Convallatoxin induces HaCaT cell necroptosis and ameliorates skin lesions in psoriasis-like mouse models.

Psoriasis is considered an immune-mediated inflammatory skin disorder that affects the quality of life of nearly four percent of the world population. Considering the side effects of existing therapeutic drugs and the urgent need for new drug development, we screened more than 250 traditional Chinese medicine compounds to identify drugs that significantly reduced the viability of human HaCaT keratinocytes, a psoriasis-related model cell line. Convallatoxin (CNT) was found to be a highly effective inhibitor of HaCaT cell viability. Subsequent mechanistic studies revealed that CNT induced HaCaT cell death by necroptosis rather than by apoptosis. CNT destroyed the membrane integrity of HaCaT cells, as detected by nuclear propidium iodide (PI) staining and lactate dehydrogenase (LDH) release. Additionally, the intercellular levels of adenosine triphosphate (ATP) were lower in HaCaT cells treated with CNT than in control HaCaT cells, and typical necroptosis-associated characteristics were observed by electron microscopy in cells treated with CNT. Furthermore, compared with control HaCaT cells, CNT-treated HaCaT cells produced more reactive oxygen species (ROS), but this effect was inhibited by the antioxidants N-acetyl-cysteine (NAC), diphenyleneiodonium chloride (DPI), and apocynin and the necroptosis inhibitor Nec-1. In addition, antioxidant treatment attenuated necroptotic cell death, suggesting that CNT-induced HaCaT necroptosis is mediated by oxidative stress. More importantly, CNT ameliorated skin lesions and inflammation in imiquimod (IMQ)- and 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced psoriasis-like mouse models. In conclusion, our results demonstrate that CNT is cytotoxic against HaCaT cells in vitro and exerts antipsoriatic activities in two mouse models of psoriasis in vivo, making CNT a potential promising candidate drug for future research.

[The influence of kordaron on the pharmacodynamic effects of strophanthin in experiments on isolated myocardial preparations and in the modelling of heart failure]. / Vliianie kordarona na farmakodinamicheskie éffekty strofantina v éksperimentakh na izolirovannykh preparatakh miokarda i v usloviiakh modelirovaniia serdechnoi nedostatochnosti.

The experiments with isolated rat atria isometrically contracting and those with simulated rat heart failure were performed to study the effects of the alpha-, beta-, and X-blocker cordarone on the pharmacodynamic effects of strophanthin. Cordarone was demonstrated to greatly decrease the toxicity of the cardiotonic in circulatory decompensation, without causing negative effects of cardiac inotropic function. Cordarone in combination with strophanthin slightly diminished the magnitude of the negative chronotropic effect of the cardiac glycoside and slowed down the rate of its cardiotonic effect.

[Effects of xin-fu-ning IV on experimental congestive heart failure in rabbits].

By use of pentobarbital sodium to produce experimental congestive heart failure (CHF) in 40 rabbits, they were treated with xin-fu-ning IV (XFN IV), the plasma atrial natriuretic factor (ANF) levels and atrial tissue ANF levels of rabbits were measured. The results showed that XFN IV had elevated ANF levels of the rabbits with CHF. It showed that XFN IV could improve endocrine function of heart, and it also showed good curative effect on CHF.

[Effect of strophanthin and digoxin on the activity of succinate and lactate dehydrogenases and membrane Na+, K+-ATPase in the heart of rats with experimental myocarditis]. / Vliianie strofantina i digoksina na aktivnost' suktsinat-laktatdegidrogenaz i membrannoi Na+, K+-ATFazy v serdtse krys s éksperimental'nym miokarditom.

In rats with adrenaline-induced myocarditis conditionally therapeutic doses of strophanthin (2.7 mg/kg) and digoxin (0.89 mg/kg) were chosen according to performance of the test of swimming until the complete fatigue. The influence of drugs in these doses on enzymatic activity was evaluated by histochemical methods in heart of control and myocarditis rats. It was found out that both of cardiac glycosides decreased lactate dehydrogenase and membrane Na+, K+-ATPase activity and increased succinate dehydrogenase activity in rats with experimental myocarditis.

[Myocardial contractile function in acute heart failure during exposure to strophanthin and its combination with alpha-tocopherol]. / Sokratitel'naia funktsiia miokarda pri ostroi serdechnoi nedostatochnosti v usloviiakh deistviia strofantina i ego sochetanii s al'fa-tokoferolom.

In experiments on rabbits it was established that strophanthin (0.05 mg/kg) administered to animals with cardiac insufficiency due to a severe overloading of the heart function by occlusion of the diaphragmatic portion of the aorta by 4/5 of its diameter improved the contractile activity and relaxing properties of the left ventricle. This effect is however transient (up to 15-30 minutes) with the subsequent reduction of its characteristic indices, the development of symptoms of intoxication and not infrequently death of animals. alpha-tocopherol administered before the pathology reproduction (10 mg/kg, 3 days) increases the period of myocardial compensation and when given in combination with strophanthin significantly potentiates the cardiac effect of glycoside manifesting by an increase of the strength and rate of contraction and intensity of diastolic relaxation of the myocardium, prolongs the animal's life.

[Possibilities for the strophanthin pharmacological correction of cardio- and hemodynamic disorders in dogs in the early stage of experimental lung-heart failure]. / Vozmozhnosti farmakologicheskoi korrektsii strofantinom narushenii kardio- i gemodinamiki u sobak na rannei stadii éksperimental'noi legochno-serdechnoi nedostatochnosti.

Experiments on intact dogs and animals with an early stage of experimental cardiopulmonary insufficiency due to chronic pneumonia were made to study the action of strophanthine on the hemodynamics of the left and right ventricles and pressure in the pulmonary artery. Administration of the glycoside to animals with cardiopulmonary insufficiency increased the contractility of the right ventricle and the intensity of diastolic relaxation of both ventricles. Strophanthine was revealed to exert the prevailing effect on the cardiodynamics of the right ventricle both in intact dogs and in animals with experimentally induced pathology. Strophanthine increased pressure in the pulmonary artery, promoting the overload of the right ventricle to a less degree than convallotoxin.

[Effect of strophanthin in adrenergic blockade on the blood supply and work of the heart in acute coronary artery occlusion]. / Vliianie strofantina v usloviiakh adrenergicheskoi blokady na krovosnabzhenie i rabotu serdtsa pri ostroi okkliuzii koronarnoi arterii.

The effects of strophathin in a dose of 0.15 mg/kg bw were investigated under alpha- and beta-adrenergic blockade by the methods of thermodilution and circulation registration in the pool of the occluded coronary artery in anesthetized dogs. It was determined that strophanthin increased the blood supply of the myocardial ischemic centres, the minute heart volume, and systemic arterial pressure and decreased the general peripheral vascular resistance. The alpha-adrenoblocker, phentolamine (0.025 mg/kg intravenously) decreased the strophanthin stimulant effect on the collateral coronary blood stream and heart activity without changing its chronotropic and vasopressive action. The beta-adrenoreceptor blockade induced by obsidan (0.5 mg/kg) made no changes in the pattern of the glycoside cardiovascular effects and diminished its chronotropic action.

[Inhibition of free-radical lipid peroxidation in myocardial infarct as affected by strophanthin]. / Tormozhenie perekisnogo svobodnoradikal'nogo okisleniia lipidov pri infarkte miokarda pod vliianiem strofantina.

It was shown in experiments on rats with experimental ischemic myocardial infarction that strophanthin inhibits free-radical lipid peroxidation, decreases (in mean and little doses) the ectopic activity of the myocardium, eliminates tachyarrhythmias arising in the presence of coronary occlusion, delays the appearance on the ECG of changes characteristic for acute myocardial infarction. In mean doses, strophanthin decreases the macrosize of the zone of infarction. It is recommended that strophanthin K (in mean and little doses) be included in a combined therapy of myocardial infarction.

[Effect of isoptin and its combination with strophanthin on collateral coronary circulation and systemic hemodynamics in acute myocardial ischemia]. / Vliianie izoptina i ego kombinatsii so strofantinom na kollateral'noe koronarnoe krovoobrashchenie i sistemnuiu gemodinamiku pri ostroi ishemii miokarda.

It was established in acute experiments on dogs with the anterior interventricular branch of the left coronary artery ligated in the middle third that isoptin increases essentially the blood flow and oxygen tension in the focus of acute myocardial ischemia, increases the cardiac stroke and minute volumes, and reduces the total peripheral vascular resistance. Strophanthin removes the favourable effect of isoptin on collateral coronary circulation and contractile myocardial activity and increases the total peripheral vascular resistance.

[Action of convallotoxin on cardiac hemodynamics in experimental stenosis of the pulmonary trunk]. / Deistvie konvallotoksina na kardiogemodinamiku pri ékpserimental'nom stenoze legochnogo stvola.

The effect of convallotoxin on hemodynamics of the right and left ventricles and pressure in the pulmonary artery was studied in intact dogs and in surgical stenosis of the pulmonary trunk. In intact anesthetized dogs, convallotoxin produced changes in hemodynamics that were more pronounced in the right than in the left ventricle (decreased intraventricular pressure, increased dp/dtmax and dp/dtmin). Administration of convallotoxin ton dogs one month after pulmonary trunk stenosis without episodes of congestive heart failure did not improve the cardiohemodynamics.

[Effects of strophanthin, mefenamic acid and dexamethasone on the inflammatory and reparative processes in the heart in experimental myocarditis]. / Vliianie strofantina, mefenamovoi kisloty i deksametazona na vospalitel'no-reparativnye protsessy v serdtse pri éksperimental'nom miokardite.

In isadrin-induced myocarditis, the rat heart shows an increase in the activity of acid phosphatase, glucose-6-phosphate dehydrogenase. The heart weight also rises, whereas ATPase activity and magnesium content fall. Under these conditions strophanthin produces a marked decrease in acid phosphatase activity, stimulates the activity of glucoso-6-phosphate dehydrogenase, and demonstrates a tendency to increasing the activity of ATP-splitting enzymes, to reducing the activity of ATP-synthetase, and to the recovery of the magnesium content. Mefenamic acid and dexamethasone also decrease the activity of acid phosphatase but this decrease is less pronounced as compared with that induced by strophanthin. They exhibit the same tendency to the inhibition of glucoso-6-phosphate dehydrogenase. Mefenamic acid affects the remaining parameters similarly to strophanthin, while dexamethasone inhibits them.

[Antifibrillatory activity of propranolol in experimental myocardial infarct and its cardiodepressive and hypotensive action]. / Antifibrilliatornaia aktivnost' propranolola pri éksperimental'nom infarkte miokarda i ego kardiodepressivnoe i gipotenzivnoe deistvie.

In experiments in nembutal anesthetized dogs the authors studied the dependence between the antifibrillation activity of propranolol, which was appraised according to the value of the ventricular fibrillation thresholds and the rate of spontaneous fibrillation after occlusion of the coronary artery, and the cardiodepressive and hypotensive action of this agent. It is shown that it is possible in principle to preserve the antifibrillation activity of propranolol infused intravenously in a dose of 1 mg/kg for correcting its cardiodepressive and hypotensive effect in combined intravenous infusion of 0.02 mg/kg corglycon. It is concluded that there is no dependence between antifibrillation activity and the cardiodepressive and hypotensive effects of propranolol.

[Effect of potassium glutamate on the manifestation of experimental arrhythmias in rabbits]. / Vliianie kaliia glutaminata na proiavleniia éksperimental'nykh aritmii u krolikov.

In rabbits and rats potassium glutaminate elicits antiarrhythmic effect in experimental arrhythmias induced by intravenous injection of strophanthine and calcium chloride, normalizes the content of electrolytes (potassium, sodium, calcium, magnesium) in the myocardium and blood of animals after they are injected strophanthine.