Cellular mechanisms of human atherosclerosis: Role of cell-to-cell communications in subendothelial cell functions

The vertebrate photoreceptor provides a drammatic example of cell polarization. Specialized to carry out phototransduction at its distal end and to synapse with retinal interneurons at its proximal end, this long slender cell has a uniquely polarized morphology which is reflected in a similarly polarized cytoskeleton. Membranes bearing photopigment are localized in the outer segment, a modified sensory cilium. Sodium pumps which maintain the dark current critical to photosensory transduction are anchored along the inner segment plasma membrane between the outer segment and the nucleus.Proximal to the nucleus is a slender axon terminating in specialized invaginating synapses with other neurons of the retina. Though photoreceptor diameter is only 3-8u, its length from the tip of the outer segment to the synapse may be as great as 200μ. This peculiar linear cell morphology poses special logistical problems and has evoked interesting solutions for numerous cell functions. For example, the outer segment membranes turn over by means of a unique mechanism in which new disks are continuously added at the proximal base of the outer segment, while effete disks are discarded at the tip and phagocytosed by the retinal pigment epithelium. Outer segment proteins are synthesized in the Golgi near the nucleus and must be transported north through the inner segment to their sites of assembly into the outer segment, while synaptic proteins must be transported south through the axon to the synapse.The role of the cytoskeleton in photoreceptor motile processes is being intensely investigated in several laboratories.

Get full-text (via PubEx)

mTORC and PKCε in Regulation of Alcohol Use Disorder

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666200624122325 ◽

2020 ◽

Vol 20 (17) ◽

pp. 1696-1708 ◽

Cited By ~ 1

Author(s):

Athirah Hanim ◽

Isa Naina Mohamed ◽

Rashidi M. Pakri Mohamed ◽

Srijit Das ◽

Norefrina Shafinaz Md Nor ◽

...

Keyword(s):

Alcohol Use ◽

Alcohol Use Disorder ◽

Alcohol Intake ◽

Potential Role ◽

Synaptic Proteins ◽

Cellular Mechanisms ◽

Kinase C ◽

Protein Kinase C Epsilon ◽

Seeking Behavior

Alcohol use disorder (AUD) is characterized by compulsive binge alcohol intake, leading to various health and social harms. Protein Kinase C epsilon (PKCε), a specific family of PKC isoenzyme, regulates binge alcohol intake, and potentiates alcohol-related cues. Alcohol via upstream kinases like the mammalian target to rapamycin complex 1 (mTORC1) or 2 (mTORC2), may affect the activities of PKCε or vice versa in AUD. mTORC2 phosphorylates PKCε at hydrophobic and turn motif, and was recently reported to be associated with alcohol-seeking behavior, suggesting the potential role of mTORC2-PKCε interactions in the pathophysiology of AUD. mTORC1 regulates translation of synaptic proteins involved in alcohol-induced plasticity. Hence, in this article, we aimed to review the molecular composition of mTORC1 and mTORC2, drugs targeting PKCε, mTORC1, and mTORC2 in AUD, upstream regulation of mTORC1 and mTORC2 in AUD and downstream cellular mechanisms of mTORCs in the pathogenesis of AUD.

Get full-text (via PubEx)

Interactome Analysis of KIN (Kin17) Shows New Functions of This Protein

Current Issues in Molecular Biology ◽

10.3390/cimb43020056 ◽

2021 ◽

Vol 43 (2) ◽

pp. 767-781

Author(s):

Vanessa Pinatto Gaspar ◽

Anelise Cardoso Ramos ◽

Philippe Cloutier ◽

José Renato Pattaro Junior ◽

Francisco Ferreira Duarte Junior ◽

...

Keyword(s):

Dna Replication ◽

Protein Interactions ◽

Ribosome Biogenesis ◽

Cell Metabolism ◽

Cell Types ◽

Protein Protein Interactions ◽

Cellular Mechanisms ◽

Cancerous Cell ◽

First Time

KIN (Kin17) protein is overexpressed in a number of cancerous cell lines, and is therefore considered a possible cancer biomarker. It is a well-conserved protein across eukaryotes and is ubiquitously expressed in all cell types studied, suggesting an important role in the maintenance of basic cellular function which is yet to be well determined. Early studies on KIN suggested that this nuclear protein plays a role in cellular mechanisms such as DNA replication and/or repair; however, its association with chromatin depends on its methylation state. In order to provide a better understanding of the cellular role of this protein, we investigated its interactome by proximity-dependent biotin identification coupled to mass spectrometry (BioID-MS), used for identification of protein–protein interactions. Our analyses detected interaction with a novel set of proteins and reinforced previous observations linking KIN to factors involved in RNA processing, notably pre-mRNA splicing and ribosome biogenesis. However, little evidence supports that this protein is directly coupled to DNA replication and/or repair processes, as previously suggested. Furthermore, a novel interaction was observed with PRMT7 (protein arginine methyltransferase 7) and we demonstrated that KIN is modified by this enzyme. This interactome analysis indicates that KIN is associated with several cell metabolism functions, and shows for the first time an association with ribosome biogenesis, suggesting that KIN is likely a moonlight protein.

Get full-text (via PubEx)

GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner

Cancers ◽

10.3390/cancers13081802 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1802

Author(s):

Nayoung Kim ◽

Mi Yeon Kim ◽

Woo Seon Choi ◽

Eunbi Yi ◽

Hyo Jung Lee ◽

...

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Negative Regulator ◽

Target Cells ◽

Dependent Manner ◽

Cell Functions ◽

Cell Based Therapy ◽

Activating Receptors ◽

Gsk 3Β

Natural killer (NK) cells are innate cytotoxic lymphocytes that provide early protection against cancer. NK cell cytotoxicity against cancer cells is triggered by multiple activating receptors that recognize specific ligands expressed on target cells. We previously demonstrated that glycogen synthase kinase (GSK)-3β, but not GSK-3α, is a negative regulator of NK cell functions via diverse activating receptors, including NKG2D and NKp30. However, the role of GSK-3 isoforms in the regulation of specific ligands on target cells is poorly understood, which remains a challenge limiting GSK-3 targeting for NK cell-based therapy. Here, we demonstrate that GSK-3α rather than GSK-3β is the primary isoform restraining the expression of NKG2D ligands, particularly ULBP2/5/6, on tumor cells, thereby regulating their susceptibility to NK cells. GSK-3α also regulated the expression of the NKp30 ligand B7-H6, but not the DNAM-1 ligands PVR or nectin-2. This regulation occurred independently of BCR-ABL1 mutation that confers tyrosine kinase inhibitor (TKI) resistance. Mechanistically, an increase in PI3K/Akt signaling in concert with c-Myc was required for ligand upregulation in response to GSK-3α inhibition. Importantly, GSK-3α inhibition improved cancer surveillance by human NK cells in vivo. Collectively, our results highlight the distinct role of GSK-3 isoforms in the regulation of NK cell reactivity against target cells and suggest that GSK-3α modulation could be used to enhance tumor cell susceptibility to NK cells in an NKG2D- and NKp30-dependent manner.

Get full-text (via PubEx)

Hippocampal Interneurons are Required for Trace Eyeblink Conditioning in Mice

Neuroscience Bulletin ◽

10.1007/s12264-021-00700-0 ◽

2021 ◽

Author(s):

Wei-Wei Zhang ◽

Rong-Rong Li ◽

Jie Zhang ◽

Jie Yan ◽

Qian-Hui Zhang ◽

...

Keyword(s):

Eyeblink Conditioning ◽

Pyramidal Cells ◽

Conditioned Eyeblink ◽

Cellular Mechanisms ◽

Sustained Activity ◽

Early Acquisition ◽

Freely Moving ◽

Trace Eyeblink Conditioning

AbstractWhile the hippocampus has been implicated in supporting the association among time-separated events, the underlying cellular mechanisms have not been fully clarified. Here, we combined in vivo multi-channel recording and optogenetics to investigate the activity of hippocampal interneurons in freely-moving mice performing a trace eyeblink conditioning (tEBC) task. We found that the hippocampal interneurons exhibited conditioned stimulus (CS)-evoked sustained activity, which predicted the performance of conditioned eyeblink responses (CRs) in the early acquisition of the tEBC. Consistent with this, greater proportions of hippocampal pyramidal cells showed CS-evoked decreased activity in the early acquisition of the tEBC. Moreover, optogenetic suppression of the sustained activity in hippocampal interneurons severely impaired acquisition of the tEBC. In contrast, suppression of the sustained activity of hippocampal interneurons had no effect on the performance of well-learned CRs. Our findings highlight the role of hippocampal interneurons in the tEBC, and point to a potential cellular mechanism subserving associative learning.

Get full-text (via PubEx)

Circulating Tfh cell and subsets distribution are associated with low‐responsiveness to hepatitis B vaccination

Molecular Medicine ◽

10.1186/s10020-021-00290-7 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Mingjuan Yin ◽

Yongzhen Xiong ◽

Dongmei Liang ◽

Hao Tang ◽

Qian Hong ◽

...

Keyword(s):

Hepatitis B ◽

Hepatitis B Vaccine ◽

Hepatitis B Vaccination ◽

Cellular Mechanisms ◽

Immunological Responses ◽

Follicular Helper ◽

Low Responders ◽

Specific Subset ◽

Antibody Titers

Abstract Background An estimated 5–10 % of healthy vaccinees lack adequate antibody response following receipt of a standard three-dose hepatitis B vaccination regimen. The cellular mechanisms responsible for poor immunological responses to hepatitis B vaccine have not been fully elucidated to date. Methods There were 61 low responders and 56 hyper responders involved in our study. Peripheral blood samples were mainly collected at D7, D14 and D28 after revaccinated with a further dose of 20 µg of recombinant hepatitis B vaccine. Results We found low responders to the hepatitis B vaccine presented lower frequencies of circulating follicular helper T (cTfh) cells, plasmablasts and a profound skewing away from cTfh2 and cTfh17 cells both toward cTfh1 cells. Importantly, the skewing of Tfh cell subsets correlated with IL-21 and protective antibody titers. Based on the key role of microRNAs involved in Tfh cell differentiation, we revealed miR-19b-1 and miR-92a-1 correlated with the cTfh cell subsets distribution and antibody production. Conclusions Our findings highlighted a decrease in cTfh cells and specific subset skewing contribute to reduced antibody responses in low responders.

Get full-text (via PubEx)

The Phosphoarginine Phosphatase PtpB from Staphylococcus aureus Is Involved in Bacterial Stress Adaptation during Infection

Cells ◽

10.3390/cells10030645 ◽

2021 ◽

Vol 10 (3) ◽

pp. 645

Author(s):

Mohamed Ibrahem Elhawy ◽

Sylvaine Huc-Brandt ◽

Linda Pätzold ◽

Laila Gannoun-Zaki ◽

Ahmed Mohamed Mostafa Abdrabou ◽

...

Keyword(s):

Oxidative Stress ◽

Staphylococcus Aureus ◽

Treatment Strategies ◽

Physiological Role ◽

Aureus Strain ◽

Stress Adaptation ◽

Cellular Mechanisms ◽

Host Interaction ◽

Liver And Kidney

Staphylococcus aureus continues to be a public health threat, especially in hospital settings. Studies aimed at deciphering the molecular and cellular mechanisms that underlie pathogenesis, host adaptation, and virulence are required to develop effective treatment strategies. Numerous host-pathogen interactions were found to be dependent on phosphatases-mediated regulation. This study focused on the analysis of the role of the low-molecular weight phosphatase PtpB, in particular, during infection. Deletion of ptpB in S. aureus strain SA564 significantly reduced the capacity of the mutant to withstand intracellular killing by THP-1 macrophages. When injected into normoglycemic C57BL/6 mice, the SA564 ΔptpB mutant displayed markedly reduced bacterial loads in liver and kidney tissues in a murine S. aureus abscess model when compared to the wild type. We also observed that PtpB phosphatase-activity was sensitive to oxidative stress. Our quantitative transcript analyses revealed that PtpB affects the transcription of various genes involved in oxidative stress adaptation and infectivity. Thus, this study disclosed first insights into the physiological role of PtpB during host interaction allowing us to link phosphatase-dependent regulation to oxidative bacterial stress adaptation during infection.

Get full-text (via PubEx)

Mitochondrial microRNAs: A Putative Role in Tissue Regeneration

Biology ◽

10.3390/biology9120486 ◽

2020 ◽

Vol 9 (12) ◽

pp. 486

Author(s):

Sílvia C. Rodrigues ◽

Renato M. S. Cardoso ◽

Filipe V. Duarte

Keyword(s):

Tissue Regeneration ◽

Protein Complexes ◽

Mitochondrial Protein ◽

Noncoding Rnas ◽

Atp Synthesis ◽

Mitochondrial Proteins ◽

Cellular Mechanisms ◽

Small Noncoding Rnas ◽

Mitochondrial Ribosome

The most famous role of mitochondria is to generate ATP through oxidative phosphorylation, a metabolic pathway that involves a chain of four protein complexes (the electron transport chain, ETC) that generates a proton-motive force that in turn drives the ATP synthesis by the Complex V (ATP synthase). An impressive number of more than 1000 mitochondrial proteins have been discovered. Since mitochondrial proteins have a dual genetic origin, it is predicted that ~99% of these proteins are nuclear-encoded and are synthesized in the cytoplasmatic compartment, being further imported through mitochondrial membrane transporters. The lasting 1% of mitochondrial proteins are encoded by the mitochondrial genome and synthesized by the mitochondrial ribosome (mitoribosome). As a result, an appropriate regulation of mitochondrial protein synthesis is absolutely required to achieve and maintain normal mitochondrial function. Regarding miRNAs in mitochondria, it is well-recognized nowadays that several cellular mechanisms involving mitochondria are regulated by many genetic players that originate from either nuclear- or mitochondrial-encoded small noncoding RNAs (sncRNAs). Growing evidence collected from whole genome and transcriptome sequencing highlight the role of distinct members of this class, from short interfering RNAs (siRNAs) to miRNAs and long noncoding RNAs (lncRNAs). Some of the mechanisms that have been shown to be modulated are the expression of mitochondrial proteins itself, as well as the more complex coordination of mitochondrial structure and dynamics with its function. We devote particular attention to the role of mitochondrial miRNAs and to their role in the modulation of several molecular processes that could ultimately contribute to tissue regeneration accomplishment.

Get full-text (via PubEx)

An autoantibody directed against human thrombin anion-binding exosite in a patient with arterial thrombosis: effects on platelets, endothelial cells, and protein C activation

Blood ◽

10.1182/blood.v84.6.1843.1843 ◽

1994 ◽

Vol 84 (6) ◽

pp. 1843-1850 ◽

Cited By ~ 14

Author(s):

E Arnaud ◽

M Lafay ◽

P Gaussem ◽

V Picard ◽

M Jandrot-Perrus ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Arterial Thrombosis ◽

Protein C ◽

Receptor Activation ◽

Anion Binding ◽

Thrombin Receptor ◽

Cell Functions ◽

Human Thrombin

Abstract An autoantibody, developed by a patient with severe and recurrent arterial thrombosis, was characterized to be directed against the anion- binding exosite of thrombin, and inhibited all thrombin interactions requiring this secondary binding site without interfering with the catalytic site. The effect of the antibody was studied on thrombin interactions with platelets and endothelial cells from human umbilical veins (HUVEC). The autoantibody specifically and concentration- dependently inhibited alpha-thrombin-induced platelet activation and prostacyclin (PGI2) synthesis from HUVEC. It had no effect when gamma- thrombin or the thrombin receptor activation peptide SFLLR were the inducers. The effect of the antibody on protein C activation has been studied. The antibody blocked the thrombin-thrombomodulin activation of protein C. The inhibition of the activation was maximal with a low concentration of thrombomodulin. The fact that the autoantibody inhibited concentration-dependent alpha-thrombin-induced platelet and endothelial cell functions emphasizes the crucial role of the anion- binding exosite of thrombin to activate its receptor. In regard to the pathology, the antibody inhibited two vascular processes implicated in thrombin-antithrombotic functions, PGI2 secretion, and protein C activation, which could be implicated in this arterial thrombotic disease.

Get full-text (via PubEx)

The role of exploratory mechanisms in evolution

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1995.0116 ◽

1995 ◽

Vol 349 (1329) ◽

pp. 297-297

Keyword(s):

Dynamic Instability ◽

Specific Mechanism ◽

Cellular Mechanisms ◽

Selection Processes ◽

Wide Range ◽

Rapid Changes ◽

Neuronal Processes ◽

History Of ◽

Variation And Selection

Many cellular mechanisms use a process of variation and selection to generate specific patterns. Among these, dynamic instability of microtubules has been shown to employ a specific mechanism to intentionally generate variation. In many systems the growth of neurons or neuronal processes is excessive, the final connections being established by stabilization of functional interactions. When changes in neuronal networks take place, such as in metamorphosis, use is made of the plasticity of neuronal connectivity. In the immune system, specific responses are generated by variation and selection. Processes that explore a wide range of conditions and a wide range of structures can be called exploratory processes. These are very robust and capable of responding to damage, variability in the environment and ontogenic changes in the organisms. Such robustness would be useful for adapting to changes that occur during phylogenetic changes as well. Given the extensive history of extinction and radiation in evolution, it may be supposed that these mechanisms have themselves been selected for their capacity to survive rapid changes in the organism and for their ability to generate cellular variation.

Get full-text (via PubEx)