Interleukin-4 (IL-4) is a potent antiinflammatory cytokine. However its use in the clinic is hampered by side effects. We here describe the identification of a novel synthetic peptide, termed Ph8, derived from α-helix C of IL-4, which interacts with IL-4 receptor α (IL-4Rα). Employing various cultured genetically engineered cell lines and primary lymphocytes, surface plasmon resonance, qPCR, ELISA and immunoblotting techniques we found that Ph8 bound IL-4Rα and mimicked the anti-inflammatory effects of IL-4 by inhibiting TNF-α production by macrophages in vitro. It induced phosphorylation of STAT6 65kD but inhibited phosphorylation of STAT6 110 kD induced by IL-4 in a B-cell line that expressed the type I receptor. It also inhibited the IL-4-stimulated expression of a STAT6-inducible reporter gene in cells that expressed the type II receptor. Ph8 inhibited the proliferation of Th1/2 cells and downregulated the production of IFN-γ in stimulated Th1 cells. Moreover, Ph8 did not induce any shift in Th1/Th2 profile. This is a favorable effect and it is indicating that Ph8 could block general T cell activation and inflammatory responses without further inducing the side effects generally associated with IL-4 signaling. These data collectively show that Ph8 is only a partial agonist of IL-4 mimicking its desirable properties. In agreement, Ph8 treatment of rats with collagen-induced arthritis, a Th1- and antibody- mediated disease of joint, delayed the manifestation of chronic inflammation and reduced acute inflammation in carrageenan-induced edema. Our findings indicate that Ph8 is a promising potential drug candidate for the treatment of inflammatory diseases.

1990-08-01·Pharmacology, biochemistry, and behavior4区 · 心理学

Comparison of DuP 996, with physostigmine, THA and 3,4-DAP on hypoxia-induced amnesia in rats

4区 · 心理学

Article

作者: L.C. Johnson ; V.J. deNoble ; K.F. deNoble ; L. Cook ; M.J. Myers ; K.R. Spencer ; R.M. Scribner

DuP 996, 3,3-bis(4-pyrindinylmethyl)-1-phenylindolin-2-one, physostigmine (PH), tetrahydroaminoacridine (THA) and 3,4-diaminopyridine (3,4-DAP) were compared for their ability to protect against hypoxia-induced performance deficits in a passive avoidance (PA) task. The ability to retain PA response was found to decrease as the oxygen concentration decreased with the largest retention deficit occurring at 6.5% oxygen. DuP 996 (0.01-0.1 mg/kg SC), 3,4-DAP (0.1-10.0 mg/kg SC), THA (0.3-5.0 mg/kg SC) and PH (0.001-0.1 mg/kg SC) administered one minute after PA training produced dose-dependent increases in retention latencies following exposure to 6.5% oxygen. In comparing each compound for side effects, DuP 996 induced tremor and mortality at 10 and 40 mg/kg SC, respectively, and PH at 0.3 and 0.8 mg/kg SC, respectively. With PH the 0.3 mg/kg SC dose also produced hypersalivation and a decrease in lift strength. THA produced tremor and mortality at 6.0 and 40 mg/kg SC, respectively, and 3,4-DAP at 50 and 200 mg/kg SC, respectively. 3,4-DAP also produced chromodacryorrhea and hypersalivation at 50 mg/kg SC. Dividing the dose necessary to produce mortality by the highest effective dose active in the hypoxia test yielded a safety ratio for DuP 996 of 400, for 3,4-DAP 20, for PH 8, and for THA 8, showing a greater safety margin for DuP 996 than the other cholinergic agents. These results suggest that DuP 996 may be of use in the treatment of diseases associated with cognitive impairment and may have a greater safety margin than other cholinergic agents.

International journal of molecular sciences2区 · 生物学

Effect of Proton Pump Inhibitors on Colorectal Cancer

2区 · 生物学

ArticleOA

作者: Nishiguchi, Yukiko ; Ohmori, Hitoshi ; Fujiwara-Tani, Rina ; Nakashima, Chie ; Hojo, Yudai ; Kishi, Shingo ; Luo, Yi ; Sasaki, Takamitsu ; Mori, Shiori ; Kawahara, Isao ; Fujii, Kiyomu ; Kuniyasu, Hiroki

Proton pump inhibitors (PPIs) are administered commonly to aged people; however, their effect on colorectal cancer (CRC) has still not been fully elucidated. Here, we examined the effect of PPIs and consequent alkalization on CRC cells. PPI administration alkalized the fecal pH and increased serum gastrin concentration. PPI and pH8 treatment (alkalization) of CMT93 mouse colon cancer cells inhibited cell growth and invasion, increased oxidative stress and apoptosis, and decreased mitochondrial volume and protein levels of cyclin D1 and phosphorylated extracellular signal-regulated kinase (pERK) 1/2. In contrast, gastrin treatment enhanced growth and invasion, decreased oxidative stress and apoptosis, and increased mitochondrial volume and cyclin D1 and pERK1/2 levels. Concurrent treatment with a PPI, pH8, and gastrin increased aldehyde dehydrogenase activity and also enhanced liver metastasis in the BALB/c strain of mice. PPI administration was associated with Clostridium perfringens enterotoxin (CPE) in CRC lesions. CPE treatment activated yes-associated protein (YAP) signals to enhance proliferation and stemness. The orthotopic colon cancer model of CMT93 cells with long-term PPI administration showed enhanced tumor growth and liver metastasis due to gastrin and YAP activation, as indicated by gastrin receptor knockdown and treatment with a YAP inhibitor. These findings suggest that PPI promotes CRC growth and metastasis by increasing gastrin concentration and YAP activation, resulting in gut flora alteration and fecal alkalization. These findings suggest that PPI use in colorectal cancer patients might create a risk of cancer promotion.

100 项与 SER-130 相关的药物交易

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