A New Cofilin-Dependent Mechanism for the Regulation of Brain Mitochondria Biogenesis and Degradation.

The aim Was to study the role of post-translational modifications of cofilin in the regulation of respiration and autophagy in murine brain mitochondria. MATERIALS AND METHODS: The experiments were performed with C57BL/6 mice. To obtain cytoplasmic and mitochondrial fractions of the brain tissue, differential centrifugation was used. Expressions of cofilin, phospho-cofilin, K48- and K63-associated chains of ubiquitin, and the autophagy marker LC3B were determined using electrophoresis, immunoprecipitation and Western blot methods. To study the processes of ubiquitination, we used PR619 - the inhibitor of deubiquitinating enzymes. Respiratory activity of brain mitochondria was evaluated using high-resolution fluorespirometry. RESULTS: Modification of cofilin by non-canonical K63 multiubiquitin chains in the cytoplasm and mitochondria from murine brain was demonstrated. Different levels of phospho-cofilin, cofilin, and its ubiquitinated proteoforms were found. PR619, the inhibitor of deubiquitinating enzymes, affects the expression of phosphorylated and ubiquitinated forms of cofilin in the mitochondria and cytoplasm, at the same time it changes the activity of tissue respiration and mitophagy. CONCLUSION: The sensitivity of cofilin to the inhibitor of deubiquitinating enzymes indicates the existence of a new non-catabolic mechanism of cofilin modification, which may be involved in the regulation of mitochondrial functions, specifically, the mitochondrial respiration and autophagy. The data help understand the molecular mechanisms of mitochondrial function in normal and pathological conditions, which may be useful in developing novel methods for the treatment of diseases of the nervous system.

[Chronic salpingo-oophoritis: clinical and physiological rationale for therapeutic application of impulse low-frequency electrostatic field].

Significant alterations in arterial and venous circulation, primarily in the vascular bed of the small pelvis, were detected in 63 patients with chronic salpingo-oophoritis. All the women received intensive therapy with impulse low-frequency electrostatic field (ILFEF). In 52 women the exposure was abdominovaginal, in 11 women the exposure was preceded by placebo procedures. ILFEF produced marked and long-term positive effects (up to 18 months): pain relief, reduction of vegetative anxiety, increased uterine motility, softening and better elasticity of the commissures in the regions of the uterine appendages, normalization of the circulation in the vascular bed of the small pelvis. This therapy is pathogenetically sound as it rests on changes in activity of central regulation resultant from trigger stimulation and normalization of hemodynamics in the vascular bed of the small pelvis (in 76.6%) especially in the veins in response to stimulation of the sympathetic nerves in the inflammation focus.

[The pathological mechanisms of the intermenstrual pain syndrome]. / Nekotorye patologicheskie mekhanizmy mezhmenstrual'nogo bolevogo sindroma.

Comprehensive clinicophysiological examinations of 80 patients suffering from the intermenstrual pain syndrome revealed organic changes in the pelvic organs of 92.5% of women and disturbances in the central structures participating in the conduction and control of pain sensitivity and vasomotor regulation in all the examinees, these changes correlating with specific vegetovascular and psychoemotional disorders. Three pathogenetic variants of development of this syndrome were defined.

[Effects of sex hormones on systemic reactions of the brain in women of different age]. / Vliianie polovykh gormonov na sistemnye reaktsii mozga v razlichnye vozrastnye periody zhizni zhenshchin.

Comparative analysis of electroencephalograms (EEG) and brain reactions to single and rhythmic photostimulation in 40 girls aged 9 to 17 with ovarian aplasia or hypofunction, 39 women of a reproductive age with ovarian exhaustion, and in 305 experimental animals aged 2 to 60 days with changed levels of estrogenic hormones showed that such changes influenced the formation of cerebral response starting from the age of 14-15 in humans and from days 15-20 in animals. The general trend of the electrical activity of the brain in hormonal deficiency manifested in all the groups by changed function of the activating brain structures. An increase of estrogen level at the age of 14-15 (in girls) and 20-30 days (in animals) caused the appearance of convulsive activity on the background EEG and an increase of rhythmic discharges of afteraction in the evoked potential. A definitive pattern of systemic reactions of the brain to changes in estrogen level was observed in girls aged 16-17 and in experimental animals aged 46-60 days.

[Autonomic nervous system activity during the normal menstrual cycle]. / Aktivnost' vegetativnoi nervnoi sistemy pri normal'nom menstrual'nom tsikle.

Body adaptation reactions to changes of the internal conditions (neurohumoral shifts related to ovulation and corpus luteum development) were studied in 15 women of a reproductive age with normal biphasic cycle in the early follicular and medium lutein phases on the basis of mathematical analysis of heart rhythm, a number of cardiovascular and respiratory system parameters, and brain electric activity. Moderate tension of the regulatory mechanisms in the lutein phase of the cycle was protective and adaptive and probably related to body preparation to a would-be pregnancy. These adaptive effects are different in different women: in some internal environment parameters vary within a wide spectrum, in others these parameters show a trend to retain their functioning regimen.

[The pathogenetic mechanisms of hyperthermia in patients with the premenstrual syndrome]. / Nekotorye patogeneticheskie mekhanizmy gipertermii u bol'nykh s predmenstrual'nym sindromom.

Functional status of the central and autonomic nervous system was analyzed in 28 patients with the premenstrual syndrome one of whose manifestations was disordered thermoregulation. The examinations were carried out during both cycle phases. Analysis of the EEG data and clinical findings has shown different patterns of autonomic thermoregulation disturbances in three groups of patients and permitted the authors to suggest that changed activity of certain neurotransmitter systems connected with hormonal secretion over the course of the cycle was responsible for these disturbances.

[The late clinical and physiological effects of different methods for the surgical treatment of patients with a uterine leiomyoma]. / Otdalennye klinicheskie i fiziologicheskie éffekty razlichnykh sposobov khirurgicheskogo lecheniia bol'nykh leiomiomoi matki.

Electroencephalographic studies and mathematical analysis of heart rhythm have shown that reconstructive plastic surgery is a more sparing and physiologic method as against supravaginal amputation of the uterus, providing normal functioning of all the body systems in late periods after surgery.

[Cerebrovascular circulation in patients with oligomenorrhea]. / Sostoianie mozgovogo krovoobrashcheniia u bol'nykh s oligomenoreei.

Brain hemodynamics was studied in 76 patients with oligomenorrhea aged 18 to 35 from the data of rheoencephalography. Disorders of the regional tone of brain vessels were different and related to the time of the menstrual cycle disorder; this may be explained by the degree of changes in various neuromediator mechanisms of brain circulation and reproductive system function regulation.

[General principles of the pathogenesis of vegetovascular and psychoemotional disorders during menstrual cycle and methodological approaches to their study]. / Obshchie printsipy patogeneza vegetososudistykh i psikhoémotsional'nykh rasstroistv v dinamike menstrual'nogo tsikla i metodicheskie podkhody k ikh izucheniiu.

Analysis of charts filled in by 79 women (mean age 31.5 +/- 4.0 years) over the course of 2-3 menstrual cycles has demonstrated the regular manifestation of various psychosomatovegetative symptoms over the entire course of the cycle (in the follicular, lutein phases, and during ovulation). Study of the brain electric activity and of the function of various sections of the autonomic nervous system, as well as examination of the emotional and mental sphere of the patients has revealed the contribution of the brain suprasegmental sections to the pathogenetic mechanisms of these disorders.

[Characteristics of the functional state of different sections of the autonomic nervous system and their role in the pathogenesis of oligomenorrhea]. / Osobennosti funktsional'nogo sostoianiia razlichnykh otdelov vegatativnoi nervnoi sistemy i ikh rol' v patogeneze oligomenorei.

Analysis of the clinical picture of oligomenorrhea and of the results of studies of the function of various sections of the autonomic nervous system (ANS) in 58 patients of a reproductive age has revealed differences in these functions, related to the time of menstrual disorders onset. Oligomenorrhea patients with menarche complained of cardiovascular, respiratory, and emotional-motivational disorders, examinations have revealed in them dysfunctional disorders and reduced reserve potentials of both ANS sections. In oligomenorrhea patients in whom the condition developed at the age of 18-25 after a period of regular menstruations the effects of various stress factors resulted in reduction of the functional activity of the ergotropic (sympathoadrenal) section of the ANS. Differences in the pathogenetic mechanisms of oligomenorrhea development in the two groups of patients are discussed.

[Characteristics of the functional state of the central nervous system in women during the menstrual cycle and in premenstrual syndrome]. / Osobennosti funktsional'nogo sostoianiia tsentral'noi nervnoi sistemy u zhenshchin v dinamike menstrual'nogo tsikla i u bol'nykh s premenstrual'nym sindromom.

Electroencephalographic examination of the function of the central nervous system in 30 healthy women and in 15 ones suffering from the premenstrual syndrome, carried out over both phases of the menstrual cycle, has revealed clear-cut differences between the two groups. 46% of the patients developed pathologic shifts at the level of the brain stem, 37% of the hypothalamic level, and 17% combined involvement of these portions of the brain. Triggering of the compensatory defense mechanisms already during the follicular phase of the cycle indicates failure of the adaptation mechanisms in the patients with the premenstrual syndrome.

[The hypothalamo-hypophyseal system in resistant ovary syndrome]. / Gipotalamo-gipofizarnaia sistema pri sindrome rezistentnykh iaichnikov.

The study has been done in 30 women with the resistant ovary syndrome diagnosed by laparoscopy, laparotomy and histologic examination of ovarian biopsy samples. Genetic study identified the feminine phenotype and genotype (46,XX). Estradiol levels corresponded to those seen in the follicular menstrual phase, prolactin levels were normal, and gonadotropin levels were above basal values and were several fold above the ovulatory peak, when tested with luteinizing hormone-releasing factor in 7 patients and after estrogen challenge in 5 patients. The tests indicated an adequate adenohypophyseal response and intact feedback mechanisms between the hypothalamic pituitary system and gonadal steroids, as confirmed by electroencephalography.