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Unsymmetric lipophilic polyamine derivatives are considered as potential antitumor agents. Here, a series of novel symmetric lipophilic polyamines (LPAs) based on norspermine and ...triethylenetetramine (TETA) backbones bearing alkyl substituents with different lengths (from decyl to octadecyl) at C(1) atom of glycerol were synthesized. Performed screening of the cytotoxicity of novel compounds on the panel of tumor cell lines (MCF-7, KB-3-1, B16) and non-malignant fibroblasts hFF3 in vitro revealed a correlation between the length of the aliphatic moieties in LPAs and their toxic effects – LPAs with the shortest decyl substituent were found to exhibit the highest cytotoxicity. Furthermore, norspermine-based LPAs displayed somewhat more pronounced cytotoxicity compared with their TETA-based counterparts. Further mechanistic studies demonstrated that hit LPAs containing the norspermine backbone and tetradecyl or decyl substituents efficiently induced apoptosis in KB-3-1 cells. Moreover, decyl-bearing LPA inhibited motility and enhanced adhesiveness of murine B16 melanoma cells in vitro, showing promising antimetastatic potential. Thus, developed novel symmetric norspermine-based LPAs can be considered as promising anticancer chemotherapeutic candidates.
Soloxolone amides are semisynthetic triterpenoids that can cross the blood-brain barrier and inhibit glioblastoma growth both in vitro and in vivo . Here we investigate the impact of these compounds ...on processes associated with glioblastoma invasiveness and therapy resistance. Screening of soloxolone amides against glioblastoma cells revealed the ability of compound 7 (soloxolone para -methylanilide) to inhibit transforming growth factor-beta 1 (TGF-β1)-induced glial-mesenchymal transition Compound 7 inhibited morphological changes, wound healing, transwell migration, and expression of mesenchymal markers (N-cadherin, fibronectin, Slug) in TGF-β1-induced U87 and U118 glioblastoma cells, while restoring their adhesiveness. Confocal microscopy and molecular docking showed that 7 reduced SMAD2/3 nuclear translocation probably by direct interaction with the TGF-β type I and type II receptors (TβRI/II). In addition, 7 suppressed stemness of glioblastoma cells as evidenced by inhibition of colony forming ability, spheroid growth, and aldehyde dehydrogenase (ALDH) activity. Furthermore, 7 exhibited a synergistic effect with temozolomide (TMZ) on glioblastoma cell viability. Using N-acetyl-L-cysteine (NAC) and flow cytometry analysis of Annexin V-FITC-, propidium iodide-, and DCFDA-stained cells, 7 was found to synergize the cytotoxicity of TMZ by inducing ROS-dependent apoptosis. Further in vivo studies showed that 7 , alone or in combination with TMZ, effectively suppressed the growth of U87 xenograft tumors in mice. Thus, 7 demonstrated promising potential as a component of combination therapy for glioblastoma, reducing its invasiveness and increasing its sensitivity to chemotherapy.
The origin of the ligand-binding ability of nuclear receptors is still a matter of discussion. Current opposing models are the early evolution of an ancestral receptor that would bind a specific ...ligand with high affinity and the early evolution of an ancestral orphan that was a constitutive transcription factor. Here we review the arguments in favour or against these two hypotheses, and we discuss an alternative possibility that the ancestor was a ligand sensor, which would be able to explain the apparently contradictory data generated in previous models for the evolution of ligand binding in nuclear receptors.
In this investigation, we extensively studied the mechanism of antitumor activity of bovine pancreatic RNase A. Using confocal microscopy, we show that after RNase A penetration into HeLa and B16 ...cells, a part of the enzyme remains unbound with the ribonuclease inhibitor (RI), resulting in the decrease in cytosolic RNAs in both types of cells and rRNAs in the nucleoli of HeLa cells. Molecular docking indicates the ability of RNase A to form a complex with Ku70/Ku80 heterodimer, and microscopy data confirm its localization mostly inside the nucleus, which may underlie the mechanism of RNase A penetration into cells and its intracellular traffic. RNase A reduced migration and invasion of tumor cells in vitro. In vivo, in the metastatic model of melanoma, RNase A suppressed metastases in the lungs and changed the expression of EMT markers in the tissue adjacent to metastatic foci; this increased Cdh1 and decreased Tjp1, Fn and Vim, disrupting the favorable tumor microenvironment. A similar pattern was observed for all genes except for Fn in metastatic foci, indicating a decrease in the invasive potential of tumor cells. Bioinformatic analysis of RNase-A-susceptible miRNAs and their regulatory networks showed that the main processes modulated by RNase A in the tumor microenvironment are the regulation of cell adhesion and junction, cell cycle regulation and pathways associated with EMT and tumor progression.
It has been suggested that highly social mammals, such as naked mole rats and humans, are long-lived due to neoteny (the prolongation of youth). In both species, aging cannot operate as a mechanism ...facilitating natural selection because the pressure of this selection is strongly reduced due to
) a specific social structure where only the "queen" and her "husband(s)" are involved in reproduction (naked mole rats) or
) substituting fast technological progress for slow biological evolution (humans). Lists of numerous traits of youth that do not disappear with age in naked mole rats and humans are presented and discussed. A high resistance of naked mole rats to cancer, diabetes, cardiovascular and brain diseases, and many infections explains why their mortality rate is very low and almost age-independent and why their lifespan is more than 30 years, versus 3 years in mice. In young humans, curves of mortality versus age start at extremely low values. However, in the elderly, human mortality strongly increases. High mortality rates in other primates are observed at much younger ages than in humans. The inhibition of the aging process in humans by specific drugs seems to be a promising approach to prolong our healthspan. This might be a way to retard aging, which is already partially accomplished via the natural physiological phenomenon neoteny.
Scale and tempo of brain expansion in the course of human evolution implies that this process was driven by a positive feedback. The “cultural drive” hypothesis suggests a possible mechanism for the ...runaway brain‐culture coevolution wherein high‐fidelity social learning results in accumulation of cultural traditions which, in turn, promote selection for still more efficient social learning. Here we explore this evolutionary mechanism by means of computer modeling. Simulations confirm its plausibility in a social species in a socio‐ecological situation that makes the sporadic invention of new beneficial and cognitively demanding behaviors possible. The chances for the runaway brain‐culture coevolution increase when some of the culturally transmitted behaviors are individually beneficial while the others are group‐beneficial. In this case, “cultural drive” is possible under varying levels of between‐group competition and migration. Modeling implies that brain expansion can receive additional boost if the evolving mechanisms of social learning are costly in terms of brain expansion (e.g., rely on complex neuronal circuits) and tolerant to the complexity of information transferred, that is, make it possible to transfer complex skills and concepts easily. Human language presumably fits this description. Modeling also confirms that the runaway brain‐culture coevolution can be accelerated by additional positive feedback loops via population growth and life span extension, and that between‐group competition and cultural group selection can facilitate the propagation of group‐beneficial behaviors and remove maladaptive cultural traditions from the population's culture, which individual selection is unable to do.
Extremely rapid brain expansion in the course of human evolution implies that this process was driven by a positive feedback. The “cultural drive” hypothesis suggests a possible mechanism for the runaway brain‐culture coevolution wherein high‐fidelity social learning results in accumulation of cultural traditions which, in turn, promote selection for still more efficient social learning. Here we explore this evolutionary mechanism by means of computer modeling and show that the conditions necessary for a powerful “cultural drive” are compatible with the current knowledge of the ecology and social organization of the Pleistocene Homo species.
Pentacyclic triterpenoids are a large class of natural isoprenoids that are widely biosynthesized in higher plants. These compounds are potent anticancer agents that exhibit antiproliferative, ...antiangiogenic, antiinflammatory and proapoptotic activities. Although their effects on multiple pathways have been reported, unifying mechanisms of action have not yet been established. To date, a huge number of semisynthetic derivatives have been synthesized in different laboratories on the basis of triterpenoid scaffolds, and many have been assayed for their biological activities. The present review focuses on natural triterpenoids of the oleanane-, ursane- and lupane-types and their semisynthetic derivatives. Here, we summarize the diverse cellular and molecular targets of these compounds and the signal pathways involved in the performance of their antitumour actions. Among the most relevant mechanisms involved are cell cycle arrest, apoptosis and autophagy triggered by the effect of triterpenoids on TGF-β and HER cell surface receptors and the downstream PI3KAkt- mTOR and IKK/NF-kB signaling axis, STAT3 pathway and MAPK cascades.
Acute lung injury (ALI) is a specific form of lung damage caused by different infectious and non-infectious agents, including SARS-CoV-2, leading to severe respiratory and systemic inflammation. To ...gain deeper insight into the molecular mechanisms behind ALI and to identify core elements of the regulatory network associated with this pathology, key genes involved in the regulation of the acute lung inflammatory response (Il6, Ccl2, Cat, Serpine1, Eln, Timp1, Ptx3, Socs3) were revealed using comprehensive bioinformatics analysis of whole-genome microarray datasets, functional annotation of differentially expressed genes (DEGs), reconstruction of protein-protein interaction networks and text mining. The bioinformatics data were validated using a murine model of LPS-induced ALI; changes in the gene expression patterns were assessed during ALI progression and prevention by anti-inflammatory therapy with dexamethasone and the semisynthetic triterpenoid soloxolone methyl (SM), two agents with different mechanisms of action. Analysis showed that 7 of 8 revealed ALI-related genes were susceptible to LPS challenge (up-regulation: Il6, Ccl2, Cat, Serpine1, Eln, Timp1, Socs3; down-regulation: Cat) and their expression was reversed by the pre-treatment of mice with both anti-inflammatory agents. Furthermore, ALI-associated nodal genes were analysed with respect to SARS-CoV-2 infection and lung cancers. The overlap with DEGs identified in postmortem lung tissues from COVID-19 patients revealed genes (Saa1, Rsad2, Ifi44, Rtp4, Mmp8) that (a) showed a high degree centrality in the COVID-19-related regulatory network, (b) were up-regulated in murine lungs after LPS administration, and (c) were susceptible to anti-inflammatory therapy. Analysis of ALI-associated key genes using The Cancer Genome Atlas showed their correlation with poor survival in patients with lung neoplasias (Ptx3, Timp1, Serpine1, Plaur). Taken together, a number of key genes playing a core function in the regulation of lung inflammation were found, which can serve both as promising therapeutic targets and molecular markers to control lung ailments, including COVID-19-associated ALI.
ABSTRACT
Recent Atacama Large Millimeter Array large surveys unveiled the presence of significant dust continuum emission in star-forming galaxies at z > 4. Unfortunately, such large programs – i.e. ...ALPINE (z ∼ 5) and REBELS (z ∼ 7) – only provide us with a single far-infrared (FIR) continuum data point for their individual targets. Therefore, high-z galaxies FIR spectral energy densities (SEDs) remain mostly unconstrained, hinging on an assumption for their dust temperature (Td) in the SED fitting procedure. This introduces uncertainties in the inferred dust masses (Md), infrared luminosities (LIR), and obscured star formation rate (SFR) fraction at z > 4. In this work, we use a method that allows us to constrain Td with a single-band measurement by combining the 158 $\mu$m continuum information with the overlying C ii emission line. We analyse the 21 C ii and FIR continuum-detected z ∼ 5 galaxies in ALPINE, finding a range of Td = 25–60 K and Md = 0.6–25.1 × 107 M⊙. Given the measured stellar masses of ALPINE galaxies, the inferred dust yields are around Md/M⋆ = (0.2–8) × 10−3, consistent with theoretical dust-production constraints. We find that eight out of the 21 ALPINE galaxies have LIR ≥ 1012 L⊙, comparable to ultraluminous IR galaxies (ULIRGs). Relying on ultraviolet-to-optical SED fitting, the SFR was underestimated by up to two orders of magnitude in four of these eight ULIRGs-like galaxies. We conclude that these four peculiar sources should be characterized by a two-phase interstellar medium structure with ‘spatially segregated’ FIR and ultraviolet emitting regions.
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