Current Pathobiology Reports最新文献

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the SARS-CoV-2 betacoronavirus and has taken over 761,426 American lives as of the date of publication and will likely result in long-term, if not permanent, tissue damage for countless patients. COVID-19 presents with diverse and multisystemic pathologic processes, including a hyperinflammatory response, acute respiratory distress syndrome (ARDS), vascular injury, microangiopathy, tissue fibrosis, angiogenesis, and widespread thrombosis across multiple organs, including the lungs, heart, kidney, liver, and brain. C-X-C chemokines contribute to these pathologies by attracting inflammatory mediators, the disruption of endothelial cell integrity and function, and the initiation and propagation of the cytokine storm. Among these, CXCL10 is recognized as a critical contributor to the hyperinflammatory state and poor prognosis in COVID-19. CXCL10 is also known to regulate growth factor-induced fibrosis, and recent evidence suggests the CXCL10-CXCR3 signaling system may be vital in targeting convergent pro-inflammatory and pro-fibrotic pathways. This review will explore the mechanistic role of CXCL10 and related chemokines in fibrotic complications associated with COVID-19 and the potential of CXCL10-targeted therapeutics for early intervention and long-term treatment of COVID-19-induced fibrosis.

Purpose of review: COVID-19 has rapidly evolved into a global pandemic infecting over two hundred and forty-four million individuals to date. In addition to the respiratory sequelae and systemic infection that ensues, an alarming number of micro and macrovascular thrombotic complications have been observed. This review examines the current understanding of COVID-19-associated thrombotic complications, potential mechanisms, and pathobiological basis for thromboses development.

Recent findings: The endothelium plays a major role in the process due to direct and indirect injury. The immune system also contributes to a pro-thrombotic environment with immune cell dysregulation leading to excessive formation of cytokines, also called cytokine storm, and an eventual promotion of a hypercoagulable environment, known as immunothrombosis. Additionally, neutrophils play an important role by forming neutrophil extracellular traps, which are shown to be pro-thrombotic and further enhanced in COVID-19 patients. A disruption of the fibrinolysis system has also been observed.

Summary: Multiple pathways likely contribute synergistically to form a pro-thrombotic milieu. A better understanding of these factors and the complex interplay between them will lead to the improvement of diagnostic and therapeutic interventions.

Nanoparticles have revolutionized biomedicine especially in the field of drug delivery due to their intriguing properties such as systemic stability, level of solubility, and target site specificity. It can, however, be both beneficial and damaging depending on the properties in different environments, thus highlighting the importance of nanotoxicology studies before use in humans. Different types of nanoparticles have been used in drug delivery, and this review summarizes the recent toxicity studies of these nanoparticles. The toxicological evaluation of three widely used nanoparticles in drug delivery that are metal, lipid, and protein nanoparticles has been discussed in detail. Studies have recorded several toxic effects of various nanoparticles such as metal-based nanoparticles have been linked to increased oxidative stress and have the potential to infiltrate the cell nucleus and protein-based nanoparticles have been observed to have hepatotoxicity and nephrotoxicity as their adverse effects. Considering the increasing application of nanoparticles in drug delivery and the growing concerns of regulatory authorities regarding the toxicity of nanocarriers in living organisms, it requires urgent attention to identify the gap in toxicity studies. The review highlights the gap in toxicity studies and potential focus areas to overcome the existing challenges.

Purpose of review: Partial differential equation (PDE) mathematical models of biological systems and the simulation approaches used to solve them are widely used to test hypotheses and infer regulatory interactions based on optimization of the PDE model against the observed data. In this review, we discuss the ability of powerful machine learning methods to accelerate the parametric screening of biophysical informed- PDE systems.

Recent findings: A major shortcoming in more broad adaptation of PDE-based models is the high computational complexity required to solve and optimize the models and it requires many simulations to traverse the very high-dimensional parameter spaces during model calibration and inference tasks. For instance, when scaling up to tens of millions of simulations for optimization and sensitivity analysis of the PDE models, compute times quickly extend from months to years for sufficient coverage to solve the problems. For many systems, this brute-force approach is simply not feasible. Recently, neural network metamodels have been shown to be an efficient way to accelerate PDE model calibration and here we look at the benefits and limitations in extending the PDE acceleration methods to improve optimization and sensitivity analysis.

Summary: We use an example simulation to quantitatively and qualitatively show how neural network metamodels can be accurate and fast and demonstrate their potential for optimization of complex spatiotemporal problems in biology. We expect these approaches will be broadly applied to speed up scientific research and discovery in biology and other systems that can be described by complex PDE systems.

Purpose of review: Alcohol associated liver disease (ALD) accounts for significant mortality and morbidity in the United States. Prolonged alcohol exposure leads to increased reactive oxygen species and oxidative stress resulting in protein misfolding and/or aggregation. Cellular protein homeostasis network is an adaptive cellular response comprised of machineries that regulate biogenesis or degradation of proteins with chaperones as central coordinators to maintain proteome integrity during stress. Two extensively studied organelle-specific transcriptional proteostasis pathways are the heat shock response (HSR) in the cytosol and unfolded protein response (UPR) in endoplasmic reticulum (ER). Here we review the pathophysiological role of HSR and UPR and their potential as therapeutic targets in ALD.

Recent findings: The HSR and UPR are emerging as important pathways in ALD pathogenesis. We reported that acute and chronic alcohol activate the HSR to discretely induce downstream target chaperones, HSPA1A/HSP70 and HSP90, respectively. HSP90 serves as a pro-inflammatory mediator in ALD by stabilizing client kinases and adapters. On the other hand, HSF1 and HSPA1A prevents liver injury due to their anti-inflammatory properties. In vivo pharmacological targeting of HSP90 reduced pro-inflammatory cytokines and NLRP3 inflammasome mediated IL-1β and IL-18. The presence of HSP90 in circulating extracellular vesicles in ALD mouse models suggests its role in pathogenesis. Activation of UPR due to prolonged ER stress is associated with apoptosis, inflammation, and lipogenesis contributing to liver injury.

Summary: This review highlights the contribution of HSR and UPR, as well as druggable chaperones in pathogenesis of ALD. Binge/moderate or chronic alcohol exposure perturbs proteostasis mediators which fail to maintain proteome integrity and disease ensues. Understanding mechanisms that regulate proteostasis pathways, HSR and UPR, could identify novel disease modulators and guide development of therapeutic targets in ALD.