Ruscogenin alleviates intestinal bleeding and blood flow induced by Dasatinib through ROCK/MLC pathway

As a second-generation broad-spectrum tyrosine kinase inhibitor, Dasatinib has the antitumor effect of inhibiting tyrosine kinases such as BCR-ABL and SRC. It is mainly used to treat chronic and acute patients with chronic myelogenous leukemia. However, Dasatinib has many side effects, including gastrointestinal bleeding, respiratory infections, and renal failure, and effective means to improve the side effects of drugs are lacking. The occurrence of gastrointestinal bleeding is mainly due to the destruction of the vascular endothelial barrier by Dasatinib. For the first time, we administered a large dose of oral administration and monitored the intestinal bleeding with a laser Doppler flowmeter. We found that Ruscogenin (RUS) can improve dasatin Side effects caused by tinib. Through Doppler flowmeter detection, it was found that after Dasatinib was administered, blood flow in mice decreased, and intestinal Evans blue leakage increased. Western blot results showed that connexin (ZO-1, VE-cadherin, Occludin) is destroyed, the activation of ROCK increases, and the phosphorylation of MLC increases. Ruscogenin can reverse the above phenomenon and improve the side effects of gastrointestinal bleeding caused by Dasatinib. In vitro, giving Ruscogenin in advance can protect the endothelial barrier damage caused by Dasatinib, reduce the remodeling of F-actin, and restore the expression of connexin (ZO-1, VE-cadherin), inhibit the activation of ROCK, and reduce Phosphorylation of MLC. This study provides a new direction for improving the side effects caused by clinical drugs.

FEATURES OF THE DAILY PROFILE OF ARTERIAL PRESSURE AND THE POSSIBILITY OF DOCLINE DIAGNOSTICS OF ARTERIAL HYPERTENSION IN CHILDREN WITH TYPE 1 DIABETES

Diabetic nephropathy takes a leading place among diseases requiring replacement therapy for renal failure, and is also a leading cause of disability and mortality among patients with type 1 diabetes. The development of arterial hypertension is one of the markers of the formation of diabetic nephropathy. We performed a prospective cohort study. A comprehensive clinical and instrumental examination of 78 children with type 1 diabetes was carried out. The features of changes in the daily profile of blood pressure and microcirculatory disorders in children before the formation of diabetic nephropathy were revealed. A mathematical model is developed for predicting the development of arterial hypertension by determining microcirculation parameters using a laser Doppler flowmeter. Early diagnosis will allow timely prescribing of pathogenetic treatment, improving the prognosis of this category of patients.

The scale of cerebral ischemia thresholds in rats

Прогноз и тактика лечения инсульта зависят от его тяжести, которая задается достигнутым ишемическом порогом. Исследование механизмов формирования ишемических порогов является актуальной патофизиологической задачей. Целью настоящего исследования явилось получение данных для построения шкалы порогов ишемии мозга у крыс. Эксперименты проводили на наркотизированных беспородных крысах-самцах. Мозговой кровоток регистрировали лазерным допплеровским флоуметром ЛАКК-02 (Лазма, Россия). Контролируемую кровопотерю осуществляли через бедренную артерию. Фиксировали системное артериальное давление (АД), при котором в условиях медленной кровопотери регистрировалось пороговое значение мозгового кровотока. На основании полученных данных строилась шкала: системное АД - кровоток - пороги ишемии мозга. Prognosis and treatment of stroke depend on its severity, which is defined by the attained ischemic threshold. Studying the mechanisms underlying the formation of ischemic thresholds is an urgent pathophysiological task. The aim of this study was to obtain data for constructing a scale of cerebral ischemia thresholds in rats. Experiments were carried out on anesthetized mongrel male rats. Cerebral blood flow was recorded with a laser Doppler flowmeter, LAKK-02 (Lazma, Russia). Controlled blood loss was performed through the femoral artery. Systemic blood pressure, at which the threshold value of cerebral blood flow was attained, was recorded under the conditions of slow blood loss. Based on the obtained data the systemic blood pressure - blood flow - thresholds of cerebral ischemia scale was constructed.

False spectra formation in the differential two-channel scheme of the laser Doppler flowmeter

Noise in the differential two-channel scheme of a classic laser Doppler flowmetry (LDF) instrument was studied. Formation of false spectral components in the output signal due to beating of electrical signals in the differential amplifier was found out. The improved block-diagram of the flowmeter was developed allowing to reduce the noise.

Abstract WP295: Remote Limb Ischemic Conditioning in Murine Focal Cerebral Ischemia

Background & Aims: Remote ischemic conditioning (RIC) could induce brain protection in cerebral ischemia. The conditioning can be divided into pre-, per- and post-conditioning. The aim of this study is to clarify which RIC is the most effective in murine focal ischemia. Methods: Adult male C57BL/6 mice were used in this study. Transient focal cerebral ischemia was produced with nylon-suture model by occluding middle cerebral artery (MCAO) for 45 minutes. Cortical cerebral blood flow (rCBF) was continuously measured during ischemia with laser Doppler flowmeter. Twenty-four hours after MCAO, the animals were sacrificed and their brains were removed. After cutting coronal 1-mm brain sections, infarct volume was measured after TTC staining. Fifty mice were divided into five groups (each n=10); sham RIC group, delayed preRIC group (RIC 24 hours before MCAO), early preRIC group (RIC 5 minutes before MCAO), perRIC group (RIC during MCAO), and postRIC group (RIC 5 minutes after MCAO). Hind limb ischemia was induced by making the snare as tight as possible using a hemostatic forceps for 5 minutes followed by loosening it for 5 minutes. Four cycles were performed as RIC. Results: Infarct volume were 58.8±10.1 mm 3 in sham RIC, 54.8±19.4 mm 3 in delayed preRIC, 69.3±10.8 mm 3 in early preRIC, 38.0±22.1 mm 3 in perRIC, and 64.5±13.5 mm 3 in postRIC groups. Infarct volume in perRIC was significantly smaller than that in sham RIC and other groups (P<0.01). However, infarct volume of other RIC groups was not different with sham RIC group. After MCAO, rCBF reduced to 15.6% of baseline level in sham RIC, 11.2% in delayed preRIC, 11.9% in early preRIC, 13.4% in perRIC, and 10.8% in postRIC group. No difference was found in residual rCBF among all groups. At the end of MCAO, rCBF compared to rCBF immediate after occlusion was 102±21% in sham RIC, 112±25% in delayed preRIC, 98±22% in early preRIC, 131±33% in perRIC and 105±19% postRIC groups. Relative rCBF change at the end of MCAO in perRIC was significantly more than that in sham RIC group (P<0.05). Conclusions: Among four RIC procedures, only perRIC showed clear brain protection against transient MCAO. Change during rCBF may suggest that enhancement of collateral circulation play a role in part on brain protective effect of perRIC.