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Experimental & Molecular Medicine

Donghee Kim, Hui Ying Li, Jong Han Lee, Yoon Sin Oh, Hee-Sook Jun
Mesangial cell proliferation has been identified as a major factor contributing to glomerulosclerosis, which is a typical symptom of diabetic nephropathy (DN). Lysophosphatidic acid (LPA) levels are increased in the glomerulus of the kidney in diabetic mice. LPA is a critical regulator that induces mesangial cell proliferation; however, its effect and molecular mechanisms remain unknown. The proportion of α-SMA+ /PCNA+ cells was increased in the kidney cortex of db/db mice compared with control mice. Treatment with LPA concomitantly increased the proliferation of mouse mesangial cells (SV40 MES13) and the expression of cyclin D1 and CDK4...
February 15, 2019: Experimental & Molecular Medicine
Minsik Park, Seunghwan Choi, Suji Kim, Joohwan Kim, Dong-Keon Lee, Wonjin Park, Taesam Kim, Jiwon Jung, Jong Yun Hwang, Moo-Ho Won, Sungwoo Ryoo, Seung Goo Kang, Kwon-Soo Ha, Young-Guen Kwon, Young-Myeong Kim
Vascular smooth muscle cells (VSMCs) play an important role in maintaining vascular function. Inflammation-mediated VSMC dysfunction leads to atherosclerotic intimal hyperplasia and preeclamptic hypertension; however, the underlying mechanisms are not clearly understood. We analyzed the expression levels of microRNA-155 (miR-155) in cultured VSMCs, mouse vessels, and clinical specimens and then assessed its role in VSMC function. Treatment with tumor necrosis factor-α (TNF-α) elevated miR-155 biogenesis in cultured VSMCs and vessel segments, which was prevented by NF-κB inhibition...
February 15, 2019: Experimental & Molecular Medicine
Daniel Scheiber, Tomas Jelenik, Elric Zweck, Patrick Horn, Heinz-Peter Schultheiss, Dirk Lassner, Udo Boeken, Diyar Saeed, Malte Kelm, Michael Roden, Ralf Westenfeld, Julia Szendroedi
The lifetime risk of developing heart failure is approximately 20%, and survival rates remain poor. Myocardial mitochondrial function has been suggested to play a pivotal role in heart failure pathophysiology. Human studies on ex vivo mitochondrial function have mostly been limited to atrial tissue obtained during open heart surgery and have provided contradictory results. This study aimed at measuring myocardial mitochondrial function in transcatheter ventricular endomyocardial biopsies and assessing the relationship between oxidative capacity and heart function...
February 14, 2019: Experimental & Molecular Medicine
Xiaozhong Zheng, Ailiang Zhang, Margaret Binnie, Kris McGuire, Scott P Webster, Jeremy Hughes, Sarah E M Howie, Damian J Mole
Acute kidney injury (AKI) following ischemia-reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking kynurenine 3-monooxygenase (KMO) activity (Kmonull mice) are protected against AKI after renal IRI. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically active kynurenine metabolites 3-hydroxykynurenine, kynurenic acid, and downstream metabolites. In experimental AKI induced by kidney IRI, Kmonull mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared with wild-type (Kmowt ) control mice...
February 13, 2019: Experimental & Molecular Medicine
Chan-Hun Jung, Eun Mi Kim, Jie-Young Song, Jong Kuk Park, Hong-Duck Um
Sublethal doses of γ-rays promote cancer cell invasion by stimulating a signaling pathway that sequentially involves p53, sulfatase 2 (SULF2), β-catenin, interleukin-6 (IL-6), signal transducer and activator of transcription 3 (STAT3), and Bcl-XL . Given that Bcl-XL can increase O2 •- production by stimulating respiratory complex I, the possible role of mitochondrial reactive oxygen species (ROS) in γ-irradiation-induced cell invasion was investigated. Indeed, γ-irradiation promoted cell invasion by increasing mitochondrial ROS levels, which was prevented by metformin, an inhibitor of complex I...
February 12, 2019: Experimental & Molecular Medicine
Susoma Jannat, Anand Balupuri, Md Yousof Ali, Seong Su Hong, Chun Whan Choi, Yun-Hyeok Choi, Jin-Mo Ku, Woo Jung Kim, Jae Yoon Leem, Ju Eun Kim, Abinash Chandra Shrestha, Ha Neul Ham, Kee-Ho Lee, Dong Min Kim, Nam Sook Kang, Gil Hong Park
We extracted 15 pterosin derivatives from Pteridium aquilinum that inhibited β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and cholinesterases involved in the pathogenesis of Alzheimer's disease (AD). (2R)-Pterosin B inhibited BACE1, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with an IC50 of 29.6, 16.2 and 48.1 µM, respectively. The Ki values and binding energies (kcal/mol) between pterosins and BACE1, AChE, and BChE corresponded to the respective IC50 values. (2R)-Pterosin B was a noncompetitive inhibitor against human BACE1 and BChE as well as a mixed-type inhibitor against AChE, binding to the active sites of the corresponding enzymes...
February 12, 2019: Experimental & Molecular Medicine
Nak-Kyun Soung, Hye-Min Kim, Yukihiro Asami, Dong Hyun Kim, Yangrae Cho, Ravi Naik, Yerin Jang, Kusic Jang, Ho Jin Han, Srinivas Rao Ganipisetti, Hyunjoo Cha-Molstad, Joonsung Hwang, Kyung Ho Lee, Sung-Kyun Ko, Jae-Hyuk Jang, In-Ja Ryoo, Yong Tae Kwon, Kyung Sang Lee, Hiroyuki Osada, Kyeong Lee, Bo Yeon Kim, Jong Seog Ahn
Hypoxia-inducible factor-1α (HIF-1α) mediates tumor cell adaptation to hypoxic conditions and is a potentially important anticancer therapeutic target. We previously developed a method for synthesizing a benzofuran-based natural product, (R)-(-)-moracin-O, and obtained a novel potent analog, MO-460 that suppresses the accumulation of HIF-1α in Hep3B cells. However, the molecular target and underlying mechanism of action of MO-460 remained unclear. In the current study, we identified heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) as a molecular target of MO-460...
February 12, 2019: Experimental & Molecular Medicine
Sunghun Lee, Dong Hun Lee, Bong-Woo Park, Riyoun Kim, Anh Duc Hoang, Sang-Keun Woo, Wenjun Xiong, Yong Jin Lee, Kiwon Ban, Hun-Jun Park
Vascular regeneration in ischemic hearts has been considered a target for new therapeutic strategies. It has been reported that ETV2 is essential for vascular development, injury-induced neovascularization and direct cell reprogramming of non-endothelial cells into endothelial cells. Thus, the objective of this study was to explore the therapeutic potential of ETV2 in murine models of myocardial infarction in vivo. Direct myocardial delivery of lentiviral ETV2 into rodents undergoing myocardial infarction dramatically upregulated the expression of markers for angiogenesis as well as anti-fibrosis and anti-inflammatory factors in vivo...
February 12, 2019: Experimental & Molecular Medicine
So-Yoon Won, Jung-Jin Park, Eun-Young Shin, Eung-Gook Kim
p21-Activated kinase 4 (PAK4), a member of the PAK family, regulates a wide range of cellular functions, including cell adhesion, migration, proliferation, and survival. Dysregulation of its expression and activity thus contributes to the development of diverse pathological conditions. PAK4 plays a pivotal role in cancer progression by accelerating the epithelial-mesenchymal transition, invasion, and metastasis. Therefore, PAK4 is regarded as an attractive therapeutic target in diverse types of cancers, prompting the development of PAK4-specific inhibitors as anticancer drugs; however, these drugs have not yet been successful...
February 12, 2019: Experimental & Molecular Medicine
Jeong Seon Kim, Eun Ju Kim, Sieun Lee, Xiaochao Tan, Xin Liu, Sanghui Park, Keunsoo Kang, Jung-Sook Yoon, Yoon Ho Ko, Jonathan M Kurie, Young-Ho Ahn
Three miR-34 family members (miR-34a, miR-34b, and miR-34c) are clustered on two different chromosomal loci, Mir34a and Mir34b/c. These miRNAs have identical seed sequences, which are predicted to target the same set of genes. However, miR-34a and miR-34c have different sets of negatively correlated genes in lung adenocarcinoma data from The Cancer Genome Atlas. Therefore, we hypothesized that the individual miR-34 family members, which are tumor suppressive miRNAs, would have varying effects on lung tumorigenesis...
January 17, 2019: Experimental & Molecular Medicine
Hyung Kwon Byeon, Minhee Ku, Jaemoon Yang
Epidermal growth factor receptor (EGFR) overexpression is common in head and neck squamous cell carcinoma. Targeted therapy specifically directed towards EGFR has been an area of keen interest in head and neck cancer research, as EGFR is potentially an integration point for convergent signaling. Despite the latest advancements in cancer diagnostics and therapeutics against EGFR, the survival rates of patients with advanced head and neck cancer remain disappointing due to anti-EGFR resistance. This review article will discuss recent multilateral efforts to discover and validate actionable strategies that involve signaling pathways in heterogenous head and neck cancer and to overcome anti-EGFR resistance in the era of precision medicine...
January 16, 2019: Experimental & Molecular Medicine
Sung-Jin Bae, Min Wook Shin, Taekwon Son, Hye Shin Lee, Ji Soo Chae, Sejin Jeon, Goo Taeg Oh, Kyu-Won Kim
Osteoclasts (OCs) are bone-resorbing cells that originate from hematopoietic stem cells and develop through the fusion of mononuclear myeloid precursors. Dysregulation of OC development causes bone disorders such as osteopetrosis, osteoporosis, and rheumatoid arthritis. Although the molecular mechanisms underlying osteoclastogenesis have been well established, the means by which OCs maintain their survival during OC development remain unknown. We found that Ninjurin1 (Ninj1) expression is dynamically regulated during osteoclastogenesis and that Ninj1-/- mice exhibit increased trabecular bone volume owing to impaired OC development...
January 16, 2019: Experimental & Molecular Medicine
Woori Jang, Joonhong Park, Ahlm Kwon, Hayoung Choi, Jiyeon Kim, Gun Dong Lee, Eunhee Han, Dong Wook Jekarl, Hyojin Chae, Kyungja Han, Jae-Ho Yoon, Seok Lee, Nack-Gyun Chung, Bin Cho, Myungshin Kim, Yonggoo Kim
We identified principal genetic alterations in 97.1% (99/102) of patients with T-acute lymphoblastic leukemia (T-ALL) using integrative genetic analyses, including massive parallel sequencing and multiplex ligation-dependent probe amplification (MLPA). A total of 133 mutations were identified in the following genes in descending order: NOTCH1 (66.7%), FBXW7 (19.6%), PHF6 (15.7%), RUNX1 (12.7%), NRAS (10.8%), and DNMT3A (9.8%). Copy number alterations were most frequently detected in CDKN2B, CDKN2A, and genes on 9p21...
January 11, 2019: Experimental & Molecular Medicine
Qian Ding, Xiao-Li Xie, Miao-Miao Wang, Jie Yin, Jin-Mei Tian, Xiao-Yu Jiang, Di Zhang, Jing Han, Yun Bai, Zi-Jin Cui, Hui-Qing Jiang
The clearance of activated hepatic stellate cells (HSCs) by apoptosis is critical for the reversibility of hepatic fibrosis. Mitochondrial homeostasis is regulated by mitophagy, which is an efficient way of clearing injured mitochondria that plays an important role in apoptosis. However, the role of mitophagy in apoptosis in HSCs and hepatic fibrosis is still unclear. Here, we show that mitophagy is enhanced in parallel with increased apoptosis in hepatic stellate cells during the reversal of hepatic fibrosis...
January 11, 2019: Experimental & Molecular Medicine
Nam-Jun Kim, Jung-Hwan Baek, JinAh Lee, HyeNa Kim, Jun-Kyu Song, Kyung-Hee Chun
Vinpocetine, a phosphodiesterase (PDE) type-1 inhibitor, increases cAMP and cGMP levels and is currently used for the management of cerebrovascular disorders, such as stroke, cerebral hemorrhage, and cognitive dysfunctions. In this study, we first determined that vinpocetine effectively suppressed adipogenesis and lipid accumulation. However, we questioned which molecular mechanism is involved because the role of PDE in adipogenesis is still controversial. Vinpocetine decreased adipogenic cell signaling, including the phosphorylation of ERK, AKT, JAK2, and STAT3, and adipokine secretion, including IL-6, IL-10, and IFN-α...
January 11, 2019: Experimental & Molecular Medicine
Arunkumar Arumugam, Ramadevi Subramani, Sushmita Bose Nandy, Daniel Terreros, Alok Kumar Dwivedi, Edward Saltzstein, Rajkumar Lakshmanaswamy
Growth hormone receptor (GHR) plays a vital role in breast cancer chemoresistance and metastasis but the mechanism is not fully understood. We determined if GHR could be a potential therapeutic target for estrogen receptor negative (ER-ve) breast cancer, which are highly chemoresistant and metastatic. GHR was stably knocked down in ER-ve breast cancer cells and its effect on cell proliferation, metastatic behavior, and chemosensitivity to docetaxel (DT) was assessed. Microarray analysis was performed to identify potential GHR downstream targets involved in chemoresistance...
January 7, 2019: Experimental & Molecular Medicine
Yeonsue Jang, Jinhyeok Choi, Narae Park, Jaewoo Kang, Myungshin Kim, Yonggoo Kim, Ji Hyeon Ju
Pluripotent stem cell transplantation is a promising regenerative strategy for treating intractable diseases. However, securing human leukocyte antigen (HLA)-matched donor stem cells is extremely difficult. The traditional approach for generating such cells is to establish homozygous pluripotent stem cell lines. Unfortunately, because of HLA diversity, this strategy is too time-consuming to be of practical use. HLA engineering of donor stem cells has been proposed recently as a means to evade graft-versus-host rejection in stem cell allotransplantation...
January 7, 2019: Experimental & Molecular Medicine
Mirim Jin
Tryptophanyl tRNA synthetase (WRS) is an essential enzyme as it catalyzes the ligation of tryptophan to its cognate tRNA during translation. Interestingly, mammalian WRS has evolved to acquire domains or motifs for novel functions beyond protein synthesis; WRS can also further expand its functions via alternative splicing and proteolytic cleavage. WRS is localized not only to the nucleus but also to the extracellular space, playing a key role in innate immunity, angiogenesis, and IFN-γ signaling. In addition, the expression of WRS varies significantly in different tissues and pathological states, implying that it plays unique roles in physiological homeostasis and immune defense...
January 7, 2019: Experimental & Molecular Medicine
Rosa Jiménez-Lucena, Antonio Camargo, Juan Francisco Alcalá-Diaz, Cristina Romero-Baldonado, Raúl Miguel Luque, Ben van Ommen, Javier Delgado-Lista, Jose María Ordovás, Pablo Pérez-Martínez, Oriol Alberto Rangel-Zúñiga, Jose López-Miranda
We aimed to explore whether changes in circulating levels of miRNAs according to type 2 diabetes mellitus (T2DM) or prediabetes status could be used as biomarkers to evaluate the risk of developing the disease. The study included 462 patients without T2DM at baseline from the CORDIOPREV trial. After a median follow-up of 60 months, 107 of the subjects developed T2DM, 30 developed prediabetes, 223 maintained prediabetes and 78 remained disease-free. Plasma levels of four miRNAs related to insulin signaling and beta-cell function were measured by RT-PCR...
December 26, 2018: Experimental & Molecular Medicine
Bing-Dong Sui, Ji Chen, Xin-Yi Zhang, Tao He, Pan Zhao, Chen-Xi Zheng, Meng Li, Cheng-Hu Hu, Yan Jin
Osteoporosis develops with high prevalence in both postmenopausal women and hypogonadal men. Osteoporosis results in significant morbidity, but no cure has been established. Mesenchymal stem cells (MSCs) critically contribute to bone homeostasis and possess potent immunomodulatory/anti-inflammatory capability. Here, we investigated the therapeutic efficacy of using an infusion of MSCs to treat sex hormone-deficient bone loss and its underlying mechanisms. In particular, we compared the impacts of MSC cytotherapy in the two genders with the aim of examining potential gender differences...
December 17, 2018: Experimental & Molecular Medicine
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