Kaitlyn G. Jackson

Perinatal hypoxic–ischemic encephalopathy (HIE) is a major contributor to infant death and neurological injury worldwide. Both neuroglia and infiltrating peripheral immune cells contribute to inflammation and oxidative stress, which leads to neuronal loss and cerebral tissue necrosis in neonates with HIE. To date, there are no approved pharmacological interventions to treat inflammatory responses in infants affected by HIE. Therapeutic hypothermia (TH) remains the only effective treatment option. Therefore, novel pharmacotherapeutics that interrupt immune-mediated brain inflammation in HIE represent a promising target for intervention. To meet this unmet need, this study tested the hypothesis that a novel anti-inflammatory peptide, RLS-0071 (pegtarazimod), could modulate neuroinflammation in a neonatal rat model of HIE. RLS-0071 was evaluated in the acute stages of hypoxic–ischemic injury utilizing the well-established Vannucci rat pup model of HIE. Rat pups subject to hypoxia-ischemic brain insult received three interventions: normothermia, hypothermia, and RLS-0071. Histopathological effects were assessed via fluorescence microscopy of the hypoxic–ischemic induced cerebral infarct in the cortex at 24 and 48 hours after controlled oxygen deprivation. Increased surviving neurons were seen at 48 hours for RLS-0071 treatment compared with hypothermia treatment as assessed by neuronal nuclear protein (NeuN) staining. Ionized calcium-binding adaptor molecule 1 (Iba1)-positive microglial recruitment was reduced by fourfold in RLS-0071 treatment or hypothermia-treated rats between 24 and 48 hours, compared to normothermia controls. Likewise, myeloperoxidase (MPO) staining showed a twofold decrease in RLS-0071 or hypothermia-treated rats between 24 and 48 hours compared to normothermia controls. Our findings suggest that RLS-0071 decreases immune cell recruitment and oxidative damage to levels comparable to TH in an animal model of HIE.

There is a clinical need for new treatment options addressing allergic disease. Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants that have anti-inflammatory properties. We tested the effects of the SSRI fluoxetine on IgE-induced function of mast cells, which are critical effectors of allergic inflammation. We showed that fluoxetine treatment of murine or human mast cells reduced IgE-mediated degranulation, cytokine production, and inflammatory lipid secretion, as well as signaling mediated by the mast cell activator ATP. In a mouse model of systemic anaphylaxis, fluoxetine reduced hypothermia and cytokine production. Fluoxetine was also effective in a model of allergic airway inflammation, where it reduced bronchial responsiveness and inflammation. These data show that fluoxetine suppresses mast cell activation by impeding an FcɛRI-ATP positive feedback loop and support the potential repurposing of this SSRI for use in allergic disease.

Background: NAFLD has become the most common chronic liver disease worldwide. Human antigen R (HuR), an RNA-binding protein, is an important post-transcriptional regulator. HuR has been reported as a key player in regulating lipid homeostasis in the liver and adipose tissues by using tissue-specific HuR knockout mice. However, the underlying mechanism by which hepatocyte-specific HuR regulates hepatic lipid metabolism under metabolic stress remains unclear and is the focus of this study. Methods: Hepatocyte-specific HuR deficient mice (HuR^hKO) and age-/gender-matched control mice, as well as long-noncoding RNA H19 knockout mice (H19^−/−), were fed a Western Diet plus sugar water (WDSW). Hepatic lipid accumulation, inflammation and fibrosis were examined by histology, RNA transcriptome analysis, qRT–PCR, and Western blot analysis. Bile acid composition was measured using LC–MS/MS. Results: Hepatocyte-specific deletion of HuR not only significantly increased hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also markedly induced inflammation by increasing immune cell infiltration and neutrophil activation under metabolic stress. In addition, hepatic deficiency of HuR disrupted bile acid homeostasis and enhanced liver fibrosis. Mechanistically, HuR is a repressor of H19 expression. Analysis of a recently published dataset (GSE143358) identified H19 as the top-upregulated gene in liver-specific HuR knockout mice. Similarly, hepatocyte-specific deficiency of HuR dramatically induced the expression of H19 and sphingosine-1 phosphate receptor 2 (S1PR2), but reduced the expression of sphingosine kinase 2 (SphK2). WDSW-induced hepatic lipid accumulation was alleviated in H19^−/− mice. Furthermore, the downregulation of H19 alleviated WDSW-induced NAFLD in HuR^hKO mice. Conclusions: HuR not only functions as an RNA binding protein to modulate post-transcriptional gene expression but also regulates H19 promoter activity. Hepatic HuR is an important regulator of hepatic lipid metabolism via modulating H19 expression.

Non-alcoholic fatty liver disease (NAFLD) is one of the fastest-growing diseases, and its global prevalence is estimated to increase >50% by 2030. NAFLD is comorbid with metabolic syndrome, obesity, type 2 diabetes, and insulin resistance. Despite extensive research efforts, there are no pharmacologic or biological therapeutics for the treatment of NAFLD. Bile acids and sphingolipids are well-characterized signaling molecules. Over the last few decades, researchers have uncovered potential mechanisms by which bile acids and sphingolipids regulate hepatic lipid metabolism. Dysregulation of bile acid and sphingolipid metabolism has been linked to steatosis, inflammation, and fibrosis in patients with NAFLD. This clinical observation has been recapitulated in animal models, which are well-accepted by experts in the hepatology field. Recent transcriptomic and lipidomic studies also show that sphingolipids are important players in the pathogenesis of NAFLD. Moreover, the identification of bile acids as activators of sphingolipid-mediated signaling pathways established a novel theory for bile acid and sphingolipid biology. In this review, we summarize the recent advances in the understanding of bile acid and sphingolipid-mediated signaling pathways as potential contributors to NAFLD. A better understanding of the pathologic effects mediated by bile acids and sphingolipids will facilitate the development of new diagnostic and therapeutic strategies for NAFLD.

Alcohol-associated liver disease (ALD) is a spectrum of diseases, the onset and progression of which are due to chronic alcohol use. ALD ranges, by increasing severity, from hepatic steatosis to alcoholic hepatitis (AH) and alcohol-associated cirrhosis (AC), and in some cases, can lead to the development of hepatocellular carcinoma (HCC). ALD continues to be a significant health burden and is now the main cause of liver transplantations in the United States. ALD leads to biological, microbial, physical, metabolic, and inflammatory changes in patients that vary depending on disease severity. ALD deaths have been increasing in recent years and are projected to continue to increase. Current treatment centers focus on abstinence and symptom management, with little in the way of resolving disease progression. Due to the metabolic disruption and gut dysbiosis in ALD, bile acid (BA) signaling and metabolism are also notably affected and play a prominent role in disease progression in ALD, as well as other liver disease states, such as non-alcoholic fatty liver disease (NAFLD). In this review, we summarize the recent advances in the understanding of the mechanisms by which alcohol consumption induces hepatic injury and the role of BA-mediated signaling in the pathogenesis of ALD.