PubMed · 6872855
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A Dorevitch. Comment on maprotiline article.. https://doi.org/10.1177/106002808301700719
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OBJECTIVE: To examine the relative importance of tumour necrosis factor-receptor 1 (TNF-R1) and TNF-R2 and their signalling pathways for pro-inflammatory and pro-destructive features of early-passage synovial fibroblasts (SFB) from rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Cells were stimulated with tumour necrosis factor (TNF)alpha or agonistic anti-TNF-R1/TNF-R2 monoclonal antibodies. Phosphorylation of p38, ERK and JNK kinases was assessed by western blot; proliferation by bromodesoxyuridine incorporation; interleukin (IL)6, IL8, prostaglandin E(2) (PGE(2)) and matrix metalloproteinase (MMP)-1 secretion by ELISA; and MMP-3 secretion by western blot. Functional assays were performed with or without inhibition of p38 (SB203580), ERK (U0126) or JNK (SP600125). RESULTS: In RA- and OA-SFB, TNFalpha-induced phosphorylation of p38, ERK or JNK was exclusively mediated by TNF-R1. Reduction of proliferation and induction of IL6, IL8 and MMP-1 were solely mediated by TNF-R1, whereas PGE(2) and MMP-3 secretion was mediated by both TNF-Rs. In general, inhibition of ERK or JNK did not significantly alter the TNFalpha influence on these effector molecules. In contrast, inhibition of p38 reversed TNFalpha effects on proliferation and IL6/PGE(2) secretion (but not on IL8 and MMP-3 secretion). The above effects were comparable in RA- and OA-SFB, except that TNFalpha-induced MMP-1 secretion was reversed by p38 inhibition only in OA-SFB. CONCLUSION: In early-passage RA/OA-SFB, activation of MAPK cascades and pro-inflammatory/pro-destructive features by TNFalpha is predominantly mediated by TNF-R1 and, for proliferation and IL6/PGE(2) secretion, exclusively regulated by p38. Strikingly, RA-SFB are insensitive to p38 inhibition of MMP-1 secretion. This indicates a resistance of RA-SFB to the inhibition of pro-destructive functions and suggests underlying structural/functional alterations of the p38 pathway, which may contribute to the pathogenesis or therapeutic sensitivity of RA, or both.
An excess of bis-1,3-(4-iodophenyl)bicyclo[1.1.1]pentane, prepared in 63 % yield by iodination of 1,3-diphenylbicyclo[1.1.1]pentane, was selectively mono-coupled with 9-ethynyl-1,5-dimethoxy-10-phenylethynylanthracene (26), and subsequently with the zinc derivatives of 1-(2-methyl/methoxy-4-methyl-5-phenylthiophen-3-yl)-2-(2-methyl/methoxy-4-methylthiophen-3-yl)perfluorocyclopentenes (38-H-41-H). Regioselective synthesis of the 2-unsubstituted thiophenes 38-H-41-H required intermediate preparation of 2-trimethylsilyl-3,5-dimethyl-4-bromothiophene (37) or 2-trimethylsilyl-5-methoxy-3-methyl-4-bromothiophene (40). Protection of the alpha-position of the thiophene ring with a 2-trimethylsilyl group blocks the rearrangement of the 4-lithio derivatives into the corresponding 2-lithiated thiophenes. With the bicyclo[1.1.1]pentane fragment linking the photochromic units 1-3 and 1,5-dimethoxy-9,10-di(phenylethynyl)anthracene as a fluorescent part, quantitative resonance energy transfer between the excited state of the fluorophore (donor) and the closed form of the photochromic units 1-3 (acceptors) was observed. The closed forms of the methoxy-substituted photochromic units 2 and 3 are less resistant to UV light (313 nm) than the closed form of 1.
Photodynamic therapy (PDT) is an established anticancer modality utilizing the photogeneration of reactive oxygen species (ROS) to kill the cancer cells and hypericin is a promising photosensitizer for the treatment of bladder tumors. In this paper we characterize the signaling pathways and the mechanisms leading to the up-regulation of the antioxidant enzyme heme oxygenase (HO-1) in PDT treated cancer cells. We show that PDT engages the p38(MAPK) and PI3K signaling cascades for HO-1 induction. p38(MAPK) inhibitors or small interfering RNA (siRNA) for p38(MAPK) suppress HO-1 induction after PDT and complete repression is attained when p38 and PI3K antagonists are combined. Blocking these signaling pathways increases additively the propensity of the cells to undergo PDT-induced apoptosis, mirroring the effect of HO-1 silencing. Conversely, increasing HO-1 protein level by hemin prior to irradiation is cytoprotective. HO-1 stimulation by PDT is dependent on transcription and de novo protein synthesis and it is preceded by the nuclear accumulation of the Nrf2 transcription factor, which is reduced by inhibitors of p38(MAPK) and PI3K. Altogether these results indicate that stimulation of HO-1 expression by hypericin-PDT is a cytoprotective mechanism governed by the p38(MAPK) and PI3K pathways, likely through the control of the nuclear availability of the Nrf2 pool.