Interferon-inducible protein SCOTIN interferes with HCV replication through the autolysosomal degradation of NS5A

Hepatitis C virus (HCV) utilizes autophagy to promote its propagation. Here we show the autophagy-mediated suppression of HCV replication via the endoplasmic reticulum (ER) protein SCOTIN. SCOTIN overexpression inhibits HCV replication and infectious virion production in cells infected with cell culture-derived HCV. HCV nonstructural 5A (NS5A) protein, which is a critical factor for HCV RNA replication, interacts with the IFN-beta-inducible protein SCOTIN, which transports NS5A to autophagosomes for degradation. Furthermore, the suppressive effect of SCOTIN on HCV replication is impaired in both ATG7-silenced cells and cells treated with autophagy or lysosomal inhibitors. SCOTIN does not affect the overall flow of autophagy; however, it is a substrate for autophagic degradation. The physical association between the transmembrane/proline-rich domain (TMPRD) of SCOTIN and Domain-II of NS5A is essential for autophagosomal trafficking and NS5A degradation. Altogether, our findings suggest that IFN-beta-induced SCOTIN recruits the HCV NS5A protein to autophagosomes for degradation, thereby restricting HCV replication.1110Ysciescopu

The orphan nuclear receptor SHP is a positive regulator of osteoblastic bone formation

The orphan nuclear receptor small heterodimer partner (SHP; NR0B2) interacts with a diverse array of transcription factors and regulates a variety of cellular events such as cell proliferation, differentiation, and metabolism. However, the role of SHP in bone formation has not yet been elucidated. SHP expression is significantly increased during osteoblast differentiation, and its expression is partially regulated by bone morphogenetic protein 2 (BMP-2), which plays an important role in bone formation. In our study, inhibition of SHP expression significantly repressed BMP-2-induced osteoblast differentiation and ectopic bone formation. In accordance with these in vitro and in vivo results, osteoblast differentiation in SHP −/− mice primary osteoblasts was significantly repressed, and the mice showed decreased bone mass resulting from decreased numbers of osteoblasts. Finally, SHP physically interacts and forms a complex with runt-related transcription factor 2 (Runx2) on the osteocalcin gene promoter, and overexpression of SHP increased Runx2 transactivity via competition with histone deacetylase 4 (HDAC4), an enzyme that inhibits DNA binding of Runx2 to its target genes. Taken together, these results indicate that SHP acts as a novel positive regulator of bone formation by augmenting osteoblast differentiation through regulation of the transcriptional activity of Runx2. © 2010 American Society for Bone and Mineral ResearchPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65055/1/90718_ftp.pd

Direct activation of Transient Receptor Potential Vanilloid 1(TRPV1) by Diacylglycerol (DAG)

The capsaicin receptor, known as transient receptor potential channel vanilloid subtype 1 (TRPV1), is activated by a wide range of noxious stimulants and putative ligands such as capsaicin, heat, pH, anandamide, and phosphorylation by protein kinase C (PKC). However, the identity of endogenous activators for TRPV1 under physiological condition is still debated. Here, we report that diacylglycerol (DAG) directly activates TRPV1 channel in a membrane-delimited manner in rat dorsal root ganglion (DRG) neurons. 1-oleoyl-2-acetyl-sn-glycerol (OAG), a membrane-permeable DAG analog, elicited intracellular Ca2+ transients, cationic currents and cobalt uptake that were blocked by TRPV1-selective antagonists, but not by inhibitors of PKC and DAG lipase in rat DRG neurons or HEK 293 cells heterologously expressing TRPV1. OAG induced responses were about one fifth of capsaicin induced signals, suggesting that OAG displays partial agonism. We also found that endogenously produced DAG can activate rat TRPV1 channels. Mutagenesis of rat TRPV1 revealed that DAG-binding site is at Y511, the same site for capsaicin binding, and PtdIns(4,5)P2binding site may not be critical for the activation of rat TRPV1 by DAG in heterologous system. We propose that DAG serves as an endogenous ligand for rat TRPV1, acting as an integrator of Gq/11-coupled receptors and receptor tyrosine kinases that are linked to phospholipase C

Clinical Characteristics of Patients Diagnosed With Odontogenic Rhinosinusitis After Dental Implants

Background and Objectives With the ongoing development of intraoral surgical treatment and invasive dental treatments such as implants, odontogenic rhinosinusitis (ORS) is on the rise. ORS related to dental implants accounts for 8% to 37% of cases. The purpose of this study is to define the characteristics of patients with ORS related to dental implants. Methods From 2015 to 2019, the medical records of 15 patients who developed maxillary sinus disease after receiving dental implants were retrospectively analyzed among patients who visited the ear nose and throat and dentistry departments. We reviewed the chief complaint, assessment, diagnosis, treatment and prognosis of these patients. Results Of the 15 patients, all were diagnosed with ORS. One patient with a post-operative cheek cyst, 1 with fungal sinusitis, 1 with an inverted papilloma, 1 with chronic rhinosinusitis, and 1 with a radicular cyst were diagnosed after surgery. Endoscopic sinus surgery was performed in 14 patients and 2 patients underwent a combined operation. One patient improved after medical treatment. The follow-up period was about 8.6 months. No recurrence was found in any of the patients. Conclusion If an implant problem is suspected based on history-taking and physical examination, active consultation with dentistry is needed to diagnose ORS

Detection of swine hepatitis E virus in the porcine hepatic lesion in Jeju Island

Swine hepatitis E virus (HEV) is an emerging zoonotic pathogen due to its close genomic similarity to human HEV. The prevalence of swine HEV in the hepatic lesion of pigs from the Jeju Island was investigated by reverse transcriptase polymerase chain reaction (RT-PCR). In total, 40 pigs with hepatitis lesions were selected from 19 different farms, based on examination by microscopy. RTPCR findings revealed swine HEV in 22 cases (55%), including 18 suckling pigs and 4 growing pigs. Several histopathological lesions, including multifocal lymphoplasmacytic hepatitis, portal inflammation, and focal hepatocellular necrosis, were observed in liver sections of swine HEV PCR-positive pigs. The present study suggests that the prevalence of swine HEV is very high in the pig population in Jeju Island, and that pigs are infected at early stages of growth (under 2 months of age). The high prevalence of swine HEV in pigs in Jeju Island and the ability of this virus to infect across species puts people with swine-associated occupations at possible risk of zoonotic infection.This work was supported by the Research Project on the Production of Bio-organs (No. 200503010403), Ministry of Agriculture and Forestry, Korea

Synaptic connectivity of the TRPV1-positive trigeminal afferents in the rat lateral parabrachial nucleus

Recent studies have shown a direct projection of nociceptive trigeminal afferents into the lateral parabrachial nucleus (LPBN). Information about the synaptic connectivity of these afferents may help understand how orofacial nociception is processed in the LPBN, which is known to be involved primarily in the affective aspect of pain. To address this issue, we investigated the synapses of the transient receptor potential vanilloid 1-positive (TRPV1+) trigeminal afferent terminals in the LPBN by immunostaining and serial section electron microscopy. TRPV1 + afferents arising from the ascending trigeminal tract issued axons and terminals (boutons) in the LPBN. TRPV1+ boutons formed synapses of asymmetric type with dendritic shafts and spines. Almost all (98.3%) TRPV1+ boutons formed synapses with one (82.6%) or two postsynaptic dendrites, suggesting that, at a single bouton level, the orofacial nociceptive information is predominantly transmitted to a single postsynaptic neuron with a small degree of synaptic divergence. A small fraction (14.9%) of the TRPV1+ boutons formed synapses with dendritic spines. None of the TRPV1+ boutons were involved in axoaxonic synapses. Conversely, in the trigeminal caudal nucleus (Vc), TRPV1+ boutons often formed synapses with multiple postsynaptic dendrites and were involved in axoaxonic synapses. Number of dendritic spine and total number of postsynaptic dendrites per TRPV1+ bouton were significantly fewer in the LPBN than Vc. Thus, the synaptic connectivity of the TRPV1+ boutons in the LPBN differed significantly from that in the Vc, suggesting that the TRPV1-mediated orofacial nociception is relayed to the LPBN in a distinctively different manner than in the Vc

A two-photon fluorescent probe for lysosomal zinc ions

The selective detection of zinc ions in lysosomes over that in cytosol is achieved with a fluorescent probe, which enabled the fluorescence imaging of endogenous zinc ions in lysosomes of NIH 3T3 cells as well as mouse hippocampal tissues by two-photon microscopy under excitation at 900 nm.open

Inhibitory Effect of KP-A038 on Osteoclastogenesis and Inflammatory Bone Loss Is Associated With Downregulation of Blimp1

Excessive osteoclastic activity results in pathological bone resorptive diseases, such as osteoporosis, periodontitis, and rheumatoid arthritis. As imidazole-containing compounds possess extensive therapeutic potential for the management of diverse diseases, we synthesized a series of imidazole derivatives and investigated their effects on osteoclast differentiation and function. In the present study, we found that a novel imidazole derivative, KP-A038, suppressed receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis and bone-resorbing activity in vitro and attenuated lipopolysaccharide (LPS)-induced bone destruction in vivo. KP-A038 significantly inhibited the induction of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and the expression of its target genes, including tartrate-resistant acid phosphatase (Acp5), cathepsin K (Ctsk), dendritic cell-specific transmembrane protein (Dcstamp), and matrix metallopeptidase 9 (Mmp9). KP-A038 upregulated the expression of negative regulators of osteoclast differentiation, such as interferon regulatory factor-8 (Irf8) and B-cell lymphoma 6 (Bcl6). Consistently, KP-A038 downregulated the expression of B lymphocyte-induced maturation protein-1 (Blimp1 encoded by Prdm1), a repressor for Irf8 and Bcl6. Moreover, administration of KP-A038 reduced LPS-induced bone erosion by suppressing osteoclast formation in vivo. Thus, our findings suggest that KP-A038 may serve as an effective therapeutic agent for the treatment and/or prevention of bone loss in pathological bone diseases, including osteoporosis and periodontitis