Psoriasis between Autoimmunity and Oxidative Stress: Changes Induced by Different Therapeutic Approaches.

Psoriasis is defined as chronic, immune-mediated disease. Regardless of the development of new therapeutic approaches, the precise etiology of psoriasis remains unknown and speculative. The aim of this review was to systematize the results of previous research on the role of oxidative stress and aberrant immune response in the pathogenesis of psoriasis, as well as the impact of certain therapeutic modalities on the oxidative status in patients with psoriasis. Complex immune pathways of both the innate and adaptive immune systems appear to be major pathomechanisms in the development of psoriasis. Oxidative stress represents another important contributor to the pathophysiology of disease, and the redox imbalance in psoriasis has been reported in skin cells and, systemically, in plasma and blood cells, and more recently, also in saliva. Current immune model of psoriasis begins with activation of immune system in susceptible person by some environmental factor and loss of immune tolerance to psoriasis autoantigens. Increased production of IL-17 appears to be the most prominent role in psoriasis pathogenesis, while IL-23 is recognized as master regulator in psoriasis having a specific role in cross bridging the production of IL-17 by innate and acquired immunity. Other proinflammatory cytokines, including IFN-γ, TNF-α, IL-1ß, IL-6, IL-22, IL-26, IL-29, or IL-36, have also been reported to play important roles in the development of psoriasis. Oxidative stress can promote inflammation through several signaling pathways. The most noticeable and most powerful antioxidative effects exert various biologics compared to more convenient therapeutic modalities, such as methotrexate or phototherapy. The complex interaction of redox, immune, and inflammatory signaling pathways should be focused on further researches tackling the pathophysiology of psoriasis, while antioxidative supplementation could be the solution in some refractory cases of the disease.

Virtual screening, drug-likeness analysis, and molecular docking study of potential severe acute respiratory syndrome coronavirus 2 main protease inhibitors.

Due to the length of time required to develop specific antiviral agents, the World Health Organization adopted the strategy of repurposing existing medications to treat Coronavirus disease 2019 infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease is possible biological target for potential antiviral drugs. We selected various compounds from PubChem database based on the structure of main protease inhibitors in Protein Data Bank database. Ten compounds showed nontumorigenic and nonmutagenic potential and met Egan's and Lipinski's rules. Molecular docking analysis was performed using AutoDock Vina software. Based on number and type of key binding interactions, as well as docking scores, we selected compounds 6, 8, and 17 that demonstrated the highest binding affinity for the target protein. Molecular dynamics simulations were then carried out on the protein-top docked ligand complexes which were subjected to molecular mechanics/generalized Born and surface area calculations. The molecular dynamics simulation results indicated that protein-top docked ligand complexes showed good conformational stability. Among analyzed molecules, compound 17 emerged as the best in silico hit based on the docking score, MM/GBSA binding energy and MD results.

Garlic Derived Diallyl Trisulfide in Experimental Metabolic Syndrome: Metabolic Effects and Cardioprotective Role.

This study aimed to examine the effects of diallyl trisulfide (DATS), the most potent polysulfide derived from garlic, on metabolic syndrome and myocardial function in rats with metabolic syndrome (MetS). For that purpose, we used 36 male Wistar albino rats divided into control rats, rats with MetS and MetS rats treated with 40 mg/kg of DATS every second day for 3 weeks. In the first part, we studied the impact of DATS on MetS control and found that DATS significantly raised H2S, decreased homocysteine and glucose levels and enhanced lipid and antioxidative, while reducing prooxidative parameters. Additionally, this polysulfide improved cardiac function. In the second part, we investigated the impact of DATS on ex vivo induced ischemia/reperfusion (I/R) heart injury and found that DATS consumption significantly improved cardiodynamic parameters and prevented oxidative and histo-architectural variation in the heart. In addition, DATS significantly increased relative gene expression of eNOS, SOD-1 and -2, Bcl-2 and decreased relative gene expression of NF-κB, IL-17A, Bax, and caspases-3 and -9. Taken together, the data show that DATS can effectively mitigate MetS and have protective effects against ex vivo induced myocardial I/R injury in MetS rat.

The cardioprotective effects of diallyl trisulfide on diabetic rats with ex vivo induced ischemia/reperfusion injury.

Diallyl trisulfide (DATS) is distinguished as the most potent polysulfide isolated from garlic. The aim of our study was to investigate effects of oral administration of DATS on healthy and diabetic rats, with special attention on heart function. Rats were randomly divided into four groups: CTRL (healthy rats), DATS (healthy rats treated with DATS), DM (diabetic rats), DM + DATS (diabetic rats treated with DATS). DATS (40 mg/kg of body weight) was administered every other day for 3 weeks, at the end of which rats underwent echocardiography, glycemic measurement and redox status assessment. Isolated rat hearts were subjected to 30 min global ischemia and 60 min reperfusion, after which heart tissue was counterstain with hematoxylin and eosin and cardiac Troponin T staining (cTnT), while expression of Bax, B cell lymphoma 2 (Bcl-2), caspase-3, caspase-9 and superoxide dismutase-2 were examined in the left ventricle. DATS treatment significantly reduced blood glucose levels of diabetic rats, and improved cardiac function recovery, diminished oxidation status, attenuated cardiac remodeling and inhibited myocardial apoptosis in healthy and diabetic rats. DATS treatment causes promising cardioprotective effects on ex vivo-induced ischemia/reperfusion (I/R) injury in diabetic and healthy rat heart probably mediated by inhibited myocardial apoptosis. Moreover, appropriate DATS consumption may provide potential co-therapy or prevention of hyperglycemia and various cardiac complications in rats with DM.

The perfusion of cisplatin and cisplatin structural analogues through the isolated rat heart: The effects on coronary flow and cardiodynamic parameters.

The therapeutic use of cisplatin for the treatment of solid tumours is associated with organ toxicity. Amongst those, the cardiotoxicity is an occasional but very serious and severe side effect. To prevent or reduce these negative effects, many cisplatin analogues have been synthesized and evaluated in terms of being a less toxic and more effective agent. In present study, we examined the effects of cisplatin and its three analogues in the isolated rat heart to determine whether changes in the structure of the platinum complexes (changing of carrier ligands - ethylenediamine; 1,2-diaminocyclohexane; 2,2':6',2''-terpyridine) can influence their cardiotoxic effects. The results of our research indicate that the introduction of aromatic rings in the structure of the platinum complexes has a negative influence on the heart function. Conversely, the other two examined complexes had less negative effects on heart function compared to cisplatin. Our findings may be of interest for a possible synthetic strategy of introducing a carrier ligand that will exert a less cardiotoxic effect.

Efficiency of atorvastatin and simvastatin in improving cardiac function during the different degrees of hyperhomocysteinemia.

The aim of this study was to assess the impact of atorvastatin and simvastatin on myocardial contractility during the different degrees of hyperhomocysteinemia (HHcy) in rats. Study was conducted on adult male Wistar albino rats (n = 90; 4 weeks old; 100 ± 15 g body mass) in which HHcy was achieved by dietary manipulation. Animals were exposed to pharmacology treatment with atorvastatin in dose of 3 mg/kg per day i.p. or simvastatin in dose of 5 mg/kg per day i.p. at the same time every day, according to equivalent therapeutic doses of these statins (10 mg atorvastatin = 20 mg simvastatin). After the dietary manipulation and pharmacological treatment and confirmation of HHcy, all animals were sacrificed, hearts were isolated, and cardiac function was tested according to the Langendorff technique. Size of recovery of maximum rate of left ventricular development (dp/dtmax), minimum rate of left ventricular development (dp/dtmin), systolic left ventricular development, diastolic left ventricular development, heart rate, and coronary flow at the 40, 60, 80, 100, and 120 cmH2O coronary perfusion pressure were measured in state of physiological condition (homocysteine less than 15 µmol/L), mild HHcy, and moderate HHcy. Atorvastatin treatment significantly attenuated homocysteine-induced impairment of myocyte contractility and dominantly decreased dp/dtmax, dp/dtmin, and heart rate and induced greater changes in systolic left ventricular development compared with simvastatin. Treatment with atorvastatin seems able to revert systolic abnormalities and improve contractility during the different degrees of HHcy.

The Effects of Potassium Cyanide on the Functional Recovery of Isolated Rat Hearts after Ischemia and Reperfusion: The Role of Oxidative Stress.

This investigation is aimed at examining the effects of pharmacological PostC with potassium cyanide (KCN) on functional recovery, gene expression, cytochrome c expression, and redox status of isolated rat hearts. Rats were divided into the control and KCN groups. The hearts of male Wistar albino rats were retrogradely perfused according to the Langendorff technique at a constant perfusion pressure of 70 cmH2O. After stabilisation, control hearts were subjected to global ischemia (5 minutes), followed by reperfusion (5 minutes), while experimental hearts underwent global ischemia (5 minutes) followed by 5 minutes of reperfusion with 10 µmol/L KCN. The following parameters of heart function were measured: maximum and minimum rates of pressure development, systolic and diastolic left ventricular pressure, heart rate, and coronary flow. Levels of superoxide anion radical, hydrogen peroxide, nitrites, and index of lipid peroxidation (measured as thiobarbituric acid-reactive substances) were measured in coronary venous effluent, and activity of catalase was determined in heart tissue. Expression of Bax, Bcl-2, SOD-1, SOD-2, and cytochrome c was studied as well. It was shown that expression of Bax, Bcl-2, and SOD-2 genes did not significantly differ between groups, while expression of SOD-1 gene and cytochrome c was lower in the KCN group. Our results demonstrated that KCN improved the recovery of myocardial contractility and systolic and diastolic function, enhanced catalase activity, and diminished generation of prooxidants. However, all possible mechanisms and potential adverse effects of KCN should be further examined in the future.

Cisplatin and cisplatin analogues perfusion through isolated rat heart: the effects of acute application on oxidative stress biomarkers.

Drug-induced oxidative stress can occur in numerous tissues and organ systems (liver, kidney, ear, nervous system, and cardiovascular system). Cancer therapy with cisplatin is associated with side effects to which oxidative stress may contribute. We have compared the influences of cisplatin (reference compound) and its' analogues (dichloro(1,2-diaminocyclohexane)platinum(II) and chloro(2,2':6',2″-terpyridine)platinum(II)) in a model of isolated rat heart using the Langendorff technique. The production of oxidative stress biomarkers, antioxidant enzymes, myocardial damage, and expression of Bax, OH-1, and SODs were studied. Cisplatin and the analogues were perfused at concentration of 10-6 and 10-5 M during 30 min. The results of this study showed that examined platinum complexes had different ability to induce oxidative stress of isolated perfused rat heart. Varying the carrier ligands, such as 1,2-diaminocyclohexane and 2,2':6',2″-terpyridine, related to amino ligands (cisplatin) directly influenced the strength to induce production of oxidative stress biomarkers. Introducing 2,2':6',2″-terpyridine ligands provoked the smallest changes in antioxidant enzymes activity, lipid peroxidation, and expression of heme oxygenase-1, that undoubtedly indicated that this complex had the lowest impact on redox status in heart tissue. These findings may be useful in synthesis of novel platinum analogues with lower potential for oxidative stress induction. However, the fact that platinum complexes could induce toxic effects in the heart by other mechanisms should be taken into the consideration.

Acute effects of nandrolone decanoate on cardiodynamic parameters in isolated rat heart.

Despite worldwide use of anabolic steroids in last decades, there is still contradictory information about their acute influence on myocardium. The aim of this study was to examine the acute effects of nandrolone decanoate (ND) on cardiodynamics and coronary flow in isolated rat heart. The hearts of male Wistar albino rats (n = 48, 12 per group, age 8 weeks, body mass 180-200 g) were excised and perfused according to the Langendorff technique at gradually increased coronary perfusion pressures (40-120 cmH2O). After the control sets of experiments, the hearts in different groups were perfused with different doses of ND (1, 10, or 100 µmol/L separately). Using a sensor placed in the left ventricle, we registered maximum and minimum rate of pressure development in the left ventricle (dP/dtmax and dP/dtmin), systolic and diastolic left ventricular pressure (SLVP and DLVP), and heart rate (HR). Coronary flow (CF) was measured flowmetrically. The results clearly show the depression in cardiac function caused by higher doses of ND. The highest concentration of ND (100 µmol/L) induced the most deleterious impact on the myocardial function and perfusion of the heart (coronary circulation), which could be of clinical significance.