Macrophage RAGE activation is proinflammatory in NASH.

Intrahepatic macrophages in nonalcoholic steatohepatitis (NASH) are heterogenous and include proinflammatory recruited monocyte-derived macrophages. The receptor for advanced glycation endproducts (RAGE) is expressed on macrophages and can be activated by damage associated molecular patterns (DAMPs) upregulated in NASH, yet the role of macrophage-specific RAGE signaling in NASH is unclear. Therefore, we hypothesized that RAGE-expressing macrophages are proinflammatory and mediate liver inflammation in NASH. Compared with healthy controls, RAGE expression was increased in liver biopsies from patients with NASH. In a high-fat, -fructose, and -cholesterol-induced (FFC)-induced murine model of NASH, RAGE expression was increased, specifically on recruited macrophages. FFC mice that received a pharmacological inhibitor of RAGE (TTP488), and myeloid-specific RAGE KO mice (RAGE-MKO) had attenuated liver injury associated with a reduced accumulation of RAGE+ recruited macrophages. Transcriptomics analysis suggested that pathways of macrophage and T cell activation were upregulated by FFC diet, inhibited by TTP488 treatment, and reduced in RAGE-MKO mice. Correspondingly, the secretome of ligand-stimulated BM-derived macrophages from RAGE-MKO mice had an attenuated capacity to activate CD8+ T cells. Our data implicate RAGE as what we propose to be a novel and potentially targetable mediator of the proinflammatory signaling of recruited macrophages in NASH.

Extracellular Vesicles in Hepatobiliary Health and Disease.

Extracellular vesicles (EVs) are membrane-bound nanoparticles released by cells and are an important means of intercellular communication in physiological and pathological states. We provide an overview of recent advances in the understanding of EV biogenesis, cargo selection, recipient cell effects, and key considerations in isolation and characterization techniques. Studies on the physiological role of EVs have relied on cell-based model systems due to technical limitations of studying endogenous nanoparticles in vivo . Several recent studies have elucidated the mechanistic role of EVs in liver diseases, including nonalcoholic fatty liver disease, viral hepatitis, cholestatic liver disease, alcohol-associated liver disease, acute liver injury, and liver cancers. Employing disease models and human samples, the biogenesis of lipotoxic EVs downstream of endoplasmic reticulum stress and microvesicles via intracellular activation stress signaling are discussed in detail. The diverse cargoes of EVs including proteins, lipids, and nucleic acids can be enriched in a disease-specific manner. By carrying diverse cargo, EVs can directly confer pathogenic potential, for example, recruitment and activation of monocyte-derived macrophages in NASH and tumorigenicity and chemoresistance in hepatocellular carcinoma. We discuss the pathogenic role of EVs cargoes and the signaling pathways activated by EVs in recipient cells. We review the literature that EVs can serve as biomarkers in hepatobiliary diseases. Further, we describe novel approaches to engineer EVs to deliver regulatory signals to specific cell types, and thus use them as therapeutic shuttles in liver diseases. Lastly, we identify key lacunae and future directions in this promising field of discovery and development. © 2023 American Physiological Society. Compr Physiol 13:4631-4658, 2023.

Psychotic Symptoms in Heroin Withdrawal: A Case Report.

Opiate withdrawal-induced severe exacerbation of psychosis after the sudden withdrawal of an opiate is a known yet uncommon clinical manifestation. We present the case of opiate withdrawal-induced psychosis in a 25-year-old married male patient without any prior psychiatric history of illness, family history, or past hospitalization records. The patient presented with psychotic symptoms such as irritability, delusions of parasitosis, and auditory and visual hallucinations at the time of hospitalization. Symptoms were in a fluctuating course and were not constant throughout the day. Through this case report, our aim is to present a rare instance of heroin-withdrawal-induced psychosis and its successful treatment with antipsychotics.

Infective Endocarditis Leading to Intracranial Abscess: A Case Report and Literature Review.

Neurologic complications are a hallmark of infective endocarditis (IE). IE leading to intracranial abscess has an unfavorable prognosis. A 17-year-old boy with a past medical history of aortic valve replacement presented with fever and seizure. On examination, he had tachycardia, systolic murmur, slurred speech, meningeal signs, and right homonymous hemianopia. His laboratory analysis revealed an elevated erythrocyte sedimentation rate and C-reactive protein. The brain's magnetic resonance imaging revealed multiple ring-enhancing lesions in the frontal, occipital lobe, and occipitotemporal lobe, consistent with intracranial abscess. Transthoracic echocardiogram revealed a mobile mass adjacent to aortic value, consistent with possible infective vegetation. He was diagnosed with multiple cerebral septic emboli leading to intracranial abscess due to IE. Blood and cerebrospinal fluid culture revealed methicillin-sensitive Staphylococcus aureus growth. He was started on intravenous nafcillin and gentamycin. His condition improved gradually, and he became afebrile on hospital day four. On his recent follow-up, he was doing well.