The Epithelial to Mesenchymal Transition in Colorectal Cancer Progression: The Emerging Role of Succinate Dehydrogenase Alterations and Succinate Accumulation.

Colorectal cancer (CRC) stands as the third most significant contributor to cancer-related mortality worldwide. A major underlying reason is that the detection of CRC usually occurs at an advanced metastatic stage, rendering therapies ineffective. In the progression from the in situ neoplasia stage to the advanced metastatic stage, a critical molecular mechanism involved is the epithelial-to-mesenchymal transition (EMT). This intricate transformation consists of a series of molecular changes, ultimately leading the epithelial cell to relinquish its features and acquire mesenchymal and stem-like cell characteristics. The EMT regulation involves several factors, such as transcription factors, cytokines, micro RNAs and long noncoding RNAs. Nevertheless, recent studies have illuminated an emerging link between metabolic alterations and EMT in various types of cancers, including colorectal cancers. In this review, we delved into the pivotal role played by EMT during CRC progression, with a focus on highlighting the relationship between the alterations of the tricarboxylic acid cycle, specifically those involving the succinate dehydrogenase enzyme, and the activation of the EMT program. In fact, emerging evidence supports the idea that elucidating the metabolic modifications that can either induce or inhibit tumor progression could be of immense significance for shaping new therapeutic approaches and preventative measures. We conclude that an extensive effort must be directed towards research for the standardization of drugs that specifically target proteins such as SDH and SUCNR1, but also TRAP1, PDH, ERK1/2, STAT3 and the HIF1-α catabolism.

Potential endocrine correlation with exposure to domoic acid in Southern Right Whale (Eubalaena australis) at the Península Valdés breeding ground.

In waters off Península Valdés (PV), Argentina, southern right whales (SRW, Eubalaena australis) are occasionally exposed to domoic acid (DA), a neurotoxin produced by diatoms of the genus Pseudo-nitzschia. Domoic acid toxicity in marine mammals can cause gastrointestinal and neurological clinical signs, alterations in hematologic and endocrine variables, and can be fatal in extreme cases. In this study, we validated an enzyme immunoassay to quantify fecal glucocorticoid metabolites (fGCm) in 16 SRW fecal samples from live and dead stranded whales in PV from 2013 to 2018 and assessed fGCm levels associated with DA exposure. Overall, fGCm levels were significantly lower in SRWs with detectable fecal DA (n = 3) as compared to SRWs with undetectable fecal DA levels (n = 13). The highest fecal DA was observed in a live lactating female, which had low fGCm compared to the other lactating females studied. The highest fGCm was observed in a lactating female with undetectable DA; interestingly, at the time of sample collection, this female was sighted with two calves, an extremely unusual occurrence in this species. Though the sample size of these exceptionally rare breeding-season fecal samples was unavoidably small, our study provides evidence of potential adrenal alterations in whales exposed to an environmental neurotoxin such as DA.

Occurrence of Toxigenic Microalgal Species and Phycotoxin Accumulation in Mesozooplankton in Northern Patagonian Gulfs, Argentina.

In the Northern Patagonian gulfs of Argentina (Golfo Nuevo and Golfo San José), blooms of toxigenic microalgae and the detection of their associated phycotoxins are recurrent phenomena. The present study evaluated the transfer of phycotoxins from toxigenic microalgae to mesozooplankton in Golfo Nuevo and Golfo San José throughout an annual cycle (December 2014-2015 and January 2015-2016, respectively). In addition, solid-phase adsorption toxin tracking (SPATT) samplers were deployed for the first time in these gulfs, to estimate the occurrence of phycotoxins in the seawater between the phytoplankton samplings. Domoic acid was present throughout the annual cycle in SPATT samplers, whereas no paralytic shellfish poisoning toxins were detected. Ten toxigenic species were identified: Alexandrium catenella, Dinophysis acuminata, Dinophysis acuta, Dinophysis tripos, Dinophysis caudata, Prorocentrum lima, Pseudo-nitzschia australis, Pseudo-nitzschia calliantha, Pseudo-nitzschia fraudulenta, and Pseudo-nitzschia pungens. Lipophilic and hydrophilic toxins were detected in phytoplankton and mesozooplankton from both gulfs. Pseudo-nitzschia spp. were the toxigenic species most frequent in these gulfs. Consequently, domoic acid was the phycotoxin most abundantly detected and transferred to upper trophic levels. Spirolides were detected in phytoplankton and mesozooplankton for the first time in the study area. Likewise, dinophysistoxins were found in mesozooplankton from both gulfs, and this is the first report of the presence of these phycotoxins in zooplankton from the Argentine Sea. The dominance of calanoid copepods indicates that they were the primary vector of phycotoxins in the pelagic trophic web. Environ Toxicol Chem 2019;38:2209-2223. © 2019 SETAC.

Domoic acid in a marine pelagic food web: Exposure of southern right whales Eubalaena australis to domoic acid on the Península Valdés calving ground, Argentina.

The gulfs that surround Península Valdés (PV), Golfo Nuevo and Golfo San José in Argentina, are important calving grounds for the southern right whale Eubalaena australis. However, high calf mortality events in recent years could be associated with phycotoxin exposure. The present study evaluated the transfer of domoic acid (DA) from Pseudo-nitzschia spp., potential producers of DA, to living and dead right whales via zooplanktonic vectors, while the whales are on their calving ground at PV. Phytoplankton and mesozooplankton (primary prey of the right whales at PV and potential grazers of Pseudo-nitzschia cells) were collected during the 2015 whale season and analyzed for species composition and abundance. DA was measured in plankton and fecal whale samples (collected during whale seasons 2013, 2014 and 2015) using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The genus Pseudo-nitzschia was present in both gulfs with abundances ranging from 4.4×102 and 4.56×105 cell l-1. Pseudo-nitzschia australis had the highest abundance with up to 4.56×105 cell l-1. DA in phytoplankton was generally low, with the exception of samples collected during a P. australis bloom. No clear correlation was found between DA in phytoplankton and mesozooplankton samples. The predominance of copepods in mesozooplankton samples indicates that they were the primary vector for the transfer of DA from Pseudo-nitzschia spp. to higher trophic levels. High levels of DA were detected in four whale fecal samples (ranging from 0.30 to 710µgg-1 dry weight of fecal sample or from 0.05 and 113.6µgg-1 wet weight assuming a mean water content of 84%). The maximum level of DA detected in fecal samples (710µg DA g-1 dry weight of fecal sample) is the highest reported in southern right whales to date. The current findings demonstrate for the first time that southern right whales, E. australis, are exposed to DA via copepods as vectors during their calving season in the gulfs of PV.