• Biomolecules & Therapeutics
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• 제26권1호
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• pp.4-9
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• 2018

Cancer metabolism as a field of research was founded almost 100 years ago by Otto Warburg, who described the propensity for cancers to convert glucose to lactate despite the presence of oxygen, which in yeast diminishes glycolytic metabolism known as the Pasteur effect. In the past 20 years, the resurgence of interest in cancer metabolism provided significant insights into processes involved in maintenance metabolism of non-proliferating cells and proliferative metabolism, which is regulated by proto-oncogenes and tumor suppressors in normal proliferating cells. In cancer cells, depending on the driving oncogenic event, metabolism is re-wired for nutrient import, redox homeostasis, protein quality control, and biosynthesis to support cell growth and division. In general, resting cells rely on oxidative metabolism, while proliferating cells rewire metabolism toward glycolysis, which favors many biosynthetic pathways for proliferation. Oncogenes such as MYC, BRAF, KRAS, and PI3K have been documented to rewire metabolism in favor of proliferation. These cell intrinsic mechanisms, however, are insufficient to drive tumorigenesis because immune surveillance continuously seeks to destroy neo-antigenic tumor cells. In this regard, evasion of cancer cells from immunity involves checkpoints that blunt cytotoxic T cells, which are also attenuated by the metabolic tumor microenvironment, which is rich in immuno-modulating metabolites such as lactate, 2-hydroxyglutarate, kynurenine, and the proton (low pH). As such, a full understanding of tumor metabolism requires an appreciation of the convergence of cancer cell intrinsic metabolism and that of the tumor microenvironment including stromal and immune cells.

• 한국수산과학회지
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• 제49권5호
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• pp.594-599
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• 2016

Infection with HIV (Human immunodeficiency virus), over time, develops into acquired immunodeficiency syndrome (AIDS). The development of non-toxic and effective anti-HIV drugs is one of the most promising strategies for the treatment of AIDS. In this study, we investigated the anti-HIV-1 activity of gelatin hydrolysates from Alaska pollack skin. Gelatin hydrolysates were prepared using four enzymes (alcalase, flavourzyme, neutrase, and pronase E). Among these, the pronase E gelatin hydrolysate was found to inhibit HIV-1 infection in the human T cell-line MT4. It exhibited inhibitory activity on HIV-1_IIIB-induced cell lysis, reverse transcriptase activity, and viral p24 production at noncytotoxic concentrations. Moreover, it decreased the activation of matrix metalloproteinase-2 (MMP-2) in vitro. Because HIV infection-induced activation of MMP-2 can accelerate collagen resolution and collapse of the immune system, pronase E gelatin hydrolysate might prevent the activation of MMP-2 in cells, resulting in collagen stabilization and immune cell homeostasis consistent with anti-HIV activation. These results suggest that pronase E gelatin hydrolysate could potentially be incorporated into a novel therapeutic agent for HIV/AIDS patients.

• Molecules and Cells
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• 제26권4호
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• pp.323-328
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• 2008

Eukaryotic cells continuously integrate intrinsic and extrinsic signals to adapt to the environment. When exposed to stressful conditions, cells activate compartment-specific adaptive responses. If these are insufficient, apoptosis ensues as an organismal defense line. The mechanisms that sense stress and set the transition from adaptive to maladaptive responses, activating apoptotic programs, are the subject of intense studies, also for their potential impact in cancer and degenerative disorders. In the former case, one would aim at lowering the threshold, in the latter instead to increase it. Protein synthesis, consuming energy for anabolic processes as well as for byproducts disposal, can be a significant source of stress, particularly when difficult-to-fold proteins are produced. Recent work from our and other laboratories on the differentiation of antibody secreting cells, revealed a regulatory circuit that integrates protein synthesis, secretion and degradation (proteostasis), into cell lifespan determination. The apoptotic elimination - after an industrious, yet short lifetime - of terminal immune effectors is crucial to maintain immune homeostasis. Linking proteostasis to cell death, this paradigm might prove useful for biotechnological purposes, and the design of novel anti-cancer therapies.

• BMB Reports
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• 제56권8호
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• pp.417-425
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• 2023

In various organisms, the Hippo signaling pathway has been identified as a master regulator of organ size determination and tissue homeostasis. The Hippo signaling coordinates embryonic development, tissue regeneration and differentiation, through regulating cell proliferation and survival. The YAP and TAZ (YAP/TAZ) act as core transducers of the Hippo pathway, and they are tightly and exquisitely regulated in response to various intrinsic and extrinsic stimuli. Abnormal regulation or genetic variation of the Hippo pathway causes a wide range of human diseases, including cancer. Recent studies have revealed that Hippo signaling plays a pivotal role in the immune system and cancer immunity. Due to pathophysiological importance, the emerging role of Hippo signaling in blood cell differentiation, known as hematopoiesis, is receiving much attention. A number of elegant studies using a genetically engineered mouse (GEM) model have shed light on the mechanistic and physiological insights into the Hippo pathway in the regulation of hematopoiesis. Here, we briefly review the function of Hippo signaling in the regulation of hematopoiesis and immune cell differentiation.

• IMMUNE NETWORK
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• 제22권3호
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• pp.28.1-28.11
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• 2022

The 26S proteasome irreversibly hydrolyzes polyubiquitylated substrates to maintain protein homeostasis; it also regulates immune responses by generating antigenic peptides. An alternative form of the 26S proteasome is the immunoproteasome, which contains substituted catalytic subunits (β1i/PSMB9, β2i/PSMB10, and β5i/PSMB8) instead of constitutively expressed counterparts (β1/PSMB6, β2/PSMB7, and β5/PSMB5). The immunoproteasome expands the peptide repertoire presented on MHC class I molecules. However, how its activity changes in this context is largely elusive, possibly due to the lack of a standardized methodology to evaluate its specific activity. Here, we describe an assay protocol that measures the immunoproteasome activity of whole-cell lysates using commercially available fluorogenic peptide substrates. Our results showed that the most accurate assessment of immunoproteasome activity could be achieved by combining β5i-targeting substrate Ac-ANW-AMC and immunoproteasome inhibitor ONX-0914. This simple and reliable protocol may contribute to future studies of immunoproteasomes and their pathophysiological roles during viral infection, inflammation, and tumorigenesis.

• IMMUNE NETWORK
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• 제16권5호
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• pp.281-285
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• 2016

CD4⁺ regulatory T cells (Tregs) are essential for normal immune surveillance, and their dysfunction can lead to the development of autoimmune diseases, such as type-1 diabetes (T1D). T1D is a T cell-mediated autoimmune disease characterized by islet b cell destruction, hypoinsulinemia, and severely altered glucose homeostasis. Tregs play a critical role in the development of T1D and participate in peripheral tolerance. Pluripotent stem cells (PSCs) can be utilized to obtain a renewable source of healthy Tregs to treat T1D as they have the ability to produce almost all cell types in the body, including Tregs. However, the right conditions for the development of antigen (Ag)-specific Tregs from PSCs (i.e., PSC-Tregs) remain undefined, especially molecular mechanisms that direct differentiation of such Tregs. Auto Ag-specific PSC-Tregs can be programmed to be tissue-associated and infiltrate to local inflamed tissue (e.g., islets) to suppress autoimmune responses after adoptive transfer, thereby avoiding potential overall immunosuppression from non-specific Tregs. Developing auto Ag-specific PSC-Tregs can reduce overall immunosuppression after adoptive transfer by accumulating inflamed islets, which drives forward the use of therapeutic PSC-Tregs for cell-based therapies in T1D.

• IMMUNE NETWORK
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• 제16권2호
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• pp.85-98
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• 2016

The mitogen-activated protein kinases (MAPKs) are key regulators of cell growth and survival in physiological and pathological processes. Aberrant MAPK signaling plays a critical role in the development and progression of human cancer, as well as in determining responses to cancer treatment. The MAPK phosphatases (MKPs), also known as dual-specificity phosphatases (DUSPs), are a family of proteins that function as major negative regulators of MAPK activities in mammalian cells. Studies using mice deficient in specific MKPs including MKP1/DUSP1, PAC-1/DUSP2, MKP2/DUSP4, MKP5/DUSP10 and MKP7/DUSP16 demonstrated that these molecules are important not only for both innate and adaptive immune responses, but also for metabolic homeostasis. In addition, the consequences of the gain or loss of function of the MKPs in normal and malignant tissues have highlighted the importance of these phosphatases in the pathogenesis of cancers. The involvement of the MKPs in resistance to cancer therapy has also gained prominence, making the MKPs a potential target for anti-cancer therapy. This review will summarize the current knowledge of the MKPs in cancer development, progression and treatment outcomes.

• 한국축산식품학회지
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• 제34권5호
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• pp.630-637
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• 2014

We previously demonstrated that water-soluble egg yolk extract is not related to elevation of serum immunoglobulin E, which can initiate allergic reactions; however, it increases the level of high density lipoprotein (HDL)-cholesterol and the activity of B lymphocytes. In this study, egg white (EW) was fed to BALB/c mice to determine its influence on growth efficiency, immune modulation, and changes in serum lipid levels. A total of 50 five-wk-old BALB/c male mice were divided into 5 groups, 4 of which were fed 0, 10, 50, or 100 mg/d EW for 4 wk. Mice with an uptake of 10, 50 and 100 mg/d EW showed no significant changes in daily weight gain, feed efficiency rate, or populations of white blood cells. However, the activities of both B and T lymphocytes were significantly increased in all three EW groups at the final week of treatment. Interestingly, serum levels immunoglobulin E were not altered by EW consumption, but the IgG level was significantly increased in the 100 mg/d EW group. Serum lipid profile analyses showed no significant changes in total cholesterol, HDL, low density lipoprotein, or triglyceride levels by EW consumption. Taken together, these data demonstrate that consumption of EW promotes immune cell activities and the upregulation of serum IgG levels. However, we found no changes in serum lipid profiles and IgE levels. Therefore, our study suggests that consumption of EW might not be related to the risk of food allergy, but could be an excellent candidate for the maintenance of physiological homeostasis.

• IMMUNE NETWORK
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• 제2권2호
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• pp.109-114
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• 2002

Background: To investigate the role of sympathetic nervous system (SNS) in moxibustion-induced immunomodulation, the effects of chemical sympathectomy on moxibustion-induced changes in splenic NK cell cytotoxicity, T and B cell proliferation were studied in Sprague-Dawley male rats. Methods: Chemical sympathectomy was achieved with intraperitoneal injection of 6-hydroxydopamine 50 mg/kg/day for 3 successive days. Direct moxibustion (6-minute interval, 9 moxa ball, each of which weighing 0.007 g and burning for 40 seconds) was applied on unilateral anterior tibial muscle region where Zusanli (ST36) acupoint is located, once a day for 7 successive days. NK cell cytotoxicity was measured by $4hr-^{51}Cr$ release assay. Mitogen-induced lymphocyte proliferation was analyzed by [$^3H$]-thymidine incorporation assay. Results: NK cell cytotoxicity was suppressed by moxibustion, more in sympathectomized rats than in vehicle-treated rats. T cell proliferation induced by concanavalin A was not affected by moxibustion. B cell proliferation induced by lipopolysaccharide showed no significant change in vehicle-treated rats, but an increase in sympathectomized rats by moxibustion. Sympathectomy alone induced augmentation of NK cell cytotoxicity and suppression of T cell proliferation. Conclusion: These results suggest that SNS has no direct relation with moxibution-induced immunomodulation but has an important role in the mechanism to keep the homeostasis of immune system by tonically inhibiting excessive changes of various immune components.

• Molecules and Cells
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• 제43권3호
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• pp.251-263
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• 2020

Flagellin, a major structural protein of the flagellum found in all motile bacteria, activates the TLR5- or NLRC4 inflammasome-dependent signaling pathway to induce innate immune responses. Flagellin can also serve as a specific antigen for the adaptive immune system and stimulate anti-flagellin antibody responses. Failure to recognize commensal-derived flagellin in TLR5-deficient mice leads to the reduction in anti-flagellin IgA antibodies at steady state and causes microbial dysbiosis and mucosal barrier breach by flagellated bacteria to promote chronic intestinal inflammation. Despite the important role of anti-flagellin antibodies in maintaining the intestinal homeostasis, regulatory mechanisms underlying the flagellin-specific antibody responses are not well understood. In this study, we show that flagellin induces interferon-β (IFN-β) production and subsequently activates type I IFN receptor signaling in a TLR5- and MyD88-dependent manner in vitro and in vivo. Internalization of TLR5 from the plasma membrane to the acidic environment of endolysosomes was required for the production of IFN-β, but not for other pro-inflammatory cytokines. In addition, we found that anti-flagellin IgG2c and IgA responses were severely impaired in interferon-alpha receptor 1 (IFNAR1)-deficient mice, suggesting that IFN-β produced by the flagellin stimulation regulates anti-flagellin antibody class switching. Our findings shed a new light on the regulation of flagellin-mediated immune activation and may help find new strategies to promote the intestinal health and develop mucosal vaccines.