Frontiers in molecular medicine最新文献

Stroke is a condition characterized by sudden deprivation of blood flow to a brain region and defined by different post-injury phases, which involve various molecular and cellular cascades. At an early stage during the acute phase, fast initial cell death occurs, followed by inflammation and scarring. This is followed by a sub-acute or recovery phase when endogenous plasticity mechanisms may promote spontaneous recovery, depending on various factors that are yet to be completely understood. At later time points, stroke leads to greater neurodegeneration compared to healthy controls in both clinical and preclinical studies, this is evident during the chronic phase when recovery slows down and neurodegenerative signatures appear. Astrocytes have been studied in the context of ischemic stroke due to their role in glutamate re-uptake, as components of the neurovascular unit, as building blocks of the glial scar, and synaptic plasticity regulators. All these roles render astrocytes interesting, yet understudied players in the context of stroke-induced neurodegeneration. With this review, we provide a summary of previous research, highlight astrocytes as potential therapeutic targets, and formulate questions about the role of astrocytes in the mechanisms during the acute, sub-acute, and chronic post-stroke phases that may lead to neurorestoration or neurodegeneration.

Mutations in the mitochondrial-DNA or mitochondria related nuclear-encoded-DNA lead to various multisystemic disorders collectively termed mitochondrial diseases. One in three cases of mitochondrial disease affects the heart muscle, which is called mitochondrial cardiomyopathy (MCM) and is associated with hypertrophic, dilated, and noncompact cardiomyopathy. The heart is an organ with high energy demand, and mitochondria occupy 30%-40% of its cardiomyocyte-cell volume. Mitochondrial dysfunction leads to energy depletion and has detrimental effects on cardiac performance. However, disease development and progression in the context of mitochondrial and nuclear DNA mutations, remains incompletely understood. The system of induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM) is an excellent platform to study MCM since the unique genetic identity to their donors enables a robust recapitulation of the predicted phenotypes in a dish on a patient-specific level. Here, we focus on recent insights into MCM studied by patient-specific iPSC-CM and further discuss research gaps and advances in metabolic maturation of iPSC-CM, which is crucial for the study of mitochondrial dysfunction and to develop novel therapeutic strategies.

Introduction: Wound therapies are capable of modulating the complex molecular signaling profile of tissue regeneration. However traditional, bulk tissue analysis results in nonspecific expressional profiles and diluted signaling that lacks temporal-spatial information. Methods: An acute incisional porcine wound model was developed in the context of negative pressure wound therapy (NPWT). Dressing materials were inserted into wounds with or without NPWT exposure and evaluated over 8-hours. Upon wound explantation, tissue was stratified and dissected into the epidermis, dermis, or subcutaneous layer, or left undissected as a bulk sample and all groups processed for RNAseq. RNAseq of stratified layers provided spatial localization of expressional changes within defined tissue regions, including angiogenesis, inflammation, and matrix remodeling. Results: Different expressional profiles were observed between individual tissue layers relative to each other within a single wound group and between each individual layer relative to bulk analysis. Tissue stratification identified unique differentially expressed genes within specific layers of tissue that were hidden during bulk analysis, as well as amplification of weak signals and/or inversion of signaling between two layers of the same wound, suggesting that two layers of skin can cancel out signaling within bulk analytical approaches. Discussion: The unique wound stratification and spatial RNAseq approach in this study provides a new methodology to observe expressional patterns more precisely within tissue that may have otherwise not been detectable. Together these experimental data offer novel insight into early expressional patterns and genomic profiles, within and between tissue layers, in wound healing pathways that could potentially help guide clinical decisions and improve wound outcomes.

The energy demand of cardiomyocytes changes continuously in response to variations in cardiac workload. Cardiac excitation-contraction coupling is fueled primarily by adenosine triphosphate (ATP) production by oxidative phosphorylation in mitochondria. The rate of mitochondrial oxidative metabolism is matched to the rate of ATP consumption in the cytosol by the parallel activation of oxidative phosphorylation by calcium (Ca²⁺) and adenosine diphosphate (ADP). During cardiac workload transitions, Ca²⁺ accumulates in the mitochondrial matrix, where it stimulates the activity of the tricarboxylic acid cycle. In this review, we describe how mitochondria internalize and extrude Ca²⁺, the relevance of this process for ATP production and redox homeostasis in the healthy heart, and how derangements in ion handling cause mitochondrial and cardiomyocyte dysfunction in heart failure.

Extraskeletal myxoid chondrosarcoma (EMC) is an ultra-rare cancer that makes up less than 3% of all soft tissue sarcomas. It most often arises in the soft tissues of the proximal limbs and has a higher incidence in males. Though EMC has a good prognosis, it has an indolent course with high rates of local recurrence as well as metastasis to the lungs. EMC is characterized in 70% of cases by an EWS1-NR4A3 translocation, leading to constitutive expression of NR4A3. Structural variants (SVs) in EMC, especially large-scale genomic alterations, have not been well studied and studies are severely limited by sample size. In this study, we describe Whole Genome Sequencing (WGS) of a rare case of matched EMC primary tumor, lung metastasis, and pelvic metastasis to identify genomic alterations. We examined somatic variants, copy number variants (CNVs), and larger scale SVs such as translocations and breakend points. While the primary tumor and lung metastasis had similar somatic variations and CNVs, the pelvic metastasis had more unique SVs with especially increased mutational burden of SVs in chromosome 2. This suggests that different molecular drivers appear in more advanced, relapsing EMC compared with the primary tumor and early lung metastasis. Genomic studies such as ours may identify novel molecular complexities in rare cancers that may be leveraged for therapeutic strategies and precision medicine.

Often considered the "housekeeping" cells of the brain, astrocytes have of late been rising to the forefront of neurodegenerative disorder research. Identified as crucial components of a healthy brain, it is undeniable that when astrocytes are dysfunctional, the entire brain is thrown into disarray. We offer epilepsy as a well-studied neurological disorder in which there is clear evidence of astrocyte contribution to diseases as evidenced across several different disease models, including mouse models of hippocampal sclerosis, trauma associated epilepsy, glioma-associated epilepsy, and beta-1 integrin knockout astrogliosis. In this review we suggest that astrocyte-driven neuroinflammation, which plays a large role in the pathology of epilepsy, is at least partially modulated by interactions with perineuronal nets (PNNs), highly structured formations of the extracellular matrix (ECM). These matrix structures affect synaptic placement, but also intrinsic neuronal properties such as membrane capacitance, as well as ion buffering in their immediate milieu all of which alters neuronal excitability. We propose that the interactions between PNNs and astrocytes contribute to the disease progression of epilepsy vis a vis neuroinflammation. Further investigation and alteration of these interactions to reduce the resultant neuroinflammation may serve as a potential therapeutic target that provides an alternative to the standard anti-seizure medications from which patients are so frequently unable to benefit.

There are a lot of evidences on the beneficial effects mediated by exercise on the prevention of not communicable diseases (NCDs) including different type of cancer. The production of circulating exerkines transported in exosomes represents a novel pathway activated by exercise. However, the biological mechanisms that could explain the role of exosomes in cancer prevention have been not fully elucidated. The aim of this mini-review is to provide an update on the biological mechanisms bringing the release of muscle-derived exosomes during exercise and cancer prevention.