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Cytosolic AND pH

K P Sigdel, L A Wilt, B P Marsh, A G Roberts, G M King
The membrane-bound P-glycoprotein (Pgp) transporter plays a major role in human disease and drug disposition because of its ability to efflux a chemically diverse range of drugs through ATP hydrolysis and ligand-induced conformational changes. Deciphering these structural changes is key to understanding the molecular basis of transport and to developing molecules that can modulate efflux. Here, atomic force microscopy (AFM) is used to directly image individual Pgp transporter molecules in a lipid bilayer under physiological pH and ambient temperature...
August 16, 2018: Biochemical Pharmacology
Filip Vasilev, Nunzia Limatola, Dae-Ryoung Park, Uh-Hyun Kim, Luigia Santella, Jong Tai Chun
BACKGROUND/AIMS: Eggs of all animal species display intense cytoplasmic Ca2+ increases at fertilization. Previously, we reported that unfertilized eggs of Astropecten aranciacus exposed to an actin drug latrunculin A (LAT-A) exhibit similar Ca2+ waves and cortical flashes after 5-10 min time lag. Here, we have explored the molecular mechanisms underlying this unique phenomenon. METHODS: Starfish eggs were pretreated with various agents such as other actin drugs or inhibitors of phospholipase C (PLC), and the changes of the intracellular Ca2+ levels were monitored by use of Calcium Green in the presence or absence of LAT-A...
August 10, 2018: Cellular Physiology and Biochemistry
Mara Reifenrath, Eckhard Boles
Many cellular processes are regulated via pH, and maintaining the pH of different organelles is crucial for cell survival. A pH-sensitive GFP variant, the so-called pHluorin, has proven to be a valuable tool to study the pH of the cytosol, mitochondria and other organelles in vivo. We found that the fluorescence intensity of Endoplasmic Reticulum (ER)-targeted pHluorin in the yeast Saccharomyces cerevisiae was very low and barely showed pH sensitivity, probably due to misfolding in the oxidative environment of the ER...
August 10, 2018: Scientific Reports
Chenxu Yan, Zhiqian Guo, Yajing Liu, Ping Shi, He Tian, Wei-Hong Zhu
The translation of biomarker sensing into programmable diagnostics or therapeutic applications in vivo is greatly challenging, especially for eliminating the 'false positive' signals from OR logic gates. Herein we present a sense-of-logic dual-channel nanoprobe, operating through a sequence-activated AND logic gate by responding ultra-sensitively to pH changes and being subsequently triggered with biothiol for the controllable release of anti-cancer drugs. Specifically, programmable drug release is conducted in a multistage tumor microenvironment (acidic endocytic organelles followed by abnormal glutathione-overexpressing cell cytosol), which is synchronous with dual-channel near-infrared (NIR) fluorescence output...
August 7, 2018: Chemical Science
Meenakshi B Tellis, Nidhi N Gujar, Rakesh S Joshi
Trehalase catalyzes the breakdown of trehalose into two glucose moieties and is ubiquitous in all organisms. Here, we provide insights into the enigmatic origin and evolution of trehalase in major species. Study of taxonomic distribution, orthology, phylogeny and functional domains indicated that trehalase possibly originates from bacteria and was transmitted to other taxa through horizontal gene transfer. Domain analysis showed that glycosyl hydrolase family 37 is present in most of the sequences and represents dominant activity during evolution...
July 27, 2018: Journal of Biomolecular Structure & Dynamics
Laura Rinaldi, Sofya Pozdniakova, Vignesh Jayarajan, Christian Troidl, Yaser Abdallah, Muhammad Aslam, Yury Ladilov
AIMS: Disturbance of mitochondrial function significantly contributes to the myocardial injury that occurs during reperfusion. Increasing evidence suggests a role of intra-mitochondrial cyclic AMP (cAMP) signaling in promoting respiration and ATP synthesis. Mitochondrial levels of cAMP are controlled by type 10 soluble adenylyl cyclase (sAC) and phosphodiesterase 2 (PDE2), however their role in the reperfusion-induced injury remains unknown. Here we aimed to examine whether sAC may support cardiomyocyte survival during reperfusion...
July 22, 2018: Biochimica et Biophysica Acta
Sandro Hofstetter, Andreas Beck, Stefan Trapp, Anke Buchholz
Foliar-applied systemic agrochemicals require entrance into the plant vascular system or into specific subcellular compartments to reach their target in planta or to be imbibed by piercing/sucking pests. An inappropriate subcellular localization, like accumulation of aphicides in vacuoles, might lower the compound's efficiency due to reduced exposure to the target. Permeabilities and mass distributions of 16 compounds covering a broad range of properties were measured across a pH gradient in a PAMPA ("parallel artificial membrane permeability assay") system, providing experimental evidence for ion trapping of acids and bases in basic and acidic compartments, respectively...
August 8, 2018: Journal of Agricultural and Food Chemistry
Kazuhiro Iwama, Hitoshi Osaka, Takahiro Ikeda, Satomi Mitsuhashi, Satoko Miyatake, Atsushi Takata, Noriko Miyake, Shuichi Ito, Takeshi Mizuguchi, Naomichi Matsumoto
The mammalian Na+ /H+ exchanger isoform one (NHE1), encoded by Solute Carrier Family 9, member 1 (SLC9A1), consists of 12 membrane domains and a cytosolic C-terminal domain. NHE1 plays an important role in maintaining intracellular pH homeostasis by exchanging one intracellular proton for one extracellular sodium ion. Mice with a homozygous null mutation in Slc9a1 (Nhe1) exhibited ataxia, recurrent seizures, and selective neuronal cell death. In humans, three unrelated patients have been reported: a patient with a homozygous missense mutation in SLC9A1, c...
July 17, 2018: Journal of Human Genetics
Huiyan Sun, Chi Zhang, Sha Cao, Tao Sheng, Ning Dong, Ying Xu
We present a computational study of tissue transcriptomic data of 14 cancer types to address: what may drive cancer cell division? Our analyses point to that persistent disruption of the intracellular pH by Fenton reactions may be at the root of cancer development. Specifically, we have statistically demonstrated that Fenton reactions take place in cancer cytosol and mitochondria across all the 14 cancer types, based on cancer tissue gene-expression data integrated via the Michaelis-Menten equation. In addition, we have shown that (i) Fenton reactions in cytosol of the disease cells will continuously increase their pH, to which the cells respond by generating net protons to keep the pH stable through a combination of synthesizing glycolytic ATPs and consuming them by nucleotide syntheses, which may drive cell division to rid of the continuously synthesized nucleotides; and (ii) Fenton reactions in mitochondria give rise to novel ways for ATP synthesis with electrons ultimately coming from H2O2, largely originated from immune cells...
July 16, 2018: Journal of Molecular Cell Biology
Takamasa Inoue, Pengwei Zhang, Wei Zhang, Kylia Goodner-Bingham, Allison Dupzyk, Daniel DiMaio, Billy Tsai
Despite their importance as human pathogens, entry of human papillomaviruses (HPVs) into cells is poorly understood. The transmembrane protease γ-secretase executes a crucial function during the early stages of HPV infection, but the role of γ-secretase in infection and the identity of its critical substrate are unknown. Here we demonstrate that γ-secretase harbors a previously uncharacterized chaperone function, promoting low pH-dependent insertion of the HPV L2 capsid protein into endosomal membranes. Upon membrane insertion, L2 recruits the cytosolic retromer, which enables the L2 viral genome complex to enter the retrograde transport pathway and traffic to the Golgi en route for infection...
July 13, 2018: Journal of Cell Biology
Lei Li, Dian Li, Mingzu Zhang, Jinlin He, Jian Liu, Peihong Ni
Shell cross-linked (SCL) polymeric prodrug micelles have the advantages of good blood circulation stability and high drug content. Herein, we report on a new kind of pH/redox responsive dynamic covalent SCL micelle, which was fabricated by self-assembly of a multifunctional polymeric prodrug. At first, a macroinitiator PBYP- ss- iBuBr was prepared via ring-opening polymerization (ROP), wherein PBYP represents poly[2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane]. Subsequently, PBYP- hyd-DOX- ss-P(DMAEMA- co-FBEMA) prodrug was synthesized by a one-pot method with a combination of atom transfer radical polymerization (ATRP) and a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction using a doxorubicin (DOX) derivative containing an azide group to react with the alkynyl group of the side chain in the PBYP block, while DMAEMA and FBEMA are the abbriviations of N, N-(2-dimethylamino)ethyl methacrylate and 2-(4-formylbenzoyloxy)ethyl methacrylate, respectively...
July 30, 2018: Bioconjugate Chemistry
Udo Bonnet, Dieter Bingmann, Erwin-Josef Speckmann, Martin Wiemann
The intracellular pH (pHi) in the cytosol of mammalian central neurons is tightly regulated and small pHi-fluctuations are deemed to modulate inter-/intracellular signaling, excitability, and synaptic plasticity. The resting pHi of young rodent hippocampal pyramidal neurons is known to decrease alongside aging for about 0.1 pH-units. There is no information about the relationship between age and pHi of human central neurons. We addressed this knowledge gap using 26 neocortical slices from 12 patients (1-56-years-old) who had undergone epilepsy surgery...
July 11, 2018: Journal of Neural Transmission
James E O Rosling, Melanie C Ridgway, Robert L Summers, Kiaran Kirk, Adele M Lehane
The antimalarial activity of chemically diverse compounds, including the clinical candidate cipargamin, has been linked to the ATPase PfATP4 in the malaria-causing parasite Plasmodium falciparum The characterization of PfATP4 has been hampered by the inability thus far to achieve its functional expression in a heterologous system. Here we optimized a membrane ATPase assay to probe the function of PfATP4 and its chemical sensitivity. We found that cipargamin inhibited the Na+ -dependent ATPase activity present in P...
July 9, 2018: Journal of Biological Chemistry
Sudhakar Srivastava, Munish Kumar Upadhyay, Ashish Kumar Srivastava, Mostafa Abdelrahman, Penna Suprasanna, Lam-Son Phan Tran
Phosphorus (P) is an essential element required for incorporation into several biomolecules and for various biological functions; it is, therefore, vital for optimal growth and development of plants. The extensive research on identifying the processes underlying the uptake, transport, and homeostasis of phosphate (Pi) in various plant organs yielded valuable information. The transport of Pi occurs from the soil into root epidermal cells, followed by loading into the root xylem vessels for distribution into other plant organs...
June 29, 2018: International Journal of Molecular Sciences
Nadine Mundt, Marc Spehr, Polina V Lishko
Ion channels control the ability of human sperm to fertilize the egg by triggering hyperactivated motility, which is regulated by membrane potential, intracellular pH, and cytosolic calcium. Previous studies unraveled three essential ion channels that regulate these parameters: (1) the Ca2+ channel CatSper, (2) the K+ channel KSper, and (3) the H+ channel Hv1. However, the molecular identity of the sperm Na+ conductance that mediates initial membrane depolarization and, thus, triggers downstream signaling events is yet to be defined...
July 2, 2018: ELife
Rajeev Sharma, Surabhi Dubey, Nishi Mody, Gajanand Sharma, Varun Kushwah, Sanyog Jain, Om Prakash Katare, Suresh P Vyas
The aim of present approach was to design and develop mannose functionalized reverse polymeric nanocomposite(s) system based on release promoter (MRPRPNs). Thus, the composition of the present formulation was optimized by employing the systematic design of experiments (DoE) for screening and optimization using L8-Array Taguchi and 3-level-3-factor Box-Behnken Design (BBD). Further, the developed formulation was observed for its preferential internalization by professional antigen presenting cells (macrophages/dendritic cells) and prompt release of loaded antigen in a pH-dependent manner...
July 2, 2018: Artificial Cells, Nanomedicine, and Biotechnology
Faraj Hijaz, Yasser Nehela, Nabil Killiny
In the current study, we showed that exogenous GABA supplementation increases the endogenous GABA level, several amino acids, and phytohormones in citrus plants, suggesting that GABA works in harmony with phytohormones. Gamma-aminobutyric acid (GABA) plays a key role in cytosolic regulation of pH, controlling of carbon and nitrogen metabolism, and protection against biotic and abiotic stresses. Although it is well-known that GABA is implicated in plant defense and it could act as a signaling molecule, its effect on phytohormones is not completely understood...
June 30, 2018: Planta
Priscilla Marys Costa Dos Santos, Deividi Amaral, Ana Lucia Tararthuch, Ricardo Fernandez
BACKGROUND: The calcium-sensing receptor (CaSR) is localized in the apical membrane of proximal tubules in close proximity to the transporters responsible for proton secretion. Therefore, the aim of the present study was to analyze the effects of CaSR stimulation on the biochemical activity of the vacuolar H+ -ATPase in a cellular model of proximal tubule cells, OKP cells. METHODS: Biochemical activity of H+ -ATPase was performed using cell homogenates, and the inorganic phosphate released was determined by a colorimetric method...
June 30, 2018: Clinical and Experimental Nephrology
Sergiy M Nadtochiy, Yves T Wang, Keith Nehrke, Josh Munger, Paul S Brookes
Stimulation of the cytosolic NAD+ dependent deacetylase SIRT1 is cardioprotective against ischemia-reperfusion (IR) injury. NAD+ precursors including nicotinamide mononucleotide (NMN) are thought to induce cardioprotection via SIRT1. Herein, while NMN protected perfused hearts against IR (functional recovery: NMN 42 ± 7% vs. vehicle 11 ± 3%), this protection was insensitive to the SIRT1 inhibitor splitomicin (recovery 47 ± 8%). Although NMN-induced cardioprotection was absent in Sirt3-/- hearts (recovery 9 ± 5%), this was likely due to enhanced baseline injury in Sirt3-/- (recovery 6 ± 2%), since similar injury levels in WT hearts also blunted the protective efficacy of NMN...
June 26, 2018: Journal of Molecular and Cellular Cardiology
Julia Smirnova, Ekaterina Kabin, Vello Tõugu, Peep Palumaa
Zinc finger (ZF) protein motifs, stabilized by binding of Zn(II), typically function as interaction modules that bind nucleic acids, proteins and other molecules. The elucidation of the redox states of ZF proteins in cellular conditions, which depend on their midpoint redox potentials, is important for understanding of ZF functioning. In the present study we determined the midpoint redox potentials for representatives of Cys2 His2 and Cys4 types of ZF proteins in apo and Zn(II)-bound forms using electrospray ionization mass spectrometry...
June 2018: FEBS Open Bio
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