Bile salt export pump (BSEP) is responsible for biliary secretion of bile acids, a rate limiting step in the enterohepatic circulation of bile acids and transactivated by nuclear receptor farnesoid x receptor (FXR). Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent disorder among diseases unique to pregnancy and primarily occurs in the third trimester of pregnancy with a hallmark of elevated serum bile acids. Currently, the transcriptional regulation of BSEP during pregnancy and its underlying mechanisms and involvement in ICP are not fully understood. In this study, the dynamics of BSEP transcription in vivo in the same group of pregnant mice before, during and after gestation were established with in vivo imaging system (IVIS). BSEP transcription was markedly repressed in the later stages of pregnancy and immediately recovered after parturition, resembling the clinical course of ICP in human. The transcriptional dynamics of BSEP was inversely correlated with serum 17β-estradiol (E2) levels before, during and after gestation. Further studies showed that E2 repressed BSEP expression in human primary hepatocytes, Huh 7 cells and in vivo in mice. Such transrepression of BSEP by E2 in vitro and in vivo required estrogen receptor α (ERα). Mechanistic studies with chromatin immunoprecipitation (ChIP), protein co-immunoprecipitation (Co-IP) and bimolecular fluorescence complementation (BiFC) assays demonstrated that ERα directly interacted with FXR in living cells and in vivo in mice. In conclusion, BSEP expression was repressed by E2 in the late stages of pregnancy through a non-classical E2/ERα transrepressive pathway, directly interacting with FXR. E2-mediated repression of BSEP expression represents an etiological contributing factor to ICP and therapies targeting the ERα/FXR interaction may be developed for prevention and treatment of ICP.

As a canalicular bile acid effluxer, bile salt export pump (BSEP) plays a vital role in maintaining bile acid homeostasis. BSEP deficiency leads to severe cholestasis and hepatocellular carcinoma (HCC) in young children. Regardless of the etiology, chronic inflammation is the common pathological process for HCC development. Clinical studies showed that bile acid homeostasis is disrupted in HCC patients with elevated serum bile acid level as a proposed marker for HCC. However, the underlying mechanisms remain largely unknown. In this study, we found that BSEP expression was severely diminished in HCC tissues and markedly reduced in adjacent non-tumor tissues. In contrast to mouse, human BSEP was regulated by farnesoid x receptor (FXR) in an isoform-dependent manner. FXRα2 exhibited a much more potent activity than FXRα1 in transactivating human BSEP in vitro and in vivo. The decreased BSEP expression in HCC was associated with altered relative expression of FXRα1 and FXRα2. The FXRα1/FXRα2 ratios were significantly increased with undetectable FXRα2 expression in one third of the HCC tumor samples. Similar correlation between BSEP and FXR isoform expression was confirmed in hepatoma Huh 7 and HepG2 cells. Further studies showed that intrahepatic proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were significantly elevated in HCC tissues. Treatment of Huh 7 cells with IL-6 and TNF-α resulted in a marked increase in the FXRα1/FXRα2 ratio concurrent with a significant decrease in BSEP expression. In conclusion, BSEP expression was severely diminished in HCC patients associated with alteration of FXR isoform expression induced by inflammation, and the restoration of BSEP expression through suppressing inflammation in the liver may re-establish the bile acid homeostasis.

One of the most complex forms of congenital heart disease (CHD) involving single ventricle physiology is hypoplastic left heart syndrome (HLHS), characterized by underdevelopment of the left ventricle (LV), mitral and aortic valves, and narrowing of the ascending aorta. The underdeveloped LV is incapable of providing long-term systemic flow, and if left untreated, the condition is fatal. Current treatment for this condition consists of three consecutive staged palliative operations: the first is conducted within the first few weeks of birth, the second between 4 to 6 months, and the third and final surgery within the first 4 years. At the conclusion of the third surgery, systemic perfusion is provided by the right ventricle (RV), and deoxygenated blood flows passively to the pulmonary vasculature. Despite these palliative interventions, the RV, which is ill suited to provide long-term systemic perfusion, is prone to eventual failure. In the absence of satisfying curative treatments, stem cell therapy may represent one innovative approach to the management of RV dysfunction in HLHS patients. Several stem cell populations from different tissues (cardiac and non-cardiac), different age groups (adult- neonate-derived), and different donors (autologous allogeneic), are under active investigation. Preclinical trials in small and large animal models have elucidated several mechanisms by which these stem cells affect the injured myocardium, and are driving the shift from a paradigm based upon cellular engraftment and differentiation to one based primarily on paracrine effects. Recent studies have comprehensively evaluated the individual components of the stem cells' secretomes, shedding new light on the intracellular and extracellular pathways at the center of their therapeutic effects. This research has laid the groundwork for clinical application, and there are now several trials of stem cell therapies in pediatric populations that will provide important insights into the value of this therapeutic strategy in the management of HLHS and other forms of CHD. This article reviews the many stem cell types applied to CHD, their preclinical investigation and the mechanisms by which they might affect RV dysfunction in HLHS patients, and finally, the completed and ongoing clinical trials of stem cell therapy in patients with CHD.

Hypoplastic left heart syndrome is a type of congenital heart disease characterized by underdevelopment of the left ventricle, outflow tract, and aorta. The condition is fatal if aggressive palliative operations are not undertaken, but even after the complete 3-staged surgical palliation, there is significant morbidity because of progressive and ultimately intractable right ventricular failure. For this reason, there is interest in developing novel therapies for the management of right ventricular dysfunction in patients with hypoplastic left heart syndrome. Stem cell therapy may represent one such innovative approach. The field has identified numerous stem cell populations from different tissues (cardiac or bone marrow or umbilical cord blood), different age groups (adult versus neonate-derived), and different donors (autologous versus allogeneic), with preclinical and clinical experience demonstrating the potential utility of each cell type. Preclinical trials in small and large animal models have elucidated several mechanisms by which stem cells affect the injured myocardium. Our current understanding of stem cell activity is undergoing a shift from a paradigm based on cellular engraftment and differentiation to one recognizing a primarily paracrine effect. Recent studies have comprehensively evaluated the individual components of the stem cells' secretomes, shedding new light on the intracellular and extracellular pathways at the center of their therapeutic effects. This research has laid the groundwork for clinical application, and there are now several trials of stem cell therapies in pediatric populations that will provide important insights into the value of this therapeutic strategy in the management of hypoplastic left heart syndrome and other forms of congenital heart disease. This article reviews the many stem cell types applied to congenital heart disease, their preclinical investigation and the mechanisms by which they might affect right ventricular dysfunction in patients with hypoplastic left heart syndrome, and finally, the completed and ongoing clinical trials of stem cell therapy in patients with congenital heart disease.

A hypothesis about a correlation between threshold pain sensitivity and antibody production is proposed and experimentally validated. Immunodeficient mouse strains are characterized by a higher threshold sensitivity to pain than animals with a normal immune response. A highly reliable negative correlation between threshold sensitivity to pain assessed by the hot plate test and the number of antibody-producing cells in the spleen after immunization with sheep red cells is observed in 77% of (CBAxC57B1/ 6) F 1 mice examined. The negative correlation is observed both in spontaneous variations of threshold pain sensitivity and during an elevation of this threshold under the effect of preceding nociceptive stimulation.

No abstract

Bone marrow cells, produce soluble mediators with structural and functional heterogeneity. They were found to stimulate antibody production at the peak of the immune response, owing to compounds of a peptide nature (M1 2000–1300). Active material was isolated by means of gel chromatography and electrophoresis. This material positively reacts with ninhydrin, and has maximum absorption close to 278 nm. Its antibody‐stimulating activity decreased or stopped completely after treatment with proteolytic enzymes. Apart from the immunostimulating activity, bone marrow mediators have opiate‐like activity. They have an analgetic effect, and interact with the opiate receptors of brain nerve cells. After a physicochemical and functional analysis, we concluded that bone marrow produces regulatory peptides that were previously unknown. We called them myelopeptides.

1 ФГБОУ ВО «Первый Московский государственный медицинский университет им. и.М. Сеченова» Минздрава России, Москва, Россия;2 ФГБУ «Российский научный центр медицинской реабилитации и курортологии» Минздрава России, Москва, Россия В статье представлены доказательства преимущества персонифицированного подхода при лечении пациентов с гиперто-нической болезнью (ГБ), дорсопатией поясничного отдела позвоночника, хронической обструктивной болезнью легких (ХОБл) и язвенной болезнью двенадцатиперстной кишки (ЯБДк) на основании измерений напряжения тестирования (Uтест) в реперной точке. Цель -разработать алгоритм определения достаточного количества процедур (оптимальной длительности) курсового лечения по Uтест в реперной точке. Пациенты и методы. В исследование были включены 647 пациентов (439 женщин и 208 мужчин в возрасте от 25 до 72 лет) с ГБ i-ii стадии, ЯБДк в стадии обострения, дорсопати-ей поясничного отдела позвоночника ii-iii стадии, ХОБл ii-iii стадии, подписавших информированное согласие. Паци-енты были разделены на 3 группы: в 1-й группе применялась стандартная терапия; во 2-й -динамическая электронейро-стимуляция (ДЭНС) на фоне стандартной терапии; в 3-й -персонифицированная ДЭНС (путем определения достаточно-го количества процедур) на фоне стандартной терапии. результаты. При ГБ у пациентов 3-й группы снижение артериаль-ного давления было более выраженным по сравнению с больными 1-й (на 9%) и 2-й (на 3%) групп; при дорсопатиях по-ясничного отдела позвоночника болевой синдром по визуальной аналоговой шкале в 3-й группе уменьшился в 2 раза, тогда как в 1-й -в 1,2 раза, а во 2-й -в 1,8 раза; при ЯБДк уровень рН в желудке в 3-й группе увеличился на 33,3%, тогда как в 1-й -на 12,5%, а во 2-й -на 21,8%; при ХОБл жизненная емкость легких в 3-й группе пациентов увеличилась в среднем на 612 мл, во 2-й -на 477 мл, а в 1-й -на 219 мл. Заключение. Результаты проведенных исследований дока-зали преимущества персонифицированного подхода путем определения достаточного количества процедур при курсовом лечении, основанного на измерении Uтест. Определение Uтест в реперной точке является способом оценки функцио-нального состояния организма и методом, направленным на управление лечебным процессом. This article was designed to present evidence of the advantages of the personified approach to the treatment of the patients presenting with arterial hypertension (ah), lumbar spinal dorsopathy (lSD), chronic obstructive pulmonary disease (coPD), and duodenal ulcer (DU) at the stage of exacerbation obtained by the measurements of testing voltage at the reference point (Utest). aim. The objective of the present study was to develop the algorithm for the determination of the sufficient number (optimal duration) of therapeutic procedures of the protracted treatment with the use of the Utest at the reference point. The patients and methods. The study included 647 patients (439 women and 208 men at the age varying from 25 to 72 years) with grade i-ii ah, DU at the stage of exacerbation, grades ii and iii lumbar spinal dorsopathy, grade ii-ii...