Phenotypes of Polish primary care patients using hierarchical clustering: Exploring the risk of mortality in the LIPIDOGEN2015 study cohort.

BACKGROUND: Comorbidities in primary care do not occur in isolation but tend to cluster together causing various clinically complex phenotypes. This study aimed to distinguish phenotype clusters and identify the risks of all-cause mortality in primary care. METHODS: The baseline cohort of the LIPIDOGEN2015 sub-study involved 1779 patients recruited by 438 primary care physicians. To identify different phenotype clusters, we used hierarchical clustering and investigated differences between clinical characteristics and mortality between clusters. We then performed causal analyses using causal mediation analysis to explore potential mediators between different clusters and all-cause mortality. RESULTS: A total of 1756 patients were included (mean age 51.2, SD 13.0; 60.3% female), with a median follow-up of 5.7 years. Three clusters were identified: Cluster 1 (n = 543) was characterised by overweight/obesity (body mass index ≥ 25 kg/m2), older (age ≥ 65 years), more comorbidities; Cluster 2 (n = 459) was characterised by non-overweight/obesity, younger, fewer comorbidities; Cluster 3 (n = 754) was characterised by overweight/obesity, younger, fewer comorbidities. Adjusted Cox regression showed that compared with Cluster 2, Cluster 1 had a significantly higher risk of all-cause mortality (HR 3.87, 95% CI: 1.24-15.91), whereas this was insignificantly different for Cluster 3. Causal mediation analyses showed that decreased protein thiol groups mediated the hazard effect of all-cause mortality in Cluster 1 compared with Cluster 2, but not between Clusters 1 and 3. CONCLUSION: Overweight/obesity older patients with more comorbidities had the highest risk of long-term all-cause mortality, and in the young group population overweight/obesity insignificantly increased the risk in the long-term follow-up, providing a basis for stratified phenotypic risk management.

The effect of cytochrome c on Na,K-ATPase.

Na,K-ATPase is a crucial enzyme responsible for maintaining Na+, K+-gradients across the cell membrane, which is essential for numerous physiological processes within various organs and tissues. Due to its significance in cellular physiology, inhibiting Na,K-ATPase can have profound physiological consequences. This characteristic makes it a target for various pharmacological applications, and drugs that modulate the pump's activity are thus used in the treatment of several medical conditions. Cytochrome c (Cytc) is a protein with dual functions in the cell. In the mitochondria, it is essential for ATP synthesis and energy production. However, in response to apoptotic stimuli, it is released into the cytosol, where it triggers programmed cell death through the intrinsic apoptosis pathway. Aside from its role in canonical intrinsic apoptosis, Cytc also plays additional roles. For instance, Cytc participates in certain non-apoptotic functions -those which are less well-understood in comparison to its role in apoptosis. Within this in vitro study, we have shown the impact of Cytc on Na,K-ATPase for the first time. Cytc has a biphasic action on Na,K-ATPase, with activation at low concentrations (0.06 ng/ml; 6 ng/ml) and inhibition at high concentration (120 ng/ml). Cytc moreover displays isoform/subunit specificity and regulates the Na+ form of the enzyme, while having no effect on the activity or kinetic parameters of the K+-dependent form of the enzyme. Changing the affinity of p-chloromercuribenzoic acid (PCMB) by Cytc is therefore both a required and sufficient condition for confirming that PCMB and Cytc share the same target, namely the thiol groups of cysteine in Na,K-ATPase.

Selenite ameliorates the ATP hydrolysis of mitochondrial F1FO-ATPase by changing the redox state of thiol groups and impairs the ADP phosphorylation.

Selenite as an inorganic form of selenium can affect the redox state of mitochondria by modifying the thiol groups of cysteines. The F1FO-ATPase has been identified as a mitochondrial target of this compound. Indeed, the bifunctional mechanism of ATP turnover of F1FO-ATPase was differently modified by selenite. The activity of ATP hydrolysis was stimulated, whereas the ADP phosphorylation was inhibited. We ascertain that a possible new protein adduct identified as seleno-dithiol (-S-Se-S-) mercaptoethanol-sensitive caused the activation of F-ATPase activity and the oxidation of free -SH groups in mitochondria. Conversely, the inhibition of ATP synthesis by selenite might be irreversible. The kinetic analysis of the activation mechanism was an uncompetitive mixed type with respect to the ATP substrate. Selenite bound more selectively to the F1FO-ATPase loaded with the substrate by preferentially forming a tertiary (enzyme-ATP-selenite) complex. Otherwise, the selenite was a competitive mixed-type activator with respect to the Mg2+ cofactor. Thus, selenite more specifically bound to the free enzyme forming the complex enzyme-selenite. However, even if the selenite impaired the catalysis of F1FO-ATPase, the mitochondrial permeability transition pore phenomenon was unaffected. Therefore, the reversible energy transduction mechanism of F1FO-ATPase can be oppositely regulated by selenite.

Contribution of Physical Activity to the Oxidative and Antioxidant Potential in 60-65-Year-Old Seniors.

Both acute exercise and regular physical activity (PA) are directly related to the redox system. However, at present, there are data suggesting both positive and negative relationships between the PA and oxidation. In addition, there is a limited number of publications differentiating the relationships between PA and numerous markers of plasma and platelets targets for the oxidative stress. In this study, in a population of 300 participants from central Poland (covering the age range between 60 and 65 years), PA was assessed as regards energy expenditure (PA-EE) and health-related behaviors (PA-HRB). Total antioxidant potential (TAS), total oxidative stress (TOS) and several other markers of an oxidative stress, monitored in platelet and plasma lipids and proteins, were then determined. The association of PA with oxidative stress was determined taking into the account basic confounders, such as age, sex and the set of the relevant cardiometabolic factors. In simple correlations, platelet lipid peroxides, free thiol and amino groups of platelet proteins, as well as the generation of superoxide anion radical, were inversely related with PA-EE. In multivariate analyses, apart from other cardiometabolic factors, a significant positive impact of PA-HRB was revealed for TOS (inverse relationship), while in the case of PA-EE, the effect was found to be positive (inverse association) for lipid peroxides and superoxide anion but negative (lower concentration) for free thiol and free amino groups in platelets proteins. Therefore, the impact of PA may be different on oxidative stress markers in platelets as compared to plasma proteins and also dissimilar on platelet lipids and proteins. These associations are more visible for platelets than plasma markers. For lipid oxidation, PA seems to have protective effect. In the case of platelets proteins, PA tends to act as pro-oxidative factor.

Captodative Effect Facilitates the Excitation in Diboron Molecule (CAAC)2 B2 (SH)2.

Given the extraordinary versatility in chemical reactions and applications, boron compounds have gained increasing attentions in the past two decades. One of the remarkable advances is the unprecedented preparation of unsaturated boron species. Notably, Braunschweig et al. found that the cyclic (alkyl)(amino) carbenes (CAACs) stabilized diboron molecules (CAAC)2 B2 (SR)2 host unpaired electrons and exist in the 90°-twisted diradical form, while other analogues, such as N-heterocyclic carbenes (NHCs), stabilized diboron molecules prefer a conventional B=B double bond. Since previous studies recognized the differences in the steric effect between CAAC and NHC carbenes, here we focused on the role of thiol substituents in (CAAC)2 B2 (SR)2 by gradually localizing involved electrons. The co-planarity of the thiol groups and the consequent captodative effect were found to be the culprit for the 90°-twisted diradical form of (CAAC)2 B2 (SR)2 . Computational analyses identified two forces contributing to the π electron movements. One is the "push" effect of lone pairs on the sulfur atoms which boosts the π electron delocalization between the BB center and CAACs. The other is the π electron delocalization within each (CAAC)B(SR) fragment where the pull effect originates from the π electron withdrawal by CAACs. There are two such independent and orthogonal push-pull channels which function mainly in individual (CAAC)B(SR) fragments. This enhanced π push-pull effect in the triplet state facilitates the electronic excitation in (CAAC)2 B2 (SR)2 by reducing the singlet-triplet gap.

Effect of H2O2 on Na,K-ATPase.

Na,K-ATPase is a member of the P-type ATPase family, which transforms the energy of ATP to the transmembrane Na/K gradient that is used to create membrane potential, support the excitability of neurons and myocytes, control pH, and transport substances. The regulation of the Na,K-ATPase function by physiological regulators also comprises a central role in the adaptation of organisms to different conditions. H2O2 is one of the main signaling molecules in redox metabolism and plays important function in cellular physiology. H2O2 also regulates signaling pathways via the specific oxidation of proteins harboring redox-sensitive moieties, like metal centers or cysteine residues, which control their activity. The Na,K-ATPase is redox-sensitive with an "optimal redox potential range," where the reactive oxygen species (ROS), levels beyond this "optimal range" are responsible for enzyme inhibition. Thus reactive oxygen species manifest a hermetic effect, which is expressed by biphasic action; stimulation by low doses and inhibition by high doses. This study was aimed to reveal redox-sensitivity of brain synaptic membrane fractions Na,K-ATPase via H2O2 effects. Different concentrations of H2O2 change the kinetic parameters of the enzyme system for MgATP complex, Na+, and K+ differently. Moreover, H2O2 changes p-chloromercuribenzoic acids (PCMB) affinity. H2O2 targets thiols of the Na,K-ATPase - low and high concentrations of H2O2 change the oxidative state of thiolate (S-) from Cys differently, resulting in the corresponding activation or inhibition of the enzyme. Targeting thiols of the Na,K-ATPase tunes the activity of the Na,K-ATPase to the cellular demands and sustains the enzyme activity at the "optimal" level.

Gefitinib-loaded polydopamine-coated hollow mesoporous silica nanoparticle for gastric cancer application.

Gastric cancer is a common malignancy that is the second cancer-associated mortality worldwide. This study aimed to develop a pH-sensitive drug delivery system including hollow mesoporous silica nanoparticles (HMSNs) loaded with gefitinib (GB) and encapsulated with mussel-inspired polydopamine (PDA) (HMSNs-GB-PDA) for the treatment of gastric cancer; where the HMSNs mainly function as drug storage platforms, and GB interrupts signaling through the epidermal growth factor receptor (EGFR) in cancer cells. In addition, PDA was used as an anticancer factor, mucoadhesive enhancing agent, stimuli, and gatekeeper to mediate the GB release. The drug delivery kinetics (in vitro), mucoadhesive properties (ex vivo), and cytocompatibility in both healthy (HGF) and gastric cancer (AGS) cell lines of this formulation were also investigated. The results showed that HMSNs-GB-PDA not only selectively killed AGS cells but also had no toxic effect on HGF cells, in such a way that more than 70% of AGS cells were eliminated at a GB concentration of 150 ug/ml, whereas only about 15% of HGF cells were killed at the same concentration. In addition, the PDA coating served as a gatekeeper, inhibited burst release, and resulted in a sustained release that lasted for a long time. The ex vivo mucoadhesiveness evaluation revealed the high mucoadhesive property (93.88%) of PDA-coated nanocarriers. According to the results, the suggested HMSNs-GB-PDA could potentially be used to treat gastric cancer.

Oxidative Stress and High-Mobility Group Box 1 Assay in Dogs with Gastrointestinal Parasites.

This study aimed to evaluate the concentration of reactive oxidative metabolites, the antioxidant barrier, thiol groups of plasma compounds, and high-mobility group box 1 in shelter dogs naturally infected with helminths. In addition, the correlation between clinical signs and oxidative stress was investigated. Sixty-six (41 male and 25 female) adult mixed-breed dogs housed in a shelter with the diagnosis of gastrointestinal nematodes (i.e., Ancylostoma spp., Uncinaria stenocephala, Toxocara canis, Toxascaris leonina, or Trichuris vulpis) were enrolled in Group 1 (G1) and twenty healthy adult dogs were included in Group 2 (G2), which served as the control. A clinical assessment was performed using a physician-based scoring system. Oxidative stress variables and high-mobility group box 1 were assessed and compared by the means of unpaired t-tests (p < 0.05). Spearman's rank correlation was performed to calculate the correlation between oxidative stress variables, high-mobility group box 1, hematological parameters, and clinical signs. The results showed statistically significant values for reactive oxidative metabolites, thiol groups of plasma compounds, and high-mobility group box 1 in G1. Negative correlations between thiol groups and the number of red cells and hemoglobin were recorded. These preliminary results support the potential role of oxidative stress and HGMB-1 in the pathogenesis of gastrointestinal helminthiasis in dogs.

The structure, antioxidant and antibacterial properties of thiol-modified soy protein isolate induced by allicin.

This study investigated the effect of allicin binding on the structure, antioxidant and antibacterial properties of soy protein isolate (SPI). Results showed that allicin bound to 82.6 % free thiol groups of SPI at a molar ratio of 0.5. The combination of allicin and SPI significantly affected the structure of protein. Result of circular dichroism showed that the content of α-helix decreased by 26.9 % and the content of ß-sheet increased by 12.2 % over control when the molar ratio was 0.5. The result of surface hydrophobicity signified the unfolding of SPI with the action of allicin. These results implied that allicin binding might be a suitable method for the modification of SPI. Furthermore, the antibacterialand antioxidant experiments indicated that allicin-SPI conjugates not only had the capacity to inhibit the growth of Escherichia coli and Staphyloccocus aureus, but also had DPPH and ABTS radicals scavenging activities.

Functionalized Mesoporous Silica as Doxorubicin Carriers and Cytotoxicity Boosters.

Mesoporous silica nanoparticles (MSNs) bearing methyl, thiol or glucose groups were synthesized, and their encapsulation and release behaviors for the anticancer drug Doxorubicin (Dox) were investigated in comparison with nonporous homologous materials. The chemical modification of thiol-functional silica with a double bond glucoside was completed for the first time, by green thiol-ene photoaddition. The MSNs were characterized in terms of structure (FT-IR, Raman), morphology (TEM), porosity (nitrogen sorption-desorption) and Zeta potential measurements. The physical interactions responsible for the Dox encapsulation were investigated by analytic methods and MD simulations, and were correlated with the high loading efficiency of MSNs with thiol and glucose groups. High release at pH 5 was observed in most cases, with thiol-MSN exhibiting 98.25% cumulative release in sustained profile. At pH 7.4, the glucose-MSN showed 75.4% cumulative release, while the methyl-MSN exhibited a sustained release trend. The in vitro cytotoxicity was evaluated on NDHF, MeWo and HeLa cell lines by CellTiter-Glo assay, revealing strong cytotoxic effects in all of the loaded silica at low equivalent Dox concentration and selectivity for cancer cells. Atypical applications of each MSN as intravaginal, topical or oral Dox administration route could be proposed.

Oxidative changes in cooled and cooked pale, soft, exudative (PSE) chicken meat.

The mechanisms involved in the development of oxidative changes in pale, soft, exudative (PSE) chicken meat during storage in the dark at 4 °C for 5 days and after cooking at 80 °C for 30 min, light exposure and reheating were explored in this study. The results indicate that myoglobin, lipid and protein oxidation occurred concomitantly during both treatments in PSE chicken meat during storage, and each process seemed to promote the others. Transition metals and metmyoglobin played pivotal roles in the generation of free radicals that triggered lipid and protein oxidation in cooled and cooked PSE, respectively. In contrast, light played a secondary role as an oxidative inducer of these processes. Different pathways triggered the production of compounds from the interactions between oxidative reactions in cooled and cooked PSE chicken meat. The impact of these reactions on the functionality of PSE chicken meat requires further study.

Oxidative Stress Evaluation in Dogs Affected with Canine Monocytic Ehrlichiosis.

The study aimed to evaluate the concentration of reactive oxidative metabolites (R-OOHs), the antioxidant barrier (OXY), and the ratio between R-OOHs and OXY (OSi) and thiol groups of plasma compounds (SHp) in in canine monocytic ehrlichiosis. Thirty dogs affected with monocytic ehrlichiosis (canine monocytic ehrlichiosis group-CME group) and ten healthy dogs (control group-CTR group) were evaluated. CME was diagnosed by the presence of clinical signs and the detection of anti-Ehlichia canis antibodies. Oxidative stress parameters of two groups were compared using the Mann-Whitney test. Significance was set at p < 0.05. Spearman rank correlation was performed to analyze oxidative stress, and hematological and biochemical variables in the CME group. All dogs affected with CME showed a wide spectrum of clinical signs such as lethargy, anorexia, fever, weight loss, lymph adenomegaly, splenomegaly, subcutaneous and mucosal petechial and ecchymosis, and vomiting. Anaemia, leukocytosis, thrombocytopenia, hyperglobulinemia, hypoalbuminemia and an increase of blood urea nitrogen and creatinine are also detected. Results showed significantly lower values of SHp in the CME group than in CTR. A statistically significant difference in the number of white blood cells, platelets, and blood urea nitrogen concentration was assayed comparing to the two groups. A negative correlation between SHp and hemoglobin concentration was recorded. These preliminary results may suggest a possible function of oxidative stress in the onset of clinical signs during the course of CME.

St. Thomas Modified Cardioplegia Effects on Myoblasts' Viability and Morphology.

Background and Objectives: The cardioplegic arrest of the heart during cardiosurgical procedures is the crucial element of a cardioprotection strategy. Numerous clinical trials compare different cardioplegic solutions and cardioprotective protocols, but a relatively small number of papers apply to in vitro conditions using cultured cells. This work aimed to analyze whether it is possible to use the rat heart myocardium cells as an in vitro model to study the protective properties of St. Thomas cardioplegia (ST2C). Methods: The rat heart myocardium cells-H9C2 were incubated with cold cardioplegia for up to 24 h. After incubation, we determined: viability, confluency, and cell size, the thiol groups' level by modifying Ellman's method, Ki67, and Proliferating Cell Nuclear Antigen expression (PCNA). The impact on cells' morphology was visualized by the ultrastructural (TEM) study and holotomograpic 3D imaging. Results: The viability and confluency analysis demonstrated that the safest exposure to ST2C, should not exceed 4h. An increased expression of Ki67 antigen and PCNA was observed. TEM and 3D imaging studies revealed vacuolization after the longest period of exposure (24). Conclusions: According to obtained results, we conclude that STC can play a protective role in cardiac surgery during heart arrest.

Efficient Removal of Hg(II) from Water under Mildly Acidic Conditions with Hierarchical SiO2 Monoliths Functionalized with -SH Groups.

In this work, novel adsorbents based on 3D hierarchical silica monoliths functionalized with thiol groups were used for the removal of Hg(II) ions from an acidic aqueous solution (pH 3.5). Silica monoliths were synthesized by using two different pluronic triblock polymers (P123 and F127) to study the effect of porous structure on their sorption capacity. Before and after functionalization by grafting with 3-mercaptopropyltrimethoxysilane (MPTMS), the monoliths were characterized by several techniques, and their Hg(II) removal potential was evaluated in batch experiments at 28 °C and pH 3.5, using different initial concentrations of Hg(II) ions in water (200-500 mg L-1). The thiol groups of the monoliths calcined at 550 °C showed thermal stability up to 300 °C (from TG/DTG). The functionalized monolith synthesized with P123 polymer and polyethylene glycol showed favorable hierarchical macro-mesopores for Hg(II) adsorption. M(P123)-SH exhibited 97% removal of Hg(II) at concentration 200 mg L-1. Its maximum adsorption capacity (12.2 mmol g-1) was two times higher than that of M(F127)-SH, demonstrating that the 3D hierarchical macro-mesoporosity allowing accessibility of Hg(II) to thiol groups favors the physical and chemical adsorption of Hg(II) under slightly acidic conditions.

Antioxidant properties of hispidulin.

There are conflicting reports on the antioxidant activity of hispidulin. Antioxidant activity of hispidulin was evaluated using assays of ABTS• reduction, ferric ion reducing antioxidant power (FRAP) assay, DPPH reduction assay, and protection of erythrocyte membranes against lipid peroxidation and protein thiol oxidation. ABTS• reduction assay pointed to the involvement of all three phenol groups of hispidulin in ABTS• reduction. The reactivity of hispidulin in the FRAP assay and DPPH reduction assay was low (0.09 and 0.019 of the reactivity of Trolox). However, hispidulin was effective in protection against erythrocyte membrane lipid peroxidation and highly effective in protection against erythrocyte membrane protein thiol group oxidation (more effective than Trolox). These results point to the necessity of caution in extrapolating the antioxidant activity evaluated in simple cell-free systems on more complex systems.

Improvement of thiol groups and total antioxidant capacity in patients with non-alcoholic fatty liver after treatment with pioglitazone.

OBJECTIVE: The aim of the present study was to evaluate oxidative stress state in non-alcoholic fatty liver (NAFLD) patients at the time of diagnosis and by passing three months from the treatment. METHODS: 37 patients with NAFLD in summer 2019 were enrolled in this study. Also, 37 healthy controls that were matched for sex and age were included as a control group. Oxidative stress parameters such as lipid peroxidation (MDA), total antioxidant capacity (TAC), and Thiols were measured by standard methods and were then compared with before treatment. RESULTS: At the time of diagnosis, MDA levels were significantly increased and FRAP and Thiol levels were significantly decreased. After 3 months of treatment with pioglitazone, MDA levels decreased and FRAP and Thiol group increased. CONCLUSIONS: Non-alcoholic fatty liver disease is associated with the higher levels of MDA and lower serum levels of total antioxidant capacity and Thiol group levels.

Protocatechuic Acid, a Simple Plant Secondary Metabolite, Induced Apoptosis by Promoting Oxidative Stress through HO-1 Downregulation and p21 Upregulation in Colon Cancer Cells.

Gastrointestinal cancers, particularly colorectal cancer, are mainly influenced by the dietary factor. A diet rich in fruits and vegetables can help to reduce the incidence of colorectal cancer thanks to the phenolic compounds, which possess antimutagenic and anticarcinogenic properties. Polyphenols, alongside their well-known antioxidant properties, also show a pro-oxidative potential, which makes it possible to sensitize tumor cells to oxidative stress. HO-1 combined with antioxidant activity, when overexpressed in cancer cells, is involved in tumor progression, and its inhibition is considered a feasible therapeutic strategy in cancer treatment. In this study, the effects of protocatechuic acid (PCA) on the viability of colon cancer cells (CaCo-2), annexin V, LDH release, reactive oxygen species levels, total thiol content, HO-1, γ-glutamylcysteine synthetase, and p21 expression were evaluated. PCA induced, in a dose-dependent manner, a significantly reduced cell viability of CaCo-2 by oxidative/antioxidant imbalance. The phenolic acid induced modifications in levels of HO-1, non-proteic thiol groups, γ-glutamylcysteine synthetase, reactive oxygen species, and p21. PCA induced a pro-oxidant effect in cancer cells, and the in vitro pro-apoptotic effect on CaCo-2 cells is mediated by the modulation of redox balance and the inhibition of the HO-1 system that led to the activation of p21. Our results suggest that PCA may represent a useful tool in prevention and/or therapy of colon cancer.

Identification of a metallothionein gene and the role of biological thiols in stress induced by short-term Cd exposure in Ostrinia nubilalis.

Cadmium (Cd) is a non-essential metal that is highly toxic to all living forms, characterized by an extremely high affinity for thiol (SH) groups. The aim of this work was to identify and experimentally verify metallothionein gene and to analyze the role of biological thiols in stress induced by short-term Cd exposure in Ostrinia nubilalis, one of the most important corn pests. The coding region of a metallothionein (MT) gene in O. nubilalis was identified, encoding protein, OnMT1, which contains 46 amino acids, including 12 cysteine residues, and has no aromatic amino acids. Phylogenetic analysis revealed that OnMT1 clustered together with metallothionein from Bombyx mori. Structural bioinformatics analysis strongly suggests that OnMT1 is a metallothionein with affinity for multiple transition metals. Further, in order to elucidate the role of biological thiols, O. nubilalis L5 larvae were exposed to increasing Cd concentrations in diet (6.85, 41.71, 77.35 mg kg-1) during a 48 h period, after which Cd concentration in larvae was measured (3.50, 12.02, 47.37 mg kg-1, respectively). Due to short-term Cd exposure, concentration of free protein SH groups and relative expression of OnMT1 and thioredoxin (Trx) genes was elevated, while the reduced glutathione content remained unchanged. The presented results provide evidence that OnMT1 plays a role in Cd detoxification and homeostasis, and confirm the importance of biological thiols, especially OnMT1 and Trx, in the early response of O. nubilalis to Cd poisoning, indicating interaction between Cd and thiol-linked redox reactions. Insects provide valuable insight into molecular adaptations to metals.

Effects of Tl+ on the inner membrane thiol groups, respiration, and swelling in succinate-energized rat liver mitochondria were modified by thiol reagents.

The effects of both Tl+ and thiol reagents were studied on the content of the inner membrane free SH-groups, detected with Ellman reagent, and the inner membrane potential as well as swelling and respiration of succinate-energized rat liver mitochondria in medium containing TlNO3 and KNO3. These effects resulted in a rise in swelling and a decrease in the content, the potential, and mitochondrial respiration in 3 and 2,4-dinitrophenol-uncoupled states. A maximal effect was seen when phenylarsine oxide reacting with thiol groups recessed into the hydrophobic regions of the membrane. Compared with phenylarsine oxide, the effective concentrations of other reagents were approximately one order of magnitude higher in experiments with mersalyl and 4,4'-diisothiocyanostilbene-2,2'-disulfonate, and two orders of magnitude higher in experiments with tert-butyl hydroperoxide and diamide. The above effects of Tl+ and the thiol reagents became even more pronounced with calcium overload of mitochondria. However, the effects were suppressed by inhibitors of the mitochondrial permeability transition pore (cyclosporine A, ADP, and n-ethylmaleimide). These findings suggest that opening of the pore induced by Tl+ in the inner membrane can be dependent on the conformation state of the adenine nucleotide translocase, which depends on the activity of its thiol groups.

Dietary nutrients and their control of the redox bioenergetic networks as therapeutics in redox dysfunctions sustained pathologies.

Electrons exchange amongst the chemical species in an organism is a pivotal concomitant activity carried out by individual cells for basic cellular processes and continuously contribute towards the maintenance of bioenergetic networks plus physiological attributes like cell growth, phenotypic differences and nutritional adaptations. Humans exchange matter and energy via complex connections of metabolic pathways (redox reactions) amongst cells being a thermodynamically open system. Usually, these reactions are the real lifeline and driving forces of health and disease in the living entity. Many shreds of evidence support the secondary role of reactive species in the cellular process of control apoptosis and proliferation. Disrupted redox mechanisms are seen in malaises, like degenerative and metabolic disorders, cancerous cells. This review targets the importance of redox reactions in the body's normal functioning and the effects of its alterations in cells to obtain a better understanding. Understanding the redox dynamics in a pathological state can provide an opportunity for cure or diagnosis at the earlier stage and serve as an essential biomarker to predict in advance to give personalized therapy. Understanding redox metabolism can also highlight the use of naturally available antioxidant in the form of diet.