Favorable versus detrimental cardiovascular responses to intermittent hypoxia conditioning (IHC) are heavily dependent on experimental or pathological conditions, including the duration, frequency and intensity of the hypoxia exposures. Recently, we demonstrated that a program of moderate, normobaric IHC (FIO2 9.5-10% for 5-10 min/cycle, with intervening 4 min normoxia, 5-8 cycles/day for 20 days) in dogs afforded robust cardioprotection against infarction and arrhythmias induced by coronary artery occlusion-reperfusion, but this protection has not been verified in other species. Accordingly, in this investigation cardio- as well as vasoprotection were examined in male Wistar rats completing the normobaric IHC program or a sham program in which the rats continuously breathed atmospheric air. Myocardial ischemia and reperfusion (IR) was imposed by occlusion and reperfusion of the left anterior descending coronary artery in in situ experiments and by subjecting isolated, perfused hearts to global ischemia-reperfusion. Cardiac arrhythmias and myocardial infarct size were quantified in in situ experiments. Endothelial function was evaluated from the relaxation to acetylcholine of norepinephrine-precontracted aortic rings taken from in situ IR experiments, and from the increase in coronary flow produced by acetylcholine in isolated hearts. IHC sharply reduced cardiac arrhythmias during ischemia and decreased infarct size by 43% following IR. Endothelial dysfunction in aorta was marked after IR in sham rats, but not significant in IHC rats. Similar findings were found for the coronary circulations of isolated hearts. These findings support the hypothesis that moderate, normobaric IHC is cardio- and vasoprotective in a rat model of IR.
A course of transauricular electrostimulation (TES) consisting of 10 sessions was administered to rats before the induction of myocardial infarction by Selye's method and to rats that were left intact. In the latter animals, the electrostimulation did not influence cardiac contractile function at rest (as judged by heart rate, developed pressure, and Katz's index), but exerted beneficial chronotropic and inotropic effects during the maximum isometric tension produced by compression of the ascending aorta. In the TES-pretreated rats with a 2-day-old myocardial infarct, cardiac contractile function was depressed significantly less, both at rest and during isometric tension, than in infarcted rats not exposed to TES.
Иммунотерапия обеспечивает значительный прогресс в лечении рака, однако, не у всех, и не всегда. В обзоре мы кратко проанализировали основные методы иммунотерапии рака и обозначили новый подход для повышения их эффективности. Проблему иммунотерапии рака мы рассмотрели через призму концепции адаптации к факторам среды. В контексте этой концепции высокая выживаемость опухолевой клетки может быть обусловлена адаптацией к лекарствам и агрессивным факторам иммунитета, таким как свободные радикалы и воспалительные цитокины. В онкологической клинике врач с помощью иммунотерапии пытается усилить иммунитет больного. Эта тактика оправдана, если удается увеличить силу иммунной атаки до уровня, который убивает опухоль. Но если стимулирование иммунитета недостаточно сильное, чтобы убить опухолевую клетку, это приводит к дополнительной адаптации опухоли и повышению ее устойчивости. Отсюда следует важная для клиники гипотеза: снизить выживаемость опухолевых клеток можно с помощью нарушения ее механизмов адаптации. Концепция адаптации предлагает два способа решения: 1) блокировать активацию генов и синтез белков, необходимых для формирования адаптивного системного структурного следа (ССС); и 2) прекратить действие адаптирующих факторов, и благодаря этому вызвать исчезновение ССС, дезадаптацию и утрату опухолью приобретенной устойчивости. Применительно к иммунотерапии рака второй способ порождает, на первый взгляд абсурдную идею, «отключить» иммунную систему на период до стадии дезадаптации опухоли, и только затем применить иммунотерапию к утратившим устойчивость опухолевых клеток. Эта гипотеза нуждается в проверке, но уже сейчас с ней согласуются косвенные данные. Снижение адаптивной устойчивости опухолевых клеток могло бы существенно увеличить антиопухолевый потенциал иммунотерапии рака. Immunotherapy provides significant progress in treatment of cancer although not for all and not always. In this review, we briefly analyzed major immunotherapies for cancer and outlined a new approach to improve their effectiveness. We examined the issue of cancer immunotherapy through the prism of the concept of adaptation to environmental factors. In the context of this concept, the high survival rate of tumor cells may be due to cell adaptation to drugs and aggressive immunity factors, such as free radicals and inflammatory cytokines. In the oncological clinic, physicians try to enhance the patient’s immunity with immunotherapy. This tactic is warranted if the physician would manage to increase the potency of immune attack to a level that kills the tumor. However, if the enhanced power of immunity attack is insufficient to kill a tumor cell, the tumor may additionally adjust and stabilize. Therefore, a clinically important hypothesis ensues: the tumor cell survival may be impaired by disrupting its adaptive mechanisms. The concept of adaptation offers two options: 1) to block activated synthesis of the genes and proteins that are required for formation of an adaptive systemic structural trace (SST) and 2) to stop the action of adapting factors, and, thereby, to erase the SST and induce maladaptation with loss of the acquired resistance of the tumor. With regard to cancer immunotherapy, the second option creates, at the first glance, an absurd idea, to “turn off” the immune system for a period preceding the stage of tumor maladaptation, and only then to apply immunotherapy to the tumor cells that have become less resistant. This hypothesis needs to be verified but some indirect data are already consistent with it. Reducing the adaptive resistance of tumor cells could significantly increase the antitumor potential of cancer immunotherapy.
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