Chemical synthesis and biological screening of 2-aminoimidazole-based bacterial and fungal antibiofilm agents.

A collection of 2-aminoimidazole/triazole amides has been synthesized and screened for antibiofilm activity. This class of small molecules was found to modulate the biofilm activity of Pseudomonas aeruginosa, a multidrug-resistant strain of Acinetobacter baumannii (MDRAB), a methicillin-resistant Staphylococcus aureus strain (MRSA), Escherichia coli, Rhodospirillum salexigens, Staphylococcus epidermidis, Vibrio vulnificus, and vancomycin-resistant Enterococcus faecium as well as the yeast Candida albicans and Cryptococcus neoformans. Furthermore, lead compounds were found to not lyse red blood cells at active concentrations.

Effects of acute doxorubicin treatment on hepatic proteome lysine acetylation status and the apoptotic environment.

AIM: To determine if doxorubicin (Dox) alters hepatic proteome acetylation status and if acetylation status was associated with an apoptotic environment. METHODS: Doxorubicin (20 mg/kg; Sigma, Saint Louis, MO; n = 8) or NaCl (0.9%; n = 7) was administered as an intraperitoneal injection to male F344 rats, 6-wk of age. Once animals were treated with Dox or saline, all animals were fasted until sacrifice 24 h later. RESULTS: Dox treatment decreased proteome lysine acetylation likely due to a decrease in histone acetyltransferase activity. Proteome deacetylation may likely not be associated with a proapoptotic environment. Dox did not increase caspase-9, -8, or -3 activation nor poly (adenosine diphosphate-ribose) polymerase-1 cleavage. Dox did stimulate caspase-12 activation, however, it likely did not play a role in apoptosis induction. CONCLUSION: Early effects of Dox involve hepatic proteome lysine deacetylation and caspase-12 activation under these experimental conditions.

Doxorubicin alters the mitochondrial dynamics machinery and mitophagy in the liver of treated animals.

Doxorubicin (Dox) is an effective chemotherapeutic agent, but known to cause cardiac and hepatic toxicity. Mechanisms of toxicity have not been clearly identified, but shown to involve oxidative stress and mitochondrial dysfunction. However, antioxidant supplementation has only shown modest protection from Dox-induced toxicity in clinical trials. Therefore, further research is required to discern alternative mechanisms that may also play an important role in Dox-induced toxicity. Thus, we aimed to investigate the role of mitochondrial fusion and fission in Dox-induced hepatic toxicity, which has not yet been investigated. Six-week-old male F344 rats were injected IP with 20 mg/kg of Dox or saline. Once administered, both groups of animals were fasted with no food or water until sacrifice 24 h later. Dox decreased content of primary regulators of mitochondrial fusion (OPA1, MFN1, and MFN2) with no effect on regulators of fission (DRP1 and FIS1), thus shifting the balance favoring mitochondrial fission. Moreover, it was determined that mitochondrial fission was likely not coupled to cell proliferation or cytochrome c release leading to the activation of mitochondrial-mediated apoptotic signaling. Rather, mitochondrial fission may be coupled to mitophagy and may be an adaptive response to protect against Dox-induced hepatic toxicity. This is the first study to report the role of altered mitochondrial dynamics and mitophagy machinery in Dox-induced hepatic injury.

Can short-term fasting protect against doxorubicin-induced cardiotoxicity?

Doxorubicin (Dox) is one of the most effective chemotherapeutic agents used in the treatment of several types of cancer. However the use is limited by cardiotoxicity. Despite extensive investigation into the mechanisms of toxicity and preventative strategies, Dox-induced cardiotoxicity still remains a major cause of morbidity and mortality in cancer survivors. Thus, continued research into preventative strategies is vital. Short-term fasting has proven to be cardioprotective against a variety of insults. Despite the potential, only a few studies have been conducted investigating its ability to prevent Dox-induced cardiotoxicity. However, all show proof-of-principle that short-term fasting is cardioprotective against Dox. Fasting affects a plethora of cellular processes making it difficult to discern the mechanism(s) translating fasting to cardioprotection, but may involve suppression of insulin and insulin-like growth factor-1 signaling with stimulated autophagy. It is likely that additional mechanisms also contribute. Importantly, the literature suggests that fasting may enhance the antitumor activity of Dox. Thus, fasting is a regimen that warrants further investigation as a potential strategy to prevent Dox-induced cardiotoxicity. Future research should aim to determine the optimal regimen of fasting, confirmation that this regimen does not interfere with the antitumor properties of Dox, as well as the underlying mechanisms exerting the cardioprotective effects.