Glutathione, Protein Thiols, and Metal Homeostasis

Abstract The ability of pathogens to maintain homeostatic levels of essential biometals is known to be important for survival and virulence in a host, which itself regulates metal availability as part of its response to infection. Given this importance of metal homeostasis, we sought to address how the availability of copper in particular impacts the response of the opportunistic fungal pathogen Candida albicans to treatment with the antifungal drug fluconazole. The present study reports whole transcriptome analysis via time-course RNA-seq of C. albicans cells exposed to fluconazole with and without 10 µM supplemental CuSO4 added to the growth medium. The results show widespread impacts of small changes in Cu availability on the transcriptional response of C. albicans to fluconazole. Of the 2359 genes that were differentially expressed under conditions of cotreatment, 50% were found to be driven uniquely by exposure to both Cu and fluconazole. The breadth of metabolic processes that were affected by cotreatment illuminates a fundamental intersectionality between Cu metabolism and fungal response to drug stress. More generally, these results show that seemingly minor fluctuations in Cu availability are sufficient to shift cells’ transcriptional response to drug stress. Ultimately, the findings may inform the development of new strategies that capitalize on drug-induced vulnerabilities in metal homeostasis pathways.

Download Full-text

Oxidative damage, inflammation, genotoxic effect, and global DNA methylation caused by inhalation of formaldehyde and the purpose of melatonin

Toxicology Research ◽

10.1093/toxres/tfaa079 ◽

2020 ◽

Vol 9 (6) ◽

pp. 778-789

Author(s):

Letícia Bernardini ◽

Eduardo Barbosa ◽

Mariele Feiffer Charão ◽

Gabriela Goethel ◽

Diana Muller ◽

...

Keyword(s):

Dna Methylation ◽

Bone Marrow ◽

Oxidative Damage ◽

Bronchoalveolar Lavage ◽

Bone Marrow Cells ◽

Histological Study ◽

Global Dna Methylation ◽

Protective Effects ◽

Global Methylation ◽

Protein Thiols

Abstract Formaldehyde (FA) exposure has been proven to increase the risk of asthma and cancer. This study aimed to evaluate for 28 days the FA inhalation effects on oxidative stress, inflammation process, genotoxicity, and global DNA methylation in mice as well as to investigate the potential protective effects of melatonin. For that, analyses were performed on lung, liver and kidney tissues, blood, and bone marrow. Bronchoalveolar lavage was used to measure inflammatory parameters. Lipid peroxidation (TBARS), protein carbonyl (PCO), non-protein thiols (NPSH), catalase activity (CAT), comet assay, micronuclei (MN), and global methylation were determined. The exposure to 5-ppm FA resulted in oxidative damage to the lung, presenting a significant increase in TBARS and NO levels and a decrease in NPSH levels, besides an increase in inflammatory cells recruited for bronchoalveolar lavage. Likewise, in the liver tissue, the exposure to 5-ppm FA increased TBARS and PCO levels and decreased NPSH levels. In addition, FA significantly induced DNA damage, evidenced by the increase of % tail moment and MN frequency. The pretreatment of mice exposed to FA applying melatonin improved inflammatory and oxidative damage in lung and liver tissues and attenuated MN formation in bone marrow cells. The pulmonary histological study reinforced the results observed in biochemical parameters, demonstrating the potential beneficial role of melatonin. Therefore, our results demonstrated that FA exposure with repeated doses might induce oxidative damage, inflammatory, and genotoxic effects, and melatonin minimized the toxic effects caused by FA inhalation in mice.

Download Full-text

Manganese privation induced transcriptional upregulation of the class IIa bacteriocin plantaricin 423 in Lactobacillus plantarum 423

Applied and Environmental Microbiology ◽

10.1128/aem.00976-21 ◽

2021 ◽

Author(s):

Ross Vermeulen ◽

Shelly Deane ◽

Leon Dicks ◽

Johann Rohwer ◽

Anton Du Preez van Staden

Keyword(s):

Transition Metal ◽

Lactobacillus Plantarum ◽

Foodborne Pathogens ◽

Economic Value ◽

Metal Homeostasis ◽

Culture Conditions ◽

Reporter System ◽

Precursor Peptide ◽

Enterocin A ◽

Leucocin A

Plantaricin 423 is produced by Lactobacillus plantarum 423 using the pla biosynthetic operon located on the 8188 bp plasmid, pPLA4. As with many class IIa bacteriocin operons, the pla operon encodes biosynthetic genes ( plaA : precursor peptide, plaB : immunity, plaC : accessory and plaD : ABC transporter) but does not encode local regulatory genes. Little is known about the regulatory mechanisms involved in the expression of the apparently regulationless class IIa bacteriocins such as plantaricin 423. In this study, phylogenetic analysis of class IIa immunity proteins indicated that at least three distinct clades exist, which were then used to subgroup the class IIa operons. It became evident that the absence of classical quorum sensing genes on mobile bacteriocin encoding elements is a predisposition of the subgroup which includes plantaricin 423, pediocin AcH/PA-1, divercin V41, enterocin A, leucocin-A and -B, mesentericin Y105 and sakacin G. Further analysis of the subgroup suggested that the regulation of these class IIa operons may be linked to transition metal homeostasis in the host. By using a fluorescent promoter-reporter system in Lactobacillus plantarum 423, transcriptional regulation of plantaricin 423 was shown to be upregulated in response to manganese privation. IMPORTANCE Lactic acid bacteria hold huge industrial application and economic value, especially bacteriocinogenic strains which further aids in the exclusion of specific foodborne pathogens. Since bacteriocinogenic strains are sought after it is equally important to understand the mechanism of bacteriocin regulation. This is currently an understudied aspect of class IIa operons. Our research suggests the existence of a previously undescribed mode of class IIa bacteriocin regulation, whereby bacteriocin expression is linked to management of the producer’s transition metal homeostasis. This delocalized metalloregulatory model may fundamentally affect the selection of culture conditions for bacteriocin expression and change our understanding of class IIa bacteriocin gene transfer dynamics in a given microbiome.

Download Full-text