No abstract

CXCL2 has been known to regulate immune functions mainly by chemo-attracting neutrophils. In this study, we show that CXCL2 can be induced by receptor activator of NF-κB ligand, the osteoclast (OC) differentiation factor, through JNK and NF-κB signaling pathways in OC precursor cells. CXCL2 in turn enhanced the proliferation of OC precursor cells of bone marrow-derived macrophages (BMMs) through the activation of ERK. Knockdown of CXCL2 inhibited both the proliferation of and the ERK activation in BMMs. During osteoclastogenesis CXCL2 stimulated the adhesion and the migration of BMMs. Moreover, the formation of OCs from BMMs was significantly increased on treatment with CXCL2. Conversely, the CXCL2 antagonist repertaxin and a CXCL2 neutralizing Ab potently reduced receptor activator of NF-κB ligand-induced osteoclastogenesis. Furthermore, CXCL2 evoked fulminant bone erosion in the in vivo mouse experiments. Finally, prominent upregulation of CXCL2 was detected in synovial fluids and sera from rheumatoid arthritis patients, suggesting a potential involvement of CXCL2-mediated osteoclastogenesis in rheumatoid arthritis-associated bone destruction. Thus, CXCL2 is a novel therapeutic target for inflammatory bone destructive diseases.

Clevudine (CLV) is a nucleoside analog with potent antiviral activity against chronic hepatitis B virus (HBV)infection. Viral resistance to CLV in patients receiving CLV therapy has not been reported. The aim of this study was to characterize CLV-resistant HBV in patients with viral breakthrough (BT) during long-term CLV therapy. The gene encoding HBV reverse transcriptase (RT) was analyzed from chronic hepatitis B patients with viral BT during CLV therapy. Sera collected from the patients at baseline and at the time of viral BT were studied. To characterize the mutations of HBV isolated from the patients, we subjected the HBV mutants to in vitro drug susceptibility assays. Several conserved mutations were identified in the RT domain during viral BT, with M204I being the most common. In vitro phenotypic analysis showed that the mutation M204I was predominantly associated with CLV resistance, whereas L229V was a compensatory mutation for the impaired replication of the M204I mutant. A quadruple mutant (L129M, V173L, M204I, and H337N) was identified that conferred greater replicative ability and strong resistance to both CLV and lamivudine. All of the CLV-resistant clones were lamivudine resistant. They were susceptible to adefovir, entecavir, and tenofovir, except for one mutant clone. In conclusion, the mutation M204I in HBV RT plays a major role in CLV resistance and leads to viral BT during long-term CLV treatment. Several conserved mutations may have a compensatory role in replication. Drug susceptibility assays reveal that adefovir and tenofovir are the most effective compounds against CLV-resistant mutants. These data may provide additional therapeutic options for CLV-resistant patients.Chronic hepatitis B virus (HBV) infection is a major health problem worldwide and leads to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (13). Antiviral treatment for chronic hepatitis B improves the outcome of the disease and prevents the development of hepatocellular carcinoma (14). Currently, several oral antiviral agents, including lamivudine (LMV), adefovir (ADV), and entecavir (ETV), have been approved for the treatment of chronic HBV infections (8). However, oral antiviral treatment does not provide a cure or durable remission and it has limited long-term efficacy due to the emergence of resistance (12). Long-term treatment with nucleos(t)ide analogs is associated with an increased risk of drug resistance. Antiviral drug resistance in patients infected with HBV is associated with subsequent virologic breakthrough (BT), viral rebound, and biochemical BT.Clevudine [1-(2-deoxy-2-fluoro-␤-arabinofuranosyl)thymine, L-FMAU] (CLV) is a pyrimidine analog with potent antiviral activity against HBV (4). CLV inhibits the DNA-dependent DNA activity of HBV polymerase, as well as reverse transcription and priming (1, 16). Phase III clinical trial results have shown that CLV therapy for 24 weeks has a potent and sustained antiviral effect in both HBeAg-positive and -negative chronic hepatitis B patients (23,24). Clinica...

The present study is the first to investigate the participation of central cyclooxygenase (COX) pathways in modulating the antinociceptive effects of intracisternally administered cannabinoid on nociception induced by inflammation of the temporomandibular joint (TMJ) in freely moving rats. Following intra-articular injection of 5% formalin in the TMJ, nociceptive scratching behavior was recorded for nine successive 5-min intervals in Sprague-Dawley rats. Intracisternal injection of 30 microg of WIN 55,212-2, a synthetic non-subtype-selective CB1/2 agonist, administered 20 min prior to formalin injection significantly reduced the number of scratches and duration of scratching induced by formalin compared with the vehicle-treated group. Antinociceptive effect of WIN 55,212-2 was blocked by intracisternal injection of 10 microg of AM251, a CB1 receptor-selective antagonist, but not by AM630, a CB2 receptor-selective antagonist. A 10 microg dose of WIN 55,212-2 that was ineffective in producing antinociception became effective following intracisternal administration of NS-398, a selective COX-2 inhibitor; indomethacin, a non-selective COX 1/2 inhibitor; acetaminophen, a putative COX-3 inhibitor, but not following pretreatment with the selective COX-1 inhibitor, SC-560. The ED(50) value of WIN 55,212-2 in the NS-398-treated group was significantly lower than that in the vehicle-treated group. Importantly, administration of low doses of COX inhibitors alone did not attenuate nociception. These results indicate that inhibition of central COX pathways, presumably via COX-2 inhibition, reduces inflammatory pain by enhancing the cannabinoid-induced antinociceptive effect. Based on our observations, combined administration of cannabinoids with COX inhibitors may hold a therapeutic promise in the treatment of inflammatory TMJ pain.

Endoscopic biopsy is necessary to confirm a histopathologic diagnosis. Currently, 6 to 8 biopsies are recommended for diagnosis of a suspected malignant lesion. However, multiple biopsies may result in several problems, such as an increased risk of bleeding, procedure prolongation, and increased workload to pathologists. The aim of this study was to clarify the optimal number of endoscopic biopsy specimens required in diagnosis of advanced gastrointestinal cancer. Patients who were diagnosed with advanced gastrointestinal cancer during endoscopy were included. Five specimens were obtained sequentially from viable tissue of the cancer margin. Experienced pathologists evaluated each specimen and provided diagnoses. A total of 91 patients were enrolled. Fifty-nine subjects had advanced gastric cancer, and 32 had advanced colon cancer. Positive diagnosis rates of the first, second, and third advanced gastric cancer specimens were 81.3%, 94.9%, and 98.3%, respectively, while positive diagnosis rates of advanced colon cancer specimens were 78.1%, 87.5%, and 93.8%. Further biopsies did not increase positive diagnosis cumulative rates. This study demonstrated that three specimens were sufficient to make correct pathologic diagnoses in advanced gastrointestinal cancer. Therefore, we recommend 3 or 4 biopsies from viable tissue in advanced gastrointestinal cancer to make a pathologic diagnosis during endoscopy.

Extracellular vesicles (EVs), released by cells, are associated with cell-to-cell communication and regulate various cellular processes. EVs draw parallels with viruses for their similar structures and functions. Increasing evidences from recent studies indicate that cells infected with viruses release a variety of EVs. Delineating the functions and mechanisms of EVs released during virus infection is essential for understanding the molecular basis of viral infection and replication as well as associated pathogenesis. The most challenging obstacle for these studies is the separation of EVs from viruses. In this study, we successfully isolated the EVs from de novo Kaposi’s sarcoma-associated herpesvirus (KSHV) infected-human endothelial cells during the period between virus entry and production. Intriguingly, a proteomics analysis of these EVs has revealed alterations of the complement system. Additionally, we have discovered that the EVs from KSHV-infected endothelial cells are potent activators of an alternative pathway of the complement system via exploitation of the endogenous C3 complement protein and properdin. Furthermore, we have found that complement activation promotes KSHV persistent latent infection by activating the NF-κB pathway, which enhances the survival of KSHV-infected cells and inhibits viral lytic replication. Our work identifies a novel role of EVs induced by KSHV during de novo infection and the underlying mechanism of complement activation by EVs.

No convincing evidence was obtained that double-dose new-generation PPIs have better H. pylori eradication rates and tolerability than omeprazole.

Microinjection of formalin (5%, 50 microl) into a temporomandibular joint (TMJ) causes noxious behavioral responses in freely moving rats. In the present study, we investigated the role of central cyclooxygenase (COX) pathways in IL-1beta-induced hyperalgesia with formalin-induced TMJ pain model. Intra-articular injection of 100 pg or 1 ng of IL-1beta significantly facilitated formalin-induced behavior by 130 or 174% in the number of scratches. Intracisternal administration of 100 pg or 1 ng of IL-1beta also significantly increased formalin-induced behavior by 166 or 82% in the number of scratches. IL-1beta-induced hyperalgesia was blocked by pretreatment with IL-1 receptor antagonist. Intracisternal pretreatment with SC-560, a selective COX-1 inhibitor, or NS-398, a selective COX-2 inhibitor, abolished intra-articular administration of IL-1beta-induced hyperalgesic response. Intracisternal pretreatment with NS-398, a selective COX-2 inhibitor, abolished the intracisternal administration of IL-1beta-induced hyperalgesic response, while pretreatment with SC-560, a selective COX-1 inhibitor, did not change IL-1beta-induced hyperalgesic responses. On the other hand, pretreatment with acetaminophen, a tentative COX-3 inhibitor, also abolished both intra-articular and intracisternal administration of IL-1beta-induced hyperalgesic responses. These results indicate that central COX-2 plays important role in the central administration of IL-1beta-induced hyperalgesia and that central COX-1/2 pathways mediate peripheral administration of IL-1beta-induced hyperalgesia in the TMJ. Central COX-3 inhibitor seems to play an important role in the nociceptive process associated with both peripheral and central administration of IL-1beta-induced hyperalgesia in TMJ. It is concluded that central acting of COX-3 inhibitors may be of therapeutic value in the treatment of inflammatory pain in TMJ.