Aztreonam/avibactam is effective against serious infections caused by Gram-negative bacteria including Enterobacterales harboring metallo-β-lactamases. While the utility of this combination has been established in vitro and in clinical trials, the purpose of this study is to enhance our understanding of the underlying mechanism responsible for their activities through metabolomic profiling of a multidrug-resistant Escherichia coli clinical isolate. Metabolomic analyses of time-dependent changes in endogenous bacterial metabolites in a clinical isolate of a multidrug-resistant E. coli treated with aztreonam and avibactam were performed. E. coli metabolomes were compared at 15 min, 1 h and 24 h following treatments with either avibactam (4 mg/L), aztreonam (4 mg/L), or aztreonam (4 mg/L) + avibactam (4 mg/L). Drug treatment affected 326 metabolites with magnitude changes of at least 2-fold, most of which are involved primarily in peptidoglycan biosynthesis, nucleotide metabolism, and lipid metabolism. The feedstocks for peptidoglycan synthesis were depleted by aztreonam/avibactam combination; a significant downstream increase in nucleotide metabolites and a release of lipids were observed at the three timepoints. The findings indicate that the aztreonam/avibactam combination accelerates structural damage to the bacterial membrane structure and their actions were immediate and sustained compared to aztreonam or avibactam alone. By inhibiting the production of crucial cell wall precursors, the combination may have inflicted damages on bacterial DNA.

Natural bromophenols are important secondary metabolites in marine algae. Derivatives of these bromophenol are potential candidates for the drug development due to their biological activities, such as antioxidant, anticancer, anti-diabetic and anti-inflammatory activity. In our present study, we have designed and synthesized a series of new methylated and acetylated bromophenol derivatives from easily available materials using simple operation procedures and evaluated their antioxidant and anticancer activities on the cellular level. The results showed that 2.,3-dibromo-1-(((2-bromo-4,5-dimethoxybenzyl)oxy)methyl)-4,5-dimethoxybenzene (3b-9) and (oxybis(methylene))bis(4-bromo-6-methoxy-3,1-phenylene) diacetate (4b-3) compounds ameliorated H2O2-induced oxidative damage and ROS generation in HaCaT keratinocytes. Compounds 2.,3-dibromo-1-(((2-bromo-4,5-dimethoxybenzyl)oxy)methyl)-4,5-dimethoxybenzene (3b-9) and (oxybis(methylene) )bis(4-bromo-6-methoxy-3,1-phenylene) diacetate (4b-3) also increased the TrxR1 and HO-1 expression while not affecting Nrf2 expression in HaCaT. In addition, compounds (oxybis(methylene)bis(2-bromo-6-methoxy-4,1-phenylene) diacetate (4b-4) inhibited the viability and induced apoptosis of leukemia K562 cells while not affecting the cell cycle distribution. The present work indicated that some of these bromophenol derivatives possess significant antioxidant and anticancer potential, which merits further investigation.

Antibiotic abuse can lead to gut microbiota disturbance and intestinal inflammation, which in turn may lead to serious inflammatory bowel disease and metabolic syndromes. To investigate the effect of fucoidan on alleviation of the side effects of antibiotics and its structure-activity relationship, we compared the effects of two fucoidan fractions with medium and low molecular weights (MF and LF) from Laminaria japonica on microbiota dysbiosis, colonic inflammation and intestinal mucosal damage in a cefoperazone-induced intestinal injury mouse model. Our results showed that oral administration of 200 mg kg-1 LF (Mw = 1.13 kDa) and MF (Mw = 26.7 kDa) together with 100 mg kg-1 cefoperazone for 10 days could significantly alleviate weight loss, colon shortening and enlargement, mucosal structural damage in the small intestine, cecum and colon induced by cefoperazone in mice. Meanwhile, LF and MF also significantly suppressed the overproduction of TNF-α, IFN-γ, and IL-6 in the colon; however, LF can restore the decrease in the levels of TNF-α and IL-6 in the small intestine and the decrease in the levels of TNF-α, IFN-γ, and IL-6 in the cecum induced by cefoperazone in mice. We found that the molecular weight of fucoidan plays an important role in the regulation of the gut microbiota in antibiotic-treated mice. Interestingly, fucoidans with different molecular weights resulted in quite different caecal microbiota communities. MF exhibited a much better effect on the restoration of the gut microbiota community richness and diversity and the beneficial bacterium Muribaculaceae. However, LF resulted in the dominance of bacteria including Staphylococcus in cefoperazone treated mice, without an increase in the community richness and diversity of caecal microbiota. In the LF and MF treated mice, an increase in the abundance of beneficial bacteria, Muribaculaceae, Acinetobacter_lwoffii and Alloprevotella, and a decrease in the abundance of harmful bacteria, e.g., Parasutterella, Helicobacter and Enterococcus were also observed. Considering the negative effect of LF on the gut microbiota, MF with a molecular weight of 26.7 kDa seemed to be a more suitable choice of prebiotics for patients receiving cefoperazone treatment.

Excessive reactive oxygen species (ROS) promotes the oxidative stress of keratinocytes, eventually causing cell damage. The natural bromophenol bis (2,3,6-tribromo-4,5-dihydroxybenzyl) ether (BTDE) from marine red algae has been reported to have a varied bioactivity; however, its antioxidant effect has yet to be investigated systemically. Our present work aimed to explore the antioxidant effect of BTDE both on the molecular and cellular models and also to illustrate the antioxidant mechanisms. Our results showed that BTDE could effectively scavenge ABTS free radicals and protect HaCaT cells from damage induced by H2O2. Mechanism studies in HaCaT cells demonstrated that BTDE attenuated hydrogen peroxide (H2O2)-induced ROS production, reduced the malondialdehyde (MDA) level, decreased the oxidized glutathione (GSSG)/glutathione (GSH) ratio, and increased the antioxidant enzyme superoxide dismutase (SOD). Moreover, BTDE could inhibit the expression of Kelch-like epichlorohydrin-associated protein 1 (Keap1) and increase the expression of both nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream proteins TrXR1, HO-1, and NQO1. BTDE also activated the upstream signaling pathway of Nrf2 such as AKT pathway, while not activating the ERK or AMPKα pathways. In general, BTDE is a promising antioxidant to protect HaCaT cells against oxidative damage via Nrf2-mediated pathways.

Angiogenesis, including the growth of new capillary blood vessels from existing ones and the malignant tumors cells formed vasculogenic mimicry, is quite important for the tumor metastasis. Anti-angiogenesis is one of the significant therapies in tumor treatment, while the clinical angiogenesis inhibitors usually exhibit endothelial cells dysfunction and drug resistance. Bis(2,3,6-tribromo-4,5-dihydroxybenzyl)ether (BTDE), a marine algae-derived bromophenol compound, has shown various biological activities, however, its anti-angiogenesis function remains unknown. The present study illustrated that BTDE had anti-angiogenesis effect in vitro through inhibiting human umbilical vein endothelial cells migration, invasion, tube formation, and the activity of matrix metalloproteinases 9 (MMP9), and in vivo BTDE also blocked intersegmental vessel formation in zebrafish embryos. Moreover, BTDE inhibited the migration, invasion, and vasculogenic mimicry formation of lung cancer cell A549. All these results indicated that BTDE could be used as a potential candidate in anti-angiogenesis for the treatment of cancer.

Trimethyltin chloride (TMT) is an organotin contaminant, widely detected in aqueous environments, posing potential human and environmental risks. In the present study, the embryo and larvae of sea urchin Strongylocentyotus intermedius were used as a model to investigate the toxic effects of TMT. Data obtained from the TMT acute toxicity tests were evaluated using the Probit Analysis Statistical Method. The results show that TMT pollution decreased the fertilization ability of sperms, but no obvious effect on the eggs and fertilization ability. The 4-arm stage larva and the sperms are sensitive to TMT. It is suggest that low levels (36.63 μg/L) of TMT in the aquatic environment may have a significant effect on the reproduction and development of sea urchin.