• BMB Reports
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• v.48 no.5
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• pp.266-270
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• 2015

Over the last decade, comprehensive genome-wide sequencing studies have enabled us to find out unexpected genetic alterations of metabolism in cancer. An example is the identification of arginine missense mutations of isocitrate dehydrogenases-1 and -2 (IDH1/2) in glioma, acute myeloid leukemia (AML), chondrosarcomas, and cholangiocarcinoma. These alterations are closely associated with the production of a new stereospecific metabolite, (R)-2-hydroxyglutarate (R-2HG). A large number of follow-up studies have been performed to address the molecular mechanisms of IDH1/2 mutations underlying how these events contribute to malignant transformation. In the meanwhile, the development of selective mutant IDH1/2 chemical inhibitors is being actively pursued in the scientific community and pharmaceutical industry. The present review article briefly discusses the important findings that highlight the molecular mechanisms of IDH1/2 mutations in cancer and provides a current status for development of selective mutant IDH1/2 chemical inhibitors. [BMB Reports 2015; 48(5): 266-270]

• BMB Reports
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• v.52 no.6
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• pp.360-372
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• 2019

Macrophages play an essential role not only in mediating the first line of defense but also in maintaining tissue homeostasis. In response to extrinsic factors derived from a given tissue, macrophages activate different functional programs to produce polarized macrophage populations responsible for inducing inflammation against microbes, removing cellular debris, and tissue repair. However, accumulating evidence has revealed that macrophage polarization is pivotal in the pathophysiology of metabolic syndromes and cancer, as well as in infectious and autoimmune diseases. Recent advances in transcriptomic and metabolomic studies have highlighted the link between metabolic rewiring of macrophages and their functional plasticity. These findings imply that metabolic adaption to their surrounding microenvironment instructs activation of macrophages with functionally distinct phenotypes, which in turn probably leads to the pathogenesis of a wide spectrum of diseases. In this review, we have introduced emerging concepts in immunometabolism with focus on the impact on functional activation of macrophages. Furthermore, we have discussed the implication of macrophage plasticity on the pathogenesis of metabolic syndromes and cancer, and how the disease microenvironment manipulates macrophage metabolism with regard to the pathophysiology.

• 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.

• The Korean Journal of Physiology and Pharmacology
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• v.28 no.3
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• pp.183-196
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• 2024

Ferroptosis is a novel mechanism of programmed cell death, characterized by intracellular iron overload, intensified lipid peroxidation, and abnormal accumulation of reactive oxygen species, which ultimately resulting in cell membrane impairment and demise. Research has revealed that cancer cells exhibit a greater demand for iron compared to normal cells, indicating a potential susceptibility of cancer cells to ferroptosis. Stomach and colorectal cancers are common gastrointestinal malignancies, and their elevated occurrence and mortality rates render them a global health concern. Despite significant advancements in medical treatments, certain unfavorable consequences and drug resistance persist. Consequently, directing attention towards the phenomenon of ferroptosis in gastric and colorectal cancers holds promise for enhancing therapeutic efficacy. This review aims to elucidate the intricate cellular metabolism associated with ferroptosis, encompassing lipid and amino acid metabolism, as well as iron metabolic processes. Furthermore, the significance of ferroptosis in the context of gastric and colorectal cancer is thoroughly examined and discussed.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.5
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• pp.2027-2033
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• 2014

Background: We aimed to assess RET proto-oncogene polymorphisms in three different Iranian families with medullary thyroid cancer (MTC), and performed molecular dynamics simulations and free energy stability analysis of these mutations. Materials and Methods: This study consisted of 48 patients and their first-degree relatives with MTC confirmed by pathologic diagnosis and surgery. We performed molecular dynamics simulations and free energy stability analysis of mutations, and docking evaluation of known RET proto-oncogene inhibitors, including ZD-6474 and ponatinib, with wild-type and mutant forms. Results: The first family consisted of 27 people from four generations, in which nine had the C.G2901A (P.C634Y) mutation; the second family consisted of six people, of whom three had the C.G2901T (P.C634F) mutation, and the third family, who included 12 individuals from three generations, three having the C.G2251A (P.G691S) mutation. The automated 3D structure of RET protein was predicted using I-TASSER, and validated by various protein model verification programs that showed more than 96.3% of the residues in favored and allowed regions. The predicted instability indices of the mutated structures were greater than 40, which reveals that mutated RET protein is less thermo-stable compared to the wild-type form (35.4). Conclusions: Simultaneous study of the cancer mutations using both in silico and medical genetic procedures, as well as onco-protein inhibitor binding considering mutation-induced drug resistance, may help in better overcoming chemotherapy resistance and designing innovative drugs.

• Endocrinology and Metabolism
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• v.33 no.4
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• pp.459-465
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• 2018

Background: Differentiated thyroid carcinoma (DTC) shows a very good prognosis, but older patients have a higher recurrence rate and those show poor prognosis than younger patients. The aim of this study was to determine the clinical outcomes of thyroid cancer patients who experienced recurrence in old age according to the treatment strategy used. Methods: This retrospective observational cohort study was conducted at Asan Medical Center, Seoul, Korea. Among DTC patients with no evidence of disease after initial treatment, we enrolled 86 patients who experienced recurrence at an age >65 years from 1994 to 2012. Sixty-nine patients had local recurrence and 17 patients showed distant metastasis. Results: The mean age of patients at recurrence was 72 years. Patients were followed up for a median of 4.1 years after recurrence. Sixty-three of the 69 patients with local recurrence received additional treatment, while the other six received conservative care. The cancer-specific mortality rate was 15.5% in the local recurrence group. Airway problems were the main cause of death in patients who did not receive further treatment for local recurrence. Among the 17 patients with distant metastasis, 10 underwent specific treatment for metastasis and seven received only supportive management. Seven of those 17 patients died, and the cancer-specific mortality rate was 35% in the distant metastasis group. Conclusion: The overall cancer-specific mortality rate was 20% in DTC patients in whom recurrence was first detected at an age >65 years. Mortality due to uncontrolled local disease occurred frequently in patients who did not receive definitive management for recurrence.

• Journal of Gastric Cancer
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• v.21 no.1
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• pp.103-109
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• 2021

Gastric adenocarcinoma of the fundic gland mucosa type (GA-FGM) was proposed as a new variant of gastric adenocarcinoma of the fundic gland type (GA-FG). However, at present, the influence of Helicobacter pylori and the speed of progression and degree of malignancy in GA-FGM remain unclear. Herein, we report the first case of intramucosal GA-FGM that was endoscopically observed before and after H. pylori eradication over 15 years. The lesion showed the same tumor size with no submucosal invasion and a low MIB-1 labeling index 15 years after its detection using endoscopy. The endoscopic morphology changed from 0-IIa before H. pylori eradication to 0-IIa+IIc and then 0-I after H. pylori eradication. These findings suggest that the unaltered tumor size reflects low-grade malignancy and slow growth, and that the endoscopic morphology is influenced by H. pylori eradication.

• Journal of Preventive Medicine and Public Health
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• v.42 no.6
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• pp.360-370
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• 2009

Genetic factors clearly play a role in carcinogenesis, but migrant studies provide unequivocal evidence that environmental factors are critical in defining cancer risk. Therefore, one may expect that the lower availability of substrate for biochemical reactions leads to more genetic changes in enzyme function; for example, most studies have indicated the variant MTHFR genotype 677TT is related to biomarkers, such as homocysteine concentrations or global DNA methylation particularly in a low folate diet. The modification of a phenotype related to a genotype, particularly by dietary habits, could support the notion that some of inconsistencies in findings from molecular epidemiologic studies could be due to differences in the populations studied and unaccounted underlying characteristics mediating the relationship between genetic polymorphisms and the actual phenotypes. Given the evidence that diet can modify cancer risk, gene-diet interactions in cancer etiology would be anticipated. However, much of the evidence in this area comes from observational epidemiology, which limits the causal inference. Thus, the investigation of these interactions is essential to gain a full understanding of the impact of genetic variation on health outcomes. This report reviews current approaches to gene-diet interactions in epidemiological studies. Characteristics of gene and dietary factors are divided into four categories: one carbon metabolism-related gene polymorphisms and dietary factors including folate, vitamin B group and methionines; oxidative stress-related gene polymorphisms and antioxidant nutrients including vegetable and fruit intake; carcinogen-metabolizing gene polymorphisms and meat intake including heterocyclic amins and polycyclic aromatic hydrocarbon; and other gene-diet interactive effect on cancer.

• Journal of Applied Biological Chemistry
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• v.65 no.4
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• pp.387-396
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• 2022

Skeletal muscle accounts for about 40-50% of body weight and is an important tissue that performs various functions, such as maintaining posture, supporting soft tissues, maintaining body temperature, and respiration. Cancer, which occurs widely around the world, causes cancer cachexia accompanied by muscular atrophy, which reduces the effectiveness of anticancer drugs and greatly reduces the quality of life and survival rate of cancer patients. Therefore, research to improve cancer cachexia is ongoing. However, there are few studies on the link between cancer and muscle atrophy. Cancer cells exhibit distinct microenvironment and metabolism from tumor cells, including tumor-associated macrophages (TAM), tumor-associated neutrophils (TAN), and insulin resistance due to the Warburg effect. Therefore, we summarize the microenvironment and metabolic characteristics of cancer cells, and the molecular mechanisms of muscle atrophy that can be affected by cytokine and insulin resistance. In addition, this suggests the possibility of improving cancer cachexia of substances affecting TAM, TAN, and Warburg effect. We also summarize the mechanisms identified so far through single agents and the signaling pathways mediated by them that may ameliorate cancer cachexia.

• Proceedings of the Korean Society of Toxicology Conference
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• 2001.10a
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• pp.33-34
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• 2001

Cancer chemoprevention Chemoprevention with strategies using food phytochemicals is currently regarded ascompose one of the noticeable most visible and promising scientific fields for cancer control. A large body of data from both epidemiologic and rodent studies has demonstrated that the ingestion of various vegetables and fruits is occasionally beneficial for cancer risk reduction of cancer risks in humans.(omitted)