Iron catalysis of lipid peroxidation in ferroptosis: Regulated enzymatic or random free radical reaction?

Duality of iron as an essential cofactor of many enzymatic metabolic processes and as a catalyst of poorly controlled redox-cycling reactions defines its possible biological beneficial and hazardous role in the body. In this review, we discuss these two "faces" of iron in a newly conceptualized program of regulated cell death, ferroptosis. Ferroptosis is a genetically programmed iron-dependent form of regulated cell death driven by enhanced lipid peroxidation and insufficient capacity of thiol-dependent mechanisms (glutathione peroxidase 4, GPX4) to eliminate hydroperoxy-lipids. We present arguments favoring the enzymatic mechanisms of ferroptotically engaged non-heme iron of 15-lipoxygenases (15-LOX) in complexes with phosphatidylethanolamine binding protein 1 (PEBP1) as a catalyst of highly selective and specific oxidation reactions of arachidonoyl- (AA) and adrenoyl-phosphatidylethanolamines (PE). We discuss possible role of iron chaperons as control mechanisms for guided iron delivery directly to their "protein clients" thus limiting non-enzymatic redox-cycling reactions. We also consider opportunities of loosely-bound iron to contribute to the production of pro-ferroptotic lipid oxidation products. Finally, we propose a two-stage iron-dependent mechanism for iron in ferroptosis by combining its catalytic role in the 15-LOX-driven production of 15-hydroperoxy-AA-PE (HOO-AA-PE) as well as possible involvement of loosely-bound iron in oxidative cleavage of HOO-AA-PE to oxidatively truncated electrophiles capable of attacking nucleophilic targets in yet to be identified proteins leading to cell demise.

Regularities of free radical processes and involutional changes of face and neck skin in different age groups.

AIM: The purpose of this study was to examine the role of free radical oxygen and peroxide- lipid processes along with conducting the study of blood flow level and oxygen saturation of facial tissues in patients of different ages with varying degrees of involutional changes in the skin of the face and neck. MATERIALS AND METHODS: One hundred and fifty-three people (84.3% women and 15.7% men) aged from 26 to 78 years with varying degrees of involutional changes in facial skin were examined. The clinical and laboratory evaluation was carried out dynamically and included various indicators of free radical processes, objective and subjective clinical visualization, and laser Doppler flowmetry (LDF) of the facial skin and transcutaneous oximetry (TcpO2) performed at 10 points on the face. To assess the state of free radical processes, the authors investigated the basal indicator of chemiluminescence intensity (ICb), the intensity of chemiluminescence stimulated (ICs) by zymosan, the activity coefficient (AC) of chemiluminescence, antiperoxide activity of plasma, and malondialdehyde (MDA). RESULTS: With aging, the imbalance of the oxygen constituents of free radical processes grows with the increase in ROS. Proportional to age, the ICs increased 2.1 times on average in people older than 55 years compared to that in people younger than 30 years and ICb decreased by 1.8 times. As a result, the AC increased by 5.6 times. This correlates with involuntary skin changes and with regression of microcirculation and TcpO2. According to LDF, it was established that average total blood flow in people younger than 30 years and people older than 55 years was 8.1 and 6.4 mL/min, respectively The difference between the indicators of TcpO2 in people younger than 30 years and people older than 55 years was 1.6 times (average 56 vs 35 mm Hg). The stability of the indicators of the peroxide-lipid link of oxidative stress in different age groups demonstrated that the activation of ROS formation in mitochondria is not a cause but a consequence of microcirculation and metabolic processes in the face and neck and aging in general. CONCLUSION: The tissue metabolism and microcirculation parameters naturally regress with aging, which is associated with the increase of ROS. The excess of species leads to the intensification of peroxide processes. This, in turn, is reflected in the aesthetic appearance manifested by aging.

[Energokorrektion of hemorrhagic stroke in the elderly].

The study included 102 elderly patients with hemorrhagic stroke of different size, location, and severity; the treatment was conservative. The results of the study demonstrate the important pathogenetic significance of free radical processes for hemorrhagic stroke. Severity of oxidative stress being a direct reflection of the energy deficiency correlates with the severity of the patients, with the volume of intracerebral hematoma, hyperglycemia, and determines the outcome. Assignment Cytoflavin leads to the elimination of free radical imbalance, a more rapid recovery of the impaired consciousness and focal neurological deficiency with the improvement of the functional outcome of the disease, and disability also decreased.

[Free radical processes in the pathogenesis of involutional skin changes].

AIM: To study the role of free radical processes (FRP) in the development of involutional skin changes and their correction. SUBJECTS AND METHODS: One hundred and twenty patients aged 18 to 74 years with various degrees of involutional facial and cervical skin changes were examined. Clinical and laboratory assessments were made over time. The oxygen and lipid peroxidase parameters of FRP were estimated; objective and subjective visualization, Doppler flowmetry of the facial skin, and colorimetric study of the skin color spectrum were done. RESULTS: The imbalance between oxygen and lipid peroxide components of FRP was found to increase with advancing age. These processes correlate with the severity of involutional skin changes and objectify the early use of energy-correcting therapy (ECT). The incorporation of ECT with cytoflavin positively affects FRP values and clinical and instrumental findings of involutional facial and cervical skin changes, by improving microcirculation. The patients with first-second degree involutional skin changes achieved the best results. CONCLUSION: The findings permit cytoflavin to be recommended as one of the components of therapy aimed to stabilize intradermal exchange processes as part cosmetic manipulations in aesthetic medicine.

[Oxidative stress in patients with mechanical jaundice of different origin and severity].

This randomized clinical study included 118 patients with mechanical jaundice (MJ) of different origin and severity. It highlighted the role of free radical-generation processes (FRP) in the development of the disease within 1 day after its onset. Disbalance of FRP affects oxygen and lipid components of oxidative stress and is especially well pronounced in severe cases and in patients with tumours. It becomes increasingly apparent with time from the onset of jaundice and endotoxicosis. FRP disbalance precedes clinical manifestation of jaundice and persists for a long time even after alleviation of its clinical symptoms. Certain signs have a prognostic values. Therapy with reamberin at a daily dose of 400 ml is shown to effectively correct oxidative stress associated with MJ of tumorous and non-tumorous origin regardless of the severity of the disease. Positive effect of antioxidative therapy is accompanied by the improvement of laboratory characteristics, clinical picture, and outcome of the disease.

[Free radical processes in patients with the acute calculous cholecystitis].

The role of the free radical processes (FRP) is shown and objectified in the development of the acute calculous cholecystitis (ACC). It is revealed on the first day of hospitalization already. In catarrhal and phlegmonic ACC free radical processes changes apply mostly to the oxygen part of the oxidation process. The greatest imbalance of the FRP is registered in the gangrenous ACC. It appeared like decrease of the oxygen and activation of the lipid FRP disregulation. On the first day FRP changes refer to the oxygen part of the oxidation process only. Starts with a second day from the disease début changes in the lipid component of the oxidative stress join the disregulation process. It is proved by the decrease of the antiperoxidant activity of plasma and increase of malondialdehyde. Malondialdehyde level and its rate of rise serve as prognostic criteria of the course and outcome of disease. FRP changes correlate with the clinical presentations of disease. They last till the patient's discharge. The high efficiency of the energetic corrector reamberin in a dose of 400-800 ml was shown in patients with ACC.

[Oxidative stress and combined antioxidant energy correction in the treatment of periodontitis].

Experimental-clinical study with inclusion of 50 Wistar rats with modeled parodontitis and 71 patients with chronic generalized parodontitis of different severity degree was conducted. Significance of oxidation stress in disease development and running was established in the course of the study. Disbalance of free-radical processes (FRP) in case of periodontal diseases affects oxygen stage of the oxidation stress in bigger degree and continues for a long time. In the course of experiment positive influence of cytoflavine preparation as energy-correction and antioxidant was confirmed as well as its combination with calcium-D3. In the course of comprehensive clinical study the efficacy of cytoflavine use was verified by the example of FRP correction that was accompanied by clinical picture and treatment results improvement.

[Free radical processes in patients with the gastro-intestinal bleedings].

The role of the free radical processes (FRP) is shown and objectified in the development of the ulcer gastro-intestinal bleedings (UGIB). It is revealed on the first day of hospitalization already. The greatest imbalance of the FRP is registered in heavy patients with acute UGIB. It appeared like decrease of the oxygen and activation of the lipid FRP disregulation. Unheavy patients have FRP changes refer to the oxygen part of the oxidation process only. Intensification FRP in process of increase of weight disease consists in decrease activity oxygen and increase a lipid disbalance. FRP disbalance has long time proceeds, last till the patient's discharge. Results of the research prove as much as possible early inclusion in a complex of medical actions antoixidant therapy. The high efficiency of the energetic corrector reamberin in a dose of 400-800 ml was shown in patients with UGIB.

[Course of free radical processes and prognosis of ischemic and hemorrhagic stroke].

A study of free radical processes (FRP) markers in 381 patients with ischemic and hemorrhagic stroke revealed the importance of oxidant stress that was most severe in patients with large volumes of stroke. Intensification of FRP consists in the reduction or inversion of oxygen FRP activity and increase in lipid free radical FRP that last till the patient discharge from a hospital. FRP indicators are early prognostic markers of stroke course and outcome. An inverse correlation between the level of anti peroxide plasma activity (APA) and the dynamics of the increase in stroke lesion from 1 to 20 days, and direct correlation between malondialdehyde (MDA) titer and the risk of hemorrhagic transformation and growth of the lesion from 5 to 20 days of disease were revealed. The results indicate that inclusion of antoixidant therapy should be conducted as early as possible after stroke using high doses of drugs in severe cases. The high efficacy of antioxidant cytoflavin in a daily dose of 20 ml in patients with stroke of different character and severity was shown. The positive effect of cytoflavin on FRP markers was accompanied by the improvement of clinical and morphological presentations and stroke outcome.

[Effect of early correction of energy and free-radical homeostasis on the clinical-morphological presentation of cerebral infarction].

A randomized comparative prospective 35-day clinical-instrumental trial of 30 patients with an ischemic hemispheric stroke hospitalized on the first day of disease was carried out. In addition to basic therapy, 16 patients of the main group were treated with the antioxidant power-normalizing drug cytoflavin used in dosage 20 ml/day intravenous in drops from the 1st to 10th day and 2 tablets twice a day from the 11th to 35th day. Fourteen patients of the comparison group received basic therapy only. Patient's state was assessed at 0-24 h and 5, 11, 21, 35 days of stroke. Assessment of neurological status (the Glasgow Coma Scale, the NIH stroke scale, a short version of MMSE), brain MRI (brain lesion volume), a study of antioxidant stress markers, assessment of functional outcome (the Barthel index and the modified Rankin scale) were conducted. The early active correction of power and free radical homeostasis by cytoflavin improved the dynamics of brain morphological changes and free-radical changes that was correlated with the activation of consciousness and reduction of neurologic deficit that resulted in the decrease of disability.

[Free radical processes at patients with pathologies of biliary ducts and methods of their correction].

The main objective of a research in the early diagnostics of a functional condition of a liver, is to estimate the degree of the level of its expressiveness and timely pathogenetic correction on the basis of the free radical system processes of studying of patients with mechanical jaundice. Results were carried out among 61 patients with pathologies of bile tracts( biliary ducts) which proved the essential role of free radical processes with strengthening of peroxidation of membrane lipids against the absolute or relative insufficiency of endogenic antioxidants in the mechanism of development of hepatic insufficiency at the given category of patients with the highest degree expressed at the serious conditions of the patients with malignant diseases. It is revealed that the inclusion of energy corrector antioxidants of reamberin to the therapy as a part of standard schemes of treatment promoted positive regressing dynamics of parameters of free radical processes that are correlated with positive clinical symptoms and outcome of diseases.

Histo- and cytoarchitectonics of the hippocampus in young rats injected with propofol and mexidol.

Light microscopic examination of the hippocampus was carried out in young rats (intact and injected with propofol and mexidol according to different protocols). Propofol had a negative effect on hippocampal neurons causing an almost 2-fold increase in the count of modified cells in comparison with the normal level. Mexidol effectively corrected these shifts.

[Free radical processes in patients with iron deficiency anemia treated with iron medication].

AIM: To study the effects of iron salts drugs (ISD) sorbifer durules and ferro-folgamma on free radical processes in 44 patients with iron deficiency anemia (IDA). MATERIAL AND METHODS: IDA was diagnosed as a rule in women with uterine myomas, endometriosis, dysfunctional hemorrhage and other menorragias. Generation of active oxygen forms (AOF) was estimated by hemoluminescence (CL) before and after therapy. Lipid peroxidation was assessed by malonic dialdehyde (MDA) in plasma, antiperoxide plasma activity (APA)--by CL intensity in interaction with nitric peroxide. The system of antioxidant defense in ISD treatment was estimated by the activity of key antioxidant enzymes: superoxidedismutase, glutathion peroxidase and catalase. RESULTS: The studied ISD normalized hemoglobin 3-4 weeks after the treatment onset. MDA decreased. Generation of AOF and activity of plasmic antioxidant enzymes did not change much. CONCLUSION: ISD modulate free radical processes without oxidant stress.

[Vasaprostan treatment of fibrosing alveolitis in patients with pulmonary hypertension]. / Primenenie vazoprostana u bol'nykh legochnoi gipertoniei pri fibroziruiushchem al'veolite.

AIM: To study clinical efficacy of vasaprostan in patients with fibrosing alveolitis (FA) complicated by pulmonary hypertension (PH), its effect on functional activity of platelets and endothelium, intensity of free radical processes. MATERIAL AND METHODS: Seven FA patients were examined. They had either idiopathic FA or FA with diffuse diseases of the connective tissues. The following methods were used to assess the effect: standard clinical tests, high resolution computer tomography, Doppler echocardiography, definition of the complex thrombin-antithrombin (TAT) and thrombocytic factor 4 (TF-4). Generation of oxygen active forms by leukocytes was measured by luminol-dependent chemiluminescence. Morphological verification of the diagnosis was made by the results of open pulmonary biopsies. RESULTS: Vasaprostan reduced pressure in the pulmonary artery from 31.6 +/- 2.31 to 19.58 +/- 3.90 mm Hg (p < 0.05) and coagulation parameters. TAT decreased after 2 and 8 weeks of treatment from 15.25 +/- 4.5 to 5.1 +/- 0.33 and 2.4 +/- 0.31 pg/ml (p < 0.05). Initially low TF-4 (2.11 +/- 0.39 pg/ml) elevated to the end of the treatment and reached values close to control (4.37 +/- 0.25 pg/ml, p < 0.05). Moreover, vasaprostan enhanced the ability of platelets to inhibit generation of active oxygen forms (from 0.9 +/- 0.18 to 1.23 +/- 0.16 r. u., p < 0.05) and thus depressed activity of lipid peroxidation. CONCLUSION: Good effect of vasaprostan on platelet activity, free radical processes validates its use in combined treatment of various FA forms for correction of PH, its complications and as an antifibrogenic agent.