WIREs Mechanisms of Disease最新文献

Cell signaling is a fundamental cellular process that enables cells to sense and respond to information in their surroundings. At the molecular level, signaling is primarily carried out by transmembrane protein receptors that can initiate complex downstream signal transduction cascades to alter cellular behavior. In the human body, different cells can be exposed to a wide variety of environmental conditions, and cells express diverse classes of receptors capable of sensing and integrating different signals. Furthermore, different receptors and signaling pathways can crosstalk with each other to calibrate the cellular response. Crosstalk occurs through multiple mechanisms at different levels of signaling pathways. In this review, we discuss how cells sense and integrate different chemical, mechanical, and spatial signals as well as the mechanisms of crosstalk between pathways. To illustrate these concepts, we use a few well-studied signaling pathways, including receptor tyrosine kinases and integrin receptors. Finally, we discuss the implications of dysregulated cellular sensing on driving diseases such as cancer. This article is categorized under: Cancer > Molecular and Cellular Physiology Metabolic Diseases > Molecular and Cellular Physiology.

Computational modeling has well-established utility in the study of cardiovascular hemodynamics, with applications in medical research and, increasingly, in clinical settings to improve the diagnosis and treatment of cardiovascular diseases. Most cardiovascular models developed to date have been of the adult circulatory system; however, the perinatal period is unique as cardiovascular physiology undergoes drastic changes from the fetal circulation, during the birth transition, and into neonatal life. There may also be further complications in this period: for example, preterm birth (defined as birth before $37$ completed weeks of gestation) carries risks of short-term cardiovascular instability and is associated with increased lifetime cardiovascular risk. Here, we review computational models of the cardiovascular system in early life, their applications to date and potential improvements and enhancements of these models. We propose a roadmap for developing an open-source cardiovascular model that spans the fetal, perinatal, and postnatal periods. This article is categorized under: Cardiovascular Diseases > Computational Models Cardiovascular Diseases > Biomedical Engineering Congenital Diseases > Computational Models.

Peripheral nerve injury (PNI) is the most common neurological injury in civilian and military injuries, with over 360,000 PNI procedures performed in the US yearly. Segmental loss of nerve tissue results in a nerve gap precluding a tension-free primary repair, and in these cases, interpositional autologous or acellular nerve allografts are used to bridge the gap. Graft ischemia time is a critical factor in achieving satisfactory nerve regeneration. Rapid nerve graft revascularization is essential in order to sustain Schwann cell growth which in turn is crucial for axonal regeneration. Currently, nerve autografts are considered the gold standard for segmental nerve gaps but are associated with several disadvantages such as limited supply of expendable donor tissue, increased operative time, and donor site morbidity. Hence, readily available, off-the-shelf nerve allografts or scaffolds are being investigated since they provide advantages such as a virtually limitless sourcing, a wide variety of sizes to match recipient nerves, and no donor site morbidity. New, exciting advances in tissue engineering to augment revascularization of nerve allografts or conduits have been investigated. Strategies include pro-angiogenic mesenchymal stem cells, extracellular vesicles, functionalized scaffolds, bioactive peptides, and three-dimensional bioprinting. This article discusses these bioengineering advances and future strategies aimed at enhancing nerve graft and scaffold revascularization. This article is categorized under: Neurological Diseases > Biomedical Engineering Neurological Diseases > Molecular and Cellular Physiology.

The global burden of fungal disease poses a substantial threat to human, animal, and environmental health, endangering both human and livestock populations and creating vulnerabilities to food supplies world-wide. Antifungal drugs provide essential therapies to humans and animals against infections, while fungicides provide protection in agriculture. However, a limited arsenal of antifungal agents results in cross-use between agriculture and health, promoting the development of resistance, and drastically reducing our defenses against disease. Critically, antifungal resistant strains found ubiquitously within the natural environment demonstrate resistance to the same classes of antifungals used to treat human and animal infections, hindering effective treatment within the clinic. This interconnectivity supports the need for a One Health approach to combat fungal diseases and overcome antifungal resistance, ensuring that treatment and protection of a defined group does not inadvertently endanger or sacrifice other plants, animals, or humans. In this review, we present sources of antifungal resistance and discuss the integration of environmental and clinical resources to manage disease. Moreover, we explore opportunities for drug synergy and repurposing strategies, highlight fungal targets being investigated to overcome resistance, and propose technologies for the discovery of novel fungal targets. This article is categorized under: Infectious Diseases > Molecular and Cellular Physiology.

Caseous granulomas are pathological hallmarks of tuberculosis (TB), and increasing evidence suggests that TB granuloma composition is highly temporally and spatially heterogenous in both animal models and humans. Traditional pathological techniques are limited in their ability to reveal the heterogeneity present in TB granulomas. Multiplex tissue imaging tools combined with powerful, high resolution spatial analysis have enabled the detection of various cell phenotypes, aiding in the visualization of the granuloma complex and revealing the interactions between immune cells and nonimmune cells. This updated understanding of tuberculous granuloma heterogeneity offers vital insights for researchers aiming to uncover the immunoregulatory mechanisms underlying granuloma formation during TB pathogenesis. More detailed granuloma classification systems will also be of use for precision medicine, and for identifying biological targets for host-directed therapeutics in TB patients. This article is categorized under: Infectious Diseases > Genetics/Genomics/Epigenetics Infectious Diseases > Biomedical Engineering Infectious Diseases > Molecular and Cellular Physiology.

Cyclooxygenase-2 (COX-2) is a key aspect of the physiology and pathogenesis of various cancer types. Overexpression of this enzyme is responsible for the elevated prostaglandin production and characteristic feature of breast cancer. Inhibition of COX-2 derived prostanoids facilitates anti-inflammatory, analgesic, and antipyretic effects of non-steroid anti-inflammation drugs. The overexpression of COX-2 is associated with inflammation, pain, and fever. The present study provides the updated relevant literature describing the role of well-characterized isoforms of cyclooxygenase with particular emphasis on COX-2, mechanism of action, the effect of the drug, combinatorial drugs, and microarray-based differential expression analysis and network analysis. We have discussed the currently used combinatorial treatments and their challenges in breast cancer. This article is categorized under: Cancer > Computational Models Cancer > Molecular and Cellular Physiology.

Homeobox genes are protagonists in developmental and cancer biology, making comprehending their regulation pivotal in multiple molecular pathways. Exitrons, also known as intronic exons, are new players in the transcriptional organization, providing additional splicing variants whose functions are still vastly unknown. Exitron splicing sites were identified in eight homeobox genes, which has not been yet debated in the scientific literature. Due to the intimate connection between homeobox genes and tumorigenesis, it is worth investing more time in understanding how these less explored exitron-containing transcriptional isoforms could play a role in modulating the homeobox gene's biological functions. The perspectives devised in this article are meant to instigate fresh debates on how the transcriptional variants retaining exitrons identified in the human homeobox genes HOXA1, HOXA9, HOXD8, NKX3.1, and DLX6 can be examined in the context of tumorigenesis. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics.

The cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase-Stimulator of Interferon Genes (cGAS-STING) pathway is a critical innate immune mechanism for detecting the presence of double-stranded DNA (dsDNA) and prompting a robust immune response. Canonical cGAS-STING activation occurs when cGAS, a predominantly cytosolic pattern recognition receptor, binds microbial DNA to promote STING activation. Upon STING activation, transcription factors enter the nucleus to cause the production of Type I interferons, inflammatory cytokines whose primary function is to prime the host for viral infection by producing a number of antiviral interferon-stimulated genes. While the pathway was originally described in viral infection, more recent studies have implicated cGAS-STING signaling in a number of different contexts, including autoimmune disease, cancer, injury, and neuroinflammatory disease. This review focuses on how our understanding of the cGAS-STING pathway has evolved over time with an emphasis on the role of STING-mediated neuroinflammation and infection in the nervous system. We discuss recent findings on how STING signaling contributes to the pathology of pain, traumatic brain injury, and stroke, as well as how mitochondrial DNA may promote STING activation in common neurodegenerative diseases. We conclude by commenting on the current knowledge gaps that should be filled before STING can be an effective therapeutic target in neuroinflammatory disease. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology Infectious Diseases > Molecular and Cellular Physiology Immune System Diseases > Molecular and Cellular Physiology.

The past several decades have witnessed unprecedented progress in basic and clinical cancer research, and our understanding of the molecular mechanisms and pathogenesis of cancers have been greatly improved. More recently, with the availability of high-throughput sequencing and profiling platforms as well as sophisticated analytical tools and high-performance computing capacity, there have been tremendous advances in the development of diagnostic approaches in clinical oncology, especially the discovery of novel biomarkers for cancer early detection. Although tissue biopsy-based pathology has been the "gold standard" for cancer diagnosis, notable limitations such as the risk due to invasiveness and the bias due to intra-tumoral heterogeneity have limited its broader applications in oncology (e.g., screening, regular disease monitoring). Liquid biopsy analysis that exploits the genetic and epigenetic information contained in DNA/RNA materials from body fluids, particularly circulating cell-free DNA (cfDNA) in the blood, has been an intriguing alternative approach because of advantageous features such as sampling convenience and minimal invasiveness. Taking advantage of innovative enabling technologies, cfDNA has been demonstrated for its clinical potential in cancer early detection, including hepatocellular carcinoma (HCC), the most common liver cancer that causes serious healthcare burden globally. Hereby, we reviewed the current advances in cfDNA-based approaches for cancer biomarker discovery, with a focus on recent findings of cfDNA-based early detection of HCC. Future clinical investigations and trials are warranted to further validate these approaches for early detection of HCC, which will contribute to more effective prevention, control, and intervention strategies with the ultimate goal of reducing HCC-associated mortality. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics.

Cancer cells have an abnormally high mitochondrial membrane potential (ΔΨ_m ), which is associated with enhanced invasive properties in vitro and increased metastases in vivo. The mechanisms underlying the abnormal ΔΨ_m in cancer cells remain unclear. Research on different cell types has shown that ΔΨ_m is regulated by various intracellular mechanisms such as by mitochondrial inner and outer membrane ion transporters, cytoskeletal elements, and biochemical signaling pathways. On the other hand, the role of extrinsic, tumor microenvironment (TME) derived cues in regulating ΔΨ_m is not well defined. In this review, we first summarize the existing literature on intercellular mechanisms of ΔΨ_m regulation, with a focus on cancer cells. We then offer our perspective on the different ways through which the microenvironmental cues such as hypoxia and mechanical stresses may regulate cancer cell ΔΨ_m . This article is categorized under: Cancer > Environmental Factors Cancer > Biomedical Engineering Cancer > Molecular and Cellular Physiology.