A novel role for the ATP7A copper transporter in cancer

2018 ◽  
Author(s):  
◽  
Vinit C. Shanbhag
Keyword(s):  
Plasma Membrane ◽  
Signal Sequence ◽  
Copper Homeostasis ◽  
The Body ◽  
Cellular Respiration ◽  
Therapeutic Drug ◽  
Platinum Drug ◽  
Copper Transporter ◽  
Vital Functions ◽  
Intracellular Copper

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Copper is a trace metal with a ready capacity to gain or donate electrons. This property is harnessed by numerous enzymes to perform vital functions in the body. In humans, copper is required for various biochemical processes, including cellular respiration, connective tissue development, iron transport and pigmentation. The same redox property that makes copper useful can also have deleterious effects if the proper balance is not maintained. Cellular copper homeostasis is maintained by several different proteins, including CTR1 (copper transporter 1), a high affinity copper importer, as well as ATP7A and ATP7B copper exporting ATPases. ATP7A controls the cellular export of copper and this function of ATP7A is largely regulated by its subcellular localization. Under low intracellular copper concentrations, ATP7A protein is localized to the TGN (trans-Golgi network), where it transports copper to newly synthesized cuproenzymes. Under elevated intracellular copper concentrations, ATP7A traffics to the plasma membrane, subsequently releasing its copper load by fusion with the plasma membrane. To maintain copper homeostasis, ATP7A undergoes constitutive trafficking between the TGN and the plasma membrane. Several key regions in the protein are required for its internalization and successful retrieval from the plasma membrane. Previous studies had shown that a single di-leucine motif in the cytoplasmic tail of ATP7A was required for its internalization. It is hypothesized that multiple di-leucines in the carboxy-terminus of ATP7A are involved in the internalization of the protein. The study presented in this thesis, identified a second di-leucine motif in ATP7A that is a bonafide sorting signal sequence required for internalization and maintaining the steady state localization of the protein. ... Taken together, these findings identify roles for the ATP7A copper transporter at the nexus of platinum-drug resistance, tumorigenesis and metastatic pathways, underscoring its potential as a therapeutic drug target at multiple stages of carcinogenesis.

scholarly journals COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A

2015 ◽  
Vol 26 (1) ◽  
pp. 91-103 ◽  
Author(s):  
Christine A. Phillips-Krawczak ◽  
Amika Singla ◽  
Petro Starokadomskyy ◽  
Zhihui Deng ◽  
Douglas G. Osborne ◽  
...  
Keyword(s):  
Copper Homeostasis ◽  
Mechanistic Explanation ◽  
Copper Accumulation ◽  
Endosomal Trafficking ◽  
Copper Transporter ◽  
Early Endosomes ◽  
Evolutionarily Conserved ◽  
Carboxyl Terminal ◽  
Intracellular Copper

COMMD1 deficiency results in defective copper homeostasis, but the mechanism for this has remained elusive. Here we report that COMMD1 is directly linked to early endosomes through its interaction with a protein complex containing CCDC22, CCDC93, and C16orf62. This COMMD/CCDC22/CCDC93 (CCC) complex interacts with the multisubunit WASH complex, an evolutionarily conserved system, which is required for endosomal deposition of F-actin and cargo trafficking in conjunction with the retromer. Interactions between the WASH complex subunit FAM21, and the carboxyl-terminal ends of CCDC22 and CCDC93 are responsible for CCC complex recruitment to endosomes. We show that depletion of CCC complex components leads to lack of copper-dependent movement of the copper transporter ATP7A from endosomes, resulting in intracellular copper accumulation and modest alterations in copper homeostasis in humans with CCDC22 mutations. This work provides a mechanistic explanation for the role of COMMD1 in copper homeostasis and uncovers additional genes involved in the regulation of copper transporter recycling.

scholarly journals Crossroads between membrane trafficking machinery and copper homeostasis in the nerve system

Open Biology ◽  
2021 ◽  
Vol 11 (12) ◽  
Author(s):  
Meng-Hsuan Wen ◽  
Xihong Xie ◽  
Pei-San Huang ◽  
Karen Yang ◽  
Tai-Yen Chen
Keyword(s):  
Systematic Review ◽  
Membrane Trafficking ◽  
Current Knowledge ◽  
Copper Homeostasis ◽  
Copper Transporter ◽  
Membrane Compartments ◽  
Copper Dyshomeostasis ◽  
Nerve System ◽  
Intracellular Copper

Imbalanced copper homeostasis and perturbation of membrane trafficking are two common symptoms that have been associated with the pathogenesis of neurodegenerative and neurodevelopmental diseases. Accumulating evidence from biophysical, cellular and in vivo studies suggest that membrane trafficking orchestrates both copper homeostasis and neural functions—however, a systematic review of how copper homeostasis and membrane trafficking interplays in neurons remains lacking. Here, we summarize current knowledge of the general trafficking itineraries for copper transporters and highlight several critical membrane trafficking regulators in maintaining copper homeostasis. We discuss how membrane trafficking regulators may alter copper transporter distribution in different membrane compartments to regulate intracellular copper homeostasis. Using Parkinson's disease and MEDNIK as examples, we further elaborate how misregulated trafficking regulators may interplay parallelly or synergistically with copper dyshomeostasis in devastating pathogenesis in neurodegenerative diseases. Finally, we explore multiple unsolved questions and highlight the existing challenges to understand how copper homeostasis is modulated through membrane trafficking.

An Ultrastructural Study of Pericytes

1968 ◽  
Vol 26 ◽  
pp. 66-67
Author(s):  
T. M. Murad ◽  
E. von Haam
Keyword(s):  
Plasma Membrane ◽  
Endothelial Cell ◽  
Basement Membrane ◽  
Blood Vessel ◽  
Vascular Endothelial Cells ◽  
Myoepithelial Cells ◽  
Capillary Blood ◽  
The Body ◽  
Capillary Blood Vessel ◽  
Outer Plasma Membrane

Pericytes are vascular satellites present around capillary blood vessels and small venules. They have been observed in almost every tissue of the body and are thought to be related to vascular smooth muscle cells. Morphologically pericytes have great similarity to vascular endothelial cells and also slightly resemble myoepithelial cells.The present study describes the ultrastructural morphology of pericytes in normal breast tissue and in benign tumor of the breast. The study showed that pericytes are ovoid or elongated cells separated from the endothelial cell of the capillary blood vessel by the basement membrane of endothelial cell. The nuclei of pericytes are often very distinctive. Although some are round, oval, or elongated, others show marked irregularity and infolding of the nuclear membrane. The cytoplasm shows mono-or bipolar extension in which the cytoplasmic organelles are located (Fig. 1). These cytoplasmic extensions embrace the capillary blood vessel incompletely. The plasma membrane exhibits multiple areas of focal condensation called hemidesmosomes (Fig. 2, arrow). A variable number of pinocytotic vesicles are frequently seen lining the outer plasma membrane. Normally pericytes are surrounded by a basement membrane which is found more consistently on the outer plasma membrane separating the pericytes from the stromal connective tissue.

Neutral Lipids of Oats Fruit (Avena Sativa L.)

2020 ◽  
Vol 9 (4) ◽  
pp. 40-43
Author(s):  
N. K. Yuldasheva ◽  
S. D. Gusakova ◽  
D. Kh. Nurullaeva ◽  
N. T. Farmanova ◽  
R. P. Zakirova ◽  
...  
Keyword(s):  
Avena Sativa ◽  
Neutral Lipids ◽  
The Body ◽  
Biologically Active ◽  
Absorption Bands ◽  
Vital Functions ◽  
The Republic ◽  
Living Organisms ◽  
Main Components ◽  
Active Substances

Introduction. Lipids are a widespread group of biologically active substances in nature, making up the bulk of the organic substances of all living organisms. They accumulate in plants in seeds, as well as in fruits and perform a number of vital functions: they are the main components of cell membranes and the energy reserve for the body.Aim. Study of neutral lipids of sown oats (Avena sativa L.).Materials and methods. The objects of the study were fruits (grains) of oats of the sown variety "Tashkent 1," harvested in the Republic of Uzbekistan. Results and discussions. Neutral lipids of oat grains have been found to contain 13 fatty acids with a predominance of the sum of oleic, linolenic and linoleic acids. The total degree of unsaturation was almost 78%. Absorption bands characteristic of these substances were observed in the IR spectrum of MEGC.Conclusion. According to the results of the NL analysis, oat grains consisted of triacylglycerides and free LCDs, which were accompanied by hydrocarbons, phytosterols, triterpenoids and tocopherols.

Role of Rasayana in Prevention of COVID-19 - A Review

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 716-722
Author(s):  
Sneha Dhakite ◽  
Sadhana Misar Wajpeyi
Keyword(s):  
Immune System ◽  
Respiratory System ◽  
Viral Infections ◽  
Cost Effective ◽  
The Body ◽  
Healthy Life ◽  
Vital Functions ◽  
Healthy Life Style ◽  
And Control

The “Coronavirus disease 19 (COVID-19)” is caused by “Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)”, a newly discovered member of the Coronaviridae family of viruses which is a highly communicable. There is no effective medical treatment till date for Coronavirus disease hence prevention is the best way to keep disease away. Rasayana proved to be highly efficacious and cost effective for the Prevention and Control of viral infections when vaccines and standard therapies are lacking. Rasayana Chikitsa is one of the eight branches of Ashtanga Ayurveda which helps to maintain healthy life style. Rasayana improves immunity and performs many vital functions of human body. Vyadhikshamatva that is immune mechanism of the body is involved in Prevention of the occurrence of a new disease and it also decreases the virulence and progression of an existing disease. In COVID-19 the Respiratory system mainly get affected which is evident from its symptoms like cold, cough and breathlessness. Here the drugs help in enhancing immune system and strengthening functions of Respiratory system can be useful. For this purpose, the Rasayana like Chyavanprasha, Agastya Haritaki, Pippali Rasayana, Guduchi, Yashtimadhu, Haridra, Ashwagandha, Tulsi are used. Rasayana working on Respiratory system are best for Prevention of Coronavirus and boosting immune system. Rasayana Chikitsa can be effective in the Prevention as well as reducing symptoms of COVID-19.

scholarly journals Cannabinoid receptors distribution in mouse cortical plasma membrane compartments

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Hajar Miranzadeh Mahabadi ◽  
Haseeb Bhatti ◽  
Robert B. Laprairie ◽  
Changiz Taghibiglou
Keyword(s):  
Plasma Membrane ◽  
Lipid Raft ◽  
Cannabinoid Receptors ◽  
Gradient Centrifugation ◽  
Brain Regions ◽  
Cb1 Receptor ◽  
The Body ◽  
Cb2 Receptor ◽  
Cortical Tissue ◽  
Ionic Detergent

AbstractThe type 1 and type 2 cannabinoid receptors (CB1 and CB2 receptors) are class A G protein-coupled receptors (GPCRs) that are activated by endogenous lipids called endocannabinoids to modulate neuronal excitability and synaptic transmission in neurons throughout the central nervous system (CNS), and inflammatory processes throughout the body. CB1 receptor is one of the most abundant GPCRs in the CNS and is involved in many physiological and pathophysiological processes, including mood, appetite, and nociception. CB2 receptor is primarily found on immunomodulatory cells of both the CNS and the peripheral immune system. In this study, we isolated lipid raft and non-lipid raft fractions of plasma membrane (PM) from mouse cortical tissue by using cold non-ionic detergent and sucrose gradient centrifugation to study the localization of CB1 receptor and CB2 receptor. Lipid raft and non-lipid raft fractions were confirmed by flotillin-1, caveolin-1 and transferrin receptor as their protein biomarkers. Both CB1 receptor and CB2 receptor were found in non-raft compartments that is inconsistent with previous findings in cultured cell lines. This study demonstrates compartmentalization of both CB1 receptor and CB2 receptor in cortical tissue and warrants further investigation of CB1 receptor and CB2 receptor compartmental distribution in various brain regions and cell types.

scholarly journals Amine-Grafted Mesoporous Carbons as Benzocaine-Delivery Platforms

Materials ◽  
2021 ◽  
Vol 14 (9) ◽  
pp. 2188
Author(s):  
Joanna Goscianska ◽  
Aleksander Ejsmont ◽  
Anita Kubiak ◽  
Dominika Ludowicz ◽  
Anna Stasiłowicz ◽  
...  
Keyword(s):  
Release Kinetics ◽  
The Body ◽  
Therapeutic Drug ◽  
Mesoporous Carbons ◽  
Precise Control ◽  
Pharmaceutical Ingredients ◽  
Sorption Ability ◽  
Porous Carriers ◽  
Textural Parameters ◽  
Amine Groups

Smart porous carriers with defined structure and physicochemical properties are required for releasing the therapeutic drug with precise control of delivery time and location in the body. Due to their non-toxicity, ordered structure, and chemical and thermal stability, mesoporous carbons can be considered modern carriers for active pharmaceutical ingredients whose effectiveness needs frequent dosing algorithms. Here, the novel benzocaine delivery systems based on ordered mesoporous carbons of the cubic structure were obtained with the use of a hard template method and functionalization with amine groups at 40 °C for 8 h. It has been shown that amine grafting strongly modifies the surface chemistry and textural parameters of carbons. All samples indicated good sorption ability towards benzocaine, with evident improvement following the functionalization with the amine groups. The sorption capacity and drug release kinetics were strongly affected by the porosity of carbon carriers and the surface functional groups. The smallest amount of benzocaine (~12%) was released from pristine mesoporous carbon, which could be correlated with strong API–carrier interactions. Faster and more efficient release of the drug was observed in the case of triethylenetetramine modified carbon (~62%). All benzocaine delivery platforms based on amine-grafted mesoporous carbons revealed high permeability through the artificial membrane.

The history of anabolic steroids and a review of clinical experience with anabolic steroids

1985 ◽  
Vol 110 (3_Suppla) ◽  
pp. S11-S18 ◽  
Author(s):  
H. Kopera
Keyword(s):  
Protein Synthesis ◽  
Protein Metabolism ◽  
Anabolic Steroids ◽  
Muscular Activity ◽  
Living Cells ◽  
Cellular Protein ◽  
Complex Compounds ◽  
The Body ◽  
Anabolic Effect ◽  
Vital Functions

Metabolism is the term employed to embrace the various physical and chemical processes occurring within the tissues upon which the growth and heat production of the body depend and from which the energy for muscular activity, for the maintenance of vital activity and for the maintenance of vital functions is derived (Best & Taylor 1950). The destructive processes by which complex substances are converted by living cells into more simple compounds are called catabolism. Anabolism denotes the constructive processes by which simple substances are converted by living cells into more complex compounds, especially into living matter. Catabolism and anabolism are part of all metabolic processes, the carbohydrate, fat and protein metabolism. The term anabolic refers only to substances that exert an anabolic effect on protein metabolism and are unlikely to cause adverse androgenic effects. They shift the equilibrium between protein synthesis and degradation in the body as a whole in the direction of synthesis, either by promoting protein synthesis or reducing its breakdown. The protein anabolic effect of anabolic steroids is not restricted to single organs but is the result of stimulated biosynthesis of cellular protein in the whole organism.

scholarly journals Mitochondrial Dysfunction Is a Common Denominator Linking Skeletal Muscle Wasting Due to Disease, Aging, and Prolonged Inactivity

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 588
Author(s):  
Hayden W. Hyatt ◽  
Scott K. Powers
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Chronic Diseases ◽  
Muscle Mass ◽  
Cancer Chemotherapy ◽  
Muscle Wasting ◽  
The Body ◽  
Common Denominator ◽  
Skeletal Muscle Wasting ◽  
Vital Functions

Skeletal muscle is the most abundant tissue in the body and is required for numerous vital functions, including breathing and locomotion. Notably, deterioration of skeletal muscle mass is also highly correlated to mortality in patients suffering from chronic diseases (e.g., cancer). Numerous conditions can promote skeletal muscle wasting, including several chronic diseases, cancer chemotherapy, aging, and prolonged inactivity. Although the mechanisms responsible for this loss of muscle mass is multifactorial, mitochondrial dysfunction is predicted to be a major contributor to muscle wasting in various conditions. This systematic review will highlight the biochemical pathways that have been shown to link mitochondrial dysfunction to skeletal muscle wasting. Importantly, we will discuss the experimental evidence that connects mitochondrial dysfunction to muscle wasting in specific diseases (i.e., cancer and sepsis), aging, cancer chemotherapy, and prolonged muscle inactivity (e.g., limb immobilization). Finally, in hopes of stimulating future research, we conclude with a discussion of important future directions for research in the field of muscle wasting.

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