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Yushi Yao, Lei Wang, Jihao Zhou, Xinyou Zhang
BACKGROUND: Acute graft-versus-host disease (aGVHD) remains a major obstacle against favorable clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). T helper cells including Th17 play key roles in aGVHD pathogenesis. Donor regulatory T cell (Tregs) adoptive therapy reduces aGVHD without weakening graft-versus-leukemia effect (GVL) in both mouse and human, although the purification and ex vivo expansion of Tregs in clinical scenarios remain costly and technically demanding...
February 10, 2017: Journal of Translational Medicine
Yun-Sung Lim, Wonjae Cha, Min-Woo Park, Woo-Jin Jeong, Soon-Hyun Ahn
BACKGROUND: Tumor hypoxia induces hypoxia-inducible factor-1α (HIF1α), which can influence tumorigenesis and metastasis. We evaluated the expression of HIF1α and the effect of HIF1α inhibitors in adenoid cystic carcinoma (ACC). MATERIALS AND METHODS: HIF1α expression was demonstrated in ACC cell lines (ACC2 and ACCM). The effect of HIF1α inhibitors was evaluated. A systemic metastasis model was developed. The number of metastatic pulmonary nodules were analyzed...
2017: Anticancer Research
Yusuke Nagamine, Kentaro Tojo, Takuya Yazawa, Shunsuke Takaki, Yasuko Baba, Takahisa Goto, Kiyoyasu Kurahashi
Alveolar epithelial injury and increased alveolar permeability are hallmarks of acute respiratory distress syndrome. Apoptosis of lung epithelial cells via the Fas/Fas ligand (FasL) pathway plays a critical role in alveolar epithelial injury. Activation of hypoxia-inducible factor (HIF)-1 by inhibition of prolyl hydroxylase domain proteins (PHDs) is a possible therapeutic approach to attenuate apoptosis and organ injury. Here, we investigated whether treatment with dimethyloxalylglycine (DMOG), an inhibitor of PHDs, could attenuate Fas/FasL-dependent apoptosis in lung epithelial cells and lung injury...
December 2016: American Journal of Respiratory Cell and Molecular Biology
Marina Dal'Bó Pelegrini, Juliana Biar Pereira, Solange Dos Santos Costa, Myriam Janeth Salazar Terreros, Adriana Degrossoli, Selma Giorgio
OBJECTIVE: To evaluate whether hypoxia inducible factor (HIF-1α) targeting pharmacological drugs, echinomycin, resveratrol and CdCl2 which inhibit HIF-1α stimulation, and mimosine, which enhances the stability of HIF-1α present antileishmanial properties. METHODS: The leishmanicidal effect of drugs was evaluated in mouse macrophages and Balb/c mouse model for cutaneous leishmaniosis. RESULTS: Resveratrol and CdCl2 reduced the parasite load [IC50, (27...
July 2016: Asian Pacific Journal of Tropical Medicine
Thorsten Jentzsch, Stefan M Zimmermann, Flora Nicholls, Paolo Cinelli, Hans-Peter Simmen, Clément M L Werner
BACKGROUND: There is a need for effective drugs in the prevention and treatment of heterotopic ossifications (HO) after fractures. Echinomycin has been shown to prevent formation of HO in an animal model. However, before it may be considered as an option against HO, it needs to be studied whether it prevents fracture healing similar to non-steroidal anti-inflammatory drugs (NSAIDS). Therefore, the hypothesis was that echinomycin prevents fracture healing and callus formation. METHODS: In an experimental murine pilot study, standard blunt femur fractures were induced and retrograde intramedullary compression fixation of the femur was performed...
2016: Patient Safety in Surgery
Kozo Hattori, Kota Koike, Kensuke Okuda, Tasuku Hirayama, Masahiro Ebihara, Mei Takenaka, Hideko Nagasawa
Triostin A is a biosynthetic precursor of echinomycin which is one of the most potent hypoxia inducible factor 1 (HIF-1) inhibitors. An improved solution-phase synthesis of triostin A on a preparative scale has been achieved in 17.5% total yield in 13 steps. New analogues of triostin A with various aromatic chromophores, oxidized intra-peptide disulfide bridges and diastereoisomeric cyclic depsipeptide cores were also successfully synthesized. All analogues had a significant inhibitory effect on HIF-1 transcriptional activation in hypoxia and cytotoxicity on MCF-7 cells, with the exception of the derivatives containing a naphthalene chromophore or a thiosulfonate bridge...
February 14, 2016: Organic & Biomolecular Chemistry
Tomoko Tsuzuki, Hidetaka Okada, Hisayuu Shindoh, Kayo Shimoi, Akemi Nishigaki, Hideharu Kanzaki
Recent evidence points to a possible role for hypoxia-inducible factor (HIF)-1 in the pathogenesis and development of endometriosis. The objectives of this study were to investigate the critical role of HIF-1 in endometriosis and the effect of the HIF-1 inhibitor echinomycin on human ectopic endometriotic stromal cells (eESCs). Ectopic endometriotic tissues were obtained from 20 patients, who received an operation for ovarian endometriomas. We examined vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) production, HIF-1 expression, cell proliferation and apoptosis of eESCs...
2016: Gynecological Endocrinology
Xin Zhen, Ting Gong, Fu Liu, Pei-Cheng Zhang, Wan-Qi Zhou, Yan Li, Ping Zhu
Quinomycin G (1), a new analogue of echinomycin, together with a new cyclic dipeptide, cyclo-(l-Pro-4-OH-l-Leu) (2), as well as three known antibiotic compounds tirandamycin A (3), tirandamycin B (4) and staurosporine (5), were isolated from Streptomyces sp. LS298 obtained from a marine sponge Gelliodes carnosa. The planar and absolute configurations of compounds 1 and 2 were established by MS, NMR spectral data analysis and Marfey's method. Furthermore, the differences in NMR data of keto-enol tautomers in tirandamycins were discussed for the first time...
November 2015: Marine Drugs
Josipa Matić, Lidija-Marija Tumir, Marijana Radić Stojković, Ivo Piantanida
Interactions between DNA/RNA and huge variety of peptides are quite common in nature, controlling vast number of processes. Also, there are several naturally occurring small molecules which contain peptide and DNA intercalator in structure, whereby their biological activity is based on synergistic interactions of both components; for instance bis-intercalator echinomycin. Versatility of synthetic approaches to short peptides allowed their usage as simple recognition units within the DNA or RNA grooves or as backbone carriers for variety of bioactive substituents attached to amino acid side chains, one of very popular examples being PNAs...
2016: Current Protein & Peptide Science
X Y Pan, Z H Zhang, L X Wu, Z C Wang
The corpus luteum is a temporary endocrine structure in mammals that plays an important role in the female reproductive cycle and is formed from a ruptured and ovulated follicle with rapid angiogenesis. Vascular endothelial growth factor (VEGF) is thought to be vital in normal and abnormal angiogenesis in the ovary, but the molecular regulation of luteal VEGF expression during corpus luteum development in vivo is still poorly understood at present. Therefore, we examined whether hypoxia-inducible factor-1a (HIF-1a) is induced and regulates VEGF expression and luteal function in vivo using a pseudopregnant rat model treated with a small-molecule inhibitor of HIF-1a, echinomycin...
2015: Genetics and Molecular Research: GMR
Lixiang Wu, Zhenghong Zhang, Xiaoyan Pan, Zhengchao Wang
Vascular endothelial growth factor (VEGF) is vital in normal and abnormal angiogenesis in the ovary, particularly during the early development of the corpus luteum in the ovary. However, the molecular regulation of the expression VEGF during luteal development in vivo remains to be fully elucidated. As the expression of VEGF is mediated by hypoxia‑inducible factor (HIF)‑1α in luteal cells cultured in vitro, determined in our previous study, the present study was performed to confirm the hypothesis that HIF‑1α is induced and then regulates the expression of VEGF and VEGF‑dependent luteal development/function in vivo...
November 2015: Molecular Medicine Reports
Arash Boroumand Nasr, Deepika Ponnala, Someshwar Rao Sagurthi, Ramesh Kumar Kattamuri, Vijaya Kumar Marri, Suresh Gudala, Chandana Lakkaraju, Srinivas Bandaru, Anuraj Nayarisseri
UNLABELLED: Mammalian target of rapamycin (mTOR) is a key regulator of cell growth, proliferation and angiogenesis. mTOR signaling is frequently hyper activated in a broad spectrum of human cancers thereby making it a potential drug target. The current drugs available have been successful in inhibiting the mTOR signaling, nevertheless, show low oral bioavailability and suboptimal solubility. Considering the narrow therapeutic window of the available inhibitors, through computational approaches, the present study pursues to identify a compound with optimal oral bioavailability and better solubility properties in addition ensuing high affinity between FKBP12 and FRB domain of mTOR...
2015: Bioinformation
Satoshi Kambayashi, Masaya Igase, Kosuke Kobayashi, Ayana Kimura, Takako Shimokawa Miyama, Kenji Baba, Shunsuke Noguchi, Takuya Mizuno, Masaru Okuda
Hypoxic conditions in various cancers are believed to relate with their malignancy, and hypoxia inducible factor-1α (HIF-1α) has been shown to be a major regulator of the response to low oxygen. In this study, we examined HIF-1α expression in canine lymphoma using cell lines and clinical samples and found that these cells expressed HIF-1α. Moreover, the HIF-1α inhibitors, echinomycin, YC-1 and 2-methoxyestradiol, suppressed the proliferation of canine lymphoma cell lines. In a xenograft model using NOD/scid mice, echinomycin treatment resulted in a dose-dependent regression of the tumor...
November 2015: Journal of Veterinary Medical Science
Kenji Watanabe
No abstract text is available yet for this article.
February 2015: Japanese Journal of Antibiotics
Wonjae Cha, Dong-Wook Kim, Sung Dong Kim, Eun-Hui Jeon, Woo-Jin Jeong, Soon-Hyun Ahn
BACKGROUND/AIM: Despite an excellent prognosis, certain patients with thyroid cancer suffer from locally invasive disease that cannot be controlled by conventional therapy. Our previous study suggested that hypoxia inducible factor-1-alpha (HIF1α) might be an important marker for the identification of and a treatment target of intractable thyroid cancer. Therefore, in the present study, we established an orthotopic mouse surgical model of thyroid cancer that mimics the clinical setting, and evaluated the effect of perioperative treatment with a HIF1α inhibitor...
April 2015: Anticancer Research
Stefan K Alig, Yvonn Stampnik, Joachim Pircher, Raffaela Rotter, Erik Gaitzsch, Andrea Ribeiro, Markus Wörnle, Florian Krötz, Hanna Mannell
INTRODUCTION: The tyrosine phosphatase SHP-1 negatively influences endothelial function, such as VEGF signaling and reactive oxygen species (ROS) formation, and has been shown to influence angiogenesis during tissue ischemia. In ischemic tissues, hypoxia induced angiogenesis is crucial for restoring oxygen supply. However, the exact mechanism how SHP-1 affects endothelial function during ischemia or hypoxia remains unclear. We performed in vitro endothelial cell culture experiments to characterize the role of SHP-1 during hypoxia...
2015: PloS One
Ran Li, Yong Wang, Zhaofei Yang, Yunling He, Tong Zhao, Ming Fan, Xuan Wang, Lingling Zhu, Xiaomin Wang
Hypoxia is an important factor in regulation of cell behavior both under physiological and pathological conditions. The mechanisms of hypoxia-induced cell death have not been completely elucidated yet. It is well known that Ca(2+) is critically related to cell survival. Hypoxia-inducible factor-1α (HIF-1α) is a core regulatory factor during hypoxia, and L-type voltage-dependent Ca(2+) channels (L-VDCCs) have been reported to play a critical role in cell survival. This study was conducted to explore the relationship between L-VDCC expression and HIF-1α regulation in PC12 cells under hypoxia...
May 2015: Cell Stress & Chaperones
Soon-Hyun Ahn, Joo Yeon Choi, Dong Wook Kim, Doh Young Lee, Eun-Hui Jeon, Woo-Jin Jeong, Jin Ho Paik
BACKGROUND: The purpose of the present study was to evaluate the relationship between hypoxia-inducible factor 1 alpha subunit (HIF1α) and tumor initiation in squamous cell carcinoma cell lines and whether targeting HIF1α perioperatively might exert positive effects on survival or recurrence in an animal model. METHODS: The expression of HIF1α and tumorigenic potential in nude mice was compared using human head and neck squamous cell carcinoma cell lines (SNU1041, SNU1066, SNU1076, PCI01, PCI13, PCI50)...
September 2015: Annals of Surgical Oncology
Hiroki Hayase, Nobumoto Watanabe, Chung Liang Lim, Toshihiko Nogawa, Keisuke Komatsuya, Kiyoshi Kita, Hiroyuki Osada
Quinomycin A and its derivatives were identified as potent antimalarial (Plasmodium falciparum) agents in a screen of the RIKEN NPDepo chemical library. IC50 values of quinomycin A and UK-63,598 were approximately 100 times lower than that of the antimalarial drug chloroquine. This activity was mitigated by the addition of plasmid DNA, suggesting that these compounds act against parasites by intercalating into their DNA.
2015: Bioscience, Biotechnology, and Biochemistry
F Annang, G Pérez-Moreno, R García-Hernández, C Cordon-Obras, J Martín, J R Tormo, L Rodríguez, N de Pedro, V Gómez-Pérez, M Valente, F Reyes, O Genilloud, F Vicente, S Castanys, L M Ruiz-Pérez, M Navarro, F Gamarro, D González-Pacanowska
African trypanosomiasis, leishmaniasis, and Chagas disease are 3 neglected tropical diseases for which current therapeutic interventions are inadequate or toxic. There is an urgent need to find new lead compounds against these diseases. Most drug discovery strategies rely on high-throughput screening (HTS) of synthetic chemical libraries using phenotypic and target-based approaches. Combinatorial chemistry libraries contain hundreds of thousands of compounds; however, they lack the structural diversity required to find entirely novel chemotypes...
January 2015: Journal of Biomolecular Screening
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