scholarly journals Lytic Release of Cellular ATP: Physiological Relevance and Therapeutic Applications

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 700
Author(s):  
Ryszard Grygorczyk ◽  
Francis Boudreault ◽  
Olga Ponomarchuk ◽  
Ju Jing Tan ◽  
Kishio Furuya ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Physiological Mechanism ◽  
Atp Release ◽  
A549 Cells ◽  
Extracellular Atp ◽  
Lung Damage ◽  
Extracellular Nucleotides ◽  
Purinergic Signalling ◽  
Protective Effects ◽  
Therapeutic Applications

The lytic release of ATP due to cell and tissue injury constitutes an important source of extracellular nucleotides and may have physiological and pathophysiological roles by triggering purinergic signalling pathways. In the lungs, extracellular ATP can have protective effects by stimulating surfactant and mucus secretion. However, excessive extracellular ATP levels, such as observed in ventilator-induced lung injury, act as a danger-associated signal that activates NLRP3 inflammasome contributing to lung damage. Here, we discuss examples of lytic release that we have identified in our studies using real-time luciferin-luciferase luminescence imaging of extracellular ATP. In alveolar A549 cells, hypotonic shock-induced ATP release shows rapid lytic and slow-rising non-lytic components. Lytic release originates from the lysis of single fragile cells that could be seen as distinct spikes of ATP-dependent luminescence, but under physiological conditions, its contribution is minimal <1% of total release. By contrast, ATP release from red blood cells results primarily from hemolysis, a physiological mechanism contributing to the regulation of local blood flow in response to tissue hypoxia, mechanical stimulation and temperature changes. Lytic release of cellular ATP may have therapeutic applications, as exemplified by the use of ultrasound and microbubble-stimulated release for enhancing cancer immunotherapy in vivo.

Endogenous ATP release regulates Cl− secretion in cultured human and rat biliary epithelial cells

1999 ◽  
Vol 276 (6) ◽  
pp. G1391-G1400 ◽  
Author(s):  
Richard M. Roman ◽  
Andrew P. Feranchak ◽  
Kelli D. Salter ◽  
Yu Wang ◽  
J. Gregory Fitz
Keyword(s):  
Epithelial Cells ◽  
Cell Volume ◽  
Purinergic Signaling ◽  
Cell Volume Regulation ◽  
Atp Release ◽  
Extracellular Atp ◽  
Extracellular Nucleotides ◽  
Cell Swelling ◽  
Biliary Epithelial Cells ◽  
Normal Rat

P2Y receptor stimulation increases membrane Cl− permeability in biliary epithelial cells, but the source of extracellular nucleotides and physiological relevance of purinergic signaling to biliary secretion are unknown. Our objectives were to determine whether biliary cells release ATP under physiological conditions and whether extracellular ATP contributes to cell volume regulation and transepithelial secretion. With the use of a sensitive bioluminescence assay, constitutive ATP release was detected from human Mz-ChA-1 cholangiocarcinoma cells and polarized normal rat cholangiocyte monolayers. ATP release increased rapidly during cell swelling induced by hypotonic exposure. In Mz-ChA-1 cells, removal of extracellular ATP (apyrase) and P2 receptor blockade (suramin) reversibly inhibited whole cell Cl− current activation and prevented cell volume recovery during hypotonic stress. Moreover, exposure to apyrase induced cell swelling under isotonic conditions. In intact normal rat cholangiocyte monolayers, hypotonic perfusion activated apical Cl−currents, which were inhibited by addition of apyrase and suramin to bathing media. These findings indicate that modulation of ATP release by the cellular hydration state represents a potential signal coordinating cell volume with membrane Cl− permeability and transepithelial Cl−secretion.

scholarly journals Protective Effects of Liposomal N-Acetylcysteine against Paraquat-Induced Cytotoxicity and Gene Expression

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Panagiotis Mitsopoulos ◽  
Zacharias E. Suntres
Keyword(s):  
Gene Expression ◽  
Therapeutic Potential ◽  
Specific Treatment ◽  
A549 Cells ◽  
Lung Damage ◽  
Oxygen Species ◽  
Protective Effects ◽  
Cytokine Release ◽  
Cellular Gene ◽  
Conventional Drug

Paraquat (PQ) is a herbicide that preferentially accumulates in the lung and exerts its cytotoxicity via the generation of reactive oxygen species (ROS). There is no specific treatment for paraquat poisoning. Attempts have been made to increase the antioxidant status in the lung using antioxidants (e.g., superoxide dismutase, vitamin E, N-acetylcysteine) but the outcome from such treatments is limited. Encapsulation of antioxidants in liposomes improves their therapeutic potential against oxidant-induced lung damage because liposomes facilitate intracellular delivery and prolong the retention of entrapped agents inside the cell. In the present study, we compared the effectiveness of conventional N-acetylcysteine (NAC) and liposomal-NAC (L-NAC) against PQ-induced cytotoxicity and examined the mechanism(s) by which these antioxidant formulations conferred cytoprotection. The effects of NAC or L-NAC against PQ-induced cytotoxicity in A549 cells were assessed by measuring cellular PQ uptake, intracellular glutathione content, ROS levels, mitochondrial membrane potential, cellular gene expression, inflammatory cytokine release and cell viability. Pretreatment of cells with L-NAC was significantly more effective than pretreatment with the conventional drug in reducing PQ-induced cytotoxicity, as indicated by the biomarkers used in this study. Our results suggested that the delivery of NAC as a liposomal formulation improves its effectiveness in counteracting PQ-induced cytotoxicity.

scholarly journals Extracellular ATP activates hyaluronan synthase 2 (HAS2) in epidermal keratinocytes via P2Y2, Ca2+ signaling, and MAPK pathways

2018 ◽  
Vol 475 (10) ◽  
pp. 1755-1772 ◽  
Author(s):  
Leena Rauhala ◽  
Tiina Jokela ◽  
Riikka Kärnä ◽  
Geneviève Bart ◽  
Piia Takabe ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Degradation Products ◽  
Atp Release ◽  
Human Keratinocytes ◽  
Extracellular Atp ◽  
Extracellular Nucleotides ◽  
Mitogen Activated Protein Kinase ◽  
Hyaluronan Synthase ◽  
Epidermal Keratinocytes ◽  
Hyaluronan Synthase 2

Extracellular nucleotides are used as signaling molecules by several cell types. In epidermis, their release is triggered by insults such as ultraviolet radiation, barrier disruption, and tissue wounding, and by specific nerve terminals firing. Increased synthesis of hyaluronan, a ubiquitous extracellular matrix glycosaminoglycan, also occurs in response to stress, leading to the attractive hypothesis that nucleotide signaling and hyaluronan synthesis could also be linked. In HaCaT keratinocytes, ATP caused a rapid and strong but transient activation of hyaluronan synthase 2 (HAS2) expression via protein kinase C-, Ca2+/calmodulin-dependent protein kinase II-, mitogen-activated protein kinase-, and calcium response element-binding protein-dependent pathways by activating the purinergic P2Y2 receptor. Smaller but more persistent up-regulation of HAS3 and CD44, and delayed up-regulation of HAS1 were also observed. Accumulation of peri- and extracellular hyaluronan followed 4–6 h after stimulation, an effect further enhanced by the hyaluronan precursor glucosamine. AMP and adenosine, the degradation products of ATP, markedly inhibited HAS2 expression and, despite concomitant up-regulation of HAS1 and HAS3, inhibited hyaluronan synthesis. Functionally, ATP moderately increased cell migration, whereas AMP and adenosine had no effect. Our data highlight the strong influence of adenosinergic signaling on hyaluronan metabolism in human keratinocytes. Epidermal insults are associated with extracellular ATP release, as well as rapid up-regulation of HAS2/3, CD44, and hyaluronan synthesis, and we show here that the two phenomena are linked. Furthermore, as ATP is rapidly degraded, the opposite effects of its less phosphorylated derivatives facilitate a rapid shut-off of the hyaluronan response, providing a feedback mechanism to prevent excessive reactions when more persistent signals are absent.

Healing effects of curcumin nanoparticles in deep tissue injury mouse model.

2020 ◽  
Vol 18 ◽  
Author(s):  
Zirui Zhang ◽  
Shangcong Han ◽  
Panpan Liu ◽  
Xu Yang ◽  
Jing Han ◽  
...  
Keyword(s):  
Wound Healing ◽  
Mrna Expression ◽  
Tissue Injury ◽  
Inflammatory Cells ◽  
Pcr Analysis ◽  
Protective Effects ◽  
Deep Tissue ◽  
Deep Tissue Injury

Background: Chronic inflammation and lack of angiogenesis are the important pathological mechanisms in deep tissue injury (DTI). Curcumin is a well-known anti-inflammatory and antioxidant agent. However, curcumin is unstable under acidic and alkaline conditions, and can be rapidly metabolized and excreted in the bile, which shortens its bioactivity and efficacy. Objective: This study aimed to prepare curcumin-loaded poly (lactic-co-glycolic acid) nanoparticles (CPNPs) and to elucidate the protective effects and underlying mechanisms of wound healing in DTI models. Methods: CPNPs were evaluated for particle size, biocompatibility, in vitro drug release and their effect on in vivo wound healing. Results : The results of in vivo wound closure analysis revealed that CPNP treatments significantly improved wound contraction rates (p<0.01) at a faster rate than other three treatment groups. H&E staining revealed that CPNP treatments resulted in complete epithelialization and thick granulation tissue formation, whereas control groups resulted in a lack of compact epithelialization and persistence of inflammatory cells within the wound sites. Quantitative real-time PCR analysis showed that treatment with CPNPs suppressed IL-6 and TNF-α mRNA expression, and up-regulated TGF-β, VEGF-A and IL-10 mRNA expression. Western blot analysis showed up-regulated protein expression of TGF-β, VEGF-A and phosphorylatedSTAT3. Conclusion: Our results showed that CPNPs enhanced wound healing in DTI models, through modulation of the JAK2/STAT3 signalling pathway and subsequent upregulation of pro-healing factors.

scholarly journals The signaling role of extracellular ATP in co-culture of Shiraia sp. S9 and Pseudomonas fulva SB1 for enhancing hypocrellin A production

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Xin Ping Li ◽  
Lu Lu Zhou ◽  
Yan Hua Guo ◽  
Jian Wen Wang
Keyword(s):  
Atp Release ◽  
Specific Inhibitor ◽  
Extracellular Atp ◽  
Oxidase Inhibitor ◽  
Disulfonic Acid ◽  
Early Event ◽  
Fungal Metabolites ◽  
Extracellular Signaling ◽  
Hypocrellin A

Abstract Background Adenosine 5′-triphosphate (ATP) plays both a central role as an intracellular energy source, and a crucial extracellular signaling role in diverse physiological processes of animals and plants. However, there are less reports concerning the signaling role of microbial extracellular ATP (eATP). Hypocrellins are effective anticancer photodynamic therapy (PDT) agents from bambusicolous Shiraia fungi. The co-culture of Shiraia sp. S9 and a bacterium Pseudomonas fulva SB1 isolated from Shiraia fruiting bodies was established for enhanced hypocrellin A (HA) production. The signaling roles of eATP to mediate hypocrellin biosynthesis were investigated in the co-culture. Results The co-culture induced release of eATP at 378 nM to the medium around 4 h. The eATP release was interdependent on cytosolic Ca2+ concentration and reactive oxygen species (ROS) production, respectively. The eATP production could be suppressed by the Ca2+ chelator EGTA or abolished by the channel blocker La3+, ROS scavenger vitamin C and NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI). The bacterium-induced H2O2 production was strongly inhibited by reactive blue (RB), a specific inhibitor of membrane purinoceptors, but dependent on the induced Ca2+ influx in the co-culture. On the other hand, the application of exogenous ATP (exATP) at 10–300 µM to Shiraia cultures also promoted fungal conidiation and HA production, both of which were blocked effectively by the purinoceptor inhibitors pyridoxalphosphate-6-azophenyl-2′, 4′-disulfonic acid (PPADS) and RB, and ATP hydrolase apyrase. Both the induced expression of HA biosynthetic genes and HA accumulation were inhibited significantly under the blocking of the eATP or Ca2+ signaling, and the scavenge of ROS in the co-culture. Conclusions Our results indicate that eATP release is an early event during the intimate bacterial–fungal interaction and eATP plays a signaling role in the bacterial elicitation on fungal metabolites. Ca2+ and ROS are closely linked for activation of the induced ATP release and its signal transduction. This is the first report on eATP production in the fungal–bacterial co-culture and its involvement in the induced biosynthesis of fungal metabolites. Graphic abstract

scholarly journals Application of Humanized Zebrafish Model in the Suppression of SARS-CoV-2 Spike Protein Induced Pathology by Tri-Herbal Medicine Coronil via Cytokine Modulation

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5091
Author(s):  
Acharya Balkrishna ◽  
Siva Kumar Solleti ◽  
Sudeep Verma ◽  
Anurag Varshney
Keyword(s):  
Herbal Medicine ◽  
High Performance ◽  
Normal Skin ◽  
A549 Cells ◽  
Lung Epithelial Cells ◽  
Spike Protein ◽  
Protective Effects ◽  
Cell Degeneration ◽  
Zebrafish Model ◽  
Tnf Α

Zebrafish has been a reliable model system for studying human viral pathologies. SARS-CoV-2 viral infection has become a global chaos, affecting millions of people. There is an urgent need to contain the pandemic and develop reliable therapies. We report the use of a humanized zebrafish model, xeno-transplanted with human lung epithelial cells, A549, for studying the protective effects of a tri-herbal medicine Coronil. At human relevant doses of 12 and 58 µg/kg, Coronil inhibited SARS-CoV-2 spike protein, induced humanized zebrafish mortality, and rescued from behavioral fever. Morphological and cellular abnormalities along with granulocyte and macrophage accumulation in the swim bladder were restored to normal. Skin hemorrhage, renal cell degeneration, and necrosis were also significantly attenuated by Coronil treatment. Ultra-high-performance liquid chromatography (UHPLC) analysis identified ursolic acid, betulinic acid, withanone, withaferine A, withanoside IV–V, cordifolioside A, magnoflorine, rosmarinic acid, and palmatine as phyto-metabolites present in Coronil. In A549 cells, Coronil attenuated the IL-1β induced IL-6 and TNF-α cytokine secretions, and decreased TNF-α induced NF-κB/AP-1 transcriptional activity. Taken together, we show the disease modifying immunomodulatory properties of Coronil, at human equivalent doses, in rescuing the pathological features induced by the SARS-CoV-2 spike protein, suggesting its potential use in SARS-CoV-2 infectivity.

Oestrogen protects against ischaemic acute renal failure in rats by suppressing renal endothelin-1 overproduction

2002 ◽  
Vol 103 (s2002) ◽  
pp. 434S-437S ◽  
Author(s):  
Masanori TAKAOKA ◽  
Mikihiro YUBA ◽  
Toshihide FUJII ◽  
Mamoru OHKITA ◽  
Yasuo MATSUMURA
Keyword(s):  
Renal Failure ◽  
Renal Function ◽  
Acute Renal Failure ◽  
Renal Dysfunction ◽  
Tissue Injury ◽  
Male Rats ◽  
Left Renal Artery ◽  
Protective Effects ◽  
Endothelin 1 ◽  
Ischaemia Reperfusion

We investigated whether the treatment with 17β-oestradiol has renal protective effects in male rats with ischaemic acute renal failure (ARF). We also examined if the effect of 17β-oestradiol is accompanied by suppression of enhanced endothelin-1 production in postischaemic kidneys. Ischaemic ARF was induced by clamping the left renal artery and vein for 45min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function parameters such as blood urea nitrogen, plasma creatinine and creatinine clearance were measured to test the effectiveness of the steroid hormone. Renal function in ARF rats markedly decreased 24h after reperfusion. The ischaemia/reperfusion-induced renal dysfunction was dose-dependently improved by pretreatment with 17β-oestradiol (20 or 100µg/kg, intravenously). Histopathological examination of the kidney of untreated ARF rats revealed severe lesions, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, all of which were markedly improved by the higher dose of 17β-oestradiol. In addition, endothelin-1 content in the kidney after the ischaemia/reperfusion increased significantly by approx. 2-fold over sham-operated rats, and this elevation was dose-dependently suppressed by the 17β-oestradiol treatment. These results suggest that oestrogen exhibits protective effects against renal dysfunction and tissue injury induced by ischaemia/reperfusion, possibly through the suppression of endothelin-1 overproduction in postischaemic kidneys.

scholarly journals Protective Effects of Taraxacum officinale L. (Dandelion) Root Extract in Experimental Acute on Chronic Liver Failure

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 504
Author(s):  
Iulia Olimpia Pfingstgraf ◽  
Marian Taulescu ◽  
Raluca Maria Pop ◽  
Remus Orăsan ◽  
Laurian Vlase ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Failure ◽  
Tissue Injury ◽  
Taraxacum Officinale ◽  
Chronic Liver ◽  
Root Extract ◽  
Protective Effects ◽  
Stress Tests ◽  
Chronic Liver Failure

Background: Taraxacum officinale (TO) or dandelion has been frequently used to prevent or treat different liver diseases because of its rich composition in phytochemicals with demonstrated effect against hepatic injuries. This study aimed to investigate the possible preventing effect of ethanolic TO root extract (TOERE) on a rat experimental acute on chronic liver failure (ACLF) model. Methods: Chronic liver failure (CLF) was induced by human serum albumin, and ACLF was induced in CLF by D-galactosamine and lipopolysaccharide (D-Gal-LPS). Five groups (n = 5) of male Wistar rats (200–250 g) were used: ACLF, ACLF-silymarin (200 mg/kg b.w./day), three ACLF-TO administered in three doses (200 mg, 100 mg, 50 mg/kg b.w./day). Results: The in vivo results showed that treatment with TOERE administered in three chosen doses before ACLF induction reduced serum liver injury markers (AST, ALT, ALP, GGT, total bilirubin), renal tests (creatinine, urea), and oxidative stress tests (TOS, OSI, MDA, NO, 3NT). Histopathologically, TOERE diminished the level of liver tissue injury and 3NT immunoexpression. Conclusions: This paper indicated oxidative stress reduction as possible mechanisms for the hepatoprotective effect of TOERE in ACLF and provided evidence for the preventive treatment.

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