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Microcystin-LR (MC-LR) Triggers Inflammatory Responses in Macrophages.

ABSTRACT: We were the first to previously report that microcystin-LR (MC-LR) has limited effects within the colons of healthy mice but has toxic effects within colons of mice with pre-existing inflammatory bowel disease. In the current investigation, we aimed to elucidate the mechanism by which MC-LR exacerbates colitis and to identify effective therapeutic targets. Through our current investigation, we report that there is a significantly greater recruitment of macrophages into colonic tissue with pre-existing colitis in the presence of MC-LR than in the absence of MC-LR. This is seen quantitatively through IHC staining and the enumeration of F4/80-positive macrophages and through gene expression analysis for Cd68, Cd11b, and Cd163. Exposure of isolated macrophages to MC-LR was found to directly upregulate macrophage activation markers Tnf and Il1b. Through a high-throughput, unbiased kinase activity profiling strategy, MC-LR-induced phosphorylation events were compared with potential inhibitors, and doramapimod was found to effectively prevent MC-LR-induced inflammatory responses in macrophages.

SUBMITTER: Su RC

PROVIDER: S-EPMC8472269 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Differentially expressed genes in the livers of mice exposed to microcystin-LR (MC-LR)

Project description:To explore the molecular mechanisms involved in the toxicity in the livers exposed to MC-LR at the environmental level, the hepatic transcriptome was performed. A total of 210 genes were differentially expressed (P<0.05, |fold change|≥2) in response to MC-LR exposure; among them, 143 genes were significantly upregulated, and 67 genes were downregulated. Pathway enrichment analysis identified the top biological functions associated with the genes differentially expressed in response to MC-LR exposure, which were circadian regulation of gene expression, negative regulation of glucocorticoid receptor signaling pathway, the epoxygenase P450 pathway, regulation of insulin secretion, lipid metabolic process, and cell cycle pathway.

2020-03-25 | GSE145459 | GEO

Isolation and Characterization of Lake Erie Bacteria that Degrade the Cyanobacterial Microcystin Toxin MC-LR.

Project description:Microcystin-LR (MC-LR) is a cyclic hepatotoxin produced by cyanobacteria, including Microcystis sp. and Planktothrix sp. Harmful algal blooms (HABs) in Lake Erie have become a major human health concern in recent years, highlighted by the August 2014 city of Toledo, Ohio, municipal water "do not drink" order that affected nearly 500,000 residents for 3 days. Given that microcystin degrading bacteria have been reported from HAB-affected waters around the world, we hypothesized that MC-LR degrading bacteria could be isolated from Lake Erie. To test this hypothesis, 13 water samples were collected from various Lake Erie locations during the summers of 2014 and 2015, MC-LR was continuously added to each water sample for 3 to 5 weeks to enrich for MC-LR-degrading bacteria, and MC-LR was quantitated over time. Whereas MC-LR was relatively stable in sterile-filtered lake water, robust MC-LR degradation (up to 19 ppb/day) was observed in some water samples. Following the MC-LR selection process, 67 individual bacterial isolates were isolated from MC-LR degrading water samples and genotyped to exclude potential human pathogens, and MC-LR degradation by smaller groups of bacterial isolates (e.g., groups of 22 isolates, groups of 11 isolates, etc.) was examined. Of those smaller groups, selected groups of four to five bacterial isolates were found to degrade MC-LR into non-toxic forms and form robust biofilms on siliconized glass tubes. Taken together, these studies support the potential use of isolated bacterial isolates to remove MC-LR from drinking water.

| S-EPMC7402192 | biostudies-literature

Degradation of [Dha(7)]MC-LR by a Microcystin Degrading Bacterium Isolated from Lake Rotoiti, New Zealand.

Project description:For the first time a microcystin-degrading bacterium (NV-3 isolate) has been isolated and characterized from a NZ lake. Cyanobacterial blooms in New Zealand (NZ) waters contain microcystin (MC) hepatotoxins at concentrations which are a risk to animal and human health. Degradation of MCs by naturally occurring bacteria is an attractive bioremediation option for removing MCs from drinking and recreational water sources. The NV-3 isolate was identified by 16S rRNA sequence analysis and found to have 100% nucleotide sequence homology with the Sphingomonas MC-degrading bacterial strain MD-1 from Japan. The NV-3 isolate (concentration of 1.0 × 10(8) CFU/mL) at 30°C degraded a mixture of [Dha(7)]MC-LR and MC-LR (concentration 25 μ g/mL) at a maximum rate of 8.33 μ g/mL/day. The intermediate by-products of [Dha(7)]MC-LR degradation were detected and similar to MC-LR degradation by-products. The presence of three genes (mlrA, mlrB, and mlrC), that encode three enzymes involved in the degradation of MC-LR, were identified in the NV-3 isolate. This study confirmed that degradation of [Dha(7)]MC-LR by the Sphingomonas isolate NV-3 occurred by a similar mechanism previously described for MC-LR by Sphingomonas strain MJ-PV (ACM-3962). This has important implications for potential bioremediation of toxic blooms containing a variety of MCs in NZ waters.

| S-EPMC3712209 | biostudies-literature

Transcriptional and Behavioral Responses of Zebrafish Larvae to Microcystin-LR Exposure.

Project description:Microcystins are cyclic heptapeptides that constitute a diverse group of toxins produced by cyanobacteria. One of the most toxic variants of this family is microcystin-LR (MCLR) which is a potent inhibitor of protein phosphatase 2A (PP2A) and induces cytoskeleton alterations. In this study, zebrafish larvae exposed to 500 μg/L of MCLR for four days exhibited a 40% reduction of PP2A activity compared to the controls, indicating early effects of the toxin. Gene expression profiling of the MCLR-exposed larvae using microarray analysis revealed that keratin 96 (krt96) was the most downregulated gene, consistent with the well-documented effects of MCLR on cytoskeleton structure. In addition, our analysis revealed upregulation in all genes encoding for the enzymes of the retinal visual cycle, including rpe65a (retinal pigment epithelium-specific protein 65a), which is critical for the larval vision. Quantitative real-time PCR (qPCR) analysis confirmed the microarray data, showing that rpe65a was significantly upregulated at 50 μg/L and 500 μg/L MCLR in a dose-dependent manner. Consistent with the microarray data, MCLR-treated larvae displayed behavioral alterations such as weakening response to the sudden darkness and hypoactivity in the dark. Our work reveals new molecular targets for MCLR and provides further insights into the molecular mechanisms of MCLR toxicity during early development.

| S-EPMC5343900 | biostudies-literature

[D-Leu1]MC-LR and MC-LR: A Small-Large Difference: Significantly Different Effects on Phaseolus vulgaris L. (Fabaceae) Growth and Phototropic Response after Single Contact during Imbibition with Each of These Microcystin Variants.

Project description:[D-Leu1]MC-LR and MC-LR, two microcystins differing in one amino acid, constitute a sanitary and environmental problem owing to their frequent and concomitant presence in water bodies of the Americas and their association with human intoxication during recreational exposure to cyanobacterial bloom. Present in reservoirs used for irrigation as well, they can generate problems in the development of crops such as Phaseolus vulgaris, of nutritional and economic interest to the region. Although numerous works address the toxic effects of MC-LR, information on the toxicity of [D-Leu1]MC-LR is limited. Our objective was to study the toxic effects of [D-Leu1]MC-LR and MC-LR (3.5 µg/ml) on P. vulgaris after a single contact at the imbibition stage. Our findings indicate that 10 days post treatment, [D-Leu1]MC-LR generates morphological and physiological alterations more pronounced than those caused by MC-LR. In addition to the alterations produced by [D-Leu1]MC-LR in the development of seedlings and the structure of the leaves, roots and stems, we also found alterations in leaf stomatal density and conductivity, a longer delay in the phototropic response and a decrease in the maximum curvature angles achieved with respect to that observed for MC-LR. Our findings indicate that these alterations are linked to the greater inhibition of phosphatase activity generated by [D-Leu1]MC-LR, rather than to oxidative damage. We observed that 30 days after treatment with MC-LR, plants presented better development and recovery than those treated with [D-Leu1]MC-LR. Further studies are required on [D-Leu1]MC-LR and MC-LR toxicity and their underlying mechanisms of action.

| S-EPMC7551030 | biostudies-literature

Microarray Analysis of Microcystin-LR

2014-07-25 | GSE59495 | GEO

Microarray Analysis of Microcystin-LR

Project description:Microcystins are produced by the cyanobacteria, most commonly Microcystis aerµginosa. Upon ingestion, toxic microcystins are actively absorbed by fish, birds and mammals where they are primarily liver toxins. Groups of 4-6 rats were exposed to 0, 1, 10, 50 or 100 µg/kg microcystin-LR for 0.5, 1, 3 or 6 hours and gene expression analysis performed on liver with samples hybridized to whole rat genome RG230_2.0 GeneChip arrays (Affymetrix, CA).

2014-07-25 | E-GEOD-59495 | biostudies-arrayexpress

Transcriptional and Behavioral Responses of Zebrafish Larvae to Microcystin-LR Exposure

Project description:Microcystin-LR (MC-LR), the most toxic member of microcystin family, inhibits protein phosphatase PP2A, triggers oxidative stress and induces hepatotoxicity. Gene expression profiling of MC-LR treated larvae using DNA microarray analysis revealed effects in the retinal visual cycle and pigmentation synthesis pathways that have not been previously associated with MC-LR. Liver-related genes were also differentially expressed. The microarray data were confirmed by quantitative real-time PCR. Our findings provide new evidence that microcystin-LR exposure of zebrafish larvae modulates the retinal visual cycle and pigmentation synthesis pathways and ultimately alter larval zebrafish behavior

2017-02-16 | GSE73739 | GEO

Podophyllotoxin and Rutin Modulate M1 (iNOS+) Macrophages and Mitigate Lethal Radiation (LR) Induced Inflammatory Responses in Mice.

Project description:Accidental exposure to lethal doses of Gamma radiation leads to the systemic inflammatory syndrome which causes mortality. In view of this, management of hemopoietic syndrome by modulating pro-inflammatory response in clinically manageable time period seems to be the most appropriate strategy for encountering radiation induced damage and recovery. As both tissue and peripheral macrophages are critical for the management of radiation induced injuries, we have unraveled the immunomodulatory potential of radioprotective formulation (G-003M) on peripheral macrophages populations in this study. G-003M inhibited lethal radiation induced NO and Th1 effector cytokines in the exposed macrophages indicating its M1 dim polarizing capacity. In similar lines, conditioning of mice with G-003M before lethal irradiation (LR) inhibited LR induced titre of Th1 effector cytokines in both serums as well as in lung, small intestine, and spleen tissue confirming its immunomodulatory potential. G-003M potentially down modulated inflammatory response in LPS induced inflammatory model and enhanced M2 polarization of iNOS+ M1 effector macrophages providing a molecular hint on G-003M mechanism of action on macrophages. These observations revealed that G-003M potentially modulate pro-inflammatory programming of macrophages and mitigate radiation-induced inflammatory stress which is believed to contribute significantly to radioprotective attribute of G-003M. In this study, we demonstrate that Rutin and Podophyllotoxin drive M1dim/M2 polarization of LR primed macrophages apart from protecting DNA from radiation. These drugs have the capacity to programme innate immune cells like macrophages which may be involved in homeostasis during recovery.

| S-EPMC6379314 | biostudies-literature

Proteasome as a Molecular Target of Microcystin-LR.

Project description:Proteasome degrades proteins in eukaryotic cells. As such, the proteasome is crucial in cell cycle and function. This study proved that microcystin-LR (MC-LR), which is a toxic by-product of algal bloom, can target cellular proteasome and selectively inhibit proteasome trypsin-like (TL) activity. MC-LR at 1 nM can inhibit up to 54% of the purified 20S proteasome TL activity and 43% of the proteasome TL activity in the liver of the cyprinid rare minnow (Gobiocypris rarus). Protein degradation was retarded in GFP-CL1-transfected PC-3 cells because MC-LR inhibited the proteasome TL activity. Docking studies indicated that MC-LR blocked the active site of the proteasome β2 subunit; thus, the proteasome TL activity was inhibited. In conclusion, MC-LR can target proteasome, selectively inhibit proteasome TL activity, and retard protein degradation. This study may be used as a reference of future research on the toxic mechanism of MC-LR.

| S-EPMC4488699 | biostudies-literature

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