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Proceedings of the National Academy of... Jul 2023Metastasis, especially intrahepatic, is a major challenge for hepatocellular carcinoma (HCC) treatment. Cytoskeleton remodeling has been identified as a vital process...
Metastasis, especially intrahepatic, is a major challenge for hepatocellular carcinoma (HCC) treatment. Cytoskeleton remodeling has been identified as a vital process mediating intrahepatic spreading. Previously, we reported that HCC tumor adhesion and invasion were modulated by circular RNA (circRNA), which has emerged as an important regulator of various cellular processes and has been implicated in cancer progression. Here, we uncovered a nuclear circRNA, circASH2, which is preferentially lost in HCC tissues and inhibits HCC metastasis by altering tumor cytoskeleton structure. Tropomyosin 4 (TPM4), a critical binding protein of actin, turned out to be the major target of circASH2 and was posttranscriptionally suppressed. Such regulation is based on messenger RNA (mRNA)/precursormRNA splicing and degradation process. Furthermore, liquid-liquid phase separation of nuclear Y-box binding protein 1 (YBX1) enhanced by circASH2 augments TPM4 transcripts decay. Together, our data have revealed a tumor-suppressive circRNA and, more importantly, uncovered a fine regulation mechanism for HCC progression.
Topics: Humans; Liver Neoplasms; Carcinoma, Hepatocellular; RNA, Circular; RNA, Messenger; Cell Proliferation; Cytoskeletal Proteins; Cytoskeleton; Gene Expression Regulation, Neoplastic; MicroRNAs; Cell Line, Tumor; Y-Box-Binding Protein 1
PubMed: 37459535
DOI: 10.1073/pnas.2220296120 -
Nature Nov 2023The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine...
The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. The consequent glioma cell membrane depolarization drives tumour proliferation. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity and strength. Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity that contributes to memory and learning in the healthy brain. BDNF-TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF-TrkB signalling promotes malignant synaptic plasticity and augments tumour progression.
Topics: Animals; Child; Humans; Adaptation, Physiological; Brain-Derived Neurotrophic Factor; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Proliferation; Disease Progression; Glioma; Glutamic Acid; Neuronal Plasticity; Neurons; Receptor, trkB; Receptors, AMPA; Signal Transduction; Synapses; Tumor Microenvironment; Optogenetics
PubMed: 37914930
DOI: 10.1038/s41586-023-06678-1 -
The Journal of Neuroscience : the... Nov 2023Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms... (Review)
Review
Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms of action. These compounds exert their primary effects through activating serotonin 5-HT receptors, found predominantly in cortical regions. By interacting with these receptors, serotonergic psychedelics induce alterations in perception, cognition, and emotions, leading to the characteristic psychedelic experience. One of the most crucial aspects of serotonergic psychedelics is their ability to promote neuroplasticity, the formation of new neural connections, and rewire neuronal networks. This neuroplasticity is believed to underlie their therapeutic potential for various mental health conditions, including depression, anxiety, and substance use disorders. In this mini-review, we will discuss how the 5-HT receptor activation is just one facet of the complex mechanisms of action of serotonergic psychedelics. They also interact with other serotonin receptor subtypes, such as 5-HT and 5-HT receptors, and with neurotrophin receptors (e.g., tropomyosin receptor kinase B). These interactions contribute to the complexity of their effects on perception, mood, and cognition. Moreover, as psychedelic research advances, there is an increasing interest in developing nonhallucinogenic derivatives of these drugs to create safer and more targeted medications for psychiatric disorders by removing the hallucinogenic properties while retaining the potential therapeutic benefits. These nonhallucinogenic derivatives would offer patients therapeutic advantages without the intense psychedelic experience, potentially reducing the risks of adverse reactions. Finally, we discuss the potential of psychedelics as substrates for post-translational modification of proteins as part of their mechanism of action.
Topics: Humans; Hallucinogens; Serotonin; Receptor, Serotonin, 5-HT2A; Psilocybin; Anxiety
PubMed: 37940583
DOI: 10.1523/JNEUROSCI.1384-23.2023 -
Science Advances Jul 2023Intensive physical activity improves motor functions in patients with Parkinson's disease (PD) at early stages. However, the mechanisms underlying the beneficial effects...
Intensive physical activity improves motor functions in patients with Parkinson's disease (PD) at early stages. However, the mechanisms underlying the beneficial effects of exercise on PD-associated neuronal alterations have not been fully clarified yet. Here, we tested the hypothesis that an intensive treadmill training program rescues alterations in striatal plasticity and early motor and cognitive deficits in rats receiving an intrastriatal injection of alpha-synuclein (α-syn) preformed fibrils. Improved motor control and visuospatial learning in active animals were associated with a recovery of dendritic spine density alterations and a lasting rescue of a physiological corticostriatal long-term potentiation (LTP). Pharmacological analyses of LTP show that modulations of -methyl-d-aspartate receptors bearing GluN2B subunits and tropomyosin receptor kinase B, the main brain-derived neurotrophic factor receptor, are involved in these beneficial effects. We demonstrate that intensive exercise training has effects on the early plastic alterations induced by α-syn aggregates and reduces the spread of toxic α-syn species to other vulnerable brain areas.
Topics: Rats; Animals; Parkinson Disease; Neuronal Plasticity; Corpus Striatum; Long-Term Potentiation; Cognition
PubMed: 37450585
DOI: 10.1126/sciadv.adh1403 -
Nature Communications Nov 2023Major depressive disorder (MDD) is one of the most common and disabling mental disorders, and current strategies remain inadequate. Although mesenchymal stromal cells...
Major depressive disorder (MDD) is one of the most common and disabling mental disorders, and current strategies remain inadequate. Although mesenchymal stromal cells (MSCs) have shown beneficial effects in experimental models of depression, underlying mechanisms remain elusive. Here, using murine depression models, we demonstrated that MSCs could alleviate depressive and anxiety-like behaviors not due to a reduction in proinflammatory cytokines, but rather activation of dorsal raphe nucleus (DRN) 5-hydroxytryptamine (5-HT) neurons. Mechanistically, peripheral delivery of MSCs activated pulmonary innervating vagal sensory neurons, which projected to the nucleus tractus solitarius, inducing the release of 5-HT in DRN. Furthermore, MSC-secreted brain-derived neurotrophic factor activated lung sensory neurons through tropomyosin receptor kinase B (TrkB), and inhalation of a TrkB agonist also achieved significant therapeutic effects in male mice. This study reveals a role of peripheral MSCs in regulating central nervous system function and demonstrates a potential "lung vagal-to-brain axis" strategy for MDD.
Topics: Humans; Mice; Animals; Male; Serotonin; Depressive Disorder, Major; Dorsal Raphe Nucleus; Anxiety; Mesenchymal Stem Cells
PubMed: 37973914
DOI: 10.1038/s41467-023-43150-0 -
Nutrients Jul 2023Shellfish is a leading cause of food allergy and anaphylaxis worldwide. Recent advances in molecular characterization have led to a better understanding of the allergen... (Review)
Review
Shellfish is a leading cause of food allergy and anaphylaxis worldwide. Recent advances in molecular characterization have led to a better understanding of the allergen profile. High sequence homology between shellfish species and between shellfish and house dust mites leads to a high serological cross-reactivity, which does not accurately correlate with clinical cross-reactions. Clinical manifestations are immediate and the predominance of perioral symptoms is a typical feature of shellfish allergy. Diagnosis, as for other food allergies, is based on SPTs and specific IgE, while the gold standard is DBPCFC. Cross-reactivity between shellfish is common and therefore, it is mandatory to avoid all shellfish. New immunotherapeutic strategies based on hypoallergens and other innovative approaches represent the new frontiers for desensitization.
Topics: Humans; Child; Shellfish Hypersensitivity; Immunoglobulin E; Shellfish; Food Hypersensitivity; Seafood; Allergens
PubMed: 37513530
DOI: 10.3390/nu15143112 -
Oncology Letters Aug 2023The most common tumor affecting the head and neck is head and neck squamous cell carcinoma (HNSCC). The characteristics of HNSCC include a rapid onset, a lack of early... (Review)
Review
The most common tumor affecting the head and neck is head and neck squamous cell carcinoma (HNSCC). The characteristics of HNSCC include a rapid onset, a lack of early diagnosis, drug resistance, relapse and systemic adverse effects, leading to inadequate prevention, diagnosis and treatment. Notably, previous research suggests that there is an association between S100 proteins and HNSCC. S100A8, S100A9 and S100A14 interfere with tumor cell proliferation by blocking the cell cycle. The present review discusses this association. S100A4 enhances cancer stem cell properties, and interacts with actin and tropomyosin to promote tumor cell migration. S100A1, S100A8, S100A9, S100A10, S100A14 and S100P are involved in the initiation and progression of HNSCC via Hippo, nuclear factor κB, phosphatidylinositol kinase/protein kinase B/mammalian target of rapamycin and other signaling pathways. In addition, certain long non-coding RNAs and microRNAs are involved in regulating the expression of S100 proteins in HNSCC. Reducing the expression of certain members of the S100 protein family may enhance the chemosensitivity of HNSCC. Collectively, it is suggested that S100 proteins may function as markers and targets for the prevention, diagnosis and treatment of HNSCC.
PubMed: 37545618
DOI: 10.3892/ol.2023.13948 -
Foods (Basel, Switzerland) Jun 2023The dynamically growing incidence of food allergies forces the scientific community to develop new methods for their diagnosis, differentiation, and effective treatment.... (Review)
Review
The dynamically growing incidence of food allergies forces the scientific community to develop new methods for their diagnosis, differentiation, and effective treatment. Parasitoses appear much less frequently in the scientific literature, as well as among the presumed causes of numerous conditions. The similarity of inflammatory mechanisms in allergies and parasitosis necessitates a revision of current diagnostic standards. A lack of specificity and the coincidence of symptoms at an early stage of disease can lead to misdiagnosis. In this paper, we attempted to perform a comparative analysis of the similarities and differences in symptoms for these two types of diseases. We described the molecular mechanisms and metabolic pathways of food allergy and parasitosis. We presented the available research methods and directions of ongoing studies aimed at implementing precise medical techniques for differential diagnosis. We discussed the allergenic properties of certain parasite proteins, using the example of myofibrillar tropomyosins from the nematode . The literature in the fields of allergology and parasitology leads to the conclusion that it is reasonable to run parallel allergological and parasitological diagnostics in patients with non-specific symptoms. This approach will facilitate accurate and early diagnosis and implementation of effective therapy.
PubMed: 37444203
DOI: 10.3390/foods12132465 -
Nature Communications Jul 2023Platelets, small hemostatic blood cells, are derived from megakaryocytes. Both bone marrow and lung are principal sites of thrombopoiesis although underlying mechanisms...
Platelets, small hemostatic blood cells, are derived from megakaryocytes. Both bone marrow and lung are principal sites of thrombopoiesis although underlying mechanisms remain unclear. Outside the body, however, our ability to generate large number of functional platelets is poor. Here we show that perfusion of megakaryocytes ex vivo through the mouse lung vasculature generates substantial platelet numbers, up to 3000 per megakaryocyte. Despite their large size, megakaryocytes are able repeatedly to passage through the lung vasculature, leading to enucleation and subsequent platelet generation intravascularly. Using ex vivo lung and an in vitro microfluidic chamber we determine how oxygenation, ventilation, healthy pulmonary endothelium and the microvascular structure support thrombopoiesis. We also show a critical role for the actin regulator Tropomyosin 4 in the final steps of platelet formation in lung vasculature. This work reveals the mechanisms of thrombopoiesis in lung vasculature and informs approaches to large-scale generation of platelets.
Topics: Mice; Animals; Blood Platelets; Microfluidics; Megakaryocytes; Thrombopoiesis; Lung
PubMed: 37419900
DOI: 10.1038/s41467-023-39598-9