Lobohedleolide suppresses hepatitis C virus replication via JNK/c-Jun-C/EBP-mediated down-regulation of cyclooxygenase-2 expression

Abstract

Hepatitis C virus (HCV) chronically infects 2–3% people of the global population, which leads to liver cirrhosis and hepatocellular carcinoma. Drug resistance remains a serious problem that limits the effectiveness of US Food and Drug Administration (FDA)-approved direct-acting antiviral (DAA) drugs against HCV proteins. The objective of our study was to discover new antivirals from natural products to supplement current therapeutics. We demonstrated that lobohedleolide, isolated from the Formosan soft coral Lobophytum crassum, significantly reduced HCV replication in replicon cells and JFH-1 infection system, with EC50 values of 10 ± 0.56 and 22 ± 0.75 μM, respectively, at non-toxic concentrations. We further observed that the inhibitory effect of lobohedleolide on HCV replication is due to suppression of HCV-induced cyclooxygenase-2 (COX-2) expression. Based on deletion-mutant analysis of the COX-2 promoter, we identified CCAAT/enhancer-binding protein (C/EBP) as a key transcription factor for the down-regulation of COX-2 by lobohedleolide, through which lobohedleolide decreased the phosphorylation of c-Jun NH2-terminal protein kinase and c-Jun to suppress HCV-induced C/EBP expression. The combination treatment of lobohedleolide with clinically used HCV drugs synergistically reduced HCV RNA replication, indicating that lobohedleolide exhibited a high biomedical potential to be used as a supplementary therapeutic agent to control HCV infection.

Extra Hepatic Effects of Sofosbuvir on a Serous Model of Major and Minor Salivary Glands in Albino Rats

“…Thus, any defect in the mitochondrial transmembranous potentiality gives rise to a cascade of apoptosis-related signals. Moreover, Lin et al [39] declared that COX-2 is expressed in response to diverse inflammatory intracellular and extracellular stimuli such as chemicals, viral infections and ROS.…”

“…COX-2 expression is tightly controlled in most tissues [39] and is almost unnoticeable under normal physiologic conditions [7] . For this reason, the cells of SMGs and EGs in the control group of this study revealed a negative cytoplasmic and nuclear immunoreactivity to COX-2 with a moderate nuclear reaction in very few acini of SMGs.…”

“…Yet, we could recommend that the ultimate goal is to provide effective anti-oxidants as an adjuvant therapy for HCV to target the COX-2 signaling pathway beside the viral genome. Particularly, it was previously suggested as a promising strategy to eliminate HCV-related disorders, the combination of both anti-HCV and anti-inflammatory agents [39,44] .…”

Cembranoid-Related Metabolites and Biological Activities from the Soft Coral Sinularia flexibilis

“…Some cembranolides, possessing an α-methylene lactone ring, have been discovered as potent cytotoxic agents to a limited panel of cancer cell lines, for example, 14-deoxycrassin [ 20 ], and as significant anti-inflammatory agents, for example, sinulariolone acetate [ 21 ]. Additionally, cembranoids and related compounds from other coral species were also found to have notable antiviral [ 22 ], anti-inflammatory [ 23 , 24 ], and antiproliferative [ 25 , 26 , 27 , 28 ] activities. A wide variety of chemical diversity and biological activity of cembranoids encouraged us to search for more natural products from soft coral S .…”

Cembranoids from Octocoral Lobophytum crassum (von Marenzeller, 1886)

“…Western blotting results showed that cembranoid 2 at 10 µM inhibited iNOS expression, which reduced the protein level to 28.50%, as compared with cells in the control group treated with LPS only (Table 2). In previous studies, cembranoid 2 was reported to exhibit extensive bioactivities such as cytotoxic [3,5], antiviral [4,16,17], and anti-inflammatory [16,[18][19][20] activities, and the anti-inflammatory activity of 2 has been evaluated and revealed that 2 is effective against both carrageenin induced edema and cotton pellet implantation rat models [18]. Lobocrassin I (1) did not show activity, implying that the exo-methylene substituent at C-15 enhanced the bioactivity in comparison with cembranoid 2.…”