Browsing by Author "Shetty, Ashok K."

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    Dysbiosis in gastrointestinal pathophysiology: Role of the gut microbiome in Gulf War Illness
    (Wiley, 2023) Slevin, Elise; Koyama, Sachiko; Harrison, Kelly; Wan, Ying; Klaunig, James E.; Wu, Chaodong; Shetty, Ashok K.; Meng, Fanyin; Medicine, School of Medicine
    Gulf War Illness (GWI) has been reported in 25%-35% of veterans returned from the Gulf war. Symptoms of GWI are varied and include both neurological and gastrointestinal symptoms as well as chronic fatigue. Development of GWI has been associated with chemical exposure particularly with exposure to pyridostigmine bromide (PB) and permethrin. Recent studies have found that the pathology of GWI is connected to changes in the gut microbiota, that is the gut dysbiosis. In studies using animal models, the exposure to PB and permethrin resulted in similar changes in the gut microbiome as these found in GW veterans with GWI. Studies using animal models have also shown that phytochemicals like curcumin are beneficial in reducing the symptoms and that the extracellular vesicles (EV) released from gut bacteria and from the intestinal epithelium can both promote diseases and suppress diseases through the intercellular communication mechanisms. The intestinal epithelium cells produce EVs and these EVs of intestinal epithelium origin are found to suppress inflammatory bowel disease severity, suggesting the benefits of utilizing EV in treatments. On the contrary, EV from the plasma of septic mice enhanced the level of proinflammatory cytokines in vitro and neutrophils and macrophages in vivo, suggesting differences in the EV depending on the types of cells they were originated and/or influences of environmental changes. These studies suggest that targeting the EV that specifically have positive influences may become a new therapeutic strategy in the treatment of veterans with GWI.
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    Endothelial dysfunction in pathological processes of chronic liver disease during aging
    (Wiley, 2022) Wan, Ying; Li, Xuedong; Slevin, Elise; Harrison, Kelly; Li, Tian; Zhang, Yudian; Klaunig, James E.; Wu, Chaodong; Shetty, Ashok K.; Dong, X. Charlie; Meng, Fanyin; Medicine, School of Medicine
    Aging is associated with gradual changes in liver structure and physiological/pathological functions in hepatic cells including hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs). LSECs are specialized hepatic endothelial cells that regulate liver homeostasis. These cells actively impact the hepatic microenvironment as they have fenestrations and a thin morphology to allow substance exchange between circulating blood and the liver tissue. As aging occurs, LSECs have a reduction in both the number and size of fenestrations, which is referred to as pseudocapillarization. This along with the aging of the liver leads to increased oxidative stress, decreased availability of nitric oxide, decreased hepatic blood flow, and increased inflammatory cytokines in LSECs. Vascular aging can also lead to hepatic hypoxia, HSC activation, and liver fibrosis. In this review, we described the basic structure of LSECs, and the effect of LSECs on hepatic inflammation and fibrosis during aging process. We briefly summarized the changes of hepatic microcirculation during liver inflammation, the effect of aging on the clearance function of LSECs, the interactions between LSECs and immunity, hepatocytes or other hepatic nonparenchymal cells, and the therapeutic intervention of liver diseases by targeting LSECs and vascular system. Since LSECs play an important role in the development of liver fibrosis and the changes of LSEC phenotype occur in the early stage of liver fibrosis, the study of LSECs in the fibrotic liver is valuable for the detection of early liver fibrosis and the early intervention of fibrotic response.
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    miR-34a regulates macrophage-associated inflammation and angiogenesis in alcohol-induced liver injury
    (Wolters Kluwer, 2023-04-04) Wan, Ying; Slevin, Elise; Koyama, Sachiko; Huang, Chiung-Kuei; Shetty, Ashok K.; Li, Xuedong; Harrison, Kelly; Li, Tian; Zhou, Bingru; Lorenzo, Sugeily Ramos; Zhang, Yudian; Salinas, Jennifer Mata; Xu, Wenjuan; Klaunig, James E.; Wu, Chaodong; Tsukamoto, Hidekazu; Meng, Fanyin; Medicine, School of Medicine
    Background: Alcohol-associated liver disease (ALD) is a syndrome of progressive inflammatory liver injury and vascular remodeling associated with long-term heavy intake of ethanol. Elevated miR-34a expression, macrophage activation, and liver angiogenesis in ALD and their correlation with the degree of inflammation and fibrosis have been reported. The current study aims to characterize the functional role of miR-34a-regulated macrophage- associated angiogenesis during ALD. Methods results: We identified that knockout of miR-34a in 5 weeks of ethanol-fed mice significantly decreased the total liver histopathology score and miR-34a expression, along with the inhibited liver inflammation and angiogenesis by reduced macrophage infiltration and CD31/VEGF-A expression. Treatment of murine macrophages (RAW 264.7) with lipopolysaccharide (20 ng/mL) for 24 h significantly increased miR-34a expression, along with the enhanced M1/M2 phenotype changes and reduced Sirt1 expression. Silencing of miR-34a significantly increased oxygen consumption rate (OCR) in ethanol treated macrophages, and decreased lipopolysaccharide-induced activation of M1 phenotypes in cultured macrophages by upregulation of Sirt1. Furthermore, the expressions of miR-34a and its target Sirt1, macrophage polarization, and angiogenic phenotypes were significantly altered in isolated macrophages from ethanol-fed mouse liver specimens compared to controls. TLR4/miR-34a knockout mice and miR-34a Morpho/AS treated mice displayed less sensitivity to alcohol-associated injury, along with the enhanced Sirt1 and M2 markers in isolated macrophages, as well as reduced angiogenesis and hepatic expressions of inflammation markers MPO, LY6G, CXCL1, and CXCL2. Conclusion: Our results show that miR-34a-mediated Sirt1 signaling in macrophages is essential for steatohepatitis and angiogenesis during alcohol-induced liver injury. These findings provide new insight into the function of microRNA-regulated liver inflammation and angiogenesis and the implications for reversing steatohepatitis with potential therapeutic benefits in human alcohol-associated liver diseases.