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This Month in AJP

    Published:November 12, 2021DOI:https://doi.org/10.1016/j.ajpath.2021.11.002

        Modeling Nonalcoholic Steatohepatitis

        The mechanisms underlying fibrosis in nonalcoholic steatohepatitis (NASH) are unclear. Ichimura-Shimizu et al (Am J Pathol 2021, XXXXXXXX) generated a mouse model of NASH-related fibrosis to study the pathogenesis of fibrosis. Two mouse strains, one susceptible to obesity and another relatively resistant to obesity were fed high fat/cholesterol/cholate (HFCC) diet. Both the strains developed hepatic histological features of NASH with more severe features in the relatively resistant strain. These novel mouse models may help improve our understanding of fibrogenesis and pathophysiology of NASH-related fibrosis.

        Understanding Hyperhomocysteinemia

        NLRP3 inflammasome activation in podocytes is linked with increased release of exosomes containing NLRP3 inflammasome products from these cells during hyperhomocysteinemia (hHcy). Using a mouse model, Huang et al (Am J Pathol 2021, XXXXXXXX) studied the underlying mechanisms. Pharmacological treatments to manipulate exosome biogenesis, lysosome function, or acid sphingomyelinase (ASM) activity decreased glomerular inflammation and injury during hHcy. Blocking exosome release from podocytes may avert hHcy-induced glomerular inflammation and injury.

        Linking Chronic Colitis and Neuroinflammation

        The effect of chronic colitis on brain inflammation and cognitive function is unclear. Using manganese-enhanced magnetic resonance imaging, Mitchell and Kim et al (Am J Pathol 2021, XXXXXXXX) studied brain function in a chemical-induced chronic colitis mouse model. Mice with chronic colitis displayed increased blood-brain barrier permeability as well as inflammatory markers such as high-mobility group box 1 (HMGB1)—particularly in the hippocampus, reduced neuronal activity, and a decline in long-term memory. A weakened blood brain barrier and signaling through HMGB1 may cause brain inflammation in patients suffering from chronic colitis.

        Managing COVID-19 Severity and Associated Mortality

        Severe coronavirus disease 2019 (COVID-19) intensifies the risk of myocardial injury, which may contribute to mortality. Using multiparameter immunofluorescence in the postmortem hearts from COVID-19 patients and uninfected control patients with and without cardiovascular disease, Johnson et al (Am J Pathol 2021, XXXXXXXX) studied and compared cardiac thrombi. Increased thrombosis was observed in tissues from COVID-19 patients. Though endothelial activation was absent, neutrophil-platelet aggregates, neutrophil-rich clusters within microthrombi and neutrophil extracellular traps were observed. Reducing activated circulating neutrophil response may help manage myocardial injury and subsequent mortality in COVID-19 patients.

        Understanding Skeletal Muscle Dysfunction

        Though mutations in SIGMAR1 gene have been implicated in skeletal muscle dysfunction, its physiological role in skeletal muscle remains unclear. Using Sigmar1 deficient mice, Aishwarya and Abdullah et al (Am J Pathol 2021, XXXXXXXX) studied this role. Sigmar1−/− mice exhibited abnormal mitochondria, derangements in dystrophin localization in skeletal muscles, myopathy associated with increased number of central nuclei, increased collagen deposition, fibrosis, and reduced endurance and exercise capacity. Mutations in SIGMAR1 gene may be responsible for skeletal muscle pathology observed in patients with these mutations.

        Linked Article

        • Chronic Intestinal Inflammation Suppresses Brain Activity by Inducing Neuroinflammation in Mice
          The American Journal of Pathology
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            Chronic gut inflammation such as inflammatory bowel disease is believed to be associated with neurodegenerative diseases in humans. The direct evidence for and the underlying mechanism of this brain–gut interaction, however, remain elusive. We used manganese-enhanced magnetic resonance imaging to assess functional brain activity from awake and freely moving mice with chronic colitis. We found that manganese ion uptake (indicative of Ca2+ influx into neuronal cells) and accumulation were reduced in the hippocampus of chronic colitis mice compared with control mice.
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