No abstract

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.

Cancer recurrence due to tumor cell quiescence after therapy and long-term remission is associated with cancer-related death. Previous studies have used cell models that are unable to return to a proliferative state; thus, the transition between quiescent and proliferative states is not well understood. Here, we report monolayer cancer cell models wherein the human non-small cell lung carcinoma cell line H2228 and pancreatic cancer cell line AsPC-1 can be reversibly induced to a quiescent state under hypoxic and serum-starved (HSS) conditions. Transcriptome and metabolome dual-omics profiles of these cells were compared with those of the human lung adenocarcinoma cell line A549, which was unable to enter a quiescent state under HSS conditions. The quiescence-inducible cells had substantially lower intracellular pyruvate and ATP levels in the quiescent state than in the proliferative state, and their response to sudden demand for energy was dramatically reduced. Furthermore, in quiescence-inducible cells, the transition between quiescent and proliferative states of these cells was regulated by the balance between the proliferation-promoting Ras and Rap1 signaling and the suppressive AGE/RAGE signaling. These cell models elucidate the transition between quiescent and proliferative states, allowing the development of drug-screening systems for quiescent tumor cells.