Extracellular Cysteine in Connexins: Role as Redox Sensors

Frontiers in Physiology, Journal Year: 2016, Volume and Issue: 7

Published: Jan. 28, 2016

Connexin-based channels comprise hemichannels and gap junction channels. The opening of allow for the flux ions molecules from extracellular space into cell vice versa. Similarly, permits diffusional exchange between cytoplasm contacting cells. controlled has been associated with several physiological cellular processes; thereby unregulated hemichannel activity may induce loss homeostasis death. Hemichannel can be regulated through mechanisms, such as phosphorylation, divalent cations changes in membrane potential. Additionally, it was recently postulated that redox could modify properties vitro. However, molecular mechanism by which interact is poorly understood. In this work, we discuss current knowledge on connexin regulation propose hypothesis cysteine important sensing Future studies topic will offer new insight function, expanding understanding contribution to disease progression.

Language: Английский

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Identification of Lgr5-Independent Spheroid-Generating Progenitors of the Mouse Fetal Intestinal Epithelium

Cell Reports, Journal Year: 2013, Volume and Issue: 5(2), P. 421 - 432

Published: Oct. 1, 2013

Immortal spheroids were generated from fetal mouse intestine using the culture system initially developed to organoids adult intestinal epithelium. Spheroid proportion progressively decreases postnatal period, with a corresponding increase in production of organoids. Like organoids, show Wnt-dependent indefinite self-renewing properties but display poorly differentiated phenotype reminiscent incompletely caudalized progenitors. The spheroid transcriptome is strikingly different that stem cells, minimal overlap Wnt target gene expression. receptor LGR4, not LGR5, essential for their growth. Trop2/Tacstd2 and Cnx43/Gja1, two markers highly enriched spheroids, are expressed throughout embryonic-day-14 Comparison utero neonatal lineage tracing Cnx43-CreER Lgr5-CreERT2 mice identified spheroid-generating cells as developmental progenitors involved generation prenatal Ex vivo, have potential differentiate into qualifying type cell.

Language: Английский

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Mechanisms of ATP Release by Inflammatory Cells

International Journal of Molecular Sciences, Journal Year: 2018, Volume and Issue: 19(4), P. 1222 - 1222

Published: April 18, 2018

Extracellular nucleotides (e.g., ATP, ADP, UTP, UDP) released by inflammatory cells interact with specific purinergic P2 type receptors to modulate their recruitment and activation. The focus of this review is on stimuli mechanisms extracellular nucleotide release its consequences during inflammation. Necrosis leads non-specific nucleotides, whereas include vesicular exocytosis channel-mediated via connexin or pannexin hemichannels. These allow stimulated such as macrophages, neutrophils, endothelial fine-tune autocrine/paracrine responses acute chronic Key effector functions are therefore regulated signaling in diseases, making a promising target for the development new therapies.

Language: Английский

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MicroRNAs Transfer from Human Macrophages to Hepato-Carcinoma Cells and Inhibit Proliferation

The Journal of Immunology, Journal Year: 2013, Volume and Issue: 191(12), P. 6250 - 6260

Published: Nov. 14, 2013

Recent research has indicated a new mode of intercellular communication facilitated by the movement RNA between cells. There is evidence that can transfer cells in multitude ways, including complex with proteins or lipids vesicles, apoptotic bodies and exosomes. However, there remains little understanding function nucleic acid human In this article, we report macrophages microRNAs (miRNAs) to hepato-carcinoma (HCCs) manner required contact involved gap junctions. Two specific miRNAs transferred efficiently these cells--miR-142 miR-223--and both were endogenously expressed not HCCs. Transfer influenced posttranscriptional regulation HCCs, decreased expression reporter stathmin-1 insulin-like growth factor-1 receptor. Importantly, from functionally inhibited proliferation cancerous Thus, data led us propose miRNA immune could serve as defense against unwanted cell tumor growth.

Language: Английский

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Connexin and pannexin hemichannels in brain glial cells: properties, pharmacology, and roles

Frontiers in Pharmacology, Journal Year: 2013, Volume and Issue: 4

Published: Jan. 1, 2013

Functional interaction between neurons and glia is an exciting field that has expanded tremendously during the past decade. Such partnership multiple impacts on neuronal activity survival. Indeed, numerous findings indicate glial cells interact tightly with in physiological as well pathological situations. One typical feature of their high expression level gap junction protein subunits, named connexins (Cxs), thus membrane channels they form may contribute to neuroglial While participation neuroglia interactions been regularly reviewed past, other channel function Cxs, i.e. hemichannels located at cell surface, only recently received attention. provide basis for a unique direct cell-to-cell communication, Cx allow exchange ions signaling molecules cytoplasm extracellular medium, supporting autocrine paracrine communication through process referred "gliotransmission", uptake release metabolites. More recently, another family proteins, termed pannexins (Panxs), identified. These proteins share similar topology but no sequence homology Cxs. They multimeric pharmacology somewhat overlapping hemichannels. duality led several controversies literature concerning identification molecular constituents (Cxs versus Panxs) glia. In present review, we up-date discuss knowledge Panx glia, properties pharmacology, understanding contribution healthy diseased brain.

Language: Английский

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Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(6), P. 5977 - 6039

Published: Feb. 2, 2022

The stimulator of interferon genes (STING) cellular signaling pathway is a promising target for cancer immunotherapy. Activation the intracellular STING protein triggers production multifaceted array immunostimulatory molecules, which, in proper context, can drive dendritic cell maturation, antitumor macrophage polarization, T priming and activation, natural killer vascular reprogramming, and/or death, resulting immune-mediated tumor elimination generation immune memory. Accordingly, there significant amount ongoing preclinical clinical research toward further understanding role surveillance as well development modulators strategy to stimulate immunity. Yet, efficacy agonists limited by many drug delivery pharmacological challenges. Depending on class agonist desired administration route, these may include poor stability, immunocellular toxicity, immune-related adverse events, or lymph node targeting retention, low uptake delivery, complex dependence magnitude kinetics signaling. This review provides concise summary pathway, highlighting recent biological developments, immunological consequences, implications delivery. also offers critical analysis an expanding arsenal chemical strategies that are being employed enhance efficacy, safety, utility lastly draws attention several opportunities therapeutic advancements.

Language: Английский

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Extracellular ATP: A Feasible Target for Cancer Therapy

Cells, Journal Year: 2020, Volume and Issue: 9(11), P. 2496 - 2496

Published: Nov. 17, 2020

Adenosine triphosphate (ATP) is one of the main biochemical components tumor microenvironment (TME), where it can promote progression or suppression depending on its concentration and specific ecto-nucleotidases receptors expressed by immune cancer cells. ATP be released from cells via both nonspecific pathways. A non-regulated release occurs dying damaged cells, whereas active involves exocytotic granules, plasma membrane-derived microvesicles, ATP-binding cassette (ABC) transporters membrane channels (connexin hemichannels, pannexin 1 (PANX1), calcium homeostasis modulator (CALHM1), volume-regulated anion (VRACs) maxi-anion (MACs)). Extracellular acts at P2 purinergic receptors, among which P2X7R a key mediator final ATP-dependent biological effects. Over years, receptor- ecto-nucleotidase-targeting for therapy has been proposed actively investigated, while comparatively fewer studies have explored suitability TME as target. In this review, we briefly summarize available evidence suggesting that central role in determining fate is, therefore, suitable target therapy.

Language: Английский

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Extracellular nucleotides and nucleosides as signalling molecules

Immunology Letters, Journal Year: 2018, Volume and Issue: 205, P. 16 - 24

Published: Nov. 12, 2018

Language: Английский

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Communication in the Cancer Microenvironment as a Target for Therapeutic Interventions

Cancers, Journal Year: 2020, Volume and Issue: 12(5), P. 1232 - 1232

Published: May 14, 2020

The tumor microenvironment (TME) is a complex system composed of multiple cells, such as non-cancerous fibroblasts, adipocytes, immune and vascular well signal molecules mediators. Tumor cells recruit reprogram other to produce factors that maintain growth. Communication between cancerous surrounding two-way process engages diverse range mechanisms that, in consequence, can lead rapid proliferation, metastasis, drug resistance, or serve tumors-suppressor, e.g., through tumor–immune cell interaction. Cross-talk within the cancer be direct by cell-to-cell contact via adhesion molecules, electrical coupling, passage gap junctions, indirect classical paracrine signaling cytokines, growth factors, extracellular vesicles. Therapeutic approaches for modulation cell-cell communication may promising strategy combat tumors. In particular, integrative targeting combination with conventional chemotherapy seem reasonable. Currently, special attention paid suppressing formation open-ended channels blocking exosome production ablating their cargos. However, many aspects have yet clarified, and, more work needed regard bidirectional transfer. Finally, it seems some interactions TEM not only cancer-specific, but also patient-specific, recognition would help predict patient response therapy.

Language: Английский

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Gap Junction Proteins in the Blood-Brain Barrier Control Nutrient-Dependent Reactivation of Drosophila Neural Stem Cells

Developmental Cell, Journal Year: 2014, Volume and Issue: 30(3), P. 309 - 321

Published: July 24, 2014

Neural stem cells in the adult brain exist primarily a quiescent state but are reactivated response to changing physiological conditions. How do sense and respond metabolic changes? In Drosophila CNS, neural synchronously nutritional stimulus. Feeding triggers insulin production by blood-brain barrier glial cells, activating insulin/insulin-like growth factor pathway underlying stimulating their proliferation. Here we show that gap junctions glia mediate influence of changes on cell behavior, enabling signals reactivate cells. We propose required translate into synchronized calcium pulses secretion.

Language: Английский

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