• Journal of Applied Biological Chemistry
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• 제66권
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• pp.29-38
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• 2023

Recent studies have highlighted the link between diseases and inflammation across our lifespan. Our sedentary lifestyle, high-calorie diet, chronic stress, chronic infections, and exposure to pollutants and xenobiotics, collectively intensify the course and recurrence of infections and inflammation in our bodies, promoting the prevalence of chronic diseases and aging. Given such phenomena and considering additional factors such as the frequency of prescription, and easy access to over-the-counter drugs, the need for anti-inflammatory therapeutics is ever-increasing. However, the readily available anti-inflammatory treatment option comes with a greater risk of side effects or high cost (biologics). Therefore in this growing competition of discovering and developing new potent anti-inflammatory drugs, we focused on utilizing the established knowledge of traditional medicine to find lead compounds. Since lead optimization is an indispensable step toward drug development, we applied this concept for the production of potent anti-inflammatory compounds achieved by structural modification of flavonoids. The derivative obtained through acetylation of myricetin, 3,3',4',5,5',7-hexaacetate myricetin, showed a greater inhibitory effect in the production of pro-inflammatory mediators such as nitric oxide, Prostaglandin E₂, and pro-inflammatory cytokines like interleukin-6, interleukin1β, in lipopolysaccharide-stimulated RAW264.7 mouse macrophage cells compared to myricetin. The increased potency of inhibition was in conjunction with an increased inhibitory effect on inducible nitric oxide synthase and cyclooxygenase-2 proteins. Through such measures, this study supports lead optimization for well-established lead compounds from traditional medicine using a simpler and greener chemistry approach for the purpose of designing and developing potent anti-inflammatory therapeutics with possibly fewer side effects and increased bioavailability.

• Journal of Microbiology and Biotechnology
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• 제29권7호
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• pp.1022-1032
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• 2019

Probiotics are known to provide the host with immune-modulatory effects and are therefore of remarkable interest for therapeutic and prophylactic applications against various disorders, including inflammatory diseases. Weissella cibaria JW15 (JW15) has been reported to possess probiotic and antioxidant properties. However, the effect of JW15 on inflammatory responses has not yet been reported. Therefore, the objective of the current study was to evaluate the anti-inflammatory potential of JW15 against lipopolysaccharide (LPS) stimulation. The production of pro-inflammatory factors and the cellular signaling pathways following treatment with heat-killed JW15 was examined in LPS-induced RAW 264.7 cells. Treatment with heat-killed JW15 decreased nitric oxide and prostaglandin $E_2$ production via down-regulation of the inducible nitric oxide synthase and cyclooxygenase-2. In addition, treatment with heat-killed JW15 suppressed the expression of pro-inflammatory cytokines, interleukin $(IL)-1{\beta}$, IL-6, and tumor necrosis factor-${\alpha}$. The anti-inflammatory properties of treating with heat-killed JW15 were associated with mitogen-activated protein kinase signaling pathway-mediated suppression of nuclear factor-${\kappa}B$. These results indicated that JW15 possesses anti-inflammatory potential and provide a molecular basis regarding the development of functional probiotic products.

• BMB Reports
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• 제53권12호
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• pp.640-645
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• 2020

Suppressors of cytokine signaling (SOCS) exhibit diverse anti-inflammatory effects. Since ROS acts as a critical mediator of inflammation, we have investigated the anti-inflammatory mechanisms of SOCS via ROS regulation in monocytic/macrophagic cells. Using PMA-differentiated monocytic cell lines and primary BMDMs transduced with SOCS1 or shSOCS1, the LPS/TLR4-induced inflammatory signaling was investigated by analyzing the levels of intracellular ROS, antioxidant factors, inflammasome activation, and pro-inflammatory cytokines. The levels of LPS-induced ROS and the production of pro-inflammatory cytokines were notably down-regulated by SOCS1 and up-regulated by shSOCS1 in an NAC-sensitive manner. SOCS1 up-regulated an ROS-scavenging protein, thioredoxin, via enhanced expression and binding of NRF-2 to the thioredoxin promoter. SOCS3 exhibited similar effects on NRF-2/thioredoxin induction, and ROS downregulation, resulting in the suppression of inflammatory cytokines. Notably thioredoxin ablation promoted NLRP3 inflammasome activation and restored the SOCS1-mediated inhibition of ROS and cytokine synthesis induced by LPS. The results demonstrate that the anti-inflammatory mechanisms of SOCS1 and SOCS3 in macrophages are mediated via NRF-2-mediated thioredoxin upregulation resulting in the downregulation of ROS signal. Thus, our study supports the anti-oxidant role of SOCS1 and SOCS3 in the exquisite regulation of macrophage activation under oxidative stress.

• Asian Pacific Journal of Cancer Prevention
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• 제14권6호
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• pp.3909-3919
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• 2013

The aim of the present investigation was to evaluate the effect of A ferruginea extract on Dalton's lymphoma ascites (DLA) induced tumours in BALB/c mice. Experimental animals received A ferruginea extract (10 mg/kg.b.wt) intraperitoneally for 14 consecutive days after DLA tumor challenge. Treatment with extract significantly increased the life span, total white blood cell (WBC) count and haemoglobin (Hb) content and decreased the level of serum aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (${\gamma}$-GT) and nitric oxide (NO) in DLA bearing ascites tumor models. In addition, administration of extract significantly decreased the tumour volume and body weight in a DLA bearing solid tumor model. The levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-${\alpha}$), interleukin-1 beta (IL-$1{\beta}$), interleukin-6 (IL-6) and granulocyte monocyte-colony stimulating factor (GM-CSF), as well as pro-angiogenic growth factors such as vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS) were elevated in solid tumour controls, but significantly reduced by A ferruginea administration. On the other hand, the extract stimulated the production of interleukin-2 (IL-2) and interferon-gamma (IFN-${\gamma}$) in animals with DLA induced solid tumours. Increase in $CD4^+$ T-cell population suggested strong immunostimulant activity for this extract. GC/MS and LC/MS analysis showed quinone, quinoline, imidazolidine, pyrrolidine, cyclopentenone, thiazole, pyrazole, catechin and coumarin derivatives as major compounds present in the A ferruginea methanolic extract. Thus, the outcome of the present study suggests that A ferruginea extract has immunomodulatory and tumor inhibitory activities and has the potential to be developed as a natural anticancer agent.

• International Journal of Oral Biology
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• 제35권4호
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• pp.145-151
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• 2010

Periodontitis is an inflammatory disorder of the periodontium and is characterized by destruction of the tooth supporting tissues, mediated by the upregulation of synthesis and release of a variety of pro-inflammatory factors. Inflammatory cytokines and prostaglandins upregulate RANKL and its subsequent binding to RANK stimulates osteoclast formation, resorption activity, and survival. In our present study, we investigated the effects of HP08-0111, composed of Coptis japonica (Thunb.) Makino, vitamin C and vitamin E, upon inflammatory responses, osteoclastogenesis and alveolar bone loss. HP08-0111 decreased the expression of IL-1$\beta$ and COX2 on LPS-induced RAW 264.7 cells and inhibited osteoclast-specific genes such as c-Fos, MMP-9, and TRAP. HP08-0111 also exhibited protective effects against alveolar bone loss in rats with ligature-induced periodontitis. Our results suggest that HP08-0111 is potentially an important therapeutic tool for the treatment of disorders associated with bone loss such as periodontitis.

• BMB Reports
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• 제52권5호
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• pp.336-341
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• 2019

The cGAS-STING pathway plays an important role in pathogen-induced activation of the innate immune response. The 29-kDa amino-terminal fibronectin fragment (29-kDa FN-f) found predominantly in the synovial fluid of osteoarthritis (OA) patients increases the expression of catabolic factors via the toll-like receptor-2 (TLR-2) signaling pathway. In this study, we investigated whether 29-kDa FN-f induces inflammatory responses via the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) pathway in human primary chondrocytes. The levels of cGAS and STING were elevated in OA cartilage compared with normal cartilage. Long-term treatment of chondrocytes with 29-kDa FN-f activated the cGAS/STING pathway together with the increased level of gamma-H2AX, a marker of DNA breaks. In addition, the expression of pro-inflammatory cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF-2), granulocyte colony-stimulating factor (G-CSF/CSF-3), and type I interferon ($IFN-{\alpha}$), was increased more than 100-fold in 29-kDa FN-f-treated chondrocytes. However, knockdown of cGAS and STING suppressed 29-kDa FN-f-induced expression of GM-CSF, G-CSF, and $IFN-{\alpha}$ together with the decreased activation of TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), and inhibitor protein ${\kappa}B{\alpha}$ ($I{\kappa}B{\alpha}$). Furthermore, NOD2 or TLR-2 knockdown suppressed the expression of GM-CSF, G-CSF, and $IFN-{\alpha}$ as well as decreased the activation of the cGAS/STING pathway in 29-kDa FN-f-treated chondrocytes. These data demonstrate that the cGAS/STING/TBK1/IRF3 pathway plays a critical role in 29-kDa FN-f-induced expression of pro-inflammatory cytokines.

• Ocean and Polar Research
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• 제43권3호
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• pp.113-126
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• 2021

In the present study, the halophyte C. falcatum extract and its solvent fractions (n-hexane, 85% aqueous methanol, n-butanol, and water) were evaluated for antioxidant and anti-inflammatory activities. Antioxidative ability was measured by DPPH radical, intracellular reactive oxygen species (ROS) and peroxynitrite scavenging, DNA oxidation inhibition, and ferric reducing antioxidant power (FRAP). For DPPH radical and peroxynitrite scavenging, DNA oxidation inhibition, and FRAP, 85% aq.MeOH and n-BuOH fractions showed significant scavenging activity. For production of intracellular ROS in HT-1080 cells, 85% aq.MeOH fraction showed the highest scavenging activity. In addition, anti-inflammatory activity was also assessed by measuring the inhibitory effect against mRNA expression of pro-inflammatory factors (NO, IL-1β, IL-6 and COX-2) in LPS-stimulated Raw 264.7 macrophages. For NO production, crude extract exhibited a strong inhibitory effect at a concentration of 100 ㎍/ml. For mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, and COX-2), n-BuOH greatly suppressed expression levels of IL-1β and IL-6 at 100 ㎍/ml concentration while 85% aq. MeOH fraction significantly inhibited that of COX-2 even at 100 ㎍/ml. These results suggest that C. falcatum may be used as a potential source for the development of a natural antioxidant or anti-inflammatory agent.

• 생약학회지
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• 제37권4호
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• pp.235-240
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• 2006

We investigated the antioxidant activities such as DPPH radical scavenging capacity, xanthine oxidase inhibitory activity, and superoxide radical scavenging capacity of the aqueous EtOH extract and its solvent fractions of Artemisia scoparia. The ethyl acetate fraction showed high antioxidant activity, compared to positive controls such as ascorbic acid, butylated hydroxy anisole (BHA), trolox, and allopurinol in these assay systems. Moreover, we examined the inhibitory effect of solvent fractions of A. scoparia on the production of pro-inflammatory factors that the nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and prostaglandin E2 $(PGE_2)$ production activated with LPS $(1{\mu}g/ml)$ in murine macrophage cell line RAW264.7. The amounts of protein levels were determined by immunoblottting. Tn the sequential fractions of hexane and dichloromethane inhibited the NO and $PGE_2$ production and the protein level of iNOS and COX-2. These results suggest that A. scoparia may have anti-inflammatory activity through the antioxidant activity and inhibition of pro-inflammatory factors.

• The Korean Journal of Physiology and Pharmacology
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• 제27권2호
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• pp.177-185
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• 2023

The excessive inflammatory response induced by myocardial infarction exacerbates heart injury and leads to the development of heart failure. Recent studies have confirmed the involvement of multiple transcription factors in the modulation of cardiovascular disease processes. However, the role of KLF9 in the inflammatory response induced by cardiovascular diseases including myocardial infarction remains unclear. Here, we found that the expression of KLF9 significantly increased during myocardial infarction. Besides, we also detected high expression of KLF9 in infiltrated macrophages after myocardial infarction. Our functional studies revealed that KLF9 deficiency prevented cardiac function and adverse cardiac remodeling. Furthermore, the downregulation of KLF9 inhibited the activation of NF-κB and MAPK signaling, leading to the suppression of inflammatory responses of macrophages triggered by myocardial infarction. Mechanistically, KLF9 was directly bound to the TLR2 promoter to enhance its expression, subsequently promoting the activation of inflammation-related signaling pathways. Our results suggested that KLF9 is a pro-inflammatory transcription factor in macrophages and targeting KLF9 may be a novel therapeutic strategy for ischemic heart disease.

• 한국독성학회:학술대회논문집
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• 한국독성학회 2002년도 Molecular and Cellular Response to Toxic Substances
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• pp.191-191
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• 2002

Inflammatory as well as oxidative tissue damage has been associated with pathophysiology of Alzheimer's disease (AD), and nonsteroidal anti-inflammatory drugs have been shown to retard the progress of AD. In this study, we have investigated the molecular mechanisms underlying oxidative and inflammatory cell death induced by beta-amyloid (Abeta), a neurotoxic peptide associated with senile plaques formed in the brains of patients with AD, in cultured PC12 cells.(omitted)