Tehotenstvo a popôrodné obdobie sa spája s náročnými fyzickými a psychickými zmenami, ktoré neraz vedú k rozvoju psychických porúch. Depresia je diagnostikovaná u viac ako jednej zo šiestich žien po pôrode. Prevalencia popôrodnej depresie však môže byť oveľa vyššia, pretože mnohé prípady ochorenia ostávajú nediagnostikované. V prípade ťažkých foriem depresie sa pacientka nastavuje na farmakologickú liečbu, pričom najčastejšie sa u tejto diagnózy využíva sertralín. Novým liečivom používaným v terapii popôrodnej depresie je brexanolón, ktorý bol registrovaný FDA v roku 2019. Jeho výhodou oproti konvenčnej liečbe je rýchly nástup účinku. Štruktúra brexanolónu predstavuje neuroaktívny steroid – allopregnanolón, ktorý pôsobí agonisticky na δ-podjednotku GABA-A receptora a zlepšuje symptómy popôrodnej depresie. Okrem registrovaného brexanolónu sa v 3. fáze klinického skúšania nachádza aj ďalšie steroidné liečivo zuranolón v perorálnej liekovej forme. Iný syntetický analóg neuroaktívneho allopregnanolónu, známy ako ganaxolón, v druhej fáze klinického skúšania nepreukázal výrazné zlepšenie depresívnych symptómov oproti placebu. Napriek tomu má veľký terapeutický potenciál v liečbe rôznych typov epilepsie.
Pregnancy and postpartum period are associated with demanding physical and psychological changes that often lead to the development of psychological disorders. Depression is diagnosed in more than one in six women after childbirth. However, the prevalence of postpartum depression can be much higher because many cases are undiagnosed. In the case of severe depression, the patient is switched to pharmacological treatment, with sertraline being the most commonly used for this diagnosis. A new drug used in the treatment of postpartum depression is brexanolone, which was registered by FDA in 2019. The advantage over conventional therapy is its rapid onset of action. The structure represents the neuroactive steroid – allopregnanolone, which acts as an agonist on the δ-subunit of the GABA receptor and improves the symptoms of postpartum depression. In addition to the registered brexanolone, another steroidal drug, zuranolone, is available in the third phase of the clinical trial. The steroid structure was chemically altered to improve bioavailability and create an oral dosage form. Another synthetic analogue of neuroactive allopregnanolone, known as ganaxolone, did not show a significant reduction in depressive symptoms in the second phase of the clinical trial compared to placebo. Nevertheless, it has great therapeutic potential in the treatment of various types of epilepsy.
- Klíčová slova
- brexanolón, zuranolón, ganaxolón,
- MeSH
- lidé MeSH
- neurosteroidy * farmakologie terapeutické užití MeSH
- poporodní deprese * etiologie farmakoterapie psychologie MeSH
- poporodní období psychologie MeSH
- pregnanolon analogy a deriváty antagonisté a inhibitory terapeutické užití MeSH
- pregnany aplikace a dávkování terapeutické užití MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
Stem cells represent promising candidates for regenerative therapy of craniomaxillofacial bone defects, where common techniques, such as autogenous bone graft, allografts or others possess shortcomings and limitations in restoring the morphology and function in bone loss. The efficacy of regenerative therapy with mesenchymal stromal cells (MSC) depends on a combination of the interactions between transplanted MSCs and cellular and molecular components of the recipient, and any current pharmacotherapy in the recipient with effects on transplanted MSC and the bone microenvironment. In the present investigation, dental pulp stem cells (DPSC) were isolated from human impacted third molar teeth. DPSC were treated with ibuprofen in vitro at clinically relevant concentration and relative expression of selected genes were assessed. Our preliminary data suggest a significant effect of ibuprofen as indicated by upregulation of the relative expression levels of growth factors, vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). While the effects of stem cell therapy in bone regeneration are being investigated in ongoing clinical trials, the effects of commonly used pharmacotherapy should be studied for its potential impact on the paracrine effects of stem cells and consequently bone regenerative processes.
- MeSH
- antiflogistika nesteroidní farmakologie MeSH
- exprese genu MeSH
- hepatocytární růstový faktor MeSH
- ibuprofen * terapeutické užití MeSH
- kmenové buňky MeSH
- lebka patologie MeSH
- lidé MeSH
- mezenchymální kmenové buňky * MeSH
- nemoci kostí farmakoterapie terapie MeSH
- parakrinní signalizace MeSH
- polymerázová řetězová reakce MeSH
- regenerativní lékařství metody MeSH
- techniky in vitro metody MeSH
- vaskulární endoteliální růstový faktor A MeSH
- Check Tag
- lidé MeSH
Autologous stem cell therapy is the most promising alternative treatment in patients with chronic ischemic diseases, including ischemic heart disease and critical limb ischemia, which are characterized by poor prognosis related to serious impair of quality of life, high risk of cardiovascular events and mortality rates. However, one of the most serious shortcomings of stem cell transplantation are low survival after transplantation to the site of injury, as large number of stem cells are lost within 24 hours after delivery. Multiple studies suggest that combination of lipid-lowering drugs, statins, and stem cell transplantation might improve therapeutic efficacy in regenerative medicine. Statins are inhibitors of HMG-CoA reductase and belong to recommended therapy in all patients suffering from critical limb ischemia. Statins possess non-lipid effects which involve improvement of endothelial function, decrease of vascular inflammation and oxidative stress, anti-cancer and stem cell modulation capacities. These non-lipid effects are explained by inhibition of mevalonate synthesis via blocking isoprenoid intermediates synthesis, such as farnesylpyrophospate and geranylgeranylpyrophospate and result in modulation of the PI3K/Akt pathway. Moreover, statin-mediated microRNA regulation may contribute to the pleiotropic functions. MicroRNA interplay in gene regulatory network of IGF/Akt pathway may be of special significance for the treatment of critical limb ischemia. We assume further studies are needed for detailed analysis of statin interactions with microRNA at the molecular level and their link to PI3K/Akt and IGF/Akt pathway in stem cells, which are currently the most promising treatment strategy used in chronic ischemic diseases.
- MeSH
- atorvastatin * farmakologie terapeutické užití MeSH
- chronická kritická ischemie končetin * farmakoterapie terapie MeSH
- fosfatidylinositol-3-kinasy * metabolismus MeSH
- ischemie * farmakoterapie terapie MeSH
- končetiny * krevní zásobení MeSH
- kvalita života MeSH
- lidé MeSH
- statiny * farmakologie terapeutické užití MeSH
- transplantace kmenových buněk * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Sarcopenia is defined as an age-associated loss of skeletal muscle function and muscle mass and is common in older adults. Sarcopenia as a disease is currently of interest not only to orthopedists and surgeons but also to internists, endocrinologists, rheumatologists, cardiologists, diabetologists, gynaecologists, geriatricians and paediatricians. In cooperation with the 5th Internal Medicine Clinic, we, as a unit of clinical research, aimed to describe a sarcopenic specific miRNA expression profile for disease diagnostics and classification of the severity of muscle performance deterioration. This study included a total of 80 patients (age 55-86 years) hospitalized at the V. Internal medicine clinic of LFUK and UNB with different severity of muscle performance deterioration. The study participants were evaluated and classified according to short physical performance battery score (SPPB). In this study, we investigated the role of circulating miRNAs in sarcopenia in the elderly. We hypothesized that sarcopenia effects the expression of muscle tissue-specific miRNAs (MyomiRNAs), which could be potentially reflected in the blood plasma miRNA expression profile. The expression of specific circulating miRNAs in patients with different muscle performances was analyzed. Patients' blood plasma was evaluated for the expression of myomiRNAs: miRNA-29a, miRNA-29b, miRNA-1, miRNA-133a, miRNA-133b, miRNA-206, miRNA-208b and miRNA-499, and the data were correlated with diagnostic indicators of the disease. We showed a specific sarcopenia miRNA profile that could be considered a possible biomarker for the disease. Patients with low muscle performance showed increased miRNA-1, miRNA-29a and miRNA-29b expression and decreased for the miRNA-206, miRNA-133a, miRNA-133b, miRNA-208b and miRNA-499 expression. We show that the severity of muscle performance deterioration in sarcopenia correlates with specific miRNA expression. We also propose the profile of miRNAs expression in blood plasma as a specific biomarker for sarcopenia diagnostics. Future clinical studies will be necessary to eventually naturally have to elucidate the underlined molecular mechanism responsible for specific miRNAs expression in sarcopenia pathology and progression of the disease.
- MeSH
- biologické markery krev MeSH
- fyzikální vyšetření MeSH
- kosterní svaly patofyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA krev MeSH
- sarkopenie krev patofyziologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
Experimental data concerning the bioavailability of the different Mg-salts in human organism is inconsistent. Mg-absorption reported by clinical studies largely varies depending on the method used for evaluation. The aim of this study was to evaluate the bioavailability and accessibility of magnesium bound in different Mg-salt compounds, using an in vitro model of intestinal cell barrier. The study included a variety of inorganic (oxide, sulphate, chloride, carbonate) and organic salts (lactate, citrate, pidolate). Caco-2 cells were cultivated in a complete culture medium with different magnesium salts treatments in ascending concentrations. The viability and quantity of cells was analysed by FACS. Mg-absorption was analysed by a direct colorimetric assay, measured by spectrometry. T-test identified a significant decrease in cell count treatment with mg-lactate compared with citrate. Mg-pidolate showed a significantly higher cell viability compared with Mg-citrate, Mg-lactate and Mg-chloride. Even though the difference was not significant, we showed that an increase in Mg2+ salt concentration progressively decreased the cell count and the viability and the effect was universal for all the used Mg-salt treatments. Mg-citrate, chloride, and sulphate showed a significantly lower absorption compared to Mg-carbonate, pidolate and oxide. Our in vitro monolayer model of human intestinal transport showed that viability and quantity of cell decreased with increasing Mg-concentration. We admit that our experiment model may have some limitations in accurately describing an in vivo Mg2+ absorption. Moreover, it is also necessary to assess the relevance of our data in vivo and especially in clinical practice.
- MeSH
- Caco-2 buňky MeSH
- hořčík metabolismus MeSH
- lidé MeSH
- střevní sliznice metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Cardiac fibrotization is a well-known process characteristic of many cardiac pathological conditions. The key element is excessive activation of cardiac fibroblasts, their transdifferentiation into myofibroblasts, increased production, and accumulation of extracellular matrix proteins, resulting in cardiac stiffness. The exact cellular mechanisms and molecular components involved in the process are not fully elucidated, but the SOCE mechanism could play an important role. Its key molecules are the molecular sensor of calcium in ER/SR - STIM and the highly selective calcium channels Orai located in the plasma membrane. This study aims to evaluate selected SOCE-associated genes in the activation of HCF cell culture by several known substances (phenylephrine, isoprenaline) that represent cardiovascular overload. After cell cultivation, cell medium was collected to measure the soluble collagen content. From the harvested cells, qRT-PCR was performed to determine the mRNA levels of the corresponding genes. The activation of cells was based on changes in the relative expression of collagen genes as well as the collagen content in the medium of the cell culture. We detected an increase in the expression of the Orai2 isoform, a change in the Orai1/Orai3 ratio and also an increase in the expression of the STIM2 isoform. These results suggest an increased activation of the SOCE mechanism under stress conditions of fibroblasts, which supports the hypothesis of fibroblast activation in pathological processes by altering calcium homeostasis through the SOCE mechanism.
Heart remodeling occurs as a compensation mechanism for the massive loss of tissue during initial heart failure and the consequent inflammation process. During heart remodeling fibroblasts differentiate to myofibroblasts activate their secretion functions and produce elevated amounts, of extracellular matrix (ECM) proteins, mostly collagen, that form scar tissue and alter the normal degradation of ECM. Scar formation does replace the damaged tissue structurally; however, it impedes the normal contractive function of cardiomyocytes (CMs) and results in long-lasting effects after heart failure. Besides CMs and cardiac fibroblasts, endothelial cells (ECs) and circulating endothelial progenitor cells (cEPCs) contribute to heart repair. This review summarizes the current knowledge of EC-CM crosstalk in cardiac fibrosis (CF), the role of cEPCs in heart regeneration and the contribution of Endothelial-mesenchymal transition (EndoMT).
- MeSH
- endoteliální buňky fyziologie MeSH
- endoteliální progenitorové buňky fyziologie MeSH
- interakce mezi receptory a ligandy MeSH
- kardiomyocyty fyziologie MeSH
- lidé MeSH
- regenerace * MeSH
- remodelace komor * MeSH
- srdce fyziologie MeSH
- transdiferenciace buněk * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Metformin (MTF) is a widely used drug for the treatment of diabetes mellitus type 2 (DM2) and frequently used as an adjuvant therapy for polycystic ovarian syndrome, metabolic syndrome, and in some cases also tuberculosis. Its protective effect on the cardiovascular system has also been described. Recently, MTF was subjected to various analyzes and studies that showed its beneficial effects in cancer treatment such as reducing cancer cell proliferation, reducing tumor growth, inducing apoptosis, reducing cancer risk in diabetic patients, or reducing likelihood of relapse. One of the MTF's mechanisms of action is the activation of adenosine-monophosphate-activated protein kinase (AMPK). Several studies have shown that AMPK/mammalian target of rapamycin (mTOR) pathway has anticancer effect in vivo and in vitro. The aim of this review is to present the anticancer activity of MTF highlighting the importance of the AMPK/mTOR pathway in the cancer process.
- MeSH
- apoptóza účinky léků MeSH
- hypoglykemika terapeutické užití MeSH
- lidé MeSH
- metformin škodlivé účinky terapeutické užití MeSH
- nádory farmakoterapie enzymologie patologie MeSH
- přehodnocení terapeutických indikací léčivého přípravku MeSH
- proteinkinasy aktivované AMP metabolismus MeSH
- protinádorové látky škodlivé účinky terapeutické užití MeSH
- signální transdukce MeSH
- TOR serin-threoninkinasy metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The randomized trials showed that the addition of training resistance program to androgen-deprivation therapy (ADT) had many beneficial effects for prostate cancer (PC) patients (significant protective effect on the volume of muscle mass) and the studies have revealed a panel of miRNAs, which are deregulate in PC and may serve as promising biomarkers of PC risk. The primary aim of our present study was to investigate the effect of exercise training to changes in body composition (muscle strength) and the secondary endpoint was to investigate the impact of an exercise training program on plasma levels of selected myogenic microRNAs (miRNAs) (miRNA-1, miRNA-29b, and miRNA-133) in PC patients undergoing the ADT. Effect of ADT and exercise intervention showed significant increase (experimental group vs. control group) the changes in body composition, free testosterone levels, IL-6 and plasma levels of myogenic miRNAs and significant reduced insulin serum levels. In conclusion, resistance training with ADT in the treatment of PC significantly changed the physical and metabolic function and the plasma levels of specific myogenic miRNAs. Our data support with the other publicized results.
- MeSH
- antagonisté androgenů terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA krev MeSH
- nádory prostaty krev terapie MeSH
- odporový trénink * MeSH
- prospektivní studie MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
Ischemic diseases are characterized by reduced blood supply to a tissue or an organ due to obstruction of blood vessels. The most serious and most common ischemic diseases include ischemic heart disease, ischemic stroke, and critical limb ischemia. Revascularization is the first choice of therapy, but the cell therapy is being introduced as a possible way of treatment for no-option patients. One of the possibilities of cell therapy is the use of mesenchymal stem cells (MSCs). MSCs are easily isolated from bone marrow and can be defined as non-hematopoietic multipotent adult stem cells population with a defined capacity for self-renewal and differentiation into cell types of all three germ layers depending on their origin. Since 1974, when Friedenstein and coworkers (Friedenstein et al. 1974) first time isolated and characterized MSCs, MSC-based therapy has been shown to be safe and effective. Nevertheless, many scientists and clinical researchers want to improve the success of MSCs in regenerative therapy. The secret of successful cell therapy may lie, along with the homing, in secretion of biologically active molecules including cytokines, growth factors, and chemokines known as MSCs secretome. One of the intracellular signalling mechanism includes the activity of phosphatidylinositol-3-kinase (phosphoinositide 3-kinase) (PI3K) - protein kinase B (serine-threonine protein kinase Akt) (Akt) pathway. This PI3K/Akt pathway plays key roles in many cell types in regulating cell proliferation, differentiation, apoptosis, and migration. Pre-conditioning of MSCs could improve efficacy of signalling mechanism.
- MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- fyziologická neovaskularizace MeSH
- ischemie metabolismus terapie MeSH
- kinázy asociované s rho metabolismus MeSH
- lidé MeSH
- mezenchymální kmenové buňky metabolismus MeSH
- oxid dusnatý metabolismus MeSH
- oxidační stres MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- transplantace mezenchymálních kmenových buněk * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
