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E1 inhibitor

Karnam Shruthi, S Sreenivasa Reddy, P Swathi Chitra, G Bhanuprakash Reddy
The ubiquitin-proteasome system (UPS) has been implicated in the pathogenesis of many neurodegenerative diseases. Endoplasmic reticulum (ER) stress is shown to play a pathological role in the development of diabetes and its complications. Hence, the current study is aimed to investigate the role of UPS and ER stress in the cerebral cortex of diabetic rats and examine the therapeutic effect of 4-phenylbutyric acid (4-PBA), an ER stress inhibitor. Male Sprague-Dawley rats were divided into three groups: control, diabetes, and diabetes plus 4-PBA treatment group...
October 14, 2018: Journal of Cellular Biochemistry
Jian Wang, Chengchuang Song, Xiukai Cao, Hui Li, Hanfang Cai, Yilei Ma, Yongzhen Huang, Xianyong Lan, Chuzhao Lei, Yun Ma, Yueyu Bai, Fengpeng Lin, Hong Chen
Skeletal muscle is the most abundant tissue in the body. The development of skeletal muscle cell is complex and affected by many factors. A sea of microRNAs (miRNAs) have been identified as critical regulators of myogenesis. MiR-208b, a muscle-specific miRNA, was reported to have a connection with fiber type determination. However, whether miR-208b has effect on proliferation of muscle cell was under ascertained. In our study, cyclin-dependent kinase inhibitor 1A (CDKN1A), which participates in cell cycle regulation, was predicted and then validated as one target gene of miR-208b...
October 14, 2018: Journal of Cellular Physiology
Xin Li, Ming Dong, Jianping Zhou, Dehua Zhu, Jinbo Zhao, Weiwei Sheng
C6orf106 was highly expressed in lung and breast cancer, and proposed as clinicopathologic factor for the development of those types of cancer. However, its expression in pancreatic cancer and the mechanism that C6orf106 functions as an oncogene has not been confirmed. In the present study, we found that C6orf106 was also up-regulated in pancreatic cancer tissues and cell lines. Furthermore, C6orf106 expression was associated with advanced T stage (P = 0.010), positive regional lymph node metastasis (P = 0...
October 11, 2018: Molecular and Cellular Biochemistry
Xing-Rong An, Xin Li, Wei Wei, Xiao-Xue Li, Ming Xu
BACKGROUND/AIMS: The phenotype switching of vascular smooth muscle cells (VSMCs) was associated with the onset or progression of the atherogenic process in type 2 diabetes mellitus (T2DM). Alprostadil (Prostaglandin E1, PGE1) as a bioactive drug had a protective effect on vascular function. However, it is unknown whether PGE1 inhibited the phenotype switching in VSMCs via autophagy, which played a protective role in the vascular complications of diabetes. METHODS: The phenotype switching was induced by high glucose (HG, 25mM) in VSMCs, the protein expression was measured by western blot analysis and immunofluorescent staining...
October 11, 2018: Cellular Physiology and Biochemistry
Masayoshi Ishida, Naoyuki Kawao, Kiyotaka Okada, Kohei Tatsumi, Kazuko Sakai, Kazuto Nishio, Hiroshi Kaji
It is well known that sex differences exist about the severity of osteoporosis and bone metabolism, suggesting that factors other than sex hormones might be responsible for sex differences of bone metabolism. We therefore examined sex differences of the osteoblast phenotypes of mouse osteoblasts, and then performed the comparative gene expression analyses using a comprehensive DNA microarray between female and male osteoblasts. Alkaline phosphatase (ALP) activity, mineralization and the expression of Osterix, ALP, and bone sialoprotein were significantly lower in mouse female osteoblasts, compared to male...
October 9, 2018: Endocrinology
Zongyang Lv, Katelyn M Williams, Lingmin Yuan, James H Atkison, Shaun K Olsen
Ubiquitin (Ub) signaling plays a key regulatory role in nearly every aspect of eukaryotic biology and is initiated by E1 enzymes that activate and transfer Ub to E2 Ub-conjugating enzymes. Despite Ub E1's fundamental importance to the cell and its attractiveness as a target for therapeutic intervention in cancer and other diseases, its only available structural information is derived from yeast orthologs of human ubiquitin-like modifier-activating enzyme 1 (hUBA1). To illuminate structural differences between yeast and hUBA1 structures that might be exploited for the development of small-molecule therapeutics, we determined the first crystal structure of a hUBA1/Ub complex...
October 2, 2018: Journal of Biological Chemistry
Julie K Monda, Iain M Cheeseman
Cytoplasmic dynein is a minus-end-directed microtubule-based motor that acts at diverse subcellular sites. During mitosis, dynein localizes simultaneously to the mitotic spindle, spindle poles, kinetochores and the cell cortex. However, it is unclear what controls the relative targeting of dynein to these locations. As dynein is heavily post-translationally modified, we sought to test a role for these modifications in regulating dynein localization. We find that dynein rapidly and strongly accumulates at mitotic spindle poles following treatment with NSC697923, a small molecule that inhibits the ubiquitin E2 enzyme, Ubc13, or treatment with PYR-41, a ubiquitin E1 inhibitor...
September 26, 2018: Open Biology
Takako Ida, Masaru Kaku, Megumi Kitami, Masahiko Terajima, Juan Marcelo Rosales Rocabado, Yosuke Akiba, Masako Nagasawa, Mitsuo Yamauchi, Katsumi Uoshima
Fibrillar type I collagen, the predominant organic component in bone, is stabilized by lysyl oxidase (LOX)-initiated covalent intermolecular cross-linking, an important determinant of bone quality. However, the impact of collagen cross-linking on the activity of bone cells and subsequent tissue remodeling is not well understood. In this study, we investigated the effect of collagen cross-linking on bone cellular activities employing a loss-of-function approach, using a potent LOX inhibitor, β-aminopropionitrile (BAPN)...
2018: PloS One
André Wirries, Samir Jabari, Esther P Jansen, Silvia Roth, Elizabeth Figueroa-Juárez, Thaddeus T Wissniowski, Daniel Neureiter, Eckhard Klieser, Philipp Lechler, Steffen Ruchholtz, Detlef K Bartsch, Christoph K Boese, Pietro Di Fazio
Osteosarcoma is an aggressive cancer with a poor long term prognosis. Neo-adjuvant poly-chemotherapy followed by surgical resection remains the standard treatment, which is restricted by multi-drug resistance. If first-line therapy fails, disease control and patient survival rate drop dramatically. We aimed to identify alternative apoptotic mechanisms induced by the histone deacetylase inhibitor panobinostat in osteosarcoma cells. Saos-2, MG63 and U2-OS osteosarcoma cell lines, the immortalized human osteoblast line hFOB and the mouse embryo osteoblasts (MC3T3-E1) were treated with panobinostat...
August 31, 2018: Oncotarget
Qing Shu, Song Lai, Xiao-Mei Wang, Yun-Long Zhang, Xiao-Lei Yang, Hai-Lian Bi, Hui-Hua Li
Pathological cardiac hypertrophy is the main risk factor for heart diseases. The ubiquitin-proteasome system (UPS) is the major intracellular protein degradation system involved in the development of cardiac hypertrophic remodeling. Ubiquitin-activating enzyme E1, a key component of the UPS, catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation via proteasome. However, the functional role of E1 (UBA1) in regulation of hypertrophic remodeling in angiotensin II (Ang II)-infused mice remains unknown...
September 21, 2018: Biochemical and Biophysical Research Communications
Tetsu Kawabata, Haruhiko Tokuda, Go Sakai, Kazuhiko Fujita, Rie Matsushima-Nishiwaki, Takanobu Otsuka, Osamu Kozawa
Polyphenolic compounds in beverages may have benefits in the prevention of osteoporosis. It has been demonstrated previously that insulin-like growth factor-I (IGF-I) could stimulate the migration of osteoblasts. In the present study, it was investigated whether chlorogenic acid, a major polyphenol in coffee, and (-)-epigallocatechin gallate (EGCG), a major polyphenol in green tea, could affect this IGF-I-stimulated migration of osteoblast-like MC3T3-E1 cells. The IGF-I-stimulated osteoblast migration, evaluated by Transwell cell migration and wound-healing assays, was inhibited by EGCG but not chlorogenic acid...
October 2018: Biomedical Reports
Jessica L Bridgford, Stanley C Xie, Simon A Cobbold, Charisse Flerida A Pasaje, Susann Herrmann, Tuo Yang, David L Gillett, Lawrence R Dick, Stuart A Ralph, Con Dogovski, Natalie J Spillman, Leann Tilley
Artemisinin and its derivatives (collectively referred to as ARTs) rapidly reduce the parasite burden in Plasmodium falciparum infections, and antimalarial control is highly dependent on ART combination therapies (ACTs). Decreased sensitivity to ARTs is emerging, making it critically important to understand the mechanism of action of ARTs. Here we demonstrate that dihydroartemisinin (DHA), the clinically relevant ART, kills parasites via a two-pronged mechanism, causing protein damage, and compromising parasite proteasome function...
September 18, 2018: Nature Communications
Martha Ariza-Sáenz, Marta Espina, Ana Calpena, María J Gómara, Ignacio Pérez-Pomeda, Isabel Haro, María Luisa García
New therapeutic alternatives to fight against the spread of HIV-1 are based on peptides designed to inhibit the early steps of HIV-1 fusion in target cells. However, drawbacks, such as bioavailability, short half-life, rapid clearance, and poor ability to cross the physiological barriers, make such peptides unattractive for the pharmaceutical industry. Here we developed, optimized, and characterized polymeric nanoparticles (NPs) coated with glycol chitosan to incorporate and release an HIV-1 fusion inhibitor peptide (E1) inside the vaginal mucosa...
October 3, 2018: Molecular Pharmaceutics
Raphaël Dutour, Jenny Roy, Francisco Cortés-Benítez, René Maltais, Donald Poirier
Cytochrome P450 (CYP) 1B1 is involved in the bioactivation of procarcinogens and drug resistance. To obtain selective CYP1B1 inhibitors over CYP1A1, we synthesized four series of estrane derivatives: (1) 12 estrone (E1)- and 17β-estradiol (E2)-derivatives bearing a 3- or a 4-pyridinyl core at C2, C3, or C4, (2) eight estrane derivatives with different sulfur groups at C3, (3) 19 E1- and E2-derivatives bearing distinct aryls at C2, and (4) five D-ring derivatives. E2-derivatives were more active than oxidized E1-analogues, thus highlighting the key role of 17β-OH for interaction with CYP1B1...
October 3, 2018: Journal of Medicinal Chemistry
Yaqiong Yu, Xiaolin Li, Jing Mi, Liu Qu, Di Yang, Jiajie Guo, Lihong Qiu
Porphyromonas endodontalis ( P. endodontalis ) lipopolysaccharide (LPS) is associated with the progression of bone resorption in periodontal and periapical diseases. Matrix metalloproteinase-2 (MMP-2) expression and activity are elevated in apical periodontitis and have been suggested to participate in bone resorption. Therefore, inhibiting MMP-2 activation may be considered a therapeutic strategy for treating apical periodontitis. Resveratrol is a natural non-flavonoid polyphenol that has been reported to have antioxidant, anti-cancer, and anti-inflammatory properties...
September 12, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Fan Zhou, Qingqing Yuan, Wenhui Zhang, Minghui Niu, Hongyong Fu, Qianqian Qiu, Guoping Mao, Hong Wang, Liping Wen, Hongxiang Wang, Mujun Lu, Zheng Li, Zuping He
Human spermatogonial stem cells (SSCs) could have significant applications in reproductive medicine and regenerative medicine because of their great plasticity. The fate determinations of human SSCs are mediated by epigenetic factors. However, nothing is known about the regulation of non-coding RNA on human SSCs. Here we have explored for the first time the expression, function, and target of miR-663a in human SSCs. MiR-663a was upregulated in human spermatogonia compared with pachytene spermatocytes, as indicated by microRNA microarray and real-time PCR...
September 7, 2018: Molecular Therapy. Nucleic Acids
Jing-Hua Pan, Hong Zhou, Sheng-Bin Zhu, Jin-Lian Huang, Xiao-Xu Zhao, Hui Ding, Li Qin, Yun-Long Pan
Colorectal cancer (CRC) is the third most common malignancy, and the metabolic properties of CRC cells include enhanced aerobic glycolysis (the Warburg effect). Nicotinamide phosphoribosyl transferase (NAMPT) is one of the crucial enzymes that regulate the activity of nicotinamide adenine dinucleodinucleotide dependent enzymes. Targeting NAMPT is a potential method of CRC therapy. Nevertheless, the underlying clinical implications and regulatory mechanisms of NAMPT in CRC remain unclear. In this study, we showed that NAMPT protein expression was increased in subjects with rectal localization compared with those with colon localization, and NAMPT was a poor prognostic marker for the overall survival rate in patients with CRC...
September 7, 2018: Journal of Cellular Physiology
Ming-Min Chang, Meng-Shao Lai, Siou-Ying Hong, Bo-Syong Pan, Hsin Huang, Shang-Hsun Yang, Chia-Ching Wu, H Sunny Sun, Jih-Ing Chuang, Chia-Yih Wang, Bu-Miin Huang
Fibroblast growth factor 9 (FGF9) promotes cancer progression, however, its role in cell proliferation related to tumorigenesis remains elusive. We investigated how FGF9 affected MA-10 mouse Leydig tumor cell proliferation and found that FGF9 significantly induced cell proliferation by activating ERK1/2 and Rb phosphorylations within 15 minutes. Subsequently, the expressions of E2F1 and the cell cycle factors, cyclin D1, cyclin E1 and CDK4 in G1 phase and cyclin A1, CDK2 and CDK1 in S-G2/M phases were increased at 12 hours after FGF9 treatment; and cyclin B1 in G2/M phases were induced at 24 hours after FGF9 stimulation, whereas the phosphorylations of p53, p21 and p27 weren't affected by FGF9...
September 6, 2018: Cancer Science
Emre Karakus, Daniel Zahner, Gary Grosser, Regina Leidolf, Cemal Gundogdu, Alberto Sánchez-Guijo, Stefan A Wudy, Joachim Geyer
Estrogens play a pivotal role in the development and proliferation of hormone-dependent breast cancer. Apart from free estrogens, which can directly activate the estrogen receptor (ER) of tumor cells, sulfo-conjugated steroids, which maintain high plasma concentrations even after menopause, first have to be imported into tumor cells by carrier-mediated uptake and then can be cleaved by the steroid sulfatase to finally activate ERs and cell proliferation. In the present study, expression of the sodium-dependent organic anion transporter SOAT was analyzed in breast cancer and its role for hormone-dependent proliferation of T47D breast cancer cells was elucidated...
2018: Frontiers in Pharmacology
Satoru Tamura, Gang-Ming Yang, Teruaki Koitabashi, Yoshiharu Matsuura, Yasumasa Komoda, Tomikazu Kawano, Nobutoshi Murakami
The envelope proteins of the hepatitis C virus (HCV), E1 and E2, have been revealed to be essential for invasion of HCV. Thus, we were engaged in the search for the inhibitors against HCV invasion through the assay system using the model virus expressing recombinant HCV envelopes, E1 and E2. Now, we disclosed dimeric hydrolysable tannin oenothein B (1) from MeOH extract of Oenothera erythrosepala as an active principle for inhibition of HCV invasion and its potency was almost the same as that of monomeric hydrolysable tannin, tellimagrandin I (2)...
August 21, 2018: Journal of Natural Medicines
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