Disease relevance of Nodularin

• The present study characterizes the inhibitory effects of nodularin, a recently isolated hepatotoxic compound from the cyanobacterium Nodularia spumigena, on type 1 (PP1), type 2A, (PP2A), type 2B (PP2B), and type 2C (PP2C) protein phosphatases [1].
• This peptide segment is not present in nodularin, a cyclic pentapeptide of similar toxicity [2].
• A range of microcystin- and nodularin-containing laboratory strains and environmental samples of cyanobacteria were assayed by CIPPIA, and the results showed good correlation (R2 = 0.94, P < 0.00001) with the results of high-performance liquid chromatography with diode array detection for toxin analysis [3].
• The picked Aphanizomenon colonies did not contain nodularin and the dissolved nodularin concentrations were below detection limit [4].
• Many N. spumigena strains can produce nodularin, a hepatotoxic penta-peptide, which has caused several animal poisonings in the Baltic Sea area [5].

High impact information on Nodularin

• The protein phosphatase (PP) inhibitors nodularin and microcystin-LR induced apoptosis with unprecedented rapidity, more than 50% of primary hepatocytes showing extensive surface budding and shrinkage of cytoplasm and nucleoplasm within 2 min [6].
• To circumvent the inefficient uptake of microcystin and nodularin into nonhepatocytes, toxins were microinjected into 293 cells, Swiss 3T3 fibroblasts, promyelocytic IPC-81 cells, and NRK cells [6].
• Nodularin up-regulated induction of c-jun, jun-B,jun-D,c-fos,fos-B, and fra-1 mRNA transcripts in rat liver after i.p. administration, and the accumulation of the mRNA transcripts was sustained for over 9 h after treatment [7].
• Nodularin induced hyperphosphorylation of cytokeratin peptides 8 and 18 in primary cultured rat hepatocytes 20% more effectively than did microcystin-LR, suggesting that nodularin penetrates more easily into the hepatocytes than does microcystin-LR [7].
• The potent natural toxins microcystin, nodularin, and okadaic acid act rapidly to induce apoptotic cell death [8].

Chemical compound and disease context of Nodularin

• Microcystin-LR (MCYST-LR) and nodularin (NOD) produced by cyanobacteria are potent and specific hepatotoxins [9].
• A cyanobacterial hepatotoxin, nodularin-Har, having a homoarginine instead of an arginine in nodularin, was isolated from Nodularia PCC7804 [10].
• The toxicity and metabolism of the cyanobacterial toxins microcystin-LR (MCLR), Dhb-microcystin-HtyR and nodularin were investigated in the cysts, nauplii and adults of the brine shrimp Artemia salina [11].
• The toxic effects of several species of fresh water cyanobacteria, notably Microcystis species and associated toxins, the microcystins, Anabaena species (anatoxin), Nodularia sp. (nodularin), and Cylindrospermopsis raciborskii (cylindrospermopsin), are well known [12].

Biological context of Nodularin

• Both PP2A and PP1 were potently inhibited (IC50 = 0.026 and 1.8 nM, respectively) by nodularin, whereas PP2B was inhibited to a lesser extent (IC50 = 8.7 microM) [1].
• Nodularin had no apparent effect on PP2C, alkaline phosphatase, acid phosphatase, insulin receptor tyrosine kinase, protein kinase A, phosphorylase kinase, or protein kinase C. In a whole-cell extract of T51B liver cells, nodularin inhibited PP1 and PP2A activity with a potency similar to that seen with their purified catalytic subunits [1].
• Characterization of the nodularin synthetase gene cluster and proposed theory of the evolution of cyanobacterial hepatotoxins [13].
• Subsequently, additional microcystins and nodularin were compared with microcystin-LR on substrate specificity [14].
• As an extension of this observation, this study was undertaken to investigate the molecular mechanism of downregulation of testosterone and its effect on target organs in Fischer 344 male rats treated with the hepatotoxin nodularin [15].

Anatomical context of Nodularin

• Selective left-lobe atrophy by nodularin treatment accompanied by reduced protein phosphatase 1/2A and increased peroxisome proliferation in rat liver [16].
• Intraperitoneal injection of nodularin into rats induced cuboidal changes of glandular epithelium in ventral prostates and apoptotic changes of spermatogonium, for example, nuclear chromatin condensation, shrinkage, and detachment from Sertoli cells, which included many lysosomal granules [15].
• Orally administered nodularin levels in hepatopancreas rapidly decreased from initial 830 to 250 microg/kg dw in 96 h [17].
• Novel benthic Nodularia strains were isolated from the Baltic Sea and their morphology, the presence of gas vacuoles, nodularin production, gliding, 16S rRNA gene sequences, rpoB, rbcLX and ndaF genes, and gvpA-IGS regions were examined, as well as short tandemly repeated repetitive sequence fingerprints [18].
• Microcystins and nodularin penetrate into the epithelial cells of mouse skin and human fibroblasts with difficulty, which reflects tissue specificity of the compounds [19].

Associations of Nodularin with other chemical compounds

• Male Fischer 344 rats were injected with nodularin for 10 weeks from week 3 after N-nitrosodiethylamine initiation without partial hepatectomy [20].
• The activity of cathepsins D and L, arginine aminopeptidase, dipeptidase II and dipeptidase IV was determined in the lysosomal, microsomal, cytoplasmatic fractions and in the complete homogenate of the mouse hepatocytes following injection of microcystin-YR and nodularin [21].
• Microcystin-YR inhibited the synthesis of the studied proteases and caused a labialization of lysosomal membranes, whereas nodularin induced the synthesis of the enzymes and destabilized the reticulum endoplasmatic membranes [21].
• An ultrasensitive assay is described for microcystin-LR and other substances (microcystins, nodularin, okadaic acid, calyculin A, tautomycin) which block the active site of protein phosphatases (PP) 1 and 2A [22].
• Microcystin-LR and nodularin induce intracellular glutathione alteration, reactive oxygen species production and lipid peroxidation in primary cultured rat hepatocytes [23].

Gene context of Nodularin

• However, nodularin without DEN initiation significantly increased the PCNA index through initial cell death and subsequent hepatocyte proliferation [20].
• Suppression of IL-2 and IL-4 gene expression by nodularin through the reduced NF-AT binding activity [24].
• These results suggest that T lymphocyte is a possible cellular target of nodularin, and the inhibitory effect of nodularin on T-cell specific transcription factor NF-AT induces T-cell dysfunction, which leads to a diminution in IL-2 and IL-4 gene transcription [24].
• Three monoclonal antibodies (MC10E7, AD4G2, M8H5) directed against microcystins and protein phosphatase 1 (PP1) were used as off-line detectors for the HPLC separation of microcystins and nodularin in comparison to UV detection [25].
• However, nodularin significantly induced peroxisomal palmitoyl-CoA oxidase and cytochrome P-450 4A1 expression in S/N compared with D/N rats [16].

Analytical, diagnostic and therapeutic context of Nodularin

• Competitive RIA and direct ELISA revealed that the antibodies had good cross-reactivities with an MCYST-arginine-arginine variant (MCYST-RR), MCYST-LR, an MCYST-tyrosine-arginine variant (MCYST-YR), and nodularin (NODLN); but they had lower reactivities with variants MCYST-leucine-tyrosine (MCYST-LY) and MCYST-leucine-alanine (MCYST-LA) [26].
• Immunoassay methods currently used for microcystin and nodularin detection and analysis do not provide information on the toxicity of microcystin and/or nodularin variants [3].
• This observation has enabled the design of a specific 16S rRNA PCR for the rapid detection of nodularin-producing strains [27].
• In vivo EPR oximetry was used to monitor decreasing hepatic pO2 (approximately 2-fold from controls) 2-3 h following nodularin exposure [28].
• Surface-enhanced laser desorption ionization mass spectrometry (SELDI-TOFMS) was used to develop a new and useful method for determination and identification of the cyanobacterial (blue-green algae) toxins: microcystin and nodularin [29].

References