• IMMUNE NETWORK
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• v.23 no.1
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• pp.9.1-9.15
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• 2023

Cancer immunotherapies continue to face numerous obstacles in the successful treatment of solid malignancies. While immunotherapy has emerged as an extremely effective treatment option for hematologic malignancies, it is largely ineffective against solid tumors due in part to metabolic challenges present in the tumor microenvironment (TME). Tumor-infiltrating CD8⁺ T cells face fierce competition with cancer cells for limited nutrients. The strong metabolic suppression in the TME often leads to impaired T-cell recruitment to the tumor site and hyporesponsive effector functions via T-cell exhaustion. Growing evidence suggests that mitochondria play a key role in CD8⁺ T-cell activation, migration, effector functions, and persistence in tumors. Therefore, targeting the mitochondrial metabolism of adoptively transferred T cells has the potential to greatly improve the effectiveness of cancer immunotherapies in treating solid malignancies.

• Journal of Life Science
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• v.27 no.8
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• pp.873-878
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• 2017

We previously reported that NAD(P)H:quinone oxidoreductase 1 (NQO1)-knockout (KO) mice exhibited spontaneous inflammation in the gut. We also found that NQO1-KO mice showed highly increased inflammatory responses compared with NQO1-WT control mice when subjected to DSS-induced experimental colitis. In a Clostridium difficile toxin-induced mouse enteritis model, NQO1-KO mice were also sensitive compared with NQO1-WT mice. Moreover, numerous studies have shown that NQO1 is functionally associated with immune regulation. Here, we assessed whether NQO1 defects can alter macrophage activation. We found that peritoneal macrophages isolated from NQO1-KO mice produced more IL-6 and $TNF-{\alpha}$ than those isolated from NQO1-WT mice. Moreover, the dicumarol-induced inhibition of NQO1 significantly increased IL-6 and $TNF-{\alpha}$ production in peritoneal macrophages isolated from NQO1-WT mice, as well as in the cultured mouse macrophage cell line, RAW264.7. These results indicate that NQO1 may negatively regulate the activation of macrophages. Knockout or chemical inhibition of NQO1 markedly reduced the expression of $I{\kappa}B$ (inhibitor of $NF{\kappa}B$) in both mouse peritoneal macrophages and RAW264.7 cells. Finally, RAW264.7 cells treated with dicumarol exhibited morphological changes reflecting macrophage activation. Our results suggest that NQO1 may suppress the $NF{\kappa}B$ pathways in macrophages, thereby suppressing the activation of these cells. Thus, immunosuppressive activity may be among the many possible functions of NQO1.

• Korean Journal of Plant Resources
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• v.27 no.5
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• pp.567-575
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• 2014

Resveratrol is a naturally occurring stilbene which is safe and well-described compound with a potent anti-inflammatory activity. Recent studies suggested that resveratrol suppressed various inflammation mediated diseases such as asthma, chronic colitis, rheumatoid arthritis, and type 1 diabetes. These studies indicated that resveratrol might directly modulate $CD4^+$ helper T cells (Th cells)-mediated immune responses. However, it is not fully elucidated whether resveratrol directly regulates $CD4^+$ Th cell activation and differentiation. In the present study, $CD4^+$ Th cells were purified from C57BL/6 and treated with various concentrations of resveratrol. We found that resveratrol directly suppressed $CD4^+$ Th cells activation, leading to a defect in T cell proliferation. When $CD4^+$ Th cells were treated with resveratrol, cytokine production was also significantly reduced in a dose dependent manner. In accordance with these results, resveratrol even inhibited $CD4^+$ Th cells differentiation into Th1, Th2 or Th17, which produces IFN-${\gamma}$, IL-4 or IL-17 respectively. We also found that resveratrol could induce apoptosis of $CD4^+$ T cells at a high concentration. Our data demonstrated that resveratrol inhibited directly $CD4^+$ Th cells activation and differentiation. It suggests that resveratrol could be an efficient therapeutic strategy for autoimmune diseases in which $CD4^+$ Th cells play a critical role.

• IMMUNE NETWORK
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• v.11 no.2
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• pp.107-113
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• 2011

Background: Metabolic disorders, including type II diabetes and obesity, present major health risks in industrialized countries. AMP-activated protein kinase (AMPK) has become the focus of a great deal of attention as a novel therapeutic target for the treatment of metabolic syndromes. In this study, we evaluated whether dietary aloe could reduce obesity-induced inflammation and adipogenesis. Methods: Male C57BL/6 obese mice fed a high-fat diet for 54 days received a supplement of aloe formula (PAG, ALS, Aloe QDM, and Aloe QDM complex) or pioglitazone (PGZ) and were compared with unsupplemented controls (high-fat diet; HFD) or mice fed a regular diet (RD). RT-PCR and western blot analysis were used to quantify the expression of obesity-induced inflammation. Results: Aloe QDM complex downregulated fat size through suppressed expression of scavenger receptors on adipose tissue macrophages (ATMs) compared with HFD. Both white adipose tissue (WATs) and muscle exhibited increased AMPK activation through aloe supplementation, and in particular, the Aloe QDM complex. Obesity-induced inflammatory cytokines (IL-$1{\beta}$ and -6) and $HIF1{\alpha}$ mRNA and protein were decreased markedly, as was macrophage infiltration by the Aloe QDM complex. Further, the Aloe QDM complex decreased the translocation of NF-${\kappa}B$ p65 from the cytosol in the WAT. Conclusion: Dietary aloe formula reduced obesity-induced inflammatory responses by activation of AMPK in muscle and suppression of proinflammatory cytokines in the WAT. Additionally, the expression of scavenger receptors in the ATM and activation of AMPK in WAT led to reduction in the percent of body fat. Thus, we suggest that the effect of the Aloe QDM complex in the WAT and muscle are related to activation of AMPK and its use as a nutritional intervention against T2D and obesity-related inflammation.

• BMB Reports
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• v.53 no.6
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• pp.329-334
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• 2020

Inflammasomes are cytosolic, multiprotein complexes that act at the frontline of the immune responses by recognizing pathogen- or danger-associated molecular patterns or abnormal host molecules. Mesenchymal stem cells (MSCs) have been reported to possess multipotency to differentiate into various cell types and immunoregulatory effects. In this study, we investigated the expression and functional regulation of NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome in human umbilical cord blood-derived MSCs (hUCB-MSCs). hUCB-MSCs expressed inflammasome components that are necessary for its complex assembly. Interestingly, NLRP3 inflammasome activation suppressed the differentiation of hUCB-MSCs into osteoblasts, which was restored when the expression of adaptor proteins for inflammasome assembly was inhibited. Moreover, the suppressive effects of MSCs on T cell responses and the macrophage activation were augmented in response to NLRP3 activation. In vivo studies using colitic mice revealed that the protective abilities of hUCB-MSCs increased after NLRP3 stimulation. In conclusion, our findings suggest that the NLRP3 inflammasome components are expressed in hUCB-MSCs and its activation can regulate the differentiation capability and the immunomodulatory effects of hUCB-MSCs.

• Journal of Physiology & Pathology in Korean Medicine
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• v.20 no.1
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• pp.37-42
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• 2006

Matrix metalloproteinase-9 (MMP-9) is considered to be an important component in the progression of inflammation. Monocytes/macrophages are prominent at inflammation sites, and activation of these cells by stimulants such as lipopolysaccharide (LPS) leads to the production of significant amounts of MMP-9. Here, we show that LPS-induced MMP-9 production and activation was inhibited by the water extract from the fruit of Chaenomeles sinensis (CS), the root of Polygonum cuspidatum (PC), but increased by the extract from Boswellia carterii (BC). To investigate the mechanism by which those extracts inhibits MMP-9 activation, we examined the level of MMP-9 mRNA expression. We observed a significant change in the MMP-9 expression between LPS alone and LPS plus Chaenomeles sinensis and Polygonum cuspidatum extracts-treated cells. In addition, LPS significantly up-regulated MMP-9 promoter activity in Raw 264.7 cells, which was attenuated by the CS and PS extracts. However, water extracts from Boswellia carterii increased MMP-9 expression and MMP-9 promoter activity which were induced by LPS treatment in Raw 264.7 cells. These data suggest that water extracts from Chaenomeles sinensis and Polygonum cuspidatum can modulate anti-inflammatory immune response, which may be in part associated with the regulation of MMP-9 production and/or activation through the regulation of MMP-9 expression in mouse macrophage cells.

• Biomolecules & Therapeutics
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• v.27 no.6
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• pp.522-529
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• 2019

M1/M2 polarization of immune cells including microglia has been well characterized. It mediates detrimental or beneficial roles in neuroinflammatory disorders including cerebral ischemia. We have previously found that sphingosine 1-phospate receptor subtype 1 ($S1P_1$) in post-ischemic brain following transient middle cerebral artery occlusion (tMCAO) can trigger microglial activation, leading to brain damage. Although the link between $S1P_1$ and microglial activation as a pathogenesis in cerebral ischemia had been clearly demonstrated, whether the pathogenic role of $S1P_1$ is associated with its regulation of M1/M2 polarization remains unclear. Thus, this study aimed to determine whether $S1P_1$ was associated with regulation of M1/M2 polarization in post-ischemic brain. Suppressing $S1P_1$ activity with its functional antagonist, AUY954 (5 mg/kg, p.o.), attenuated mRNA upregulation of M1 polarization markers in post-ischemic brain at 1 day and 3 days after tMCAO challenge. Similarly, suppressing $S1P_1$ activity with AUY954 administration inhibited M1-polarizatioin-relevant $NF-{\kappa}B$ activation in post-ischemic brain. Particularly, $NF-{\kappa}B$ activation was observed in activated microglia of post-ischemic brain and markedly attenuated by AUY954, indicating that M1 polarization through $S1P_1$ in post-ischemic brain mainly occurred in activated microglia. Suppressing $S1P_1$ activity with AUY954 also increased mRNA expression levels of M2 polarization markers in post-ischemic brain, further indicating that $S1P_1$ could also influence M2 polarization in post-ischemic brain. Finally, suppressing $S1P_1$ activity decreased phosphorylation of M1-relevant ERK1/2, p38, and JNK MAPKs, but increased phosphorylation of M2-relevant Akt, all of which were downstream pathways following $S1P_1$ activation. Overall, these results revealed $S1P_1$-regulated M1/M2 polarization toward brain damage as a pathogenesis of cerebral ischemia.

• Journal of Life Science
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• v.32 no.2
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• pp.175-188
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• 2022

Relaxin has been demonstrated to have regulatory functions on both the smooth muscle and extracellular matrix (ECM) of blood vessels and fibrotic organs. The diverse mechanisms by which relaxin acts on small resistance arteries and fibrotic organs, including the bladder, are reviewed here. Relaxin induces vasodilation by inhibiting the contractility of vascular smooth muscles and by increasing the passive compliance of vessel walls through the reduction of ECM components, such as collagen. The primary cellular mechanism whereby relaxin induces arterial vasodilation is mediated by the endothelium-dependent production of nitric oxide (NO) through the activation of RXFP1/PI3K, Akt phosphorylation, and eNOS. In addition, relaxin triggers different alternative pathways to enhance the vasodilation of renal and mesenteric arteries. In small renal arteries, relaxin stimulates the activation of the endothelial MMPs and EtB receptors and the production of VEGF and PlGF to inhibit myogenic contractility and collagen deposition, thereby bringing about vasodilation. Conversely, in small mesenteric arteries, relaxin augments bradykinin (BK)-evoked relaxation in a time-dependent manner. Whereas the rapid enhancement of the BK-mediated relaxation is dependent on IK_Ca channels and subsequent EDH induction, the sustained relaxation due to BK depends on COX activation and PGI₂. The anti-fibrotic effects of relaxin are mediated by inhibiting the invasion of inflammatory immune cells, the endothelial-to-mesenchymal transition (EndMT), and the differentiation and activation of myofibroblasts. Relaxin also activates the NOS/NO/cGMP/PKG-1 pathways in myofibroblasts to suppress the TGF-β1-induced activation of ERK1/2 and Smad2/3 signaling and deposition of ECM collagen.

• Journal of Life Science
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• v.28 no.5
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• pp.621-626
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• 2018

We introduced the physiological responses of aging, active aging and also suggest the impact of physical exercise on body health status and elderly immunity. In this purpose, we searched the Pub Med data base for the articles (include our experimental papers) and review papers having the terms 'Aging', 'Active aging' and 'Physical activity and elderly' in the title, published from 1999 until 2018. The results were as follows: Exercise training has been extensively studied about the reduction of inflammation, oxidative stress, disease, and aging in syndrome X patients and elderly. Combined and aerobic or resistance exercise training could reduce obesity, insulin resistance, type 2 diabetes and hypertension. Exercise training has been extensively studied in cancer settings as part of prevention or treatment strategies. From this research, regular exercise has the potential to target tumor growth through regulation of inflammation and immune responses such as lactate clearance, NK cell activation (innate immunity), activation of cytotoxic immune cells, T cell activation (adaptive immunity), and immune surveillance. However, Endurance physical activity not only induces thermogenesis and diverse sports injuries but also elicits mobilization and functional enhancement of monocytes, neutrophils (which is caused by the cytokine changes such as TNF-alpha, IL-1) whereas it suppresses cell mediated immunity causing to increased susceptibility to inflammation and infections like cough and URTIs (upper respiratory track infections) in young and especially in elderly people. Therefore, Strategies to prevent physical fatigue, sports injuries include avoid overtraining, Adequate recovery and various type of rest during and after physical activity and assuring adequate nutrition supplementation such as glutamine, vitamin B, vitamin C, carbohydrate, ion or berry-contain sports beverages is helpful in physically active elderly.

• Journal of Life Science
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• v.23 no.11
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• pp.1397-1403
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• 2013

Fructus Sophorae, the dried ripe fruit of Styphnolobium japonicum (L.), is an herbal ingredient used in traditional Oriental medicine. This study was carried out to investigate the effects of Fructus Sophorae extracts (FSE) on immune modulation in a murine RAW 264.7 macrophage model. As immune response parameters, the production of prostaglandin $E_2$ ($PGE_2$) and tumor necrotic $factor-{\alpha}$ ($TNF-{\alpha}$) were evaluated. Our data revealed that FSE increased the macrophage activation and the production of $PGE_2$ and $TNF-{\alpha}$, which was consistently correlated with upregulation of cyclooxygenase-2 (COX-2) and $TNF-{\alpha}$ expression at both transcriptional and translational levels. On comparative cytokine protein array, FSE significantly increased several cytokines, which was associated with phosphorylation of mitogen- activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), p38 MAPK and c-Jun N-terminal kinase (JNK), and Akt in RAW 264.7 cells. However, each inhibitor of these molecules attenuated the FSE-induced $PGE_2$ production. These results indicate that FSE activated macrophages through the activation of MAPKs and phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathways in RAW 264.7 macrophages. These findings suggest that FSE may provide a promising source of an immunoenhancing agent.