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1.
Molecules ; 29(2)2024 Jan 19.
Article in English | MEDLINE | ID: mdl-38276591

ABSTRACT

During the synthetic studies toward 5,6,7,3',4'-monomethoxytetrahydroxyflavones, a concise pedalitin synthesis procedure was achieved. As previously reported, 6-hydroxy-2,3,4-trimethoxyacetophenone was prepared by Friedel-Crafts acylation of 1,4-dihydroxy-2,6-dimethoxybenzene with boron trifluoride diethyl etherate in acetic acid. When aldol condensation of 6-hydroxy-2,3,4-trimethoxyacetophenone 2b with vanillin was performed in basic conditions, it produced 2'-hydroxychalcone 3b, and, surprisingly, along with 3-hydroxyflavone 4 in a considerable amount. We propose that this oxidative cyclization is presumably due to the contribution of a quinone methide, likely to be subjected to aerobic oxidation. The chalcone was then subjected to oxidative cyclization with iodine in dimethyl sulfoxide to afford flavone 5 in good yield. To our delight, serial demethylation of the three methoxy groups at the 5-, 6-, and 3'-positions of 5 proceeded smoothly to produce pedalitin 1, under hydrogen bromide solution (30% in acetic acid). The crystal structures of 3-hydroxyflavone 4 and pedalitin tetraacetate 6 were unambiguously determined by X-ray crystallography.

2.
Biomol Ther (Seoul) ; 28(1): 92-97, 2020 01 01.
Article in English | MEDLINE | ID: mdl-31189299

ABSTRACT

A previous pharmacogenomic analysis identified cromolyn, an anti-allergic drug, as an effective anti-fibrotic agent that acts on hepatocytes and stellate cells. Furthermore, cromolyn was shown to be a G protein-coupled receptor 35 (GPR35) agonist. However, it has not been studied whether anti-fibrotic effects are mediated by GPR35. Therefore, in this study, the role of GPR35 in hepatic fibrosis was investigated through the use of lodoxamide, another anti-allergic drug and a potent GPR35 agonist. Longterm treatment with carbon tetrachloride induced hepatic fibrosis, which was inhibited by treatment with lodoxamide. Furthermore, CID2745687, a specific GPR35 antagonist, reversed lodoxamide-mediated anti-fibrotic effects. In addition, lodoxamide treatment showed significant effects on the mRNA expression of collagen Iα1, collagen Iα2, and TGF-ß1 in the extracellular matrix. However, a transforming growth factor α (TGF-α) shedding assay revealed lodoxamide not to be a potent agonist of mouse GPR35 in vitro. Therefore, these results showed anti-fibrotic effects of lodoxamide in mice and raise concerns how lodoxamide protects against liver fibrosis in vivo and whether GPR35 is involved in the action.

3.
Cell Signal ; 53: 190-200, 2019 01.
Article in English | MEDLINE | ID: mdl-30304698

ABSTRACT

Although GPR35 is an orphan G protein-coupled receptor, synthetic agonists and antagonists have been developed. Recently, cromolyn, a mast cell stabilizer, was reported as an agonist of GPR35 and was shown to exhibit antifibrotic effects through its actions on hepatocytes and stellate cells. In this study, the role of GPR35 in hepatic steatosis was investigated using an in vitro model of liver X receptor (LXR)-mediated hepatocellular steatosis and an in vivo model of high fat diet-induced liver steatosis. GPR35 was expressed in Hep3B human hepatoma cells and mouse primary hepatocytes. A specific LXR activator, T0901317, induced lipid accumulation in Hep3B cells. Lodoxamide, the most potent agonist of GPR35, inhibited lipid accumulation in a concentration-dependent manner. The protective effect of lodoxamide was inhibited by a specific GPR35 antagonist, CID2745687, and by siRNA-mediated knockdown of GPR35. The expression of SREBP-1c, a key transcription factor for lipid synthesis, was induced by T0901317 and the induction was inhibited by lodoxamide. Through the use of specific inhibitors of cellular signaling components, the lodoxamide-induced inhibition of lipid accumulation was found to be mediated through p38 MAPKs and JNK, but not through Gi/o proteins and ERKs. Furthermore, the protective effect of lodoxamide was confirmed in mouse primary hepatocytes. Lodoxamide suppressed high fat diet-induced fatty liver development, which suggested the protective function of GPR35 in liver steatosis. Therefore, the present data suggest that GPR35 may function to protect against fatty liver development.


Subject(s)
Fatty Liver/drug therapy , Oxamic Acid/analogs & derivatives , Protective Agents/therapeutic use , Receptors, G-Protein-Coupled/metabolism , Animals , Cell Line , Cells, Cultured , Diet, High-Fat/adverse effects , Fatty Liver/metabolism , Humans , Lipid Metabolism/drug effects , Male , Mice , Mice, Inbred C57BL , Oxamic Acid/therapeutic use
4.
Br J Pharmacol ; 175(1): 154-161, 2018 01.
Article in English | MEDLINE | ID: mdl-29068046

ABSTRACT

BACKGROUND AND PURPOSE: GPR35 has long been considered an orphan GPCR, because no endogenous ligand of GPR35 has been discovered. CXCL17 (a chemokine) has been reported to be an endogenous ligand of GPR35, and it has even been suggested that it be called CXCR8. However, at present there is no supporting evidence that CXCL17 does interact with GPR35. EXPERIMENTAL APPROACH: We applied two assay systems to explore the relationship between CXCL17 and GPR35. An AP-TGF-α shedding assay in GPR35 over-expressing HEK293 cells was used as a gain-of-function assay. GPR35 knock-down by siRNA transfection was performed in endogenously GPR35-expressing THP-1 cells. KEY RESULTS: In the AP-TGF-α shedding assay, lodoxamide, a well-known synthetic GPR35 agonist, was confirmed to be the most potent agonist among other reported agonists. However, neither human nor mouse CXCL17 had an effect on GPR35. Consistent with previous findings, G proteins Gαi/o and Gα12/13 were found to couple with GPR35. Furthermore, lodoxamide-induced activation of GPR35 was concentration-dependently inhibited by CID2745687 (a selective GPR35 antagonist). In endogenously GPR35-expressing THP-1 cells, lodoxamide concentration-dependently inhibited migration and this inhibitory effect was blocked by CID2745687 treatment or GPR35 siRNA transfection. However, even though CXCL17 stimulated the migration of THP-1 cells, which is consistent with a previous report, this stimulatory effect of CXCL17 was not blocked by CID2745687 or GPR35 siRNA. CONCLUSIONS AND IMPLICATIONS: The present findings suggest that GPR35 functions as a migration inhibitory receptor, but CXCL17-stimulated migration of THP-1 cells is not dependent on GPR35.


Subject(s)
Cell Movement/physiology , Chemokines/physiology , Oxamic Acid/analogs & derivatives , Receptors, G-Protein-Coupled/physiology , THP-1 Cells/physiology , Animals , Cell Movement/drug effects , Chemokines, CXC , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Mice , Oxamic Acid/pharmacology , THP-1 Cells/drug effects
5.
J Ethnopharmacol ; 213: 256-261, 2018 Mar 01.
Article in English | MEDLINE | ID: mdl-29158156

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Saussurea costus (Falc.) Lipsch. root has been used in Asian traditional medicine for the treatment of asthma, rheumatism, and other conditions. S. costus extracts were shown to alleviate house dust mite-induced atopic-like dermatitis in Nc/Nga mice; besides, sesquiterpene lactones were isolated from S. costus extracts. AIMS OF THE STUDY: We aimed to investigate the effects of sesquiterpene lactones (alantolactone, costunolide, and dehydrocostuslactone) in allergic asthma using female Balb/c mice and rat RBL-2H3 mast cells. MATERIALS AND METHODS: Antigen-induced degranulation was assessed by measuring ß-hexosaminidase activity in vitro. In addition, a murine ovalbumin-induced allergic asthma model was used to test the in vivo efficacy of sesquiterpene lactones. RESULTS: Sesquiterpene lactones inhibited antigen-induced degranulation, wherein dehydrocostuslactone > costunolide > alantolactone in potency. Administration of sesquiterpene lactones decreased the number of immune cells, particularly eosinophils, and reduced the expression and secretion of Th2 cytokines (IL-4 and IL-13) in the bronchoalveolar lavage fluid and lung tissues of mice with ovalbumin-induced allergic asthma. Histological studies showed that sesquiterpene lactones reduced inflammation and mucin production in the lungs. Similar to the in vitro study, dehydrocostuslactone showed the highest potency, followed by costunolide and alantolactone. CONCLUSION: These findings provide evidence that sesquiterpene lactones might be potential anti-allergic therapeutics.


Subject(s)
Anti-Allergic Agents/pharmacology , Lactones/pharmacology , Saussurea/chemistry , Sesquiterpenes, Eudesmane/pharmacology , Sesquiterpenes/pharmacology , Animals , Bronchoalveolar Lavage Fluid , Cell Degranulation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Female , Interleukin-13/biosynthesis , Interleukin-4/biosynthesis , Lung/drug effects , Lung/metabolism , Mast Cells/drug effects , Mice , Mucins/drug effects , Plant Roots/chemistry , Rats
6.
J Nanosci Nanotechnol ; 16(3): 2787-91, 2016 Mar.
Article in English | MEDLINE | ID: mdl-27455709

ABSTRACT

Organic photovoltaic Cells (OPVs) have been considered to be a next-generation energy source to overcome exhaustion of resources. Currently, OPVs are developed based on two types of donor material with polymer and small molecule. Polymeric donor materials have shown better power conversion efficiency (PCE) than small molecular donor materials, since it's easy to control the morphology of photoactive film. However, the difficulty in synthetic reproducibility and purification of polymeric donor were main drawback to overcome. And then, recently small molecule donor materials have been overcome bad morphology of OPVs film by using appropriate alkyl substituents and relatively long conjugation system. In this study, we designed and synthesized D-A-D-A-D type small molecular donor materials containing alternatively linked benzodithiophene (BDT) and diketopyrrolopyrrole (DPP) units. Also, we studied on the effect of photovoltaic performance of prepared small molecular D-A-D-A-D type donor with variation of thiophene links and with/without hexyl substituent. Our small molecular donors showed HOMO energy levels from -5.26 to -5.34 eV and optical bandgaps from 1.70 to 1.87 eV by CV (cyclic voltammetry) and UV/Vis spectroscopy, respectively. Finally, 3.4% of PCE can be obtained using a mixture of BDT(DPP)2-T2 and PCBM as an active layer with a Voc of 0.78 V, a Jsc of 9.72 mA/cm2, and a fill factor of 0.44 under 100 mW/cm2 AM 1.5G simulated light. We will discuss the performance of D-A-D-A-D type small molecular donor based OPVs with variation of both terminal substituents.


Subject(s)
Ketones/chemistry , Pyrroles/chemistry , Thiophenes/chemistry , Microscopy, Atomic Force , Proton Magnetic Resonance Spectroscopy
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