INTRODUCTION:Conventional cancer therapies are limited by systemic toxicity, poor selectivity, and drug resistance. Bacterial proteins, such as azurin, represent a promising alternative due to their tumor selectivity, low immunogenicity, and multifunctional mechanisms. This review highlights recent progress in azurin-based anticancer strategies, including mechanisms of action, structural modifications, and integration with peptide systems, nanotechnology, and gene therapy. METHODS:A search for articles using the keywords "azurin, cancer" was conducted on the Google Scholar and PubMed databases, with an emphasis on the years 2023-2024. RESULTS:Azurin and its peptide derivative p28 selectively target cancer cells by stabilizing p53, inducing apoptosis, and arresting the cell cycle, while also modulating key signaling pathways. Structural features of azurin enable interactions with multiple molecular targets, and p28 enhances cellular uptake and sensitizes tumors to chemotherapeutics. Advanced delivery platforms, including engineered bacteria (E. coli Nissle 1917, S. typhimurium VNP-20009), chimeric peptides, and nanocarriers, improve tumor targeting and therapeutic outcomes. Preclinical models and clinical trials demonstrate low toxicity and efficacy against various solid tumors and gliomas. DISCUSSION:Evidence supports azurin as a versatile anticancer agent with unique advantages over conventional therapies. Its compatibility with delivery innovations enhances precision and minimizes systemic toxicity. However, further optimization, large-scale clinical validation, and long-term safety studies are required. CONCLUSION:Azurin and its derivatives provide a promising platform for anticancer therapy, offering tumor specificity, low toxicity, and synergy with multiple treatment modalities. Their integration into advanced delivery and genetic systems may significantly improve cancer treatment and recurrence prevention.

The search for effective and safe radio-modulating compounds that reduce cancer cell radioresistance and/or the concomitant damage to normal tissues caused by radiation remains a significant challenge in radiation therapy. Peroxiredoxin 6, a member of the thiol-specific peroxidase family, is a promising candidate to solve this problem. However, often in studies, insufficient attention is paid to radiation parameters and there is no information about how different radiation parameters influence the radioprotective effect of exogenous peroxiredoxin 6. This article shows the peculiarities of the radioprotective effects of intravenous peroxiredoxin 6 at a concentration of 20 μg/g body weight and its mutant form Prx6-C47S (without peroxidase activity) administered shortly before X-ray or γ-irradiation with different dose rates and exposure times. Survival rates of the 10 Gy γ-irradiation 0.125 Gy/min and 7 Gy X-ray irradiation 1 Gy/min animal groups (an 8-fold difference in dose rate and exposure time) were correlated both for control and experimental animals.

Renal reperfusion injury develops rapidly after ischemia relief. It is with the onset of reperfusion that a cascade of pathological processes is launched, which means that measures to protect the kidney have to be taken as early as in this period. The aim of the paper was to study the effect of exogenous peroxiredoxin 6 (Prx6) on the morphofunctional state of nephrons in the initial reperfusion period following ischemia. Materials and methods. The right kidney of rats was subjected to 45-minute ischemia with prior left-sided nephrectomy and examined after 2, 5 and 24 hours of reperfusion. Exogenous Prx6 was administered intravenously 15 minutes before ischemia. Results. The research showed that nephrectomy has no effect on the morphology of a single kidney, but leads to an increase in urea and creatinine in the blood within 24 hours. We noted signs of morphological and functional damage to nephrons after 2 hours of reperfusion, which tend to increase in the course of 24 hours. In addition, we observed a rise in blood creatinine and urea concentrations, an increase in the areas of renal corpuscles, glomeruli, and Bowman’s capsule, as well as dystrophic changes in nephrocytes and an increase in the immunosignal area of the kidney injury molecule-1 (KIM-1). When exogenous Prx6 was used, we observed normalization of the size of nephron components, a decrease in KIM-1 immunosignal and an improvement in the kidney’s excretory function both in the early reperfusion period and after 24 hours. Thus, exogenous Prx6 reduces damage to nephrons during the early reperfusion period, which improves their compensatory and adaptive properties in ischemia-reperfusion injury.

Expression of LOX-1 and NOX1 genes in the human umbilical vein endotheliocytes (HUVECs) cultured in the presence of low-density lipoproteins (LDL) modified with various natural dicarbonyls was investigated for the first time. It was found that among the investigated dicarbonyl-modified LDLs (malondialdehyde (MDA)-modified LDLs, glyoxal-modified LDLs, and methylglyoxal-modified LDLs), the MDA-modified LDLs caused the greatest induction of the LOX-1 and NOX1 genes, as well as of the genes of antioxidant enzymes and genes of proapoptotic factors in HUVECs. Key role of the dicarbonyl-modified LDLs in the molecular mechanisms of vascular wall damage and endothelial dysfunction is discussed.

Реперфузионное поражение нефронов почки стремительно развивается после купирования ишемии. Запуск каскада патологических процессов происходит именно с началом реперфузии, что обусловливает необходимость проведения мероприятий по протекции органа уже в этот период. Цель работы – исследование влияния экзогенного пероксиредоксина 6 на морфофункциональное состояние нефронов почки в начальный реперфузионный период после ишемии. Материалы и методы. Правую почку крыс подвергали 45-минутной ишемии с предварительной левосторонней нефрэктомией и исследовали через 2, 5 и 24 ч реперфузии. Экзогенный пероксиредоксин 6 вводили внутривенно за 15 мин до ишемии. Результаты. Показано, что нефрэктомия не оказывает влияния на морфологию единственной почки, однако приводит к росту концентраций мочевины и креатинина в крови в течение первых суток. Признаки морфофункциональных повреждений нефронов отмечены через 2 ч реперфузии и имеют тенденцию к нарастанию в течение 24 ч. Установлены рост концентраций креатинина и мочевины в крови, площадей почечных телец, сосудистых клубочков и Боуменова пространства, развитие дистрофических изменений нефроцитов и увеличение площади иммуносигнала молекулы поражения почек KIМ-1. При использовании экзогенного пероксиредоксина 6 выявлены нормализация размеров компонентов нефронов, снижение иммуносигнала KIМ-1 и улучшение экскреторной функции почки как в ранний реперфузионный период, так и через 24 ч реперфузии. Таким образом, экзогенный пероксиредоксин 6 снижает поражение нефронов почки в ранний реперфузионный период, что способствует улучшению их компенсаторно-приспособительных свойств в условиях ишемически-реперфузионного поражения.

Acute kidney injury provokes liver dysfunction, which is an aggravating factor for effective treatment. In this study, ischemic-reperfusion kidney injury was used as a model. Since the main damaging factor in this case is the hyperproduction of reactive oxygen species, to prevent liver injury under kidney injury, an exogenous antioxidant enzyme peroxyredoxin 6 was used, which is able to neutralize the hyperproduction of a wide range of reactive oxygen species. Kidney injury was initiated by 45 min ischemia with simultaneous left-sided nephrectomy. The liver was not manipulated. Peroxiredoxin 6 was administered intravenously 15 min before ischemia. Liver condition was assessed 2, 5 and 24 h after kidney reperfusion by histological and biochemical methods. The maximum signs of liver injury were detected after 5 h of kidney reperfusion. The use of peroxiredoxin 6 led to a decrease in the severity of vascular reaction and leukocyte infiltration in the liver, a decrease in the degree of dystrophy and apoptosis of hepatocytes, the absence of an increase in the concentration of TBA-reactive products and stabilization of the level of cytokines IL-6, IL-10 in liver tissue, as well as normalization of the activity of intracellular transferases in the blood with the onset of reperfusion. The protective effect of peroxiredoxin 6 was primarily associated with its antioxidant properties, which make it possible to neutralize the hyperproduction of reactive oxygen species at the initial period of kidney reperfusion; however, the contribution of the signal-regulatory function of the protein to its protective effect should not be excluded.

Ischemia-reperfusion (I-R) injury causes a reduction in the viability of donor organs during long-term conservation. In the present study, an antioxidant enzyme peroxiredoxin 6 was used to increase the resistance of donor kidneys to I-R injury. To find the efficiency of using peroxiredoxin 6, we evaluated the morphological and functional parameters of the isolated kidney, the expression level of kidney injury molecule-1 (KIM-1) as a marker of kidney damage, and the level of malonic dialdehyde in the tissue. Cold storage of the kidney in DMEM solution, which was not customized, was shown to result in organ death during perfusion. In contrast, the use of Custodiol solution allowed the kidney to survive an episode of prolonged ischemia and perfusion. The combination of peroxiredoxin 6 with Custodiol solution led to a better outcome. In addition to a decreased damage to nephron structures, a 2.3-fold reduction of the malonic dialdehyde level was registered, thus indicating neutralization of hyperproduction of reactive oxygen species. The urinary flow rate, glomerular filtration rate, and the amount of urea in the urine increased fourfold, thereby indicating that tubular structures were preserved, as confirmed by a 1.5-fold decrease in the level of KIM-1. Thus, the use of peroxiredoxin 6, an exogenous antioxidant protein, during perfusion increases the resistance of the donor kidney to ischemia-reperfusion injury after prolonged cold storage in Custodiol solution.

Peroxiredoxin 6 (Prdx6) is a multifunctional eukaryotic antioxidant enzyme. Mammalian Prdx6 possesses peroxidase activity against a wide range of organic and inorganic hydroperoxides, as well as exhibits phospholipase A2 (aiPLA2) activity, which plays an important role in the reduction of oxidized phospholipids and cell membrane remodeling. Exogenous Prdx6 has recently been shown to be able to penetrate inside the cell. We hypothesized that this entry may be due to the phospholipase activity of Prdx6. Experiments using exogenous Prdx6 in three cell lines (3T3, A549, RAW 264.7) demonstrated that it is the phospholipase activity that promotes its penetration into the cell. Overoxidation of Prdx6 led to a suppression of the peroxidase activity and a 3-to-4-fold growth of aiPLA2, which enhanced the efficiency of its transmembrane transport into the cells by up to 15 times. A mutant form of Prdx6-S32A with an inactivated phospholipase center turned out to be unable to enter the cells in both the reduced and oxidized state of the peroxidase active center. Previously, we have shown that exogenous Prdx6 has a significant radioprotective action. However, the role of phospholipase activity in the radioprotective effects of Prdx6 remained unstudied. Trials with the mutant Prdx6-S32A form, with the use of a total irradiation model in mice, showed a nearly 50% reduction of the radioprotective effect upon aiPLA2 loss. Such a significant decrease in the radioprotective action may be due to the inability of Prdx6-S32A to penetrate animal cells, which prevents its reduction by the natural intracellular reducing agent glutathione S-transferase (πGST) and lowers the efficiency of elimination of peroxides formed from the effect of ionizing radiation. Thus, phospholipase activity may play an important role in the reduction of oxidized Prdx6 and manifestation of its antioxidant properties.

In this review, we discuss the pathogenesis of some socially significant diseases associated with the development of oxidative stress, such as atherosclerosis, diabetes, and radiation sickness, as well as the possibilities of the therapeutic application of low-molecular-weight natural and synthetic antioxidants for the correction of free radical-induced pathologies. The main focus of this review is the role of two phylogenetically close families of hydroperoxide-reducing antioxidant enzymes peroxiredoxins and glutathione peroxidases - in counteracting oxidative stress. We also present examples of the application of exogenous recombinant antioxidant enzymes as therapeutic agents in the treatment of pathologies associated with free-radical processes and discuss the prospects of the therapeutic use of exogenous antioxidant enzymes, as well as the ways to improve their therapeutic properties.

Protective effects of peroxiredoxin 6 (PRDX6) in RIN-m5F β-cells and of thymulin in mice with alloxan-induced diabetes were recently reported. The present work was aimed at studying the efficiency of thymulin and PRDX6 in a type 1 diabetes mellitus model induced by streptozotocin in mice. Effects of prolonged treatment with PRDX6 or thymic peptide thymulin on diabetes development were evaluated. We assessed the effects of the drugs on the physiological status of diabetic mice by measuring blood glucose, body weight, and cell counts in several organs, as well as effects of thymulin and PRDX6 on the immune status of diabetic mice measuring concentrations of pro-inflammatory cytokines in blood plasma (TNF-α, interleukin-5 and 17, and interferon-γ), activity of NF-κB and JNK pathways, and Hsp90α expression in immune cells. Both thymulin and PRDX6 reduced the physiological impairments in diabetic mice at various levels. Thymulin and PRDX6 provide beneficial effects in the model of diabetes via very different mechanisms. Taken together, the results of our study indicated that the thymic peptide and the antioxidant enzyme have anti-inflammatory functions. As increasing evidences show diabetes mellitus as a distinct comorbidity leading to acute respiratory distress syndrome and increased mortality in patients with COVID-19 having cytokine storm, thymulin, and PRDX6 might serve as a supporting anti-inflammatory treatment in the therapy of COVID 19 in diabetic patients.

Oxidative stress caused by ischemia–reperfusion kidney injury may play a key role in liver dysfunction. To reduce liver and kidney damage in ischemia–reperfusion kidney injury, an exogenous enzyme antioxidant peroxiredoxin 6 was used, which is able to restore a wide range of hydroperoxides and is a participant in intracellular and intercellular signal transmission. Rats were subjected to ischemic kidney injury for 45 min with simultaneous left-sided nephroectomy and examined after 24 and 48 h of reperfusion. Peroxiredoxin 6 was administered intravenously 15 min before ischemia. Injury to the renal and hepatic tissues was determined by histological methods; in addition, the concentrations of creatinine, urea, alanine aminotransferase and aspartate aminotransferase in the blood were measured to assess the functionality of the organs. Reperfusion led to an increase in the concentrations of creatinine, urea, alanine aminotransferase and aspartate aminotransferase in blood plasma; there was also violation of the architecture of renal nephrons and the development of a pronounced vascular reaction in the liver with foci of degenerative changes. The use of exogenous peroxiredoxin 6 led to a decrease in the damage to the renal and hepatic tissues and normalization of the level of renal and hepatic metabolites. Thus, peroxiredoxin 6 showed both a nephroprotective effect in renal ischemia–reperfusion and reduced morphofunctional damage to distant organs, in particular, the liver.

Окислительный стресс, вызванный ишемически-реперфузионным поражением почек, может играть ключевую роль в дисфункции печени. Для снижения поражения печени и почек при ренальном ишемически-реперфузионном поражении в работе использовали экзогенный фермент-антиоксидант пероксиредоксин 6, который способен восстанавливать широкий спектр гидропероксидов и является участником во внутриклеточной и межклеточной передаче сигналов. Крыс подвергали ишемическому поражению почек в течение 45 мин с одновременной левосторонней нефроэктомией и обследовали через 24 и 48 ч реперфузии. Пероксиредоксин 6 вводили внутривенно за 15 мин до ишемии. Повреждение почечной и печеночной тканей определяли гистологическими методами, для оценки функциональности органов измеряли концентрации креатинина, мочевины, аланинаминотрансферазы и аспартатаминотрасферазы в крови. Реперфузия привела к увеличению концентраций креатинина, мочевины, аланинаминотрансферазы и аспартатаминотрасферазы в плазме; нарушению архитектуры почечных нефронов и развитию выраженной сосудистой реакции в печени с очагами дегенеративных изменений. Использование экзогенного пероксиредоксина 6 привело к снижению поражения ренальной и печеночной тканей и нормализации уровня почечных и печеночных метаболитов. Таким образом, пероксиредоксин 6 проявляет как нефро-протекторный эффект при ренальной ишемии-реперфузии, так и уменьшает морфофункциональное повреждение отдаленных органов, в частности печени.

Defect generation rates are important parameters required by mean-field approaches to predict evolution of materials under irradiation. However, a reliable estimation of the rates is hindered by a multiscale nature of the damage process. This paper reports the results of a consistent modeling of all stages of cascade development from ballistic collisions to a long-term annealing. This consistency allows us to calculate the generation rates of defects and their clusters, that are suitable for use in mean-field approaches. As a result, we demonstrate on the example of BCC iron that a variation of the irradiation temperature or the energy spectrum of incident particles could change the generation rates by almost an order of magnitude and significantly modify their cluster-size distributions.

The discovery of high entropy alloys (HEAs) dramatically increased the number of new commercial materials. Today, multicomponent systems are some of the main objects of research in the field of materials science. However, their chemical complexity significantly complicated the materials modeling, so conventional simulations techniques are hardly applicable. In this paper, we propose a rapid high-throughput approach for an automatic detection for stable ordered structures in multicomponent alloys. High computational efficiency is achieved through the use of a novel low-rank interatomic potential. The approach was verified on several binary temperature-concentration phase diagrams. Then it was applied to search for secondary phases in CoFeNiCr, which is believed to be a single-phase high-entropy alloy. As a result, we detected the ordering of Ni and Cr in CoFeNiCr and similar alloys in a wide range of temperatures and compositions.

A chimeric recombinant protein PSH was composed of two antioxidant enzymes, human peroxiredoxin 6 (Prx6) and superoxide dismutase (MnSOD) from Escherichia coll. Analysis of physico-chemical properties of PSH protein confirmed its high antioxidant activity. PSH was shown to protect animals from lethal and sub-lethal doses of ionizing radiation. PSH was most effective after intravenous administration short time before ionizing irradiation. Dose reduction factor for PSH comprised 1.33. PSH was effectively alleviating the degree of radiation-induced leucopenia and thrombocytopenia in animals. Beside that, PSH administration decreased DNA damage in red bone marrow cells. The chimeric recombinant PSH can be considered as an effective radioprotector for minimizing the risks of damage of animal's body by ionizing radiation, and it could be a promising therapeutic molecule for prevention/suppression of pathological conditions accompanied or caused by oxidative stress.

Abstract—A rapid increase in the concentration of free radicals and reactive oxygen species at the reperfusion stage is the most dangerous stage of ischemia–reperfusion injury. An avalanche-like increase in the level of reactive oxygen species and secondary products of free radical oxidation of biological macromolecules leads to the development of oxidative stress. The use of exogenous antioxidants can reduce the concentration of reactive oxygen species in the affected tissues and suppress or correct the course of oxidative stress; thus, it significantly reduces the severity of ischemia–reperfusion injury. Acute ischemic renal failure is one of the most important social problems in a comprehensive list of pathologies associated with ischemia–reperfusion. The nephroprotective effect of a chimeric PSH antioxidant enzyme that includes human peroxiredoxin 6 and Mn-containing superoxide dismutase of Escherichia coli has been shown on an animal model of bilateral ischemia–reperfusion renal injury. The recombinant chimeric PSH protein was able to neutralize a maximally possible wide range of reactive oxygen species due to the superoxide dismutase and peroxidase activities. It has been shown with histological, biochemical, and molecular biological methods that the preliminary administration of the chimeric PSH protein before ischemia–reperfusion significantly reduced the degree of renal tissue injury and led to a quick normalization of their structural and functional state. In addition, the administration of the PSH enzyme increased the survival of experimental animals by a factor of more than 1.5. The use of the recombinant chimeric PSH enzyme can be an effective approach in the prevention and treatment of renal ischemia–reperfusion injury, as well as for maintaining an isolated kidney during transplantation.

The study of the mechanisms of disease development and monitoring the effectiveness of treatment of chronic obstructive pulmonary disease (COPD) is an important problem. Particular importance is attached to the antioxidant defense system of the body, opposing free radical aggression that accompanies inflammatory processes. In this work, we evaluated the activity of antioxidant enzymes - superoxide dismutase (SOD) and catalase in EBC in young smokers (up to 40 years old) and older (up to 65 years old) who do not have diagnosed diseases of the respiratory system, as well as in smokers with COPD. At the same time, free-radical oxidation parameters — nitric oxide (NO) metabolites and MDA— were evaluated. The control group consisted of healthy non-smoking men. It was found that the antioxidant system is activated in response to increased free radical oxidation in COPD. Catalase activity increases during exacerbation by 2.88 times (P <0.05), and SOD activity by 1.23 times (P <0.05). The activity of SOD in non-smokers was 0.419 ± 0.119 units. In healthy young smokers, its activity increases by 1.8 times (P <0.05). In older people, changes in SOD activity were not significant. Catalase activity, in contrast, decreases in healthy young smokers and increases with age. It was also found that in patients with COPD, the concentration of NO metabolites - nitrates / nitrites increases by 2.16 times (P <0.05) and MDA by 3.83 times (P <0.05) compared with the control. Thus, the study of indicators of the antioxidant defense system can improve understanding of the mechanisms of COPD pathogenesis and approaches to effective therapy.

Abstract—The aim of this study was to investigate the protective effect of exogenous peroxiredoxins with ischemia–reperfusion of an isolated kidney. The study was carried out using a model of isolated rat kidney perfusion ex vivo. A recombinant peroxiredoxin 6 was injected directly in the perfusion buffer. The high-molecular-weight dye Blue Dextran 2000 and urea were added to the perfusion buffer to determine the functionality of an isolated kidney. It was demonstrated that exogenous peroxiredoxin 6 in the cortical layer of an isolated kidney was localized in the vessels of renal glomeruli; in the medulla it was found in microvessels surrounding the thin tubules. The use of peroxiredoxin 6 decreases the degree of damage of nephron structures by two times compared with the damage in the control, which provides the preservation of ultrafiltration processes. A decrease in glomerular damage leads to a decrease in the content of Blue Dextran by two times compared with the damage in the control at the end of the perfusion period. A decrease in the damage of tubular structures indicates the active urea transport during perfusion. Thus, the inclusion of peroxiredoxin 6 in the perfusion buffer mediated a decrease in the damage of nephron structures and maintenance of the multifunctional state of renal glomeruli and tubules.