• 대한의생명과학회지
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• 제26권4호
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• pp.256-266
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• 2020

Carboxypeptidase D (CPD) is a zinc-dependent protease, which is highly expressed in macrophages, and is thought to participate in inflammatory processes. In the present study, we investigated the possible regulatory effect of all-trans retinoic acid (ATRA), which is an active form of vitamin A and plays a critical regulatory role in both the innate and adaptive immunity, on CPD expression and secretion in human monocytic THP-1 cells. CPD mRNA expression first increased, from a concentration as low as 10 nM ATRA to a maximum level of expression, at 1 μM. ATRA enhanced intracellular CPD expression in a time- and concentration-dependent manner but did not affect cell surface CPD expression. Interestingly, 9-cis-RA did not affect CPD expression. Additionally, an experiment with RAR/RXR selective agonist or antagonists demonstrated that ATRA-induced enhancement of CPD expression was RAR/RXR dependent. ATRA also enhanced CPD secretion from THP-1 cells; however, this enhancement was RAR/RXR-independent. The anti-inflammatory agent dexamethasone reversed ATRA-induced enhancement of CPD expression and secretion. Our results suggest ATRA exerts regulatory effects on expression and secretion of CPD in human monocytes, and ATRA-induced CPD secretion may be associated with inflammatory response.

• Biomolecules & Therapeutics
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• 제29권4호
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• pp.353-364
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• 2021

The gastrointestinal (GI) tract is a series of hollow organs that is responsible for the digestion and absorption of ingested foods and the excretion of waste. Any changes in the GI tract can lead to GI disorders. GI disorders are highly prevalent in the population and account for substantial morbidity, mortality, and healthcare utilization. GI disorders can be functional, or organic with structural changes. Functional GI disorders include functional dyspepsia and irritable bowel syndrome. Organic GI disorders include inflammation of the GI tract due to chronic infection, drugs, trauma, and other causes. Recent studies have highlighted a new explanatory mechanism for GI disorders. It has been suggested that autophagy, an intracellular homeostatic mechanism, also plays an important role in the pathogenesis of GI disorders. Autophagy has three primary forms: macroautophagy, microautophagy, and chaperone-mediated autophagy. It may affect intestinal homeostasis, host defense against intestinal pathogens, regulation of the gut microbiota, and innate and adaptive immunity. Drugs targeting autophagy could, therefore, have therapeutic potential for treating GI disorders. In this review, we provide an overview of current understanding regarding the evidence for autophagy in GI diseases and updates on potential treatments, including drugs and complementary and alternative medicines.

• IMMUNE NETWORK
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• 제23권1호
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• pp.5.1-5.28
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• 2023

Th cell lineage determination and functional specialization are tightly linked to the activation of lineage-determining transcription factors (TFs) that bind cis-regulatory elements. These lineage-determining TFs act in concert with multiple layers of transcriptional regulators to alter the epigenetic landscape, including DNA methylation, histone modification and threedimensional chromosome architecture, in order to facilitate the specific Th gene expression programs that allow for phenotypic diversification. Accumulating evidence indicates that Th cell differentiation is not as rigid as classically held; rather, extensive phenotypic plasticity is an inherent feature of T cell lineages. Recent studies have begun to uncover the epigenetic programs that mechanistically govern T cell subset specification and immunological memory. Advances in next generation sequencing technologies have allowed global transcriptomic and epigenomic interrogation of CD4+ Th cells that extends previous findings focusing on individual loci. In this review, we provide an overview of recent genome-wide insights into the transcriptional and epigenetic regulation of CD4+ T cell-mediated adaptive immunity and discuss the implications for disease as well as immunotherapies.

• IMMUNE NETWORK
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• 제19권1호
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• pp.2.1-2.13
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• 2019

The enhanced differentiation and activation of osteoclasts (OCs) in the inflammatory arthritis such as rheumatoid arthritis (RA) and gout causes not only local bone erosion, but also systemic osteoporosis, leading to functional disabilities and morbidity. The induction and amplification of NFATc1, a master regulator of OC differentiation, is mainly regulated by receptor activator of NF-κB (RANK) ligand-RANK and calcium signaling which are amplified in the inflammatory milieu, as well as by inflammatory cytokines such as TNFα, IL-1β and IL-6. Moreover, the predominance of CD4⁺ T cell subsets, which varies depending on the condition of inflammatory diseases, can determine the fate of OC differentiation. Anti-citrullinated peptide antibodies which are critical in the pathogenesis of RA can bind to the citrullinated vimentin on the surface of OC precursors, and in turn promote OC differentiation and function via IL-8. In addition to adaptive immunity, the activation of innate immune system including the nucleotide oligomerization domain leucine rich repeat with a pyrin domain 3 inflammasome and TLRs can regulate OC maturation. The emerging perspectives about the diverse and close interactions between the immune cells and OCs in inflammatory milieu can have a significant impact on the future direction of drug development.

• Safety and Health at Work
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• 제8권2호
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• pp.198-205
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• 2017

Background: There are a million ragpickers in India who gather and trade recyclable municipal solid wastes materials for a living. The objective of this study was to examine whether their occupation adversely affects their immunity. Methods: Seventy-four women ragpickers (median age, 30 years) and 65 age-matched control housemaids were enrolled. Flow cytometry was used to measure leukocyte subsets, and leukocyte expressions of $Fc{\gamma}$ receptor I (CD64), $Fc{\gamma}RIII$ (CD16), complement receptor 1 (CD35) and CR3 (CD11b/CD18), and CD14. Serum total immunoglobulin-E was estimated with enzyme-linked immunosorbent assay. Results: Compared with the controls, ragpickers had significantly (p < 0.0001) higher levels of CD8-T-cytotoxic, CD16+CD56+natural killer, and CD4+CD45RO+memory T-cells, but depleted levels of CD19+B-cells. The percentage of CD4+T-helper-cells was lower than the control group (p < 0.0001), but their absolute number was relatively unchanged (p = 0.42) due to 11% higher lymphocyte counts in ragpickers. In ragpickers, the percentages of CD14+CD16+intermediate and CD14dim CD16+nonclassical monocyte subsets were elevated with a decline in CD14+CD16-classical monocytes. The expressions of CD64, CD16, CD35, and CD11b/CD18 on both monocytes and neutrophils, and CD14 on monocytes were significantly higher in ragpickers. In addition, ragpickers had 2.7-times more serum immunoglobulin-E than the controls (p < 0.0001). After controlling potential confounders, the profession of ragpicking was positively associated with the changes. Conclusion: Ragpicking is associated with alterations in both innate (neutrophils, monocytes, and natural killer cell numbers and expression of complement and $Fc{\gamma}$ receptors) and adaptive immunity (numbers of circulating B cells, helper, cytotoxic, and memory T cells).

• Journal of Microbiology and Biotechnology
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• 제26권12호
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• pp.2214-2223
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• 2016

Toll-like receptors (TLRs) can recognize conserved molecular patterns and initiate a wide range of innate and adaptive immune responses against invading infectious agents. The aim of this study was to assess the transcript profile of mink TLRs (mTLRs) in mink peripheral blood mononuclear cells (PBMCs) and a range of tissues, and to explore the potential role of mTLRs in the antiviral immune response process. The results indicated that the mTLR partial nucleotide sequences had a high degree of nucleotide identity with ferret sequences (95-98%). Phylogenetic analysis showed that mammalian TLRs grouped into five TLR families, with a closer relationship of the mTLRs with those of ferret than the other mammalian sequences. Moreover, all the mTLRs were ubiquitously expressed in lymphoid organs (spleen and lymph nodes) and PBMCs. Interestingly, the mTLR expression patterns in lung, uterus, and heart showed quite a lot of similarity. Another remarkable observation was the wide expression of mTLR1-3 mRNAs in all tissues. Among the analyzed tissues, skeletal muscle was revealed to being the lowest repertoire of mTLR expression. Additionally, mink PBMCs exposed to the canine distemper virus revealed significant upregulation of mTLR2, mTLR4, mTLR7, and mTLR8 mRNAs, indicating that mTLRs have a role in innate immunity in the mink. Collectively, our results are the first to establish the basic expression patterns of mTLRs and the relationship between mTLRs and a virus, which will contribute to better understanding of the evolution and the functions of mTLRs in the innate immune system in minks.

• 대한한방내과학회지
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• 제39권6호
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• pp.1244-1255
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• 2018

Objectives: The purpose of this study is to determine the stimulatory effects of herbal medicines extracts on cytokines release of immune response in immune cells, RAW 264.7 and TK-1 cell. Methods: In a total of 18 extracts, 9 water extracts and 9 ethanol extracts, of herbal medicines, the quantities of polyphenolic compounds were measured and anti-oxidation activities were determined by colorimetric assay. The herbal medicine extracts were treated on RAW 264.7 and TK-1, respectively, and then the releasing changes of tumor necrosis factor-${\alpha}$ ($TNF-{\alpha}$), interleukin-6, and interleukin-10 from both immune cells were determined by the enzyme-linked immunosorbent assay. Results: The polyphenol contents were measured to be 1.56~0.64 mg/g of solids in the two types of extracts with 9 kinds of herbal medicines, while antioxidant activities were found to be 95.62~31.46% as compared with ascorbic acid control. In RAW 264.7 cells treated with herbal medicines extracts, the secretion of $TNF-{\alpha}$ increased to 1.31~1.18 fold, and the amounts of IL-6 were 68.4~97.9% compared with the control group treated with LPS alone. In particular, the secretion amount of anti-inflammatory cytokine IL-10 was suppressed by treatment using herbal medicine extracts. In the case of TK-1 cells, $TNF-{\alpha}$ secretion was suppressed according to the concentrations of herbal extract. The released amounts of IL-10 were shown at 10~40 pg/ml, and increased in a dose-dependent manner. Conclusions: Herbal medicines extracts act on macrophages inducing the secretion of inflammatory cytokine, thereby enhancing the activity of innate immunity. When acting on T cells involved in adaptive immunity, the secretion of anti-inflammatory cytokine is increased to induce the inhibition of the innate immune response.

• 한국식품과학회지
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• 제39권5호
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• pp.481-487
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• 2007

Toll-like receptors (TLRs) induce innate immune responses that are essential for host defenses against invading microbial pathogens, thus leading to the activation of adaptive immune responses. In general, TLRs have two major downstream signaling pathways: the MyD88- and TRIF-dependent pathways, which lead to the activation of $NF-{\kappa}B$ and IRF3. Numerous studies have demonstrated that certain phytochemicals possessing anti-inflammatory effects inhibit $NF-{\kappa}B$ activation induced by pro-inflammatory stimuli, including lipopolysaccharides and $TNF{\alpha}$. However, the direct molecular targets for such anti-inflammatory phytochemicals have not been fully identified. Identifying the direct targets of phytochemicals within the TLR pathways is important because the activation of TLRs by pro-inflammatory stimuli can induce inflammatory responses that are the key etiological conditions in the development of many chronic inflammatory diseases. In this paper we discuss the molecular targets of resveratrol, (-)-epigallocatechin-3-gallate (EGCG), and curcumin in the TLR signaling pathways. Resveratrol specifically inhibited the TRIF pathway in TLR3 and TLR4 signaling, by targetting TBK1 and RIP1 in the TRIF complex. Furthermore, EGCG suppressed the activation of IRF3 by targetting TBK1 in the TRIF-dependent signaling pathways. In contrast, the molecular target of curcumin within the TLR signaling pathways is the receptor itself, in addition to $IKK{\beta}$. Together, certain dietary phytochemicals can modulate TLR-derived signaling and inflammatory target gene expression, and in turn, alter susceptibility to microbial infection and chronic inflammatory diseases.

• Journal of Preventive Medicine and Public Health
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• 제50권4호
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• pp.278-281
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• 2017

Since 2006, type 1 diabetes in Finland has plateaued and then decreased after the authorities' decision to fortify dietary milk products with cholecalciferol. The role of vitamin D in innate and adaptive immunity is critical. A statistical error in the estimation of the recommended dietary allowance (RDA) for vitamin D was recently discovered; in a correct analysis of the data used by the Institute of Medicine, it was found that 8895 IU/d was needed for 97.5% of individuals to achieve values ${\geq}50nmol/L$. Another study confirmed that 6201 IU/d was needed to achieve 75 nmol/L and 9122 IU/d was needed to reach 100 nmol/L. The largest meta-analysis ever conducted of studies published between 1966 and 2013 showed that 25-hydroxyvitamin D levels <75 nmol/L may be too low for safety and associated with higher all-cause mortality, demolishing the previously presumed U-shape curve of mortality associated with vitamin D levels. Since all-disease mortality is reduced to 1.0 with serum vitamin D levels ${\geq}100nmol/L$, we call public health authorities to consider designating as the RDA at least three-fourths of the levels proposed by the Endocrine Society Expert Committee as safe upper tolerable daily intake doses. This could lead to a recommendation of 1000 IU for children <1 year on enriched formula and 1500 IU for breastfed children older than 6 months, 3000 IU for children >1 year of age, and around 8000 IU for young adults and thereafter. Actions are urgently needed to protect the global population from vitamin D deficiency.

• Reproductive and Developmental Biology
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• 제39권4호
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• pp.105-115
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• 2015

Toll-like receptor 7 (TLR7) is critical for the triggering of innate immune response by recognizing the conserved molecular patterns of single-stranded RNA (ssRNA) viruses and mediated antigenic adaptive immunity. To understand how TLR7 distinguish pathogen-derived molecular patterns from the host self, it is essential to be able to identify TLR7 receptor interaction interfaces, such as active sites or R848-agonist binding sites. The functional interfaces of TLR7 can serve as targets for structure-based drug design in studying the TLR7 receptor's structure-function relationship. In contrast to mammalian TLR7, chicken TLR7 (chTLR7) is unknown for its important biological function. Therefore, it has been targeted to mediate contrasting evolutionary patterns of positive selection into non-synonymous SNPs across eleven species using TLR7 conservation patterns (evolutionary conserved and class-specific trace residues), where protein sequence differences to the TLR7 receptors of interest record mutation that have passed positive section across the species. In this study, we characterized the Lys609 residue on chTLR7-ECD homodimer interfaces to reflect the current tendency of evolving positive selection to be transfer into a stabilization direction of the R848-agonist/chTLR7-ECDs complex under the phylogenetically variable position across species and we suggest a potential indicator for contrasting evolutionary patterns of both the species TLR-ECDs.