic injection of vincristine.

PPAR and Pain.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factor belonging to a nuclear hormone receptor superfamily, containing three isoforms (alpha, beta/delta, and gamma). PPARs play a critical physiological role as a primary lipid sensor and regulator of lipid metabolism. Thus, its ligands are clinically used for treatment of type 2 diabetes and hyperlipidemia.