Parthenolide, a feverfew-derived phytochemical, ameliorates obesity and obesity-induced inflammatory responses via the Nrf2/Keap1 pathway

Kim, Chae Young,Kang, Bobin,Suh, Hyung Joo,Choi, Hyeon-Son Elsevier 2019 Pharmacological research Vol.145 No.-

<P><B>Abstract</B></P> <P>Parthenolide (PL) is one of the most abundant sesquiterpene lactones found in the plant feverfew (<I>Tanacetum parthenium</I> (L.) Sch.Bip.). PL was investigated for its effect on obesity and obesity-induced inflammatory/oxidant responses <I>in vitro</I> and <I>in vivo</I>. An obesity-induced inflammatory response was induced in various co-culture systems using adipocytes (3T3-L1) and macrophages (RAW264.7) <I>in vitro</I> and the effect of PL and its mechanism of action were determined. PL effectively suppressed the adiposity-induced inflammatory responses by downregulating IL-6 (40–42%) and MCP-1 (26–37%) in 3T3-CM-cultured macrophages and contact co-culture system. PL also favorably regulated the dysregulations of adiponectin and resistin in macrophage-conditioned medium (RAW-CM)-cultured adipocytes. In transwell system of adipocyte and macrophage, PL was shown to upregulated Nrf2 and its target molecule, HO-1 by promoting nuclear translocation of Nrf2. In particular, in siRNA knockdown study, the PL-mediated anti-inflammatory response was exerted via the Nrf2/Keap1 pathway. In animal study using high-fat diet (HFD)-fed mice, PL-administered mice showed a significant reduction in body weight and white adipose tissues (WATs). This PL-mediated anti-obese effect was connected to anti-inflammatory responses with the regulation of inflammatory cytokines, and the downregulation of NF-κB and MAPKs. Furthermore, PL differentially modulated CD11c and CD206, which are pro-/anti-inflammatory phenotypes of ATMs, in stroma vascular fraction (SVF) and immunohistochemistry (IHC) staining analyses. PL also regulated the level of (anti)oxidant molecules with the activation of Nrf2/Keap1signaling. Taken together, PL inhibited obesity and obesity-induced inflammatory responses via the activation of Nrf2/Keap1 signaling, indicating a potential of PL as a functional agent to control obesity-related diseases.</P> <P><B>Graphical abstract</B></P> <P>PL inhibited obesity and the inflammatory/oxidative responses <I>in vitro</I> and <I>in vivo</I>. This PL-mediated inhibitory effect on obesity-induced inflammatory responses was shown to be exerted via the Nrf2/Keap1 signaling pathway. PL-mediated anti-inflammatory status was associated with the modulation of M1 and M2 phenotypes in obesity.</P> <P>Parthenolide inhibited adipocyte-mediated inflammatory responses in co-culture system, and suppressed HFD-induced obesity and obesity-induced inflammatory and oxidative stress responses with the increase of antioxidant responses in mice by activating Nrf2-Keap1 signaling pathway.</P> <P>[DISPLAY OMISSION]</P>

염증과 패혈증

윤지영,권재영 대한중환자의학회 2010 Acute and Critical Care Vol.25 No.1

Despite the development of modern intensive care and new antimicrobial agents, the mortality of the patients with severe sepsis and septic shock remains high. The poor outcome is considered to be a consequence of an overactive systemic inflammatory response. Sepsis is now defined as systemic inflammatory response syndrome (SIRS) in which there is an identifiable focus of infection. As a consequence of the overactive SIRS response, the function of various organ systems may be compromised, resulting in multiple organ dysfunction syndrome (MODS) and death. Systemic inflammation is a consequence of activation of the innate immune system. It is characterized by intravascular release of pro-inflammatory cytokines and other vasoactive mediators, and the concurrent activation of the innate immune cells. In addition to the pro-inflammatory reactions, the host`s anti-inflammatory mechanisms are also activated and aimed at counteracting the inflammatory response. The balance between pro- and anti-inflammatory reactions is critical for the outcome of the patient. Understanding the mechanisms of acute inflammatory responses in critical ill patients is necessary for the development of urgently needed therapeutics. The aim of this review is to provide a description of the key components and mechanisms involved in the inflammatory response in patients with SIRS and sepsis.

NF‐κB/p53‐activated inflammatory response involves in diquat‐induced mitochondrial dysfunction and apoptosis

Choi, Su Eun,Park, Yun Sun,Koh, Hyun Chul John Wiley Sons, Inc. 2018 Environmental toxicology Vol.33 No.10

<P><B>Abstract</B></P><P>Inflammation generated by environmental toxicants including pesticides could be one of the factors underlying neuronal cell damage in neurodegenerative diseases. In this study, we investigated the mechanisms by which inflammatory responses contribute to apoptosis in PC12 cells treated with diquat. We found that diquat induced apoptosis, as demonstrated by the activation of caspases and nuclear condensation, inhibition of mitochondrial complex I activity, and decreased ATP level in PC12 cells. Diquat also reduced the dopamine level, indicating that cell death induced by diquat is due to cytotoxicity of dopaminergic neuronal components in these cells. Exposure of PC12 cells to diquat led to the production of reactive oxygen species (ROS), and the antioxidant <I>N</I>‐acetyl‐cystein attenuated the cytotoxicity of caspase‐3 pathways. These results demonstrate that diquat‐induced apoptosis is involved in mitochondrial dysfunction through production of ROS. Furthermore, diquat increased expression of cyclooxygenase‐2 (COX‐2) and tumor necrosis factor‐α (TNF‐α) via inflammatory stimulation. Diquat induced nuclear accumulation of NF‐κB and p53 proteins. Importantly, an inhibitor of NF‐κB nuclear translocation blocked the increase of p53. Both NF‐κB and p53 inhibitors also blocked the diquat‐induced inflammatory response. Pretreatment of cells with meloxicam, a COX‐2 inhibitor, also blocked apoptosis and mitochondrial dysfunction. These results represent a unique molecular characterization of diquat‐induced cytotoxicity in PC12 cells. Our results demonstrate that diquat induces cell damage in part through inflammatory responses via NF‐κB‐mediated p53 signaling. This suggests the potential to generate mitochondrial damage via inflammatory responses and inflammatory stimulation‐related neurodegenerative disease.</P>

암환자의 예후인자로서 전신염증반응에 대한 고찰

윤성우,Yoon, Seong-Woo 대한암한의학회 2012 大韓癌韓醫學會誌 Vol.17 No.1

Objective : The association of cancer survival and components of the systemic inflammatory response, combined to form inflammation-based prognostic scores (modified Glasgow Prognostic Score (GPS), Neutrophil Lymphocyte Ratio, Platelet Lymphocyte Ratio) is reviewed in this article. Methods and Results : With extensive research of papers in the PubMed, there is good evidence that preoperative measures of the systemic inflammatory response predict cancer survival, independent of tumor stage, in primary operable cancer. GPS also shows its prognostic value as a predictor of survival, independent of tumor stage, performance status and treatment in a variety of advanced cancer. GPS is associated with chemotherapy related toxicities as well as response to treatment and C-reactive protein shows its clinical value as a monitor of chemotherapy response. The systemic inflammatory response is closely related to cachexia and may be suitable measure for the clinical definition of cancer cachexia. Conclusion : Anticipated survival using the inflammation-based prognostic score is a major factor to be taken into consideration when deciding whether active intervention including surgery and chemotherapy or palliation therapy including acupuncture and herb medication is appropriate.

제대혈 염증성반응증후군의 In Vitro 분석

김은재,조은경 한국보건기초의학회 2020 한국보건기초의학회지 Vol.13 No.1

Fetal inflammatory response syndrome is a multisystemic disorder, defined by elevated interleukin-6 (IL-6) in fetal plasma and associated with preterm delivery and adverse neonatal outcomes. Recent evidences indicate that the elevated concentration of matrix metalloproteinase-8 (MMP-8) is associated with fetal inflammatory response syndrome. Nuclear factor kappa B (NF-κB), has central roles in human immune response. In this study, we made in vitro model of fetal inflammatory response syndrome using lipopolysaccharide (LPS) stimulation to cord blood. The purpose of this study was to demonstrate that LPS induces a release of IL-6 and MMP-8 as well as NF-κB in cord blood. LPS stimulation increased the expression of NF-κB in a time dependent manner. MMP-8 level was significantly correlated with IL-6 level. All these results directly support that IL-6 and MMP-8 could be a useful marker for the diagnosis of fetal inflammatory response syndrome.

Therapeutic Effects of Resiniferatoxin Related with Immunological Responses for Intestinal Inflammation in Trichinellosis

José Luis Muñoz-Carrillo,José Luis Muñoz-López,José Jesús Muñoz-Escobedo,Claudia Maldonado-Tapia,Oscar Gutiérrez-Coronado,Juan Francisco Contreras-Cordero,María Alejandra Moreno-García 대한기생충학ㆍ열대의학회 2017 The Korean Journal of Parasitology Vol.55 No.6

The immune response against Trichinella spiralis at the intestinal level depends on the CD4+ T cells, which can both suppress or promote the inflammatory response through the synthesis of diverse cytokines. During the intestinal phase, the immune response is mixed (Th1/Th2) with the initial predominance of the Th1 response and the subsequent domination of Th2 response, which favor the development of intestinal pathology. In this context, the glucocorticoids (GC) are the pharmacotherapy for the intestinal inflammatory response in trichinellosis. However, its therapeutic use is limited, since studies have shown that treatment with GC suppresses the host immune system, favoring T. spiralis infection. In the search for novel pharmacological strategies that inhibit the Th1 immune response (proinflammatory) and assist the host against T. spiralis infection, recent studies showed that resiniferatoxin (RTX) had anti-inflammatory activity, which decreased the serum levels of IL-12, INF-γ, IL-1β, TNF-α, NO, and PGE2, as well the number of eosinophils in the blood, associated with decreased intestinal pathology and muscle parasite burden. These researches demonstrate that RTX is capable to inhibit the production of Th1 cytokines, contributing to the defense against T. spiralis infection, which places it as a new potential drug modulator of the immune response.

인간 내생 레트로바이러스(Human Endogenous Retrovirus, HERV)의 염증반응 조절 기작

고은지(Eun-Ji Ko),차희재(Hee-Jae Cha) 한국생명과학회 2021 생명과학회지 Vol.31 No.8

인간 내생 레트로바이러스(Human Endogenous Restrovirus, HERV)는 수백만년전 인간의 유전체에 삽입되었으며 이후 오랜 세월을 거치며 재조합, 결실 및 돌연변이 등 여러 원인에 의해 더 이상 활성화된 바이러스로 역할을 하지 못하고 감염되지 않는다. 하지만 HERV는 최근 연구들은 HERV 유래 인자들이 실제 생리현상 및 암을 비롯한 특정 질환에 관여 하고 있다는 것을 보여 주었다. HERV와 관련된 여러가지 생리 현상 중 염증반응에 초점을 맞추어 고찰해 볼 필요가 있다. HERV는 류마티스, 다발성 경화증, 근위축성 측삭경화증, 쇼그렌 증후군 같은 자가면역질환을 비롯한 여러 염증질환에 직접적으로 관여하는 것으로 보고 되고 있다. HERV의 염증 조절 기작으로는 HERV 유래 인자들이 비특이적 선천성 면역과정을 유발할 가능성과 HERV 유래의 RNA와 단백질이 특정 수용체를 통해 선택적 신호전달기작을 유발할 가능성을 고려 할 수 있다. 하지만 어떠한 방식으로 잠재되어 있던 HERV가 염증반응에서 활성화 되는지 또한 HERV와 관여된 인자들과 신호기작들이 어떠한 것들이 있는지 등 HERV의 인자들이 염증반응을 조절하는 기작에는 아직 많은 것들이 밝혀지지 않아 질병 발병에 대한 연구에 어려움이 있는 실정이다. 본 리뷰에서는 HERV 관련 자가 면역질환을 소개하고 염증반응 조절 기작에 관한 HERV의 분자수준에서의 작용 메커니즘을 제안 하고자 한다. Human endogenous retroviruses (HERVs) were inserted into the human genome millions of years ago but they are currently inactive and non-infectious due to recombinations, deletions, and mutations after insertion into the host genome. Nonetheless, recent studies have shown that HERV-derived elements are actually involved in physiological phenomena and certain diseases including cancers. Among the various physiological phenomena related to HERV-derived elements, it is necessary to focus on inflammatory response. HERV-derived elements have been reported to be directly involved in various inflammatory diseases, including autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, and Sjogren’s syndrome. As a mechanism for regulating inflammation through HERV-derived elements, the possibility that HERV-derived elements may cause nonspecific innate immune processes and that HERV-derived RNA or proteins may cause selective signaling mechanisms through specific receptors can be considered. However, the mechanism through which HERV-derived elements regulate inflammatory response, such as how silent HERV elements are activated in inflammatory response and what factors and signaling mechanisms are involved in HERV-derived elements, have not been identified to date, making it difficult to study the onset of HERV-related inflammatory disease. In this review, we introduce HERV-related autoimmune diseases and propose the mechanisms of HERV-derived elements at the molecular level of HERV in inflammatory response.

Anti-Inflammatory Role of TAM Family of Receptor Tyrosine Kinases Via Modulating Macrophage Function

이창희,전태훈 한국분자세포생물학회 2019 Molecules and cells Vol.42 No.1

Macrophage is an important innate immune cell that not only initiates inflammatory responses, but also functions in tissuerepair and anti-inflammatory responses. Regulating macrophage activity is thus critical to maintain immune homeostasis. Tyro3, Axl, and Mer are integral membrane proteins that constitute TAM family of receptor tyrosine kinases (RTKs). Growing evidence indicates that TAM family receptors play an important role in anti-inflammatory responses through modulating the function of macrophages. First, macrophages can recognize apoptotic bodies through interaction between TAM family receptors expressed on macrophages and their ligands attached to apoptotic bodies. Without TAM signaling, macrophages cannot clear up apoptotic cells, leading to broad inflammation due to over-activation of immune cells. Second, TAM signaling can prevent chronic activation of macrophages by attenuating inflammatory pathways through particular pattern recognition receptors and cytokine receptors. Third, TAM signaling can induce autophagy which is an important mechanism to inhibit NLRP3 inflammasome activation in macrophages. Fourth, TAM signaling can inhibit polarization of M1 macrophages. In this review, we will focus on mechanisms involved in how TAM family of RTKs can modulate function of macrophage associated with antiinflammatory responses described above. We will also discuss several human diseases related to TAM signaling and potential therapeutic strategies of targeting TAM signaling

Anti-Inflammatory Role of TAM Family of Receptor Tyrosine Kinases Via Modulating Macrophage Function

Lee, Chang-Hee,Chun, Taehoon Korean Society for Molecular and Cellular Biology 2019 Molecules and cells Vol.42 No.1

Macrophage is an important innate immune cell that not only initiates inflammatory responses, but also functions in tissue repair and anti-inflammatory responses. Regulating macrophage activity is thus critical to maintain immune homeostasis. Tyro3, Axl, and Mer are integral membrane proteins that constitute TAM family of receptor tyrosine kinases (RTKs). Growing evidence indicates that TAM family receptors play an important role in anti-inflammatory responses through modulating the function of macrophages. First, macrophages can recognize apoptotic bodies through interaction between TAM family receptors expressed on macrophages and their ligands attached to apoptotic bodies. Without TAM signaling, macrophages cannot clear up apoptotic cells, leading to broad inflammation due to over-activation of immune cells. Second, TAM signaling can prevent chronic activation of macrophages by attenuating inflammatory pathways through particular pattern recognition receptors and cytokine receptors. Third, TAM signaling can induce autophagy which is an important mechanism to inhibit NLRP3 inflammasome activation in macrophages. Fourth, TAM signaling can inhibit polarization of M1 macrophages. In this review, we will focus on mechanisms involved in how TAM family of RTKs can modulate function of macrophage associated with anti-inflammatory responses described above. We will also discuss several human diseases related to TAM signaling and potential therapeutic strategies of targeting TAM signaling.

L1 Cell Adhesion Molecule에 의한 대식세포 매개 염증반응의 억제 기전 분석

이영수,Yi, Young-Su 대한약학회 2016 약학회지 Vol.60 No.3

L1 cell adhesion molecule (L1CAM) is a cell surface molecule to initiate a variety of cellular responses through interacting with other cell adhesion molecules in a homophilic or heterophilic manner. Although its expression was found to be upregulated in some tumor cells, including cholangiocarcinomas, and ovarian cancers, and many studies have investigated the role of L1CAM in these cancers, its role in inflammatory responses has been poorly understood. In this study, we explored the role of L1CAM in macrophage-mediated inflammatory responses. L1CAM significantly suppressed the production of nitric oxide (NO), but induced cell proliferation in RAW264.7 cells. L1CAM expression was detectable, but its expression was markedly decreased by lipopolysaccharide (LPS) in RAW264.7 cells. In addition, the expression of pro-inflammatory genes, such as tumor necrosis factor (TNF)-${\alpha}$, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) induced by LPS was dramatically suppressed by L1CAM in RAW264.7 cells. L1CAM inhibited the transcriptional activities of NF-${\kappa}B$ and AP-1 while its cytoplasmic domain deletion form, $L1{\Delta}CD$ did not suppressed their activities in RAW264.7 cells. Moreover, L1CAM suppressed nuclear translocation of p65 and p50 as well as c-Jun, c-Fos and p-ATF2 which are transcription factors of NF-${\kappa}B$ and AP-1, respectively. In conclusion, L1CAM suppressed inflammatory responses in macrophages through inhibiting NF-${\kappa}B$ and AP-1 pathways.