Mitigation of Marine Dinoflagellates Using Hydrogen Peroxide (H2O2) Increases Toxicity towards Epithelial Gill Cells.

Hydrogen peroxide (H2O2) has been shown to efficiently remove toxic microalgae from enclosed ballast waters and brackish lakes. In this study, in vitro experiments were conducted to assess the side effects of mitigating toxic and non-toxic dinoflagellates with H2O2. Five H2O2 concentrations (50 to 1000 ppm) were used to control the cell abundances of the toxic dinoflagellates Alexandrium catenella and Karenia selliformis and the non-toxic dinoflagellates Lepidodinium chlorophorum and Prorocentrum micans. Photosynthetic efficiency and staining dye measurements showed the high efficiency of H2O2 for mitigating all dinoflagellate species at only 50 ppm. In a bioassay carried out to test cytotoxicity using the cell line RTgill-W1, control experiments (only H2O2) showed cytotoxicity in a concentration- and time- (0 to 24 h) dependent manner. The toxic dinoflagellates, especially K. selliformis, showed basal cytotoxicity that increased with the application of hydrogen peroxide. Unexpectedly, the application of a low H2O2 concentration increased toxicity, even when mitigating non-toxic dinoflagellates. This study suggests that the fatty acid composition of toxic and non-toxic dinoflagellate species can yield toxic aldehyde cocktails after lipoperoxidation with H2O2 that can persist in water for days with different half-lives. Further studies are needed to understand the role of lipoperoxidation products as acute mediators of disease and death in aquatic environments.

A small-molecule activator of mitochondrial aldehyde dehydrogenase 2 reduces the severity of cerulein-induced acute pancreatitis.

Acute pancreatitis (AP) is one of the leading causes of hospital admission for gastrointestinal disorders. Although lipid peroxides are produced in AP, it is unknown if targeting lipid peroxides prevents AP. This study aimed to investigate the role of mitochondrial aldehyde dehydrogenase 2 (ALDH2), a critical enzyme for lipid peroxide degradation, in AP and the possible underlying mechanisms. Cerulein was used to induce AP in C57BL/6 J male mice and pancreatic acinar cells were used to elucidate underlying mechanisms in vitro. Pancreatic enzymes in the serum, lipid peroxidation products malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), and Bcl-2, Bax and cleaved caspase-3 were measured. ALDH2 activation with a small-molecule activator, Alda-1, reduced the levels of the pancreatic enzymes in the serum and the lipid peroxidation products MDA and 4-HNE. In addition, Alda-1 decreased Bax and cleaved caspase-3 expression and increased Bcl-2 expression in vivo and in vitro. In conclusion, ALDH2 activation by Alda-1 has a protective effect in cerulein-induced AP by mitigating apoptosis in pancreatic acinar cells by alleviating lipid peroxidation.

Adducts formed during protein digestion decreased the toxicity of five carbonyl compounds against Caco-2 cells.

Acrolein (ACR), glyoxal (GO), methylglyoxal (MGO), hydroxymethylfurfural (HMF), and malondialdehyde (MDA) are toxic contaminants for humans. This work aimed to investigate whether intake of proteins can mitigate their toxicity. Simulated gastrointestinal digestion of proteins from pork, chicken, milk powder and soy protein isolate eliminated amount of ACR, GO, MGO, HMF, and MDA. Among six amino acids, cysteine showed highest capacity for elimination of these toxic compounds through the formation of adducts; it reached the highest elimination capacity for GO, MGO, ACR, MDA, and HMF in 40 min at pH 2.0, and 20 min at pH 7.0. The formed adducts between cysteine and GO, MGO, or ACR showed much lower toxicity against Caco-2 cells. Incubation of the cells with 8 mM GO and MGO for 48 h decreased the cell viability to 16.1%, 16.9% respectively; while incubation of the same concentration of their adducts still kept the cell viability at 82.2% and 81.6% respectively. Cysteine showed much higher detoxifying capacity for ACR than GO and MGO, which can lower the toxicity of ACR toward Caco-2 cells by 80 times.

Aldehyde dehydrogenase 2 activation ameliorates cyclophosphamide-induced acute cardiotoxicity via detoxification of toxic aldehydes and suppression of cardiac cell death.

Cyclophosphamide (CY)-induced acute cardiotoxicity is a common side effect which is dose dependent. It is reported that up to 20% of patients received high dose of CY treatment suffered from acute cardiac dysfunction. However, the effective intervention strategies and related mechanisms are still largely unknown. We aimed to investigate the effects of aldehyde dehydrogenase 2 (ALDH2), an important endogenous cardioprotective enzyme, on CY-induced acute cardiotoxicity and the underlying mechanisms. It was found that ALDH2 knockout (KO) mice were more sensitive to CY-induced acute cardiotoxicity, presenting as higher serum levels of creatine kinase-MB isoform and lactate dehydrogenase, and significantly reduced myocardial contractility compared with C57BL/6 (WT) mice. In addition, cardiac cell death, especially necrosis, was obviously increased in ALDH2 KO mice compared with WT mice after CY treatment. Furthermore, accumulation of toxic aldehydes such as acrolein and 4-HNE and reactive oxygen species (ROS) in the myocardium were significantly elevated after CY in ALDH2 KO mice. Importantly, ALDH2 activation by Alda-1 pretreatment markedly attenuated CY-induced accumulation of toxic aldehydes, cardiac cell death and cardiac dysfunction, without affecting CY's anti-tumor efficacy. In conclusion, the cardioprotective effects of ALDH2 activation against CY-induced acute cardiotoxicity are exerted via reducing toxic aldehydes accumulation and potentially interrupting the acrolein-ROS-aldehydes vicious circles, and thus alleviates myocardial cell death, without antagonizing the anti-tumor efficacy of CY. Therefore, ALDH2 might be a promising prevention and treatment target for CY-induced acute cardiotoxicity.

E-NTPDase1/CD39 modulates renin release from heart mast cells during ischemia/reperfusion: a novel cardioprotective role.

Ischemia/reperfusion (I/R) elicits renin release from cardiac mast cells (MC), thus activating a local renin-angiotensin system (RAS), culminating in ventricular fibrillation. We hypothesized that in I/R, neurogenic ATP could degranulate juxtaposed MC and that ecto-nucleoside triphosphate diphosphohydrolase 1/CD39 (CD39) on MC membrane could modulate ATP-induced renin release. We report that pharmacological inhibition of CD39 in a cultured human mastocytoma cell line (HMC-1) and murine bone marrow-derived MC with ARL67156 (100 µM) increased ATP-induced renin release (≥2-fold), whereas purinergic P2X7 receptors (P2X7R) blockade with A740003 (3 µM) prevented it. Likewise, CD39 RNA silencing in HMC-1 increased ATP-induced renin release (≥2-fold), whereas CD39 overexpression prevented it. Acetaldehyde, an I/R product (300 µM), elicited an 80% increase in ATP release from HMC-1, in turn, causing an autocrine 20% increase in renin release. This effect was inhibited or potentiated when CD39 was overexpressed or silenced, respectively. Moreover, P2X7R silencing prevented ATP- and acetaldehyde-induced renin release. I/R-induced RAS activation in ex vivo murine hearts, characterized by renin and norepinephrine overflow and ventricular fibrillation, was potentiated (∼2-fold) by CD39 inhibition, an effect prevented by P2X7R blockade. Our data indicate that by regulating ATP availability at the MC surface, CD39 modulates local renin release and thus, RAS activation, ultimately exerting a cardioprotective effect.