노화과정에서 분자염증 반응과 에너지 대사의 중요성

정해영,성보경 대한암예방학회 2005 Journal of cancer prevention Vol.10 No.1

A recent proposal of molecular inflammation hypothesis of the aging highlights this redox derangement as a plausible link between the normal aging process and age-related diseases. The hypothesis focused on the experimental observations revealing the dysregulated gene expression and transcription factors under the age-related oxidative stress. In this review, the biochemical and molecular bases of the inflammatory process will be delineated as the possible molecular mechanism for the aging and the age-related diseases. The key players involved in the proposed mechanism are the age-related upregulation of NF-κB and its regulated proinflammatory medators, all of which are attenuated by anti-aging calorie restriction (CR). Furthermore, data will be presented to describe molecular events leading to the age-related NF-κB activation, while CR blunted these activation processes. Based on these and other recent evidence, we propose to use molecular inflammation to emphasize the increased molecular proinflammatory reactions with aging, thus predisposing the aged organism to fully expressed chronic inflammatory phenomena. Restriction of calorie consumed extends longevity in many organisms. In rodents, CR showed reduction of plasma glucose and insulin-like growth factor (IGF-1) and postpones or attenuates cancer, immunosenescence, and inflammation. In organisms ranging yeast to mice, mutations in energy metabolism regulated genes (i.e. glucose or IGF-1 like signaling) extend life-span. Understandings of molecular inflammation hypothesis and life-expending energy metabolism including CR, should provide templates for anti-aging strategy and drugs that regulate aging process and age-related diseases. (Cancer Prev Res 10, 6-17, 2005)

Molecular Inflammation Hypothesis of Aging Based on the Anti-Aging Mechanism of Calorie Restriction

CHUNG, HAE YOUNG,KIM, HYON JEEN,KIM, KYU WON,CHOI, JAE SUE,YU, BYUNG PAL 부산대학교 유전공학연구소 2002 분자생물학 연구보 Vol.18 No.-

Accumulating evidence strongly suggests that oxidative stress underlies aging processes. Research provides consistent evidence that calorie restriction (CR) reduces age-related oxidative stress and has anti-inflammatory properties. However, information is lacking on the molecular mechanism that would better define the interrelation of reactive oxygen species and nitrogen species and the pro-inflammatory states of the aging process. In this review, the biochemical and molecular bases of the inflammatory process in the aging process are analyzed to delineate the molecular inflammation hypothesis of aging. The key players involved in the proposed hypothesis are the age-related upregulation of NF-κB, IL-1β, IL-6, TNFα, cyclooxygenase-2, and inducible NO synthase, all of which are attenuated by CR. Furthermore age-related NF-κB activation is associated with phosphorylation by IκB kinase/NIK and MAPKs, while CR blocked these activation processes. The modulation of these factors provides molecular insights of the anti-inflammatory action of CR in relation to the aging process. Based on available finding and our recent supporting evidence, we prefer to use "molecular inflammation" to emphasize the importance of the molecular reaction mechanisms and their aberrance, predisposing to fully expressed chronic inflammatory phenomena. It was further proposed that CR's major force of the regulation of redox-sensitive inflammation may well be its life-prolonging action. Microsc. Res. Tech. 59:264-272, 2002.

Active Molecular Chitosan alleviate Bleomycin-induced Acute Pulmonary Inflammation in Mice

( Seong-bo Yun ),( Dong-hun Kang ),( Ji-sun Choi ),( Dae-young Kim ) 한국키틴키토산학회 2019 한국키틴키토산학회지 Vol.24 No.3

Generally acute pulmonary inflammation is triggered by damage to alveolar epithelial cells due to the pollutants, viral infection, allergens and toxic substances. The active molecular chitosan (AMC, 5~8 kDa) is known to have non-toxic, bio-degradable, and biological activities including anti-tumor, anti-viral, and anti-inflammatory activities. The purpose of this study was to observe AMC’s preclinical efficacy to acute pulmonary inflammation and evaluate the therapeutic effect of a bleomycin (BLM) induced mouse model using AMC, a final product made by the hydrolysis of chitosan. Our experiments were conducted using male C57BL/6 mouse and BLM (5 mg/kg) was injected once with the intratracheal instillation (IT) method to induce pulmonary inflammation. Each group was conducted with prednisolone (PDS, 6.5 mg/kg) or AMC (100 mg/kg and 200 mg/kg, respectively) for 10 days with oral gavage. The relative lung weight measurements, histological findings in lung tissue specimens and cell counts through bronchoalveolar lavage fluid (BALF) were performed to determine the anti-inflammatory effects of AMC. The AMC treated groups with BLM induction had a decreased tendency of inflammation on our experiments. A dose of 100 mg/kg AMC induce group showed that similar aspect with control group on histological results. In addition, the lymphocyte rate appeared a noticeable on this group. The degree of lymphocyte was remarkably lower. It was inferred that inflammatory improvement in the AMC treated group. We confirmed that the BLM-induced lung disease model that progressed inflammation was inhibited by AMC. Furthermore, AMC performs an anti-inflammation function and has the possibility of use for the treatment of inflammatory disease.

Active Molecular Chitosan alleviate Bleomycin-induced Acute Pulmonary Inflammation in Mice

윤성보,강동훈,최지선,김대영 한국키틴키토산학회 2019 한국키틴키토산학회지 Vol.24 No.3

Generally acute pulmonary inflammation is triggered by damage to alveolar epithelial cells due to the pollutants, viral infection, allergens and toxic substances. The active molecular chitosan (AMC, 5~8 kDa) is known to have non-toxic, bio-degradable, and biological activities including anti-tumor, anti-viral, and anti-inflammatory activities. The purpose of this study was to observe AMC’s preclinical efficacy to acute pulmonary inflammation and evaluate the therapeutic effect of a bleomycin (BLM) induced mouse model using AMC, a final product made by the hydrolysis of chitosan. Our experiments were conducted using male C57BL/ 6 mouse and BLM (5 mg/kg) was injected once with the intratracheal instillation (IT) method to induce pulmonary inflammation. Each group was conducted with prednisolone (PDS, 6.5 mg/kg) or AMC (100 mg/kg and 200 mg/kg, respectively) for 10 days with oral gavage. The relative lung weight measurements, histological findings in lung tissue specimens and cell counts through bronchoalveolar lavage fluid (BALF) were performed to determine the anti-inflammatory effects of AMC. The AMC treated groups with BLM induction had a decreased tendency of inflammation on our experiments. A dose of 100 mg/kg AMC induce group showed that similar aspect with control group on histological results. In addition, the lymphocyte rate appeared a noticeable on this group. The degree of lymphocyte was remarkably lower. It was inferred that inflammatory improvement in the AMC treated group. We confirmed that the BLM-induced lung disease model that progressed inflammation was inhibited by AMC. Furthermore, AMC performs an anti-inflammation function and has the possibility of use for the treatment of inflammatory disease.

스트레스로 유발된 무균 염증이 우울증 발생에 미치는 영향

서미경(Mi Kyoung Seo),이정구(Jung Goo Lee),석대현(Dae-Hyun Seog),표세영(Se Young Pyo),이원희(Won Hee Lee),박성우(Sung Woo Park) 한국생명과학회 2023 생명과학회지 Vol.33 No.12

우울증은 개인과 사회에 부정적인 영향을 미치는 흔한 정신질환이지만 그 원인은 아직 명확히 밝혀져 있지 않다. 스트레스는 우울증의 주요 위험인자이며, 염증을 유발하여 우울증에 대한 취약성을 증가시키는 것으로 알려져 있다. 수많은 연구는 우울증과 염증의 강한 연관성을 제안하고 있다. 우울증 환자 혈액에서는 IL-1β, IL-6, IL-12, TNF-α 및 IFN-γ와 같은 친염증성 사이토카인이 증가하였으며, IL-4, IL-10 및 TGF-β와 같은 항염증성 사이토카인이 감소하였다. 설치류에 친염증성 사이토카인을 투여하면 우울 유사 행동이 관찰되는 반면, 항염증제를 투여하면 우울 증상이 완화된다. 이러한 연구들은 우울증의 병인에 염증의 중요성을 강조하고 있다. 우울증에서 염증이 활성화되는 기전에 관한 다양한 연구들이 진행되고 있다. 최근 연구에서는 스트레스로 유발되는 무균 염증의 중요성을 밝히고 있다. 병원균의 감염이 없는 상태에서 신체 및 심리적 스트레스로 인해 염증 과정이 활성화되는 것을 무균 염증이라 한다. 스트레스는 무균 염증을 활성화하기 위해 DAMPs (damage-associated molecular patterns)로 알려진 내인성 인자의 방출을 촉진시키며, 방출된 DAMPs는 해당 수용체인 PRRs (pattern recognition receptors)에 결합함으로서 신호전달을 통해 친염증성 사이토카인 생성을 증가시킨다. 본 종설에서 무균 염증의 조절 장애에 대한 전임상 및 임상 증거를 바탕으로 우울증에서 DAMP의 역할을 검토하고자 한다. Although depression is a common psychiatric disorder that negatively affects individuals and societies, its exact pathogenesis is not well understood. Stress is a major risk factor for depression and is known to increase susceptibility by triggering inflammation. Indeed, many preclinical and clinical studies have suggested a strong link between depression and inflammation. Depression is associated with increased levels of pro-inflammatory cytokines, such as interleukin (IL-)1β, IL-6, IL-12, tumor necrosis factor-α, and interferon-γ, and decreased levels of the anti-inflammatory IL-4, IL-10, and transforming growth factor-β. Administering pro-inflammatory cytokines causes depression-like behaviors in rodents. Conversely, administering anti-inflammatory drugs appears to ameliorate depressive symptoms. Although the importance of inflammation as a mediator of depression has been demonstrated, the mechanisms by which inflammation is activated in depression remain unclear. To address this issue, recent studies have focused on the importance of stress-induced sterile inflammation. Sterile inflammation refers to the activation of inflammatory processes due to physical and/or psychological stress in the absence of pathogens. Stress promotes the release of endogenous factors known as damage-associated molecular patterns (DAMPs), thereby triggering sterile inflammation. In turn, DAMPs are recognized by pattern recognition receptors, leading to the production of pro-inflammatory cytokines. Here, we review the role of DAMPs in depression based on preclinical and clinical evidence on the dysregulation of sterile inflammation.

Age-related inflammation and insulin resistance: a review of their intricate interdependency

박민희,김대현,이은경,김남득,임동순,이재원,유병팔,정해영 대한약학회 2014 Archives of Pharmacal Research Vol.37 No.12

Chronic inflammation is a major risk factorunderlying aging and the associated diseases of aging; ofparticular interest is insulin resistance during aging. Chronic inflammation impairs normal lipid accumulation,adipose tissue function, mitochondrial function, and causesendoplasmic reticulum (ER) stress, which lead to insulinresistance. However, some studies show that insulinresistance itself amplifies chronic inflammation. Theactivity of the insulin-dependent Akt signaling pathway ishighlighted because of its decrease in insulin-sensitiveorgans, like liver and muscle, which may underlie insulinresistance and hyperinsulinemia, and its increased levels innon-metabolic organs, such as kidney and aorta. In that theprevalence of obesity has increased substantially for all agegroups in recent years, our review summarizes the datashowing the involvement of chronic inflammation inobesity-induced insulin resistance, which perpetuatesreciprocal interactions between the chronic inflammatoryprocess and increased adiposity, thereby accelerating theaging process.

Mild traumatic brain injury-induced hippocampal gene expressions: The identification of target cellular processes for drug development

Tweedie, D.,Rachmany, L.,Kim, D.S.,Rubovitch, V.,Lehrmann, E.,Zhang, Y.,Becker, K.G.,Perez, E.,Pick, C.G.,Greig, N.H. Elsevier/North-Holland 2016 Journal of neuroscience methods Vol.272 No.-

Background: Neurological dysfunction after traumatic brain injury (TBI) poses short-term or long-lasting health issues for family members and health care providers. Presently there are no approved medicines to treat TBI. Epidemiological evidence suggests that TBI may cause neurodegenerative disease later in life. In an effort to illuminate target cellular processes for drug development, we examined the effects of a mild TBI on hippocampal gene expression in mouse. Methods: mTBI was induced in a closed head, weight drop-system in mice (ICR). Animals were anesthetized and subjected to mTBI (30g). Fourteen days after injury the ipsilateral hippocampus was utilized for cDNA gene array studies. mTBI animals were compared with sham-operated animals. Genes regulated by TBI were identified to define TBI-induced physiological/pathological processes. mTBI regulated genes were divided into functional groupings to provide gene ontologies. Genes were further divided to identify molecular/cellular pathways regulated by mTBI. Results: Numerous genes were regulated after a single mTBI event that mapped to many ontologies and molecular pathways related to inflammation and neurological physiology/pathology, including neurodegenerative disease. Conclusions: These data illustrate diverse transcriptional changes in hippocampal tissues triggered by a single mild injury. The systematic analysis of individual genes that lead to the identification of functional categories, such as gene ontologies and then molecular pathways, illustrate target processes of relevance to TBI pathology. These processes may be further dissected to identify key factors that can be evaluated at the protein level to highlight possible treatments for TBI in human disease and potential biomarkers of neurodegenerative processes.

The immune modulating properties of the heat shock proteins after brain injury

Jong Youl Kim,Midori A. Yenari 대한해부학회 2013 Anatomy & Cell Biology Vol.46 No.1

Inflammation within the central nervous system often accompanies ischemia, trauma, infection, and other neuronal injuries. The immune system is now recognized to play a major role in neuronal cell death due to microglial activation, leukocyte recruitment, and cytokine secretion. The participation of heat shock proteins (Hsps) in the immune response following in brain injury can be seen as an attempt to correct the inflammatory condition. The Hsps comprise various families on the basis of molecular size. One of the most studied is Hsp70. Hsp70 is thought to act as a molecular chaperone that is present in almost intracellular compartments, and function by refolding misfolded or aggregated proteins. Hsps have recently been studied in inflammatory conditions. Hsp70 can both induce and arrest inflammatory reactions and lead to improved neurological outcome in experimental brain injury and ischemia. In this review, we will focus on underlying inflammatory mechanisms and Hsp70 in acute neurological injury.

Mechanism of Wenshen Xuanbi Decoction in the treatment of osteoarthritis based on network pharmacology and experimental verification

You Hankun,Song Siyuan,Liu Deren,Ren Tongsen,Yin Song Jiang,Wu Peng,Mao Jun 대한약리학회 2024 The Korean Journal of Physiology & Pharmacology Vol.28 No.1

To investigate the mechanism of Wenshen Xuanbi Decoction (WSXB) in treating osteoarthritis (OA) via network pharmacology, bioinformatics analysis, and experimental verification. The active components and prediction targets of WSXB were obtained from the TCMSP database and Swiss Target Prediction website, respectively. OA-related genes were retrieved from GeneCards and OMIM databases. Protein-protein interaction and functional enrichment analyses were performed, resulting in the construction of the Herb-Component-Target network. In addition, differential genes of OA were obtained from the GEO database to verify the potential mechanism of WSXB in OA treatment. Subsequently, potential active components were subjected to molecular verification with the hub targets. Finally, we selected the most crucial hub targets and pathways for experimental verification in vitro. The active components in the study included quercetin, linolenic acid, methyl linoleate, isobergapten, and beta-sitosterol. AKT1, tumor necrosis factor (TNF), interleukin (IL)- 6, GAPDH, and CTNNB1 were identified as the most crucial hub targets. Molecular docking revealed that the active components and hub targets exhibited strong binding energy. Experimental verification demonstrated that the mRNA and protein expression levels of IL-6, IL-17, and TNF in the WSXB group were lower than those in the KOA group (p < 0.05). WSXB exhibits a chondroprotective effect on OA and delays disease progression. The mechanism is potentially related to the suppression of IL-17 and TNF signaling pathways and the down-regulation of IL-6.

Damage-Associated Molecular Patterns in Inflammatory Diseases

Roh, Jong Seong,Sohn, Dong Hyun 한국조명·전기설비학회 2018 한국조명·전기설비학회 학술대회논문집 Vol. No.

<P>Damage-associated molecular patterns (DAMPs) are endogenous danger molecules that are released from damaged or dying cells and activate the innate immune system by interacting with pattern recognition receptors (PRRs). Although DAMPs contribute to the host's defense, they promote pathological inflammatory responses. Recent studies have suggested that various DAMPs, such as high-mobility group box 1 (HMGB1), S100 proteins, and heat shock proteins (HSPs), are increased and considered to have a pathogenic role in inflammatory diseases. Here, we review current research on the role of DAMPs in inflammatory diseases, including rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, atherosclerosis, Alzheimer's disease, Parkinson's disease, and cancer. We also discuss the possibility of DAMPs as biomarkers and therapeutic targets for these diseases.</P>