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Despite numerous therapeutic options, multidrug resistance (MDR) remains an obstacle to successful breast cancer therapy. Jadomycin B, a natural product derived from Streptomyces venezuelae ISP5230, maintains cytotoxicity in MDR human breast cancer cells. Our objectives were to evaluate the pharmacokinetics, toxicity, anti-tumoral, and anti-metastatic effects of jadomycin B in zebrafish larvae and mice. In a zebrafish larval xenograft model, jadomycin B significantly reduced the proliferation of human MDA-MB-231 cells at or below its maximum tolerated dose (40 [micro]m). In female Balb/C mice, a single intraperitoneal dose (6 mg/kg) was rapidly absorbed with a maximum serum concentration of 3.4 [+ or -] 0.27 pm. Jadomycin B concentrations declined biphasically with an elimination half-life of 1.7 [+ or -] 0.058 h. In the 4T1 mouse mammary carcinoma model, jadomycin B (12 mg/kg every 12 h from day 6 to 15 after tumor cell injection) decreased primary tumor volume compared to vehicle control. Jadomycin B-treated mice did not exhibit weight loss, nor significant increases in biomarkers of impaired hepatic (alanine aminotransferase) and renal (creatinine) function. In conclusion, jadomycin B demonstrated a good safety profile and provided partial anti-tumoral effects, warranting further dose-escalation safety and efficacy studies in MDR breast cancer models. Key words: jadomycin B, breast cancer, pharmacokinetics, toxicity, zebrafish, mouse En depit de l'accessibilite de nombreuses options therapeutiques, la multiresistance aux medicaments (MRM) demeure un obstacle au succes des traitements contre le cancer du sein. La jadomycine B, un produit naturel obtenu a partir de Streptomyces venezuelae ISP5230, permet de maintenir la cytotoxicite chez des cellules de cancer du sein humaines MRM. Nous avions pour objectif d'evaluer les proprietes pharmacocinetiques, la toxicite, de meme que les effets antitumoraux et antimetastatiques de la jadomycine B chez la larve de poisson-zebre et la souris. Dans un modele de xenogreffe de larve de poisson-zebre, la jadomycine B a entraine une diminution notable de la proliferation des cellules humaines MDA-MB-231 a un degre egal ou inferieur a la dose maximale toleree (40 mM). Chez les souris femelles Balb/C, une dose unique administree par voie intraperitoneale (a 6 mg/kg) etait rapidement absorbee avec une concentration serique maximale de 3,4 [+ or -] 0,27 mM. Les concentrations de jadomycine B ont diminue selon une courbe biphasique avec une demi-vie d'elimination de 1,7 [+ or -] 0,058 heure. Dans le modele de la souris 4T1 avec carcinome mammaire, la jadomycine B (a 12 mg/kg toutes les 12 heures des jours 6 a 15 apres l'injection de cellules tumorales) entrainait une diminution du volume de la tumeur primaire comparativement aux temoins avec vehicule. Les souris auxquelles etait administree de la jadomycine B n'ont pas presente de perte de poids ni de hausse notable des biomarqueurs d'une insuffisance hepatique (alanine aminotransferase) ou renale (creatinine). En conclusion, la jadomycine B s'est revelee avoir un bon profil d'innocuite et fournir des effets antitumoraux partiels, ce qui justifierait de proceder a des etudes d'innocuite et d'efficacite avec augmentation progressive de la dose dans des modeles de cancer du sein MRM. [Traduit par la Redaction] Mots-cles : jadomycine B, cancer du sein, pharmacocinetique, toxicite, poisson-zebre, souris, Introduction Breast cancer is the most commonly diagnosed cancer in women, both in Canada and worldwide (Bray et al. 2018; Brenner et al. 2020). Metastasis is the process by which [...]

The field of metabolomics has gained tremendous interest in recent years. Whether the goal is to discover biomarkers related to certain pathologies or to better understand the impact of a drug or contaminant, numerous studies have demonstrated how crucial it is to understand variations in metabolism. Detailed knowledge of metabolic variabilities can lead to more effective treatments, as well as faster or less invasive diagnostics. Exploratory approaches are often employed in metabolomics, using relative quantitation to look at perturbations between groups of samples. Most metabolomics studies have been based on metabolite profiling using relative quantitation, with very few studies using an approach for absolute quantitation. Using accurate quantitation facilitates the comparison between different studies, as well as enabling longitudinal studies. In this review, we discuss the most widely used techniques for quantitative metabolomics using mass spectrometry (MS). Various aspects will be addressed, such as the use of external and/or internal standards, derivatization techniques, in vivo isotopic labelling, or quantitative MS imaging. The principles, as well as the associated limitations and challenges, will be described for each approach. [ABSTRACT FROM AUTHOR]

Ref: Can. J. Physiol. Pharmacol. 100(11): 1065-1076 (2022). https://doi.org/10.1139/cjpp-2022-0152. In the originally published article, the funding statement for Brendan T. McKeown (BTM) was missing the Saunder's Matthey Foundation for Cancer [...]

The green alga Scenedesmus sp. was exposed to a long-term physiological stress of 40 days induced by the combination of nitrate deficiency, different concentrations of sodium chloride, and high light irradiance. Under these conditions, the change of photosystem II (PSII) photochemical reactions of photosynthesis and cellular growth were investigated along with the synthesis of secondary carotenoids, including astaxanthin and canthaxanthin. From 10 to 40 days, the biosynthesis of these secondary carotenoids was highly induced after the deterioration of PSII complexes when chlorophyll synthesis and cell division were inhibited. In this long term study, the highest induction of carotenoid synthesis happened after the deterioration of PSII reaction centers. There was no direct relationship between the induction of secondary carotenoids and the decline of PSII photochemical efficiency, although it may contribute to carotenogenesis. Under this stressful condition, viability of cells was noted by the small change of unbleached cell density compared with control after 40 days. Therefore, Scenedesmus sp. was tolerant to the long-term chronic stress condition caused by the production of secondary carotenoids, such as astaxanthin and cantaxanthin, participating in antioxidative mechanisms to protect algal cellular system. Key words: photosystem II, green algae, Scenedesmus sp., secondary carotenoids, salt stress, carotenogenesis. L'algue verte Scenedesmus sp. a ete exposee a un stress physiologique a long terme de 40 jours, en combinant un deficit en nitrate, differentes concentrations en chlorure de sodium et une forte irradiance lumineuse. Dans ces conditions, les auteurs ont examine le changement des reactions photochimiques du photosysteme II (PSII) de la photosynthese et la croissance cellulaire, ainsi que la synthese de caroteno'ides secondaires, incluant l'astaxanthine et la canthaxantine. Du 10e au 40e jour, les auteurs ont observe une forte induction de la biosynthese de ces caroteno'ides secondaires qui a ete induite apres la deterioration des complexes du PSII, alors que la synthese de la chlorophylle et la division cellulaire etaient inhibees. Dans cette etude a long terme, la plus forte induction de la synthese des caroteno'ides est survenue apres la deterioration des centres reactionnels du PSII. Les auteurs n'ont observe aucune relation directe entre l'induction des caroteno'ides secondaires et le declin de l'efficacite photochimique du PSII, bien qu'il puisse contribuer a la carotenogenese. Sous cette condition stressante, les auteurs ont constate la viabilite des cellules par un petit changement de la densite des cellules non delavees, comparativement aux temoins, apres 40 jours. Consequemment, Scenedesmus sp. s'est avere tolerant a la condition de stress chronique a long terme, par la production de caroteno'ides secondaires, comme l'astaxanthine et la cantaxanthine, participant a des mecanismes antioxydants pour proteger le systeme cellulaire des algues. Mots-cles : photosysteme II, algue verte, Scenedesmus sp., caroteno'des secondaires, stress salin, carotenogenese. [Traduit par la Redaction], Introduction Under optimal physiological conditions, green algae synthesize different pigments in the chloroplast such as chlorophylls a and b, and also carotenoids including (β-carotene, neoxanthin, violaxanthin, and zeaxanthin, which have [...]

This present work describes the systematic experimental comparison of electrospray ionization (ESI) and matrixassisted laser desorption ionization (MALDI) for pharmacokinetic (PK) analysis of two drug candidates from rat plasma using single reaction monitoring (SRM) on a triple quadrupole mass spectrometer. The electrospray assay is an established method using a fast liquid chromatography (LC) separation of the sample extracts prior to mass spectrometry analysis. The novel MALDI assays measured the concentration levels of the drug candidates directly from the spotted sample extracts. Importantly, for both LC-ESI and MALDI the same solid-phase sample extraction protocol, internal standards, triple quadrupole mass analyzer platform, and SRM conditions were used, thus effectively standardizing all experimental parameters of the two assays. Initially, analytical figures of merit such as linearity, limit of quantitation, precision, and accuracy were determined from the calibration curves, indicating very similar performance for both LC-ESI and MALDI. Moreover, the LC-ESI rat plasma concentration time profiles of the drug candidates after orally dosing the animals were accurately reproduced by the MALDI assay, giving virtually identical PK results. The direct MALDI assay, however, was able to generate the data at least 50 x faster than the LC-ESI assay. It is shown in this study that analyzing the entire PK curve for one animal took less than 2 min using MALDI (with five replicate analyses per sample), whereas the corresponding LC-ESI assay required 80 min, however, allowing only two replicate measurements in that time frame.

Mass spectrometry (MS) instrumentation has undergone several improvements over the years, including increased sensitivity, ease-of-use, and possibilities for more sophisticated and time-efficient experiments. This article illustrates the technical principles and […]