[A protective effect of acetaminophen on ibuprofen-induced small intestinal damage in rats via the suppression of MMP-13].

BACKGROUND & AIMS: Capsule endoscopy has revealed that nonsteroidal anti-inflammatory drugs may cause damage not only to the stomach but also to the small intestine, which has become one of the most serious issues in gastroenterology. However, few studies have reported the effect of ibuprofen (IBP), which is widely prescribed worldwide, on the small intestine, and it remains unclear whether IBP can cause small intestinal damage. We have previously shown that acetaminophen (APAP), which is used as an antipyretic/analgesic drug, inhibits IBP-induced gastric damage by suppressing matrix metalloprotease-13 (MMP-13) gene expression. In this study, we investigated the ability of IBP to induce small intestinal damage and the efficacy of APAP against IBP-induced small intestinal damage in rats. MAIN METHODS: Nonfasted male Sprague-Dawley rats were orally administered with IBP (200mg/kg) and then euthanized at various time points (0, 4, 8, 16, and 24h) after the administration. The small intestine, jejunum, and ileum were removed, and intestinal lesions were measured. To elucidate the efficacy of APAP against IBP-induced small intestinal damage, the rats were treated with IBP (200mg/kg) with or without APAP (200mg/kg), and small intestinal damage was evaluated 24h after the administration. Moreover, the expression levels of GAPDH, TNFα, iNOS, and MMP-13 genes were determined at various time points (8, 16, and 24h) by RT-qPCR. KEY FINDINGS: The oral administration of IBP induced obvious small intestinal damage, which was found to be significant at 24h (p<0.05 vs 0h, Dunnett's test). The coadministration of APAP significantly prevented IBP-induced damage (p<0.05, Student's t-test). In addition, the expression levels of TNFα and iNOS genes were significantly increased by IBP (p<0.01 and p<0.05 vs. vehicle, respectively, Tukey-Kramer test), whereas the cotreatment with APAP suppressed the increases at 8h. Moreover, compared with the vehicle, the IBP treatment significantly increased the expression level of the MMP-13 gene (p<0.01) at each time point (8, 16, and 24h, Tukey-Kramer test), whereas the APAP cotreatment significantly suppressed the increase (p<0.01 vs. IBP at 8h, p<0.05 vs. IBP at 16 and 24h, Tukey-Kramer test). CONCLUSIONS: This study suggested that a single administration of IBP was associated with the risk of inducing small intestinal ulcers in rats, and APAP could prevent IBP-induced small intestinal damage by suppressing the MMP-13 gene expression.

Mechanism of aspirin-induced inhibition on the secondary hyperalgesia in osteoarthritis model rats.

AIMS: 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-1ß (IL-1ß) 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-1ß 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.

Role of LRP1 and ERK and cAMP Signaling Pathways in Lactoferrin-Induced Lipolysis in Mature Rat Adipocytes.

Lactoferrin (LF) is a multifunctional glycoprotein present in milk. A clinical study showed that enteric-coated bovine LF tablets decrease visceral fat accumulation. Furthermore, animal studies revealed that ingested LF is partially delivered to mesenteric fat, and in vitro studies showed that LF promotes lipolysis in mature adipocytes. The aim of the present study was to determine the mechanism underlying the induction of lipolysis in mature adipocytes that is induced by LF. To address this question, we used proteomics techniques to analyze protein expression profiles. Mature adipocytes from primary cultures of rat mesenteric fat were collected at various times after exposure to LF. Proteomic analysis revealed that the expression levels of hormone-sensitive lipase (HSL), which catalyzes the rate-limiting step of lipolysis, were upregulated and that HSL was activated by protein kinase A within 15 min after the cells were treated with LF. We previously reported that LF increases the intracellular concentration of cyclic adenosine monophosphate (cAMP), suggesting that LF activates the cAMP signaling pathway. In this study, we show that the expression level and the activity of the components of the extracellular signal-regulated kinase (ERK) signaling pathway were upregulated. Moreover, LF increased the activity of the transcription factor cAMP response element binding protein (CREB), which acts downstream in the cAMP and ERK signaling pathways and regulates the expression levels of adenylyl cyclase and HSL. Moreover, silencing of the putative LF receptor low-density lipoprotein receptor-related protein 1 (LRP1) attenuated lipolysis in LF-treated adipocytes. These results suggest that LF promoted lipolysis in mature adipocytes by regulating the expression levels of proteins involved in lipolysis through controlling the activity of cAMP/ERK signaling pathways via LRP1.