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BioRxiv : the Preprint Server For... Jun 2024Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease (PD). Here we show that VPS13C, a bridge-like lipid...
Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease (PD). Here we show that VPS13C, a bridge-like lipid transport protein and a PD gene, is a sensor of lysosome stress/damage. Upon lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires release of a brake, most likely an intramolecular interaction within VPS13C, which hinders access of its VAB domain to lysosome-bound Rab7. While another PD protein, LRRK2, is also recruited to stressed/damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the putative role of VPS13 proteins in bulk lipid transport, these findings suggest lipid delivery to lysosomes by VPS13C is part of an early response to lysosome damage.
PubMed: 38895395
DOI: 10.1101/2024.06.08.598070 -
Frontiers in Immunology 2024The complement system, an important part of the innate system, is known to play a central role in many immune mediated kidney diseases. All parts of the complement... (Review)
Review
The complement system, an important part of the innate system, is known to play a central role in many immune mediated kidney diseases. All parts of the complement system including the classical, alternative, and mannose-binding lectin pathways have been implicated in complement-mediated kidney injury. Although complement components are thought to be mainly synthesized in the liver and activated in the circulation, emerging data suggest that complement is synthesized and activated inside the kidney leading to direct injury. Urinary complement biomarkers are likely a better reflection of inflammation within the kidneys as compared to traditional serum complement biomarkers which may be influenced by systemic inflammation. In addition, urinary complement biomarkers have the advantage of being non-invasive and easily accessible. With the rise of therapies targeting the complement pathways, there is a critical need to better understand the role of complement in kidney diseases and to develop reliable and non-invasive biomarkers to assess disease activity, predict treatment response and guide therapeutic interventions. In this review, we summarized the current knowledge on urinary complement biomarkers of kidney diseases due to immune complex deposition (lupus nephritis, primary membranous nephropathy, IgA nephropathy) and due to activation of the alternative pathway (C3 glomerulopathy, thrombotic microangiography, ANCA-associated vasculitis). We also address the limitations of current research and propose future directions for the discovery of urinary complement biomarkers.
Topics: Humans; Biomarkers; Complement System Proteins; Kidney Diseases; Animals; Complement Activation
PubMed: 38895123
DOI: 10.3389/fimmu.2024.1357869 -
International Journal of Molecular... Jun 2024Renal ischemia/reperfusion is a serious condition that not only causes acute kidney injury, a severe clinical syndrome with high mortality, but is also an inevitable...
Renal ischemia/reperfusion is a serious condition that not only causes acute kidney injury, a severe clinical syndrome with high mortality, but is also an inevitable part of kidney transplantation or other kidney surgeries. Alterations of oxygen levels during ischemia/reperfusion, namely hypoxia/reoxygenation, disrupt mitochondrial metabolism and induce structural changes that lead to cell death. A signature mitochondrial phospholipid, cardiolipin, with many vital roles in mitochondrial homeostasis, is one of the key players in hypoxia/reoxygenation-induced mitochondrial damage. In this study, we analyze the effect of hypoxia/reoxygenation on human renal proximal tubule epithelial cell (RPTEC) cardiolipins, as well as their metabolism and mitochondrial functions. RPTEC cells were placed in a hypoxic chamber with a 2% oxygen atmosphere for 24 h to induce hypoxia; then, they were replaced back into regular growth conditions for 24 h of reoxygenation. Surprisingly, after 24 h, hypoxia cardiolipin levels substantially increased and remained higher than control levels after 24 h of reoxygenation. This was explained by significantly elevated levels of cardiolipin synthase and lysocardiolipin acyltransferase 1 (LCLAT1) gene expression and protein levels. Meanwhile, hypoxia/reoxygenation decreased ADP-dependent mitochondrial respiration rates and oxidative phosphorylation capacity and increased reactive oxygen species generation. Our findings suggest that hypoxia/reoxygenation induces cardiolipin remodeling in response to reduced mitochondrial oxidative phosphorylation in a way that protects mitochondrial function.
Topics: Humans; Cardiolipins; Mitochondria; Cell Hypoxia; Reactive Oxygen Species; Oxygen; Kidney Tubules, Proximal; Oxidative Phosphorylation; Kidney; Cell Line; Transferases (Other Substituted Phosphate Groups); Membrane Proteins
PubMed: 38892409
DOI: 10.3390/ijms25116223 -
International Journal of Molecular... May 2024The deformability of red blood cells (RBCs), expressing their ability to change their shape as a function of flow-induced shear stress, allows them to optimize oxygen...
The deformability of red blood cells (RBCs), expressing their ability to change their shape as a function of flow-induced shear stress, allows them to optimize oxygen delivery to the tissues and minimize their resistance to flow, especially in microcirculation. During physiological aging and blood storage, or under external stimulations, RBCs undergo metabolic and structural alterations, one of which is hemoglobin (Hb) redistribution between the cytosol and the membrane. Consequently, part of the Hb may attach to the cell membrane, and although this process is reversible, the increase in membrane-bound Hb (MBHb) can affect the cell's mechanical properties and deformability in particular. In the present study, we examined the correlation between the MBHb levels, determined by mass spectroscopy, and the cell deformability, determined by image analysis. Six hemoglobin subunits were found attached to the RBC membranes. The cell deformability was negatively correlated with the level of four subunits, with a highly significant inter-correlation between them. These data suggest that the decrease in RBC deformability results from Hb redistribution between the cytosol and the cell membrane and the respective Hb interaction with the cell membrane.
Topics: Humans; Erythrocyte Deformability; Erythrocyte Membrane; Hemoglobins; Erythrocytes; Protein Binding
PubMed: 38892001
DOI: 10.3390/ijms25115814 -
Proceedings of the National Academy of... Jun 2024Chaperone-mediated autophagy (CMA) is part of the mammalian cellular proteostasis network that ensures protein quality control, maintenance of proteome homeostasis, and...
Chaperone-mediated autophagy (CMA) is part of the mammalian cellular proteostasis network that ensures protein quality control, maintenance of proteome homeostasis, and proteome changes required for the adaptation to stress. Loss of proteostasis is one of the hallmarks of aging. CMA decreases with age in multiple rodent tissues and human cell types. A decrease in lysosomal levels of the lysosome-associated membrane protein type 2A (LAMP2A), the CMA receptor, has been identified as a main reason for declined CMA in aging. Here, we report constitutive activation of CMA with calorie restriction (CR), an intervention that extends healthspan, in old rodent livers and in an in vitro model of CR with cultured fibroblasts. We found that CR-mediated upregulation of CMA is due to improved stability of LAMP2A at the lysosome membrane. We also explore the translational value of our observations using calorie-restriction mimetics (CRMs), pharmacologically active substances that reproduce the biochemical and functional effects of CR. We show that acute treatment of old mice with CRMs also robustly activates CMA in several tissues and that this activation is required for the higher resistance to lipid dietary challenges conferred by treatment with CRMs. We conclude that part of the beneficial effects associated with CR/CRMs could be a consequence of the constitutive activation of CMA mediated by these interventions.
Topics: Caloric Restriction; Animals; Mice; Lysosomal-Associated Membrane Protein 2; Chaperone-Mediated Autophagy; Lysosomes; Humans; Aging; Fibroblasts; Proteostasis; Liver; Mice, Inbred C57BL; Male; Autophagy
PubMed: 38889154
DOI: 10.1073/pnas.2317945121 -
Journal of Complementary & Integrative... Jun 2024The flora of Azerbaijan is represented by one species of the genus: , belonging to the family. It is commonly found in the Greater and Lesser Caucasus regions of...
OBJECTIVES
The flora of Azerbaijan is represented by one species of the genus: , belonging to the family. It is commonly found in the Greater and Lesser Caucasus regions of Azerbaijan, as part of subalpine meadow plant communities. . is characterized by its robust, thick, tuberous roots, long-petioled and several times pinnately divided leaves, numerous (30-50) white umbels, and oval-shaped fruits. The primary objective of this research is to determine the antimicrobial potential of the aqueous extract obtained from . against both Gram-negative and Gram-positive bacteria. The plant preparations utilized in experiments were in the form of maceration, infusion, and hydrodistillation as aqueous extracts. . extract exhibited maximum (measuring 22.3 ± 1.4 mm) inhibition zones against bacteria (, , , , ) strains. Following exposure to the . plant extract, a significant reduction in bacterial cell cytoplasmic pH was observed (p≤0.04).
METHODS
In order to investigate the antimicrobial effects of the plant extract, commonly accepted procedures were followed using well-known bacterial strains, including . , . , . , . and . , which are principal causative agents of purulent-inflammatory processes. The 20 % aqueous extract was used.
RESULTS
The conducted experiment to determine the impact of the plant extract on microorganisms revealed that the extract significantly affects the bacterial cell membrane. Specifically, there is a decrease in pH, and hyperpolarization of the cell membrane occurs. The efficacy of the preservative effect is highly dependent on the environmental pH. 1. The 20 % aqueous extract from exhibited antimicrobial activity and effectively preventing the development of foodborne pathogens and putrefactive microorganisms. 2. A 20 % aqueous extract of . exhibits antimicrobial activity, effectively inhibiting the growth of foodborne pathogens and spoilage microorganisms. 3. Extract led to an increase in H concentration within bacterial cell cytoplasm, surpassing the OH concentration. 4. . species has a significant inhibitory effect on the growth of microorganisms such as . , . , . , . .
CONCLUSIONS
The results suggest that the extract from . possesses antimicrobial properties, making it a potential candidate for use as a natural food preservative. The observed hyperpolarization of the cell membrane and pH reduction further support its potential as an effective antibacterial agent.
PubMed: 38887086
DOI: 10.1515/jcim-2023-0306 -
Molecular Pharmaceutics Jun 2024Sterol derivatives are a crucial part of liposomes, as their concentration and nature can induce significant alternations in their characteristic features. For natural...
Sterol derivatives are a crucial part of liposomes, as their concentration and nature can induce significant alternations in their characteristic features. For natural liposomal-based (phospholipid-based) studies, the bulk literature is already present depicting the role of the concentration or nature of different sterol derivatives in modulation of membrane properties. However, the studies aiming at evaluating the effect of sterol derivatives on synthetic liposomal assemblies are limited to cholesterol (Chl), and a comparative effect with other sterol derivatives, such as ergosterol (Erg), has never been studied. To fill this research gap, through this work, we intend to provide insights into the concentration-dependent effect of two sterol derivatives (Chl and Erg) on a synthetic liposomal assembly (i.e., metallosomes) prepared thin film hydration route using a double-tailed metallosurfactant fabricated by modifying cetylpyridinium chloride with cobalt (Co) (i.e., Co:CPC II). The morphological evaluations with cryogenic-transmission electron microscopy (cryo-TEM), atomic force microscopy (AFM), and field emission-scanning electron microscopy (FE-SEM) indicated that metallosomes retained their spherical morphology irrespective of the nature and concentration of sterol derivatives. However, the size, ζ-potential, and lamellar width values were significantly modified with the incorporation of sterol derivatives in a concentration-dependent manner. In-depth studies affirmed that the extent of modulation of the bilayer in terms of hydrophobicity, fluidity, and rigidity was more severe with Chl than Erg. Such differences in the membrane properties lead to their contrasting behavior in the delivery of the broad-spectrum active compound "curcumin". From entrapment to behavior, the metallosomes demonstrated dissimilar behavior as even though Erg-modified metallosomes (at higher concentrations of Erg) exhibited low entrapment efficiency, they still could easily release >80% of the entrapped drug. studies conducted with bacterial cultures further revealed an interesting pattern of activity as the incorporation of Chl reduced the toxicity of the self-assembly, whereas their Erg-modified counterparts yielded slightly augmented toxicity toward these bacterial cells. Furthermore, Chl- and Erg-modified assemblies also exhibited contrasting behavior in their interaction studies with bacterial DNA.
PubMed: 38885973
DOI: 10.1021/acs.molpharmaceut.4c00376 -
Chemosphere Jun 2024Water pollutants such as heavy metal ions, pesticides, and dyes pose a worldwide issue. Their presence in water resources interferes with the normal growth mechanisms of... (Review)
Review
Water pollutants such as heavy metal ions, pesticides, and dyes pose a worldwide issue. Their presence in water resources interferes with the normal growth mechanisms of living beings and causes long or short-term diseases. For this reason, research continuously tends to develop innovative, selective, and efficient processes or technologies to detect and remove pollutants from water. This review provides an up-to-date overview on metal nanoparticles loaded in polymeric matrices, such as hydrogels and membranes, and employed as optical sensors and as removing materials for water pollutants. The synthetic pathways of nanomaterials loading into polymeric matrices have been analyzed, particularly focusing on noble metal nanoparticles, noble metal nanoclusters, and metal oxide nanoparticles. Moreover, the sensing properties of modified matrices towards water pollutants have been discussed in addition to the interaction mechanisms between the sensors and the toxic compounds. The last part of the review has been devoted to illustrating the separation mechanism and removal performance of membranes loaded with nanomaterials in the treatment and purification of water streams from different contaminants (heavy metals, dyes and pesticides).
PubMed: 38885767
DOI: 10.1016/j.chemosphere.2024.142636 -
ACS Infectious Diseases Jun 2024There are still no linear antimicrobial peptides (AMPs) available as a treatment option against bacterial infections. This is caused by several drawbacks that come with...
There are still no linear antimicrobial peptides (AMPs) available as a treatment option against bacterial infections. This is caused by several drawbacks that come with AMPs such as limited proteolytic stability and low selectivity against human cells. In this work, we screened a small library of rationally designed new peptides based on the cell-penetrating peptide sC18* toward their antimicrobial activity. We identified several effective novel AMPs and chose one out of this group to further increase its potency. Therefore, we introduced a triazole bridge at different positions to provide a preformed helical structure, assuming that this modification would improve (i) proteolytic stability and (ii) membrane activity. Indeed, placing the triazole bridge within the hydrophilic part of the linear analogue highly increased membrane activity as well as stability against enzymatic digestion. The new peptides, 8A and 8B, demonstrated high activity against several bacterial species tested including pathogenic and methicillin-resistant . Since they exhibited significantly good tolerability against human fibroblast and blood cells, these novel peptides offer true alternatives for future clinical applications and are worth studying in more detail.
PubMed: 38885643
DOI: 10.1021/acsinfecdis.4c00078 -
PloS One 2024Glenzocimab is a novel antithrombotic agent which targets platelet glycoprotein VI (GPVI) and does not induce haemorrhage. SARS-CoV-2 triggers a prothrombotic state and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Glenzocimab is a novel antithrombotic agent which targets platelet glycoprotein VI (GPVI) and does not induce haemorrhage. SARS-CoV-2 triggers a prothrombotic state and lung injury whose mechanisms include coagulopathy, endothelial dysfunction, and inflammation with dysregulated platelets.
METHODS AND PATIENTS
GARDEN was a randomised double-blind, exploratory phase II study of glenzocimab in SARS-CoV-2 respiratory failure (NCT04659109). PCR+ adults in Brazil and France (7 centres) were randomized to standard-of-care (SOC) plus glenzocimab (1000 mg/dayx3 days) or placebo, followed for 40 days. Primary efficacy endpoint was clinical progression at Day 4. All analyses concerned the intention-to-treat population.
RESULTS
Between December 2020 and August 2021, 61 patients received at least one dose (30 glenzocimab vs 32 placebo) and 58 completed the study (29 vs 29). Clinical progression of COVID-19 ARDS was not statistically different between glenzocimab and placebo arms (43.3% and 29.0%, respectively; p = 0.245). Decrease in the NEWS-2 category at D4 was statistically significant (p = 0.0290) in the glenzocimab arm vs placebo. No Serious Adverse Event (SAE) was deemed related to study drug; bleeding related events were reported in 6 patients (7 events) and 4 patients (4 events) in glenzocimab and placebo arms, respectively.
CONCLUSIONS
Therapeutic GPVI inhibition assessment during COVID-19 was conducted in response to a Public Health emergency. Glenzocimab in coagulopathic patients under therapeutic heparin was neither associated with increased bleeding, nor SAE. Clinical impact of glenzocimab on COVID-19 ARDS was not demonstrated. A potential role for GPVI inhibition in other types of ARDS deserves further experimentation. Glenzocimab is currently studied in stroke (ACTISAVE: NCT05070260) and cardiovascular indications.
Topics: Humans; Male; Female; Middle Aged; COVID-19 Drug Treatment; Aged; Double-Blind Method; COVID-19; SARS-CoV-2; Platelet Membrane Glycoproteins; Antibodies, Monoclonal, Humanized; Adult; Brazil; Treatment Outcome
PubMed: 38885234
DOI: 10.1371/journal.pone.0302897