Controllable synthesis of barium carbonate nano- and microparticles for SPECT and CT imaging.

The design and synthesis of nano- and microcarriers for preclinical and clinical imaging are highly attractive due to their unique features, for example, multimodal properties. However, broad translation of these carriers into clinical practice is postponed due to the unknown biological reactivity of the new components used for their synthesis. Here, we have developed microcarriers (∼2-3 µm) and  nanocarriers (<200 nm) made of barium carbonate (BaCO3) for multiple imaging applications in vivo. In general, barium in the developed carriers can be used for X-ray computed tomography, and the introduction of a diagnostic isotope (99mTc) into the BaCO3 structure enables in vivo visualization using single-photon emission computed tomography. The bioimaging has shown that the radiolabeled BaCO3 nano- and microcarriers had different biodistribution profiles and tumor accumulation efficiencies after intratumoral and intravenous injections. In particular, in the case of intratumoral injection, all the types of used carriers mostly remained in the tumors (>97%). For intravenous injection, BaCO3 microcarriers were mainly localized in the lung tissues. However, BaCO3 NPs were mainly accumulated in the liver. These results were supported by ex vivo fluorescence imaging, direct radiometry, and histological analysis. The BaCO3-based micro- and nanocarriers showed negligible in vivo toxicity towards major organs such as the heart, lungs, liver, kidneys, and spleen. This study provides a simple strategy for the design and fabrication of the BaCO3-based carriers for the development of dual bioimaging.

Design and evaluation of an anthropomorphic neck phantom for improved ultrasound diagnostics of thyroid gland tumors.

PURPOSE: Thyroid cancer is one of the most common cancers worldwide, with ultrasound-guided biopsy being the method of choice for its early detection. The accuracy of diagnostics directly depends on the qualifications of the ultrasonographers, whose performance can be enhanced through training with phantoms. The aim of this study is to propose a reproducible methodology for designing a neck phantom for ultrasound training and research from widely available materials and to validate its applicability. METHODS: The phantom was made using polyvinyl chloride mixed with additives to reproduce different levels of brightness on ultrasound screens. 3D printing and casting were used to create the neck model and various structures of the neck, including bones, cartilage, arteries, veins, lymph nodes, thyroid gland, and soft tissues. The small objects, such as tumor and lymph node models, were shaped manually. All the phantom's materials were carefully selected to match the ultrasonic speed and attenuation values of real soft tissues and bones. RESULTS: The thyroid gland contains models of a cancerous and cystic nodule. In the neck, there are models of carotid arteries and jugular veins filled with ultrasound-transparent gel. Additionally, there are replicas of lymph nodes and bone structures such as hyoid bone, thyroid cartilage, trachea, and vertebrae. The resulting phantom covers the entire neck area and has been positively received by practicing ultrasound specialists. CONCLUSIONS: The proposed manufacturing technology offers a reliable and cost-effective approach to produce an anthropomorphic neck phantom for ultrasound diagnosis of the thyroid gland. The realistic simulation provided by the phantom enhances the quality and accuracy of ultrasound examinations, contributing to better training for medical professionals and improved patient care. Subsequent research efforts can concentrate on refining the fabrication process and exploring additional features to enhance the phantom's capabilities.

Irreversible inhibition of estrogen receptor α signaling and the emergence of hormonal resistance in MCF7 breast cancer cells induced by DNA damage agents.

Combining chemotherapy and hormone therapy is a prevalent approach in breast cancer treatment. While the cytotoxic impact of numerous chemotherapy drugs stems from DNA damage, the exact role of these DNA alterations in modulating estrogen receptor α (ERα) machinery remains elusive. The present study aimed to analyze the impact of DNA damage agents on ERα signaling in breast cancer cells and assess the signaling pathways mediating the influence of DNA damage drugs on the ERα machinery. Cell viability was assessed using the MTT method, while the expression of signaling proteins was analyzed by immunoblotting. ERα activity in the cells treated with various drugs (17ß-estradiol, tamoxifen, 5-fluorouracil) was assessed through reporter gene assays. In vitro experiments were conducted on MCF7 breast cancer cells subjected to varying durations of 5-fluorouracil (5-FU) treatment. Two distinct cell responses to 5-FU were identified based on the duration of the treatment. A singular dose of 5-FU induces pronounced DNA fragmentation, temporally suppressing ERα signaling while concurrently activating AKT phosphorylation. This suppression reverses upon 5-FU withdrawal, restoring normalcy within ten days. However, chronic 5-FU treatment led to the emergence of 5-FU-resistant cells with irreversible alterations in ERα signaling, resulting in partial hormonal resistance. These changes mirror those observed in cells subjected to UV-induced DNA damage, underscoring the pivotal role of DNA damage in shaping estrogen signaling alterations in breast cancer cells. In summary, the results of the present study suggested that the administration of DNA damage agents to cancer cells can trigger irreversible suppression of estrogen signaling, fostering the development of partial hormonal resistance. This outcome may ultimately impede the efficacy of combined or subsequent chemo- and hormone therapy strategies.

An Open-Source Wireless Electrophysiology System for In Vivo Neuronal Activity Recording in the Rodent Brain: 2.0.

Current trends in neurobiological research focus on analyzing complex interactions within brain structures. To conduct relevant experiments, it is often essential to employ animals with unhampered mobility and utilize electrophysiological equipment capable of wirelessly transmitting data. In prior research, we introduced an open-source wireless electrophysiology system to surmount these challenges. Nonetheless, this prototype exhibited several limitations, such as a hefty weight for the wireless module, redundant system components, a diminished sampling rate, and limited battery longevity. In this study, we unveil an enhanced version of the open-source wireless electrophysiology system, tailored for in vivo monitoring of neural activity in rodent brains. This new system has been successfully tested in real-time recordings of in vivo neural activity. Consequently, our development offers researchers a cost-effective and proficient tool for studying complex brain functions.

Activation of Gq-Coupled Receptors in Astrocytes Restores Cognitive Function in Alzheimer's Disease Mice Model.

Alzheimer's disease (AD) is one of the most widespread neurodegenerative diseases. Most of the current AD therapeutic developments are directed towards improving neuronal cell function or facilitating Aß amyloid clearance from the brain. However, some recent evidence suggests that astrocytes may play a significant role in the pathogenesis of AD. In this paper, we evaluated the effects of the optogenetic activation of Gq-coupled exogenous receptors expressed in astrocytes as a possible way of restoring brain function in the AD mouse model. We evaluated the effects of the optogenetic activation of astrocytes on long-term potentiation, spinal morphology and behavioral readouts in 5xFAD mouse model of AD. We determined that in vivo chronic activation of astrocytes resulted in the preservation of spine density, increased mushroom spine survival, and improved performance in cognitive behavioral tests. Furthermore, chronic optogenetic stimulation of astrocytes resulted in the elevation of EAAT-2 glutamate uptake transporter expression, which could be a possible explanation for the observed in vivo neuroprotective effects. The obtained results suggest that the persistent activation of astrocytes may be considered a potential therapeutic approach for the treatment of AD and possibly other neurodegenerative disorders.

Fatty Acid Composition of Northern Pike from an Arctic River (Northeastern Siberia, Russia).

We assayed the fatty acid composition of muscles of the northern pike Esox lucius Linnaeus, 1758 inhabiting the Gyda River, Siberia, Russia using gas-liquid chromatography. Of 43 fatty acids identified in the pike samples, 23 fatty acids accounted for 99.3% of the total content. The most abundant saturated fatty acids (SFA, 31.6%) were palmitic (C16:0, 20.0%) and stearic (C18:0, 7.3%) acids. Among monounsaturated fatty acids (MUFA, 15.1%), oleic acid (C18:1n9, 10.2%) and palmitoleic acid (C16:1, 4.1%) demonstrated the highest levels. The most represented polyunsaturated fatty acids (PUFA, 53.3%) were arachidonic acid (C20:4n-6, 7.6%), eicosapentaenoic acid (EPA, C20:5n-3, 7.3%), and docosahexaenoic acid (DHA, C22:6n-3, 26.3%). The fatty acid profile of specimens from the Gyda River was different in comparison to profiles found in other pike populations, most likely due to different diets. Pike flesh has good nutrition quality in terms of a low n-6/n-3 ratio (0.36), low atherogenic (0.39), and thrombogenic (0.22) indices, and a high ratio of hypocholesterolemic to hypercholesterolemic fatty acids (2.83), and this species can be recommended as a replacement or alternative to other fish sources in traditional diets.

Age-related features of the content of substrates of energy metabolism and body mass index in women residing in the Subarctic and Arctic regions of Russia.

OBJECTIVES: Age is associated with a number of health risks linked to obesity caused by an imbalance in the main energy substrates-fatty acids (FA) and glucose (Glu). Therefore, the objective of this study was to identify age-related features of the metabolism of fatty acids and Glu, their correlations and the relation with the body mass index (BMI) in women of the local Caucasoid population from two northern regions of Russia with different nature, climate, and geography. METHODS: We examined women aged 21-60 years born and permanently residing in the Subarctic region (SR) and the Arctic region (AR). The participants were divided into three age groups: 21-35, 36-45, and 46-60 years. The levels of FAs, Glu, and triglycerides (TG) in the blood serum were determined by spectrophotometric and gas chromatographic methods; the values of BMI and TyG (triglyceride glucose) index were calculated. To analyze data, we used the descriptive and correlation analyses by nonparametric methods, as well as multiple linear regression analysis. RESULTS: With age, the surveyed women demonstrated elevated levels of triglyceride, the majority of the studied fatty acids, BMI and TyG index. For three fatty acids, age-related changes were noted in one of the regions only: stearic and linoleic acids in the SR, and docosahexaenoic acid in the AR; no significant changes were observed for dihomo-γ-linolenic and arachidonic acids. We found elevated Glu levels in women aged 46-60 years residing in the SR. Regional differences were due to higher concentrations of FAs and Glu in the AR. All identified correlations were positive. BMI values were associated with FAs and TG, and in women aged 46-60 years, they were additionally associated with Glu. The latter also correlated with some FAs and TG in this group. TyG index associations with saturated FAs (SFAs) became stronger with age. CONCLUSIONS: Age has a significant impact on the homeostasis of key energy substrates (Glu, TG, SFAs, monounsaturated FAs), on BMI and TyG index, which are indicators of obesity and insulin resistance. Depending on the region of residence (Subarctic or Arctic), we found changes in the FA profile undersaturation (especially long-chain polyunsaturated FAs) and some specific features of Glu homeostasis (for the age groups of 21-35 and 46-60 years) in women of Caucasoid race in the Russian North. Multiple regression analysis showed that BMI, as well as the region of residence and age, are significant predictors for almost all biochemical parameters, especially for TG and TyG index.

Bidirectional regulation by "star forces": Ionotropic astrocyte's optical stimulation suppresses synaptic plasticity, metabotropic one strikes back.

The role of astrocytes in modulating synaptic plasticity is an important question that until recently was not addressed due to limitations of previously existing technology. In the present study, we took an advantage of optogenetics to specifically activate astrocytes in hippocampal slices in order to study effects on synaptic function. Using the AAV-based delivery strategy, we expressed the ionotropic channelrhodopsin-2 (ChR2) or the metabotropic Gq-coupled Opto-a1AR opsins specifically in hippocampal astrocytes to compare different modalities of astrocyte activation. In electrophysiological experiments, we observed a depression of basal field excitatory postsynaptic potentials (fEPSPs) in the CA1 hippocampal layer following light stimulation of astrocytic ChR2. The ChR2-mediated depression increased under simultaneous light and electrical theta-burst stimulation (TBS). Application of the type 2 purinergic receptor antagonist suramin prevented depression of basal synaptic transmission, and switched the ChR2-dependent depression into potentiation. The GABAB receptor antagonist, phaclofen, did not prevent the depression of basal fEPSPs, but switched the ChR2-dependent depression into potentiation comparable to the values for TBS in control slices. In contrast, light stimulation of Opto-a1AR expressed in astrocytes led to an increase in basal fEPSPs, as well as a potentiation of synaptic responses to TBS significantly. A specific blocker of the Gq protein downstream target, the phospholipase C, U73122, completely prevented the effects of Opto-a1AR stimulation on basal fEPSPs or Opto + TBS responses. To understand molecular basis for the observed effects, we performed an analysis of gene expression in these slices using quantitative PCR approach. We observed a significant upregulation of "immediate-early" gene expression in hippocampal slices after light activation of Opto-a1AR-expressing astrocytes alone (cRel, Arc, Fos, JunB, and Egr1) or paired with TBS (cRel, Fos, and Egr1). Activation of ChR2-expressing hippocampal astrocytes was insufficient to affect expression of these genes in our experimental conditions. Thus, we concluded that optostimulation of astrocytes with ChR2 and Opto-a1AR optogenetic tools enables bidirectional modulation of synaptic plasticity and gene expression in hippocampus.

In Vivo Penetrating Microelectrodes for Brain Electrophysiology.

In recent decades, microelectrodes have been widely used in neuroscience to understand the mechanisms behind brain functions, as well as the relationship between neural activity and behavior, perception and cognition. However, the recording of neuronal activity over a long period of time is limited for various reasons. In this review, we briefly consider the types of penetrating chronic microelectrodes, as well as the conductive and insulating materials for microelectrode manufacturing. Additionally, we consider the effects of penetrating microelectrode implantation on brain tissue. In conclusion, we review recent advances in the field of in vivo microelectrodes.

Astrocyte Activation Markers.

Astrocytes are the most common type of glial cells that provide homeostasis and protection of the central nervous system. Important specific characteristic of astrocytes is manifestation of morphological heterogeneity, which is directly dependent on localization in a particular area of the brain. Astrocytes can integrate into neural networks and keep neurons active in various areas of the brain. Moreover, astrocytes express a variety of receptors, channels, and membrane transporters, which underlie their peculiar metabolic activity, and, hence, determine plasticity of the central nervous system during development and aging. Such complex structural and functional organization of astrocytes requires the use of modern methods for their identification and analysis. Considering the important fact that determining the most appropriate marker for polymorphic and multiple subgroups of astrocytes is of decisive importance for studying their multifunctionality, this review presents markers, modern imaging techniques, and identification of astrocytes, which comprise a valuable resource for studying structural and functional properties of astrocytes, as well as facilitate better understanding of the extent to which astrocytes contribute to neuronal activity.

Effects of G-Quadruplex-Binding Plant Secondary Metabolites on c-MYC Expression.

Guanine-rich DNA sequences tending to adopt noncanonical G-quadruplex (G4) structures are over-represented in promoter regions of oncogenes. Ligands recognizing G4 were shown to stabilize these DNA structures and drive their formation regulating expression of corresponding genes. We studied the interaction of several plant secondary metabolites (PSMs) with G4s and their effects on gene expression in a cellular context. The binding of PSMs with G4s formed by the sequences of well-studied oncogene promoters and telomeric repeats was evaluated using a fluorescent indicator displacement assay. c-MYC G4 folding topology and thermal stability, as well as the PMS influence on these parameters, were demonstrated by UV-spectroscopy and circular dichroism. The effects of promising PSMs on c-MYC expression were assessed using luciferase reporter assay and qPR-PCR in cancer and immortalized cultured cells. The ability of PMS to multi-targeting cell signaling pathways was analyzed by the pathway-focused gene expression profiling with qRT-PCR. The multi-target activity of a number of PSMs was demonstrated by their interaction with a set of G4s mimicking those formed in the human genome. We have shown a direct G4-mediated down regulation of c-MYC expression by sanguinarine, quercetin, kaempferol, and thymoquinone; these effects being modulated by PSM's indirect influence via cell signaling pathways.

Toxicological Properties of 7-Methylguanine, and Preliminary Data on its Anticancer Activity.

7-Methylguanine (7-MG) competitively inhibits the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) and RNA-modifying enzyme tRNA-guanine transglycosylase (TGT) and represents a potential anticancer drug candidate. Furthermore, as a natural compound, it could escape the serious side effects characteristic for approved synthetic PARP inhibitors. Here we present a comprehensive study of toxicological and carcinogenic properties of 7-MG. It was demonstrated that 7-MG does not induce mutations or structural chromosomal abnormalities, and has no blastomogenic activity. A treatment regimen with 7-MG has been established in mice (50 mg/kg per os, 3 times per week), exerting no adverse effects or changes in morphology. Preliminary data on the 7-MG anticancer activity obtained on transplantable tumor models support our conclusions that 7-MG can become a promising new component of chemotherapy.

Fatty Acid Content of Four Salmonid Fish Consumed by Indigenous Peoples from the Yamal-Nenets Autonomous Okrug (Northwestern Siberia, Russia).

We assayed fatty acids in the flesh of Arctic cisco Coregonus autumnalis (adult and juvenile), least cisco Coregonus sardinella, muksun Coregonus muksun, and Arctic charr Salvelinus alpinus inhabiting water bodies of the Gydan Peninsula, Siberia, Russia. The highest concentrations of total and polyunsaturated fatty acids (PUFAs) were found in Arctic charr (27.8 and 9.5 mg g-1) and adult Arctic cisco (20.2 and 7.6 mg g-1), while the lowest concentrations occurred in juvenile Arctic cisco (7.5 and 3.6 mg g-1). Multivariate analyses divided all studied fish into five distinct groups with the highest similarity between least cisco and muksun and the highest dissimilarity between juvenile Arctic cisco and Arctic charr. Coregonid fish from the study area had a higher content of docosahexaenoic and eicosapentaenoic acids than their conspecifics from subarctic and temperate habitats. The flesh of the studied fish is a source of a healthy diet for humans. Taking into account that all the studied fish are components of the traditional diet of indigenous peoples in northwestern Siberia, our data may be useful not only for local consumers and anglers but also for stakeholders focused on food policy and food security in the area.

Molecular Mechanisms of Anticancer Activity of N-Glycosides of Indolocarbazoles LCS-1208 and LCS-1269.

Novel indolocarbazole derivatives named LCS were synthesized by our research group. Two of them were selected as the most active anticancer agents in vivo. We studied the mechanisms of anticancer activity in accordance with the previously described effects of indolocarbazoles. Cytotoxicity was estimated by MTT assay. We analyzed LCS-DNA interactions by circular dichroism in cholesteric liquid crystals and fluorescent indicator displacement assay. The effect on the activity of topoisomerases I and II was studied by DNA relaxation assay. Expression of interferon signaling target genes was estimated by RT-PCR. Chromatin remodeling was analyzed-the effect on histone H1 localization and reactivation of epigenetically silenced genes. LCS-induced change in the expression of a wide gene set was counted by means of PCR array. Our study revealed the cytotoxic activity of the compounds against 11 cancer cell lines and it was higher than in immortalized cells. Both compounds bind DNA; binding constants were estimated-LCS-1208 demonstrated higher affinity than LCS-1269; it was shown that LCS-1208 intercalates into DNA that is typical for rebeccamycin derivatives. LCS-1208 also inhibits topoisomerases I and IIα. Being a strong intercalator and topoisomerase inhibitor, LCS-1208 upregulates the expression of interferon-induced genes. In view of LCSs binding to DNA we analyzed their influence on chromatin stability and revealed that LCS-1269 displaces histone H1. Our analysis of chromatin remodeling also included a wide set of epigenetic experiments in which LCS-1269 demonstrated complex epigenetic activity. Finally, we revealed that the antitumor effect of the compounds is based not only on binding to DNA and chromatin remodeling but also on alternative mechanisms. Both compounds induce expression changes in genes involved in neoplastic transformation and target genes of the signaling pathways in cancer cells. Despite of being structurally similar, each compound has unique biological activities. The effects of LCS-1208 are associated with intercalation. The mechanisms of LCS-1269 include influence on higher levels such as chromatin remodeling and epigenetic effects.

An Open-Source Wireless Electrophysiological Complex for In Vivo Recording Neuronal Activity in the Rodent's Brain.

Multi-electrode arrays (MEAs) are a widely used tool for recording neuronal activity both in vitro/ex vivo and in vivo experiments. In the last decade, researchers have increasingly used MEAs on rodents in vivo. To increase the availability and usability of MEAs, we have created an open-source wireless electrophysiological complex. The complex is scalable, recording the activity of neurons in the brain of rodents during their behavior. Schematic diagrams and a list of necessary components for the fabrication of a wireless electrophysiological complex, consisting of a base charging station and wireless wearable modules, are presented.

Optogenetic Activation of Astrocytes-Effects on Neuronal Network Function.

Optogenetics approach is used widely in neurobiology as it allows control of cellular activity with high spatial and temporal resolution. In most studies, optogenetics is used to control neuronal activity. In the present study optogenetics was used to stimulate astrocytes with the aim to modulate neuronal activity. To achieve this goal, light stimulation was applied to astrocytes expressing a version of ChR2 (ionotropic opsin) or Opto-α1AR (metabotropic opsin). Optimal optogenetic stimulation parameters were determined using patch-clamp recordings of hippocampal pyramidal neurons' spontaneous activity in brain slices as a readout. It was determined that the greatest increase in the number of spontaneous synaptic currents was observed when astrocytes expressing ChR2(H134R) were activated by 5 s of continuous light. For the astrocytes expressing Opto-α1AR, the greatest response was observed in the pulse stimulation mode (T = 1 s, t = 100 ms). It was also observed that activation of the astrocytic Opto-a1AR but not ChR2 results in an increase of the fEPSP slope in hippocampal neurons. Based on these results, we concluded that Opto-a1AR expressed in hippocampal astrocytes provides an opportunity to modulate the long-term synaptic plasticity optogenetically, and may potentially be used to normalize the synaptic transmission and plasticity defects in a variety of neuropathological conditions, including models of Alzheimer's disease and other neurodegenerative disorders.

Genetic Constructs for the Control of Astrocytes' Activity.

In the current review, we aim to discuss the principles and the perspectives of using the genetic constructs based on AAV vectors to regulate astrocytes' activity. Practical applications of optogenetic approaches utilizing different genetically encoded opsins to control astroglia activity were evaluated. The diversity of astrocytic cell-types complicates the rational design of an ideal viral vector for particular experimental goals. Therefore, efficient and sufficient targeting of astrocytes is a multiparametric process that requires a combination of specific AAV serotypes naturally predisposed to transduce astroglia with astrocyte-specific promoters in the AAV cassette. Inadequate combinations may result in off-target neuronal transduction to different degrees. Potentially, these constraints may be bypassed with the latest strategies of generating novel synthetic AAV serotypes with specified properties by rational engineering of AAV capsids or using directed evolution approach by searching within a more specific promoter or its replacement with the unique enhancer sequences characterized using modern molecular techniques (ChIP-seq, scATAC-seq, snATAC-seq) to drive the selective transgene expression in the target population of cells or desired brain regions. Realizing these strategies to restrict expression and to efficiently target astrocytic populations in specific brain regions or across the brain has great potential to enable future studies.

HeLa TI cell-based assay as a new approach to screen for chemicals able to reactivate the expression of epigenetically silenced genes.

Chemicals reactivating epigenetically silenced genes target diverse classes of enzymes, including DNMTs, HDACs, HMTs and BET protein family members. They can strongly influence the expression of genes and endogenous retroviral elements with concomitant dsRNA synthesis and massive transcription of LTRs. Chemicals reactivating gene expression may cause both beneficial effects in cancer cells and may be hazardous by promoting carcinogenesis. Among chemicals used in medicine and commerce, only a small fraction has been studied with respect to their influence on epigenetic silencing. Screening of chemicals reactivating silent genes requires adequate systems mimicking whole-genome processes. We used a HeLa TSA-inducible cell population (HeLa TI cells) obtained by retroviral infection of a GFP-containing vector followed by several rounds of cell sorting for screening purposes. Previously, the details of GFP epigenetic silencing in HeLa TI cells were thoroughly described. Herein, we show that the epigenetically repressed gene GFP is reactivated by 15 agents, including HDAC inhibitors-vorinostat, sodium butyrate, valproic acid, depsipeptide, pomiferin, and entinostat; DNMT inhibitors-decitabine, 5-azacytidine, RG108; HMT inhibitors-UNC0638, BIX01294, DZNep; a chromatin remodeler-curaxin CBL0137; and BET inhibitors-JQ-1 and JQ-35. We demonstrate that combinations of epigenetic modulators caused a significant increase in cell number with reactivated GFP compared to the individual effects of each agent. HeLa TI cells are competent to metabolize xenobiotics and possess constitutively expressed and inducible cytochrome P450 mono-oxygenases involved in xenobiotic biotransformation. Thus, HeLa TI cells may be used as an adequate test system for the extensive screening of chemicals, including those that must be metabolically activated. Studying the additional metabolic activation of xenobiotics, we surprisingly found that the rat liver S9 fraction, which has been widely used for xenobiotic activation in genotoxicity tests, reactivated epigenetically silenced genes. Applying the HeLa TI system, we show that N-nitrosodiphenylamine and N-nitrosodimethylamine reactivate epigenetically silenced genes, probably by affecting DNA methylation.

Optogenetic and chemogenetic modulation of astroglial secretory phenotype.

Astrocytes play a major role in brain function and alterations in astrocyte function that contribute to the pathogenesis of many brain disorders. The astrocytes are attractive cellular targets for neuroprotection and brain tissue regeneration. Development of novel approaches to monitor and to control astroglial function is of great importance for further progress in basic neurobiology and in clinical neurology, as well as psychiatry. Recently developed advanced optogenetic and chemogenetic techniques enable precise stimulation of astrocytes in vitro and in vivo, which can be achieved by the expression of light-sensitive channels and receptors, or by expression of receptors exclusively activated by designer drugs. Optogenetic stimulation of astrocytes leads to dramatic changes in intracellular calcium concentrations and causes the release of gliotransmitters. Optogenetic and chemogenetic protocols for astrocyte activation aid in extracting novel information regarding the function of brain's neurovascular unit. This review summarizes current data obtained by this approach and discusses a potential mechanistic connection between astrocyte stimulation and changes in brain physiology.

Therapy-related acute myeloid leukemia and its prevention.

BACKGROUND: Secondary tumors, including therapy-related acute myeloid leukemia (t-AML), represent one of the most undesirable side effects of chemotherapy, which arise several years after primary cancer treatment. This review aims to analyze the current data on molecular pathogenesis of t-AML revealing potential criteria for predicting predisposition to the disease. Another objective is to analyze the information on promising approaches for t-AML prevention. METHODS: We analyzed studies regarding t-AML and possible approaches for cancer prevention of drug-induced tumors. Publications in the databases, such as SciVerse Scopus (948), PubMed (1837) and Web of Science (935) were used. Among 92 the most important publications cited in the review, 79 were published during the last decade. RESULTS: The review provides the information concerning t-AML pathogenesis, molecular markers of primary cancer patients with high risk of t-AML. The role of the bone marrow niche in clonal hematopoiesis and t-AML pathogenesis is discussed. Current approaches for t-AML prevention both at the stage of therapy and at the latent period are described. Inhibition effects of polyphenols on cell proliferation and on the appearance of hemopoetic clones of indeterminate potential are proposed for t-AML prevention. CONCLUSION: The problem of the t-AML, a cancer induced by genotoxic chemotherapeutic drugs, is considered from the point of view of the fundamental mechanisms of chemical carcinogenesis, highlighting initiation and promotion stages. It enables to reveal the possible markers for the group of patients with high risk for t-AML and to demonstrate perspectives for the use of plant polyphenols for t-AML prevention.