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1.
Sci Rep ; 12(1): 13446, 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927386

RESUMO

Hemoglobin (Hb) is a powerful promoter of lipid oxidation, particularly in muscle of small pelagic fish species and fish by-products, both having high Hb-levels and highly unsaturated lipids. As Hb is located within the red blood cells (RBCs) it is here hypothesized that the perishable polyunsaturated fatty acids (PUFAs) can be protected from oxidation by limiting hemolysis during early fish processing. Using a model system consisting of washed-resuspended trout (Oncorhynchus mykiss) RBCs (wr-RBCs), the aim of this study was to evaluate how RBC lysis under cold storage was affected by selected parameters linked to blood or muscle: bacterial growth, energy status, pH, RBC membrane lipid oxidation and colloidal osmotic pressure (COP). The results indicated that bacterial growth had a modest effect on hemolysis while pH-values typical for post mortem fish muscle (6.4-6.8), and absence of glucose or albumin stimulated hemolysis. The rapid hemolysis observed at pH 6.4-6.8 correlated with lipid oxidation of the RBC membrane, while the lower hemolysis at pH 7.2-8.0 occurred with low, or without any RBC membrane lipid oxidation. When hemin was added to the RBCs at pH 6.8 hemolysis was induced without parallel RBC membrane oxidation, pointing at Hb-autoxidation and hemin-release per se as important events triggering lysis in fish muscle. Altogether, the study provided valuable findings which ultimately can aid development of new tools to combat lipid oxidation in post mortem fish muscle by limiting hemolysis.


Assuntos
Hemólise , Oncorhynchus mykiss , Animais , Eritrócitos , Ácidos Graxos Insaturados/farmacologia , Hemina/farmacologia , Hemoglobinas/farmacologia , Lipídeos de Membrana/farmacologia , Músculos
2.
Biochim Biophys Acta Gen Subj ; 1866(10): 130200, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35820640

RESUMO

The molecular structure of membrane lipids is formed by mono- or polyunsaturations on their aliphatic tails that make them susceptible to oxidation, facilitating the incorporation of hydroperoxide (R-OOH) functional groups. Such groups promote changes in both composition and complexity of the membrane significantly modifying its physicochemical properties. Human Langerhans islets amyloid polypeptide (hIAPP) is the main component of amyloid deposits found in the pancreas of patients with type-2 diabetes (T2D). hIAPP in the presence of membranes with oxidized lipid species accelerates the formation of amyloid fibrils or the formation of intermediate oligomeric structures. However, the molecular bases at the initial stage of the anchoring and stabilization of the hIAPP in a hydroperoxidized membrane are not yet well understood. To shed some light on this matter, in this contribution, three bilayer models were modeled: neutral (POPC), anionic (POPS), and oxidized (POPCOOH), and full atom Molecular Dynamics (MD) simulations were performed. Our results show that the POPCOOH bilayer increases the helicity in hIAPP when compared to POPC or POPS bilayer. The modification in the secondary structure covers the residues of the so-called amyloidogenic core of the hIAPP. Overall, the hydroperoxidation of the neutral lipids modifies both the anchoring and the stabilization of the peptide hIAPP by reducing the random conformations of the peptide and increasing of hydrogen bond population with the hydroperoxidized lipids.


Assuntos
Polipeptídeo Amiloide das Ilhotas Pancreáticas , Bicamadas Lipídicas , Amiloide/metabolismo , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Bicamadas Lipídicas/metabolismo , Lipídeos de Membrana , Estrutura Secundária de Proteína
3.
Chem Pharm Bull (Tokyo) ; 70(8): 524-532, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35908917

RESUMO

P4-ATPases, which are subfamily members of P-type ATPase superfamily, translocate membrane lipids from the exoplasmic/luminal leaflet to the cytoplasmic leaflet, thus regulating trans-bilayer lipid asymmetry. Mammalian P4-ATPases localize to the specific subcellular organelles or the plasma membrane where they translocate the specific lipids. Although recent advances in the structural analysis of P4-ATPases have improved our understanding of lipid transporting machinery, the mechanism of substrate specificity and the regulatory mechanism of the enzymes remain largely unknown. Recent studies have uncovered several specific localization and regulatory mechanisms of P4-ATPases. Here, we review the current understanding of the regulatory mechanism of P4-ATPase activity and localization in mammalian cells.


Assuntos
Adenosina Trifosfatases , Lipídeos de Membrana , Adenosina Trifosfatases/metabolismo , Animais , Transporte Biológico , Membrana Celular/metabolismo , Mamíferos/metabolismo , Fosfolipídeos/metabolismo , Especificidade por Substrato
4.
Appl Microbiol Biotechnol ; 106(13-16): 4995-5006, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35819513

RESUMO

The influences of three wheat gluten peptides (WGP-LL, WGP-LML, and WGP-LLL) on the osmotic stress tolerance and membrane lipid component in brewer's yeast were investigated. The results demonstrated that the growth and survival of yeast under osmotic stress were enhanced by WGP supplementation. The addition of WGP upregulated the expressions of OLE1 (encoded the delta-9 fatty acid desaturase) and ERG1 (encoded squalene epoxidase) genes under osmotic stress. At the same time, WGP addition enhanced palmitoleic acid (C16:1) content, unsaturated fatty acids/saturated fatty acids ratio, and the amount of ergosterol in yeast cells under osmotic stress. Furthermore, yeast cells in WGP-LL and WGP-LLL groups were more resistant to osmotic stress. WGP-LL and WGP-LLL addition caused 25.08% and 27.02% increase in membrane fluidity, 22.36% and 29.54% reduction in membrane permeability, 18.38% and 14.26% rise in membrane integrity in yeast cells, respectively. In addition, scanning electron microscopy analysis revealed that the addition of WGP was capable of maintaining yeast cell morphology and reducing cell membrane damage under osmotic stress. Thus, alteration of membrane lipid component by WGP was an effective approach for increasing the growth and survival of yeast cells under osmotic stress. KEY POINTS: •WGP addition enhanced cell growth and survival of yeast under osmotic stress. •WGP addition increased unsaturated fatty acids and ergosterol contents in yeast. •WGP supplementation improved membrane homeostasis in yeast at osmotic stress.


Assuntos
Saccharomyces cerevisiae , Triticum , Ergosterol/metabolismo , Ácidos Graxos Insaturados/metabolismo , Glutens/metabolismo , Lipídeos de Membrana/metabolismo , Pressão Osmótica , Peptídeos/metabolismo , Saccharomyces cerevisiae/metabolismo , Triticum/metabolismo
5.
ACS Chem Neurosci ; 13(15): 2338-2345, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35867037

RESUMO

5-HT3 receptors are members of the family of pentameric ligand-gated ion channels. Each subunit has an extracellular, transmembrane, and intracellular domain. Only part of the intracellular domain structure has been solved, revealing it contains two α-helical segments; one, the MA helix, is an extension of M4, while the other, the MX helix, is formed from residues located close to the end of M3. This MX helix is in distinct locations in open and closed receptor structures, suggesting it may play a role in function. Here, we explore this hypothesis using functional responses of Ala-substituted mutant receptors expressed in HEK293 cells. The data show altering many of the MX residues results in a small decrease in EC50 (up to 5-fold), although in one (H232A) this is increased. Radiolabeled ligand binding on selected mutants showed no change in binding affinity, indicating an effect on gating and not binding. In addition, five mutations (P316A, V317A, P318A, D319A, and H323A) initially resulted in nonfunctional receptors, but the function could be rescued by coexpression with a chaperone protein, suggesting a likely role in assembly or folding. Examination of previously obtained MD simulation data shows that the extent of MX encompassed by membrane lipids differs considerably in the open and closed structures, suggesting that lipid-protein interactions in this region could have a major effect on channel opening propensity. We conclude that the MX helix can modulate the function of the receptor and propose that its interactions with membrane lipids play a major role in this.


Assuntos
Receptores 5-HT3 de Serotonina , Serotonina , Sequência de Aminoácidos , Células HEK293 , Humanos , Lipídeos de Membrana , Receptores 5-HT3 de Serotonina/genética , Receptores 5-HT3 de Serotonina/metabolismo
6.
J Cell Sci ; 135(15)2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35791809

RESUMO

The cytoplasmic domain of receptor tyrosine kinases (RTKs) plays roles as a kinase and a protein scaffold; however, the allocation of these two functions is not fully understood. Here, we analyzed the assembly of the transmembrane (TM)-juxtamembrane (JM) region of EGFR, one of the best studied members of RTKs, by combining single-pair fluorescence resonance energy transfer (FRET) imaging and a nanodisc technique. The JM domain of EGFR contains a threonine residue (T654) that is phosphorylated after ligand association. We observed that the TM-JM peptides of EGFR form anionic lipid-induced dimers and cholesterol-induced oligomers. The two forms involve distinct molecular interactions, with a bias toward oligomer formation upon threonine phosphorylation. We further analyzed the functions and oligomerization of whole EGFR molecules, with or without a substitution of T654 to alanine, in living cells. The results suggested an autoregulatory mechanism in which T654 phosphorylation causes a switch of the major function of EGFR from kinase-activating dimers to scaffolding oligomers.


Assuntos
Lipídeos de Membrana , Treonina , Receptores ErbB/genética , Receptores ErbB/metabolismo , Lipídeos de Membrana/metabolismo , Fosforilação , Transdução de Sinais , Treonina/metabolismo
7.
Proc Natl Acad Sci U S A ; 119(31): e2123193119, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35905325

RESUMO

Archaeal membrane lipids are widely used for paleotemperature reconstructions, yet these molecular fossils also bear rich information about ecology and evolution of marine ammonia-oxidizing archaea (AOA). Here we identified thermal and nonthermal behaviors of archaeal glycerol dialkyl glycerol tetraethers (GDGTs) by comparing the GDGT-based temperature index (TEX86) to the ratio of GDGTs with two and three cyclopentane rings (GDGT-2/GDGT-3). Thermal-dependent biosynthesis should increase TEX86 and decrease GDGT-2/GDGT-3 when the ambient temperature increases. This presumed temperature-dependent (PTD) trend is observed in GDGTs derived from cultures of thermophilic and mesophilic AOA. The distribution of GDGTs in suspended particulate matter (SPM) and sediments collected from above the pycnocline-shallow water samples-also follows the PTD trend. These similar GDGT distributions between AOA cultures and shallow water environmental samples reflect shallow ecotypes of marine AOA. While there are currently no cultures of deep AOA clades, GDGTs derived from deep water SPM and marine sediment samples exhibit nonthermal behavior deviating from the PTD trend. The presence of deep AOA increases the GDGT-2/GDGT-3 ratio and distorts the temperature-controlled correlation between GDGT-2/GDGT-3 and TEX86. We then used Gaussian mixture models to statistically characterize these diagnostic patterns of modern AOA ecology from paleo-GDGT records to infer the evolution of marine AOA from the Mid-Mesozoic to the present. Long-term GDGT-2/GDGT-3 trends suggest a suppression of today's deep water marine AOA during the Mesozoic-early Cenozoic greenhouse climates. Our analysis provides invaluable insights into the evolutionary timeline and the expansion of AOA niches associated with major oceanographic and climate changes.


Assuntos
Amônia , Archaea , Archaea/genética , Glicerol , Lipídeos de Membrana , Oxirredução , Filogenia , Água
8.
Int J Mol Sci ; 23(13)2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35806322

RESUMO

Small heat shock proteins (sHSPs) have been demonstrated to interact with lipids and modulate the physical state of membranes across species. Through these interactions, sHSPs contribute to the maintenance of membrane integrity. HSPB1 is a major sHSP in mammals, but its lipid interaction profile has so far been unexplored. In this study, we characterized the interaction between HSPB1 and phospholipids. HSPB1 not only associated with membranes via membrane-forming lipids, but also showed a strong affinity towards highly fluid membranes. It participated in the modulation of the physical properties of the interacting membranes by altering rotational and lateral lipid mobility. In addition, the in vivo expression of HSPB1 greatly affected the phase behavior of the plasma membrane under membrane fluidizing stress conditions. In light of our current findings, we propose a new function for HSPB1 as a membrane chaperone.


Assuntos
Proteínas de Choque Térmico Pequenas , Animais , Membrana Celular/metabolismo , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico Pequenas/metabolismo , Mamíferos/metabolismo , Lipídeos de Membrana/química , Membranas/metabolismo , Fosfolipídeos
9.
Anticancer Res ; 42(7): 3313-3324, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35790250

RESUMO

BACKGROUND/AIM: Resistance to chemotherapy is a major obstacle for patients with unresectable colorectal cancer (CRC); however, the factors that induce chemoresistance have not been elucidated. Lipid composition influences neoplastic behaviour. Therefore, this study examined whether lipid composition affects sensitivity to chemotherapeutic agents in CRC. MATERIALS AND METHODS: We performed a lipidomic analysis of a CRC xenograft-derived spheroid model to identify potential relationships between the lipid profile and chemoresistance to 5-fluorouracil (5-FU). Genetic and pharmacological modulation of lipid synthesis were also used in the HCT-116 and DLD-1 CRC cell lines to further characterize resistance to 5-FU. RESULTS: Our lipidomic profiling revealed that phospholipids with saturated fatty acids (SFAs) were more abundant in 5-FU-resistant spheroids. The importance of phospholipids containing SFA in chemoresistance was confirmed by showing that in HCT-116 and DLD-1 cells, genetic or pharmacological inactivation of stearoyl-CoA desaturase-1, a key enzyme that converts SFAs to monounsaturated fatty acids, increased the proportion of SFAs in membranous phospholipids and reduced cell membrane fluidity, and this ultimately resulted in resistance to 5-FU. CONCLUSION: These data suggest that the saturated to monounsaturated fatty acid ratio in cellular membranous phospholipids affects sensitivity to chemotherapeutic agents.


Assuntos
Neoplasias Colorretais , Fluoruracila , Neoplasias Colorretais/genética , Ácidos Graxos , Ácidos Graxos Monoinsaturados , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Lipídeos de Membrana/uso terapêutico
10.
Int J Mol Sci ; 23(11)2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35682621

RESUMO

As a new field of oxidative stress-based therapy, cold physical plasma is a promising tool for several biomedical applications due to its potential to create a broad diversity of reactive oxygen and nitrogen species (RONS). Although proposed, the impact of plasma-derived RONS on the cell membrane lipids and properties is not fully understood. For this purpose, the changes in the lipid bilayer functionality under oxidative stress generated by an argon plasma jet (kINPen) were investigated by electrochemical techniques. In addition, liquid chromatography-tandem mass spectrometry was employed to analyze the plasma-induced modifications on the model lipids. Various asymmetric bilayers mimicking the structure and properties of the erythrocyte cell membrane were transferred onto a gold electrode surface by Langmuir-Blodgett/Langmuir-Schaefer deposition techniques. A strong impact of cholesterol on membrane permeabilization by plasma-derived species was revealed. Moreover, the maintenance of the barrier properties is influenced by the chemical composition of the head group. Mainly the head group size and its hydrogen bonding capacities are relevant, and phosphatidylcholines are significantly more susceptible than phosphatidylserines and other lipid classes, underlining the high relevance of this lipid class in membrane dynamics and cell physiology.


Assuntos
Bicamadas Lipídicas , Lipídeos de Membrana , Membrana Celular , Colesterol/química , Bicamadas Lipídicas/química , Estresse Oxidativo , Espécies Reativas de Nitrogênio
11.
Int J Mol Sci ; 23(11)2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35682708

RESUMO

Fatty acids have an important place in both biological and nutritional contexts and, from a clinical point of view, they have known consequences for diseases' onset and development, including cancer. The use of fatty acid-based food and nutraceuticals to support cancer therapy is a multidisciplinary subject, involving molecular and clinical research. Knowledge regarding polyunsaturated fatty acids essentiality/oxidizability and the role of lipogenesis-desaturase pathways for cell growth, as well as oxidative reactivity in cancer cells, are discussed, since they can drive the choice of fatty acids using their multiple roles to support antitumoral drug activity. The central role of membrane fatty acid composition is highlighted for the application of membrane lipid therapy. As fatty acids are also known as biomarkers of cancer onset and progression, the personalization of the fatty acid-based therapy is also possible, taking into account other important factors such as formulation, bioavailability and the distribution of the supplementation. A holistic approach emerges combining nutra- and pharma-strategies in an appropriate manner, to develop further knowledge and applications in cancer therapy.


Assuntos
Ácidos Graxos , Neoplasias , Suplementos Nutricionais , Ácidos Graxos/metabolismo , Ácidos Graxos Insaturados/metabolismo , Humanos , Lipídeos de Membrana , Neoplasias/tratamento farmacológico
12.
J Phys Chem B ; 126(24): 4415-4430, 2022 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-35696090

RESUMO

Biological membranes are complex organized molecular assemblies of lipids and proteins that provide cells and membrane-bound intracellular organelles their individual identities by morphological compartmentalization. Membrane dipole potential originates from the electrostatic potential difference within the membrane due to the nonrandom arrangement (orientation) of amphiphile and solvent (water) dipoles at the membrane interface. In this Feature Article, we will focus on the measurement of dipole potential using electrochromic fluorescent probes and highlight interesting applications. In addition, we will focus on ratiometric fluorescence microscopic imaging technique to measure dipole potential in cellular membranes, a technique that can be used to address novel problems in cell biology which are otherwise difficult to address using available approaches. We envision that membrane dipole potential could turn out to be a convenient tool in exploring the complex interplay between membrane lipids and proteins and could provide novel insights in membrane organization and function.


Assuntos
Bicamadas Lipídicas , Compostos de Piridínio , Membrana Celular/metabolismo , Bicamadas Lipídicas/metabolismo , Lipídeos de Membrana/metabolismo , Potenciais da Membrana
13.
Biomed Res Int ; 2022: 6028045, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35734346

RESUMO

Background: The bacterial membrane plays a critical role in the survival of bacteria and the effectiveness of antimicrobial peptides in protecting the host. The lipid constituents of the bacterial membrane are not evenly distributed, and they could be affected by clustering anionic lipids with cationic peptides with multiple positive charges. That could be harmful to bacteria because it prevents lipids from interacting with other molecular components of the cell membrane, disrupts existing natural domains, or creates phase boundary defects between the clustered lipids and the bulk of the membrane. This preliminary quantitative study is aimed at assembling a correlation between antibiotic resistance and bacterial lipid composition in E. coli, based on the function and arrangement of the bilipid coating of the bacterial cell, intimately associated with the path of antimicrobials through membranes. Methods: Fifteen multiresistant E. coli samples are collected from swine with enterocolitis tested for resistance levels using the disc diffusimetric method (Kirby-Bauer disc diffusion). Pathogen identification completed using the API 20E multitest system revealed the E. coli presence in 11 samples. In these samples, bacterial membrane detection of fatty acid methyl esters (FAME) operating a 240 MS Ion Trap (Varian) GC/MS (Agilent Technologies, Santa Clara, CA, USA) was performed, using the MIDI Sherlock recognition software model. Results: Interpreting the descriptive statistical method, the correlation matrix, and regression curves and after ANOVA analysis, we ascertained that the studied E. coli population statistically confirmed different degrees of resistance in most of the samples analyzed in this test. Conclusions: In one case, the methyl-(Z)-11-tetradecenoate acid was observed to have a relationship with the susceptibility evaluation by using the disc diffusimetric method, which has revealed the lowest rate of antimicrobial resistance, so it has importance in further resistance evaluation studies.


Assuntos
Infecções por Escherichia coli , Lipídeos de Membrana , Animais , Antibacterianos/química , Bactérias , Farmacorresistência Bacteriana , Resistência Microbiana a Medicamentos , Escherichia coli , Lipídeos de Membrana/metabolismo , Testes de Sensibilidade Microbiana , Suínos
14.
J Biol Chem ; 298(7): 102104, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35679899

RESUMO

The outermost lipid-exposed α-helix (M4) in each of the homologous α, ß, δ, and γ/ε subunits of the muscle nicotinic acetylcholine receptor (nAChR) has previously been proposed to act as a lipid sensor. However, the mechanism by which this sensor would function is not clear. To explore how the M4 α-helix from each subunit in human adult muscle nAChR influences function, and thus explore its putative role in lipid sensing, we functionally characterized alanine mutations at every residue in αM4, ßM4, δM4, and εM4, along with both alanine and deletion mutations in the post-M4 region of each subunit. Although no critical interactions involving residues on M4 or in post-M4 were identified, we found that numerous mutations at the M4-M1/M3 interface altered the agonist-induced response. In addition, homologous mutations in M4 in different subunits were found to have different effects on channel function. The functional effects of multiple mutations either along M4 in one subunit or at homologous positions of M4 in different subunits were also found to be additive. Finally, when characterized in both Xenopus oocytes and human embryonic kidney 293T cells, select αM4 mutations displayed cell-specific phenotypes, possibly because of the different membrane lipid environments. Collectively, our data suggest different functional roles for the M4 α-helix in each heteromeric nAChR subunit and predict that lipid sensing involving M4 occurs primarily through the cumulative interactions at the M4-M1/M3 interface, as opposed to the alteration of specific interactions that are critical to channel function.


Assuntos
Canais Iônicos de Abertura Ativada por Ligante , Receptores Nicotínicos , Adulto , Alanina , Humanos , Canais Iônicos de Abertura Ativada por Ligante/química , Lipídeos de Membrana/química , Conformação Proteica em alfa-Hélice , Receptores Nicotínicos/metabolismo
15.
J Cell Physiol ; 237(6): 2613-2631, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35661356

RESUMO

Cilium, a tiny microtubule-based cellular appendage critical for cell signalling and physiology, displays a large variety of receptors. The composition and turnover of ciliary lipids and receptors determine cell behaviour. Due to the exclusion of ribosomal machinery and limited membrane area, a cilium needs adaptive logistics to actively reconstitute the lipid and receptor compositions during development and differentiation. How is this dynamicity generated? Here, we examine whether, along with the Intraflagellar-Transport, targeted changes in sector-wise lipid composition could control the receptor localisation and functions in the cilia. We discuss how an interplay between ciliary lipid composition, localised lipid modification, and receptor function could contribute to cilia growth and signalling. We argue that lipid modification at the cell-cilium interface could generate an added thrust for a selective exchange of membrane lipids and the transmembrane and membrane-associated proteins.


Assuntos
Cílios , Proteínas de Membrana , Transporte Biológico , Cílios/metabolismo , Lipídeos de Membrana/metabolismo , Proteínas de Membrana/metabolismo , Microtúbulos/metabolismo
16.
Arch Biochem Biophys ; 726: 109230, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35660300

RESUMO

The concentrations of lipid-soluble, chain-breaking antioxidants in human plasma and in erythrocyte ghosts have been determined for the first time by an inhibited autoxidation method. The results are very similar to the concentrations of vitamin E measured for the same blood components by the HPLC method. It is concluded that vitamin E, which is largely present as α-tocopherol, is the only significant lipid-soluble, chain-breaking type of antioxidant present in human blood. The concentration of vitamin E in the plasma lipids divided by the concentration of vitamin E in the ghost membrane lipids is approximately a constant despite the large differences in vitamin E-intake and in plasma lipid concentrations in different individuals. Vitamin E/lipid ratios for plasma and ghosts were larger for subjects taking a supplement of α-to- copherol acetate of 100 IU per week, compared to nonsupplemented subjects (based on data from a limited number of subjects). A larger supplement of 2800 IU per week did not significantly increase the vitamin E/lipid ratios.


Assuntos
Antioxidantes , Vitamina E , Antioxidantes/farmacologia , Membrana Eritrocítica/metabolismo , Humanos , Peroxidação de Lipídeos , Lipídeos de Membrana/metabolismo , Plasma
17.
Khirurgiia (Mosk) ; (6): 80-87, 2022.
Artigo em Russo | MEDLINE | ID: mdl-35658140

RESUMO

THE PURPOSE OF THE WORK: Based on the determination of the mechanisms of negative manifestations of surgical aggression in open interventions, compared with laparoscopic, to determine ways to optimize the early postoperative period when using them. MATERIAL AND METHODS: The work is based on clinical and laboratory analysis of 147 patients with acute appendicitis complicated by acute peritonitis. In the first group (n=58), patients were operated with traditional laparotomy access. In the second group (n=47) - laparoscopic interventions were used. In the first and second groups, traditional therapy was carried out according to clinical recommendations. In the third group (n=42), patients were operated with traditional laparotomy access, and in the early postoperative period, their therapy included remaxol (intravenous injections of 800.0 ml of the drug in the first two days, then within three days - 400.0 ml). Laboratory and instrumental studies were carried out in patients, including the level of hydrophilic and hydrophobic toxins in the blood, the intensity of peroxidation of membrane lipids and antioxidant enzyme potential, the activity of phospholipase A2. The functional status of the intestine and liver was assessed. RESULTS: It was found that the most important manifestation of the reduction of surgical aggression in the early stages after surgery, which is characteristic of laparoscopic operations, are significantly low phenomena of endogenous intoxication against the background of a significant decrease in the activity of peroxidation of membrane lipids and phospholipase systems - triggers of catabolic phenomena and lesions of various organs and systems, including the intestine and liver. The inclusion of remaxol in complex therapy for patients who have undergone open surgical operations leads to a number of positive clinical and laboratory effects. The most important of them is the reduction of endogenous intoxication. This beneficial effect is associated with the restoration of the functional status of the intestine and liver, as well as a decrease in the severity of catabolic phenomena. The effectiveness of complex therapy with remaxol was marked by reducing the number of postoperative complications and the length of the patient's stay in the hospital. CONCLUSION: The use of remaxol in patients with acute peritonitis complicated by peritonitis who have undergone open surgical interventions, due to the relatively rapid restoration of the functional status of the intestine and liver, reduction of catabolic phenomena, reduces the severity of endogenous intoxication syndrome, which was the basis for a significant improvement in the course of the early postoperative period, bringing it closer to that when using laparoscopic technology.


Assuntos
Apendicite , Laparoscopia , Peritonite , Apendicite/cirurgia , Humanos , Laparoscopia/efeitos adversos , Laparotomia/efeitos adversos , Lipídeos de Membrana , Peritonite/diagnóstico , Peritonite/etiologia , Peritonite/cirurgia
18.
J Chem Phys ; 156(20): 205101, 2022 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-35649882

RESUMO

CP29, a chlorophyll a/b-xanthophyll binding protein, bridges energy transfer between the major LHCII antenna complexes and photosystem II reaction centers. It hosts one of the two identified quenching sites, making it crucial for regulated photoprotection mechanisms. Until now, the photophysics of CP29 has been studied on the purified protein in detergent solutions since spectrally overlapping signals affect in vivo measurements. However, the protein in detergent assumes non-native conformations compared to its physiological state in the thylakoid membrane. Here, we report a detailed photophysical study on CP29 inserted in discoidal lipid bilayers, known as nanodiscs, which mimic the native membrane environment. Using picosecond time-resolved fluorescence and femtosecond transient absorption (TA), we observed shortening of the Chl fluorescence lifetime with a decrease of the carotenoid triplet formation yield for CP29 in nanodiscs as compared to the protein in detergent. Global analysis of TA data suggests a 1Chl* quenching mechanism dependent on excitation energy transfer to a carotenoid dark state, likely the proposed S*, which is believed to be formed due to a carotenoid conformational change affecting the S1 state. We suggest that the accessibility of the S* state in different local environments plays a key role in determining the quenching of Chl excited states. In vivo, non-photochemical quenching is activated by de-epoxidation of violaxanthin into zeaxanthin. CP29-zeaxanthin in nanodiscs further shortens the Chl lifetime, which underlines the critical role of zeaxanthin in modulating photoprotection activity.


Assuntos
Complexos de Proteínas Captadores de Luz , Lipídeos de Membrana , Carotenoides/metabolismo , Clorofila A , Detergentes , Complexos de Proteínas Captadores de Luz/química , Zeaxantinas
19.
Cell Rep ; 39(9): 110870, 2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35649368

RESUMO

Overcoming resistance to chemotherapies remains a major unmet need for cancers, such as triple-negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid ß-oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclear. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-coenzyme A (CoA). Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.


Assuntos
Membranas Mitocondriais , Neoplasias de Mama Triplo Negativas , Acetilcoenzima A/metabolismo , Apoptose , Ácidos Graxos/metabolismo , Humanos , Lipídeos de Membrana/metabolismo , Membranas Mitocondriais/metabolismo , Oxirredução , Fosfolipídeos/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo
20.
mSphere ; 7(3): e0011722, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35574679

RESUMO

Antibiotic resistance is one of the most prominent threats to modern medicine. In the latest World Health Organization list of bacterial pathogens that urgently require new antibiotics, 9 out of 12 are Gram-negative, with four being of "critical priority." One crucial barrier restricting antibiotic efficacy against Gram-negative bacteria is their unique cell envelope. While fatty acids are a shared constituent of all structural membrane lipids, their biosynthesis pathway in bacteria is distinct from eukaryotes, making it an attractive target for new antibiotic development that remains less explored. Here, we interrogated the redundant components of the bacterial type II fatty acid synthesis (FAS II) pathway, showing that disrupting FAS II homeostasis in Escherichia coli through deletion of the fabH gene damages the cell envelope of antibiotic-susceptible and antibiotic-resistant clinical isolates. The fabH gene encodes the ß-ketoacyl acyl carrier protein synthase III (KAS III), which catalyzes the initial condensation reactions during fatty acid biosynthesis. We show that fabH null mutation potentiated the killing of multidrug-resistant E. coli by a broad panel of previously ineffective antibiotics, despite the presence of relevant antibiotic resistance determinants, for example, carbapenemase kpc2. Enhanced antibiotic sensitivity was additionally demonstrated in the context of eradicating established biofilms and treating established human cell infection in vitro. Our findings showcase the potential of FabH as a promising target that could be further explored in the development of therapies that may repurpose currently ineffective antibiotics or rescue failing last-resort antibiotics against Gram-negative pathogens. IMPORTANCE Gram-negative pathogens are a major concern for global public health due to increasing rates of antibiotic resistance and the lack of new drugs. A major contributing factor toward antibiotic resistance in Gram-negative bacteria is their formidable outer membrane, which acts as a permeability barrier preventing many biologically active antimicrobials from reaching the intracellular targets and thus limiting their efficacy. Fatty acids are the fundamental building blocks of structural membrane lipids, and their synthesis constitutes an attractive antimicrobial target, as it follows distinct pathways in prokaryotes and eukaryotes. Here, we identified a component of fatty acid synthesis, FabH, as a gate-keeper of outer membrane barrier function. Without FabH, Gram-negative bacteria become susceptible to otherwise impermeable antibiotics and are resensitized to killing by last-resort antibiotics. This study supports FabH as a promising target for inhibition in future antimicrobial therapies.


Assuntos
Antibacterianos , Escherichia coli , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Bactérias , Ácidos Graxos/metabolismo , Bactérias Gram-Negativas , Humanos , Lipídeos de Membrana/metabolismo , Lipídeos de Membrana/farmacologia , Transferases (Outros Grupos de Fosfato Substituídos)
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