• The Korean Journal of Physiology and Pharmacology
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• 제14권6호
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• pp.377-384
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• 2010

The present study examined whether metformin treatment prevents isoporterenol-induced cardiac hypertrophy in mice. Chronic subcutaneous infusion of isoproterenol (15 mg/kg/24 h) for 1 week using an osmotic minipump induced cardiac hypertrophy measured by the heart-to-body weight ratio and left ventricular posterior wall thickness. Cardiac hypertrophy was accompanied with increased interleukin-6 (IL-6), transforming growth factor (TGF)-${\beta}$, atrial natriuretic peptide (ANP), collagen I and III, and matrix metallopeptidase 2 (MMP-2). Coinfusion of metformin (150 mg/kg/24 h) with isoproterenol partially inhibited cardiac hypertrophy that was followed by reduced IL-6, TGF-${\beta}$, ANP, collagen I and III, and MMP-2. Chronic subcutaneous infusion of metformin did not increase AMP-activated protein kinase (AMPK) activity in heart, although acute intraperitoneal injection of metformin (10 mg/kg) increased AMPK activity. Isoproterenol increased nitrotyrosine levels and mRNA expression of antioxidant enzyme glutathione peroxidase and metformin treatment normalized these changes. These results suggest that metformin inhibits cardiac hypertrophy through attenuating oxidative stress.

• 한국임상약학회지
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• 제25권3호
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• pp.131-137
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• 2015

Background: The protective effect of metformin against breast cancer is inconclusive. Objective: To evaluate the effect of metformin on breast cancer risk and mortality in patients with type 2 diabetes. Method: A comprehensive literature search was performed for pertinent articles published prior to June 30, 2014, using PubMed and EMBASE. Study heterogeneity was estimated with $I^2$ statistic. The data from the included studies were pooled and weighted by random-effects model. The quality of each included study was assessed on the basis of the 9-star Newcastle-Ottawa Scale and publication bias was evaluated by visual inspection of a funnel plot. Results: Ten studies were included in the meta-analysis of the association of metformin and breast cancer risk. By synthesizing the data from the studies, the pooled odds ratio (OR) was 0.72 (95% CI: 0.59, 0.87) (p = 0.0005). Three cohort studies were included for meta-analysis of the association between metformin and breast cancer-related mortality. Metformin was associated with a significant decrease in mortality (Risk ratio: 0.68; 95% CI: 0.51, 0.90, p = 0.007). Conclusion: The present meta-analysis suggests that metformin appears to be associated with a lower risk of breast cancer incidence and mortality in patients with type 2 diabetes.

• The Korean Journal of Physiology and Pharmacology
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• 제10권1호
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• pp.1-6
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• 2006

To evaluate whether metformin restores leptin sensitivity in aged rats with leptin resistance, we measured leptin sensitivity in aged (2 year old) and adult (5 month old) rats after 4 weeks of treatment with metformin (300 mg/kg/D, mixing in drinking water), by measuring food intake, body weight and visceral fat losing effects. Leptin ($15{\mu}g/D$) was administered by intracerobroventricular (i.c.v.) infusion through osmotic minipump for 1 week. Metformin treatment decreased body weight and daily food intake in both adult and aged rats compared with their control rats, however, these effects were more prominent in aged rats than in adult rats. Anorexic and fat losing responses following i.c.v. leptin were attenuated in aged rats compared to adult rats. However, these responses of aged rats to leptin were restored by metformin treatment. Moreover, serum concentration of leptin in aged rats was significantly decreased by combined treatment with metformin and leptin. These results suggest that metformin enhances leptin sensitivity in aged rat model, and that combination therapy with metformin and leptin would be helpful for treatment of aging-associated obesity.

• International Journal of Oral Biology
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• 제42권2호
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• pp.39-45
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• 2017

Metformin (1,1-dimethylbiguanide hydrochloride), derived from French lilac (Galega officinalis), is a first-line anti-diabetic drug prescribed for patients with type 2 diabetes. However, the role of metformin in odontoblastic cell differentiation is still unclear. This study therefore undertook to examine the effect of metformin on regulating odontoblast differentiation in MDPC-23 mouse odontoblastic cells derived from mouse dental papilla cells. As compared to controls, metformin significantly accelerated the mineralization, significantly increased and accelerated the expressions of ALP and Col I mRNAs, and significantly increased the accelerated expressions of DSPP and DMP-1 mRNAs, during differentiation of MDPC-23 cells. There was no alteration in cell proliferation of MDPC-23 cells, on exposure to metformin. These results suggest that the effect of metformin on MDPC-23 mouse odontoblastic cells derived from mouse dental papilla cells, facilitates the odontoblast differentiation and mineralization, without altering the cell proliferation.

• 한국발생생물학회지:발생과생식
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• 제23권2호
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• pp.119-128
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• 2019

Melanoma is one of the most aggressive and treatment-resistant malignancies. Antidiabetic drug metformin has been reported to inhibit cell proliferation and metastasis in many cancers, including melanoma. Metformin suppresses the mammalian target of rapamycin (mTOR) and our previous study showed that it also inhibits the activity of extracellular signal-regulated kinase (ERK). Paclitaxel is currently prescribed for treatment of melanoma. However, paclitaxel induced the activation of ERK/mitogen-activated protein kinase (MAPK) pathway, a cell signaling pathway implicated in cell survival and proliferation. Therefore, we reasoned that combined treatment of paclitaxel with metformin could be more effective in the suppression of cell proliferation than treatment of paclitaxel alone. Here, we investigated the combinatory effect of paclitaxel and metformin on the cell survival in SK-MEL-28 melanoma cell line. Our study shows that the combination of paclitaxel and metformin has synergistic effect on cell survival and suppresses the expression of proteins involved in cancer metastasis. These findings suggest that the combination of paclitaxel and metformin can be a possible therapeutic option for treatment of melanoma.

• Asian Pacific Journal of Cancer Prevention
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• 제15권9호
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• pp.4019-4023
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• 2014

Metformin has been shown to be useful in reducing insulin resistance by restoring sensitivity. Recent evidence suggests that metformin might also possess anti-tumour activity. This study aimed to investigate the effects of cisplatin combined with metformin on the proliferation, invasion and migration of HNE1/DDP human nasopharyngeal carcinoma (NPC) cells, and to provide a new target for treating metastasis. The MTT assay was used to assess viability of HNE1/DDP cells after exposure to different concentrations of 2, 5-diaminopyrimidine-4, 6-diol (DDP; 2, 4, 8, 16, and $32{\mu}mol{\cdot}L^{-1}$), metformin (5, 10, 15, 20, and $25{\mu}mol{\cdot}L^{-1}$), and $4{\mu}mol{\cdot}L^{-1}$ of DDP combined with metformin. Wound healing and transwell migration assays were performed to assess cell migration and invasion, and expression of E-cadherin and MMP-9 was detected using Western blotting. MTT assay results showed that DDP could inhibit the proliferation of HNE1/DDP cells in a time- and concentration-dependent manner, with an IC50 of $32.0{\mu}mol{\cdot}L^{-1}$ at 24 h (P < 0.05), whereas low concentrations of DDP had almost no inhibitory effects on cell invasion and migration. DDP combined with metformin significantly inhibited cell invasion and migration. In addition, genes related to migration and invasion, such as those of E-cadherin and MMP-9, showed differential expression in the NPC cell line HNE1/DDP. In the present study, with an increasing concentration of metformin, the expression of MMP-9 was downregulated whereas that of E-cadherin was significantly upregulated. Taken together, our results show that cisplatin combined with metformin has effects on proliferation, invasion, and migration of human NPC cells.

• Asian Pacific Journal of Cancer Prevention
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• 제14권2호
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• pp.765-768
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• 2013

Background and Aims: Prostate cancer is the most commonly diagnosed cancer in males in many populations. Metformin is the most widely used anti-diabetic drug in the world, and there is increasing evidence of a potential efficacy of this agent as an anti-cancer drug. Metformin inhibits the proliferation of a range of cancer cells including prostate, colon, breast, ovarian, and glioma lines. MicroRNAs (miRNAs) are a class of small, non-coding, single-stranded RNAs that downregulate gene expression. We aimed to evaluate the effects of metformin treatment on changes in miRNA expression in PC-3 cells, and possible associations with biological behaviour. Materials and Methods: Average cell viability and cytotoxic effects of metformin were investigated at 24 hour intervals for three days using the xCELLigence system. The $IC_{50}$ dose of metformin in the PC-3 cells was found to be 5 mM. RNA samples were used for analysis using custom multi-species microarrays containing 1209 probes covering 1221 human mature microRNAs present in miRBase 16.0 database. Results: Among the human miRNAs investigated by the arrays, 10 miRNAs were up-regulated and 12 miRNAs were down-regulated in the metformin-treated group as compared to the control group. In conclusion, expression changes in miRNAs of miR-146a, miR-100, miR-425, miR-193a-3p and, miR-106b in metformin-treated cells may be important. This study may emphasize a new role of metformin on the regulation of miRNAs in prostate cancer.

• 대한임상독성학회지
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• 제5권2호
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• pp.126-130
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• 2007

Metformin is antihyperglycemic, not hypoglycemic. It causes neither insulin release from the pancreas nor hypo glycemia, even when taken in large doses. But, there are several reports of metformin-associated lactic acidosis (MALT). We present a case report of severe lactic acidosis most probably resulting from high doses of metformin in a patient with no known contraindications for metformin. A 43-year-old female was admitted to the emergency department due to a metformin overdose. She had diabetes for 6 years, well-controlled with metformin and novolet. One hour before admission, she impulsively took 50g metformin (100 mg or 100 tablets). Physical examination for symptoms revealed only irritability, and laboratory evaluation revealed only mild leukocytosis. After one hour the patient was drowsy, and arterial blood gas analysis showed severe lactic acidemia Seven hours after ED arrival, she commenced hemofiltration treatment and was admitted to the intensive care unit. Continuous venovenous hemodiafiltration was initiated. Forty-eight hours later, full clinical recovery was observed, with return to a normal serum lactate level. The patient was discharged from the intensive care unit on the third day. A progressive recovery was observed and she was discharged from the general word on the thirteenth day.

• Clinical and Experimental Pediatrics
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• 제59권9호
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• pp.374-380
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• 2016

Purpose: Patients with unresectable, relapsed, or refractory osteosarcoma need a novel therapeutic agent. Metformin is a biguanide derivative used in the treatment of type II diabetes, and is recently gaining attention in cancer research. Methods: We evaluated the effect of metformin against human osteosarcoma. Four osteosarcoma cell lines (KHOS/NP, HOS, MG-63, U-2 OS) were treated with metformin and cell proliferation was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle progression and apoptosis were evaluated using flow cytometric analysis, and migration and wound healing assay were performed. Fourteen female Balb/c-nude mice received KHOS/NP cell grafts in their thigh, and were allowed access to metformin containing water (2 mg/mL) ad libitum. Tumor volume was measured every 3-4 days for a period of 4 weeks. Results: Metformin had a significant antiproliferative effect on human osteosarcoma cells. In particular, metformin inhibited the proliferation and migration of KHOS/NP cells by activation of AMP-activated protein kinase and consequent inhibition of the mammalian target of rapamycin pathway. It also inhibited the proliferation of cisplatin-resistant KHOS/NP clone cells. Analysis of KHOS/NP xenograft Balb/c-nude models indicated that metformin displayed potent in vivo antitumor effects. Conclusion: Further studies are necessary to explore metformin's therapeutic potential and the possibilities for its use as an adjuvant agent for osteosarcoma.

• 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.