Gonadal hormone 17β-estradiol (E2) and its receptors are key regulators of gene transcription by binding to estrogen responsive elements in the genome. Besides the classical genomic action, E2 ...regulates gene transcription via the modification of epigenetic marks on DNA and histone proteins. Depending on the reaction partner, liganded estrogen receptor (ER) promotes DNA methylation at the promoter or enhancer regions. In addition, ERs are important regulators of passive and active DNA demethylation. Furthermore, ERs cooperating with different histone modifying enzymes and chromatin remodeling complexes alter gene transcription. In this review, we survey the basic mechanisms and interactions between estrogen receptors and DNA methylation, demethylation and histone modification processes as well as chromatin remodeling complexes. The particular relevance of these mechanisms to physiological processes in memory formation, embryonic development, spermatogenesis and aging as well as in pathophysiological changes in carcinogenesis is also discussed.
Inflammation has a well-known suppressive effect on fertility. The function of gonadotropin-releasing hormone (GnRH) neurons, the central regulator of fertility is substantially altered during ...inflammation in females. In our review we discuss the latest results on how the function of GnRH neurons is modified by inflammation in females. We first address the various effects of inflammation on GnRH neurons and their functional consequences. Second, we survey the possible mechanisms underlying the inflammation-induced actions on GnRH neurons. The role of several factors will be discerned in transmitting inflammatory signals to the GnRH neurons: cytokines, kisspeptin, RFamide-related peptides, estradiol and the anti-inflammatory cholinergic pathway. Since aging and obesity are both characterized by reproductive decline our review also focuses on the mechanisms and pathophysiological consequences of the impact of inflammation on GnRH neurons in aging and obesity.
Recently, electrospinning (ES) of fibers has been shown to be an attractive strategy for drug delivery. One of the main features of ES is that a wide variety of drugs can be loaded into the fibers to ...improve their bioavailability, to enhance dissolution, or to achieve controlled release. Besides, ES is a continuous technology with low energy consumption, which can make it a very economic production alternative to the widely used freeze drying and spray drying. However, the low production rate of laboratory‐scaled ES has limited the industrial application of the technology so far. This article covers the various ES technologies developed for scaled‐up fiber production with an emphasis on pharmaceutically relevant examples. The methods used for increasing the productivity are complied, which is followed by a review of specific examples from literature where these technologies are utilized to produce oral drug delivery systems. The different technologies are compared in terms of their basic principles, advantages, and limitations. Finally, the different downstream processing options to prepare tablets or capsules containing the electrospun drug are covered as well.
This article is categorized under:
Therapeutic Approaches and Drug Discovery > Emerging Technologies
Application of scaled‐up electrospinning in oral drug delivery.
Patients surviving traumatic brain injury (TBI) face numerous neurological and neuropsychological problems significantly affecting their quality of life. Extensive studies over the past decades have ...investigated pharmacological treatment options in different animal models, targeting various pathological consequences of TBI. Sex and gender are known to influence the outcome of TBI in animal models and in patients, respectively. Apart from its well-known effects on reproduction, 17β-estradiol (E2) has a neuroprotective role in brain injury. Hence, in this review, we focus on the effect of E2 in TBI in humans and animals. First, we discuss the clinical classification and pathomechanism of TBI, the research in animal models, and the neuroprotective role of E2. Based on the results of animal studies and clinical trials, we discuss possible E2 targets from early to late events in the pathomechanism of TBI, including neuroinflammation and possible disturbances of the endocrine system. Finally, the potential relevance of selective estrogenic compounds in the treatment of TBI will be discussed.
Membrane nanotubes are cell protrusions that grow to tens of micrometres and functionally connect cells. Actin filaments are semi-flexible polymers, and their polymerisation provides force for the ...formation and growth of membrane nanotubes. The molecular bases for the provision of appropriate force through such long distances are not yet clear. Actin filament bundles are likely involved in these processes; however, even actin bundles weaken when growing over long distances, and there must be a mechanism for their regeneration along the nanotubes. We investigated the possibility of the formation of periodic molecular relay stations along membrane nanotubes by describing the interactions of actin with full-length IRSp53 protein and its N-terminal I-BAR domain. We concluded that I-BAR is involved in the early phase of the formation of cell projections, while IRSp53 is also important for the elongation of protrusions. Considering that IRSp53 binds to the membrane along the nanotubes and nucleates actin polymerisation, we propose that, in membrane nanotubes, IRSp53 establishes molecular relay stations for actin polymerisation and, as a result, supports the generation of force required for the growth of nanotubes.
Background: The aims of our study were to investigate the changes in anthropometric and physical parameters and fasting hormonal levels among pre-pubertal female handball players (n = 14, age: 11.53 ...± 0.58 yrs, height: 153.36 ± 5.12 cm, body mass: 43.59 ± 6.14 kg) in the pre-season period following 8 weeks of handball training, and to analyze the contribution of hormones, physical performance and anthropometric parameters. Methods: Prior to and immediately following the training period, several anthropometric, strength, and cardiorespiratory variables, including fasting hormonal concentrations (plasma cortisol, estradiol, testosterone and growth hormones) were measured. Athletes performed concurrent resistance and aerobic exercises, including game-based trainings during the 8-week training period. Results: Significant elevations were found in all strength parameters (maximal handgrip strength dominant (D): 16.40%, p < 0.01; non-dominant (ND): 25.15%, p < 0.05; maximal concentric (MVC) torque of quadriceps D: 13.82%, p < 0.05; ND: 12.61%, p < 0.05; MVC torque of hamstring D: 12.14%, p < 0.01; ND: 12.44%, p < 0.01), including plasma cortisol levels (C, 34.30%, p < 0.05) and peak respiratory quotient (5.24%, p < 0.05). Body composition and maximal oxygen uptake (VO2max) remained unchanged. Percentage changes in thigh (r = 0.316, p < 0.05), hand (r = 0.361, p < 0.05), and hip circumference (r = 0.297, p < 0.05) correlated with C changes. Percentage changes in plasma growth hormone levels (GH) contributed to the magnitude of gains in handgrip strength (r = 0.553, p < 0.05). Percentage changes in maximal exercise pulmonary ventilation (MVE) correlated with elevated C (r = −0.592, p < 0.05). Discussion: Changes in anthropometric variables and fasting hormone levels (estradiol, testosterone and cortisol) were poor indicators of developing VO2max and strength during pre-pubertal years. Physical adaptation may not be explained in consideration of the athletes’ hormonal or anthropometric characteristics. Conclusion: Gradually increased training volume followed by a summer break should be applied to youth handball, considering the anti-hypertrophic responses and the inhibitory effect of elevating C on pre-pubertal maturation.
Long-term cellular stress maintains high intracellular Ca2+ concentrations which ultimately initiates apoptosis. Our interest is focused on how the gelsolin (GSN) and junctional mediating and ...regulating Y protein (JMY) play important roles in stress response. Both of these proteins can bind p53 and actin. We investigated using in vitro fluorescence spectroscopy and found that the p53 competes with actin in GSN to inhibit p53–JMY complex formation. A high Ca2+ level initializes p53 dimerization; the dimer competes with actin on JMY, which can lead to p53–JMY cotransport into the nucleus. Here we investigated how the motility and division rate of HeLa cells changes due to low-voltage electroporation of GSN or JMY in scratching assays. We revealed that JMY inhibits their motion, but that it can accelerate the cell division. GSN treatment slows down cell division but does not affect cell motility. HeLa cells fully recovered the gap 20 h after the electroporation with JMY and then started to release from the glass slides. Taken together, our in vitro results indicate that GSN and JMY may play an important role in the cellular stress response.
The ionic environment within the nucleoplasm might diverge from the conditions found in the cytoplasm, potentially playing a role in the cellular stress response. As a result, it is conceivable that ...interactions of nuclear actin and actin-binding proteins (ABPs) with apoptosis factors may differ in the nucleoplasm and cytoplasm. The primary intracellular stress response is Ca
influx. The junctional mediating and regulating Y protein (JMY) is an actin-binding protein and has the capability to interact with the apoptosis factor p53 in a Ca
-dependent manner, forming complexes that play a regulatory role in cytoskeletal remodelling and motility. JMY's presence is observed in both the cytoplasm and nucleoplasm. Here, we show that ex vivo ectocervical squamous cells subjected to electroporation with JMY protein exhibited varying morphological alterations. Specifically, the highly differentiated superficial and intermediate cells displayed reduced nuclear size. In inflamed samples, nuclear enlargement and simultaneous cytoplasmic reduction were observable and showed signs of apoptotic processes. In contrast, the less differentiated parabasal and metaplastic cells showed increased cytoplasmic activity and the formation of membrane protrusions. Surprisingly, in severe inflammation, vaginosis or ASC-US (Atypical Squamous Cells of Undetermined Significance), JMY appears to influence only the nuclear and perinuclear irregularities of differentiated cells, and cytoplasmic abnormalities still existed after the electroporation. Our observations can provide an appropriate basis for the exploration of the relationship between cytopathologically relevant morphological changes of epithelial cells and the function of ABPs. This is particularly important since ABPs are considered potential diagnostic and therapeutic biomarkers for both cancers and chronic inflammation.
Hereditary angioedema (HAE) is a rare disease belonging to the group of bradykinin-mediated angioedemas, characterized by recurring edematous episodes involving the subcutaneous and/or submucosal ...tissues. Most cases of HAE are caused by mutations in the
gene encoding C1-inhibitor (C1-INH-HAE); however, mutation analysis identified seven further types of HAE: HAE with Factor XII mutation (FXII-HAE), with plasminogen gene mutation (PLG-HAE), with angiopoietin-1 gene mutation (ANGPT1-HAE), with kininogen-1 gene mutation (KNG1-HAE), with a myoferlin gene mutation (MYOF-HAE), with a heparan sulfate-glucosamine 3-sulfotransferase 6 (
) mutation, and hereditary angioedema of unknown origin (U-HAE). We sequenced DNA samples stored from 124 U-HAE patients in the biorepository for exon 9 of the
gene. One of the 124 subjects carried the mutation causing a lysine to glutamic acid amino acid exchange at position 330 (K330E). Later, the same
mutation was identified in the patient's son. The introduction of new techniques into genetic testing has increased the number of genes identified. As shown by this study, a biorepository creates the means for the ex-post analysis of recently identified genes in stored DNA samples of the patients. This makes the diagnosis more accurate with the possibility of subsequent family screening and the introduction of appropriate therapy.
Tunneling nanotubes (TNTs) are long intercellular connecting structures providing a special transport route between two neighboring cells. To date TNTs have been reported in different cell types ...including immune cells such as T-, NK, dendritic cells, or macrophages. Here we report that mature, but not immature, B cells spontaneously form extensive TNT networks under conditions resembling the physiological environment. Live-cell fluorescence, structured illumination, and atomic force microscopic imaging provide new insights into the structure and dynamics of B cell TNTs. Importantly, the selective interaction of cell surface integrins with fibronectin or laminin extracellular matrix proteins proved to be essential for initiating TNT growth in B cells. These TNTs display diversity in length and thickness and contain not only F-actin, but their majority also contain microtubules, which were found, however, not essential for TNT formation. Furthermore, we demonstrate that Ca
2+
-dependent cortical actin dynamics exert a fundamental control over TNT growth-retraction equilibrium, suggesting that actin filaments form the TNT skeleton. Non-muscle myosin 2 motor activity was shown to provide a negative control limiting the uncontrolled outgrowth of membranous protrusions. Moreover, we also show that spontaneous growth of TNTs is either reduced or increased by B cell receptor- or LPS-mediated activation signals, respectively, thus supporting the critical role of cytoplasmic Ca
2+
in regulation of TNT formation. Finally, we observed transport of various GM
1
/GM
3
+
vesicles, lysosomes, and mitochondria inside TNTs, as well as intercellular exchange of MHC-II and B7-2 (CD86) molecules which may represent novel pathways of intercellular communication and immunoregulation.
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