MicroRNAs (miRNAs) are important regulators of heart function and then an intriguing therapeutic target for plenty of diseases. The problem raised is that many data in this area are contradictory, thus limiting the use of miRNA-based therapy. The goal of this review is to describe the hub-mechanisms regulating the biogenesis and function of miRNAs, which could help in clarifying some contradictions in the miRNA world. With this scope, we analyse an array of factors, including several known agents of stress response, mediators of epigenetic changes, regulators of alternative splicing, RNA editing, protein synthesis and folding and proteolytic systems. All these factors are important in cardiovascular function and most of them regulate miRNA biogenesis, but their influence on miRNAs was shown for non-cardiac cells or some specific cardiac pathologies. Finally, we consider that studying the stress response factors, which are upstream regulators of miRNA biogenesis, in the diseased heart could help in (1) explaining some contradictions concerning miRNAs in heart pathology, (2) making the role of miRNAs in pathogenesis of cardiovascular disease more clear, and therefore, (3) getting powerful targets for its molecular therapy.

• Klíčová slova
• cardiac pathophysiology, hub-mechanisms, miRNAs biogenesis, stress response,
• MeSH
• biologické modely MeSH
• epigeneze genetická MeSH
• fyziologický stres genetika   MeSH
• kardiovaskulární nemoci genetika   MeSH
• lidé MeSH
• mikro RNA biosyntéza   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• mikro RNA MeSH

Background Chikungunya virus (CHIKV) infection poses a significant global health threat, necessitating a deeper understanding of its molecular mechanisms for effective management and treatment. This study aimed to understand the molecular and genetic mechanisms of CHIKV infection by analyzing microarray expression data. Methodology National Center for Biotechnology Information (NCBI) GEO2R with an adjusted p-value cut-off of <0.05 and |log2FC ≥ 1.5| was used to identify the differentially expressed genes involved in CHIKV infection using microarray data from the Gene Expression Omnibus (GEO) database, followed by enrichment analysis, protein-protein interaction (PPI) network construction, and, finally, hub gene identification. Results Analysis of the microarray dataset revealed 25 highly significant differentially expressed genes (DEGs), including 21 upregulated and four downregulated genes. PPI network analysis elucidated interactions among these DEGs, with hub genes such as ACTB and CTNNB1 exhibiting central roles. Enrichment analysis identified crucial pathways, including leukocyte transendothelial migration, regulation of actin cytoskeleton, and thyroid hormone signaling, implicating their involvement in CHIKV infection. Furthermore, the study highlights potential therapeutic targets such as ACTB and CTNNB1, which showed significant upregulation in infected cells. Conclusions These findings underscore the complex interplay between viral infection and host cellular processes, shedding light on novel avenues for diagnostic marker discovery and advancing antiviral strategies. In this study, we shed light on the molecular and genetic mechanisms of CHIKV infection and the potential role of ACTB and CTNNB1 genes.

• Klíčová slova
• cellular signaling pathways, chikungunya virus (chikv), differentially expressed genes (degs), hub genes, protein-protein interaction (ppi) network,
• Publikační typ
• časopisecké články MeSH

Significance: Mitochondria determine glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells by elevating ATP synthesis. As the metabolic and redox hub, mitochondria provide numerous links to the plasma membrane channels, insulin granule vesicles (IGVs), cell redox, NADH, NADPH, and Ca2+ homeostasis, all affecting insulin secretion. Recent Advances: Mitochondrial redox signaling was implicated in several modes of insulin secretion (branched-chain ketoacid [BCKA]-, fatty acid [FA]-stimulated). Mitochondrial Ca2+ influx was found to enhance GSIS, reflecting cytosolic Ca2+ oscillations induced by action potential spikes (intermittent opening of voltage-dependent Ca2+ and K+ channels) or the superimposed Ca2+ release from the endoplasmic reticulum (ER). The ATPase inhibitory factor 1 (IF1) was reported to tune the glucose sensitivity range for GSIS. Mitochondrial protein kinase A was implicated in preventing the IF1-mediated inhibition of the ATP synthase. Critical Issues: It is unknown how the redox signal spreads up to the plasma membrane and what its targets are, what the differences in metabolic, redox, NADH/NADPH, and Ca2+ signaling, and homeostasis are between the first and second GSIS phase, and whether mitochondria can replace ER in the amplification of IGV exocytosis. Future Directions: Metabolomics studies performed to distinguish between the mitochondrial matrix and cytosolic metabolites will elucidate further details. Identifying the targets of cell signaling into mitochondria and of mitochondrial retrograde metabolic and redox signals to the cell will uncover further molecular mechanisms for insulin secretion stimulated by glucose, BCKAs, and FAs, and the amplification of secretion by glucagon-like peptide (GLP-1) and metabotropic receptors. They will identify the distinction between the hub β-cells and their followers in intact and diabetic states. Antioxid. Redox Signal. 36, 920-952.

• Klíčová slova
• ATP-sensitive K+ channel, GLP-1, TRPM channels, branched-chain ketoacid oxidation, fatty acid-stimulated insulin secretion, insulin secretion, mitochondrial Ca2+ transport, pancreatic β-cell metabolism, redox signaling,
• MeSH
• adenosintrifosfát metabolismus   MeSH
• beta-buňky * metabolismus   MeSH
• glukosa metabolismus   MeSH
• inzulin metabolismus   MeSH
• Langerhansovy ostrůvky * metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• NAD metabolismus   MeSH
• NADP metabolismus   MeSH
• sekrece inzulinu MeSH
• sekretagoga metabolismus   MeSH
• vápník metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• adenosintrifosfát MeSH
• glukosa MeSH
• inzulin MeSH
• NAD MeSH
• NADP MeSH
• sekretagoga MeSH
• vápník MeSH

Exosomes are small vesicles of endosomal origin that are released by almost all cell types, even those that are pathologically altered. Exosomes widely participate in cell-to-cell communication via transferring cargo, including nucleic acids, proteins, and other metabolites, into recipient cells. Tumour-derived exosomes (TDEs) participate in many important molecular pathways and affect various hallmarks of cancer, including fibroblasts activation, modification of the tumour microenvironment (TME), modulation of immune responses, angiogenesis promotion, setting the pre-metastatic niche, enhancing metastatic potential, and affecting therapy sensitivity and resistance. The unique exosome biogenesis, composition, nontoxicity, and ability to target specific tumour cells bring up their use as promising drug carriers and cancer biomarkers. In this review, we focus on the role of exosomes, with an emphasis on their protein cargo, in the key mechanisms promoting cancer progression. We also briefly summarise the mechanism of exosome biogenesis, its structure, protein composition, and potential as a signalling hub in both normal and pathological conditions. Video Abstract.

• Klíčová slova
• Angiogenesis, Biomarkers, Cancer, Cancer-associated fibroblasts, Cell death, Exosomal proteins, Exosomes, Extracellular vesicles, Immune evasion, Metastasis, Therapy resistance, Tumour microenvironment,
• MeSH
• exozómy * MeSH
• extracelulární vezikuly * MeSH
• lidé MeSH
• mezibuněčná komunikace MeSH
• nádorové mikroprostředí MeSH
• nádory * MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• audiovizuální média MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Functional and molecular alterations in the cerebellum are among the most widely recognised associates of autism spectrum disorders (ASD). As a critical computational hub of the brain, the cerebellum controls and coordinates a range of motor, affective and cognitive processes. Despite well-described circuits and integrative mechanisms, specific changes that underlie cerebellar impairments in ASD remain elusive. Studies in experimental animals have been critical in uncovering molecular pathology and neuro-behavioural correlates, providing a model for investigating complex disease conditions. Herein, we review commonalities and differences of the most extensively characterised genetic lines of ASD with reference to the cerebellum. We revisit structural, functional, and molecular alterations which may contribute to neurobehavioral phenotypes. The cross-model analysis of this study provides an integrated outlook on the role of cerebellar alterations in pathobiology of ASD that may benefit future translational research and development of therapies.

• Klíčová slova
• Autism spectrum disorders, Cerebellum, Fmr1, Mecp2, Nlgn3/4, Purkinje neurons, Tsc1/2,
• MeSH
• modely genetické MeSH
• modely nemocí na zvířatech * MeSH
• mozeček * patofyziologie   patologie   MeSH
• poruchy autistického spektra * genetika   patologie   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The underlying mechanism of tumor immune evasion is a highly concerning subject for researchers. Increasing evidences reveal that the over-activated signal transducer and activator of transcription 3 (STAT3) is a crucial molecular hub in malignant tumors. STAT3 controls autophagy molecules that impair CTL-mediated tumor cell lysis, inhibiting natural killer cells and inducing apoptosis in T lymphocytes to create an immunosuppressive environment. STAT3 signaling regulates the expression of immune factors and recruits immunosuppressive cells to establish a tolerant tumor microenvironment (TME). STAT3 signaling regulates the expression of immune factors and recruits immunosuppressive cells to create an immunosuppressive environment. All this aid tumor cells in escaping from immune surveillance. In this review, we outlined the STAT3-mediated mechanisms involved in tumor immune evasion and their potential regulatory functions in the TME. We discussed the impact of STAT3 signaling on PD-L1, HIF-1α, exosome, lncRNA, and autophagy in the promotion of tumor immune evasion and highlighted the recent research on STAT3 signaling and tumor immune evasion that may assist in developing effective STAT3-targeted drugs for advancing immunotherapy.

• Klíčová slova
• Hypoxia, Immune evasion, STAT3, Tumor microenvironment, lncRNA,
• MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí MeSH
• signální transdukce MeSH
• transkripční faktor STAT3 * metabolismus   MeSH
• únik nádoru z imunitní kontroly * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• transkripční faktor STAT3 * MeSH

For patients with advanced stage non-small cell lung cancer (NSCLC), treatment strategies have changed significantly due to the introduction of targeted therapies and immunotherapy. In the last few years, we have seen an explosive growth of newly introduced targeted therapies in oncology and this development is expected to continue in the future. Besides primary targetable aberrations, emerging diagnostic biomarkers also include relevant co-occurring mutations and resistance mechanisms involved in disease progression, that have impact on optimal treatment management. To accommodate testing of pending biomarkers, it is necessary to establish routine large-panel next-generation sequencing (NGS) for all patients with advanced stage NSCLC. For cost-effectiveness and accessibility, it is recommended to implement predictive molecular testing using large-panel NGS in a dedicated, centralized expert laboratory within a regional oncology network. The central molecular testing center should host a regional Molecular Tumor Board and function as a hub for interpretation of rare and complex testing results and clinical decision-making.

• Klíčová slova
• Next-generation sequencing, Non-small cell lung cancer, Predictive biomarker testing,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Iron oxide-based nanoparticles have been repeatedly shown to affect lysosomal-mediated signaling. Recently, nanoparticles have demonstrated an ability to modulate autophagic flux via lysosome-dependent signaling. However, the precise underlying mechanisms of such modulation as well as the impact of cellular genetic background remain enigmatic. In this study, we investigated how lysosomal-mediated signaling is affected by iron oxide nanoparticle uptake in three distinct hepatic cell lines. We found that nanoparticle-induced lysosomal dysfunction alters sub-cellular localization of pmTOR and p53 proteins. Our data indicate that alterations in the sub-cellular localization of p53 protein induced by nanoparticle greatly affect the autophagic flux. We found that cells with high levels of Bcl-2 are insensitive to autophagy initiated by nanoparticles. Altogether, our data identify lysosomes as a central hub that control nanoparticle-mediated responses in hepatic cells. Our results provide an important fundamental background for the future development of targeted nanoparticle-based therapies.

• Klíčová slova
• autophagy, iron oxide nanoparticles, lysosomes, magnetic resonance imaging, nano-bio interactions, p53,
• MeSH
• autofagie genetika   MeSH
• buněčné linie MeSH
• hepatocyty metabolismus   MeSH
• lidé MeSH
• lyzozomy metabolismus   MeSH
• magnetické nanočástice oxidů železa * MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• BCL2 protein, human MeSH Prohlížeč
• MTOR protein, human MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH
• protoonkogenní proteiny c-bcl-2 MeSH
• TOR serin-threoninkinasy MeSH

Directional intercellular transport of the phytohormone auxin mediated by PIN-FORMED (PIN) efflux carriers has essential roles in both coordinating patterning processes and integrating multiple external cues by rapidly redirecting auxin fluxes. PIN activity is therefore regulated by multiple internal and external cues, for which the underlying molecular mechanisms are not fully elucidated. Here, we demonstrate that 3'-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE1 (PDK1), which is conserved in plants and mammals, functions as a molecular hub that perceives upstream lipid signalling and modulates downstream substrate activity through phosphorylation. Using genetic analysis, we show that the loss-of-function Arabidopsis pdk1.1 pdk1.2 mutant exhibits a plethora of abnormalities in organogenesis and growth due to defective polar auxin transport. Further cellular and biochemical analyses reveal that PDK1 phosphorylates D6 protein kinase, a well-known upstream activator of PIN proteins. We uncover a lipid-dependent phosphorylation cascade that connects membrane-composition-based cellular signalling with plant growth and patterning by regulating morphogenetic auxin fluxes.

• MeSH
• Arabidopsis metabolismus   MeSH
• buněčná membrána metabolismus   MeSH
• fosfolipidy metabolismus   MeSH
• kyseliny indoloctové metabolismus   MeSH
• membránové transportní proteiny metabolismus   fyziologie   MeSH
• proteinkinasy PDK fyziologie   MeSH
• proteiny huseníčku fyziologie   MeSH
• regulátory růstu rostlin metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fosfolipidy MeSH
• kyseliny indoloctové MeSH
• membránové transportní proteiny MeSH
• proteinkinasy PDK MeSH
• proteiny huseníčku MeSH
• regulátory růstu rostlin MeSH

Root hairs (RH) are excellent model systems for studying cell size and polarity since they elongate several hundred-fold their original size. Their tip growth is determined both by intrinsic and environmental signals. Although nutrient availability and temperature are key factors for a sustained plant growth, the molecular mechanisms underlying their sensing and downstream signaling pathways remain unclear. We use genetics to address the roles of the cell surface receptor kinase FERONIA (FER) and the nutrient sensing TOR Complex 1 (TORC) in RH growth. We identified that low temperature (10°C) triggers a strong RH elongation response in Arabidopsis thaliana involving FER and TORC. We found that FER is required to perceive limited nutrient availability caused by low temperature. FERONIA interacts with and activates TORC-downstream components to trigger RH growth. In addition, the small GTPase Rho of plants 2 (ROP2) is also involved in this RH growth response linking FER and TOR. We also found that limited nitrogen nutrient availability can mimic the RH growth response at 10°C in a NRT1.1-dependent manner. These results uncover a molecular mechanism by which a central hub composed by FER-ROP2-TORC is involved in the control of RH elongation under low temperature and nitrogen deficiency.

• Klíčová slova
• Arabidopsis, FERONIA, ROP2, TOR kinase, cell surface, low temperature, nitrogen, root hairs,
• MeSH
• Arabidopsis * metabolismus   MeSH
• dusičnany farmakologie   metabolismus   MeSH
• dusík metabolismus   MeSH
• fosfotransferasy metabolismus   MeSH
• kořeny rostlin metabolismus   MeSH
• proteiny huseníčku * metabolismus   MeSH
• proteiny přenášející anionty metabolismus   MeSH
• rostlinné proteiny metabolismus   MeSH
• teplota MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dusičnany MeSH
• dusík MeSH
• fosfotransferasy MeSH
• NRT1.1 protein, Arabidopsis MeSH Prohlížeč
• proteiny huseníčku * MeSH
• proteiny přenášející anionty MeSH
• rostlinné proteiny MeSH