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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 Jul 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.
Topics: Ergosterol; Cobalt; Liposomes; Cholesterol; Lipid Bilayers; Microscopy, Atomic Force
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 -
European Journal of Cardio-thoracic... Jun 2024
Topics: Humans; Extracorporeal Membrane Oxygenation; Norwood Procedures; Postoperative Care; Infant, Newborn; Heart Ventricles; Univentricular Heart
PubMed: 38885367
DOI: 10.1093/ejcts/ezae210 -
The Journal of Clinical Investigation Jun 2024Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes...
Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes in addition to bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in IFITM5. Here, we generated a conditional Rosa26 knock-in mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with the pathology reported in OI type V patients. Surprisingly, expression of mutant Ifitm5 in mature osteoblasts caused no obvious skeletal abnormalities. In contrast, earlier expression in osteo-chondroprogenitors was associated with increase in the skeletal progenitor population within the periosteum. Lineage tracing showed that chondrogenic cells expressing the mutant Ifitm5 showed decreased differentiation into osteoblastic cells in diaphyseal bone. Moreover, mutant IFITM5 disrupts early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals. These data identify the contribution of a signaling defect altering osteo-chondroprogenitor differentiation as a driver in the pathogenesis of OI type V.
PubMed: 38885336
DOI: 10.1172/JCI170369 -
Transfusion Jun 2024Blood collection from donors on testosterone therapy (TT) is restricted to red blood cell (RBC) concentrates to avoid patient exposure to supraphysiological testosterone...
Testosterone supplementation increases red blood cell susceptibility to oxidative stress, decreases membrane deformability, and decreases survival after cold storage and transfusion.
BACKGROUND
Blood collection from donors on testosterone therapy (TT) is restricted to red blood cell (RBC) concentrates to avoid patient exposure to supraphysiological testosterone (T). The objective of this study was to identify TT-related changes in RBC characteristics relevant to transfusion effectiveness in patients.
STUDY DESIGN
This was a two-part study with cohorts of patients and blood donors on TT. In part 1, we conducted longitudinal evaluation of RBCs collected before and at three time points after initiation of T. RBC assays included storage and oxidative hemolysis, membrane deformability (elongation index), and oximetry. In part 2, we evaluated the fate of transfused RBCs from TT donors in immunodeficient mice and by retrospective analyses of NIH's vein-to-vein databases.
RESULTS
TT increased oxidative hemolysis (1.45-fold change) and decreased RBC membrane deformability. Plasma free testosterone was positively correlated with oxidative hemolysis (r = .552) and negatively correlated with the elongation index (r = -.472). Stored and gamma-irradiated RBCs from TT donors had lower posttransfusion recovery in mice compared to controls (41.6 ± 12 vs. 55.3 ± 20.5%). Recipients of RBCs from male donors taking T had 25% lower hemoglobin increments compared to recipients of RBCs from non-TT male donors, and had increased incidence (OR, 1.80) of requiring additional RBC transfusions within 48 h of the index transfusion event.
CONCLUSIONS
TT is associated with altered RBC characteristics and transfusion effectiveness. These results suggest that clinical utilization of TT RBCs may be less effective in recipients who benefit from longer RBC survival, such as chronically transfused patients.
PubMed: 38884364
DOI: 10.1111/trf.17922 -
Virus Research Jun 2024Although it is generally believed that large DNA viruses capture genes by horizontal gene transfer (HGT), the detailed manner of such transfer has not been fully...
Although it is generally believed that large DNA viruses capture genes by horizontal gene transfer (HGT), the detailed manner of such transfer has not been fully elucidated. Here, we searched for genes in the coleopteran entomopoxvirus (EV) Anomala cuprea entomopoxvirus (ACEV) that might have been gained by ACEV by HGT. We classified the potential source organisms for HGT into three categories: the host A. cuprea; other organisms, including viruses unrelated to EVs; and organisms with uncertain host attribution. Of the open reading frames (ORFs) of the ACEV genome, 2.1 % were suggested to have been gained from the host by ACEV or its recent ancestor via HGT; 8.7 % were possibly from organisms other than the host, and 3.7 % were possibly from the third category of organisms via HGT. The analysis showed that ACEV contains some interesting ORFs obtained by HGT, including a large ATP-binding cassette protein (ABC transporter) ORF and a tenascin ORF (IDs ACV025 and ACV123, respectively). We then performed a detailed analysis of the HGT of the ACEV large ABC transporter ORF-the largest of the ACEV ORFs. mRNA sequences obtained by RNA-seq from fat bodies-sites of ACEV replication-and midgut tissues-sites of initial infection-of the virus's host A. cuprea larvae were subjected to BLAST analysis. One type of ABC transporter ORF from the fat bodies and two types from the midgut tissues, one of which was identical to that in the fat bodies, had the greatest identity to the ABC transporter ORF of ACEV. The two types from the host had high levels of identity to each other (approximately 95 % nucleotide sequence identity), strongly suggesting that the host ABC transporter group consisting of the two types was the origin of ACV025. We then determined the sequence (12,381 bp) containing a full-length gene of the A. cuprea ABC transporter. It turned out to be a transcription template for the abovementioned mRNA found in both tissues. In addition, we determined a large part (ca. 6.9 kb) of the template sequence for the mRNA found only in the midgut tissues. The results showed that the ACEV ABC transporter ORF is missing parts corresponding to introns of the host ABC transporter genes, indicating that the ORF was likely acquired by HGT in the form of mRNA. The presence of definite duplicated sequences adjacent to the ACEV ABC transporter genes-a sign of LINE-1 retrotransposon-mediated HGT-was not observed. An approximately 2-month ACV025 transcription experiment suggested that the transporter sequence is presumed to be continuously functional. The amino acid sequence of ACV025 suggests that its product might function in the regulation of phosphatide in the host-cell membranes.
PubMed: 38880337
DOI: 10.1016/j.virusres.2024.199418