ß-Caryophyllene alleviates D-galactosamine and lipopolysaccharide-induced hepatic injury through suppression of the TLR4 and RAGE signaling pathways.

Agastache rugosa (A. rugosa, Labiatae), a perennial herb spread throughout Korean fields, is widely consumed as a wild edible vegetable and is used in folk medicine. This study examined the hepatoprotective mechanisms of ß-caryophyllene (BCP), a major bicyclic sesquiterpene of A. rugosa, against D-galactosamine (GalN) and lipopolysaccharide (LPS)-induced hepatic failure. Mice were given an intraperitoneal injection of BCP (50, 100 and 200 mg/kg) 1 h before GalN (800 mg/kg)/LPS (40 µg/kg) injection and were killed 1 h or 6 h after GalN/LPS injection. GalN/LPS markedly increased mortality and serum aminotransferase activity, both of which were attenuated by BCP. BCP also attenuated increases in serum tumor necrosis factor-α, interleukin 6, and high-mobility group protein B1 levels by GalN/LPS. GalN/LPS significantly increased toll-like receptor (TLR) 4 and receptor for advanced glycation end products (RAGE) protein expression, extracellular signal-related kinase, p38 and c-Jun N-terminal kinase phosphorylation, nuclear factor κB (NF-κB), early growth response protein-1, and macrophage inflammatory protein-2 protein expression. These increases were attenuated by BCP. Furthermore, BCP suppressed increased TLR4 and RAGE protein expression and proinflammatory cytokines production in LPS-treated isolated Kupffer cells. Our findings suggest that BCP protects against GalN/LPS-induced liver injury through down-regulation of the TLR4 and RAGE signaling.

HS-23, a Lonicera japonica extract, reverses sepsis-induced immunosuppression by inhibiting lymphocyte apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Lonicera japonica Thunberg, a widely used traditional Chinese medicine, possesses antibacterial, antiviral, and antiendotoxin activities. This study investigated the molecular mechanisms of HS-23, the ethanol extract of the dried flower buds of L. japonica, on sepsis-induced immunosuppression. MATERIALS AND METHODS: Male ICR mice were intravenously administered HS-23 (10, 20, and 40mg/kg) immediately (0h) and 22h after cecal ligation and puncture (CLP). The spleen was isolated for biochemical assays 24h after CLP. RESULTS: HS-23 improved sepsis-induced mortality. CLP induced a marked decrease in the number of splenocytes, B cells, and natural killer cells, which was attenuated by HS-23. HS-23 also attenuated CLP-induced apoptosis in CD4(+) and CD8(+) T cells and inhibited both the intrinsic and extrinsic apoptotic pathway in the spleen. HS-23 attenuated the CLP-induced decrease in interleukin (IL)-17 production. CLP significantly decreased splenic production of tumor necrosis factor-α and IL-2, and these effects were attenuated by HS-23. CONCLUSION: Our findings suggest that HS-23 reverses immunosuppression during the late phase of sepsis by inhibiting lymphocyte apoptosis and enhancing Th1 cytokine production. HS-23 warrants further evaluation as a potential therapeutic agent for the treatment of sepsis.

Identification and characterization of clevudine-resistant mutants of hepatitis B virus isolated from chronic hepatitis B patients.

Clevudine (CLV) is a nucleoside analog with potent antiviral activity against chronic hepatitis B virus (HBV) infection. Viral resistance to CLV in patients receiving CLV therapy has not been reported. The aim of this study was to characterize CLV-resistant HBV in patients with viral breakthrough (BT) during long-term CLV therapy. The gene encoding HBV reverse transcriptase (RT) was analyzed from chronic hepatitis B patients with viral BT during CLV therapy. Sera collected from the patients at baseline and at the time of viral BT were studied. To characterize the mutations of HBV isolated from the patients, we subjected the HBV mutants to in vitro drug susceptibility assays. Several conserved mutations were identified in the RT domain during viral BT, with M204I being the most common. In vitro phenotypic analysis showed that the mutation M204I was predominantly associated with CLV resistance, whereas L229V was a compensatory mutation for the impaired replication of the M204I mutant. A quadruple mutant (L129M, V173L, M204I, and H337N) was identified that conferred greater replicative ability and strong resistance to both CLV and lamivudine. All of the CLV-resistant clones were lamivudine resistant. They were susceptible to adefovir, entecavir, and tenofovir, except for one mutant clone. In conclusion, the mutation M204I in HBV RT plays a major role in CLV resistance and leads to viral BT during long-term CLV treatment. Several conserved mutations may have a compensatory role in replication. Drug susceptibility assays reveal that adefovir and tenofovir are the most effective compounds against CLV-resistant mutants. These data may provide additional therapeutic options for CLV-resistant patients.