Redox State Research Articles

Enhancing growing rabbit heat stress resilience through dietary supplementation with natural antioxidants

Animal husbandry development is influenced by various factors, with heat stress (HS) being a significant factor. The aim of this experiment was to explore the potential of natural antioxidants such as vitamin C (VITC), vitamin E (VITE), lycopene (LYC), and allicin (AL) in enhancing growth, immune function and maintaining the redox status of fattening rabbits under HS. Male weaning rabbits (n = 150, 5 weeks of age) were randomly assigned to 5 groups. The rabbits were fed a basal diet (control group) or supplemented with 40 mg of vitamin E (VE40), 5 mg of vitamin C (VC5), 150 mg of lycopene (LYC150), or 150 mg of allicin (AL150) per kg of diet, respectively, under summer Egyptian conditions. The overall temperature humidity index (THI) value was 29.76, indicating severe HS during the experimental period. The findings indicated that all dietary supplemented groups showed significant improvements in live body weight at 8 weeks (P < 0.0001) and 11 weeks (P < 0.05) of age compared to the control group. The feed conversion ratio (FCR) was improved with all additives (P < 0.05), while feed intake and carcass traits were not affected by the treatments (P > 0.05). The AL group had the highest dressing percentage compared to the other groups (P < 0.05). Feeding stressed rabbits with antioxidant supplements resulted in a higher hemoglobin concentration compared to the control group (P < 0.05). Aspartate transaminase (AST), triglycerides, and creatinine levels were decreased with all additives as compared to the control group (P < 0.05). Total protein and albumin were significantly higher in AL group than in other groups (P < 0.05). The serum Immunoglobulin G (IgG) was significantly increased, while tumor necrosis factor alpha (TNF-α), interleukin-4 (IL-4), and interferon gamma (IFN-γ) were decreased by all feed additives (P < 0.05). Immunoglobulins (IgA and IgM) did not differ among all experimental groups (P > 0.05). Serum total antioxidant capacity (TAC) and glutathione (GSH) levels were higher in all supplement groups compared to the HS group (P < 0.05). All dietary supplements significantly reduced malondialdehyde (MDA) levels in liver tissues and blood serum compared to the control group (P < 0.05). Collectively, allicin emerged as a potent shield against heat stress, bettering lycopene and vitamins E and C in safeguarding the well-being of growing rabbits.

Altering the redox status of Chlamydia trachomatis directly impacts its developmental cycle progression.

Chlamydia trachomatis is an obligate intracellular bacterial pathogen with a unique developmental cycle. It differentiates between two functional and morphological forms: the elementary body (EB) and the reticulate body (RB). The signals that trigger differentiation from one form to the other are unknown. EBs and RBs have distinctive characteristics that distinguish them, including their size, infectivity, proteome, and transcriptome. Intriguingly, they also differ in their overall redox status as EBs are oxidized and RBs are reduced. We hypothesize that alterations in redox may serve as a trigger for secondary differentiation. To test this, we examined the function of the primary antioxidant enzyme alkyl hydroperoxide reductase subunit C (AhpC), a well-known member of the peroxiredoxins family, in chlamydial growth and development. Based on our hypothesis, we predicted that altering the expression of ahpC would modulate chlamydial redox status and trigger earlier or delayed secondary differentiation. Therefore, we created ahpC overexpression and knockdown strains. During ahpC knockdown, ROS levels were elevated, and the bacteria were sensitive to a broad set of peroxide stresses. Interestingly, we observed increased expression of EB-associated genes and concurrent higher production of EBs at an earlier time in the developmental cycle, indicating earlier secondary differentiation occurs under elevated oxidation conditions. In contrast, overexpression of AhpC created a resistant phenotype against oxidizing agents and delayed secondary differentiation. Together, these results indicate that redox potential is a critical factor in developmental cycle progression. For the first time, our study provides a mechanism of chlamydial secondary differentiation dependent on redox status.

Irisin-mediated KEAP1 degradation alleviates oxidative stress and ameliorates pancreatitis.

Oxidative stress (OS) injury is pivotal in acute pancreatitis (AP) pathogenesis, contributing to inflammatory cascades. Irisin, a ubiquitous cytokine, exhibits antioxidant properties. However, the role of irisin in AP remains inconclusive. Our study aims to elucidate irisin expression in AP patients and investigate its mechanism of action to propose a novel treatment strategy for AP. Serum irisin levels in 65 AP patients were quantified using an enzyme-linked immunosorbent assay and correlated with disease severity scores. Core genes implicated in AP-related oxidative stress were identified and screened via bioinformatics analysis. The therapeutic efficacy of irisin in AP was confirmed using a murine cerulein-induced AP model. The intrinsic mechanism of irisin's antioxidative stress action was investigated and verified in pancreatic AR42J cells (Supplementary Fig.1). Common targets shared by irisin and AP were further validated using a molecular docking model which was constructed for virtual docking analysis. This study investigated alterations in redox status in AP and found a significant reduction in serum irisin levels, correlating inversely with AP severity. In a murine AP model, we showed that irisin triggers an antioxidative stress program via the KEAP1 gene; this process helps reestablish redox balance by decreasing the buildup of reactive oxygen species (ROS) and suppressing the secretion of inflammatory mediators within pancreatic tissues Notably, increased KEAP1 expression counteracted the antioxidative effects of irisin. Our findings unveil a novel therapeutic mechanism for AP, wherein irisin inhibits KEAP1 to alleviate OS. Increasing irisin levels in vivo presents a promising strategy for AP treatment.

Biodegradable Vanadium-Based Nanomaterials for Photothermal-Enhanced Tumor Ferroptosis and Pyroptosis.

The designability and high reactivity of nanotechnology provide strategies for antitumor therapy by regulating the redox state in tumor cells. Here, we synthesize a kind of vanadium dioxide nanoparticle encapsulated in bovine serum albumin and containing disulfide bonds (VSB NPs) for photothermal-enhanced ferroptosis and pyroptosis effects. Mechanism studies show that disulfide bonds can effectively consume overexpressed glutathione (GSH) in the tumor microenvironment, leading to a decrease in glutathione peroxidase 4 (GPX4) activity. Simultaneously, tetravalent vanadium can induce a catalytic reaction of overexpressed H2O2, producing plenty of toxic hydroxyl radicals (·OH) and singlet oxygen (1O2), leading to tumor cell ferroptosis. In addition, the consumption of disulfide bonds can also lead to the degradation of nanoparticles into high-valent vanadates, activating thermal protein domain-associated protein 3 (NLRP3) inflammasomes and causing tumor cell pyroptosis. It is worth mentioning that VSB NPs can not only ablate tumor cells under near-infrared light irradiation but also further disrupt the redox homeostasis of the tumor microenvironment, thereby enhancing the ferroptosis and pyroptosis of tumor cells induced by biodegradable vanadium-based nanomaterials. This strategy, based on the biological effects of vanadium to regulate the redox state in tumor cells, provides possibilities for cancer treatment.

Something Is Rotten in the State of Redox

Something Is Rotten in the State of Redox

Resveratrol Anti-inflammatory Effect against Palmitate-induced Cytotoxicity in Raw 264.7 Macrophages.

Resveratrol (RES) is a phytochemical bioactive compound with suggested therapeutic benefits. The current work aimed to evaluate the anti-inflammatory effect of RES against palmitate (PA) induced lipotoxicity in raw 264.7 macrophages cell line. The cells viability was assessed by lactate dehydrogenase assay. Then the effects of RES and PA on nitric oxide (NO), triglyceride (TG) content, and cytokines release were studied. The effect of RES and PA on the treated cells bioenergetics and redox status was evaluated via different assays Results: The results showed that at doses of 10 and 20μM, RES dramatically increased the vitality of PA-exposed macrophages with dramatic significant decrease in the release the proinflammatory cytokines TNF-α, MHGB-1, IL-1β, and IL-6 and their coding genes expression with marked improvement in the cells phagocytic capacity. In addition, RES dramatically lowered the levels of NO and TG in PA-stimulated macrophages. In addition, PA markedly decreased mitochondrial complexes I and III activities with decreased mitochondrial membrane potential and lowered ATP production with induction of oxidative stress. RES was shown to mitigate the effect of PA on macrophages bioenergetics and the oxidative damage and counteracted PA effect on genes linked to oxidative damage, such as Nrf2, Ho-1, NF-κB p65, SOD1, and SOD2. RES could reduce PA-induced lipotoxicity in macrophages via enhancing their viability and counteracting the excess release of cytokines through alleviating PAinduced bioenergetic disruption and oxidative damage with a suggested positive impact of RES on obesity related illnesses caused by triggered cellular inflammation.

A shallow-water oxygen minimum zone in an oligotrophic Tonian basin

The Tonian Period (1000–720 Ma) bore witness to the transition from a prokaryote-dominated marine ecosystem to one characterized by the proliferation of eukaryotes. This fundamental shift has generally been attributed to evolving marine redox states. Here, we present sedimentological and geochemical analyses of the early Tonian Huainan, Feishui, and Huaibei groups in the Xuhuai basin of the North China craton. Multiple redox proxies show consistent, water depth-dependent variations across the Xuhuai basin. Excess barium contents and Ba/Al ratios further highlight spatial variations in primary productivity which ultimately regulate basinal redox structures. We propose that a shallow-water oxygen minimum zone sandwiched between the oxic/suboxic mid-depth and surface layer water masses occur in the oligotrophic Xuhuai basin, which is analogous to, but much shallower than modern oxygen minimum zones. Such marine redox architectures may benefit the maintenance of a bioavailable nitrate reservoir in the ocean, foreboding the subsequent expansion of eukaryotes.

Biodegradable and Stimuli-Responsive Nanomaterials for Targeted Drug Delivery in Autoimmune Diseases

Autoimmune diseases present complex therapeutic challenges due to their chronic nature, systemic impact, and requirement for precise immunomodulation to avoid adverse side effects. Recent advancements in biodegradable and stimuli-responsive nanomaterials have opened new avenues for targeted drug delivery systems capable of addressing these challenges. This review provides a comprehensive analysis of state-of-the-art biodegradable nanocarriers such as polymeric nanoparticles, liposomes, and hydrogels engineered for targeted delivery in autoimmune therapies. These nanomaterials are designed to degrade safely in the body while releasing therapeutic agents in response to specific stimuli, including pH, temperature, redox conditions, and enzymatic activity. By achieving localized and controlled release of anti-inflammatory and immunosuppressive agents, these systems minimize systemic toxicity and enhance therapeutic efficacy. We discuss the underlying mechanisms of stimuli-responsive nanomaterials, recent applications in treating diseases such as rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease, and the design considerations essential for clinical translation. Additionally, we address current challenges, including biocompatibility, scalability, and regulatory hurdles, as well as future directions for integrating advanced nanotechnology with personalized medicine in autoimmune treatment. This review highlights the transformative potential of biodegradable and stimuli-responsive nanomaterials, presenting them as a promising strategy to advance precision medicine and improve patient outcomes in autoimmune disease management.

Source Rock Characteristics and Petroleum‐Geological Significance of Paleogene Niubao Formation in the Nima Basin, Central Tibet, China

ABSTRACTNima Basin, as a typical Tethys area, is a Cenozoic oil‐bearing basin in the middle of Qinghai‐Tibet Plateau, which is expected to become an important target for petroleum exploration. The main controlling factors and models of organic matter enrichment are not yet clear. To identify the organic geochemical characteristics of high‐quality source rocks and the main controlling factors of their formation, this study analyzes the paleoclimate and paleo‐salinity indexes based on the analysis of the major and trace elements through systematic sampling of the muddy sediments of Niubao Formation in Well Shuangdi 1, Cebuco Depression. The results show that the organic matter of the E1‐2n source rocks in Nima Basin is differentially enriched, which shows that the organic matter of the middle E1‐2n source rocks is more enriched than that of the upper E1‐2n source rocks. Hydrocarbon source rocks of the middle E1‐2n are mainly of type I organic matter, while those of the upper E1‐2n are mainly of type Ⅱ1 organic matter, both of which are in the mature stage. Organic matter enrichment is primarily governed by a combination of climate and redox conditions, with humid climate and reducing environments emerging as the dominant factors, whereas salinity exerts a lesser influence. On the one hand, this study can supplement the accumulation mechanism of organic matter in the Tethys domain in Asia; on the other hand, it will fill the gap in the geological research of Nima Basin, contributing to the prediction and exploration of oil and gas resources in the Nima Basin.

Searching for nitroxyl modulators in Arabidopsis thaliana - a new paradigm of redox signaling in plant.

Through extensive research, nitroxyl (HNO) has emerged as a newly recognized redox signal in plant developmental and stress responses. The interplay between nitric oxide (●NO) and HNO entails a complex network of signaling molecules and regulatory elements sensitive to the environment's specific redox conditions. However, functional implications for HNO in cell signaling require more detailed studies, starting with identifying HNO-level switches. To obtain insight into possible physiologically relevant HNO modulators, we examined via real-time detection the HNO/●NO production triggered by selected plant-related compounds (PRCs), including non-protein amino acids, antioxidants, and phytohormones both in vitro and in vivo in the model plant Arabidopsis thaliana. Hydrogen sulfide, ascorbic acid, and salicylic acid were identified as superior PRCs in driving HNO/●NO interconversion in the cellular medium so that these PRCs could provide ubiquitous bioavailability of HNO in plants. Meanwhile, resistance-inducing compounds tended to downregulate HNO in Arabidopsis leaves. The present study indicates that non-enzymatic HNO/●NO interconversion mediated by functionally important PRCs constitutes a significant route for controlling endogenous HNO levels, providing ubiquitous HNO bioavailability in plant cells. Moreover, concurrent HNO/●NO monitoring shows that the redox signals are highly integrated and create a redox code that can be translated into a specific cell response.

Humic acid from vermicompost effectively regulates the redox status and mitigates the progression of experimental periodontitis.

The progression of periodontal disease (PD) involves the action of oxidative stress mediators. Antioxidant agents may potentially attenuate the development of this condition. Thus, we aimed to evaluate the effects of different doses of humic acid (HA), extracted from biomass vermicomposting, on redox status and parameters related to PD progression in rats. Fifty-four adult male Wistar rats were distributed into six experimental groups (control; PD; PD + 40mg/kg of HA; PD + 80mg/kg of HA; PD + 160mg/kg of HA; PD + 320mg/kg of HA). HA was administered by gavage for 28days, and PD was induced by ligature on the mandibular first molars on the 14th day of treatment. After euthanasia, alveolar bone loss, oxidative stress in the gum and erythrocytes, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine were analyzed. Animals treated with HA showed less bone loss at the dose of 80mg/kg compared to the untreated PD group (p < 0.05). Animals treated with HA at doses higher than 80mg/kg showed improvements in local and systemic redox status parameters (total antioxidant activity, thiobarbituric reactive substances, carbonyl derivatives, and superoxide dismutase) compared to the PD group (p < 0.05). Treatment with HA reduced serum levels of creatinine (at doses of 80 and 160mg/kg) and AST (at doses of 40 and 80mg/kg) compared to the PD group (p < 0.05). HA treatment attenuated alveolar bone loss and improved local and systemic oxidative stress parameters in ligature-induced PD rats.

Pomegranate juice ameliorates craving and oxidative stress on patients under medication for opioid addiction treatment with methadone and buprenorphine: A ranzomised controlled trial.

Buprenorphine and methadone are drugs used as medication for addiction treatment for patients with opioid use disorders (OUDs). However, scarce evidence indicates that they induce oxidative stress, which contributes to the deterioration of psychosocial parameters, thus complicating successful rehab. Therefore, a dietary antioxidant intervention such as pomegranate could be beneficial for that group of patients. Therefore, the aim of this study, whose protocol has been registered in the international database ClinicalTrials.gov (Identifier: NCT05861544), was to examine the putative beneficial role of consumption of natural pomegranate juice that possesses potent antioxidant properties on craving, a psychosocial parameter of utmost importance, and blood redox status of patients with OUDs. The juice was administered at the following dosage: 250ml/day, 7 days/week, 120 days. The heroine craving questionnaire was completed to assess craving and blood was collected by the volunteers at three time points, namely days 1, 60 and 120 and well-established redox biomarkers were measured in blood. Overall, craving of all patients was improved due to the nutritional treatment applied. Moreover, their blood antioxidant potential was enhanced due to pomegranate juice consumption. As a conclusion, the obtained evidence is promising, thus, it appears that pomegranate juice consumption could be considered as an auxiliary nutritional intervention in parallel with medication towards rehab of opioid-addicted patients.

Nrf2 mediates mitochondrial and NADPH oxidase-derived ROS during mild heat stress at 40 °C.

Hyperthermia is an adjuvant to chemotherapy and radiotherapy and sensitizes tumors to these treatments. However, repeated heat treatments result in acquisition of heat resistance (thermotolerance) in tumors. Thermotolerance is an adaptive survival response that appears to be mediated by upregulated cellular defenses. However, the mechanisms of activation remain unclear. When HeLa cells were exposed to mild heat shock at 40 °C for 3 h, levels of superoxide and peroxides increased. Cells were treated with mitochondrial antioxidant MitoQ and NADPH oxidase (NOX) inhibitor apocynin to characterize the contribution of these two sources to the total reactive oxygen species (ROS) pool. We found that both mitochondria and NOX are sources of ROS during mild heat shock at 40 °C. Heat-derived ROS are thought to activate the adaptive survival response at 40 °C. Nrf2, the master regulator of the cellular antioxidant response, is thought to play a pivotal role in establishing the adaptive survival response. Nrf2 was overexpressed or knocked down to assess its role. Moreover, Nrf2 levels correlate with the cellular redox state, and do so via scavenging of mitochondria- and NOX-derived ROS. Knockdown of Nrf2 markedly increased levels of ROS that were scavenged by either apocynin or MitoQ. Finally, critical defense proteins such as DJ-1 and PGAM5 seemed to require a two-key activation system mediated by Nrf2 and mitochondrial ROS. Our study characterized mitochondrial and NOX-derived ROS as being essential in activating cellular defenses alongside Nrf2 and underlines potential therapeutic targets that may contribute to the acquisition of thermotolerance.

Effect of ketosis induced by on delayed-onset muscle soreness, inflammation and redox status: a randomized, open-label, crossover pilot study.

Previous studies show that ketosis caused by the consumption of low-carbohydrate diets improves cognitive functions and that ketogenic diets can be used to treat epilepsy. In vivo and in vitro experiments have shown that ketosis regulates pain, inflammation, and oxidative stress. Thus, we investigated the effects of ketosis induced by a low-carbohydrate diet on muscle soreness, inflammation, and redox status in human subjects. The research method was an open-label, crossover, pilot study. The study included eight men with no exercise habits associated with muscle soreness and consumed a low-carbohydrate and a normal diet for 6 days. Each dietary intake was for 3 days, and the participants performed the isotonic exercise on the fourth day. Before and after the exercise (immediately after, 24 h later, and 48 h later), the subjective value of muscle soreness, interleukin-6 level, tumor necrosis factor-alpha level, total ketone bodies, and redox status biomarkers were measured. The results revealed that the low-carbohydrate-diet group showed no significant difference in the subjective value of muscle soreness, whereas the normal diet group showed a significant increase in the subjective muscle soreness scale after 24 h. There were no significant changes in biomarkers of inflammation and redox status in either group. This result suggests that ketosis caused by consuming a low-carbohydrate diet suppresses delayed-onset muscle soreness. However, the ketosis state did not suppress inflammation or oxidative stress markers.

Angiotensin type 1 and type 2 receptors-induced mitochondrial dysfunction promotes ferroptosis in cardiomyocytes.

Previous studies suggest that ferroptosis is involved in cardiovascular diseases. The aim of the present study is to investigate the causal relationship between angiotensin II type 1 and type 2 receptors (AT1/2R) activities and mitochondrial dysfunction in induction of cardiomyocyte ferroptosis. Human AC16 cardiomyocytes were first pre-treated with an AT1/2R blockers, before stimulated with angiotensin II (Ang II) for 24 h. The redox status of the cardiomyocytes were assessed by measuring the cellular malondialdehyde (MDA), superoxide dismutase (SOD), and Nicotinamide-adenine dinucleotide phosphate, (NADPH) levels using biochemical methods. Mitochondrial reactive oxygen specifics (mitROS), mitochondrial memebrane potential, and Fe2+ levels were determined using flow cytometry. The signaling pathways, including the glutathione peroxidase 4 (GPX4), heme oxygenase-1 (HO-1), sirtuin1, and ferroptosis suppressor protein 1 (FSP1)-coenzyme Q10 (CoQ10) pathways, were evaluated using western blotting. Our results demonstrated that Ang II significantly elevated the levels of MDA, Fe2+, mitoROS, and FtMt and markedly reduced SOD, NADPH, mitochondrial membrane potential, GPX4, HO-1, Sirt1, SFXN1, Nrf2, and FSP1 levels in cardiomyocyte, which were reversed by blockade of AT1/2R. Our results suggest that AT1/2R signaling can induce myocardial ferroptosis by impairing mitochondrial function via multiple signaling pathways, including the cyst (e)ine /GSH/GPX4 axis and FSP1/coenzyme Q10 (CoQ10) axis.

Oral amoxicillin treatment disrupts the gut microbiome and metabolome without interfering with luminal redox potential in the intestine of Wistar Han rats.

Oral antibiotic treatment is well known to be one of the main factors affecting gut microbiota composition by altering bacterial diversity. It decreases the abundance of butyrate-producing bacteria such as Lachnospiraceae and Ruminococcaceae, while increasing abundance of Enterobacteriaceae. The recovery time of commensal bacteria post-antibiotic treatment varies among individuals, and often, complete recovery is not achieved. Recently, gut microbiota disruption has been associated with increased gut oxygen levels and higher redox potential in faecal samples. Given that redox balance is crucial for microbial metabolism and gut health, influencing fermentation processes and maintaining anaerobic conditions, we investigated the impact of oral amoxicillin treatment on the redox potential in the caecum. We used 24 Wistar Han male rats and measured caecal redox potential in situ with a probe, before and after 7 days of amoxicillin treatment, as well as after 7 days of recovery. Additionally, we analysed caecal weight, pH, antioxidant capacity, caecal microbiota, metabolome, and colonic tissue expression of relevant genes involved in the redox potential state. Our findings show that oral amoxicillin treatment significantly reduced archaeal load, and decreased the bacterial alpha diversity and affected bacterial composition of the caecal microbiome. The caecal metabolome was also significantly affected, exemplified by reduced amounts of short chain fatty acids during amoxicillin treatment. While the caecal metabolome fully recovered seven days post amoxicillin treatment, the microbiome did not fully recover within this time frame. However, amoxicillin did not lead to an increase in luminal redox potential in the cecum during or post amoxicillin treatment. Limited differences were observed for colonic expression of genes involved in intestinal barrier function and generation of reactive oxygen species, except for the catalase gene, which was significantly upregulated post-amoxicillin treatment. Our results suggest that while oral amoxicillin disrupts the gut microbiome and metabolome, it does not directly interfere with gut luminal redox state.

Metabolic stimulation improves bioenergetics and haematologic indices of circulating erythrocytes from sickle cell mice.

Circulating mature red blood cells (RBCs) from patients and mice with sickle cell disease (SCD) abnormally retain mitochondria, a factor shown to contribute to the disease's pathobiology. To further understand the functional implications of RBC mitochondria retention in SCD, we used mitochondria inhibitors and metabolites/substrates from the tricarboxylic acid cycle, oxidative phosphorylation and glycolysis pathways (ADP, glutamate, malate, pyruvate, succinate or all metabolites combined) and examined RBC bioenergetics, reactive oxygen species (ROS) levels, calcium flux and hydration. In RBCs from sickle mice, mitochondria inhibition reduced ATP levels by 30%-60%, whereas control RBCs were unaffected. Conversely, in vitro treatment with metabolites/substrates known to stimulate mitochondria function increased RBC ATP levels and reduced RBC ROS, and these effects were notably more pronounced in sickle RBCs compared to those in control mice. In sickle RBCs, the increases in ATP and decreases in ROS were associated with greater decreases in RBC baseline calcium concentration and improvements in calcium flux. These changes also led to greater increases in RBC volume and hydration, and greater decreases in mean corpuscular haemoglobin concentration in sickle RBCs compared to control RBCs. These results propose a novel model of RBC metabolism in SCD, where retained mitochondria in circulating RBCs are functional and can significantly impact RBC bioenergetics, ATP production and RBC hydration and redox status. These in vitro findings could inform the development of in vivo strategies aimed at increasing RBC ATP, reducing RBC ROS, improving RBC hydration, which could decrease sickling and prove beneficial in SCD. KEY POINTS: Red blood cells (RBCs) from humans and mice with sickle cell disease (SCD) abnormally retain mitochondria. Mitochondria inhibitors lower ATP in circulating RBCs from sickle mice indicating that retained mitochondria contribute to ATP levels in sickle RBC. Metabolic stimulation of mitochondria function improves RBC bioenergetics, redox state and calcium flux, and increases RBC hydration. These data propose a new model of RBC metabolism in SCD, where in addition to glycolysis, retained mitochondria contribute to RBC ATP production. The effects of metabolic stimulation of RBCs resulting in improved RBC bioenergetics and hydration may prove beneficial in SCD.

Additive CHARMM Force Field for Pterins and Folates.

Folates comprise a crucial class of biologically active compounds related to folic acid, playing a vital role in numerous enzymatic reactions. One-carbon metabolism, facilitated by the folate cofactor, supports numerous physiological processes, including biosynthesis, amino acid homeostasis, epigenetic maintenance, and redox defense. Folates share a common pterin heterocyclic ring structure capable of undergoing redox reactions and existing in various protonation states. This study aimed to derive molecular mechanics (MM) parameters compatible with the CHARMM36 all-atom additive force field for pterins and biologically important folates, including pterin, biopterin, and folic acid. Three redox forms were considered: oxidized, dihydrofolate, and tetrahydrofolate states. Across all protonation states, a total of 18 folates were parameterized. Partial charges were derived using the CHARMM force field parametrization protocol, based on targeting reference quantum mechanics monohydrate interactions, electrostatic potential, and dipole moment. Bonded terms were parameterized using one-dimensional adiabatic potential energy surface scans, and two-dimensional scans to parametrize in-ring torsions associated with the puckering states of dihydropterin and tetrahydropterin. The quality of the model was demonstrated through simulations of three protein complexes using optimized and initial parameters. These simulations underscored the significantly enhanced performance of the folate model developed in this study compared to the initial model without optimization in reproducing structural properties of folate-protein complexes. Overall, the presented MM model will be valuable for modeling folates in various redox states and serve as a starting point for parameterizing other folate derivatives.

The Effect of a Secondary Stressor on the Morphology and Membrane Structure of an Already Challenged Maternal and Foetal Red Blood Cell Population.

The red blood cell (RBC) membrane is unique and crucial for maintaining structural-functional relationships. Maternal smoking induces significant changes in the morphological, rheological, and functional parameters of both maternal and foetal RBCs, mainly due to the continuous generation of the free radicals. The major aim of this study was to follow the consequences of a secondary stressor, like fungal infection, on the already compromised RBC populations. The impact of Candida infection, a growing health concern, was investigated on four blood sample groups: mothers and their neonates originating from non-smoking versus smoking populations. Here, we searched for phenotypical and molecular markers that precisely reflected the effect of Candida infection on the RBC membrane; this included the level of hemolysis, appearance of morphological variants, formation of the lipid peroxidation marker 4-hydroxyl-nonenal, arrangement of the Band 3 molecules and activation of the Caspase 3. In most of the examined cases, the fungal infection increased the adverse symptoms induced by smoking, indicating a general stress response, likely due to an altered redox state of the cells. However, we were able to identify an atypical phenotype (clustered populations with shrinkage and membrane blebbing) in both the non-smoking and smoking populations, which might be a unique marker for Candida spp. infection.

Impact of galectin-1's redox state on its lectin activity and monomer-dimer equilibrium. Focusing on oxidized Gal-1.

Galectin-1 (Gal-1) displays unique sensitivity to oxidative inactivation which appears critical in regulating its spatial and temporal activity. The two physicochemical states, i.e. monomer-dimer equilibrium and redox states, are related to Gal-1 varying functionality. In this work, we used chronopotentiometric stripping analysis, intrinsic fluorescence spectroscopy, and mobility shift assay to follow changes in the structure and lectin activity of reduced and oxidized Gal-1 forms. Our results show that monomers and dimers are similarly distributed under mild reduction and oxidation conditions. Gal-1 after its oxidation consists of at least three different monomeric forms while reduced Gal-1 only one. Lectin activity, affinity to N-acetyllactosamine, is relatively similar for low Gal-1 concentrations for both, reduced and oxidized Gal-1. However, at higher Gal-1 concentrations, we observed a ten times higher affinity for reduced than oxidized form. Further, our data indicate that the monoclonal antibodies bind preferentially to Gal-1 dimers and specifically to only some forms of its oxidized form.