Medical students’ thought process while solving problems in 3 different types of clinical assessments in Korea: clinical performance examination, multimedia case-based assessment, and modified essay question / 보건의료교육평가

Purpose@#This study aimed to explore students’ cognitive patterns while solving clinical problems in 3 different types of assessments—clinical performance examination (CPX), multimedia case-based assessment (CBA), and modified essay question (MEQ)—and thereby to understand how different types of assessments stimulate different patterns of thinking. @*Methods@#A total of 6 test-performance cases from 2 fourth-year medical students were used in this cross-case study. Data were collected through one-on-one interviews using a stimulated recall protocol where students were shown videos of themselves taking each assessment and asked to elaborate on what they were thinking. The unit of analysis was the smallest phrases or sentences in the participants’ narratives that represented meaningful cognitive occurrences. The narrative data were reorganized chronologically and then analyzed according to the hypothetico-deductive reasoning framework for clinical reasoning. @*Results@#Both participants demonstrated similar proportional frequencies of clinical reasoning patterns on the same clinical assessments. The results also revealed that the three different assessment types may stimulate different patterns of clinical reasoning. For example, the CPX strongly promoted the participants’ reasoning related to inquiry strategy, while the MEQ strongly promoted hypothesis generation. Similarly, data analysis and synthesis by the participants were more strongly stimulated by the CBA than by the other assessment types. @*Conclusion@#This study found that different assessment designs stimulated different patterns of thinking during problem-solving. This finding can contribute to the search for ways to improve current clinical assessments. Importantly, the research method used in this study can be utilized as an alternative way to examine the validity of clinical assessments.

Ursolic acid in health and disease

Ursolic acid (UA) is a natural triterpene compound found in various fruits and vegetables. There is a growing interest in UA because of its beneficial effects, which include anti-inflammatory, anti-oxidant, anti-apoptotic, and anti-carcinogenic effects. It exerts these effects in various tissues and organs: by suppressing nuclear factor-kappa B signaling in cancer cells, improving insulin signaling in adipose tissues, reducing the expression of markers of cardiac damage in the heart, decreasing inflammation and increasing the level of anti-oxidants in the brain, reducing apoptotic signaling and the level of oxidants in the liver, and reducing atrophy and increasing the expression levels of adenosine monophosphate-activated protein kinase and irisin in skeletal muscles. Moreover, UA can be used as an alternative medicine for the treatment and prevention of cancer, obesity/diabetes, cardiovascular disease, brain disease, liver disease, and muscle wasting (sarcopenia). In this review, we have summarized recent data on the beneficial effects and possible uses of UA in health and disease managements.

Time-dependent proteomic and genomic alterations in Toll-like receptor-4-activated human chondrocytes: increased expression of lamin A/C and annexins

Activation of Toll-like receptor-4 (TLR-4) in articular chondrocytes increases the catabolic compartment and leads to matrix degradation during the development of osteoarthritis. In this study, we determined the proteomic and genomic alterations in human chondrocytes during lipopolysaccharide (LPS)-induced inflammation to elucidate the underlying mechanisms and consequences of TLR-4 activation. Human chondrocytes were cultured with LPS for 12, 24, and 36 h to induce TLR-4 activation. The TLR-4-induced inflammatory response was confirmed by real-time PCR analysis of increased interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) expression levels. In TLR-4-activated chondrocytes, proteomic changes were determined by two-dimensional electrophoresis and matrix-assisted laser desorption/ionization-mass spectroscopy analysis, and genomic changes were determined by microarray and gene ontology analyses. Proteomics analysis identified 26 proteins with significantly altered expression levels; these proteins were related to the cytoskeleton and oxidative stress responses. Gene ontology analysis indicated that LPS treatment altered specific functional pathways including ‘chemotaxis’, ‘hematopoietic organ development’, ‘positive regulation of cell proliferation’, and ‘regulation of cytokine biosynthetic process’. Nine of the 26 identified proteins displayed the same increased expression patterns in both proteomics and genomics analyses. Western blot analysis confirmed the LPS-induced increases in expression levels of lamin A/C and annexins 4/5/6. In conclusion, this study identified the time-dependent genomic, proteomic, and functional pathway alterations that occur in chondrocytes during LPS-induced TLR-4 activation. These results provide valuable new insights into the underlying mechanisms that control the development and progression of osteoarthritis.

NecroX-5 protects mitochondrial oxidative phosphorylation capacity and preserves PGC1alpha expression levels during hypoxia/reoxygenation injury

Although the antioxidant and cardioprotective effects of NecroX-5 on various in vitro and in vivo models have been demonstrated, the action of this compound on the mitochondrial oxidative phosphorylation system remains unclear. Here we verify the role of NecroX-5 in protecting mitochondrial oxidative phosphorylation capacity during hypoxia-reoxygenation (HR). Necrox-5 treatment (10 microM) and non-treatment were employed on isolated rat hearts during hypoxia/reoxygenation treatment using an ex vivo Langendorff system. Proteomic analysis was performed using liquid chromatography-mass spectrometry (LC-MS) and non-labeling peptide count protein quantification. Real-time PCR, western blot, citrate synthases and mitochondrial complex activity assays were then performed to assess heart function. Treatment with NecroX-5 during hypoxia significantly preserved electron transport chain proteins involved in oxidative phosphorylation and metabolic functions. NecroX-5 also improved mitochondrial complex I, II, and V function. Additionally, markedly higher peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1alpha) expression levels were observed in NecroX-5-treated rat hearts. These novel results provide convincing evidence for the role of NecroX-5 in protecting mitochondrial oxidative phosphorylation capacity and in preserving PGC1alpha during cardiac HR injuries.

Mitochondrial calcium uniporter inhibition attenuates mouse bone marrow-derived mast cell degranulation induced by beta-1,3-glucan

Mast cells are primary mediators of allergic inflammation. Beta-1,3-glucan (BG) protects against infection and shock by activating immune cells. Activation of the BG receptor induces an increase in intracellular Ca2+, which may induce exocytosis. However, little is known about the precise mechanisms underlying BG activation of immune cells and the possible role of mitochondria in this process. The present study examined whether BG induced mast cell degranulation, and evaluated the role of calcium transients during mast cell activation. Our investigation focused on the role of the mitochondrial calcium uniporter (MCU) in BG-induced degranulation. Black mouse (C57) bone marrow-derived mast cells were stimulated with 0.5 microg/ml BG, 100 microg/ml peptidoglycan (PGN), or 10 microM A23187 (calcium ionophore), and dynamic changes in cytosolic and mitochondrial calcium and membrane potential were monitored. BG-induced mast cell degranulation occurred in a time-dependent manner, and was significantly reduced under calcium-free conditions. Ruthenium red, a mitochondrial Ca2+ uniporter blocker, significantly reduced mast cell degranulation induced by BG, PGN, and A23187. These results suggest that the mitochondrial Ca2+ uniporter has an important regulatory role in BG-induced mast cell degranulation.

Voluntary stand-up physical activity enhances endurance exercise capacity in rats

Involuntary physical activity induced by the avoidance of electrical shock leads to improved endurance exercise capacity in animals. However, it remains unknown whether voluntary stand-up physical activity (SPA) without forced simulating factors improves endurance exercise capacity in animals. We examined the eff ects of SPA on body weight, cardiac function, and endurance exercise capacity for 12 weeks. Twelve male Sprague-Dawley rats (aged 8 weeks, n=6 per group) were randomly assigned to a control group (CON) or a voluntary SPA group. The rats were induced to perform voluntary SPA (lifting a load equal to their body weight), while the food height (18.0 cm) in cages was increased progressively by 3.5 every 4 weeks until it reached 28.5 cm for 12 weeks. The SPA group showed a lower body weight compared to the CON group, but voluntary SPA did not affect the skeletal muscle and heart weights, food intake, and echocardiography results. Although the SPA group showed higher grip strength, running time, and distance compared to the CON group, the level of irisin, corticosterone, genetic expression of mitochondrial biogenesis, and nuclei numbers were not affected. These findings show that voluntary SPA without any forced stimuli in rats can eff ectively reduce body weight and enhance endurance exercise capacity, suggesting that it may be an important alternative strategy to enhance endurance exercise capacity.

NecroX-5 exerts anti-inflammatory and anti-fibrotic effects via modulation of the TNFα/Dcn/TGFβ1/Smad2 pathway in hypoxia/reoxygenation-treated rat hearts

Inflammatory and fibrotic responses are accelerated during the reperfusion period, and excessive fibrosis and inflammation contribute to cardiac malfunction. NecroX compounds have been shown to protect the liver and heart from ischemia-reperfusion injury. The aim of this study was to further define the role and mechanism of action of NecroX-5 in regulating infl ammation and fi brosis responses in a model of hypoxia/reoxygenation (HR). We utilized HR-treated rat hearts and lipopolysaccharide (LPS)-treated H9C2 culture cells in the presence or absence of NecroX-5 (10 µmol/L) treatment as experimental models. Addition of NecroX-5 signifi cantly increased decorin (Dcn) expression levels in HR-treated hearts. In contrast, expression of transforming growth factor beta 1 (TGFβ1) and Smad2 phosphorylation (pSmad2) was strongly attenuated in NecroX-5-treated hearts. In addition, signifi cantly increased production of tumor necrosis factor alpha (TNFα), TGFβ1, and pSmad2, and markedly decreased Dcn expression levels, were observed in LPS-stimulated H9C2 cells. Interestingly, NecroX-5 supplementation effectively attenuated the increased expression levels of TNFα, TGFβ1, and pSmad2, as well as the decreased expression of Dcn. Thus, our data demonstrate potential antiinflammatory and anti-fibrotic effects of NecroX-5 against cardiac HR injuries via modulation of the TNFα/Dcn/TGFβ1/Smad2 pathway.

Repeated Glucose Deprivation/Reperfusion Induced PC-12 Cell Death through the Involvement of FOXO Transcription Factor

BACKGROUND: Cognitive impairment and brain damage in diabetes is suggested to be associated with hypoglycemia. The mechanisms of hypoglycemia-induced neural death and apoptosis are not clear and reperfusion injury may be involved. Recent studies show that glucose deprivation/reperfusion induced more neuronal cell death than glucose deprivation itself. The forkhead box O (FOXO) transcription factors are implicated in the regulation of cell apoptosis and survival, but their role in neuronal cells remains unclear. We examined the role of FOXO transcription factors and the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt and apoptosis-related signaling pathways in PC-12 cells exposed to repeated glucose deprivation/reperfusion. METHODS: PC-12 cells were exposed to control (Dulbecco's Modified Eagle Medium [DMEM] containing 25 mM glucose) or glucose deprivation/reperfusion (DMEM with 0 mM glucose for 6 hours and then DMEM with 25 mM glucose for 18 hours) for 5 days. MTT assay and Western blot analysis were performed for cell viability, apoptosis, and the expression of survival signaling pathways. FOXO3/4',6-diamidino-2-phenylindole staining was done to ascertain the involvement of FOXO transcription factors in glucose deprivation/reperfusion conditions. RESULTS: Compared to PC-12 cells not exposed to hypoglycemia, cells exposed to glucose deprivation/reperfusion showed a reduction of cell viability, decreased expression of phosphorylated Akt and Bcl-2, and an increase of cleaved caspase-3 expression. Of note, FOXO3 protein was localized in the nuclei of glucose deprivation/reperfusion cells but not in the control cells. CONCLUSION: Repeated glucose deprivation/reperfusion caused the neuronal cell death. Activated FOXO3 via the PI3K/Akt pathway in repeated glucose deprivation/reperfusion was involved in genes related to apoptosis.

Using standardized patients versus video cases for representing clinical problems in problem-based learning / 한국의학교육

PURPOSE: The quality of problem representation is critical for developing students' problem-solving abilities in problem-based learning (PBL). This study investigates preclinical students' experience with standardized patients (SPs) as a problem representation method compared to using video cases in PBL. METHODS: A cohort of 99 second-year preclinical students from Inje University College of Medicine (IUCM) responded to a Likert scale questionnaire on their learning experiences after they had experienced both video cases and SPs in PBL. The questionnaire consisted of 14 items with eight subcategories: problem identification, hypothesis generation, motivation, collaborative learning, reflective thinking, authenticity, patient-doctor communication, and attitude toward patients. RESULTS: The results reveal that using SPs led to the preclinical students having significantly positive experiences in boosting patient-doctor communication skills; the perceived authenticity of their clinical situations; development of proper attitudes toward patients; and motivation, reflective thinking, and collaborative learning when compared to using video cases. The SPs also provided more challenges than the video cases during problem identification and hypotheses generation. CONCLUSION: SPs are more effective than video cases in delivering higher levels of authenticity in clinical problems for PBL. The interaction with SPs engages preclinical students in deeper thinking and discussion; growth of communication skills; development of proper attitudes toward patients; and motivation. Considering the higher cost of SPs compared with video cases, SPs could be used most advantageously during the preclinical period in the IUCM curriculum.

Mitochondrial pyruvate dehydrogenase phosphatase 1 regulates the early differentiation of cardiomyocytes from mouse embryonic stem cells

Mitochondria are crucial for maintaining the properties of embryonic stem cells (ESCs) and for regulating their subsequent differentiation into diverse cell lineages, including cardiomyocytes. However, mitochondrial regulators that manage the rate of differentiation or cell fate have been rarely identified. This study aimed to determine the potential mitochondrial factor that controls the differentiation of ESCs into cardiac myocytes. We induced cardiomyocyte differentiation from mouse ESCs (mESCs) and performed microarray assays to assess messenger RNA (mRNA) expression changes at differentiation day 8 (D8) compared with undifferentiated mESCs (D0). Among the differentially expressed genes, Pdp1 expression was significantly decreased (27-fold) on D8 compared to D0, which was accompanied by suppressed mitochondrial indices, including ATP levels, membrane potential, ROS and mitochondrial Ca²⁺. Notably, Pdp1 overexpression significantly enhanced the mitochondrial indices and pyruvate dehydrogenase activity and reduced the expression of cardiac differentiation marker mRNA and the cardiac differentiation rate compared to a mock control. In confirmation of this, a knockdown of the Pdp1 gene promoted the expression of cardiac differentiation marker mRNA and the cardiac differentiation rate. In conclusion, our results suggest that mitochondrial PDP1 is a potential regulator that controls cardiac differentiation at an early differentiation stage in ESCs.

The Critical Roles of Zinc: Beyond Impact on Myocardial Signaling

Zinc has been considered as a vital constituent of proteins, including enzymes. Mobile reactive zinc (Zn2+) is the key form of zinc involved in signal transductions, which are mainly driven by its binding to proteins or the release of zinc from proteins, possibly via a redox switch. There has been growing evidence of zinc's critical role in cell signaling, due to its flexible coordination geometry and rapid shifts in protein conformation to perform biological reactions. The importance and complexity of Zn2+ activity has been presumed to parallel the degree of calcium's participation in cellular processes. Whole body and cellular Zn2+ levels are largely regulated by metallothioneins (MTs), Zn2+ importers (ZIPs), and Zn2+ transporters (ZnTs). Numerous proteins involved in signaling pathways, mitochondrial metabolism, and ion channels that play a pivotal role in controlling cardiac contractility are common targets of Zn2+. However, these regulatory actions of Zn2+ are not limited to the function of the heart, but also extend to numerous other organ systems, such as the central nervous system, immune system, cardiovascular tissue, and secretory glands, such as the pancreas, prostate, and mammary glands. In this review, the regulation of cellular Zn2+ levels, Zn2+-mediated signal transduction, impacts of Zn2+ on ion channels and mitochondrial metabolism, and finally, the implications of Zn2+ in health and disease development were outlined to help widen the current understanding of the versatile and complex roles of Zn2+.

Development of guide to clinical performance and basic clinical skills for medical students / 한국의학교육

The aim of this report was to discuss the development and content of a guide on clinical performance and basic clinical skills for medical students. We published the first edition of this guide in 2010 and will publish the second edition in 2016. Initially, we took a survey on important clinical presentations and fundamental clinical and technical skills in 41 medical schools in Korea. Ultimately, we chose 80 core clinical presentations and 56 clinical skills. In the guide to basic clinical skills, we described the physical examination and technical skills according to the preprocedural preparation, procedure, and postprocedural process. In the guide on clinical performance, we reviewed patient encounters-from history taking and the physical examination to patient education. We included communication skills, principles of patient safety, and clinical reasoning schemes into the guides. In total, 43 academic faculty members helped develop the basic clinical skills guide, 75 participated in establishing the clinical performance guide, and 16 advisors from 14 medical specialty societies contributed to the guide. These guides can help medical students approach patients holistically and safely.

Allergic reaction to recombinant human insulin

Insulin-induced allergy is a rare adverse drug reaction since the introduction of recombinant human insulin. However, recombinant insulin-induced allergy is still being reported in 0.1% to 2% of all patients treated with insulin. This allergic reaction varies from mild localized skin reactions to life-threatening anaphylaxis. It has been shown that one-third of insulin allergy cases is related to insulin itself and the remaining occur due to preservatives contained in the insulin preparations, such as protamine, zinc, or metacresol. This case report describes a 75-year-old woman with poorly controlled diabetes who experienced insulin allergy. She complained of urticaria with itching after the injection of insulin. Allergic skin tests showed positive responses to all available human insulin preparations, and specific IgE to human insulin was also detected, which suggested that her urticaria was developed by insulin itself. This is the first case of insulin allergy that was sensitive to all available human insulin preparations and confirmed by the presence of specific IgE to human insulin. It is important to remember that allergic reactions to insulin may be directly associated with adherence and can be the reason of poor glucose control.

Development of a portfolio for competency-based assessment in a clinical clerkship curriculum / 한국의학교육

The purpose of this report was to describe our experience in planning and developing a portfolio for a clinical clerkship curriculum. We have developed a portfolio for assessing student competency since 2007. During an annual workshop on clinical clerkship curricula, clerkship directors from five Paik hospitals of Inje University met to improve the assessment of the portfolio. We generated templates for students to record their activities and reflection and receive feedback. We uploaded these templates to our school's website for students to download freely. Annually, we have held a faculty development seminar and a workshop for portfolio assessment and feedback. Also, we established an orientation program on how to construct a learning portfolio for students. Future actions include creating a ubiquitous portfolio system, extending the portfolio to the entire curriculum, setting up an advisor system, and managing the quality of the portfolio. This study could be helpful for medical schools that plan to improve their portfolio assessment with an outcome-based approach.

Co-Culture of alpha TC-6 Cells and beta TC-1 Cells: Morphology and Function

BACKGROUND: In vitro experiments using only beta-cell lines instead of islets are limited because pancreatic islets are composed of four different types of endocrine cells. Several recent studies have focused on cellular interactions among these cell types, especially alpha- and beta-cells. Because islet isolation needs time and experience, we tested a simple co-culture system with alpha- and beta-cells. Their morphology and function were assessed by comparison to each single cell culture and pancreatic islets. METHODS: alpha TC-6 cells and beta TC-1 cells were maintained in Dulbecco's Minimal Essential Medium containing 5 mM glucose and 10% fetal bovine serum. Cells were mixed at a 1:1 ratio (5x10(5)) in 6-well plates and cultured for 24, 48, and 72 hours. After culture, cells were used for insulin and glucagon immunoassays and tested for glucose-stimulated insulin secretion (GSIS). RESULTS: alpha TC-6 and beta TC-1 cells became condensed by 24 hours and were more strongly compacted after 48 hours. beta TC-1 cells showed both beta-beta and beta-alpha cell contacts. GSIS increased with increasing glucose concentration in co-cultured cells, which showed lower secreted insulin levels than beta TC-1 cells alone. The increase in the secreted insulin/insulin content ratio was significantly lower for co-cultured cells than for beta-cells alone (P=0.04). Compared to islets, the alpha-/beta-cell co-culture showed a higher ratio of GSIS to insulin content, but the difference was not statistically significant (P=0.09). CONCLUSION: alpha TC-6 and beta TC-1 cells in the co-culture system showed cell-to-cell contacts and a similar stimulated insulin secretion pattern to islets. The co-culture system may be used to better mimic pancreatic islets in in vitro assessments.

Factors Associated for Mild Cognitive Impairment in Older Korean Adults with Type 2 Diabetes Mellitus

BACKGROUND: The aim of this study was to identify factors associated with mild cognitive impairment (MCI) in older Korean adults with type 2 diabetes mellitus. METHODS: A total of 226 older (age > or =65 years) adults without a history of cerebrovascular disease or dementia participated in this study. Cognitive function was assessed with the Montreal Cognitive Assessment-Korean version (MoCA-K). A MoCA-K score or =74 years old vs. 65-68 years old; odds ratio [OR], 3.69; 95% confidence interval [CI], 1.55 to 8.82; P=0.003), educational background (college graduation vs. no school or elementary school graduation; OR, 0.16; 95% CI, 0.05 to 0.46; P=0.001), and systolic blood pressure (> or =135 mm Hg vs. < or =120 mm Hg; OR, 3.25; 95% CI, 1.29 to 8.17; P=0.012) were associated with MCI. CONCLUSION: More concentrated efforts focused on early detection and appropriate management of MCI may be required in older Korean adults with type 2 diabetes mellitus.

Peer assessment of small-group presentations by medical students and its implications / 한국의학교육

PURPOSE: The purpose of this study was to explore the relationships among medical students' assessments on peers' group presentations, instructors' assessments of those presentations, and students' educational achievements in other assignments and tests. METHODS: A total of 101 first-year students from a medical school participated in the study. The students' educational achievements in a 4-week long integrated curriculum were analyzed. Student's final grades were comprised of the following education criteria: two written tests (60%), 15 group reports (25%), one individual report (7%), and four group presentations (15%). We compared scores of the group presentation assessed by the peers and the two instructors. Furthermore, we compared peers' assessment scores with each component of the evaluation criteria. RESULTS: Pearson correlation analysis showed significant correlaton for the assessments between peers and instructors (r=0.775, p<0.001). Peer assessment scores also correlated significantly with scores for the group assignments (r=0.777, p<0.001), final grades on the curriculum (r=0.345, p<0.001), and scores for individual assignments (r=0.334, p<0.001); however, no significant correlation was observed between the peer-assessed group presentation scores and the two written test scores. CONCLUSION: Peer assessments may be a reliable and valid method for evaluating medical students' performances in an integrated curriculum, especially if the assessments are used to academic processes, such as presentations, with explicit evaluation and judgment criteria. Peer assessments on group presentations might assess different learning domains compared to written tests that primarily evaluate limited medical knowledge and clinical reasoning.

Glycated Hemoglobin Value for Fasting Plasma Glucose of 126 mg/dL in Korean: The 2011 Korea National Health and Nutrition Examination Survey

We aimed to estimate the cutoff value of glycated hemoglobin (HbA1c, A1c) for fasting plasma glucose (FPG) of 126 mg/dL in the Korean adult population, using the 2011 Korea National Health and Nutrition Examination Survey. A total of 5,421 participants without a history of diabetes and over 19 years of age were included in the analysis. A point-wise area under the receiver operating characteristic curve was used to estimate the optimal A1c cutoff value. A1c threshold of 6.1% produced the highest sum of sensitivity (85.2%) and specificity (90.5%) for FPG of 126 mg/dL (area under the curve, 0.941, P or =6.5% might be acceptable in the Korean adult population.

Effects of aged garlic extract and endurance exercise on skeletal muscle FNDC-5 and circulating irisin in high-fat-diet rat models

BACKGROUND/OBJECTIVES: Irisin, a newly identified hormone, is associated with energy homeostasis. We investigated whether aged garlic extract (AGE) and exercise training intervention could improve body weight, insulin sensitivity, skeletal muscle fibronectin domain containing protein 5 (FNDC-5) levels, and plasma irisin in high-fat diet (HFD). MATERIALS/METHODS: Male Sprague Dawley rats were fed a ND (normal diet, n = 5) or HFD (n = 28) for 6 weeks. After 6 weeks, all rats were divided into 5 groups for the next 4 weeks: ND, (normal diet, n = 5), HFD (high-fat diet, n = 7), HFDA (high-fat diet + aged garlic extract, n = 7), HFDE (high-fat diet + exercise, n = 7), and HFDEA (high-fat diet + exercise + aged garlic extract, n = 7). Exercise groups performed treadmill exercises for 15-60 min, 5 days/week, and AGE groups received AGE (2.86 g/kg, orally injected) for 4 weeks. RESULTS: Significant decreases in body weight were observed in the ND, HFDE, and HFDEA groups, as compared with the HFD group. Neither intervention affected the masses of the gastrocnemius muscle or liver. There were no significant differences in glucose levels across the groups. The homeostatic model assessments of insulin resistance were significantly higher in the HFD group, as compared with the ND, HFDA, HFDE, and HFDEA groups. However, skeletal muscle FNDC-5 levels and plasma irisin concentrations were unaffected by AGE or exercise in obese rats. AGE supplementation and exercise training did not affect skeletal muscle FNDC-5 or plasma irisin, which are associated with insulin sensitivity in obese rats. CONCLUSION: Our results suggest that the protection against HFD-induced increases in body fat/weight and insulin resistance that are provided by AGE supplementation and exercise training may not be mediated by the regulation of FNDC-5 or irisin.

Combination treatment with 2-methoxyestradiol overcomes bortezomib resistance of multiple myeloma cells

Bortezomib is a proteasome inhibitor used for the treatment of relapsed/refractory multiple myeloma (MM). However, intrinsic and acquired resistance to bortezomib has already been observed in MM patients. In a previous report, we demonstrated that changes in the expression of mitochondrial genes lead to changes in mitochondrial activity and bortezomib susceptibility or resistance, and their combined effects contribute to the differential sensitivity or resistance of MM cells to bortezomib. Here we report that the combination treatment of bortezomib and 2-methoxyestradiol (2ME), a natural estrogen metabolite, induces mitochondria-mediated apoptotic cell death of bortezomib-resistant MM KMS20 cells via mitochondrial reactive oxygen species (ROS) overproduction. Bortezomib plus 2ME treatment induces a higher level of cell death compared with treatment with bortezomib alone and increases mitochondrial ROS and Ca2+ levels in KMS20 cells. Pretreatment with the antioxidant N-acetyl-L-cysteine scavenges mitochondrial ROS and decreases cell death after treatment with bortezomib plus 2ME in KMS20 cells. Moreover, we observed that treatment with bortezomib plus 2ME maintains the activation of c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase kinase kinase 4/7 (MKK4/7). Collectively, combination treatment with bortezomib and 2ME induces cell death via JNK-MKK4/7 activation by overproduction of mitochondrial ROS. Therefore, combination therapy with specific mitochondrial-targeting drugs may prove useful to the development of novel strategies for the treatment of bortezomib-resistant MM patients.