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1.
Toxins (Basel) ; 14(12)2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-36548732

RESUMEN

Epidemiological studies have reported a strong association between liver injury and incidences of hepatocellular carcinoma in sections of humans globally. Several preclinical studies have shown a strong link between cyanotoxin exposure and the development of nonalcoholic steatohepatitis, a precursor of hepatocellular carcinoma. Among the emerging threats from cyanotoxins, new evidence shows cylindrospermopsin release in freshwater lakes. A known hepatotoxin in higher concentrations, we examined the possible role of cylindrospermopsin in causing host gut dysbiosis and its association with liver pathology in a mouse model of toxico-pharmacokinetics and hepatic pathology. The results showed that oral exposure to cylindrospermopsin caused decreased diversity of gut bacteria phyla accompanied by an increased abundance of Clostridioides difficile and decreased abundance of probiotic flora such as Roseburia, Akkermanssia, and Bacteroides thetaiotamicron, a signature most often associated with intestinal and hepatic pathology and underlying gastrointestinal disease. The altered gut dysbiosis was also associated with increased Claudin2 protein in the intestinal lumen, a marker of gut leaching and endotoxemia. The study of liver pathology showed marked liver inflammation, the release of damage-associated molecular patterns, and activation of toll-like receptors, a hallmark of consistent and progressive liver damage. Hepatic pathology was also linked to increased Kupffer cell activation and stellate cell activation, markers of progressive liver damage often linked to the development of liver fibrosis and carcinoma. In conclusion, the present study provides additional evidence of cylindrospermopsin-linked progressive liver pathology that may be very well-linked to gut dysbiosis, though definitive evidence involving this link needs to be studied further.


Asunto(s)
Carcinoma Hepatocelular , Microbioma Gastrointestinal , Neoplasias Hepáticas , Animales , Ratones , Humanos , Carcinoma Hepatocelular/metabolismo , Macrófagos del Hígado/metabolismo , Macrófagos del Hígado/patología , Microbioma Gastrointestinal/fisiología , Disbiosis , Hígado/metabolismo , Cirrosis Hepática/patología , Neoplasias Hepáticas/metabolismo , Inflamación/metabolismo
2.
Sci Rep ; 12(1): 11516, 2022 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-35799048

RESUMEN

A strong association between exposure to the common harmful algal bloom toxin microcystin and the altered host gut microbiome has been shown. We tested the hypothesis that prior exposure to the cyanotoxin microcystin-LR may alter the host resistome. We show that the mice exposed to microcystin-LR had an altered microbiome signature that harbored antibiotic resistance genes. Host resistome genotypes such as mefA, msrD, mel, ant6, and tet40 increased in diversity and relative abundance following microcystin-LR exposure. Interestingly, the increased abundance of these genes was traced to resistance to common antibiotics such as tetracycline, macrolides, glycopeptide, and aminoglycosides, crucial for modern-day treatment of several diseases. Increased abundance of these genes was positively associated with increased expression of PD1, a T-cell homeostasis marker, and pleiotropic inflammatory cytokine IL-6 with a concomitant negative association with immunosurveillance markers IL-7 and TLR2. Microcystin-LR exposure also caused decreased TLR2, TLR4, and REG3G expressions, increased immunosenescence, and higher systemic levels of IL-6 in both wild-type and humanized mice. In conclusion, the results show a first-ever characterization of the host resistome following microcystin-LR exposure and its connection to host immune status and antimicrobial resistance that can be crucial to understand treatment options with antibiotics in microcystin-exposed subjects in clinical settings.


Asunto(s)
Microbioma Gastrointestinal , Inmunosenescencia , Microcistinas , Animales , Antibacterianos/farmacología , Farmacorresistencia Bacteriana , Homeostasis , Interleucina-6 , Ratones , Microcistinas/toxicidad , Receptor Toll-Like 2
3.
Toxicology ; 461: 152901, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34416350

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) has been shown to be associated with extrahepatic comorbidities including neuronal inflammation and Alzheimer's-like pathology. Environmental and genetic factors also act as a second hit to modulate severity and are expected to enhance the NAFLD-linked neuropathology. We hypothezied that environmental microcystin-LR (MC-LR), a toxin produced by harmful algal blooms of cyanobacteria, exacerbates the neuroinflammation and degeneration of neurons associated with NAFLD. Using a mouse model of NAFLD, exposed to MC-LR subsequent to the onset of fatty liver, we show that the cyanotoxin could significantly increase proinflammatory cytokine expression in the frontal cortex and cause increased expression of Lcn2 and HMGB1. The above effects were NLRP3 inflammasome activation-dependent since the use of NLRP3 knockout mice abrogated the increase in inflammation. NLRP3 was also responsible for decreased expression of the blood-brain barrier (BBB) tight junction proteins Occludin and Claudin 5 suggesting BBB dysfunction was parallel to neuroinflammation following microcystin exposure. An increased circulatory S100B release, a hallmark of astrocyte activation in MC-LR exposed NAFLD mice also confirmed BBB integrity loss, but the astrocyte activation observed in vivo was NLRP3 independent suggesting an important role of a secondary S100B mediated crosstalk. Mechanistically, conditioned medium from reactive astrocytes and parallel S100B incubation in neuronal cells caused increased inducible NOS, COX-2, and higher BAX/ Bcl2 protein expression suggesting oxidative stress-mediated neuronal cell apoptosis crucial for neurodegeneration. Taken together, MC-LR exacerbated neuronal NAFLD-linked comorbidities leading to cortical inflammation, BBB dysfunction, and neuronal apoptosis.


Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Toxinas Marinas/toxicidad , Microcistinas/toxicidad , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Animales , Apoptosis/efectos de los fármacos , Barrera Hematoencefálica/patología , Modelos Animales de Enfermedad , Exposición a Riesgos Ambientales/efectos adversos , Inflamasomas/metabolismo , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedades Neuroinflamatorias/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismo
4.
Artículo en Inglés | MEDLINE | ID: mdl-32781293

RESUMEN

Clinical studies implicated an increased risk of intestinal fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Our previous studies have shown that microcystin-LR (MC-LR) exposure led to altered gut microbiome and increased abundance of lactate producing bacteria and intestinal inflammation in underlying NAFLD. This led us to further investigate the effects of the MC-LR, a PP2A inhibitor in activating the TGF-ß fibrotic pathway in the intestines that might be mediated by increased lactate induced redox enzyme NOX2. Exposure to MC-LR led to higher lactate levels in circulation and in the intestinal content. The higher lactate levels were associated with NOX2 activation in vivo that led to increased Smad2/3-Smad4 co-localization and high alpha-smooth muscle actin (α-SMA) immunoreactivity in the intestines. Mechanistically, primary mouse intestinal epithelial cells treated with lactate and MC-LR separately led to higher NOX2 activation, phosphorylation of TGFßR1 receptor and subsequent Smad 2/3-Smad4 co-localization inhibitable by apocynin (NOX2 inhibitor), FBA (a peroxynitrite scavenger) and DMPO (a nitrone spin trap), catalase and superoxide dismutase. Inhibition of NOX2-induced redox signaling also showed a significant decrease in collagen protein thus suggesting a strong redox signaling induced activation of an ectopic fibrotic manifestation in the intestines. In conclusion, the present study provides mechanistic insight into the role of microcystin in dysbiosis-linked lactate production and subsequently advances our knowledge in lactate-induced NOX2 exacerbation of the cell differentiation and fibrosis in the NAFLD intestines.


Asunto(s)
Fibrosis/patología , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Ácido Láctico/metabolismo , Microcistinas/toxicidad , NADPH Oxidasa 2/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Línea Celular , Inhibidores Enzimáticos/toxicidad , Fibrosis/enzimología , Fibrosis/etiología , Mucosa Intestinal/efectos de los fármacos , Intestinos/enzimología , Intestinos/patología , Ácido Láctico/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , NADPH Oxidasa 2/antagonistas & inhibidores , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/enzimología , Enfermedad del Hígado Graso no Alcohólico/patología , Fosforilación
5.
Environ Toxicol Pharmacol ; 80: 103457, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32687983

RESUMEN

Evidence from pediatric studies show that infants and children are at risk for early exposure to microcystin. The present report tests the hypothesis that early life exposure to microcystin (MC), a principal component of harmful algal blooms followed by a juvenile exposure to high-fat diet feeding potentiate the development of nonalcoholic fatty liver disease phenotype in adulthood. Results showed classical symptoms of early NAFLD linked inflammation. Cytokines and chemokines such as CD68, IL-1ß, MCP-1, and TNF-α, as well as α-SMA were increased in the groups that were exposed to MC-LR with the high-fat diet compared to the vehicle group. Also, mechanistically, NLRP3 KO mice showed a significant decrease in the inflammation and NAFLD phenotype and resisted the metabolic changes such as insulin resistance and glucose metabolism in the liver. The data suggested that MC-LR exposure and subsequent NLRP3 inflammasome activation in childhood could impact liver health in juveniles.


Asunto(s)
Inflamasomas/metabolismo , Resistencia a la Insulina , Toxinas Marinas/toxicidad , Microcistinas/toxicidad , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Contaminantes Químicos del Agua/toxicidad , Animales , Dieta Alta en Grasa/efectos adversos , Hígado/efectos de los fármacos , Hígado/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/metabolismo
6.
Environ Toxicol Pharmacol ; 73: 103281, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31706246

RESUMEN

NAFLD often results in cardiovascular, intestinal and renal complications. Previous reports from our laboratory highlighted NAFLD induced ectopic inflammatory manifestations in the kidney that gave rise to glomerular inflammation. Extending our studies, we hypothesized that existing inflammatory conditions in NAFLD could make the kidneys more susceptible to environmental toxicity. Our results showed that exposure of Microcystin-LR (MC) in NAFLD mice caused a marked increase in cellular scarring with a concomitant increase in mesangial cell activation as observed by increased α-SMA in the extracellular matrix surrounding the glomeruli. Renal tissue surrounding the glomeruli also showed increased NOX2 activation as shown by greater co-localization of p47 Phox and its membrane component gp91Phox both in the mesangial cell and surrounding tissue. Mechanistically, mesangial cells incubated with apocynin, nitrone spin trap DMPO and miR21 inhibitor showed significantly decreased α-SMA, miR21 levels and proinflammatory cytokine release in the supernatant. In parallel, mice lacking miR21, known to be activated by NOX2, when exposed to MC in NAFLD showed decreased mesangial cell activation. Strikingly, phenyl boronic acid incubated cells that were exposed to MC showed significantly decreased mesangial cell activation showing that peroxynitrite might be the major reactive species involved in mediation of the activation process, release of proinflammatory micro RNAs and cytokines that are crucial for renal toxicity. Thus, in conclusion, MC exposure causes NOX2 activation that leads to mesangial cell activation and toxicity via release of peroxynitrite that also represses PTEN by the upregulation of miR21 thus amplifying the toxicity.


Asunto(s)
Microcistinas/toxicidad , Enfermedad del Hígado Graso no Alcohólico , Contaminantes Químicos del Agua/toxicidad , Animales , Inflamación , Riñón/efectos de los fármacos , Riñón/metabolismo , Enfermedades Renales , Ratones , MicroARNs , Transducción de Señal
7.
Am J Physiol Gastrointest Liver Physiol ; 317(4): G408-G428, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31393787

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is an emerging global pandemic. Though significant progress has been made in unraveling the pathophysiology of the disease, the role of protein phosphatase 2A (PP2A) and its subsequent inhibition by environmental and genetic factors in NAFLD pathophysiology remains unclear. The present report tests the hypothesis that an exogenous PP2A inhibitor leads to hepatic inflammation and fibrogenesis via an NADPH oxidase 2 (NOX2)-dependent pathway in NAFLD. Results showed that microcystin (MC) administration, a potent PP2A inhibitor found in environmental exposure, led to an exacerbation of NAFLD pathology with increased CD68 immunoreactivity, the release of proinflammatory cytokines, and stellate cell activation, a process that was attenuated in mice that lacked the p47phox gene and miR21 knockout mice. Mechanistically, leptin-primed immortalized Kupffer cells (a mimicked model for an NAFLD condition) treated with apocynin or nitrone spin trap 5,5 dimethyl-1- pyrroline N-oxide (DMPO) had significantly decreased CD68 and decreased miR21 and α-smooth muscle actin levels, suggesting the role of NOX2-dependent reactive oxygen species in miR21-induced Kupffer cell activation and stellate cell pathology. Furthermore, NOX2-dependent peroxynitrite generation was primarily responsible for cellular events observed following MC exposure since incubation with phenylboronic acid attenuated miR21 levels, Kupffer cell activation, and inflammatory cytokine release. Furthermore, blocking of the AKT pathway attenuated PP2A inhibitor-induced NOX2 activation and miR21 upregulation. Taken together, we show that PP2A may have protective roles, and its inhibition exacerbates NAFLD pathology via activating NOX2-dependent peroxynitrite generation, thus increasing miR21-induced pathology.NEW & NOTEWORTHY Protein phosphatase 2A inhibition causes nonalcoholic steatohepatitis (NASH) progression via NADPH oxidase 2. In addition to a novel emchanism of action, we describe a new tool to describe NASH histopathology.


Asunto(s)
Inhibidores Enzimáticos/toxicidad , MicroARNs/metabolismo , NADPH Oxidasa 2/metabolismo , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Proteína Fosfatasa 2/antagonistas & inhibidores , Animales , Antígenos CD/biosíntesis , Antígenos de Diferenciación Mielomonocítica/biosíntesis , Citocinas/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Macrófagos del Hígado/efectos de los fármacos , Macrófagos del Hígado/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/genética , Microcistinas/toxicidad , NADPH Oxidasa 2/genética , NADPH Oxidasas/metabolismo , Ácido Peroxinitroso/metabolismo
8.
Sci Rep ; 9(1): 8742, 2019 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-31217465

RESUMEN

With increased climate change pressures likely to influence harmful algal blooms, exposure to microcystin, a known hepatotoxin and a byproduct of cyanobacterial blooms can be a risk factor for NAFLD associated comorbidities. Using both in vivo and in vitro experiments we show that microcystin exposure in NAFLD mice cause rapid alteration of gut microbiome, rise in bacterial genus known for mediating gut inflammation and lactate production. Changes in the microbiome were strongly associated with inflammatory pathology in the intestine, gut leaching, tight junction protein alterations and increased oxidative tyrosyl radicals. Increased lactate producing bacteria from the altered microbiome was associated with increased NOX-2, an NADPH oxidase isoform. Activationof NOX2 caused inflammasome activation as shown by NLRP3/ASCII and NLRP3/Casp-1 colocalizations in these cells while use of mice lacking a crucial NOX2 component attenuated inflammatory pathology and redox changes. Mechanistically, NOX2 mediated peroxynitrite species were primary to inflammasome activation and release of inflammatory mediators. Thus, in conclusion, microcystin exposure in NAFLD could significantly alter intestinal pathology especially by the effects on microbiome and resultant redox status thus advancing our understanding of the co-existence of NAFLD-linked inflammatory bowel disease phenotypes in the clinic.


Asunto(s)
Exposición a Riesgos Ambientales/efectos adversos , Microbioma Gastrointestinal/efectos de los fármacos , Enfermedades Intestinales , Microcistinas/administración & dosificación , NADPH Oxidasa 2/metabolismo , Enfermedad del Hígado Graso no Alcohólico , Animales , Modelos Animales de Enfermedad , Inflamación/inducido químicamente , Inflamación/enzimología , Inflamación/microbiología , Inflamación/patología , Enfermedades Intestinales/inducido químicamente , Enfermedades Intestinales/enzimología , Enfermedades Intestinales/microbiología , Enfermedades Intestinales/patología , Masculino , Ratones , Ratones Noqueados , Microcistinas/farmacología , Enfermedad del Hígado Graso no Alcohólico/enzimología , Enfermedad del Hígado Graso no Alcohólico/microbiología , Enfermedad del Hígado Graso no Alcohólico/patología
9.
Appl Environ Microbiol ; 72(2): 1226-30, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16461670

RESUMEN

Typing of F-specific RNA (FRNA) coliphages has been proposed as a useful method for distinguishing human from animal fecal contamination in environmental samples. Group II and III FRNA coliphages are generally associated with human wastes, but several exceptions have been noted. In the present study, we have genotyped and partially sequenced group III FRNA coliphage field isolates from swine lagoons in North Carolina (NC) and South Carolina (SC), along with isolates from surface waters and municipal wastewaters. Phylogenetic analysis of a region of the 5' end of the maturation protein gene revealed two genetically different group III FRNA subclusters with 36.6% sequence variation. The SC swine lagoon isolates were more closely related to group III prototype virus M11, whereas the isolates from a swine lagoon in NC, surface waters, and wastewaters grouped with prototype virus Q-beta. These results suggest that refining phage genotyping systems to discriminate M11-like phages from Q-beta-like phages would not necessarily provide greater discriminatory power in distinguishing human from animal sources of pollution. Within the group III subclusters, nucleotide sequence diversity ranged from 0% to 6.9% for M11-like strains and from 0% to 8.7% for Q-beta-like strains. It is demonstrated here that nucleotide sequencing of closely related FRNA strains can be used to help track sources of contamination in surface waters. A similar use of phage genomic sequence information to track fecal pollution promises more reliable results than phage typing by nucleic acid hybridization and may hold more potential for field applications.


Asunto(s)
Colifagos/genética , Colifagos/aislamiento & purificación , Heces/virología , Fagos ARN/genética , Fagos ARN/aislamiento & purificación , Sus scrofa/virología , Microbiología del Agua , Animales , Secuencia de Bases , Colifagos/clasificación , ADN Viral/genética , Variación Genética , Humanos , Datos de Secuencia Molecular , North Carolina , Filogenia , Fagos ARN/clasificación , Aguas del Alcantarillado , South Carolina , Eliminación de Residuos Líquidos , Contaminación del Agua
10.
Sci Total Environ ; 284(1-3): 249-61, 2002 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-11846169

RESUMEN

The objective of this study was to determine inorganic and organic contaminant concentrations in edible tissue of fish collected from eight coastal areas receiving wastewater discharges and from two reference locations. Trace metal residues were statistically similar regardless of the collection site. Zinc (100% detection in all samples), total mercury (100%), total arsenic (92%), copper (92%), and selenium (88%) were the more commonly detected trace metals. Mercury concentrations exceeded the Florida health-based standard of 0.5 microg/g for limited fish consumption in 30% of the total samples and averaged 0.40 (+/- 1 S.D. = 0.22, range < or = 0.08 to 0.85) microg/g wet weight. The average total PAH concentrations were 1.79 (+/- 1.60) ng/g (reference areas) and 2.17 (+/- 3.29) ng/g (wastewater-impacted areas). Pyrene was detected most frequently (63% of the total samples) and averaged 0.74 (+/- 0.35) ng/g wet wt. The average total PCB concentrations were 4.8 (+/- 7.1) ng/g (reference areas) and 31.6 (+/- 31.3) ng/g (wastewater-impacted areas) Concentrations of dieldrin and cis-chlordane were approximately eight times greater, respectively, in fish collected from wastewater receiving waters, whereas total DDT and total pesticide concentrations were not elevated in the same areas. Concentrations of total PCBs and all chlorinated pesticides were below US health-based standards. The lack of a published reference data base for fish tissue quality in near-coastal areas of the Gulf of Mexico restricts an assessment of the environmental significance of results from this and similar studies investigating the fate of point source contaminants.


Asunto(s)
DDT/análisis , Peces , Insecticidas/análisis , Metales Pesados/análisis , Hidrocarburos Policíclicos Aromáticos/análisis , Contaminantes Químicos del Agua/análisis , Animales , Exposición a Riesgos Ambientales , México , Distribución Tisular , Estados Unidos , Eliminación de Residuos Líquidos , Movimientos del Agua
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