• Proceedings of the PSK Conference
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• 2003.04a
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• pp.245.1-245.1
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• 2003

As part of our research to discover novel synthetic flavonoids which can be applied to chronic inflammation diseases, many structurally modified flavone analogs have been synthesized to obtain information concerning the relationships between structures and the anti-inflammatory activities. We previously reported that 7-methoxyflavone analogs generally exhibited strong inhibitory activities against cyclooxygenase-2 catalyzed prostaglandin production. (omitted)

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.184.1-184.1
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• 2003

HDAC and HAT (histone acetyltransferase) are involved in co-regulation in chromatin remodeling and the functional regulation of gene transcription. Abnormal recruitment of HDAC is related to carcinogenesis. Thus, the identification of potent histone deacetylase (HDAC) inhibitor has been considered as very intriguing approach for development for cancer chemotherapy. More recently, anti-inflammatory activity of SAHA cytokines was reported via reduction of proinflammatory cytokinres in vitro and in vivo. (omitted)

• Archives of Pharmacal Research
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• v.27 no.5
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• pp.467-470
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• 2004

Comparative molecular field analysis and comparative molecular similarity indices analysis were performed on twenty five analogues of pimarane COX-2 inhibitor to optimize their cyclooxygenase-2 (COX-2) selective anti-inflammatory activities.

• Bulletin of the Korean Chemical Society
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• v.35 no.8
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• pp.2494-2504
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• 2014

P38 mitogen activated protein (MAP) kinase is an important anti-inflammatory drug target, which can be activated by responding to various stimuli such as stress and immune response. Based on the conformation of the conserved DFG loop (in or out), binding inhibitors are termed as type-I and II. Type-I inhibitors are ATP competitive, whereas type-II inhibitors bind in DFG-out conformation of allosteric pocket. It remains unclear that how these allosteric inhibitors stabilize the DFG-out conformation and interact. Organosilicon compounds provide unusual opportunity to enhance potency and diversity of drug molecules due to their low toxicity. However, very few examples have been reported to utilize this property. In this regard, we performed docking of an inhibitor (BIRB) and its silicon analog (Si-BIRB) in an allosteric binding pocket of p38. Further, molecular dynamics (MD) simulations were performed to study the dynamic behavior of the simulated complexes. The difference in the biological activity and mechanism of action of the simulated inhibitors could be explained based on the molecular mechanics/generalized Born surface area (MM/GBSA) binding free energy per residue decomposition. MM/GBSA showed that biological activities were related with calculated binding free energy of inhibitors. Analyses of the per-residue decomposed energy indicated that van der Waals and non-polar interactions were predominant in the ligand-protein interactions. Further, crucial residues identified for hydrogen bond, salt bridge and hydrophobic interactions were Tyr35, Lys53, Glu71, Leu74, Leu75, Ile84, Met109, Leu167, Asp168 and Phe169. Our results indicate that stronger hydrophobic interaction of Si-BIRB with the binding site residues could be responsible for its greater binding affinity compared with BIRB.

• Korean Journal of Clinical Laboratory Science
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• v.50 no.3
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• pp.225-235
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• 2018

Phellinus gilvus is a medicinal mushroom used that has been used in folk medicine in Asian countries for centuries. The aim of this study was to investigate the anti-xanthine oxidase, anti-cholinesterase, and anti-inflammatory activities of methanol (ME) and hot water (HW) extracts prepared from fruiting bodies of Ph. gilvus. ME and HW had good anti-xanthine oxidase (XO) activities compared to allopurinol, an inhibitor of xanthine oxidase. ME showed comparable and slightly lower inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), respectively, than galanthamine, a standard AChE and BChE inhibitor. ME also showed a protective effect against glutamate-induced cytotoxicity at 40 mg/mL and 100 mg/mL in PC-12 cells. ME (0.5~2.0 mg/mL) significantly inhibited nitric oxide (NO) production in RAW 264.7 murine macrophage cells stimulated with lipopolysaccharide (LPS). Carrageenan-induced hind-paw edema in rats was significantly reduced 2~6 hr after treatment with 50 mg/kg of ME, which was comparable to administration of 5 mg/kg of indomethacin, the positive control. These results demonstrate that ME and HW of Ph. gilvus fruiting bodies possess good anti-xanthine oxidase, anti-cholinesterase, and anti-inflammatory activities.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2003.11a
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• pp.101-101
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• 2003

Prostaglandins (PGs) and nitric oxide (NO) produced by inducible cyclooygenase (COX-2) and nitric oxide synthase (iNOS), respectively, have been implicated as important mediators in the process of inflammation and carcinogenesis. On this line, the potential COX-2 or iNOS inhibitors have been considered as anti-inflammatory and cancer chemopreventive agents. In our continuing efforts of searching for novel cancer chemopreventive agents from natural products, we isolated natural sesquiterpenoids as potential COX-2 and iNOS inhibitors in cultured lipopolysaccharide (LPS)-activated mouse macrophage RAW 264.7 cells. Alantolactone, a natural eudesmane-type sesquiterpenoid, exhibited a potent inhibition of COX-2 (IC50 = 0.4 $\mu\textrm{g}$/$m\ell$) and iNOS activity (IC50 = 0.08 $\mu\textrm{g}$/$m\ell$) in the assay system determined by PGE2 and NO accumulation, respectively. The inhibitory potential of alantolactone on the PGE2 and NO production was well coincided with the suppression of COX-2 and iNOS protein and mRNA expression in LPS-induced macrophages. Furthermore, alantolactone inhibited NF-kB but not AP-l binding activity on nuclear extracts evoked by LPS-stimulated macrophage cells, suggesting the possible involvement of NF-kB in the regulation of COX-2 and iNOS expression. In further study with COX-2-expressing human colon HT-29 cells, alantolactone inhibited the cell proliferation, down-regulated COX-2, and inhibited the ERK phosphorylation in the early time. These results suggest that a natural sesquiterpenoid alantolactone might be a potential lead candidate for further developing COX-2 or iNOS inhibitor possessing cancer chemopreventive or anti-inflammatory activity

• Biomolecules & Therapeutics
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• v.24 no.4
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• pp.387-394
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• 2016

Sepsis, a serious clinical problem, is characterized by a systemic inflammatory response to infection and leads to organ failure. Toll-like receptor (TLR) signaling is intimately implicated in hyper-inflammatory responses and tissue injury during sepsis. Histone deacetylase (HDAC) inhibitors have been reported to exhibit anti-inflammatory properties. The aim of this study was to investigate the hepatoprotective mechanisms of trichostatin A (TSA), a HDAC inhibitor, associated with TLR signaling pathway during sepsis. The anti-inflammatory properties of TSA were assayed in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Polymicrobial sepsis was induced in mice by cecal ligation and puncture (CLP), a clinically relevant model of sepsis. The mice were intraperitoneally received TSA (1, 2 or 5 mg/kg) 30 min before CLP. The serum and liver samples were collected 6 and 24-h after CLP. TSA inhibited the increased production of tumor necrosis factor (TNF)-${\alpha}$ and interleukin (IL)-6 in LPS-stimulated RAW264.7 cells. TSA improved sepsis-induced mortality, attenuated liver injury and decreased serum TNF-${\alpha}$ and IL-6 levels. CLP increased the levels of TLR4, TLR2 and myeloid differentiation primary response protein 88 (MyD88) protein expression and association of MyD88 with TLR4 and TLR2, which were attenuated by TSA. CLP increased nuclear translocation of nuclear factor kappa B and decreased cytosolic inhibitor of kappa B ($I{\kappa}B$) protein expression, which were attenuated by TSA. Moreover, CLP decreased acetylation of $I{\kappa}B$ kinase (IKK) and increased association of IKK with $I{\kappa}B$ and TSA attenuated these alterations. Our findings suggest that TSA attenuates liver injury by inhibiting TLR-mediated inflammatory response during sepsis.

• IMMUNE NETWORK
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• v.22 no.1
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• pp.9.1-9.23
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• 2022

In the past few decades, biological drugs and small molecule inhibitors targeting inflammatory cytokines, immune cells, and intracellular kinases have become the standard-of-care to treat autoimmune diseases. Inhibition of TNF, IL-6, IL-17, and IL-23 has revolutionized the treatment of autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, and psoriasis. B cell depletion therapy using anti-CD20 mAbs has shown promising results in patients with neuroinflammatory diseases, and inhibition of B cell survival factors is approved for treatment of systemic lupus erythematosus. Targeting co-stimulatory molecules expressed on Ag-presenting cells and T cells is also expected to have therapeutic potential in autoimmune diseases by modulating T cell function. Recently, small molecule kinase inhibitors targeting the JAK family, which is responsible for signal transduction from multiple receptors, have garnered great interest in the field of autoimmune and hematologic diseases. However, there are still unmet medical needs in terms of therapeutic efficacy and safety profiles. Emerging therapies aim to induce immune tolerance without compromising immune function, using advanced molecular engineering techniques.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.378.1-378.1
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• 2002

Prostaglandins (PGs) and nitric oxide (NO) are essential to maintain homeostasis and defensa systems in human beings. However. overproduced PGs and NO by inducible cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS), respectively. cause tissue damages. chronic inflammation. and carcinogenesis. In this view. the potential COX-2 or iNOS inhibitors have been considered as anti-inflammatory or cancer chemopreventive agents. (omitted)

• Proceedings of the PSK Conference
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• 2003.04a
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• pp.145.1-145.1
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• 2003

Several lines of recent evidences have shown that several pro-inflammatory genes or mediators, such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 and cytokines (e.g., tumor necrosis factor $\alpha$ and interleukin-1$\beta$), are strongly expressed in the ischemic brain. Inflammation is now recognized as a significant contributing mechanism in cerebral ischemia because anti-inflammatory compounds or inhibitors of iNOS and cyclooxygenase-2 have been proven to reduce ischemic brain damage. (omitted)