Water extract of green tea attenuates alcohol-related hepatitis by inhibiting liver inflammation and gut microbiota disturbance in mice.

Green tea is one of the main types of tea in China, and it has been widely consumed in the world. This study aims to investigate the potential mechanism by which the water extract of green tea (GTWE) may be effective in the treatment of alcohol-related hepatitis (ARH), utilizing a combination of network pharmacology, molecular docking, and experimental validation. Through network pharmacology analysis, seven active components and 45 potential targets were identified, with TLR4 being confirmed as the central target. Experimental findings demonstrate that GTWE exhibits significant efficacy in mitigating alcohol-induced liver inflammation and steatosis. Furthermore, the administration of GTWE has demonstrated significant efficacy in mitigating alcohol-induced intestinal inflammation and microbiota disturbance while concurrently restoring intestinal barrier function. Consequently, GTWE exhibits considerable potential as a pharmacological intervention and warrants further research and development as a lead compound for the treatment of ARH. Moreover, the prospective utilization of green tea in prolonged intakes exhibits potential as a prophylactic nutritive regimen against ARH.

Adenosine receptor A2B mediates alcoholic hepatitis by regulating cAMP levels and the NF-KB pathway.

Alcoholic hepatitis is a serious form of liver damage. Inflammation is a key factor in alcoholic hepatitis and plays a key role in the progression of alcoholic liver disease. Adenosine receptor A2B (A2BAR) is a member of the adenosine receptor family and generally considered to be a negative regulator of the inflammatory response. We found that A2BAR was the most highly expressed adenosine receptor in ETOH-fed mouse liver tissue and was also highly expressed in primary Kupffer cells and ETOH-induced RAW264.7 cells. In addition, injection of BAY 60-6583 stimulated A2BAR, induced upregulation of the expression levels of cAMP, and reduced ETOH-induced steatosis and inflammation in mice. At the same time, knockdown of A2BAR in vitro increased the inflammatory response in RAW264.7 cells triggered by ETOH. After knockdown of A2BAR in vitro, the release of the inflammatory cytokines IL-6, IL-1ß and TNF-α was increased. After overexpression of A2BAR in vitro, the cAMP level was significantly increased, PKA expression was increased, the expression of phosphorylated proteins in the NF-kB signal transduction pathway was significantly affected, and the expression of the key phosphorylated protein p-P65 was decreased. However, after the simultaneous overexpression of A2BAR and inhibition of PKA, the expression of the key phosphorylated protein p-P65 was still significantly decreased. In addition, after the expression of A2BAR increased or decreased in RAW264.7 cells, AML-12 cells were cultured in the supernatant of RAW264.7 cells stimulated by ETOH, and the apoptosis rate was significantly changed by flow cytometry. These results suggest that A2BAR can reduce alcoholic steatohepatitis by upregulating cAMP levels and negatively regulating the NF-kB pathway. Overall, these findings suggest the significance of A2BAR-mediated inflammation in alcoholic liver disease.

Redeploying ß-Lactam Antibiotics as a Novel Antivirulence Strategy for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections.

Innovative approaches to the use of existing antibiotics is an important strategy in efforts to address the escalating antimicrobial resistance crisis. We report a new approach to the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections by demonstrating that oxacillin can be used to significantly attenuate the virulence of MRSA despite the pathogen being resistant to this drug. Using mechanistic in vitro assays and in vivo models of invasive pneumonia and sepsis, we show that oxacillin-treated MRSA strains are significantly attenuated in virulence. This effect is based primarily on the oxacillin-dependent repression of the accessory gene regulator quorum-sensing system and altered cell wall architecture, which in turn lead to increased susceptibility to host killing of MRSA. Our data indicate that ß-lactam antibiotics should be included in the treatment regimen as an adjunct antivirulence therapy for patients with MRSA infections. This would represent an important change to current clinical practice for treatment of MRSA infection, with the potential to significantly improve patient outcomes in a safe, cost-effective manner.

Molecular cloning and characterization of chondroitin-4-O-sulfotransferase-3. A novel member of the HNK-1 family of sulfotransferases.

We have identified and characterized an N-acetylgalactosamine-4-O-sulfotransferase designated chondroitin-4-sulfotransferase-3 (C4ST-3) (GenBank accession number AY120869) based on its homology to HNK-1 sulfotransferase (HNK-1 ST). The cDNA predicts an open reading frame encoding a type II membrane protein of 341 amino acids with a 12-amino acid cytoplasmic domain and a 311-amino acid luminal domain containing a single potential N-linked glycosylation site. C4ST-3 has the greatest amino acid sequence identity when aligned with chondroitin-4-O-sulfotransferase 1 (C4ST-1) (45%) but also shows significant amino acid identity with chondroitin-4-O-sulfotransferase 2 (C4ST-2) (27%), dermatan-4-O-sulfotransferase 1 (29%), HNK-1 ST (26%), N-acetylgalactosamine-4-O-sulfotransferase 1 (26%), and N-acetylgalactosamine-4-O-sulfotransferase 2 (23%). C4ST-3 transfers sulfate to the C-4 hydroxyl of beta1,4-linked GalNAc that is substituted with a beta-linked glucuronic acid at the C-3 hydroxyl. The open reading frame of C4ST-3 is encoded by three exons located on human chromosome 3q21.3. Northern blot analysis reveals a single 2.1-kilobase transcript. C4ST-3 message is expressed in adult liver and at lower levels in adult kidney, lymph nodes, and fetal liver. Although C4ST-3 and C4ST-1 have similar specificities, the highly restricted pattern of expression seen for C4ST-3 suggests that it has a different role than C4ST-1.