• Molecules and Cells
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• 제42권4호
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• pp.292-300
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• 2019

Immunometabolism, defined as the interaction of metabolic pathways with the immune system, influences the pathogenesis of metabolic diseases. Metformin and carbon monoxide (CO) are two pharmacological agents known to ameliorate metabolic disorders. There are notable similarities and differences in the reported effects of metformin and CO on immunometabolism. Metformin, an anti-diabetes drug, has positive effects on metabolism and can exert anti-inflammatory and anti-cancer effects via adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. CO, an endogenous product of heme oxygenase-1 (HO-1), can exert anti-inflammatory and antioxidant effects at low concentration. CO can confer cytoprotection in metabolic disorders and cancer via selective activation of the protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) pathway. Both metformin and CO can induce mitochondrial stress to produce a mild elevation of mitochondrial ROS (mtROS) by distinct mechanisms. Metformin inhibits complex I of the mitochondrial electron transport chain (ETC), while CO inhibits ETC complex IV. Both metformin and CO can differentially induce several protein factors, including fibroblast growth factor 21 (FGF21) and sestrin2 (SESN2), which maintain metabolic homeostasis; nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant response; and REDD1, which exhibits an anticancer effect. However, metformin and CO regulate these effects via different pathways. Metformin stimulates p53- and AMPK-dependent pathways whereas CO can selectively trigger the PERK-dependent signaling pathway. Although further studies are needed to identify the mechanistic differences between metformin and CO, pharmacological application of these agents may represent useful strategies to ameliorate metabolic diseases associated with altered immunometabolism.

• 대한수의학회지
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• 제62권3호
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• pp.20.1-20.8
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• 2022

5-Fluorouracil, doxorubicin, and vincristine are chemotherapy agents used to treat various cancers, such as breast cancer and lymphoma for decades, and their effects on cancer have been proven. On the other hand, these anti-cancer drugs cause fatal side effects, including immunosuppression. This study investigated whether sonicated Bordetella bronchiseptica bacterin (B. bronchiseptica) can attenuate the immunosuppression of spleen cells induced by these chemotherapy agents and which subsets of spleen cells were affected. B. bronchiseptica increased the metabolic activity of spleen cells treated with 3 anti-cancer drugs. Cell death analysis using Annexin V/propidium iodide showed that B. bronchiseptica markedly decreased the death of spleen cells. The subsets of spleen cells were analyzed by flow cytometry using a surface marker-specific antibody. B. bronchiseptica increased nitric oxide production in the spleen cells treated with anti-cancer drugs (p < 0.0001). Despite the pharmacological effects of anti-cancer drugs, many patients suffer from the fatal side effects of immunosuppression. This study provides valuable information on how to overcome chemotherapy-induced immunosuppression.

• 생명과학회지
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• 제34권10호
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• pp.744-754
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• 2024

암세포는 통제되지 않는 세포분열 과정 중, 생체 에너지와 생합성 중간체를 제공하기 위하여 정상세포와는 현저히 다른 독특한 대사과정을 나타낸다. 포도당으로부터 생성된 pyruvate의 대부분을 lactate로 전환하여 비효율적으로 ATP 생성하는 호기적 해당작용(Warburg effect)으로 glutamine 대사를 통해 부족한 에너지를 해결하고 있다. Glutamine은 혈액과 근육에서 가장 풍부한 아미노산으로서, glutaminolysis를 통해 TCA cycle을 통한 생체 에너지, 지질과 대사산물의 합성뿐만 아니라 아미노산과 뉴클레오티드 합성에 사용된다. 암세포가 정상세포보다 glutamine에 의존하여 TCA cycle 대사산물의 절반 이상이 glutamine에서 파생되는 glutamine 중독 현상을 나타낸다. 종양유전자 c-Myc는 glutamine 대사에 관련된 glutamine 대사 유전자의 발현을 조절하고, glutamine의 흡수를 촉진한다. Glutaminase가 종양을 유발하거나 종양을 억제하는지는 isoenzymes의 관점에서 논란의 여지가 있으나 GLS1은 발암 가능성이 더 높아 유망한 치료 대상인 반면에 GLS2는 종양 저해제로서 작용하는 것으로 알려졌다. 암 대사체의 복잡하고 정교한 네트워크에 기반한 4세대 대사항암제는 암세포의 에너지 대사를 직접 제어하여 영양 공급을 차단해 부작용 없이 항암효과를 극대화하는 요법으로 2010년대 중반 이후 연구가 활발히 진행되고 있다. Glutaminolysis에서 glutaminase는 초기 단계를 촉매하는 효소로서 암 대사 및 종양 진행에 매우 중요하여 glutaminase 효소를 약물 표적화하는 새로운 기전의 항암제 개발이 유망한 전략으로 떠오르고 있다.

• 한국환경성돌연변이발암원학회지
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• 제18권1호
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• pp.1-8
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• 1998

Chemoprevention refers to the use of non-toxic chemical agents to prevent the neoplastic development by inhibiting, delaying, or reversing a multi-stage carcinogenesis. The primary goal of chemoprevention research is to identify or produce effective agents and strategies for clinical trials for applications to normal or high risk human populations. A large number of compounds have been tested for their possible chemopreventive activities, and it is of interest to note that many of them are naturally occurring substances. Thus, a variety of plant and vegetable constituents, particularly those included in our daily diet, have been found to possess substantial protective properties against experimental carcinogenesis. These substances, collectively known as dietary phytochemicals, exert their chemopreventive effects by influencing specific step(s) of multi-stage carcinogenesis: some inhibit metabolic activation or enhance detoxification of carcinogens, others interfere with covalent interactions between ultimate eloctrophilic carcinogens and the target cell DNA and still others may exert anti-promoting or anti-progressing effects. Mechanism-based interventions by use of safe dietary phytochemicals may provide one of the most practical and promising cancer chemopreventive strategies.

• Journal of Preventive Veterinary Medicine
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• 제42권4호
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• pp.177-181
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• 2018

Disulfiram is a drug used to treat alcohol dependence. Recent studies have shown that disulfiram also has anti-cancer effects. Considering that many anti-cancer agents have side effects, including immunosuppression, it is important to check if disulfiram has some cytotoxicity to immune cells. In this study, mouse spleen cells were treated with disulfiram and the metabolic activity was measured. Disulfiram increased the cell death of spleen cells according to annexin V-FITC/PI staining analysis. In addition, disulfiram decreased the mitochondrial membrane potential of spleen cells. The toxicity of disulfiram was concentration dependent. Interestingly, disulfiram affected the population of lymphocytes and the subset of spleen cells was altered. This study provides clinicians and researchers with valuable information regarding the toxicity of disulfiram to mouse spleen cells, particularly lymphocytes.

• 비만대사연구학술지
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• 제1권1호
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• pp.43-45
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• 2022

Intensive lifestyle modifications and anti-obesity medications are essential for obesity treatment. Antiobesity medications should be selected according to the patient's comorbidities, symptoms, and preferences. This case report describes the treatment of a morbidly obese patient with a history of depression, who complained of tingling and numbness after total thyroidectomy for papillary thyroid cancer. Very low-dose controlled-release phentermine/topiramate was prescribed and intensive lifestyle modifications were encouraged. As a result, the patient effectively lost weight and reached a near-normal weight without adverse drug effects. This implies that even an off-label anti-obesity medication low dose may be better for some patients, and the most important factor in obesity treatment is patient-tailored treatment.

• 비만대사연구학술지
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• 제1권2호
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• pp.66-73
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• 2022

Obesity is an increasing public health and medical issue worldwide. It has been associated with several comorbidities, including diabetes, cardiovascular disease, stroke, and cancer. Chronic kidney disease (CKD) is another important comorbidity of obesity. Other major causes of CKD include hypertension and diabetes. However, the association between obesity and CKD is often overlooked. Among patients with CKD, patients with obesity were more vulnerable to have rapid kidney function decline than that of those with normal weight. Additionally, CKD is more prevalent among patients with obesity. These aggravations are induced through multiple mechanisms, specifically metabolic impairment of obesity and mechanical burden because of increasing intraabdominal renal pressure. Furthermore, the inflammation and lipotoxicity, caused by obesity, are critical in the CKD aggravation in patients with obesity. To prevent this, all adult patients with obesity are tested for CKD. The workup includes the estimated glomerular filtration rate and regular follow-up. Step-wise management is required for patients with obesity with CKD. Prompt reduction and management of obesity effectively delay CKD progression among patients with obesity and CKD. Therefore, weight loss is a core management for patients with obesity and CKD. Based on several studies, this article focused on the association between CKD and obesity, as well as the diagnosis and weight management of patients with obesity and CKD.

• 한국융합학회논문지
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• 제13권1호
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• pp.161-166
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• 2022

HIF-2α는 저산소 조건에서 활성화되는 전사인자로 암, 대사증후군, 관절염, 간염 등의 발병 기전에서 핵심 역할을 한다고 보고된 바 있다. 이에 HIF-2α 저해제를 도출하고자 기존 약리활성 구조를 도입한 N'-arylisonicotinolyhydrazide를 골격으로 설정하고 화합물 라이브러리로부터 해당 화합물들을 선택하여 HIF-2α 저해활성을 측정하였다. 이를 위해 HRE-luciferase를 HTB-94세포에 transfection하고 아데노바이러스를 이용하여 HIF-2α를 세포 내로 도입하여 luciferase reporter gene assay를 수행하였다. 2-hydroxy-1-naphthyl 기를 포함한 화합물에서 저해활성이 발견됨에 따라 이 구조를 포함하는 골격을 다시 설정하고 해당 화합물들을 선정하여 활성을 측정하였다. 그 결과 HIF-2α 저해활성과 위양성 시험을 통하여 2 종의 HIF-2α 저해제를 도출하였다. 본 연구는 생물학과 화학의 융합연구로 수행되었으며 도출된 저해제는 후속 저해제 탐색 연구와 HIF-2α의 기능 연구에 활용될 수 있고 관련 질환의 치료제 개발에도 기여 할 것으로 사료된다.

• Journal of Ginseng Research
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• 제11권2호
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• pp.145-252
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• 1987

Isolated rat adipocytes are well known to possess opposite pathways of lipid metabolism: lipolysis and ipogenesis. Both of the metabolism respond to various biologically active substances such as epinephrine, ACTH and insulin. Epinephrine and ACTH stimulate lipolysis and insulin accelerates lipogenesis. Recently, Korean red ginseng powder was found to contain adenosine and an acidic poptide which inhibited epinephrine-induced lipolysis and sl imulated insulin-mediated lipogenesis from added glucose. The acidic peptide is consisted mainly of glutamic acid and glucose. Ginsenosides Rb1 and Re inhibited ACTH-induced lipolysis in isolated rat adipocytes, while they did not affect insulinstimulated lipogenesis, Thus, all these substances extracted from Korean red ginseng exhibited selective modulations toward the opposite metabolic pathways in rat adipocyte; They inhibited the lipolysis but not the lipogenesis. We call these substances"selective modulators". Recently, we isolated a toxic substance named "toxohormone-L " from ascites fluid of patients with various malignant tumors. The toxohormone-L stimulated lipolysis in rat adipocytes and induced anorexia in rats. Both the lipolytic and the anorexigenic actions of toxohormone-L were found to be inhibited by ginsenoside Rb2 in Korean red ginseng. Based on these results, physiological signifi¬cances of these substances in Korean red ginseng were discussed. Pan ax ginseng is a medicinal plant long used in treatment of various pathological states including general complaints such as head ache, shoulder ache, chilly constitution and anorexia in cancer patients, There have been many pharmacological studies on Panax ginseng roots. Petkovllreported that oral administration of an aqueous alcoholic extract of ginseng roots decreased the blood sugar levtl of rabbits. Saito2lreported that Panax ginseng suppressed hyperglycemia induced by epinephrine and high carbohydrate diets. These findings suggest that Panax ginseng roots contain insulin-like substances. Previously, we demonstrated that gin¬seng roots contain an insulin-like peptide which inhibits epinephrine-induced lipolysis and stimulated insulin-mediated lipogenesis. In 1984, we suggested that such an insulin-like substance should be called a selective modulator4). Present investigation describes the details of the selective modulators in ginseng roots. During progressive weight loss in patients with various neoplastic disease, depletion of fat stores have been observed. The depletion of body fat during growth of neoplasms is associated with increase in plasma free fatty acids. Recently, we found that the ascites fluid from patients with hepatoma or ovarian tumor and the pleural fluid from patients with malignant lymphoma elicited fatty acid release in slices of rat adipose tissue in vitro. The lipolytic factor, named"toxohormone-L". was purifed from the ascites fluid of patients with hepatoma. The isolated preparation gave a single band on both disc gel electrophoresis and sodium dodecyl sulfate(SDS)-acrylamide gel electrophoresis in the presence of ${\beta}$-mercaptoethanol. Its molecular weight was determined to be 70,000-75,000 and 65,000 by SDS-acrylamide gel electrophoresis and analytical ultracentrifugation, respectively. Injection of toxohormone-L into the lateral ventricle of rats significantly suppressed food and water intakes. There was at least 5 hr delay between its injection and appearance of its suppressive effect. In the present study, we also tried to find a inhibitory substance toward toxohormone-L from root powder of ginseng.