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2.
Rev Assoc Med Bras (1992) ; 70(4): e20231120, 2024.
Article in English | MEDLINE | ID: mdl-38716937

ABSTRACT

OBJECTIVE: We aimed to examine the effect of remission status on thiol-disulfide homeostasis in celiac patients and thus to indirectly determine the effect of oxidative stress and inflammation caused by non-compliance with the diet. METHODS: Between February 2019 and December 2021, 117 patients diagnosed with celiac disease were included in this prospective randomized and controlled study. In addition to routine tests of celiac patients, thiol and disulfide measurements were made from the blood both at the beginning of the study and at the end of the first year. RESULTS: While 52 of the patients (44.4%) were in remission, 65 patients (55.6%) were not. There was an evident increase in native thiol levels of the patients who were initially not in remission but went into at the end of the first year (347.4±46.7 µmol/L vs. 365.3±44.0 µmol/L; p=0.001). Mean plasma disulfide levels of patients with celiac going into remission became reduced in the first year from the level of 14.5±5.1 µmol/L down to 8.9±4.2 µmol/L (p<0.001). In celiac patients who entered remission, disulfide and anti-tissue transglutaminase immunoglobulin A levels decreased in a correlation (r=0.526; p<0.001). CONCLUSION: Not being in remission in celiac disease leads to increased oxidative stress, and thiol-disulfide homeostasis is an indirect indicator of this. Additionally, providing remission in celiac patients reduces oxidative stress.


Subject(s)
Celiac Disease , Diet, Gluten-Free , Disulfides , Oxidative Stress , Patient Compliance , Sulfhydryl Compounds , Humans , Celiac Disease/diet therapy , Celiac Disease/blood , Oxidative Stress/physiology , Female , Male , Disulfides/blood , Prospective Studies , Sulfhydryl Compounds/blood , Adult , Remission Induction , Young Adult , Adolescent , Middle Aged , Immunoglobulin A/blood , Transglutaminases/blood
3.
Methods Mol Biol ; 2758: 331-340, 2024.
Article in English | MEDLINE | ID: mdl-38549023

ABSTRACT

Spider venoms are composed of hundreds of proteins and peptides. Several of these venom toxins are cysteine-rich peptides in the mass range of 3-9 kDa. Small peptides (<3 kDa) can be fully characterized by mass spectrometry analysis, while proteins are generally identified by the bottom-up approach in which proteins are first digested with trypsin to generate shorter peptides for MS/MS characterization. In general, it is sufficient for protein identification to sequence two or more peptides, but for venom peptidomics it is desirable to completely elucidate peptide sequences and the number of disulfide bonds in the molecules. In this chapter, we describe a methodology to completely sequence and determine the number of disulfide bonds of spider venom peptides in the mass range of 3-9 kDa by multiple enzyme digestion, mass spectrometry of native and digested peptides, de novo analysis, and sequence overlap alignment.


Subject(s)
Spider Venoms , Spiders , Animals , Tandem Mass Spectrometry , Spider Venoms/chemistry , Peptides/chemistry , Amino Acid Sequence , Disulfides/analysis , Spiders/metabolism
4.
FEBS J ; 291(4): 778-794, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37985387

ABSTRACT

We have studied the reduction reactions of two cytosolic human peroxiredoxins (Prx) in their disulfide form by three thioredoxins (Trx; two human and one bacterial), with the aim of better understanding the rate and mechanism of those reactions, and their relevance in the context of the catalytic cycle of Prx. We have developed a new methodology based on stopped-flow and intrinsic fluorescence to study the bimolecular reactions, and found rate constants in the range of 105 -106 m-1 s-1 in all cases, showing that there is no marked kinetic preference for the expected Trx partner. By combining experimental findings and molecular dynamics studies, we found that the reactivity of the nucleophilic cysteine (CN ) in the Trx is greatly affected by the formation of the Prx-Trx complex. The protein-protein interaction forces the CN thiolate into an unfavorable hydrophobic microenvironment that reduces its hydration and results in a remarkable acceleration of the thiol-disulfide exchange reactions by more than three orders of magnitude and also produces a measurable shift in the pKa of the CN . This mechanism of activation of the thiol disulfide exchange may help understand the reduction of Prx by alternative reductants involved in redox signaling.


Subject(s)
Peroxiredoxins , Thioredoxins , Humans , Thioredoxins/chemistry , Peroxiredoxins/chemistry , Peroxiredoxins/metabolism , Oxidation-Reduction , Sulfhydryl Compounds/chemistry , Disulfides/chemistry
5.
J Inorg Biochem ; 247: 112313, 2023 10.
Article in English | MEDLINE | ID: mdl-37467661

ABSTRACT

The interactions of the heme iron of hemeproteins with sulfide and disulfide compounds are of potential interest as physiological signaling processes. While the interaction with hydrogen sulfide has been described computationally and experimentally, the reaction with disulfide, and specifically the molecular mechanism for ligand binding has not been studied in detail. In this work, we study the association process for disulfane and its conjugate base disulfanide at different pH conditions. Additionally, by means of advanced sampling techniques based on multiple steered molecular dynamics, we provide free energy profiles for ligand migration for both acid/base species, showing a similar behavior to the previously reported for the related H2S/HS¯ pair. Finally, we studied the ligand interchange reaction (H2O/H2S, HS¯ and H2O/HSSH, HSS¯) by means of hybrid quantum mechanics-molecular mechanics calculations. We show that the anionic species are able to displace more efficiently the H2O bound to the iron, and that the H-bond network in the distal cavity can help the neutral species to perform the reaction. Altogether, we provide a molecular explanation for the experimental information and show that the global association process depends on a fine balance between the migration towards the active site and the ligand interchange reaction.


Subject(s)
Hemeproteins , Hemeproteins/chemistry , Metmyoglobin/chemistry , Disulfides , Ligands , Sulfides/metabolism , Iron
6.
Toxins (Basel) ; 15(6)2023 06 03.
Article in English | MEDLINE | ID: mdl-37368679

ABSTRACT

Phα1ß (PnTx3-6) is a neurotoxin from the spider Phoneutria nigriventer venom, originally identified as an antagonist of two ion channels involved in nociception: N-type voltage-gated calcium channel (CaV2.2) and TRPA1. In animal models, Phα1ß administration reduces both acute and chronic pain. Here, we report the efficient bacterial expression system for the recombinant production of Phα1ß and its 15N-labeled analogue. Spatial structure and dynamics of Phα1ß were determined via NMR spectroscopy. The N-terminal domain (Ala1-Ala40) contains the inhibitor cystine knot (ICK or knottin) motif, which is common to spider neurotoxins. The C-terminal α-helix (Asn41-Cys52) stapled to ICK by two disulfides exhibits the µs-ms time-scale fluctuations. The Phα1ß structure with the disulfide bond patterns Cys1-5, Cys2-7, Cys3-12, Cys4-10, Cys6-11, Cys8-9 is the first spider knottin with six disulfide bridges in one ICK domain, and is a good reference to other toxins from the ctenitoxin family. Phα1ß has a large hydrophobic region on its surface and demonstrates a moderate affinity for partially anionic lipid vesicles at low salt conditions. Surprisingly, 10 µM Phα1ß significantly increases the amplitude of diclofenac-evoked currents and does not affect the allyl isothiocyanate (AITC)-evoked currents through the rat TRPA1 channel expressed in Xenopus oocytes. Targeting several unrelated ion channels, membrane binding, and the modulation of TRPA1 channel activity allow for considering Phα1ß as a gating modifier toxin, probably interacting with S1-S4 gating domains from a membrane-bound state.


Subject(s)
Cystine-Knot Miniproteins , Spider Venoms , Spiders , Toxins, Biological , Rats , Animals , TRPA1 Cation Channel/genetics , Spiders/chemistry , Neurotoxins , Magnetic Resonance Spectroscopy , Disulfides , Spider Venoms/pharmacology , Spider Venoms/chemistry
7.
J Inorg Biochem ; 245: 112256, 2023 08.
Article in English | MEDLINE | ID: mdl-37244768

ABSTRACT

The mechanism of the metal centered reduction of metmyoglobin (MbFeIII) by inorganic disulfide species has been studied by combined spectroscopic and kinetic analyses, under argon atmosphere. The process is kinetically characterized by biexponential time traces, for variable ratios of excess disulfide to protein, in the pH interval 6.6-8.0. Using UV-vis and resonance Raman spectroscopies, we observed that MbFeIII is converted into a low spin hexacoordinated ferric complex, tentatively assigned as MbFeIII(HSS-)/MbFeIII(SS2-), in an initial fast step. The complex is slowly converted into a pentacoordinated ferrous form, assigned as MbFeII according to the resonance Raman records. The reduction is a pH-dependent process, but independent of the initial disulfide concentration, suggesting the unimolecular decomposition of the intermediate complex following a reductive homolysis. We estimated the rate of the fast formation of the complex at pH 7.4 (kon = 3.7 × 103 M-1 s-1), and a pKa2 = 7.5 for the equilibrium MbFeIII(HSS-)/MbFeIII(SS2-). Also, we estimated the rate for the slow reduction at the same pH (kred = 10-2 s-1). A reaction mechanism compliant with the experimental results is proposed. This mechanistic study provides a differential kinetic signature for the reactions of disulfide compared to sulfide species on metmyoglobin, which may be considered in other hemeprotein systems.


Subject(s)
Hemeproteins , Metmyoglobin , Metmyoglobin/chemistry , Metmyoglobin/metabolism , Disulfides , Spectrum Analysis , Hemeproteins/metabolism , Iron , Oxidation-Reduction , Kinetics
8.
Gene ; 877: 147506, 2023 Aug 15.
Article in English | MEDLINE | ID: mdl-37224934

ABSTRACT

Bacteria can communicate to each other via quorum sensing, a cell density-dependent gene regulation system that stimulates the expression of virulence factors in the neighboring cells. Although the interaction of the natural product ajoene with the Hfq protein has been associated with the disruption of the quorum sensing system in Pseudomonas aeruginosa, there is no information concerning the corresponding ligand-target interaction process. Herein we observed a strong correlation (p < 0.00001) between the estimated affinities for the binding of 23 ajoene analogues at the proximal site of the Hfq protein of P. aeruginosa and their corresponding IC50 values, which reflect the reduction in the transcription of a virulence factor after quorum sensing inhibition. In this concern, our analyses reinforces previous propositions suggesting that ajoene could target the Hfq protein and affects its interaction with RNAs. Based on docking simulations, we tried to elucidate the binding mode of ajoene into the proximal Hfq site and we also established the minimum set of groups that would be necessary for a good interaction at this site, which includes a single hydrogen bond acceptor feature surrounded by groups that interact via π-sulfur (i.e., disulfide sulfurs) and/or π-alkyl/π-π stacking interactions (e.g., vinyl or small aryl/heteroaryl/heterocyclic groups). Because of the widespread role of Hfq as a matchmaker between messenger and small regulatory RNAs in Gram-negatives, we believe the discussion here provided for P. aeruginosa could be extrapolated for Gram-negatives in general, while the interaction of ajoene over the Hfq protein of Gram-positives would still remain more controversial.


Subject(s)
Pseudomonas aeruginosa , Quorum Sensing , Quorum Sensing/genetics , Pseudomonas aeruginosa/genetics , Pseudomonas aeruginosa/metabolism , RNA/metabolism , Disulfides/metabolism , Virulence Factors/genetics , Virulence Factors/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Gene Expression Regulation, Bacterial
9.
Food Res Int ; 168: 112729, 2023 06.
Article in English | MEDLINE | ID: mdl-37120195

ABSTRACT

ß-Lactoglobulin (ß-Lg) is the main protein in whey and is known for its allergenicity and resistance to the digestion of pepsin and trypsin. The UV-C photoinduced cleavage of disulfide bonds in ß-Lactoglobulin, as promoted by excitation of tryptophan residues (Trp), is shown to induce changes in the protein's secondary structure, significantly reducing the protein's resistance to pepsin digestion. The UV-C light-induced changes in the protein secondary structure are marked by an increase in the contribution of ß-sheet and α-helix structures with a concomitantly smaller contribution of the ß-turn structural motif. The photoinduced cleavage of disulfide bonds in ß-Lg has an apparent quantum yield of ф = 0.0015 ± 0.0003 and was shown by transient absorption laser flash photolysis to arise by two different pathways: a) the reduction of the disulfide bond Cys66Cys160 occurs by direct electron transfer from the triplet-excited 3Trp to the disulfide bond due to the existence of a CysCys/Trp triad (Cys66Cys160/Trp61) and b) the reduction of the buried Cys106Cys119 disulfide bond involves a reaction with a solvated electron originated by the photoejection of electrons from the triplet-excited 3Trp decay. The in vitro gastric digestion index for UV-C-treated ß-Lg is revealed to have increased significantly by 36 ± 4 % and 9 ± 2 % under simulated elderly and young adult digestive conditions, respectively. When compared to the native protein, the peptide mass fingerprint profile of digested UV-C-treated ß-Lg shows a higher content and variety of peptides, including the production of some exclusive bioactive peptides such as PMHIRL and EKFDKALKALPMH.


Subject(s)
Lactoglobulins , Pepsin A , Humans , Aged , Lactoglobulins/chemistry , Pepsin A/metabolism , Stomach , Digestion , Disulfides/chemistry
10.
FEBS J ; 290(10): 2692-2705, 2023 05.
Article in English | MEDLINE | ID: mdl-36560841

ABSTRACT

Pore forming toxins rely on oligomerization for membrane insertion to kill their targets. Bacillus thuringiensis produces insecticidal Cry-proteins composed of three domains that form pores that kill the insect larvae. Domain I is involved in oligomerization and membrane insertion, whereas Domains II and III participate in receptor binding and specificity. However, the structural changes involved in membrane insertion of these proteins remain unsolved. The most widely accepted model for membrane insertion, the 'umbrella model', proposed that the α-4/α-5 hairpin of Domain I swings away and is inserted into the membrane. To determine the topology of Cry1Ab in the membrane, disulfide bonds linking α-helices of Domain I were introduced to restrict their movement. Disulfide bonds between helices α-2/α-3 or α-3/α-4 lost oligomerization and toxicity, indicating that movement of these helices is needed for insecticidal activity. By contrast, disulfide bonds linking helices α-5/α-6 did not affect toxicity, which contradicts the 'umbrella model'. Additionally, Föster resonance energy transfer closest approach analyses measuring distances of different points in the toxin to the membrane plane and collisional quenching assays analysing the protection of specific fluorescent-labeled residues to the soluble potassium iodide quencher in the membrane inserted state were performed. Overall, the data show that Domain I from Cry1Ab may undergo a major conformational change during its membrane insertion, where the N-terminal region (helices α-1 to α-4) participates in oligomerization and toxicity, probably forming an extended helix. These data break a paradigm, showing a new 'folding white-cane model', which better explains the structural changes of Cry toxins during insertion into the membrane.


Subject(s)
Bacillus thuringiensis , Insecticides , Animals , Insecticides/toxicity , Bacillus thuringiensis/genetics , Bacillus thuringiensis/chemistry , Bacillus thuringiensis/metabolism , Bacterial Proteins/metabolism , Endotoxins/chemistry , Hemolysin Proteins/metabolism , Disulfides/metabolism , Larva/metabolism
11.
Mol Biol Rep ; 49(12): 11715-11727, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36198848

ABSTRACT

BACKGROUND: Neuregulins comprise a large family of growth factors containing an epidermal growth factor (EGF) domain. NRG1 acts in signaling pathways involved in proliferation, apoptosis, migration, differentiation, and adhesion of many normal cell types and in human diseases. The EGF domain of NRG1 mediates signaling by interaction with members of the ErbB family of receptors. Easy access to correctly folded hNRG1α EGF domain can be a valuable tool to investigate its function in different cell types. MATERIALS AND METHODS: The EGF domain of hNRG1α was produced in Escherichia coli in fusion with TrxA and purified after cleavage of TrxA. Conformation and stability analyses were performed by using biophysical methods and the disulfide bonds were mapped by mass spectrometry. The activity of the hNRG1α EGF domain was demonstrated in cell proliferation and migration assays. RESULTS: Approximately 3.3 mg of hNRG1α EGF domain were obtained starting from a 0.5 L of E. coli culture. Correct formation of the three disulfide bonds was demonstrated by mass spectrometry with high accuracy. Heat denaturation assays monitored by circular dichroism and dynamic light scattering revealed that it is a highly stable protein. The recombinant EGF domain of hNRG1α purified in this work is highly active, inducing cell proliferation at concentration as low as 0.05 ng/mL. It induces also cell migration as demonstrated by a gap closure assay. CONCLUSION: The EGF domain of hNRG1α was produced in E. coli with the correct disulfide bonds and presented high stimulation of HeLa cell proliferation and NDFH cell migration.


Subject(s)
Epidermal Growth Factor , Neuregulins , Humans , Epidermal Growth Factor/metabolism , Neuregulins/metabolism , Escherichia coli/genetics , Escherichia coli/metabolism , HeLa Cells , Disulfides/chemistry , Disulfides/metabolism
12.
Rev Assoc Med Bras (1992) ; 68(9): 1259-1263, 2022 Sep.
Article in English | MEDLINE | ID: mdl-36134773

ABSTRACT

OBJECTIVE: Lipoid proteinosis is a rare autosomal recessive genetic dermatological disease that occurs due to the accumulation of hyaline material in the skin and mucous membranes. This study aimed to investigate whether dynamic thiol-disulfide homeostasis is a new marker of oxidative stress in patients suffering from lipoid proteinosis. METHODS: The study group involved 17 patients with lipoid proteinosis and 17 healthy controls with same gender and age. Native thiol, total thiol, disulfide levels, and thiol-disulfide indexes were measured with the fully automated spectrophotometric method described by Erel and Neselioglu, and the results of the two groups were statistically analyzed. RESULTS: Serum total thiol and native thiol levels were significantly lower in lipoid proteinosis group compared to the control group (p=0.020 and p=0.014, respectively). The disulfide levels were found to be higher in lipoid proteinosis group, but there was no significant difference between two groups. CONCLUSIONS: Impaired dynamic thiol-disulfide homeostasis was observed in lipoid proteinosis patients, suggesting that thiol-disulfide homeostasis may have a role in the pathogenesis of this disease.


Subject(s)
Lipoid Proteinosis of Urbach and Wiethe , Disulfides , Homeostasis , Humans , Lipoid Proteinosis of Urbach and Wiethe/pathology , Skin/pathology , Sulfhydryl Compounds
13.
Oper Dent ; 47(5): E211-E221, 2022 Sep 01.
Article in English | MEDLINE | ID: mdl-36121721

ABSTRACT

PURPOSE: The aim of this study was to evaluate the effects of a new irrigant solution on the post space cleaning and the adhesive resistance of fiber posts. METHODS AND MATERIALS: Eighty roots of bovine teeth were randomly allocated into eight groups (n=10 for each group). Evaluations were performed in two different time points for each irrigant. The irrigants included a control group with distilled water (DW), 2.5% NaOCl and 17% EDTA (SH), 1% peracetic acid (PA), and 5% boric acid and 1% citric acid (EX). The time points were 24 hours (I-immediate) and 6 months (D-delayed). The push-out test was performed using a universal testing machine with a 5 kN load cell operating at a crosshead speed of 0.5 mm/minute. The dentinal cementation system was analyzed using a laser confocal microscope (LSM5, Zeiss, Jena, Germany), and incidence of residue on radicular dentin was evaluated by scanning electron microscopy (SEM). The incidence of residue was evaluated by the Kruskal-Wallis test and push-out bond strength and dentin penetrability were evaluated via a one-way analysis of variance (ANOVA) and Tukey tests (α=0.05). RESULTS: The EX irrigation protocol demonstrated the lowest incidence of residue on the dentin surface (p<0.05), independently of the evaluated third. In the cervical and the middle post thirds, EXI, EXD, SHI, and SHD groups exhibited similar push-out bond strength values (p>0.05). EXI, EXD, PAI, and PAD exhibited the greatest dentinal penetrability of the cementation system in all the post thirds (p<0.05). CONCLUSIONS: A solution containing 5% boric acid and 1% citric acid can be a promising irrigant for radicular post space cleaning. It has adequate potential for cleaning the dentin surface without interfering with the adhesive interface between the dentin and the cementation system.


Subject(s)
Dental Bonding , Post and Core Technique , Animals , Boric Acids , Cattle , Citric Acid/analysis , Citric Acid/pharmacology , Dental Bonding/methods , Dental Cements/therapeutic use , Dental Pulp Cavity , Dentin , Disulfides , Edetic Acid/chemistry , Materials Testing , Peracetic Acid/analysis , Peracetic Acid/pharmacology , Resin Cements/chemistry , Resin Cements/therapeutic use , Root Canal Irrigants/analysis , Root Canal Irrigants/chemistry , Root Canal Irrigants/therapeutic use , Thiones , Water
14.
Diabetes ; 71(12): 2764-2776, 2022 12 01.
Article in English | MEDLINE | ID: mdl-36170669

ABSTRACT

The stress response protein regulated in development and DNA damage response 1 (REDD1) has been implicated in visual deficits in patients with diabetes. The aim here was to investigate the mechanism responsible for the increase in retinal REDD1 protein content that is observed with diabetes. We found that REDD1 protein expression was increased in the retina of streptozotocin-induced diabetic mice in the absence of a change in REDD1 mRNA abundance or ribosome association. Oral antioxidant supplementation reduced retinal oxidative stress and suppressed REDD1 protein expression in the retina of diabetic mice. In human retinal Müller cell cultures, hyperglycemic conditions increased oxidative stress, enhanced REDD1 expression, and inhibited REDD1 degradation independently of the proteasome. Hyperglycemic conditions promoted a redox-sensitive cross-strand disulfide bond in REDD1 at C150/C157 that was required for reduced REDD1 degradation. Discrete molecular dynamics simulations of REDD1 structure revealed allosteric regulation of a degron upon formation of the disulfide bond that disrupted lysosomal proteolysis of REDD1. REDD1 acetylation at K129 was required for REDD1 recognition by the cytosolic chaperone HSC70 and degradation by chaperone-mediated autophagy. Disruption of REDD1 allostery upon C150/C157 disulfide bond formation prevented the suppressive effect of hyperglycemic conditions on REDD1 degradation and reduced oxidative stress in cells exposed to hyperglycemic conditions. The results reveal redox regulation of REDD1 and demonstrate the role of a REDD1 disulfide switch in development of oxidative stress.


Subject(s)
Diabetes Mellitus, Experimental , Hyperglycemia , Humans , Mice , Animals , Diabetes Mellitus, Experimental/metabolism , Disulfides/pharmacology , Transcription Factors/metabolism , Oxidative Stress , Oxidation-Reduction
15.
Braz J Biol ; 84: e262697, 2022.
Article in English | MEDLINE | ID: mdl-35976350

ABSTRACT

Garlic (Allium sativum) is an important cash food crop, and the biotechnology industry has considerable interest in the plant because of its medicinal importance. These medicinal properties are attributed to organosulphur compounds as the accumulation of these compounds varies according to genotype, locality, light quality, and cultivation practices. In this study, we compared a newly developed garlic variety NARC-G1 by National Agricultural Research Centre (NARC), Islamabad, Pakistan with three different garlic cultivars and highlighted the distinctive attributes like phenotypic characteristics, the content of allicin, elemental profile, and gene polymorphism. Phenotypic analysis showed NARC-G1 has significantly higher bulb weight (66.36g ± 18.58), single clove weight (5.87g ± 1.041), and clove width (17.41mm ± 0.95) which directly correlates to the size of the garlic. The analytical analysis showed the highest allicin content (4.82 ± 0.001) in NARC-G1. Genotyping of the alliinase in all four cultivars showed indels in the gene resulting in distinguishable changes in organosulphur compounds' profile. NARC-G1 is unique from other garlic cultivars and could be the best choice for mass production with proper cultivation and irrigation management. Moreover, for Pakistan NARC-G1 could be a potential contender to earn the industrial benefits with inland cultivation instead of importing garlic alleviating the economic burden.


Subject(s)
Garlic , Antioxidants , Disulfides , Garlic/chemistry , Garlic/genetics , Humans , Sulfinic Acids/analysis
16.
Int J Mol Sci ; 23(16)2022 Aug 13.
Article in English | MEDLINE | ID: mdl-36012349

ABSTRACT

Cardiovascular diseases (CVDs) are a group of diseases in which the common denominator is the affection of blood vessels, heart tissue, and heart rhythm. The genesis of CVD is complex and multifactorial; therefore, approaches are often based on multidisciplinary management and more than one drug is used to achieve the optimal control of risk factors (dyslipidemia, hypertension, hypertrophy, oxidative stress, endothelial dysfunction, inflammation). In this context, allicin, a sulfur compound naturally derived from garlic, has shown beneficial effects on several cardiovascular risk factors through the modulation of cellular mechanisms and signaling pathways. Effective pharmacological treatments for CVD or its risk factors have not been developed or are unknown in clinical practice. Thus, this work aimed to review the cellular mechanisms through which allicin exerts its therapeutic effects and to show why it could be a therapeutic option for the prevention or treatment of CVD and its risk factors.


Subject(s)
Cardiovascular Diseases , Garlic , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/prevention & control , Disulfides/therapeutic use , Humans , Sulfinic Acids/pharmacology , Sulfinic Acids/therapeutic use
17.
Arq Bras Cardiol ; 119(3): 426-435, 2022 09.
Article in English, Portuguese | MEDLINE | ID: mdl-35703665

ABSTRACT

BACKGROUND: Abdominal aortic intima media thickness (A-IMT) may be an early marker of subclinical atherosclerosis and an objective indicator of increased oxidative stress in beta-thalassemia minor patients. OBJECTIVE: To evaluate whether aortic and carotid IMTs change with oxidative stress and to assess the relationship between these parameters in beta-thalassemia minor patients. METHODS: The study included 80 patients diagnosed with beta-thalassemia minor, and 50 healthy individuals with similar age and gender. After routine procedures, blood samples were collected from the study groups for thiol-disulfide hemostasis and ischemia-modified albumin (IMA). C-IMT measurements were performed in four different regions (right and left internal and external carotid artery) by ultrasonography. In addition, A-IMT measurement was performed by abdominal ultrasonography. Statistically significant p value was set as <0.05 for all comparisons. RESULTS: In beta-thalassemia minor patients, native thiol, total thiol and native thiol / total thiol ratio were lower, and the IMA, disulfide / native thiol ratio and disulfide / total thiol ratios were higher than in healthy control group. A-IMT measurement was significantly higher in beta-thalassemia minor group than controls (1.46±0.37 vs 1.23±0.22 and p<0.001). When the parameters associated with A-IMT in univariate analysis were evaluated by multivariate linear regression analysis, A-IMT was positively related, and native thiol and total thiol levels were negatively and closely related to IMA (p<0.01). CONCLUSION: We demonstrated, for the first time, that oxidative stress status increased with increased A-IMT, while C-IMT remained unchanged in beta-thalassemia minor patients.


FUNDAMENTO: A espessura médio-intimal (EMI) da artéria aorta abdominal (EMI-A) pode ser um marcador precoce de aterosclerose subclínica e um indicador objetivo de estresse oxidativo em pacientes com talassemia menor. OBJETIVO: Avaliar se as EMIs da artéria aorta e da artéria carótida (EMI-C) se alteram com estresse oxidativo, e examinar a relação entre esses parâmetros em pacientes com talassemia menor. MÉTODOS: O estudo incluiu 80 pacientes diagnosticados com talassemia menor, e 50 indivíduos sadios com idade e sexo similares. Após procedimentos de rotina, as amostras de sangue foram coletadas dos grupos de estudo para a medida da homeostase tiol/dissulfeto e da albumina modificada pela isquemia (AMI). As medidas da EMI-C foram realizadas a partir de quatro regiões diferentes (artéria carótida externa direita e esquerda e artéria carótida interna direita e esquerda) por ultrassonografia, e a medida da EMI-A foi realizada por ultrassonografia abdominal. Um valor de p<0,05 foi definido como estatisticamente significativo. RESULTADOS: Nos pacientes com talassemia menor, os níveis de tiol nativo e tiol total, e a razão tiol nativo/tiol total foram mais baixos, e os valores de AMI, razão dissulfeto/tiol nativo, e razão dissulfeto/tiol total foram mais altos que no grupo controle. A EMI-A foi significativamente maior no grupo de pacientes com talassemia menor que nos controles (1,46±0,37 vs 1,23±0,22 e p<0,001). Quando os parâmetros associados com EMI-A na análise univariada foram avaliados por regressão linear multivariada, EMI-A apresentou uma relação positiva, e os níveis de tiol nativo e tiol total apresentaram uma forte relação negativa com AMI (p<0,01). CONCLUSÃO: Nós demonstramos, pela primeira vez, um aumento no estresse oxidativo com a elevação da EMI-A, e valores inalterados da EMI-C em pacientes com talassemia menor.


Subject(s)
beta-Thalassemia , Biomarkers , Carotid Intima-Media Thickness , Disulfides , Humans , Oxidative Stress , Serum Albumin , Sulfhydryl Compounds , beta-Thalassemia/diagnostic imaging
18.
São Paulo med. j ; São Paulo med. j;140(3): 390-397, May-June 2022. tab, graf
Article in English | LILACS | ID: biblio-1377390

ABSTRACT

ABSTRACT BACKGROUND: Reduced antioxidant defenses may reflect a poor protective response against oxidative stress and this may be implicated in progression of gestational diabetes mellitus (GDM). Oxidative stress induced by hyperglycemia plays a major role in micro and macrovascular complications, which imply endothelial dysfunction. OBJECTIVE: Our aim in this study was to investigate the association between GDM and oxidative stress markers measured in plasma, with regard to revealing changes to total antioxidant capacity (TAC) and total oxidant status (TOS) among mothers showing impairments in oral glucose tolerance tests (OGTTs). DESIGN AND SETTING: Prospective study at a university hospital in Turkey. METHODS: The study group consisted of 50 mothers with GDM, and 59 healthy mothers served as controls. Umbilical cord blood samples were taken from all mothers during delivery and breast milk samples on the fifth day after delivery. TAC, TOS, thiol and disulfide levels were measured. RESULTS: No statistically significant relationship between the blood and milk samples could be found. An analysis on correlations between TAC, TOS and certain parameters revealed that there were negative correlations between TOS and total thiol (r = -0.386; P < 0.001) and between TOS and disulfide (r = -0.388; P < 0.001) in milk in the control group. However, these findings were not observed in the study group. CONCLUSION: Our findings suggested that a compensatory mechanism of oxidative stress was expected to be present in gestational diabetes mellitus and that this might be ameliorated through good glycemic regulation and antioxidant supplementation.


Subject(s)
Humans , Animals , Female , Pregnancy , Diabetes, Gestational , Sulfhydryl Compounds/analysis , Prospective Studies , Oxidative Stress/physiology , Milk/metabolism , Milk/chemistry , Disulfides/analysis , Fetal Blood/metabolism , Fetal Blood/chemistry , Antioxidants/analysis
19.
Sao Paulo Med J ; 140(3): 390-397, 2022.
Article in English | MEDLINE | ID: mdl-35508001

ABSTRACT

BACKGROUND: Reduced antioxidant defenses may reflect a poor protective response against oxidative stress and this may be implicated in progression of gestational diabetes mellitus (GDM). Oxidative stress induced by hyperglycemia plays a major role in micro and macrovascular complications, which imply endothelial dysfunction. OBJECTIVE: Our aim in this study was to investigate the association between GDM and oxidative stress markers measured in plasma, with regard to revealing changes to total antioxidant capacity (TAC) and total oxidant status (TOS) among mothers showing impairments in oral glucose tolerance tests (OGTTs). DESIGN AND SETTING: Prospective study at a university hospital in Turkey. METHODS: The study group consisted of 50 mothers with GDM, and 59 healthy mothers served as controls. Umbilical cord blood samples were taken from all mothers during delivery and breast milk samples on the fifth day after delivery. TAC, TOS, thiol and disulfide levels were measured. RESULTS: No statistically significant relationship between the blood and milk samples could be found. An analysis on correlations between TAC, TOS and certain parameters revealed that there were negative correlations between TOS and total thiol (r = -0.386; P < 0.001) and between TOS and disulfide (r = -0.388; P < 0.001) in milk in the control group. However, these findings were not observed in the study group. CONCLUSION: Our findings suggested that a compensatory mechanism of oxidative stress was expected to be present in gestational diabetes mellitus and that this might be ameliorated through good glycemic regulation and antioxidant supplementation.


Subject(s)
Diabetes, Gestational , Animals , Antioxidants/analysis , Disulfides/analysis , Female , Fetal Blood/chemistry , Fetal Blood/metabolism , Humans , Milk/chemistry , Milk/metabolism , Oxidative Stress/physiology , Pregnancy , Prospective Studies , Sulfhydryl Compounds/analysis
20.
FEBS J ; 289(18): 5480-5504, 2022 09.
Article in English | MEDLINE | ID: mdl-35490402

ABSTRACT

Protein phosphorylation is a major post-translational modification involved in cell signalling that regulates many physiological and pathological processes. Despite their biological importance, protein phosphatases are less studied than protein kinases. Importantly, the activity of Cys-based protein tyrosine phosphatases (PTPs) can be regulated by reversible oxidation. The initial two-electron oxidation product of the active site Cys is a sulfenic acid (Cys-SOH) that can then undergo distinct outcomes, such as the disulfide bond or a sulfenyl amide formation. Here, we review the biochemical and structural features of PTPs to find patterns that might specify their oxidation products, aiming to get insights into redox regulatory mechanisms. Initially, the structure and biochemistry of PTP1B is presented. Then, we describe structural aspects that are relevant for substrate recognition and catalysis. Notably, all PTPs contain critical Cys residues for the catalysis of dephosphorylation that is prone to oxidative inactivation, which are frequently found oxidized in cells under physiological conditions, such as upon growth factor stimuli. However, direct oxidations of Cys residues in PTPs by H2 O2 are rather slow. Therefore, we discuss possible mechanisms that may account for this apparent contradiction between biological and chemical redox aspects of PTPs. Furthermore, we performed a systematic analysis of the distance between active site cysteine and its backdoor cysteine with the attempt to analyse the preference between disulfide bond formation or sulfenyl amide interaction upon oxidation. In summary, PTPs have been showing many possibilities to auto-protect from irreversible oxidation, which is important for cell signalling regulation.


Subject(s)
Cysteine , Sulfenic Acids , Amides/chemistry , Cysteine/chemistry , Disulfides/metabolism , Oxidation-Reduction , Phosphoprotein Phosphatases/metabolism , Protein Kinases/metabolism , Protein Tyrosine Phosphatases/genetics , Protein Tyrosine Phosphatases/metabolism , Sulfenic Acids/chemistry , Sulfenic Acids/metabolism
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