WIREs Mechanisms of Disease最新文献

The emergence of resistance to anti-infective agents poses a significant threat to successfully treating infections caused by bacteria. Bacteria acquire random mutations due to exposure to environmental stresses, which may increase their fitness to other selection pressures. Interestingly, for bacteria, the frequency of anti-microbial resistance (AMR) seems to be increasing in tandem with the human lifespan. Based on evidence from previous literature, we speculate that increased levels of free radicals (Reactive Oxygen Species-ROS and Reactive Nitrosative Species-RNS), elevated inflammation, and the altered tissue microenvironment in aged individuals may drive pathogen mutagenesis. If these mutations result in the hyperactivation of efflux pumps or alteration in drug target binding sites, it could confer AMR, thus rendering antibiotic therapy ineffective while leading to the selection of novel drug-resistant variants. This article is categorized under: Immune System Diseases > Genetics/Genomics/Epigenetics Infectious Diseases > Environmental Factors Metabolic Diseases > Environmental Factors.

Endometriosis is a disease with a heterogeneous pathogenesis, explained by multiple theories, and also with a polymorphic presentation. The purpose of this literature review is to systematize the genetic, inflammatory, and environmental factors related to the pathophysiology of endometriosis. Current evidence suggests that endometriosis is a complex inherited genetic condition, in which the genes that determine susceptibility to the disease interact with the environment to develop different phenotypes. Genetic variants associated with risk of endometriosis have been identified in several genome-wide association studies, in addition to a group of genes related to the pathophysiology of endometriosis, namely the estrogen, progesterone and androgen receptors and the cytochrome P450 gene, as well as the p53 gene. The role of inflammation is controversial; however, it is an essential process, both in the initiation and perpetuation of the disease, in and outside the pelvis. Alterations in reactive oxygen species pathways that consequently determine oxidative stress are typical in the inflammatory environment of endometriosis. The role of environmental factors is a relatively new and broad-spectrum topic, with inconsistent evidence. Multiple factors have been studied such as endocrine-disrupting chemicals, metals, intrauterine exposure to diethylstilbesterol and lifestyle risk factors. In conclusion, endometriosis remains a mysterious condition, with multifactorial factors involved in its pathophysiology. The progress that has been made in the genetic predisposition to endometriosis may allow the establishment of new therapeutic targets. On the other hand, understanding the role of the environment in this disease may allow preventive intervention, minimizing its incidence and/or severity. This article is categorized under: Reproductive System Diseases > Molecular and Cellular Physiology Reproductive System Diseases > Environmental Factors Reproductive System Diseases > Genetics/Genomics/Epigenetics.

Cystic fibrosis (CF) is widely known as a disease of the lung, even though it is in truth a systemic disease, whose symptoms typically manifest in gastrointestinal dysfunction first. CF ultimately impairs not only the pancreas and intestine but also the lungs, gonads, liver, kidneys, bones, and the cardiovascular system. It is caused by one of several mutations in the gene of the epithelial ion channel protein CFTR. Intense research and improved antimicrobial treatments during the past eight decades have steadily increased the predicted life expectancy of a person with CF (pwCF) from a few weeks to over 50 years. Moreover, several drugs ameliorating the sequelae of the disease have become available in recent years, and notable treatments of the root cause of the disease have recently generated substantial improvements in health for some but not all pwCF. Yet, numerous fundamental questions remain unanswered. Complicating CF, for instance in the lung, is the fact that the associated insufficient chloride secretion typically perturbs the electrochemical balance across epithelia and, in the airways, leads to the accumulation of thick, viscous mucus and mucus plaques that cannot be cleared effectively and provide a rich breeding ground for a spectrum of bacterial and fungal communities. The subsequent infections often become chronic and respond poorly to antibiotic treatments, with outcomes sometimes only weakly correlated with the drug susceptibility of the target pathogen. Furthermore, in contrast to rapidly resolved acute infections with a single target pathogen, chronic infections commonly involve multi-species bacterial communities, called "infection microbiomes," that develop their own ecological and evolutionary dynamics. It is presently impossible to devise mathematical models of CF in its entirety, but it is feasible to design models for many of the distinct drivers of the disease. Building upon these growing yet isolated modeling efforts, we discuss in the following the feasibility of a multi-scale modeling framework, known as template-and-anchor modeling, that allows the gradual integration of refined sub-models with different granularity. The article first reviews the most important biomedical aspects of CF and subsequently describes mathematical modeling approaches that already exist or have the potential to deepen our understanding of the multitude aspects of the disease and their interrelationships. The conceptual ideas behind the approaches proposed here do not only pertain to CF but are translatable to other systemic diseases. This article is categorized under: Congenital Diseases > Computational Models.

Follicular microenvironment is paramount in the acquisition of oocyte competence, which is dependent on two interconnected and interdependent processes: nuclear and cytoplasmic maturation. Extensive research conducted in human and model systems has provided evidence that those processes are disturbed with female aging. In fact, advanced maternal age (AMA) is associated with a lower chance of pregnancy and live birth, explained by the age-related decline in oocyte quality/competence. This decline has largely been attributed to mitochondria, essential for oocyte maturation, fertilization, and embryo development; with mitochondrial dysfunction leading to oxidative stress, responsible for nuclear and mitochondrial damage, suboptimal intracellular energy levels, calcium disturbance, and meiotic spindle alterations, that may result in oocyte aneuploidy. Nuclear-related mechanisms that justify increased oocyte aneuploidy include deoxyribonucleic acid (DNA) damage, loss of chromosomal cohesion, spindle assembly checkpoint dysfunction, meiotic recombination errors, and telomere attrition. On the other hand, age-dependent cytoplasmic maturation failure is related to mitochondrial dysfunction, altered mitochondrial biogenesis, altered mitochondrial morphology, distribution, activity, and dynamics, dysmorphic smooth endoplasmic reticulum and calcium disturbance, and alterations in the cytoskeleton. Furthermore, reproductive somatic cells also experience the effects of aging, including mitochondrial dysfunction and DNA damage, compromising the crosstalk between granulosa/cumulus cells and oocytes, also affected by a loss of gap junctions. Old oocytes seem therefore to mature in an altered microenvironment, with changes in metabolites, ribonucleic acid (RNA), proteins, and lipids. Overall, understanding the mechanisms implicated in the loss of oocyte quality will allow the establishment of emerging biomarkers and potential therapeutic anti-aging strategies. This article is categorized under: Reproductive System Diseases > Molecular and Cellular Physiology.

Severe acute respiratory syndrome coronavirus 2 is the virus that is responsible for the current pandemic, COVID-19 (SARS-CoV-2). MiRNAs, a component of RNAi technology, belong to the family of short, noncoding ssRNAs, and may be crucial in the battle against this global threat since they are involved in regulating complex biochemical pathways and may prevent viral proliferation, translation, and host expression. The complicated metabolic pathways are modulated by the activity of many proteins, mRNAs, and miRNAs working together in miRNA-mediated genetic control. The amount of omics data has increased dramatically in recent years. This massive, linked, yet complex metabolic regulatory network data offers a wealth of opportunity for iterative analysis; hence, extensive, in-depth, but time-efficient screening is necessary to acquire fresh discoveries; this is readily performed with the use of bioinformatics. We have reviewed the literature on microRNAs, bioinformatics, and COVID-19 infection to summarize (1) the function of miRNAs in combating COVID-19, and (2) the use of computational methods in combating COVID-19 in certain noteworthy studies, and (3) computational tools used by these studies against COVID-19 in several purposes. This article is categorized under: Infectious Diseases > Computational Models.

Fungi, being a necessary component of the gut microbiome, potentially have direct or indirect effects on the health and illness status of the host. The gut mycobiome is an inducer of the host's immunity, maintaining intestinal homeostasis, and protecting against infections, as well as a reservoir of opportunistic microorganisms and a potential cofactor when the host is immunocompromised. In addition, gut fungi interact with a diverse range of microbes in the intestinal niches. In this article, we reviewed the composition of gut mycobiome, their association with host health and illness, and summarized the specific Candida albicans-host interactions, in order to provide insights and directions for the ongoing study of fungi. This article is categorized under: Infectious Diseases > Molecular and Cellular Physiology.

Astrocytes respond to traumatic brain injury (TBI) with changes to their molecular make-up and cell biology, which results in changes in astrocyte function. These changes can be adaptive, initiating repair processes in the brain, or detrimental, causing secondary damage including neuronal death or abnormal neuronal activity. The response of astrocytes to TBI is often-but not always-accompanied by the upregulation of intermediate filaments, including glial fibrillary acidic protein (GFAP) and vimentin. Because GFAP is often upregulated in the context of nervous system disturbance, reactive astrogliosis is sometimes treated as an "all-or-none" process. However, the extent of astrocytes' cellular, molecular, and physiological adjustments is not equal for each TBI type or even for each astrocyte within the same injured brain. Additionally, new research highlights that different neurological injuries and diseases result in entirely distinctive and sometimes divergent astrocyte changes. Thus, extrapolating findings on astrocyte biology from one pathological context to another is problematic. We summarize the current knowledge about astrocyte responses specific to TBI and point out open questions that the field should tackle to better understand how astrocytes shape TBI outcomes. We address the astrocyte response to focal versus diffuse TBI and heterogeneity of reactive astrocytes within the same brain, the role of intermediate filament upregulation, functional changes to astrocyte function including potassium and glutamate homeostasis, blood-brain barrier maintenance and repair, metabolism, and reactive oxygen species detoxification, sex differences, and factors influencing astrocyte proliferation after TBI. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology.

Chronological age causes structural and functional vascular deterioration and is a well-established risk factor for the development of cardiovascular diseases, leading to more than 40% of all deaths in the elderly. The etiology of vascular aging is complex; a significant impact arises from impaired cholesterol homeostasis. Cholesterol level is balanced through synthesis, uptake, transport, and esterification, the processes executed by multiple organelles. Moreover, organelles responsible for cholesterol homeostasis are spatially and functionally coordinated instead of isolated by forming the membrane contact sites. Membrane contact, mediated by specific protein-protein interaction, pulls opposing organelles together and creates the hybrid place for cholesterol transfer and further signaling. The membrane contact-dependent cholesterol transfer, together with the vesicular transport, maintains cholesterol homeostasis and has intimate implications in a growing list of diseases, including vascular aging-related diseases. Here, we summarized the latest advances regarding cholesterol homeostasis by highlighting the membrane contact-based regulatory mechanism. We also describe the downstream signaling under cholesterol homeostasis perturbations, prominently in cholesterol-rich conditions, stimulating age-dependent organelle dysfunction and vascular aging. Finally, we discuss potential cholesterol-targeting strategies for therapists regarding vascular aging-related diseases. This article is categorized under: Cardiovascular Diseases > Molecular and Cellular Physiology.

By harnessing structural hierarchical insights, plausibly simulate better ones imagination to figure out the best choice of methods for reaching out the unprecedented developments of the tissue engineering products as a next level. Constructing a functional tissue that incorporates two-dimensional (2D) or higher dimensions requires overcoming technological or biological limitations in order to orchestrate the structural compilation of one-dimensional and 2D sheets (microstructures) simultaneously (in situ). This approach enables the creation of a layered structure that can be referred to as an ensemble of layers or, after several days of maturation, a direct or indirect joining of layers. Here, we have avoided providing a detailed methodological description of three-dimensional and 2D strategies, except for a few interesting examples that highlight the higher alignment of cells and emphasize rarely remembered facts associated with vascular, peripheral nerve, muscle, and intestine tissues. The effective directionality of cells in conjunction with geometric cues (in the range of micrometers) is well known to affect a variety of cell behaviors. The curvature of a cell's environment is one of the factors that influence the formation of patterns within tissues. The text will cover cell types containing some level of stemness, which will be followed by their consequences for tissue formation. Other important considerations pertain to cytoskeleton traction forces, cell organelle positioning, and cell migration. An overview of cell alignment along with several pivotal molecular and cellular level concepts, such as mechanotransduction, chirality, and curvature of structure effects on cell alignments will be presented. The mechanotransduction term will be used here in the context of the sensing capability that cells show as a result of force-induced changes either at the conformational or the organizational levels, a capability that allows us to modify cell fate by triggering downstream signaling pathways. A discussion of the cells' cytoskeleton and of the stress fibers involvement in altering the cell's circumferential constitution behavior (alignment) based on exposed scaffold radius will be provided. Curvatures with size similarities in the range of cell sizes cause the cell's behavior to act as if it was in an in vivo tissue environment. The revision of the literature, patents, and clinical trials performed for the present study shows that there is a clear need for translational research through the implementation of clinical trial platforms that address the tissue engineering possibilities raised in the current revision. This article is categorized under: Infectious Diseases > Biomedical Engineering Neurological Diseases > Biomedical Engineering Cardiovascular Diseases > Biomedical Engineering.

The genesis and functioning of the central nervous system are one of the most intricate and intriguing aspects of embryogenesis. The big lacuna in the field of human CNS development is the lack of accessibility of the human brain for direct observation during embryonic and fetal development. Thus, it is imperative to establish alternative animal models to gain deep mechanistic insights into neurodevelopment, establishment of neural circuitry, and its function. Neurodevelopmental events such as neural specification, differentiation, and generation of neuronal and non-neuronal cell types have been comprehensively studied using a variety of animal models and in vitro model systems derived from human cells. The experimentations on animal models have revealed novel, mechanistic insights into neurogenesis, formation of neural networks, and function. The models, thus serve as indispensable tools to understand the molecular basis of neurodevelopmental disorders (NDDs) arising from aberrations during embryonic development. Here, we review the spectrum of in vivo models such as fruitfly, zebrafish, frog, mice, and nonhuman primates to study neurogenesis and NDDs like microcephaly and Autism Spectrum Disorder. We also discuss nonconventional models such as ascidians and the recent technological advances in the field to study neurogenesis, disease mechanisms, and pathophysiology of human NDDs. This article is categorized under: Cancer > Stem Cells and Development Congenital Diseases > Stem Cells and Development Neurological Diseases > Stem Cells and Development Congenital Diseases > Genetics/Genomics/Epigenetics.