Lysosomal Reacidification Ameliorates Vinyl Carbamate-Induced Toxicity and Disruption on Lysosomal pH

2020 ◽  
Vol 68 (33) ◽  
pp. 8951-8961
Author(s):  
Yuting Li ◽  
Dongwen Hu ◽  
Jifeng Qi ◽  
Sunliang Cui ◽  
Wei Chen
Keyword(s):  
Lysosomal Ph ◽  
Vinyl Carbamate

scholarly journals Distinct uptake, amplification, and release of SARS-CoV-2 by M1 and M2 alveolar macrophages

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jiadi Lv ◽  
Zhenfeng Wang ◽  
Yajin Qu ◽  
Hua Zhu ◽  
Qiangqiang Zhu ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Mouse Model ◽  
Alveolar Macrophages ◽  
Transgenic Mouse Model ◽  
Lysosomal Ph ◽  
Viral Spread ◽  
Lysosomal System ◽  
Endosomal Ph ◽  
Alternatively Activated ◽  
Classically Activated

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades the alveoli, where abundant alveolar macrophages (AMs) reside. How AMs respond to SARS-CoV-2 invasion remains elusive. Here, we show that classically activated M1 AMs facilitate viral spread; however, alternatively activated M2 AMs limit the spread. M1 AMs utilize cellular softness to efficiently take up SARS-CoV-2. Subsequently, the invaded viruses take over the endo-lysosomal system to escape. M1 AMs have a lower endosomal pH, favoring membrane fusion and allowing the entry of viral RNA from the endosomes into the cytoplasm, where the virus achieves replication and is packaged to be released. In contrast, M2 AMs have a higher endosomal pH but a lower lysosomal pH, thus delivering the virus to lysosomes for degradation. In hACE2 transgenic mouse model, M1 AMs are found to facilitate SARS-CoV-2 infection of the lungs. These findings provide insights into the complex roles of AMs during SARS-CoV-2 infection, along with potential therapeutic targets.

Real-time tracking lysosomal pH changes under heatstroke and redox stress with a novel near-infrared emissive probe

Talanta ◽  
2021 ◽  
Vol 228 ◽  
pp. 122184
Author(s):  
Qingfeng Xia ◽  
Shumin Feng ◽  
Jiaxin Hong ◽  
Guoqiang Feng
Keyword(s):  
Real Time ◽  
Near Infrared ◽  
Redox Stress ◽  
Lysosomal Ph ◽  
Ph Changes ◽  
Real Time Tracking ◽  
Emissive Probe

scholarly journals COVID-19/SARS-CoV-2 Infection: Lysosomes and Lysosomotropism Implicate New Treatment Strategies and Personal Risks

2020 ◽  
Vol 21 (14) ◽  
pp. 4953 ◽  
Author(s):  
Markus Blaess ◽  
Lars Kaiser ◽  
Martin Sauer ◽  
René Csuk ◽  
Hans-Peter Deigner
Keyword(s):  
Viral Entry ◽  
Cathepsin L ◽  
Treatment Strategies ◽  
Disease Process ◽  
Host Cells ◽  
Cytokine Release ◽  
Early Administration ◽  
Lysosomal Ph ◽  
New Treatment ◽  
Exposure Prophylaxis

In line with SARS and MERS, the SARS-CoV-2/COVID-19 pandemic is one of the largest challenges in medicine and health care worldwide. SARS-CoV-2 infection/COVID-19 provides numerous therapeutic targets, each of them promising, but not leading to the success of therapy to date. Neither an antiviral nor an immunomodulatory therapy in patients with SARS-CoV-2 infection/COVID-19 or pre-exposure prophylaxis against SARS-CoV-2 has proved to be effective. In this review, we try to close the gap and point out the likely relationships among lysosomotropism, increasing lysosomal pH, SARS-CoV-2 infection, and disease process, and we deduce an approach for the treatment and prophylaxis of COVID-19, and cytokine release syndrome (CRS)/cytokine storm triggered by bacteria or viruses. Lysosomotropic compounds affect prominent inflammatory messengers (e.g., IL-1B, CCL4, CCL20, and IL-6), cathepsin-L-dependent viral entry of host cells, and products of lysosomal enzymes that promote endothelial stress response in systemic inflammation. As supported by recent clinical data, patients who have already taken lysosomotropic drugs for other pre-existing conditions likely benefit from this treatment in the COVID-19 pandemic. The early administration of a combination of antivirals such as remdesivir and lysosomotropic drugs, such as the antibiotics teicoplanin or dalbavancin, seems to be able to prevent SARS-CoV-2 infection and transition to COVID-19.

Design and Expeditious Synthesis of Quinoline‐Pyrene‐Based Ratiometric Fluorescent Probes for Targeting Lysosomal pH

ChemBioChem ◽  
2020 ◽  
Vol 21 (10) ◽  
pp. 1492-1498
Author(s):  
Pankaj E. Hande ◽  
Manjari Mishra ◽  
Fariyad Ali ◽  
Shobhna Kapoor ◽  
Anindya Datta ◽  
...  
Keyword(s):  
Fluorescent Probes ◽  
Lysosomal Ph

scholarly journals HIF-1α Inhibition Sensitized Pituitary Adenoma Cells to Temozolomide by Regulating Presenilin 1 Expression and Autophagy

2016 ◽  
Vol 15 (6) ◽  
pp. NP95-NP104 ◽  
Author(s):  
Zhang kun ◽  
Yang yuling ◽  
Wang dongchun ◽  
Xie bingbing ◽  
Li xiaoli ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Pituitary Adenomas ◽  
Ph Value ◽  
Hypoxia Inducible Factor ◽  
Presenilin 1 ◽  
Gh3 Cells ◽  
Lysosomal Ph ◽  
Hypoxia Inducible Factor 1Α ◽  
Anticancer Effects ◽  
Autophagy Induction

Pituitary adenomas usually develop temozolomide resistance, which could compromise the anticancer effects of temozolomide. Suppression of hypoxia-inducible factor 1α has been shown to sensitize glioblastoma cells to temozolomide treatment according to previous reports. However, whether and how the suppression of hypoxia-inducible factor 1α could sensitize pituitary adenomas to temozolomide treatment are still poorly understood. In the present study, using hypoxia-inducible factor 1α knockdown strategy, we demonstrated for the first time that hypoxia-inducible factor 1α knockdown could inhibit temozolomide-induced autophagy in rat pituitary adenoma GH3 cells and thus increase antitumor efficacy of temozolomide. Furthermore, we found hypoxia-inducible factor 1α knockdown could block autophagy process through neutralizing lysosomal pH value but not inhibiting autophagy induction. Finally, we found hypoxia-inducible factor 1α could regulate lysosomal pH value through regulating full length presenilin 1 expression, and exogenous reexpression of presenilin 1could restore lysosome acidic levels. Our data indicated hypoxia-inducible factor 1α knockdown could be a potential approach to improve the efficacy of temozolomide therapy for pituitary adenomas.

Dynamic measurements of the acute and chronic effects of lysosomotropic agents on hepatocyte lysosomal pH using flow cytometry

Hepatology ◽  
1995 ◽  
Vol 22 (5) ◽  
pp. 1519-1526 ◽  
Author(s):  
Brent M. Myers ◽  
Pamela S. Tietz ◽  
James E. Tarara ◽  
Nicholas F. Larusso
Keyword(s):  
Flow Cytometry ◽  
Dynamic Measurements ◽  
Lysosomal Ph ◽  
Chronic Effects ◽  
Lysosomotropic Agents ◽  
Acute And Chronic Effects

scholarly journals Lysosomal Cholesterol Accumulation Inhibits Subsequent Hydrolysis of Lipoprotein Cholesteryl Ester

2008 ◽  
Vol 14 (2) ◽  
pp. 138-149 ◽  
Author(s):  
W. Gray Jerome ◽  
Brian E. Cox ◽  
Evelyn E. Griffin ◽  
Jody C. Ullery
Keyword(s):  
Cholesteryl Ester ◽  
Free Cholesterol ◽  
Oxidized Ldl ◽  
Lipoprotein Metabolism ◽  
Foam Cells ◽  
Acidic Ph ◽  
Cholesterol Accumulation ◽  
Lysosomal Ph ◽  
Subsequent Hydrolysis ◽  
Hydrolysis Of

Human macrophages incubated for prolonged periods with mildly oxidized LDL (oxLDL) or cholesteryl ester-rich lipid dispersions (DISP) accumulate free and esterified cholesterol within large, swollen lysosomes similar to those in foam cells of atherosclerosis. The cholesteryl ester (CE) accumulation is, in part, the result of inhibition of lysosomal hydrolysis due to increased lysosomal pH mediated by excessive lysosomal free cholesterol (FC). To determine if the inhibition of hydrolysis was long lived and further define the extent of the lysosomal defect, we incubated THP-1 macrophages with oxLDL or DISP to produce lysosome sterol engorgement and then chased with acetylated LDL (acLDL). Unlike oxLDL or DISP, CE from acLDL normally is hydrolyzed rapidly. Three days of incubation with oxLDL or DISP produced an excess of CE in lipid-engorged lysosomes, indicative of inhibition. After prolonged oxLDL or DISP pretreatment, subsequent hydrolysis of acLDL CE was inhibited. Coincident with the inhibition, the lipid-engorged lysosomes failed to maintain an acidic pH during both the initial pretreatment and subsequent acLDL incubation. This indicates that the alterations in lysosomes were general, long lived, and affected subsequent lipoprotein metabolism. This same phenomenon, occurring within atherosclerotic foam cells, could significantly affect lesion progression.

Harnessing Lysosomal pH through PLGA Nanoemulsion as a Treatment of Lysosomal-Related Neurodegenerative Diseases

2018 ◽  
Vol 29 (12) ◽  
pp. 4083-4089 ◽  
Author(s):  
Geoffrey Prévot ◽  
Federico N. Soria ◽  
Marie-Laure Thiolat ◽  
Jonathan Daniel ◽  
Jean Baptiste Verlhac ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Lysosomal Ph

Mutagenicity, Metabolism, and DNA Interactions of Urethane

1990 ◽  
Vol 6 (1) ◽  
pp. 71-108 ◽  
Author(s):  
Rene E. Sotomayor ◽  
Thomas F.X. Collins
Keyword(s):  
Molecular Mechanisms ◽  
Case Reports ◽  
The Body ◽  
Alcoholic Beverages ◽  
Fermented Foods ◽  
X Rays ◽  
Spermatogenic Cells ◽  
Dna Interactions ◽  
Specific Locus ◽  
Vinyl Carbamate

Urethane, a known animal carcinogen, has been the subject of intensive research efforts spanning 40 years. Recent concerns have focused on the presence of urethane in a variety of fermented foods and alcoholic beverages, although no epidemiological studies or human case reports have been published. Much information is available about the mutagenesis, metabolism, and DNA interactions of urethane in experimental systems. Urethane is generally not mutagenic in bacteria although in some instances it acts as a weak mutagen. Urethane is not mutagenic in Neurospora but is weakly mutagenic in Saccharomyces. Drosophila appear to be the only organisms that consistently give positive mutagenic results with urethane, but its mutagenicity is weak and in many cases shows no clear dose dependence. Urethane is a good clastogen in mammalian somatic cells in vivo, but it shows variable results with cells in vitro. It efficiently induces sister chromatid exchanges in a variety of cells. Mammalian spermatogenic cells are insensitive to the induction of specific locus and dominant lethal mutations by urethane. Mutational synergism has been reported to occur between ethyl methanesulfonate and urethane when administered two generations apart, and some investigators have suggested possible synergism for cancer-causing mutations in mice exposed to X-rays and urethane one generation apart. These studies are controversial and have not been confirmed. Studies on the induction of cancer-causing dominant mutations by urethane are at variance with results from extensive studies with the specific locus test in mice. Urethane studies with the unscheduled DNA synthesis assay in mouse spermatogenic cells and with the sperm abnormality test have given negative results. Urethane is rapidly and evenly distributed in the body. The rate of elimination of urethane from plasma is a saturable process and varies according to the strain and age of the animal. Recent studies have concentrated on the effect of ethanol on urethane metabolism. At concentrations similar to those in wine, ethanol inhibits the tissue distribution of urethane in mice. These results are important because they suggest a lower carcinogenic/mutagenic risk than expected from exposure to urethane in alcoholic beverages. Although research on the metabolic activation of urethane has been extensive, no conclusive results have been obtained about its active metabolite, at one time thought to be N-hydroxyurethane. More recently, it has been postulated that urethane is actived to vinyl carbamate and that this metabolite is capable of reacting with DNA. Vinyl carbamate is more carcinogenic and more mutagenic than the parental compound, but despite intensive efforts it has not been identified as a metabolite in animals treated with urethane. Urethane binding to DNA appears to correlate well with tissue susceptibility to cancer. Various studies have attempted to elucidate the molecular nature of the bound molecule and the binding site. Some results have indicated the formation of a single DNA adduct, 7-(2-oxoethyl)guanine. This adduct may isomerize to O6,7-(1'-hydroxyethano)guanine, which might be more mutagenic than the 2-oxoethyl adduct; however, this possibility seems unlikely. Despite extensive research, urethane's metabolism and molecular mechanisms of mutation are still not clearly understood.

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