Neutralization Of Reactive Oxygen Species Research Articles

Synthetic modulation of ROS scavenging during host—Sclerotinia sclerotiorum interaction: a new strategy for the development of highly resistant plants

Sclerotinia sclerotiorum is a widespread fungal pathogen responsible for significant crop losses across the globe. The challenge of breeding resistant varieties is exacerbated by the fungus's sophisticated pathogenic mechanisms. A pivotal factor in the host-pathogen interaction is the regulation of reactive oxygen species (ROS) within both the fungi and the host plants. However, there is currently no efficient strategy to leverage this interaction mechanism for developing disease-resistant crop varieties. Here, we introduce an engineered ROS scavenging system designated as syn-ROS for impairing ROS neutralization in S. sclerotiorum while concurrently fortifying it in the host. The syn-ROS system comprises gene silencing constructs targeting the S. sclerotiorum Cu/Zn superoxide dismutase (SsSOD) and its copper chaperone (SsCCS), alongside overexpression constructs for the Arabidopsis thaliana AtSOD1 and AtCCS. Transgenic plants carrying the syn-ROS system demonstrated a marked enhancement in resistance to S. sclerotiorum. Upon infection, the expression of SsSOD and SsCCS was reduced, while the expression of AtSOD1 and AtCCS was enhanced in syn-ROS transgenic plants. Moreover, the infected syn-ROS plants showed decreased Cu/Zn SOD enzyme activity and elevated ROS concentrations within the fungal cells. In contrast, the cells of A. thaliana manifested increased Cu/Zn SOD enzyme activity and lowered ROS levels. Collectively, these findings suggest a novel and promising approach for contriving plants with robust resistance by synthetically manipulating ROS scavenging activities in the interaction between the host and S. sclerotiorum.

Antioxidants of Non-Enzymatic Nature: Their Function in Higher Plant Cells and the Ways of Boosting Their Biosynthesis.

Plants are exposed to a variety of abiotic and biotic stresses leading to increased formation of reactive oxygen species (ROS) in plant cells. ROS are capable of oxidizing proteins, pigments, lipids, nucleic acids, and other cell molecules, disrupting their functional activity. During the process of evolution, numerous antioxidant systems were formed in plants, including antioxidant enzymes and low molecular weight non-enzymatic antioxidants. Antioxidant systems perform neutralization of ROS and therefore prevent oxidative damage of cell components. In the present review, we focus on the biosynthesis of non-enzymatic antioxidants in higher plants cells such as ascorbic acid (vitamin C), glutathione, flavonoids, isoprenoids, carotenoids, tocopherol (vitamin E), ubiquinone, and plastoquinone. Their functioning and their reactivity with respect to individual ROS will be described. This review is also devoted to the modern genetic engineering methods, which are widely used to change the quantitative and qualitative content of the non-enzymatic antioxidants in cultivated plants. These methods allow various plant lines with given properties to be obtained in a rather short time. The most successful approaches for plant transgenesis and plant genome editing for the enhancement of biosynthesis and the content of these antioxidants are discussed.

Phytochemical screening, Antiradical and Anti-inflammatory activity of aqueous bark extract acquired from Acacia nilotica

Herbal medicaments are applied in the healing for numerous human illnesses from the sprouting of human civilization. The chemicals existed naturally within the plants displays antiradical features which are the principal agent for the neutralization of reactive oxygen species created within the living entities. Acacia nilotica from the Fabaceae family is a tree with magnificent therapeutic properties. Various sections of this tree are implemented in the traditional healing system. Specifically, the bark are applied to treat numerous health complaints. Here, owned to the medicinal features of bark of A.nilotica in the traditional practices, we prepared the aqueous bark extract from this tree and evaluated the antioxidant (antiradical) and anti-inflammatory activities. Hydroxyl radical scavenging protocol presented dose-based upsurge in the radical inhibition activity of the bark extract with maximum activity at 60 µg/ml and the IC50 value appeared as 43.35µg/ml. ABTS radical scavenging assay executed also displayed dose-lineated upsurge in the radical scavenging property of the tested bark extract with IC50 value as 41.07µg/ml. In both the radical scavenging assays, vitamin C was implemented for reference purpose. Even, the anti-inflammatory nature of the aqueous bark extract was performed applying egg albumin denaturation inhibition protocol. In a dose-lined way, the bark extract presented anti-inflammatory activity with an IC50 calculated value as 73.62µg/ml with diclofenac sodium as reference medicament. Additionally, the phytochemical qualitative scrutiny presented the existence of steroids, saponins, terpenoids, alkaloids, tannins, anthraquinones, carbohydrates, phenols and flavonoids which were chiefly responsible for the pharmacological activities of bark aqueous extract.

NRF2 is essential for adaptative browning of white adipocytes

White adipose tissue browning, defined by accelerated mitochondrial metabolism and biogenesis, is considered a promising mean to treat or prevent obesity-associated metabolic disturbances. We hypothesize that redox stress acutely leads to increased production of reactive oxygen species (ROS), which activate electrophile sensor nuclear factor erythroid 2-Related Factor 2 (NRF2) that over time results in an adaptive adipose tissue browning process. To test this, we have exploited adipocyte-specific NRF2 knockout mice and cultured adipocytes and analyzed time- and dose-dependent effect of NAC and lactate treatment on antioxidant expression and browning-like processes.We found that short-term antioxidant treatment with N-acetylcysteine (NAC) induced reductive stress as evident from increased intracellular NADH levels, increased ROS-production, reduced oxygen consumption rate (OCR), and increased NRF2 levels in white adipocytes. In contrast, and in line with our hypothesis, longer-term NAC treatment led to a NRF2-dependent browning response. Lactate treatment elicited similar effects as NAC, and mechanistically, these NRF2-dependent adipocyte browning responses in vitro were mediated by increased heme oxygenase-1 (HMOX1) activity. Moreover, this NRF2-HMOX1 axis was also important for β3-adrenergic receptor activation-induced adipose tissue browning in vivo.In conclusion, our findings show that administration of exogenous antioxidants can affect biological function not solely through ROS neutralization, but also through reductive stress. We also demonstrate that NRF2 is essential for white adipose tissue browning processes.

Recent Advances in Polyoxometalate Based Nanoplatforms Mediated Reactive Oxygen Species Cancer Therapy.

The potential of reactive oxygen species (ROS) cancer therapy in tumor treatment has been greatly enhanced by the introduction of catalytically superior polyoxometalate (POM)-based nanoplatforms, mainly composed of atomic clusters consisting of pre-transition metals and oxygen. These nanoplatforms have unique advantages, such as Fenton activity at neutral pH, induction of cellular ferroptosis instead of just apoptosis, and sensitivity to external field stimulation. However, there are also inevitable challenges such as neutralization of ROS by the antioxidant system of the tumor microenvironment (TME), hypoxia, and limited hydrogen peroxide concentrations. This review article aims to provide an overview of recent research advancements in POM-based nanoplatforms for ROS therapy from the perspective of chemical reactions and biological processes, addressing endogenous and exogenous factors that affect the antitumor efficacy. Endogenous factors include the mechanism of ROS generation by POM, the impact of pH and antioxidant systems on POM, and the various manners of tumor cell death. Exogenous stimuli mainly include light, heat, X-rays, and electricity. The article analyzes the specific mechanisms of action of each influencing factor in the first two sections, concluding with the limitations of the present study and some possible directions for future research.

Monocarboxylate Transporter-1 (MCT1)-Mediated Lactate Uptake Protects Pancreatic Adenocarcinoma Cells from Oxidative Stress during Glutamine Scarcity Thereby Promoting Resistance against Inhibitors of Glutamine Metabolism.

Metabolic compartmentalization of stroma-rich tumors, like pancreatic ductal adenocarcinoma (PDAC), greatly contributes to malignancy. This involves cancer cells importing lactate from the microenvironment (reverse Warburg cells) through monocarboxylate transporter-1 (MCT1) along with substantial phenotype alterations. Here, we report that the reverse Warburg phenotype of PDAC cells compensated for the shortage of glutamine as an essential metabolite for redox homeostasis. Thus, oxidative stress caused by glutamine depletion led to an Nrf2-dependent induction of MCT1 expression in pancreatic T3M4 and A818-6 cells. Moreover, greater MCT1 expression was detected in glutamine-scarce regions within tumor tissues from PDAC patients. MCT1-driven lactate uptake supported the neutralization of reactive oxygen species excessively produced under glutamine shortage and the resulting drop in glutathione levels that were restored by the imported lactate. Consequently, PDAC cells showed greater survival and growth under glutamine depletion when utilizing lactate through MCT1. Likewise, the glutamine uptake inhibitor V9302 and glutaminase-1 inhibitor CB839 induced oxidative stress in PDAC cells, along with cell death and cell cycle arrest that were again compensated by MCT1 upregulation and forced lactate uptake. Our findings show a novel mechanism by which PDAC cells adapt their metabolism to glutamine scarcity and by which they develop resistance against anticancer treatments based on glutamine uptake/metabolism inhibition.

Transcriptome Analysis of Redox Systems and Polyamine Metabolic Pathway in Hepatoma and Non-Tumor Hepatocyte-like Cells.

Reactive oxygen species (ROS) play a major role in the regulation of various processes in the cell. The increase in their production is a factor contributing to the development of numerous pathologies, including inflammation, fibrosis, and cancer. Accordingly, the study of ROS production and neutralization, as well as redox-dependent processes and the post-translational modifications of proteins, is warranted. Here, we present a transcriptomic analysis of the gene expression of various redox systems and related metabolic processes, such as polyamine and proline metabolism and the urea cycle in Huh7.5 hepatoma cells and the HepaRG liver progenitor cell line, that are widely used in hepatitis research. In addition, changes in response to the activation of polyamine catabolism that contribute to oxidative stress were studied. In particular, differences in the gene expression of various ROS-producing and ROS-neutralizing proteins, the enzymes of polyamine metabolisms and proline and urea cycles, as well as calcium ion transporters between cell lines, are shown. The data obtained are important for understanding the redox biology of viral hepatitis and elucidating the influence of the laboratory models used.

Impact of hypoxia conditions on the Mnemiopsis leidyi A. Agassiz, 1865 bioluminescence.

The findings of the study on the impact of hypoxia on the glow of the Black Sea ctenophore Mnemiopsis leidyi A. Agassiz, 1865 of three size groups (20-30, 30-45, and 45-60 mm) were obtained under experimental conditions. Peculiarities of ctenophore bioluminescence were studied during mechanical and chemical stimulation under the conditions of normoxia (at an oxygen concentration of 5.6-6.7 mg O2 ·L-1 ), moderate hypoxia (2.5-2.8 mg O2 ·L-1 ), and acute hypoxia (1.2-1.5 mg O2 ·L-1 ). An increase in the amplitude and energy of luminescence of the ctenophores mechanically and chemically stimulated was observed at an oxygen concentration of 1.2-1.5 mg O2 ·L-1 (acute hypoxia) in two size groups in the lobate form (30-45 and 45-60 mm). The inhibition of amplitude, energy, and duration of the signal was registered in M. leidyi ctenophores at the transitional stage from larva to the lobate form under conditions of acute hypoxia. It was noted that in normoxia, the values of the amplitude and energy of the bioluminescent signal of M. leidyi increase along with a size growth of an individual. This phenomenon was observed both during mechanical and chemical stimulations. Under conditions of acute hypoxia, this trend was mainly preserved. The universality of the relation between the bioluminescence of the organisms and their bioenergetics is obvious. The bioluminescent system of ctenophores has the role of an antioxidant system and is engaged in the neutralization of reactive oxygen species, that is the process during which photons are emitted. The response of the bioluminescent system to a decrease in О2 concentration can be associated with an increase in the production of ROS that provides high values of the ctenophore luminescence under hypoxic conditions.

The effect of antioxidants on increased oocyte competence in IVM: a review

In vitro maturation (IVM) is considered a potential assisted reproductive technology that is a safer and simpler alternative to conventional in vitro fertilization. It is primarily used in patients with impaired oocyte maturation and for the treatment of infertile women who are at risk of fertility loss. In addition, IVM is currently used mainly in polycystic ovarian syndrome patients with a high ovarian response and is still considered an experimental option in fertility preservation. Producing highly competent oocytes during IVM is considered a key step in the success of in vitro production (IVP) of embryos. Some factors, such as culture medium conditions and other supplements, have a significant impact on oocyte IVM performance. One of the known disruptors of oocyte developmental competence in IVP is oxidative stress (OS), which is caused by an imbalance between the production and neutralization of reactive oxygen species (ROS). In vitro conditions induce supraphysiological ROS levels due to exposure to an oxidative environment and the isolation of the oocyte from the follicle protective antioxidant milieu. Given the importance of OS in oocyte competence, the establishment of standardized antioxidant IVM systems is critical for improving the overall success of IVP. This review focuses on the main antioxidants tested to protect oocytes against OS in IVM.

Near Infrared-Activatable Methylene Blue Polypeptide Codelivery of the NO Prodrug via π-π Stacking for Cascade Reactive Oxygen Species Amplification-Mediated Photodynamic Therapy.

The application of photodynamic therapy (PDT) has attracted remarkable interest in cancer treatment because of the advantages of noninvasiveness and spatiotemporal selectivity. However, the PDT efficiency is considerably limited by photosensitizer (PS) quenching and severe hypoxia in solid tumors. Herein, a kind of near infrared (NIR)-activatable methylene blue (MB) peptide nanocarrier was developed for codelivery of nitric oxide (NO) prodrug JSK, expecting a cascade of reactive oxygen species (ROS) amplification-mediated antitumor PDT. In detail, MB was conjugated to water-soluble polyethylene glycol-polylysine (PEG-PLL) through NIR-photocleavable 10-N-carbamoyl bonds, and the subsequent amphiphilic conjugates (mPEG-PLL-MB) self-assembled into nanoparticles (NPs), which allowed JSK codelivery via π-π stacking interactions. MB in quenched state in mPEG-PLL-MB/JSK NPs could be photoactivated by NIR light locoregionally in a controlled manner due to the photocleavage of carbamoyl bonds. Apart from ROS production, assembly disturbance and even disintegration of mPEG-PLL-MB/JSK occurred along with MB activation that subsequently freed JSK, which was further triggered by intracellularly overexpressed glutathione (GSH) and glutathione S-transferase (GST) to sustain the release of NO. NO then served as a hypoxia relief agent through inhibition of cellular respiration to economize O2, cooperating with MB activation and GSH depletion, which synergistically enabled a cascade of ROS amplification to augment PDT for mitochondrial apoptosis-mediated tumor inhibition in vitro and in vivo. Therefore, this pioneering strategy of cascade amplification of ROS addressed the key issues of PS inactivation, hypoxia resistance, and ROS neutralization in a three-pronged approach, which hold great promise in efficient antitumor PDT.

Melamine Barbiturate as a Light-Induced Nanostructured Supramolecular Material for a Bioinspired Oxygen and Organic Radical Trap and Stabilization.

Use of coantioxidant systems is a prospective way to increase the effectiveness of antioxidant species in tissue repair and regeneration. In this paper, we introduce a novel scheme of a reactive oxygen species (ROS) trap and neutralization during self-assembly of supramolecular melamine barbiturate material. The performed reaction chain mimics the biological process of ROS generation in key stages and enables one to obtain stable hydroperoxyl and organic radicals in a melamine barbiturate structure. Melamine barbiturate also neutralizes hydroxyl radicals, and the effectiveness of the radical trap is controlled with ROS scavenger incorporation. The number of radicals dramatically increases during light-inducing and depends on pH. The proposed scheme of the ROS trap and neutralization opens a way to the use of supramolecular assemblies as a component of coantioxidant systems and a source of organic radicals.

A putative xanthine dehydrogenase is critical for Borrelia burgdorferi survival in ticks and mice.

Borrelia burgdorferi is a pathogenic bacterium and the causative agent of Lyme disease. It is exposed to reactive oxygen species (ROS) in both the vertebrate and tick hosts. While some mechanisms by which B. burgdorferi ameliorates the effects of ROS exposure have been studied, there are likely other unknown mechanisms of ROS neutralization that contribute to virulence. Here, we follow up on a three gene cluster of unknown function, bb_0554, bb_0555, and bb_0556, that our prior unbiased transposon insertional sequencing studies implicated in both ROS survival and survival in Ixodes scapularis. We confirmed these findings through genetic knockout and provide evidence that these genes are co-transcribed as an operon to produce a xanthine dehydrogenase. In agreement with these results, we found that B. burgdorferi exposure to either uric acid (a product of xanthine dehydrogenase) or allopurinol (an inhibitor of xanthine dehydrogenase) could modulate sensitivity to ROS in a bb_0554-bb_0556 dependent manner. Together, this study identifies a previously uncharacterized three gene operon in B. burgdorferi as encoding a putative xanthine dehydrogenase critical for virulence. We propose renaming this locus xdhACB.

Methyltransferase Set7/9 as a Multifaceted Regulator of ROS Response.

Reactive oxygen species (ROS) induce multiple signaling cascades in the cell and hence play an important role in the regulation of the cell's fate. ROS can cause irreversible damage to DNA and proteins resulting in cell death. Therefore, finely tuned regulatory mechanisms exist in evolutionarily diverse organisms that are aimed at the neutralization of ROS and its consequences with respect to cellular damage. The SET domain-containing lysine methyltransferase Set7/9 (KMT7, SETD7, SET7, SET9) post-translationally modifies several histones and non-histone proteins via monomethylation of the target lysines in a sequence-specific manner. In cellulo, the Set7/9-directed covalent modification of its substrates affects gene expression, cell cycle, energy metabolism, apoptosis, ROS, and DNA damage response. However, the in vivo role of Set7/9 remains enigmatic. In this review, we summarize the currently available information regarding the role of methyltransferase Set7/9 in the regulation of ROS-inducible molecular cascades in response to oxidative stress. We also highlight the in vivo importance of Set7/9 in ROS-related diseases.

Radioresistance and radiosensitivity: a biophysical approach on bacterial cells robustness.

The study of radiosensitivity and radioresistance of organisms exposed to ionizing radiation has acquired additional relevance since a new bio-concept, coined as The primacy of Proteome over Genome, was proposed and demonstrated elsewhere a few years ago. According to that finding, genome integrity would require an actively functioning Proteome. However, when exposure to radiation takes place, Reactive Oxygen Species (ROS) from water radiolysis induce protein carbonylation (PC), an irreversible oxidative Proteome damage. The bio-models used in that study were the radiosensitive Escherichia coli and the extraordinarily robust Deinococcus radiodurans. The production of ROS induces protective reactions rendering them non-reactive forms. Protective entities present in the cytosol, moieties smaller than 3kDa, shield the Proteome against ROS, yielding protection against carbonylation. Shown in the present study is the fact that the fate of proteins functionality is determined by the magnitude of the Protein Carbonylation Yield (YPC), a quantity here analytically defined using published YPC numerical results. Analytical YPC expressions for E. coli and D. radiodurans were the input for a phenomenological approach, where the radiobiological magnitudes PP and PN, the probabilities for production of protein damage and ROS neutralization, respectively, were also analytically deduced. These highly relevant magnitudes, associated with key radiosensitivity and radioresistance issues, are addressed and discussed in this study. Among the plethora of information and conclusions derived from the present study, those endowed with higher conceptual degree, vis-à-vis the "Primacy of Proteome over Genome" concept, are as follows: (1) the ROS neutralization process in D. radiodurans reaches a maximum at a dose interval corresponding to the repairing shoulder. Therefore, it is a signature of the higher efficiency of the PC neutralization process. (2) ROS neutralization in D. radiodurans is nearly one order of magnitude higher than in E. coli, thus accounting for its extraordinary radioresistance. (3) Both physical (ROS-induced carbonyl radicals) and biological (protein modifications) processes are imbedded in the Protein Carbonylation Yield. The amalgamation of these two processes was accomplished by means of a statistical formalism.

Hepatoprotective potential of isolated flavonoids from Trapa natans L. against the paracetamol induced oxidative stress in rats

Overdose of paracetamol causes liver toxicity, due to oxidative stress by the reactive oxygen species (ROS) that increases the levels of ALT and AST, and reduces the level of the antioxidant enzymes. Flavonoids are a source of natural antioxidants that assist in neutralization of ROS. Several studies have suggested that flavonoids can help protect the liver. The Water Chestnut, Trapa natans L. plants have long been used in the traditional system of medicine and possess considerable antioxidant potential. In this study, we tried to isolate flavonoids from T. natans L. and evaluate the hepatoprotective potential of the isolated compound. We isolated flavonoids from the extract of the aerial part of plant and characterized by UV, IR, NMR and Mass spectroscopy. The isolated flavonoid was induced orally once a day (30 mg/kg). The test drug (isolated compound) could lower the elevated levels of serum enzymes such as glutamate oxaloacetate transaminase (AST), serum glutamate pyruvate transaminase (ALT), alkaline phosphatase (ALP) and total bilirubin. Silymarin (30 mg/kg) was taken as a standard drug that exhibits significant hepatoprotective activity against the paracetamol induced hepatotoxicity model in Wistar albino rats. The histopathological study of rat liver also strengthens biochemical evaluation analysis. Based on the experimental results, it can be concluded that the isolated flavonoids act as hepatoprotective agents in rats.

Role of antioxidants in fertility preservation of sperm - A narrative review.

Male fertility is affected by multiple endogenous stressors, including reactive oxygen species (ROS), which greatly deteriorate the fertility. However, physiological levels of ROS are required by sperm for the proper accomplishment of different cellular functions including proliferation, maturation, capacitation, acrosomal reaction, and fertilization. Excessive ROS production creates an imbalance between ROS production and neutralization resulting in oxidative stress (OS). OS causes male infertility by impairing sperm functions including reduced motility, deoxyribonucleic acid damage, morphological defects, and enhanced apoptosis. Several in-vivo and in-vitro studies have reported improvement in quality-related parameters of sperm following the use of different natural and synthetic antioxidants. In this review, we focus on the causes of OS, ROS production sources, mechanisms responsible for sperm damage, and the role of antioxidants in preserving sperm fertility.

P66Shc (Shc1) Zebrafish Mutant Line as a Platform for Testing Decreased Reactive Oxygen Species in Pathology.

Reactive oxygen species (ROS) dysregulation exacerbates many pathologies but must remain within normal ranges to maintain cell function. Since ROS-mediated pathology and routine cell function are coupled, in vivo models evaluating low-ROS background effects on pathology are limited. Some models alter enzymatic antioxidant expression/activity, while others involve small molecule antioxidant administration. These models cause non-specific ROS neutralization, decreasing both beneficial and detrimental ROS. This is detrimental in cardiovascular pathology, despite the negative effects excessive ROS has on these pathologies. Thus, current trends in ROS-mediated pathology have shifted toward selective inhibition of ROS producers that are dysregulated during pathological insults, such as p66Shc. In this study, we evaluated a zebrafish heterozygote p66Shc hypomorphic mutant line as a low-ROS myocardial infarction (MI) pathology model that mimics mammalian MI. Our findings suggest this zebrafish line does not have an associated negative phenotype, but has decreased body mass and tissue ROS levels that confer protection against ROS-mediated pathology. Therefore, this line may provide a low-ROS background leading to new insights into disease.

Platelet Redox Imbalance in Hypercholesterolemia: A Big Problem for a Small Cell.

The imbalance between reactive oxygen species (ROS) synthesis and their scavenging by anti-oxidant defences is the common soil of many disorders, including hypercholesterolemia. Platelets, the smallest blood cells, are deeply involved in the pathophysiology of occlusive arterial thrombi associated with myocardial infarction and stroke. A great deal of evidence shows that both increased intraplatelet ROS synthesis and impaired ROS neutralization are implicated in the thrombotic process. Hypercholesterolemia is recognized as cause of atherosclerosis, cerebro- and cardiovascular disease, and, closely related to this, is the widespread acceptance that it strongly contributes to platelet hyperreactivity via direct oxidized LDL (oxLDL)-platelet membrane interaction via scavenger receptors such as CD36 and signaling pathways including Src family kinases (SFK), mitogen-activated protein kinases (MAPK), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In turn, activated platelets contribute to oxLDL generation, which ends up propagating platelet activation and thrombus formation through a mechanism mediated by oxidative stress. When evaluating the effect of lipid-lowering therapies on thrombogenesis, a large body of evidence shows that the effects of statins and proprotein convertase subtilisin/kexin type 9 inhibitors are not limited to the reduction of LDL-C but also to the down-regulation of platelet reactivity mainly by mechanisms sensitive to intracellular redox balance. In this review, we will focus on the role of oxidative stress-related mechanisms as a cause of platelet hyperreactivity and the pathophysiological link of the pleiotropism of lipid-lowering agents to the beneficial effects on platelet function.

Melatonin ameliorates diabetic hyperglycaemia-induced impairment of Leydig cell steroidogenic function through activation of SIRT1 pathway

BackgroundDiabetes mellitus (DM)-related complications are important health problems worldwide. The underlying mechanisms for diabetic male subfertility/infertility are considerably complicated and need to be unveiled for therapeutic intervention. Melatonin treatment was investigated to assess the beneficial effects on injured steroidogenic function in DM due to its regulatory roles in mitochondria and autophagy.MethodsDiabetic hyperglycaemia was induced in rats injected with streptozotocin (STZ, 55 mg/kg/d) or simulated in TM3 Leydig cell line cultured with medium containing 30 mM D-glucose. Then, diabetic rats or the TM3 cells under high glucose were treated with melatonin. The diabetic rats were randomly divided into diabetes mellitus group (DM group), insulin treatment group (DM + INS group) and melatonin treatment group (DM + MT group). The TM3 Leydig cells were divided into a normal glucose control group (NG group), a high glucose treatment group (HG group), and a melatonin treatment group (HG + MT group). Then, Sirt1 (silent mating type information regulation 2 homologue) 1 expression was knocked down by siRNA.ResultsThe results showed that hyperglycaemia induced a decline in steroidogenesis, accompanied by autophagy defects, mitochondrial dysfunction and oxidative stress, in rats in the DM group or TM3 Leydig cells in the HG group. Furthermore, reduced SIRT1 expression levels and hyperacetylation were found in Leydig cells of DM group. Melatonin treatment ameliorated hyperglycaemia-induced impairment of Leydig cell function with simultaneous stimulation of 5’-adenosine monophosphate activated protein kinase (AMPK)/SIRT1 activity and the expression of autophagy-related genes. With regards to mitochondrial function, it promoted mitochondrial biogenesis with elevated PGC-1α, NRF1 and mtTFA, improved mitochondrial morphology, increased BNIP3L-related mitophagy and alleviated oxidative stress. Further results revealed that knockdown of Sirt1 in Leydig cells prevented the protective effects provided by melatonin against high glucose treatment, and interestingly, neutralization of reactive oxygen species (ROS) by N-acetyl-L-cysteine pretreatment abolished the stimulatory effect of melatonin on AMPK/SIRT1 activity in Leydig cells and prevented the induction of autophagy and mitochondrial biogenesis in the context of high glucose, indicating that modulation of SIRT1 pathway by melatonin was closely linked to ROS levels and oxidative stress.ConclusionsThese findings suggest that SIRT1 pathway plays essential roles in the pleiotropic actions of melatonin on Leydig cells and in the prevention of hyperglycaemia-induced steroidogenic dysfunction. The stimulatory action of melatonin on SIRT1 pathway is related to oxidative stress and its antioxidant property. Our data provide new evidence for the relationship of melatonin and SIRT1 pathway in the context of hyperglycaemia, and melatonin as a combination therapy may be useful to combat DM-related complications, especially male reproductive system injury.

The role of molecular-biological characteristics of the organism in the development of professional sensorineural hearing loss

The researchers have analyzed the data available in domestic and foreign literature sources on the modern representation and the role of molecular biological features of the body in the development of professional sensorineural hearing loss is carried out. Genetically determined sensorineural hearing loss occurs twice as often in developed countries as in underdeveloped ones. Hearing impairment affects up to 30% of the global community, and 70 million people are deaf. Modern scientists devote their research to the study of the contribution of genetic factors in the formation of phenotypic features of the development and course of a number of occupational diseases. The analysis of genetic markers associations with occupational diseases makes it possible to identify groups of people with an increased risk of developing certain diseases among workers and to develop timely preventive measures. The results of the literature analysis made it possible to systematize the data on the study of the influence of molecular biological characteristics of the body on the formation of sensorineural hearing loss. The researchers presented the data on the studied candidate genes of predisposition to noise-induced sensorineural hearing loss. An in-depth analysis of the results of recent studies shows that the main targets in the analysis of genetic factors of predisposition to professional sensorineural hearing loss are genes encoding proteins of the systems of activation and regulation of the heat shock factor, neutralization of reactive oxygen species and transmission of signals of the immune system. Ethics. The authors have conducted the study in compliance with the ethical principles of conducting medical research with the participation of a person as a subject; personal responsibility of the authors for the conclusions and results obtained in the study; confidentiality, non-proliferation of information; scientific validity of the research methods and techniques used; objectivity in the interpretation of results, conclusions; professional competence (self-respect and self-restraint).