The daily activity of osteoarthritis (OA) patients is limited by chronic pain and central sensitization.Although non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are the first-line drugs for the treatment of OA-related pain, their efficacy on central sensitization remains unclear. In the present study, we evaluated the effect of acetylsalicylic acid (ASA, Aspirin) using an OA model induced by monosodium iodoacetate (MIA), which has a similar disease progression to human OA. Main methods: Secondary hyperalgesia was assessed at the plantar surface of the hind paw by Von Frey test. We evaluated the expression of acid-sensing ion channel 3 (ASIC3) in dorsal root ganglia and that of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the spinal cord, which may cause secondary hyperalgesia in OA, by immunohistochemical analysis and real-time qPCR. Key findings: The administration of ASA attenuated secondary hyperalgesia at 1-3 weeks after MIA, while celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, failed to attenuate secondary hyperalgesia at week 2 after MIA injection, suggesting that ASA exerts its analgesic effect through a COX-2-independent pathway. Immunohistochemical analysis of the dorsal root ganglia indicated that ASA reduced the expression of ASIC3 during OA progression. Expression of TNF-α mRNA, but not IL-1β mRNA, in the spinal cord following MIA injection was suppressed by ASA administration. Significance: These findings suggest that ASA may have the ability to attenuate secondary hyperalgesia through suppression of ASIC3 and/or TNF-α expression. ASA is therefore a clinically useful analgesic drug for treatment of secondary hyperalgesia in OA.
Fe-doped TiO2(Fe/TiO2) film photocatalyst was prepared by sol-gel and dip-coating process to extend its photoresponsivity to the visible spectrum. To promote the CO2reduction performance with the photocatalyst, some types of base materials used for coating Fe/TiO2, which were netlike glass fiber and Cu disc, were investigated. The characterization of prepared Fe/TiO2film coated on netlike glass fiber and Cu disc was analyzed by SEM and EPMA. In addition, the CO2reduction performance of Fe/TiO2film coated on netlike glass disc, Cu disc, and their overlap was tested under a Xe lamp with or without ultraviolet (UV) light, respectively. The results show that the concentration of produced CO increases by Fe doping irrespective of base material used under the illumination condition with UV light as well as that without UV light. Since the electron transfer between two overlapped photocatalysts is promoted, the peak concentration of CO for the Fe/TiO2double overlapping is approximately 1.5 times as large as the Fe/TiO2single overlapping under the illumination condition with UV light, while the promotion ratio is approximately 1.1 times under that without UV light.
Early detection of pancreatic cancer is key to overcoming its poor prognosis. a v b 3 -integrin is often overexpressed in pancreatic tumor cells, whereas it is scarcely expressed in normal pancreatic cells. In this study, we investigated the usefulness of SPECT imaging with 111 In-1,4,7,10-tetraazacylododecane-N,N9,N$,N999-tetraacetic acidcyclo-(Arg-Gly-Asp-D-Phe-Lys) [ 111 In-DOTA-c(RGDfK)], an imaging probe of a v b 3 -integrin, for the early detection of pancreatic cancer in a hamster pancreatic carcinogenesis model. Methods: Hamsters were subcutaneously injected with the pancreatic duct carcinogen N-nitrosobis(2-oxopropyl)amine to induce pancreatic cancer. N-nitrosobis(2-oxopropyl)amine-treated hamsters underwent in vivo SPECT with 111 In-DOTA-c(RGDfK). After imaging, the tumorto-normal pancreatic tissue radioactivity ratios in excised pancreatic samples were measured with autoradiography (ARG) and compared with the immunopathologic findings for a v b 3 -integrin. In a mouse model in which inflammation was induced with turpentine, the uptake of 111 In-DOTA-c(RGDfK) in inflammatory regions was evaluated with ARG and compared with that of 18 F-FDG. Results: 111 In-DOTA-c(RGDfK) was clearly visualized in pancreatic cancer lesions as small as 3 mm in diameter. ARG analysis revealed high tumor-to-normal pancreatic tissue radioactivity ratios (4.6 6 1.0 [mean 6 SD] in adenocarcinoma and 3.3 6 1.4 in atypical hyperplasia). The uptake of 111 In-DOTA-c(RGDfK) strongly correlated with a v b 3 -integrin expression. In the inflammatory model, inflammation-to-muscle ratios for In-DOTA-c(RGDfK) were 8.37 6 4.37 and 1.98 6 0.60, respectively. These results imply that 111 In-DOTA-c(RGDfK) has a lower rate of false-positive tumor detection than 18 F-FDG. Conclusion: Our findings suggest that SPECT with 111 In-DOTA-c(RGDfK) has great potential for the early and accurate detection of pancreatic cancer.
An escape mutant of human parainfluenza virus type 1 (hPIV1), which was selected by serial passage in the presence of a sialidase inhibitor, 4-O-thiocarbamoylmethyl-2-deoxy-2,3-didehydro-N-acetylneur-aminic acid (TCM-Neu5Ac2en), exhibited remarkable syncytium formation and virus-induced cell death in LLC-MK2 cells but no difference in susceptibility for the sialidase inhibitor TCM-Neu5Ac2en from that of wild-type hPIV1 strain C35 (WT). The mutant virus also had higher replication and plaque formation abilities. The mutant virus acquired two amino acid mutations, Glu to Gly at position 170 and Ala to Glu 442 in fusion (F) glycoprotein, but no mutations in haemaggulutinin-neuraminidase (HN) glycoprotein. Using cells co-expressing F and HN genes with site-specific mutagenesis, we demonstrated that a point mutation of Glu to Gly at position 170, which was estimated to be located in hPIV1 F glycoprotein heptad repeat 1, was required for obvious syncytium formation and caspase-3-dependent cell death. In contrast, wild-type F glycoprotein induced no synctium formation or cell death. The findings suggest that a single amino acid mutation of hPIV1 F glycoprotein promotes syncytium formation that is followed by caspase-3-dependent cell death.
Novel sialidase inhibitors 11 having an α-acylaminoamido group at the C-4 position of Neu5Ac2en 1 against human parainfluenza virus type 1 (hPIV-1) were synthesized using one-pot isocyanide-based fourcomponent condensation, and their inhibitory activities against hPIV-1 sialidase were studied. Compound 11b showed inhibitory activity (IC 50 =5.1 mm) against hPIV-1 sialidase. The degree of inhibition of 11b was much weaker than that of 1 (IC 50 =0.3 mm).Key words human parainfluenza virus type 1; sialidase inhibitor; sialic acid; 4-isocyano Neu5Ac2en derivative; isocyanide-based four-component coupling Human parainfluenza viruses (hPIVs), members of the human parainfluenza viruses (hPIVs), which are part of the Paramyxoviridae family, are important respiratory tract pathogens in infants and children. Four different types of hPIV have been identified, all of which cause a spectrum of illnesses of the upper and lower respiratory tracts of children.
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