Synthesis, recyclization under the action of methanol and analgetic activity of N'-(5-aryl-2-oxofuran-3(2H)-ylidene)furan-2-carbohydrazides

New methyl 5-aryl-1-(furan-2-carbonyl)-1H-pyrazole-3-carboxylates were obtained via decyclization reaction of N'-(5-aryl-2-oxofuran-3(2H)-ylidene)furan-2-carbohydrazides under the action of methanol. Starting N'-(5-aryl-2-oxofuran-3(2H)-ylidene)furan-2-carbohydrazides were obtained by intramolecular cyclization of substituted 4-aryl-2-[2-(furan-2-ylcarbonyl)hydrazinylidene]-4-oxobutanoic acids in propionic anhydride. The structure of the compounds obtained was confirmed by the 1H NMR spectroscopy, IR spectrometry and elemental analysis methods. Analgesic activity of some obtained compounds was studied by the “hot plate” method on outbred white mice of both sexes with intraperitoneal injection

Genome-wide sequence analyses of ethnic populations across Russia

The Russian Federation is the largest and one of the most ethnically diverse countries in the world, however no centralized reference database of genetic variation exists to date. Such data are crucial for medical genetics and essential for studying population history. The Genome Russia Project aims at filling this gap by performing whole genome sequencing and analysis of peoples of the Russian Federation. Here we report the characterization of genome-wide variation of 264 healthy adults, including 60 newly sequenced samples. People of Russia carry known and novel genetic variants of adaptive, clinical and functional consequence that in many cases show allele frequency divergence from neighboring populations. Population genetics analyses revealed six phylogeographic partitions among indigenous ethnicities corresponding to their geographic locales. This study presents a characterization of population-specific genomic variation in Russia with results important for medical genetics and for understanding the dynamic population history of the world's largest country

Phenological shifts of abiotic events, producers and consumers across a continent

Ongoing climate change can shift organism phenology in ways that vary depending on species, habitats and climate factors studied. To probe for large-scale patterns in associated phenological change, we use 70,709 observations from six decades of systematic monitoring across the former Union of Soviet Socialist Republics. Among 110 phenological events related to plants, birds, insects, amphibians and fungi, we find a mosaic of change, defying simple predictions of earlier springs, later autumns and stronger changes at higher latitudes and elevations. Site mean temperature emerged as a strong predictor of local phenology, but the magnitude and direction of change varied with trophic level and the relative timing of an event. Beyond temperature-associated variation, we uncover high variation among both sites and years, with some sites being characterized by disproportionately long seasons and others by short ones. Our findings emphasize concerns regarding ecosystem integrity and highlight the difficulty of predicting climate change outcomes. The authors use systematic monitoring across the former USSR to investigate phenological changes across taxa. The long-term mean temperature of a site emerged as a strong predictor of phenological change, with further imprints of trophic level, event timing, site, year and biotic interactions.Peer reviewe

BNIP3 in Lung Cancer: To Kill or Rescue?

Bcl-2/adenovirus E1B 19kDa interacting protein 3 (BNIP3) is a pro-apoptotic BH3-only protein of the Bcl-2 family. Initially, BNIP3 was described as one of the mediators of hypoxia-induced apoptotic cell death in cardiac myocytes and neurons. Besides apoptosis, BNIP3 plays a crucial role in autophagy, metabolic pathways, and metastasis-related processes in different tumor types. Lung cancer is one of the most aggressive types of cancer, which is often diagnosed at an advanced stage. Therefore, there is still urgent demand for reliable biochemical markers for lung cancer and its efficient treatment. Mitochondria functioning and mitochondrial proteins, including BNIP3, have a strong impact on lung cancer development and progression. Here, we summarized current knowledge about the BNIP3 gene and protein features and their role in cancer progression, especially in lung cancer in order to develop new therapeutic approaches associated with BNIP3

Urokinase Receptor uPAR Downregulation in Neuroblastoma Leads to Dormancy, Chemoresistance and Metastasis

uPAR is a membrane receptor that binds extracellular protease urokinase, contributes to matrix remodeling and plays a crucial role in cellular adhesion, proliferation, survival, and migration. uPAR overexpression in tumor cells promotes mitogenesis, opening a prospective avenue for targeted therapy. However, uPAR targeting in cancer has potential risks. We have recently shown that uPAR downregulation in neuroblastoma promotes epithelial-mesenchymal transition (EMT), potentially associated with metastasis and chemoresistance. We used data mining to evaluate the role of uPAR expression in primary and relapsed human neuroblastomas. To model the decreased uPAR expression, we targeted uPAR using CRISPR/Cas9 and shRNA in neuroblastoma Neuro2a cells and evaluated their chemosensitivity in vitro as well as tumor growth and metastasis in vivo. We demonstrate that the initially high PLAUR expression predicts poor survival in human neuroblastoma. However, relapsed neuroblastomas have a significantly decreased PLAUR expression. uPAR targeting in neuroblastoma Neuro2a cells leads to p38 activation and an increased p21 expression (suggesting a dormant phenotype). The dormancy in neuroblastoma cells can be triggered by the disruption of uPAR-integrin interaction. uPAR-deficient cells are less sensitive to cisplatin and doxorubicin treatment and exhibit lower p53 activation. Finally, low uPAR-expressing Neuro2a cells formed smaller primary tumors, but more frequent metastasis in mice. To the best of our knowledge, this is the first study revealing the pathological role of dormant uPAR-deficient cancer cells having a chemoresistant and motile phenotype

Peripheral Groups of Dicationic Pyrazinoporphyrins Regulate Lipid Membrane Binding

Photodynamic therapy (PDT) is a widely used technique for skin cancer treatment and antimicrobial therapy. An improvement in PDT efficiency requires not only an increase in quantum yield of photosensitizer (PS) molecules but also their applicability for biological systems. Recently, we demonstrated that the activity of porphyrin-based PSs in the lipid membrane environment depends on the nature of the cation in the macrocycle due to its interactions with the lipid phosphate moiety, as well as the orientation of the PS molecules inside the membrane. Here, we report the synthesis, membrane binding properties and photodynamic efficiency of novel dicationic free-base, Ni(II) and Zn(II) pyrazinoporphyrins with terminal tetraalkylammonium units (2H-1, Ni-1 and Zn-1), to show the possibility to enhance the membrane binding of PS molecules, regardless of the central cation. All of these substances adsorb at the lipid membrane, while free-base and Zn(II) porphyrins actively generate singlet oxygen (SO) in the membranes. Thus, this study reveals a new way to tune the PDT activity of PSs in biological membranes through designing the structure of the peripheral groups in the macrocyclic photosensitizer

Glial Cell Architecture Dynamics in Dentate Gyrus and CA4 Area of Wistar Rat Hippocampus Following 20-minute Occlusion of Common Carotid Arteries

Aim. To study the distribution and spatial organization of dentate gyrus (DG) astrocytes and CA4 area of hippocampus of Wistar rats following 20-minute occlusion of common carotid arteries (OCCA) compared to sham-operated control animals.Material and methods. Histological (Nissl staining with hematoxylin and eosin), immunohistochemical (GFAP, MAP-2) and morphometric methods were used. Astrocytes and neurons in control (sham-operated animals, n = 5) group, after 6 hours (n=5), 1 days (n=5), 3 days (n=5), 7 days (n=5), 14 days (n=5) and 30 days (n=5) after 20-minute OCCA were studied on thin (4 µm) serial frontal sections of the hippocampus. Fractal analysis (ImageJ 1.52; fraclac 2.5 plugin) was used to obtain additional quantitative information on the spatial organization of astrocyte networks. Statistical hypotheses were tested using nonparametric criteria.Results. 30 days after the 20-minute OCCA, only 5.3% of CA4 neurons were irreversibly destroyed and the total numerical density of DG granular cells remained at the control level. Hypertrophy and increased complexity of the spatial organization of astrocyte processes were observed 6 hours and 1 day after OCCA and persisted for 30 days. Astrogliosis was accompanied by an increased relative area of GFAP-positive material and fractal dimension and reduced lacunarity of the astrocyte network. The latter was especially evident in 1, 14 and 30 days after the OCCA.Conclusion. After the 20-minute OCCA, the density of GFAP-positive material increased, the fibroarchitecture reorganized and gained more complexity due to the branching of astrocyte processes. At the same time, the total numerical density of neurons changed only slightly. All this indicated the probable role of astrocytes in post-ischemic activation of natural neuroprotection mechanisms

Prognostic signature based on mitochondria quality control proteins for the prediction of lung adenocarcinoma patients survival

Abstract Lung cancer is the leading cause of cancer mortality worldwide. In recent years, the incidence of lung cancer subtype lung adenocarcinoma (LUAD) has steadily increased. Mitochondria, as a pivotal site of cell bioenergetics, metabolism, cell signaling, and cell death, are often dysregulated in lung cancer cells. Mitochondria maintenance and integrity depend on mitochondrial quality control proteins (MQCPs). During lung cancer progression, the levels of MQCPs could change and promote cancer cell adaptation to the microenvironment and stresses. Here, univariate and multivariate proportional Cox regression analyses were applied to develop a signature based on the level of MQCPs (dimeric form of BNIP3, DRP1, and SIRT3) in tumorous and non-tumorous samples of 80 patients with LUAD. The MQCP signature could be used to separate the patients with LUAD into high- and low-risk groups. Survival analysis indicated that patients in the high-risk group had dramatically shorter overall survival compared with the low-risk patients. Moreover, a nomogram combining clinicopathologic features and the MQCP signature was constructed and validated to predict 1-, 3-, and 5-year overall survival of the patients. Thus, this study presents a novel signature based on MQCPs as a reliable prognostic tool to predict overall survival for patients with LUAD

Fluorescence Anisotropy in Radachlorin and Chlorin e6 in Water–Methanol Solutions under One- and Two-Photon Excitation

The fluorescence anisotropy of photosensitizers Radachlorin and chlorin e6 was studied using the time-resolved single photon-counting technique under one- and two-photon excitation within the Soret absorption band. A very small negative anisotropy was observed in both photosensitizers under one-photon excitation in the vicinity of the absorption maximum within the wavelength range of 395–405 nm. Meanwhile, two-photon excitation of the photosensitizers in the same spectral range demonstrated high fluorescence anisotropy with the maximum value of about 0.43. The drastic difference of the fluorescence anisotropy parameters at one- and two-photon excitation modes was suggested to be due to the different symmetries of one- and two-photon absorption tensors when two-photon absorption tensor components have comparable values. The variation of excitation wavelengths in the spectral range of 375–425 nm demonstrated nonlinear wavelength dependence of anisotropy of both Radachlorin and chlorin e6, with opposite tendencies at one- and two-photon excitation. The data obtained suggest that one-photon excitation at about 405 nm often utilized in FLIM experiments is not sensitive to fluorescence anisotropy in Radachlorin and chlorin e6 and therefore cannot be used for the determination of anisotropy/rotational diffusion time in these molecules. Meanwhile, two-photon excitation can provide high fluorescence anisotropy and accurate determination of the rotational diffusion time. At the same time, one-photon excitation at about 405 nm can be used for the accurate evaluation of fluorescence lifetimes within the standard FLIM schematic where fluorescence polarization is not taken into account