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Soonsil Hyun, Yoonhwa Choi, Ha Neul Lee, Changki Lee, Donghoon Oh, Dong-Ki Lee, Changjin Lee, Yan Lee, Jaehoon Yu
A hydrocarbon stapled peptide based strategy was used to develop an optimized cell penetrating peptide for siRNA delivery. Various stapled peptides, having amphipathic Leu- and Lys-rich regions, were prepared and their cell penetrating potentials were evaluated. One peptide, stEK, was found to have high cell penetration and siRNA delivery abilities at low nanomolar concentrations. In order to improve its ability to promote gene silencing, stEK was modified by replacing several Lys residues with His moieties...
April 21, 2018: Chemical Science
Hongyan Su, Yi Yang
Cyclophilin A (CyPA), an abundantly expressed protein belonging to the immunophilin family, is involved in a variety of physiological and pathological activities together with its extracellular receptor, CD147. Many studies have provided compelling evidence supporting critical roles of CyPA in immune and infectious diseases and malignant tumours. Recent studies have revealed that both CyPA and CD147 strongly promote cardiovascular inflammation, myocardial ischaemia-reperfusion injury, and myocardial remodelling processes...
May 14, 2018: Experimental and Molecular Pathology
Chen-Shu Chang, Shih-Li Su, Chen-Ling Kuo, Ching-Shan Huang, Wan-Min Tseng, Song-Shei Lin, Chin-San Liu
BACKGROUND: Cyclophilin A plays a pathogenic role in the development and progression of atherosclerosis, which can be assessed by measuring carotid intima-media thickness. The primary aim of this study was to examine the interaction between plasma Cyclophilin A level and carotid intima-media thickness in patients with acute ischemic stroke. METHOD: Plasma concentration of Cyclophilin A was measured on admission in 66 consecutive patients who had been hospitalized for acute cerebral stroke and in 52 case-control subjects without a history of acute stroke...
May 16, 2018: Current Neurovascular Research
Quentin Nevers, Isaac Ruiz, Nazim Ahnou, Flora Donati, Rozenn Brillet, Laurent Softic, Maxime Chazal, Nolwenn Jouvenet, Slim Fourati, Camille Baudesson, Patrice Bruscella, Muriel Gelin, Jean-François Guichou, Jean-Michel Pawlotsky, Abdelhakim Ahmed-Belkacem
Despite Flaviviridae viruses display high incidence, morbidity and mortality rates, the development of specific antiviral drugs for each virus is unlikely. Cyclophilins, a family of host peptidyl-prolyl cis / trans isomerase (PPIase), play a pivotal role in the lifecycle of many viruses and therefore represent an attractive target for broad-spectrum antiviral development. We report here the pan-genotypic anti-hepatitis C virus (HCV) activity of a small-molecule cyclophilin inhibitor (SMCypI). Mechanistic and modeling studies revealed that SMCypI bound to cyclophilin A in competition with Cyclosporin A (CsA), inhibited its PPIase activity and disrupted the CypA/NS5A interaction...
May 14, 2018: Antimicrobial Agents and Chemotherapy
Fanny Tzelepis, Julianna Blagih, Nargis Khan, Joshua Gillard, Laura Mendonca, Dominic G Roy, Eric H Ma, Philippe Joubert, Russell G Jones, Maziar Divangahi
Mycobacterium tuberculosis ( Mtb ) is one of the most ancient human pathogens, yet the exact mechanism(s) of host defense against Mtb remains unclear. Although one-third of the world's population is chronically infected with Mtb , only 5 to 10% develop active disease. This indicates that, in addition to resistance mechanisms that control bacterial burden, the host has also evolved strategies to tolerate the presence of Mtb to limit disease severity. We identify mitochondrial cyclophilin D (CypD) as a critical checkpoint of T cell metabolism that controls the expansion of activated T cells...
May 11, 2018: Science Immunology
Jason G Walling, Leslie A Zalapa, Marcus A Vinje
Reverse transcription quantitative polymerase chain reaction (RT-qPCR) is a popular method for measuring transcript abundance. The most commonly used method of interpretation is relative quantification and thus necessitates the use of normalization controls (i.e. reference genes) to standardize transcript abundance. The most popular gene targets for RT-qPCR are housekeeping genes because they are thought to maintain a static transcript level among a variety of samples. However, more recent studies have shown, several housekeeping genes are not reliably stable...
2018: PloS One
Aaron S Dhanda, Katarina T Lulic, A Wayne Vogl, Margaret M Mc Gee, Robert H Chiu, Julian A Guttman
Listeria generate actin-rich tubular protrusions at the plasma membrane that propel the bacteria into neighbouring cells. The precise molecular mechanisms governing the formation of these protrusions remain poorly defined. Here we demonstrate that the PPIase Cyclophilin A (CypA) is hijacked by Listeria at membrane protrusions used for cell-to-cell spreading. CypA localizes within the F-actin of these structures and is crucial for their proper formation, as in cells depleted of CypA, these extended actin-rich structures are mis-shaped and collapsed due to changes within the F-actin network...
May 4, 2018: Journal of Infectious Diseases
Katharina Ernst, Nina Eberhardt, Ann-Katrin Mittler, Michael Sonnabend, Anna Anastasia, Simon Freisinger, Cordelia Schiene-Fischer, Miroslav Malešević, Holger Barth
The Bordetella pertussis toxin (PT) is one important virulence factor causing the severe childhood disease whooping cough which still accounted for approximately 63,000 deaths worldwide in children in 2013. PT consists of PTS1, the enzymatically active (A) subunit and a non-covalently linked pentameric binding/transport (B) subunit. After endocytosis, PT takes a retrograde route to the endoplasmic reticulum (ER), where PTS1 is released into the cytosol. In the cytosol, PTS1 ADP-ribosylates inhibitory alpha subunits of trimeric GTP-binding proteins (Giα) leading to increased cAMP levels and disturbed signalling...
May 1, 2018: Toxins
Songfeng Chen, Xiao Lv, Binwu Hu, Lei Zhao, Shuai Li, Zhiliang Li, Xiangcheng Qing, Hongjian Liu, Jianzhong Xu, Zengwu Shao
The aim of this study was to investigate whether RIPK1 mediated mitochondrial dysfunction and oxidative stress contributed to compression-induced nucleus pulposus (NP) cells necroptosis and apoptosis, together with the interplay relationship between necroptosis and apoptosis in vitro. Rat NP cells underwent various periods of 1.0 MPa compression. To determine whether compression affected mitochondrial function, we evaluated the mitochondrial membrane potential, mitochondrial permeability transition pore (mPTP), mitochondrial ultrastructure and ATP content...
April 28, 2018: Apoptosis: An International Journal on Programmed Cell Death
Dan Mu, Jia-Wu Zhu, Feng-Liang Liu, Hong-Yi Zheng, Yong-Tang Zheng
TRIM5α restricts retroviruses in a species-specific manner. Cyclophilin A was independently retrotransposed into the TRIM5 loci in different species, leading to the generation of antiviral TRIM5-cyclophilin A (TRIMCyp) proteins. Previously, we found that assam macaques express a TRIMCyp chimera (amTRIMCyp), along with a TRIM5α allelic protein (amTRIM5α). Herein, we investigated the antiviral activity of amTRIMCyp and amTRIM5α individually, as well as their interaction and joint effects. amTRIMCyp showed a divergent restriction pattern from amTRIM5α...
April 26, 2018: Science China. Life Sciences
Juan Jiang, Hongling Yin, Yao Sun, Huaiqiu Huang, Xuchu Hu
Cyclophilin A (CyPA), ubiquitously existing in cytoplasm of all eukaryotes, can be secreted in response to inflammatory stimuli. Extracellular CyPA plays a prominent role in the pathological processes of inflammatory diseases, acting as a proinflammatory mediator, exerting chemotactic effects, promoting apoptosis of endothelial cells and amplifying ROS generation, thus being considered as a potential treatment target of sepsis, a systemic inflammatory response syndrome. Our previous study found that antibodies against cyclophilin A of Clonorchis sinensis (CsCyPA) could neutralize mouse cyclophilin A (MuCyPA)...
April 18, 2018: International Immunopharmacology
Debabrata Panja, Christian A Vedeler, Manja Schubert
AIM: Neurodegeneration is associated with dysfunction of calcium buffering capacity and thereby sustained cellular and mitochondrial calcium overload. Paraneoplastic cerebellar degeneration (PCD), characterized by progressive Purkinje neuron degeneration following paraneoplastic Yo antibody internalisation and binding to cerebellar degeneration-related protein CDR2 and CDR2L, has been linked to intracellular calcium homeostasis imbalance due to calbindin D28k malfunction. Therefore, we hypothesized that Yo antibody internalisation affects not only calbindin calcium binding capacity but also calcium-sensitive mitochondrial-associated signalling, causing mitochondrial calcium overload and thereby Purkinje neuron death...
April 21, 2018: Neuropathology and Applied Neurobiology
Xueqi Gan, Ling Zhang, Beilei Liu, Zhuoli Zhu, Yuting He, Junsheng Chen, Junfei Zhu, Haiyang Yu
Bone is a dynamic organ, the bone-forming osteoblasts and bone-resorbing osteoclasts form the physiological basis of bone remodeling process. During pathological process of numerous inflammatory diseases, these two aspects are uncoupled and the balance is usually tipped in favor of bone destruction. Evidence suggests that the inflammatory destruction of bone is mainly attributed to oxidative stress and is closely related to mitochondrial dysfunction. The mechanisms underlying osteogenic dysfunction in inflammation still need further investigation...
April 20, 2018: Journal of Physiology and Biochemistry
Mert Gur, Elizabeth A Blackburn, Jia Ning, Vikram Narayan, Kathryn L Ball, Malcolm D Walkinshaw, Burak Erman
Cyclophilin 40 (Cyp40) is a member of the immunophilin family that acts as a peptidyl-prolyl-isomerase enzyme and binds to the heat shock protein 90 (Hsp90). Its structure comprises an N-terminal cyclophilin domain and a C-terminal tetratricopeptide (TPR) domain. Cyp40 is overexpressed in prostate cancer and certain T-cell lymphomas. The groove for Hsp90 binding on the TPR domain includes residues Lys227 and Lys308, referred to as the carboxylate clamp, and is essential for Cyp40-Hsp90 binding. In this study, the effect of two mutations, K227A and K308A, and their combinative mutant was investigated by performing a total of 5...
April 14, 2018: Journal of Chemical Physics
Xinlong Luo, Wei Yang, Guangxia Gao
HIV-1 can infect non-dividing cells via passing through the nuclear pore complex. The nuclear membrane imbedded protein SUN2 was recently reported to be involved in the nuclear import of HIV-1. Whether SUN1, which shares many functional similarities with SUN2, is involved in this process remained to be explored. Here, we report that overexpression of SUN1 specifically inhibited the infection of HIV-1, but not simian immunodeficiency virus (SIV) or murine leukemia virus (MLV). Overexpression of SUN1 did not affect reverse transcription, but led to reduced accumulation of the 2-LTR circular DNA and integrated viral DNA, suggesting a block in the process of nuclear import...
April 11, 2018: Journal of Virology
Jane A Armstrong, Nicole J Cash, Yulin Ouyang, Jack C Morton, Michael Chvanov, Diane Latawiec, Muhammad Awais, Alexei V Tepikin, Robert Sutton, David N Criddle
Mitochondrial dysfunction lies at the core of acute pancreatitis (AP). Diverse AP stimuli induce Ca2+ -dependent formation of the mitochondrial permeability transition pore (MPTP), a solute channel modulated by cyclophilin D (CypD), whose formation causes ATP depletion and necrosis. Oxidative stress reportedly triggers MPTP formation and is elevated in clinical AP, but how reactive oxygen species influence cell death is unclear. Here, we assessed potential MPTP involvement in oxidant-induced effects on pancreatic acinar cell bioenergetics and fate...
April 6, 2018: Journal of Biological Chemistry
Bevan S Main, Sonia Villapol, Stephanie S Sloley, David J Barton, Maia Parsadanian, Chinyere Agbaegbu, Kathryn Stefos, Mondona S McCann, Patricia M Washington, Olga C Rodriguez, Mark P Burns
BACKGROUND: Traumatic Brain Injury (TBI) is a major cause of disability and mortality, to which there is currently no comprehensive treatment. Blood Brain Barrier (BBB) dysfunction is well documented in human TBI patients, yet the molecular mechanisms that underlie this neurovascular unit (NVU) pathology remains unclear. The apolipoprotein-E (apoE) protein has been implicated in controlling BBB integrity in an isoform dependent manner, via suppression of Cyclophilin A (CypA)-Matrix metallopeptidase-9 (MMP-9) signaling cascades, however the contribution of this pathway in TBI-induced BBB permeability is not fully investigated...
April 4, 2018: Molecular Neurodegeneration
Tesmine Martin, Yuan-Chao Lou, Chun-Chi Chou, Shu-Yi Wei, Sushant Sadotra, Chao-Cheng Cho, Meng-Hsuan Lin, Jung-Hsiang Tai, Chun-Hua Hsu, Chinpan Chen
Cyclophilin 1 (TvCyP1), a cyclophilin type peptidyl-prolyl isomerase present in the human parasite Trichomonas vaginalis, interacts with Myb1 and assists in its nuclear translocation. Myb1 regulates the expression of ap65-1 gene that encodes for a disease causing cytoadherence enzyme. Here, we determined the crystal structures of TvCyP1 and its complex with the minimum TvCyP1-binding sequence of Myb1 (Myb1104-111 ), where TvCyP1 formed a homodimer, unlike other single domain cyclophilins. In the complex structure, one Myb1104-111 peptide was bound to each TvCyP1 protomer, with G106-P107 and Y105 fitting well into the active site and auxiliary S2 pocket, respectively...
April 3, 2018: Scientific Reports
João Soeiro Teodoro, Ana Teresa Varela, Filipe Valente Duarte, Ana Patrícia Gomes, Carlos Marques Palmeira, Anabela Pinto Rolo
BACKGROUND: Fatty livers are considerably more susceptible to acute stressors, such as ischemia/reperfusion (I/R). Since the incidence of I/R is high due to surgical events and some pathologies, there is an urgent need to find strategies against I/R injury (I/RI) in fatty livers. We postulate that an acute pre-treatment with Indirubin-3'-oxime (Ind) or NAD+ prevents mitochondrial dysfunction associated with warm I/RI in fatty livers. MATERIALS AND METHODS: Zucker fatty rats were subjected to warm ischemia and 12 hrs of reperfusion...
March 30, 2018: European Journal of Clinical Investigation
Imre Varjú, Veronika Judit Farkas, László Kőhidai, László Szabó, Ádám Zoltán Farkas, Lívia Polgár, Christos Chinopoulos, Krasimir Kolev
In the course of thrombosis, platelets are exposed to a variety of activating stimuli classified as 'strong' (e.g. thrombin and collagen) or 'mild' (e.g. ADP). In response, activated platelets adhere to injured vasculature, aggregate, and stabilise the three-dimensional fibrin scaffold of the expanding thrombus. Since 'strong' stimuli also induce opening of the mitochondrial permeability transition pore (MPTP) in platelets, the MPTP-enhancer Cyclophilin D (CypD) has been suggested as a critical pharmacological target to influence thrombosis...
March 29, 2018: Scientific Reports
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