Orexin A ameliorates HBV X protein-induced cytotoxicity and inflammatory response in human hepatocytes

Abstract

Hepatitis B virus is one of the main causes of hepatitis and hepatocellular carcinoma (HCC). Hepatitis B virus-encoded X protein (HBx) has been shown to be involved in many aspects of the pathogenicity of liver diseases. Orexin A is a small peptide produced in the hippocampus. Orexin A and its receptor have become important therapeutic targets for certain metabolic disorders. In this study, we show that orexin A has a protective role against HBx-induced cytotoxicity and inflammation in hepatocytes. The ectopic expression of HBx in hepatocytes reduces orexin A receptor 1 (OX1R) expression. When orexin A is added to the cells, it mitigates HBx-induced oxidative stress indicator 4-hydroxynonenal (4-HNE) and reactive oxygen species (ROS) as well the NADPH subunit NADPH oxidase 4 (NOX-4). Orexin A also ameliorates HBx-mediated mitochondrial membrane potential and adenosine triphosphate (ATP) reduction. Moreover, orexin A significantly inhibits HBx-induced production of pro-inflammatory cytokines including interleukin 8 (IL-8), tumour necrosis factor a (TNF-a) and chemokine ligand 2 (CXCL2). The presence of orexin A ameliorates HBx-induced lactate dehydrogenase (LDH) release, indicating that it could protect hepatocytes from cytotoxicity. Mechanistically, we found that orexin A suppresses c-Jun N-terminal kinase (JNK) phosphorylation, accumulation of nuclear factor-jB (NF-jB) protein p65 in nuclei, and NF-jB promoter activity, suggesting that orexin A suppresses JNK and NF-jB pathway activation. In conclusion, our study demonstrates that orexin A peptide possesses a protective role against HBx-mediated cytotoxicity and inflammation in hepatocytes.

Role of Vitamin E and the Orexin System in Neuroprotection

“…It has been seen that this was attenuated by the pretreatment with OXA, in line with a study by Bihamta et al conducted on cardiomyocyte cells [44]. This is believed to be thanks to the ability of OXA to activate the PI3K/MEK1/2/ERK1/2 signaling pathway and to attenuate the H 2 O 2 -induced increase in apoptosis and decrease in SH-SY5Y cell viability [42]. In another set of experiments, Hah Y.S et al showed how the level of ROS in TNF-α-induced fibroblast-like synoviocytes was found to be reduced in the presence of orexin A.…”

“…Among those analyzed [39][40][41], we find a study by Butterick et al [39] that shows how, in a hypothalamic cell line, the use of OXA leads to changes in cell survival following oxidative stress, particularly after H 2 O 2 ; this study, in fact, has demonstrated that OXA is a neuroprotective molecule, partly because it reduces caspase-committed apoptosis and lipid peroxidation. There are also further studies regarding the orexin system and the reduction in oxidative stress, such as s study by Wang et al, which demonstrates how a neuroblastoma cell line reduces its oxidative stress induced by H 2 O 2 following pretreatment with OXA [42]. H 2 O 2 treatment is commonly used to induce oxidative stress [43].…”

miR‐488 mediates negative regulation of the AKT/NF‐κB pathway by targeting Rac1 in LPS‐induced inflammation

“…ROS play an important role in physiological health, and are mainly involved in immune responses, signal transduction and gene expression regulation in vivo (Lou, Li, & Han, ). Studies have shown that ROS is closely related to the activation of the NF‐κB pathway mediated by multiple factors (Nisr, Shah, Ganley, & Hundal, ; Wang, He, Wan, Wang, & Zhang, ). The current results showed that miR‐488 mimics can significantly inhibit LPS‐induced ROS enrichment in BEND cells.…”

Ursolic acid protects against cisplatin‑induced ototoxicity by inhibiting oxidative stress and TRPV1‑mediated Ca2+‑signaling

“…In the present study, the levels of 4-HNE, a highly toxic lipid peroxidation product of aldehydes (54), were observed to increase as a result. High 4-HNE levels can induce the release of cytochrome c from the mitochondria by activating the mitogen-activated protein kinase/JNK cell death signal cascade (55). In the cytoplasm, cytochrome c activates caspase-9 and caspase-3, eventually leading to apoptosis of cochlear cells (56,57).…”