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https://read.qxmd.com/read/30899386/herbacetin-treatment-remitted-lps-induced-inhibition-of-osteoblast-differentiation-through-blocking-akt-nf-%C3%AE%C2%BAb-signaling-pathway
#1
Pengshan Cai, Teng Cai, Xiaobin Li, Lei Fan, Guang Chen, Bofan Yu, Tao Liu
Inflammation, a common situation during the process of bone healing, is reported to play a negative role in bone regeneration. Up to date, therapeutic strategies for inflammation triggered inhibition of osteoblast differentiation are still limited. The aim of this study was to explore the potential roles and molecular mechanisms of Herbacetin in the process of osteoblast differentiation under LPS-mediated inflammatory environment. By using MC3T3-E1, C2C12 and primary mouse calvarial osteoblast (PMCO) cells as experimental models, we observed that LPS stimulation suppressed osteoblast differentiation via inhibiting alkaline phosphatase (ALP) activity and the expression of several osteoblastic genes (osterix, runx2 and osteocalcin)...
2019: American Journal of Translational Research
https://read.qxmd.com/read/30898011/suppression-of-autophagy-during-mitosis-via-cul4-ring-ubiquitin-ligases-mediated-wipi2-polyubiquitination-and-proteasomal-degradation
#2
Guang Lu, Juan Yi, Andrea Gubas, Ya-Ting Wang, Yihua Wu, Yi Ren, Man Wu, Yin Shi, Chenxi Ouyang, Hayden Weng Siong Tan, Tianru Wang, Liming Wang, Nai-Di Yang, Shuo Deng, Dajing Xia, Ruey-Hwa Chen, Sharon A Tooze, Han-Ming Shen
Macroautophagy/autophagy is a cellular process in which cytosolic contents are degraded by lysosome in response to various stress conditions. Apart from its role in the maintenance of cellular homeostasis, autophagy also involves in regulation of cell cycle progression under nutrient-deprivation conditions. However, whether and how autophagy is regulated by the cell cycle especially during mitosis remains largely undefined. Here we show that WIPI2/ATG18B (WD repeat domain, phosphoinositide interacting 2), an autophagy-related (ATG) protein that plays a critical role in autophagosome biogenesis, is a direct substrate of CUL4-RING ubiquitin ligases (CRL4s)...
March 22, 2019: Autophagy
https://read.qxmd.com/read/30896842/vitamin-k2-stimulates-mc3t3%C3%A2-e1-osteoblast-differentiation-and-mineralization-through-autophagy-induction
#3
Weiwei Li, Shaokun Zhang, Jie Liu, Yongyi Liu, Qingwei Liang
Vitamin K2 likely exerts its protective effects during osteoporosis by promoting osteoblast differentiation and mineralization. However, the precise mechanism remains to be fully elucidated. Autophagy maintains cell homeostasis by breaking down and eliminating damaged proteins and organelles. Increasing evidence in recent years has implicated autophagy in the development of osteoporosis. The aim of the present study was to verify whether vitamin K2 (VK2) can induce autophagy during the differentiation and mineralization of osteoblasts...
March 15, 2019: Molecular Medicine Reports
https://read.qxmd.com/read/30884976/jnk-inactivation-suppresses-osteogenic-differentiation-but-robustly-induces-osteopontin-expression-in-osteoblasts-through-the-induction-of-inhibitor-of-dna-binding-4-id4
#4
Joji Kusuyama, Muhammad Subhan Amir, Brent G Albertson, Kenjiro Bandow, Tomokazu Ohnishi, Toshiaki Nakamura, Kazuyuki Noguchi, Kaori Shima, Ichiro Semba, Tetsuya Matsuguchi
Osteoblasts are versatile cells involved in multiple whole-body processes, including bone formation and immune response. Secretory amounts and patterns of osteoblast-derived proteins such as osteopontin (OPN) and osteocalcin (OCN) modulate osteoblast function. However, the regulatory mechanism of OPN and OCN expression remains unknown. Here, we demonstrate that p54/p46 c-jun N-terminal kinase (JNK) inhibition suppresses matrix mineralization and OCN expression but increases OPN expression in MC3T3-E1 cells and primary osteoblasts treated with differentiation inducers, including ascorbic acid, bone morphogenic protein-2, or fibroblast growth factor 2...
March 18, 2019: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://read.qxmd.com/read/30854973/pharmaceutical-interfering-of-neddylation-as-promising-treatments-for-various-cancers
#5
Lina Yin, Yuanyuan Xue, Qiannan Shang, Haichao Zhu, Meihua Liu, Yingxiang Liu, Qingzhong Hu
BACKGROUND: Neddylation is an important post-translational modification of proteins, in which a NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8, ) is covalently introduced onto the substrate proteins to regulate their functions and homeostasis. As neddylation is frequently up-regulated in various cancers, its interference was proposed as a promising therapy of related diseases. OBJECTIVE: The recent advances in developing neddylation interfering agents were summarized to provide an overview of current achievements and perspectives for future development...
March 10, 2019: Current Topics in Medicinal Chemistry
https://read.qxmd.com/read/30824796/peptide-assembly-on-the-membrane-determines-the-hiv-1-inhibitory-activity-of-dual-targeting-fusion-inhibitor-peptides
#6
Maria J Gomara, Yolanda Perez, Javier P Martinez, Ramon Barnadas-Rodriguez, Anke Schultz, Hagen von Briesen, Alex Peralvarez-Marin, Andreas Meyerhans, Isabel Haro
Novel strategies in the design of HIV-1 fusion/entry inhibitors are based on the construction of dual-targeting fusion proteins and peptides with synergistic antiviral effects. In this work we describe the design of dual-targeting peptides composed of peptide domains of E2 and E1 envelope proteins from Human Pegivirus with the aim of targeting both the loop region and the fusion peptide domains of HIV-1 gp41. In a previous work, we described the inhibitory role of a highly conserved fragment of the E1 protein (domain 139-156) which interacts with the HIV-1 fusion peptide at the membrane level...
March 1, 2019: Scientific Reports
https://read.qxmd.com/read/30794786/discovery-of-a-first-in-class-covalent-allosteric-inhibitor-of-sumo-e1-activating-enzyme
#7
Robert S Magin, Laura M Doherty, Sara J Buhrlage
SUMOylation is a post-translational modification with important roles in normal physiology and whose dysregulation is associated with human diseases. In this issue of Cell Chemical Biology, Li et al. (2019) describe a covalent, allosteric inhibitor of the SUMO E1 enzyme and demonstrate its anti-tumor activity in preclinical models of colorectal cancer.
February 21, 2019: Cell Chemical Biology
https://read.qxmd.com/read/30786811/the-hgf-met-axis-coordinates-liver-cancer-metabolism-and-autophagy-for-chemotherapeutic-resistance
#8
Xing Huang, Guangming Gan, Xiaoxiao Wang, Ting Xu, Wei Xie
Notwithstanding the numerous drugs available for liver cancer, emerging evidence suggests that chemotherapeutic resistance is a significant issue. HGF and its receptor MET play critical roles in liver carcinogenesis and metastasis, mainly dependent on the activity of receptor tyrosine kinase. However, for unknown reasons, all HGF-MET kinase activity-targeted drugs have failed or have been suspended in clinical trials thus far. Macroautophagy/autophagy is a protective 'self-eating' process for resisting metabolic stress by recycling obsolete components, whereas the impact of autophagy-mediated reprogrammed metabolism on therapeutic resistance is largely unclear, especially in liver cancer...
February 20, 2019: Autophagy
https://read.qxmd.com/read/30786016/human-papillomavirus-type-8-oncoproteins-e6-and-e7-cooperate-in-downregulation-of-the-cellular-checkpoint-kinase-1
#9
Baki Akgül, Matthias Kirschberg, Alan Storey, Martin Hufbauer
Human papillomavirus 8 (HPV8) is associated with the development of squamous cell carcinomas (SCC) of the skin. HPV-infected keratinocytes are able to over-ride normal checkpoint control mechanisms and sustain cell cycle activity, allowing for synthesis of cellular proteins necessary for viral genome amplification. To study how HPV8 may disrupt cell-cycle control, we analysed the impact of HPV8 early gene expression on one of the key regulators of cell cycle and DNA damage response, checkpoint kinase-1 (CHK1)...
February 20, 2019: International Journal of Cancer. Journal International du Cancer
https://read.qxmd.com/read/30785236/chemical-inhibition-of-kir-channels-reduces-salivary-secretions-and-phloem-feeding-of-the-cotton-aphid-aphis-gossypii-glover
#10
Zhilin Li, Jeffrey A Davis, Daniel R Swale
BACKGROUND: The unique feeding biology of aphids suggests novel insecticide targets are likely to exist outside of the nervous system. Therefore, we aimed to directly test the hypothesis that pharmacological inhibition of inward rectifier potassium (Kir) channels would result in salivary gland failure and reduced sap ingestion by the cotton aphid, Aphis gossypii. RESULTS: The Kir inhibitors VU041 and VU590 reduced the length of the salivary sheath in a concentration dependent manner, indicating that the secretory activity of the salivary gland is reduced by Kir inhibition...
February 19, 2019: Pest Management Science
https://read.qxmd.com/read/30772377/ubc9-regulates-cardiac-sodium-channel-na-v-1-5-ubiquitination-degradation-and-sodium-current-density
#11
Bo Tang, Yushuang Hu, Zhijie Wang, Chen Cheng, Pengyun Wang, Lina Liang, Hongbo Xiong, Chunyan Luo, Chengqi Xu, Qiuyun Chen, Qing Kenneth Wang
Voltage-gated sodium channel Nav 1.5 is critical for generation and conduction of cardiac action potentials. Mutations and expression level changes of Nav 1.5 are associated with cardiac arrhythmias and sudden death. The ubiquitin (Ub) conjugation machinery utilizes three enzyme activities, E1, E2, and E3, to regulate protein degradation. Previous studies from us and others showed that Nedd4-2 acts as an E3 ubiquitin-protein ligase involved in ubiquitination and degradation of Nav 1.5, however, more key regulators remain to be identified...
February 14, 2019: Journal of Molecular and Cellular Cardiology
https://read.qxmd.com/read/30769006/a-central-hydrophobic-e1-region-controls-the-ph-range-of-hepatitis-c-virus-membrane-fusion-and-susceptibility-to-fusion-inhibitors
#12
Dominic H Banda, Paula M Perin, Richard J P Brown, Daniel Todt, Wladimir Solodenko, Patrick Hoffmeyer, Kamlesh Kumar Sahu, Michael Houghton, Philip Meuleman, Rolf Müller, Andreas Kirschning, Thomas Pietschmann
BACKGROUND & AIMS: Hepatitis C virus infection causes chronic liver disease. Antivirals have been developed and cure infection. However, resistance can emerge and salvage therapies with alternative modes of action could be useful. Several licensed drugs have emerged as HCV entry inhibitors representing candidates for drug repurposing. We aimed to dissect their mode of action, identify improved derivatives and determine their viral targets. METHODS: HCV entry inhibition was tested for a panel of structurally related compounds, using chimeric viruses representing diverse genotypes, in addition to viruses containing previously determined resistance mutations...
February 12, 2019: Journal of Hepatology
https://read.qxmd.com/read/30738887/sirt1-suppresses-p53-dependent-apoptosis-by-modulation-of-p21-in-osteoblast-like-mc3t3-e1-cells-exposed-to-fluoride
#13
Xiaolong Gu, Zhi Wang, Jian Gao, Dandan Han, Limei Zhang, Peng Chen, Guangjian Luo, Bo Han
Fluoride is very crucial for development of teeth and bones. Excessive fluoride, however, causes damage to teeth and bones resulting in serious public health problem. SIRT1 regulates physiological and pathological processes such as apoptosis and cell cycle. Although SIRT1 inhibits p53-mediated transactivation, how SIRT1 regulates p53 in fluorosis remains unclear. This study aims to investigate the involvement of SIRT1 in fluoride-induced cell cycle arrest and apoptosis in MC3T3-E1 cells and the underlying mechanism...
February 7, 2019: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://read.qxmd.com/read/30738836/the-isoquinoline-alkaloid-berberine-inhibits-human-cytomegalovirus-replication-by-interfering-with-the-viral-immediate-early-2-ie2-protein-transactivating-activity
#14
Anna Luganini, Beatrice Mercorelli, Lorenzo Messa, Giorgio Palù, Giorgio Gribaudo, Arianna Loregian
The identification and validation of new small molecules able to inhibit the replication of human cytomegalovirus (HCMV) remains a priority to develop alternatives to the currently used DNA polymerase inhibitors, which are often burdened by long-term toxicity and emergence of cross-resistance. To contribute to this advancement, here we report on the characterization of the mechanism of action of a bioactive plant-derived alkaloid, berberine (BBR), selected in a previous drug repurposing screen expressly devised to identify early inhibitors of HCMV replication...
February 8, 2019: Antiviral Research
https://read.qxmd.com/read/30737236/ubiquitin-activating-enzyme-inhibition-induces-an-unfolded-protein-response-and-overcomes-drug-resistance-in-myeloma
#15
Junling Zhuang, Fazal Shirazi, Ram Kumar Singh, Isere Kuiatse, Hua Wang, Hans C Lee, Zuzana Berkova, Allison Berger, Marc Hyer, Nibedita Chattopadhyay, Sakeena Syed, Judy Qiuju Shi, Jie Yu, Vaishali Shinde, Stephen Tirrell, Richard Julian Jones, Zhiqiang Wang, R Eric Davis, Robert Z Orlowski
Three proteasome inhibitors have garnered regulatory approvals in various multiple myeloma settings but drug resistance is an emerging challenge, and this has prompted interest in blocking upstream components of the ubiquitin-proteasome pathway. One such attractive target is the E1 ubiquitin activating enzyme (UAE), and we therefore evaluated the activity of TAK-243, a novel and specific UAE inhibitor. TAK-243 potently suppressed myeloma cell line growth, induced apoptosis, and activated caspases while decreasing the abundance of ubiquitin-protein conjugates...
February 8, 2019: Blood
https://read.qxmd.com/read/30697261/lipid-levels-and-selected-biomarkers-of-vascular-changes-in-children-with-idiopathic-headaches-a-preliminary-report
#16
Joanna Sordyl, Ilona Kopyta, Beata Sarecka-Hujar, Tomasz Francuz, Paweł Matusik, Ewa Małecka-Tendera
Introduction: Elevated lipid concentrations were observed in adults with headaches. However, studies in children are scarce. Recent data suggest new potential risk factors for atherosclerosis, which may be associated with headaches. The aim of the study was to analyse the blood levels of lipids and new markers of atherosclerosis in children with idiopathic headaches. Material and methods: The study population comprised 65 children (39 with idiopathic headaches and 26 healthy children)...
January 2019: Archives of Medical Science: AMS
https://read.qxmd.com/read/30692021/design-synthesis-and-biological-evaluation-of-novel-inhibitors-against-cyanobacterial-pyruvate-dehydrogenase-multienzyme-complex-e1
#17
Jiangtao Feng, Haifeng He, Yuan Zhou, Xiaoliang Guo, Honglin Liu, Meng Cai, Fang Wang, Lingling Feng, Hongwu He
Cyanobacterial pyruvate dehydrogenase multienzyme complex E1 (PDHc E1) is a potential target enzyme for finding inhibitors to control harmful cyanobacterial blooms. In this study, a series of novel triazole thiamin diphosphate (ThDP) analogs were designed and synthesized by modifying the substituent group of triazole ring and optimizing triazole-benzene linker as potential cyanobacterial PDHc E1 (Cy-PDHc E1) inhibitors. Their inhibitory activities against Cy-PDHc E1 in vitro and algicide activities in vivo were further examined...
January 22, 2019: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/30676680/20-hydroxy-and-20-carboxy-leukotriene-lt-b-4-downregulate-ltb-4-mediated-responses-of-human-neutrophils-and-eosinophils
#18
Anne-Sophie Archambault, Samuel Poirier, Julie-S Lefebvre, Philippe-Pierre Robichaud, Marie-Chantal Larose, Caroline Turcotte, Cyril Martin, Véronique Provost, Luc H Boudreau, Patrick P McDonald, Michel Laviolette, Marc E Surette, Nicolas Flamand
Leukotriene B4 (LTB4 ) plays a prominent role in innate immunity as it induces phagocyte recruitment, the release of antimicrobial effectors, and as it potentiates the ingestion and killing of pathogens. In humans, LTB4 has a short half-life and is rapidly metabolized by leukocytes, notably into 20-OH- and 20-COOH-LTB4 by neutrophils. Although these LTB4 metabolites bind to the BLT1 receptor with high affinity, they activate neutrophils to a much lower extent than LTB4 . We thus postulated that LTB4 metabolites could dampen BLT1 -mediated responses, therefore limiting the impact of LTB4 on human neutrophil functions...
January 24, 2019: Journal of Leukocyte Biology
https://read.qxmd.com/read/30668413/berberine-inhibits-hepatitis-c-virus-entry-by-targeting-the-viral-e2-glycoprotein
#19
Ting-Chun Hung, Alagie Jassey, Ching-Hsuan Liu, Chien-Ju Lin, Chun-Ching Lin, Shu Hui Wong, Jonathan Y Wang, Ming-Hong Yen, Liang-Tzung Lin
BACKGROUND: Despite the advent of direct-acting antivirals (DAAs), HCV remains an important public health problem globally. There is at present no effective vaccine against the virus, and the DAAs in current use cannot prevent de novo infection, including in liver transplant setting wherein donor livers inevitably become re-infected. Developing inhibitors to HCV entry using nature-derived small molecules may help to expand/complement the current treatment options. PURPOSE: In this study, we explored the effect of the plant alkaloid berberine (BBR) on HCV early viral entry...
February 2019: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://read.qxmd.com/read/30668150/the-perk-eif2%C3%AE-atf4-signaling-branch-regulates-osteoblast-differentiation-and-proliferation-by-pth
#20
Kefan Zhang, Miaomiao Wang, Yingjiang Li, Chunping Li, Shaidi Tang, Xiuxia Qu, Ninghan Feng, Yu Wu
Parathyroid hormone (PTH) and its related peptide (PTH related peptide 1-34) are one of FDA-approved bone-promoting drugs for age-related osteoporosis. Treatment with PTH stimulates bone formation. But the molecular mechanisms of PTH-mediated osteoblast differentiation and cell proliferation are still not completely understood. In this study, we showed that PTH induced endoplasmic reticulum (ER) stress in osteoblasts through the PERK-EIF2α-ATF4-signaling pathway. After separately blocking PERK-EIF2α-ATF4 signaling with two different inhibitors (AMG'44 and ISRIB), or specific small interfering RNA for PERK and ATF4, the following targets were all downregulated: expression of osteoblast differentiation markers (Runx2, Alp, Col1a1 and Ocn), cell proliferation markers (CyclinE, CyclinD and CDC2), amino acid import (Glyt1) and metabolism-related genes (Asns)...
January 22, 2019: American Journal of Physiology. Endocrinology and Metabolism
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