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1.
J Cell Biochem ; 123(8): 1281-1284, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-2013552

ABSTRACT

COVID-19 has been proposed to be an endothelial disease, as endothelial damage and oxidative stress contribute to its systemic inflammatory and thrombotic events. Polyphenols, natural antioxidant compounds appear as promising agents to prevent and treat COVID-19. Polyphenols bind and inhibit the F1 Fo -ATP synthase rotary catalysis. An early target of polyphenols may be the ectopic F1 Fo -ATP synthase expressed on the endothelial plasma membrane. Among the pleiotropic beneficial action of polyphenols in COVID-19, modulation of the ecto-F1 Fo -ATP synthase, lowering the oxidative stress produced by the electron transfer chain coupled to it, would not be negligible.


Subject(s)
COVID-19 , Polyphenols , Adenosine Triphosphate/metabolism , COVID-19/drug therapy , Cell Membrane/metabolism , Humans , Mitochondrial Proton-Translocating ATPases/metabolism , Polyphenols/pharmacology , Polyphenols/therapeutic use , Proton-Translocating ATPases/metabolism
2.
Exp Biol Med (Maywood) ; 247(13): 1112-1123, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-2009311

ABSTRACT

The cytokine storm (CS) in hyperinflammation is characterized by high levels of cytokines, extreme activation of innate as well as adaptive immune cells and initiation of apoptosis. High levels of apoptotic cells overwhelm the proper recognition and removal system of these cells. Phosphatidylserine on the apoptotic cell surface, which normally provides a recognition signal for removal, becomes a target for hemostatic proteins and secretory phospholipase A2. The dysregulation of these normal pathways in hemostasis and the inflammasome result in a prothrombotic state, cellular death, and end-organ damage. In this review, we provide the argument that this imbalance in recognition and removal is a common denominator regardless of the inflammatory trigger. The complex reaction of the immune defense system in hyperinflammation leads to self-inflicted damage. This common endpoint may provide additional options to monitor the progression of the inflammatory syndrome, predict severity, and may add to possible treatment strategies.


Subject(s)
Apoptosis , Cytokine Release Syndrome , Cell Membrane , Cytokines , Humans , Inflammasomes
3.
Adv Healthc Mater ; 11(7): e2101349, 2022 04.
Article in English | MEDLINE | ID: covidwho-1381824

ABSTRACT

White blood cells (WBCs) are immune cells that play essential roles in critical diseases including cancers, infections, and inflammatory disorders. Their dynamic and diverse functions have inspired the development of WBC membrane-coated nanoparticles (denoted "WBC-NPs"), which are formed by fusing the plasma membranes of WBCs, such as macrophages, neutrophils, T cells, and natural killer cells, onto synthetic nanoparticle cores. Inheriting the entire source cell antigens, WBC-NPs act as source cell decoys and simulate their broad biointerfacing properties with intriguing therapeutic potentials. Herein, the recent development and medical applications of WBC-NPs focusing on four areas, including WBC-NPs as carriers for drug delivery, as countermeasures for biological neutralization, as nanovaccines for immune modulation, and as tools for the isolation of circulating tumor cells and fundamental research is reviewed. Overall, the recent development and studies of WBC-NPs have established the platform as versatile nanotherapeutics and tools with broad medical application potentials.


Subject(s)
Nanoparticles , Neoplasms , Cell Membrane/metabolism , Drug Delivery Systems , Humans , Leukocytes , Neoplasms/drug therapy , Neoplasms/metabolism
4.
Int J Mol Sci ; 21(11)2020 May 29.
Article in English | MEDLINE | ID: covidwho-1934082

ABSTRACT

Starting from fertilization, through tissue growth, hormone secretion, synaptic transmission, and sometimes morbid events of carcinogenesis and viral infections, membrane fusion regulates the whole life of high organisms. Despite that, a lot of fusion processes still lack well-established models and even a list of main actors. A merger of membranes requires their topological rearrangements controlled by elastic properties of a lipid bilayer. That is why continuum models based on theories of membrane elasticity are actively applied for the construction of physical models of membrane fusion. Started from the view on the membrane as a structureless film with postulated geometry of fusion intermediates, they developed along with experimental and computational techniques to a powerful tool for prediction of the whole process with molecular accuracy. In the present review, focusing on fusion processes occurring in eukaryotic cells, we scrutinize the history of these models, their evolution and complication, as well as open questions and remaining theoretical problems. We show that modern approaches in this field allow continuum models of membrane fusion to stand shoulder to shoulder with molecular dynamics simulations, and provide the deepest understanding of this process in multiple biological systems.


Subject(s)
Cell Membrane/physiology , Lipid Bilayers/chemistry , Membrane Fusion , Molecular Dynamics Simulation , Animals , Elasticity , Humans , Models, Biological , Normal Distribution
5.
Cells ; 11(11)2022 05 25.
Article in English | MEDLINE | ID: covidwho-1924204

ABSTRACT

Herein, we have verified the interaction between the functional peptides from the SARS-CoV-2 and cell membrane, and we further proved that peptides exhibit little membrane disruption. The specific amino acids (Lys, Ile, Glu, Asn, Gln, etc.) with charge or hydrophobic residues play a significant role during the functional-peptide binding to membrane. The findings could provide the hints related to viral infection and also might pave the way for development of new materials based on peptides with membrane-binding activity, which would enable functional peptides further as peptide adjuvants, in order to help deliver the cancer drug into tumor cells for the efficient tumor therapy.


Subject(s)
COVID-19 , Molecular Dynamics Simulation , Amino Acid Sequence , Cell Membrane/metabolism , Humans , Peptides/metabolism , SARS-CoV-2 , Trypsin/metabolism
6.
Pharm Res ; 39(6): 1031-1034, 2022 06.
Article in English | MEDLINE | ID: covidwho-1913991
7.
Viruses ; 14(5)2022 05 19.
Article in English | MEDLINE | ID: covidwho-1903492

ABSTRACT

Since the end of 2019, the whole world has been struggling with the life-threatening pandemic amongst all age groups and geographic areas caused by Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). The Coronavirus Disease 2019 (COVID-19) pandemic, which has led to more than 468 million cases and over 6 million deaths reported worldwide (as of 20 March 2022), is one of the greatest threats to human health in history. Meanwhile, the lack of specific and irresistible treatment modalities provoked concentrated efforts in scientists around the world. Various mechanisms of cell entry and cellular dysfunction were initially proclaimed. Especially, mitochondria and cell membrane are crucial for the course of infection. The SARS-CoV-2 invasion depends on angiotensin converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), and cluster of differentiation 147 (CD147), expressed on host cells. Moreover, in this narrative review, we aim to discuss other cell organelles targeted by SARS-CoV-2. Lastly, we briefly summarize the studies on various drugs.


Subject(s)
COVID-19 , Cell Membrane/metabolism , Humans , Organelles/metabolism , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2
8.
ACS Sens ; 7(7): 2084-2092, 2022 Jul 22.
Article in English | MEDLINE | ID: covidwho-1900429

ABSTRACT

With the rapid spread and multigeneration variation of coronavirus, rapid drug development has become imperative. A major obstacle to addressing this issue is adequately constructing the cell membrane at the molecular level, which enables in vitro observation of the cell response to virus and drug molecules quantitatively, shortening the drug experiment cycle. Herein, we propose a rapid and label-free supported lipid bilayer-based lab-on-a-chip biosensor for the screening of effective inhibition drugs. An extended gate electrode was prepared and functionalized by an angiotensin-converting enzyme II (ACE2) receptor-incorporated supported lipid bilayer (SLB). Such an integrated system can convert the interactions of targets and membrane receptors into real-time charge signals. The platform can simulate the cell membrane microenvironment in vitro and accurately capture the interaction signal between the target and the cell membrane with minimized interference, thus observing the drug action pathway quantitatively and realizing drug screening effectively. Due to these label-free, low-cost, convenient, and integrated advantages, it is a suitable candidate method for the rapid drug screening for the early treatment and prevention of worldwide spread of coronavirus.


Subject(s)
Biosensing Techniques , Coronavirus , Cell Membrane/metabolism , Coronavirus/metabolism , Lab-On-A-Chip Devices , Lipid Bilayers/metabolism
9.
Int J Mol Sci ; 23(11)2022 May 27.
Article in English | MEDLINE | ID: covidwho-1892895

ABSTRACT

Identification of alternative attenuation targets of Mycobacterium tuberculosis (Mtb) is pivotal for designing new candidates for live attenuated anti-tuberculosis (TB) vaccines. In this context, the CtpF P-type ATPase of Mtb is an interesting target; specifically, this plasma membrane enzyme is involved in calcium transporting and response to oxidative stress. We found that a mutant of MtbH37Rv lacking ctpF expression (MtbΔctpF) displayed impaired proliferation in mouse alveolar macrophages (MH-S) during in vitro infection. Further, the levels of tumor necrosis factor and interferon-gamma in MH-S cells infected with MtbΔctpF were similar to those of cells infected with the parental strain, suggesting preservation of the immunogenic capacity. In addition, BALB/c mice infected with Mtb∆ctpF showed median survival times of 84 days, while mice infected with MtbH37Rv survived 59 days, suggesting reduced virulence of the mutant strain. Interestingly, the expression levels of ctpF in a mouse model of latent TB were significantly higher than in a mouse model of progressive TB, indicating that ctpF is involved in Mtb persistence in the dormancy state. Finally, the possibility of complementary mechanisms that counteract deficiencies in Ca2+ transport mediated by P-type ATPases is suggested. Altogether, our results demonstrate that CtpF could be a potential target for Mtb attenuation.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Animals , Calcium , Calcium-Transporting ATPases , Cell Membrane/pathology , Mice , Tuberculosis/microbiology , Virulence/genetics
10.
Eur J Cell Biol ; 101(2): 151222, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1881962

ABSTRACT

Clathrin-mediated endocytosis (CME) is the major route through which cells internalise various substances and recycle membrane components. Via the coordinated action of many proteins, the membrane bends and invaginates to form a vesicle that buds off-along with its contents-into the cell. The contribution of the actin cytoskeleton to this highly dynamic process in mammalian cells is not well understood. Unlike in yeast, where there is a strict requirement for actin in CME, the significance of the actin cytoskeleton to mammalian CME is variable. However, a growing number of studies have established the actin cytoskeleton as a core component of mammalian CME, and our understanding of its contribution has been increasing at a rapid pace. In this review, we summarise the state-of-the-art regarding our understanding of the endocytic cytoskeleton, its physiological significance, and the questions that remain to be answered.


Subject(s)
Actin Cytoskeleton , Clathrin , Actin Cytoskeleton/metabolism , Actins/metabolism , Animals , Cell Membrane/metabolism , Clathrin/metabolism , Cytoskeleton/metabolism , Endocytosis/physiology , Mammals/metabolism , Saccharomyces cerevisiae/metabolism
13.
J Phys Chem Lett ; 13(21): 4642-4649, 2022 Jun 02.
Article in English | MEDLINE | ID: covidwho-1860273

ABSTRACT

Like all viral infections, SARS-CoV-2 acts at multiple levels, hijacking fundamental cellular functions and assuring its replication and immune system evasion. In particular, the viral 3' Open Reading Frame (ORF3a) codes for a hydrophobic protein, which embeds in the cellular membrane, where it acts as an ion viroporin and is related to strong inflammatory response. Here we report equilibrium and enhanced sampling molecular dynamic simulation of the SARS-CoV-2 ORF3a in a model lipid bilayer, showing how the protein permeabilizes the lipid membrane, via the formation of a water channel, which in turn assures ion transport. We report the free energy profile for both K+ and Cl- transfer from the cytosol to the extracellular domain. The important role of ORF3a in the viral cycle and its high conservation among coronaviruses may also make it a target of choice for future antiviral development, further justifying the elucidation of its mechanism at the atomistic level.


Subject(s)
COVID-19 , Cell Membrane , Viroporin Proteins , Cell Membrane/virology , Humans , Lipids , SARS-CoV-2
14.
Virology ; 570: 1-8, 2022 05.
Article in English | MEDLINE | ID: covidwho-1839383

ABSTRACT

Enveloped viruses such as Coronaviridae (CoV) enter the host cell by fusing the viral envelope directly with the plasma membrane (PM) or with the membrane of the endosome. Replication of the CoV genome takes place in membrane compartments formed by rearrangement of the endoplasmic reticulum (ER) membrane network. Budding of these viruses occurs from the ER-Golgi intermediate compartment (ERGIC). The relationship between proteins and various membranes is crucial for the replication cycle of CoVs. The role of transmembrane domains (TMDs) and pre-transmembrane domains (pre-TMD) of viral proteins in this process is gaining more recognition. Here we present a thorough analysis of physico-chemical parameters, such as accessible surface area (ASA), average hydrophobicity (Hav), and contribution of specific amino acids in TMDs and pre-TMDs of single-span membrane proteins of human viruses. We focus on unique properties of these elements in CoV and postulate their role in adaptation to diverse host membranes and regulation of retention of membrane proteins during replication.


Subject(s)
Coronaviridae , Cell Membrane/metabolism , Endoplasmic Reticulum/metabolism , Humans , Membrane Proteins/genetics , Membrane Proteins/metabolism , Protein Domains , Viral Proteins/metabolism
15.
Int J Pharm ; 621: 121790, 2022 Jun 10.
Article in English | MEDLINE | ID: covidwho-1814550

ABSTRACT

Biomimetic nanotechnology could serve as an advancement in the domain of drug delivery and diagnosis with the application of natural cell membrane or synthetically-derived membrane nanoparticles (NPs). These biomimetic NPs endow significant therapeutic and diagnostic efficacy by their unique properties, such as immune invasion and better targeting ability. Additionally, these NPs have a unique ability to retain the inherent properties of cell membrane and membrane's intrinsic functionalities, which helps them to exhibit superior therapeutic effects. In this review, we describe how these membrane-clocked NPs endow superior therapeutic effects by immune invasion; along with this, the development of membrane-coated NPs and their method of preparation and characterization has been clearly described in the manuscript. Moreover, Various developed membrane-coated NPs such as red blood cell membrane-coated NPs, white blood cells membrane-coated NPs, platelet membrane coated, cancer cell membrane coated, bacterial membrane vesicles and, mesenchymal stem cells membrane-coated NPs have been established in this manuscript. At last, the discussion on the role of membrane-coated NPs as theranostics, and notably, the literature that demonstrates the shreds of evidences of these NPs in targeting and neutralizing the SARS-CoV-2 virus have also been incorporated.


Subject(s)
COVID-19 , Nanoparticles , COVID-19/drug therapy , Cell Membrane , Drug Delivery Systems , Humans , SARS-CoV-2
16.
Int J Pharm ; 620: 121757, 2022 May 25.
Article in English | MEDLINE | ID: covidwho-1796680

ABSTRACT

Pulmonary diseases are currently one of the major threats of human health, especially considering the recent COVID-19 pandemic. However, the current treatments are facing the challenges like insufficient local drug concentrations, the fast lung clearance and risks to induce unexpected inflammation. Cell-derived membrane biomimetic nanocarriers are recently emerged delivery strategy, showing advantages of long circulation time, excellent biocompatibility and immune escape ability. In this review, applications of using cell-derived membrane biomimetic nanocarriers from diverse cell sources for the targeted therapy of pulmonary disease were summarized. In addition, improvements of the cell-derived membrane biomimetic nanocarriers for augmented therapeutic ability against different kinds of pulmonary diseases were introduced. This review is expected to provide a general guideline for the potential applications of cell-derived membrane biomimetic nanocarriers to treat pulmonary diseases.


Subject(s)
Biomimetic Materials , COVID-19 , Nanoparticles , Biomimetics , COVID-19/drug therapy , Cell Membrane/metabolism , Drug Carriers/metabolism , Drug Delivery Systems , Humans , Pandemics
17.
Nature ; 603(7902): 706-714, 2022 03.
Article in English | MEDLINE | ID: covidwho-1764186

ABSTRACT

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron's evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis.


Subject(s)
COVID-19/pathology , COVID-19/virology , Membrane Fusion , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Serine Endopeptidases/metabolism , Virus Internalization , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19 Vaccines/immunology , Cell Line , Cell Membrane/metabolism , Cell Membrane/virology , Chlorocebus aethiops , Convalescence , Female , Humans , Immune Sera/immunology , Intestines/pathology , Intestines/virology , Lung/pathology , Lung/virology , Male , Middle Aged , Mutation , Nasal Mucosa/pathology , Nasal Mucosa/virology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Tissue Culture Techniques , Virulence , Virus Replication
18.
Int J Mol Sci ; 23(4)2022 Feb 12.
Article in English | MEDLINE | ID: covidwho-1715397

ABSTRACT

The state of red blood cells (RBCs) and their functional possibilities depend on the structural organization of the membranes. Cell morphology and membrane nanostructure are compositionally and functionally related to the cytoskeleton network. In this work, the influence of agents (hemin, endogenous oxidation during storage of packed RBCs, ultraviolet (UV) radiation, temperature, and potential of hydrogen (pH) changes) on the relationships between cytoskeleton destruction, membrane nanostructure, and RBC morphology was observed by atomic force microscope. It was shown that the influence of factors of a physical and biochemical nature causes structural rearrangements in RBCs at all levels of organization, forming a unified mechanism of disturbances in relationships "cytoskeleton-membrane nanosurface-cell morphology". Filament ruptures and, consequently, large cytoskeleton pores appeared. The pores caused membrane topological defects in the form of separate grain domains. Increasing loading doses led to an increase in the number of large cytoskeleton pores and defects and their fusion at the membrane nanosurfaces. This caused the changes in RBC morphology. Our results can be used in molecular cell biology, membrane biophysics, and in fundamental and practical medicine.


Subject(s)
Cell Membrane/ultrastructure , Cytoskeleton/ultrastructure , Erythrocytes/pathology , Adult , Cells, Cultured , Erythrocytes/drug effects , Erythrocytes/radiation effects , Female , Hemin/toxicity , Humans , Hydrogen-Ion Concentration , Light/adverse effects , Male , Middle Aged , Oxidants/toxicity
19.
ChemistryOpen ; 11(2): e202100260, 2022 02.
Article in English | MEDLINE | ID: covidwho-1704277

ABSTRACT

Cationic conjugated oligoelectrolytes (COEs) are a class of compounds that can be tailored to achieve relevant in vitro antimicrobial properties with relatively low cytotoxicity against mammalian cells. Three distyrylbenzene-based COEs were designed containing amide functional groups on the side chains. Their properties were compared to two representative COEs with only quaternary ammonium groups. The optimal compound, COE2-3C-C3-Apropyl, has an antimicrobial efficacy against Escherichia coli with an MIC=2 µg mL-1 , even in the presence of human serum albumin low cytotoxicity (IC50 =740 µg mL-1 ) and minimal hemolytic activity. Moreover, we find that amide groups increase interactions between COEs and a bacterial lipid mimic based on calcein leakage assay and allow COEs to readily permeabilize the cytoplasmic membrane of E. coli. These findings suggest that hydrogen bond forming moieties can be further applied in the molecular design of antimicrobial COEs to further improve their selectivity towards bacteria.


Subject(s)
Anti-Infective Agents , Escherichia coli , Amides/analysis , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/analysis , Anti-Infective Agents/chemistry , Bacteria , Cell Membrane , Gram-Negative Bacteria , Humans , Mammals
20.
Comput Math Methods Med ; 2022: 9735626, 2022.
Article in English | MEDLINE | ID: covidwho-1677416

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was characterized as a pandemic by the World Health Organization (WHO) in Dec. 2019. SARS-CoV-2 binds to the cell membrane through spike proteins on its surface and infects the cell. Furin, a host-cell enzyme, possesses a binding site for the spike protein. Thus, molecules that block furin could potentially be a therapeutic solution. Defensins are antimicrobial peptides that can hypothetically inhibit furin because of their arginine-rich structure. Theta-defensins, a subclass of defensins, have attracted attention as drug candidates due to their small size, unique structure, and involvement in several defense mechanisms. Theta-defensins could be a potential treatment for COVID-19 through furin inhibition and an anti-inflammatory mechanism. Note that inflammatory events are a significant and deadly condition that could happen at the later stages of COVID-19 infection. Here, the potential of theta-defensins against SARS-CoV-2 infection was investigated through in silico approaches. Based on docking analysis results, theta-defensins can function as furin inhibitors. Additionally, a novel candidate peptide against COVID-19 with optimal properties regarding antigenicity, stability, electrostatic potential, and binding strength was proposed. Further in vitro/in vivo investigations could verify the efficiency of the designed novel peptide.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/metabolism , Defensins/pharmacology , Drug Design , Furin/antagonists & inhibitors , Animals , COVID-19/drug therapy , Catalytic Domain , Cell Membrane/virology , Computer Simulation , Data Mining , Furin/chemistry , Humans , Inflammation , Models, Molecular , Molecular Docking Simulation , Peptides/chemistry , Software , Spike Glycoprotein, Coronavirus , Static Electricity
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