RESUMEN
Dechlorane 602 (Dec 602) has biomagnification potential. Our previous studies suggested that exposure to Dec 602 for 7 days induced colonic inflammation even after 7 days of recovery. To shed some light on the underlying mechanisms, disturbances of gut immunity and gene expression were further studied. Adult C57BL/6 mice were administered orally with Dec 602 for 7 days, then allowed to recover for another 7 days. Colonic type 3 innate lymphoid cells (ILC3s) in lamina propria lymphocytes (LPLs) and lymphocytes in mesenteric lymph nodes (MLNs) were examined by flow cytometry. Expressions of genes in the gut were determined by RNA-Seq. It was found that Dec 602 exposure up-regulated the percentage of CD4+ T cells in MLNs. The mean fluorescent intensity (MFI) of interleukin (IL)- 22 in LPLs was decreased, while the MFI of IL-17a as well as the percentage of IL-17a+ ILC3s in LPLs were increased after exposure to Dec 602. Genes involved in the formation of blood vessels and epithelial-mesenchymal transition were up-regulated by Dec 602. Ingenuity pathway analysis of differentially expressed genes predicted that exposure to Dec 602 resulted in the activation of liver X receptor/retinoid X receptor (LXR/RXR) and suppression of muscle contractility. Our results, on one hand, verified that the toxic effects of Dec 602 on gut immunity could last for at least 14 days, and on the other hand, these results predicted other adverse effects of Dec 602, such as muscle dysfunction. Overall, our studies provided insights for the further investigation of Dec 602 and other emerging environmental pollutants.
Asunto(s)
Hidrocarburos Clorados , Interleucina-17 , Linfocitos , Compuestos Policíclicos , Animales , Ratones , Interleucina-17/metabolismo , Inmunidad Innata , Ratones Endogámicos C57BL , Expresión GénicaRESUMEN
Bisphenols are common chemicals found in plastics and epoxy resins. Over the past decades, many studies have shown that bisphenol A (BPA) is a potential endocrine-disrupting chemical that may cause multisystem toxicity. However, the relative safety of BPA analogues is a controversial subject. Herein, we conducted a review of the reproductive toxicity, neurotoxicity, immunotoxicity, metabolic toxicity and gut microbiome toxicity of the BPA analogues in various species, including Caenorhabditis elegans, zebrafish, turtles, sheep, rodents, and humans. In addition, the mechanisms of action were discussed with focus on bisphenol S and bisphenol F. It was found that these BPA analogues exert their toxic effects on different organs and systems through various mechanisms including epigenetic modifications and effects on cell signaling pathways, microbiome, and metabolome in different species. More research is needed to study the relative toxicity of the lesser-known BPA analogues compared to BPA, both systemically and organ specifically, and to better define the underlying mechanisms of action, in particular, the potentials of disrupting microbiome and metabolism.
Asunto(s)
Compuestos de Bencidrilo/toxicidad , Sistema Inmunológico/efectos de los fármacos , Fenoles/toxicidad , Animales , Disruptores Endocrinos , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Reproducción/efectos de los fármacos , Ovinos , Sulfonas , Pez CebraRESUMEN
The healthy and diverse microbes living in our gut provide numerous benefits to our health. It is increasingly recognized that the gut microbiome affects the host's neurobehavioral state through production of metabolites, modulation of intestinal immunity (e.g., cytokines) and other mechanisms (e.g., gut neuropeptides). By sending the sensed information (e.g., metabolic and immunologic mediators) about the state of the inner organs to the brain via afferent fibers, the vagus nerve maintains one of the connections between the brain and GI tract, and oversees many critical bodily functions (e.g., mood, immune response, digestion and heart rate). The microbiota-gut-brain axis is a bidirectional communication between the gut, its microbiome, and the nervous system. In the present review, the roles of microbiome in neuroendocrine and neuroimmune interactions have been discussed using naturally occurring isoflavones, particularly the phytoestrogen genistein, as there are sex differences in the interactions among the microbiome, hormones, immunity and disease susceptibility. A deep understanding of the mechanisms underlying the interactions among the endocrine modulators, brain, endocrine glands, gut immune cells, vagus nerve, enteric nervous system and gut microbiome will provide important knowledges that may ultimately lead to treatment and prevention of debilitating disorders characterized by deficits of microbiome-neuroendocrine-neuroimmune relationships.
Asunto(s)
Microbioma Gastrointestinal/efectos de los fármacos , Genisteína/farmacología , Animales , Tracto Gastrointestinal/fisiología , Humanos , Neuroinmunomodulación/efectos de los fármacos , Sistemas NeurosecretoresRESUMEN
Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic ß-cell destruction can be mediated by dysbiosis, infiltration of pro-inflammatory immune cells, and cytokines/chemokines. Exposure to bisphenol A (BPA), an endocrine disruptor (ED), can lead to aberrant immunity and gut microbiota. We determined whether BPA had age-dependent effects on T1D by modulating immune homeostasis following various windows of exposure in non-obese diabetic (NOD) mice. Juvenile NOD females were orally exposed to 0 or 30 µg BPA/kg BW from postnatal day (PND) 28 to PND56. Adult NOD females were exposed to 0 or 300 µg BPA/kg BW. Female and male NOD offspring were exposed to 0 or 300 µg BPA/kg BW perinatally from gestation day 5 to PND28 by dosing the dams. It was found that BPA increased T1D risk in juvenile females with gut microbiota shifted towards pro-inflammation (e.g. increased Jeotgalicoccus). In agreement with our previous study, adult females had a trend of increased T1D and a general increase in immune responses. However, female offspring had a reduced T1D development. Consistently, female offspring had a shift towards anti-inflammation (e.g. decreased pro-inflammatory F4/80+Gr1+ cells). In contrast, BPA had minimal effects on immunity and T1D in male offspring. Thus, it was concluded that BPA had age- and sex-dependent effects on T1D with the alteration of gut microbiota and inflammation being the primary mechanisms for T1D exacerbation in juvenile exposure and decreases of inflammation being responsible for attenuated T1D in perinatally exposed females.
Asunto(s)
Envejecimiento/efectos de los fármacos , Compuestos de Bencidrilo/toxicidad , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Tipo 1/inducido químicamente , Disruptores Endocrinos/toxicidad , Fenoles/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Caracteres Sexuales , Envejecimiento/inmunología , Animales , Compuestos de Bencidrilo/administración & dosificación , Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Experimental/microbiología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/microbiología , Disruptores Endocrinos/administración & dosificación , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/inmunología , Edad Gestacional , Masculino , Ratones Endogámicos NOD , Fenoles/administración & dosificación , Embarazo , Efectos Tardíos de la Exposición Prenatal/inmunología , Efectos Tardíos de la Exposición Prenatal/microbiologíaRESUMEN
Type 1 diabetes (T1D) is an autoimmune disease caused by immune-mediated pancreatic ß-cell destruction. The endocrine disrupting chemical bisphenol A (BPA) has widespread human exposure and can modulate immune function and the gut microbiome (GMB), which may contribute to the increasing T1D incidence worldwide. It was hypothesized that BPA had sex-dependent effects on T1D by modulating immune homeostasis and GMB. Adult female and male non-obese diabetic (NOD) mice were orally administered BPA at environmentally relevant doses (30 or 300 µg/kg). Antibiotic-treated adult NOD females were exposed to 0 or 30 µg/kg BPA. BPA accelerated T1D development in females, but delayed males from T1D. Consistently, females had a shift towards pro-inflammation (e.g., increased macrophages and Bacteroidetes), while males had increases in anti-inflammatory immune factors and a decrease in both anti- and pro-inflammatory GMB. Although bacteria altered during sub-acute BPA exposure differed from bacteria altered from chronic BPA exposure in both sexes, the GMB profile was consistently pro-inflammatory in females, while males had a general decrease of both anti- and pro-inflammatory gut microbes. However, treatment of females with the antibiotic vancomycin failed to prevent BPA-induced glucose intolerance, suggesting changes in Gram-positive bacteria were not a primary mechanism. In conclusion, BPA exposure was found to have sex dimorphic effects on T1D with detrimental effects in females, and immunomodulation was identified as the primary mechanism.
Asunto(s)
Compuestos de Bencidrilo/toxicidad , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Tipo 1/inducido químicamente , Disruptores Endocrinos/toxicidad , Fenoles/toxicidad , Caracteres Sexuales , Animales , Citocinas/sangre , Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Femenino , Prueba de Tolerancia a la Glucosa , Inmunoglobulina G/sangre , Resistencia a la Insulina , Masculino , Ratones , Ratones Endogámicos NOD , Especificidad de Órganos , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/patologíaRESUMEN
Although studies have linked soy phytoestrogen 4,7,4-trihydroxyisoflavone genistein (GEN) to reduced type 1 diabetes (T1D) risk, the mechanism of dietary GEN on T1D remains unknown. In our studies, adult non-obese diabetic (NOD) mouse model was employed to investigate the effects of GEN exposure on blood glucose level (BGL), glucose tolerance, gut microbiome, and immune responses. Adult male and female NOD mice were fed with either soy-based or casein-based diet, and received GEN at 20mg/kg body weight by gavage daily. The BGL and immune responses (represented by serum antibodies, cytokines and chemokines, and histopathology) were monitored, while the fecal gut microbiome was sequenced for 16S ribosomal RNA to reveal any alterations in gut microbial communities. A significantly reduced BGL was found in NOD males fed with soy-based diet on day 98 after initial dosing, and an improved glucose tolerance was observed on both diets. In addition, an anti-inflammatory response (suggested by reduced IgG2b and cytokine/chemokine levels, and alterations in the microbial taxonomy) was accompanied by an altered ß-diversity in gut microbial species. Among the NOD females exposed to GEN, a later onset of T1D was observed. However, the profiles of gut microbiome, antibodies and cytokines/chemokines were all indicative of pro-inflammation. This study demonstrated an association among GEN exposure, gut microbiome alteration, and immune homeostasis in NOD males. Although the mechanisms underlying the protective effects of GEN in NOD mice need to be explored further, the current study suggested a GEN-induced sex-specific effect in inflammatory status and gut microbiome.
Asunto(s)
Microbioma Gastrointestinal , Genisteína/farmacología , Intolerancia a la Glucosa/tratamiento farmacológico , Hiperglucemia/prevención & control , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/prevención & control , Heces/química , Heces/microbiología , Femenino , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/microbiología , Homeostasis/efectos de los fármacos , Insulina/sangre , Masculino , Ratones , Ratones Endogámicos NOD , Fitoestrógenos/farmacología , Análisis de Secuencia de ADNRESUMEN
Antimicrobial peptides are promising anti-infective agent candidates because they have a broad antimicrobial spectrum and bioactivity and are unlikely to elicit antibiotic resistance. The bogorols represent a new cationic antibiotic peptide and possess great therapeutic potential because of their bioactivity and precise mode of action. Here, we report that Bogorol B-JX (BBJX), a peptide previously isolated from Brevibacillus laterosporus JX-5 by us, has significant antibacterial and antitumor activities in vitro. BBJX was found to inhibit methicillin-resistant Staphylococcus aureus (MRSA) at 2.5 µg/mL with distinct mechanisms of action from those against Bacillus bombyseptieus and Escherichia coli. It penetrates MRSA membrane with little visible destruction and binds to genomic DNA. BBJX could inhibit the proliferation of human histiocytic lymphoma cell line U-937 and ConA-activated spleen cells at 5 µg/mL, but was not cytotoxic to the Jurkat cells, resting spleen cells or differentiated macrophage-like U-937 immunocytes. Moreover, BBJX caused apoptosis of U-937 cells by opening the mitochondrial permeability transition pore and stimulating the production of reactive oxygen species. Taken together, these studies provided basis for future medical application of the bogorols.
Asunto(s)
Antibacterianos/aislamiento & purificación , Antineoplásicos/aislamiento & purificación , Proteínas Bacterianas/aislamiento & purificación , Brevibacillus/química , Antibacterianos/farmacología , Antineoplásicos/farmacología , Bacillus/efectos de los fármacos , Proteínas Bacterianas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Humanos , Células Jurkat , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Péptidos/aislamiento & purificación , Péptidos/farmacologíaRESUMEN
An increasing body of evidence has shown the important role of the gut microbiome in mediating toxicity following environmental contaminant exposure. The goal of this study was to determine if the adverse metabolic effects of chronic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure would be sufficient to exacerbate hyperglycemia, and to further determine if these outcomes were attributable to the gut microbiota alteration. Adult male CD-1 mice were exposed to TCDD (6µg/kg body weight biweekly) by gavage and injected (i.p.) with STZ (4×50mg/kg body weight) to induced hyperglycemia. 16S rRNA sequencing was used to characterize the changes in the microbiome community composition. Glucose monitoring, flow cytometry, histopathology, and organ characterization were performed to determine the deleterious phenotypic changes of TCDD exposure. Chronic TCDD treatment did not appear to exacerbate STZ-induced hyperglycemia as blood glucose levels were slightly reduced in the TCDD treated mice; however, polydipsia and polyphagia were observed. Importantly, TCDD exposure caused a dramatic change in microbiota structure, as characterized at the phylum level by increasing Firmicutes and decreasing Bacteroidetes while at the family level most notably by increasing Lactobacillaceae and Desulfovibrionaceae, and decreasing Prevotellaceae and ACK M1. The changes in microbiota were further found to be broadly associated with phenotypic changes seen from chronic TCDD treatment. In particular, the phylum level Bacteroidetes to Firmicutes ratio negatively correlated with both liver weight and liver pathology, and positively associated with %CD3(+)NK(+) T cells, a key mediator of host-microbial interactions. Collectively, these findings suggest that the dysregulated gut microbiome may contribute to the deleterious effects (e.g., liver toxicity) seen with TCDD exposure.
Asunto(s)
Tracto Gastrointestinal/microbiología , Hiperglucemia/fisiopatología , Microbiota/efectos de los fármacos , Dibenzodioxinas Policloradas/toxicidad , Animales , Bacteroidetes/efectos de los fármacos , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Firmicutes/efectos de los fármacos , Citometría de Flujo , Hiperglucemia/inducido químicamente , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Tamaño de los Órganos , Fenotipo , Reacción en Cadena de la Polimerasa , ARN Ribosómico 16S , Bazo/patología , Estreptozocina/farmacologíaRESUMEN
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure in humans is associated with marked immune suppressions and increased incidence of lymphoblastic diseases. To elucidate mechanisms of impairments in humoral immune responses, we used a murine model. Following a 20-week administration of low doses of TCDD, we observed severely reduced antibody titers, dramatically decreased number of splenic Th1 and Th2 cells and an increase in CD19(+) B cells. Transcriptional profiling of CD19(+) B cells showed that markers of pre-B cells were significantly elevated, indicating delayed B cell maturation. These changes in B cells were accompanied by decreases of T helper cell numbers and reduced IgM and IgG titers. A transcriptome analysis of splenic B cells followed by Ingenuity Pathway Analysis (IPA) revealed a set of differentially expressed genes known to play roles in tumorigenesis, cell-proliferation and cell-migration. The most up-regulated transcript gene was Eph receptor A2 (EphA2), a known oncogene, and the most down-regulated transcript was ZBTB16 that codes for a negative transcriptional regulator important in epigenetic chromatin remodeling. IPA identified cAMP-responsive element modulator (CREM) and cAMP-responsive element binding protein 1 (CREB1) as top upstream regulators. Consistently, a MAPPER promoter database analysis showed that all top dysregulated genes had CREM and/or CREB1 binding sites in their promoter regions. In summary, our data showed that chronic TCDD exposure in mice caused suppressed humoral immunity accompanied with profound dysregulation of gene expression in splenic B-lymphocytes, likely through cAMP-dependent pathways. This dysregulation resulted in impairments in T-cell and B-cell differentiation and activation of the tumorigenic transcription program.
Asunto(s)
Linfocitos B/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Dibenzodioxinas Policloradas/toxicidad , Bazo/inmunología , Células TH1/efectos de los fármacos , Células Th2/efectos de los fármacos , Animales , Linfocitos B/citología , Linfocitos B/metabolismo , Peso Corporal/efectos de los fármacos , Ritmo Circadiano/efectos de los fármacos , Humanos , Inmunidad Humoral/efectos de los fármacos , Inmunidad Humoral/genética , Inmunoglobulinas/metabolismo , Interleucina-6/metabolismo , Interleucinas/metabolismo , Linfoma no Hodgkin/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Células TH1/citología , Células TH1/metabolismo , Células Th2/citología , Células Th2/metabolismo , Interleucina-22RESUMEN
The objective of this study was to determine the effects of the phytoestrogen genistein (GEN) on the time of onset and/or the incidence of type 1 diabetes (T1D) in female nonobese diabetic (NOD) mice, when administered GEN by gavage once every day for up to 180 days. Five groups of mice (approximately 24 animals/group; 6-7 weeks of age) were included: naive control, vehicle control (25 mM Na2CO3 in water), and 3 GEN treatment groups (2 mg/kg, 6 mg/kg, and 20 mg/kg). Mice were maintained on a soy- and alfalfa-free diet (5K96) during the study and were monitored for blood glucose changes every week. When compared to the vehicle control, exposure to 2-mg/kg GEN produced significant decreases ranging from 55 to 79% in the total incidences of diabetes (blood glucose ≥ 250 mg/dl) and severe diabetes (blood glucose ≥ 400 mg/dl) starting at week 14 of the study. However, during the later stages of the study (i.e., after week 23), the 2-mg/kg dose had no effect on disease incidence. In animals treated with 6-mg/kg and 20-mg/kg GEN, significant decreases in the total incidence of diabetes were observed starting at week 16, while the incidence of severe diabetes was significantly decreased with the changes being observed initially at weeks 18 and 17 for the 6-mg/kg and 20-mg/kg GEN treatment groups, respectively. Several lines of evidence, including histopathological analysis, suggested that GEN protected the pancreas from autoimmune destruction. However, this protective effect of GEN was absent when female NOD mice were maintained on NTP-2000 rodent diet, which contained 5% soybean meal and 7.5% alfalfa meal (the total concentrations of phytoestrogens ranged between 95 and 134 mg/kg). In summary, oral dosing of GEN reduced the incidence and increased the time to onset of T1D in female NOD mice but only when fed a soy- and alfalfa-free diet.
Asunto(s)
Diabetes Mellitus Tipo 1/prevención & control , Genisteína/farmacología , Glycine max , Medicago sativa , Fitoestrógenos/farmacología , Animales , Autoanticuerpos/análisis , Glucemia/metabolismo , Creatinina/sangre , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/psicología , Diabetes Mellitus Tipo 1/patología , Dieta , Femenino , Insulina/sangre , Insulina/inmunología , Riñón/patología , Ratones , Ratones Endogámicos NOD , Páncreas/patologíaRESUMEN
The establishment of safe and effective methods for controlling fungal disease is an urgent issue in agriculture and forestry. Microbiological control of plant disease is expected to achieve better results than use of chemically derived fungicides. This study aimed to establish Brevibacillus laterosporus JX-5 as a potential microbiological control agent of poplar canker. The bacterium was isolated from the poplar rhizosphere and demonstrated significant growth inhibition of several pathogenic fungi in vitro. The antifungal components of Br. laterosporus JX-5 were isolated and identified. The fermentation broth of Br. laterosporus JX-5 and its main antifungal component, designated as component B, reduced Botryosphaeria dothidea associated canker of the excised poplar branch by 70 and 90%, respectively. Component B is considerably heat-stable, adaptable to a broad pH range, and UV-resistant. It could inhibit Bo. dothidea by permeating the fungal membrane, fracturing the nuclei, damaging the cell wall, and eventually killing the pathogenic fungus. The antifungal activity exhibited by Br. laterosporus JX-5 and its bioactive metabolic products indicate its feasibility as a potential biocontrol agent for plant diseases.
Asunto(s)
Antibiosis , Antifúngicos/metabolismo , Ascomicetos/efectos de los fármacos , Brevibacillus/fisiología , Antifúngicos/aislamiento & purificación , Ascomicetos/crecimiento & desarrollo , Brevibacillus/clasificación , Brevibacillus/aislamiento & purificación , Brevibacillus/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/fisiología , Análisis por Conglomerados , ADN Bacteriano/química , ADN Bacteriano/genética , ADN Ribosómico/química , ADN Ribosómico/genética , Viabilidad Microbiana/efectos de los fármacos , Datos de Secuencia Molecular , Permeabilidad/efectos de los fármacos , Filogenia , Enfermedades de las Plantas/microbiología , Populus/microbiología , ARN Ribosómico 16S/genética , Rizosfera , Análisis de Secuencia de ADN , Microbiología del SueloRESUMEN
Diet and phytoestrogens affect the development and progression of diabetes. The objective of the present study was to determine if oral exposure to phytoestrogen genistein (GE) by gavage changed blood glucose levels (BGL) through immunomodulation in streptozotocin (STZ)-induced diabetic male B6C3F1 mice fed with three different diets. These three diets were: NTP-2000 diet (NTP), soy- and alfalfa-free 5K96 diet (SOF) and high fat diet (HFD) with 60% of kcal from fat, primarily rendered fat of swine. The dosing regimen for STZ consisted of three 100mg/kg doses (i.p.): the first dose was administered at approximately 2weeks following the initiation of daily GE (20mg/kg) gavage, and the second dose was on day 19 following the first dose, and the third dose was on day 57 following the first dose. In mice on the NTP diet, GE treatment decreased BGL with statistical significances observed on days 33 and 82 following the first STZ injection. In mice fed the HFD diet, GE treatment produced a significant decrease and a significant increase in BGL on days 15 and 89 following the first STZ injection, respectively. In mice fed the SOF diet, GE treatment had no significant effects on BGL. Although GE treatment affected phenotypic distributions of both splenocytes (T cells, B cells, natural killer cells and neutrophils) and thymocytes (CD4/CD8 and CD44/CD25), and their mitochondrial transmembrane potential and generation of reactive oxygen species, indicators of cell death (possibly apoptosis), GE modulation of neutrophils was more consistent with its diabetogenic or anti-diabetic potentials. The differential effects of GE on BGL in male B6C3F1 mice fed with three different diets with varied phytoestrogen contents suggest that the estrogenic properties of this compound may contribute to its modulation of diabetes.
Asunto(s)
Glucemia/inmunología , Diabetes Mellitus Experimental/inducido químicamente , Genisteína/farmacología , Fitoestrógenos/farmacología , Estreptozocina/administración & dosificación , Animales , Recuento de Células Sanguíneas , Glucemia/análisis , Cruzamientos Genéticos , Diabetes Mellitus Experimental/inmunología , Dieta , Femenino , Citometría de Flujo , Masculino , Potenciales de la Membrana/inmunología , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Bazo/citología , Bazo/inmunología , Estadísticas no Paramétricas , Timo/citología , Timo/inmunologíaRESUMEN
Aflatoxin B1 (AFB1) is immunotoxic to animals and a suspected immunosuppressant in humans. In this study, we investigated the effects of AFB1 on splenic lymphocyte phenotypes and the inflammatory cytokine expression in male F344 rats. Exposure of animals to AFB1 [5-75 µg kg(-1) body weight (BW)] for 1 week showed dose-dependent decreases in the percentage of splenic CD8(+) T cells and CD3(-) CD8a(+) NK cells. A general inhibition of the expression of interleukin (IL)-4 and interferon (IFN)-γ by CD4(+) T cells, IL-4 and IFN-γ by CD8a(+) cells, and tumor necrosis factor (TNF)-α expression by natural killer (NK) cells was also found; however, no concurrent histological changes in spleen tissue were present, suggesting acute immunosuppression without overt toxicity. Five-week exposure with AFB1 significantly increased the percentages of CD3(+) and CD8(+) T cells, especially at low doses (≤ 25 µg kg(-1)). AFB1 treatment significantly decreased the anti-inflammatory cytokine IL-4 expression by CD4(+) T cells and significantly increased the pro-inflammatory cytokine IFN-γ expression by CD4(+) T cells and TNF-α expression by NK cells. These results indicated that repeated AFB1 exposure promotes inflammatory responses by regulating cytokine expression. Our data provides novel insights into the mechanisms by which AFB1 exposure differentially modulates the cell-mediated immune responses and suggests the involvement of an inflammatory response upon repeated exposure.
Asunto(s)
Aflatoxina B1/toxicidad , Citocinas/biosíntesis , Contaminantes Ambientales/toxicidad , Linfocitos/efectos de los fármacos , Bazo/efectos de los fármacos , Administración Oral , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Linfocitos/inmunología , Masculino , Fenotipo , Ratas , Ratas Endogámicas F344 , Bazo/inmunología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunologíaRESUMEN
In the nematode Caenorhabditis elegans, stress resistance can be regulated by dauer formation (daf) genes. In the present study, regulation of heavy metal lead (Pb) toxicity by the 90-kDa heat shock proteins (Hsp90; daf-21) was investigated in both wild-type C. elegans and daf-21/Hsp90 mutants by focusing on the effects of varied temperatures below (15°C) or above (25 and 30°C) the presumptive optimum growth temperature (20°C). More acute toxicity of Pb, indicated by the 24-h median lethal concentrations (LC50), was observed in wild-type adults than in the daf-21 mutant adults at 15, 20 and 25°C; however, the daf-21 mutant adults showed more sensitivity at 30°C. Enhanced Pb sensitivity (e.g., decrease LC50) in both types of C. elegans was observed with both increased and decreased temperatures when compared to that at 20°C. Additional examined endpoints included time course of toxicity at LC50s, pharyngeal pumping, reproduction, life span, and Hsp90 expression. Collective results showed that temperatures both above and below 20°C exacerbated Pb toxicity, and that the protein level of daf-21/Hsp90 was one of the most sensitive indicators of Pb toxicity in wild-type C. elegans, while pharyngeal pumping was more Pb sensitive in daf-21 mutants. Therefore, the expression of daf-21/Hsp90 has apparent utility for the prediction and assessment of Pb-induced toxicity in nematodes. Further, the stress responses related to Hsp90 expression in C. elegans may have considerable potential as sensitive biomarkers for the monitoring of environmental Pb contamination.
Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/fisiología , Proteínas HSP90 de Choque Térmico/genética , Proteínas HSP90 de Choque Térmico/metabolismo , Plomo/toxicidad , Temperatura , Animales , Caenorhabditis elegans/metabolismo , Contaminantes Ambientales/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Dosificación Letal Mediana , Reproducción/efectos de los fármacosRESUMEN
Brominated flame retardants are used in many household products to reduce flammability, but often leach into the surrounding environment over time. Hexabromocyclododecane (HBCD) is one brominated flame retardant detected in human blood across the world. HBCD exposure can result in neurological problems and altered lipid metabolism, but to date the two remain unlinked. As lipids constitute â¼50% of brain dry weight, lipid metabolism plays a critical role in neuronal function and homeostasis. To determine the effect of HBCD exposure on brain lipid metabolism, young adult male C57BL/6 mice were exposed to 1 mg/kg HBCD every 3 days for 28 days. Major lipid classes were found to change across brain regions, including the membrane glycerolipids phosphatidylcholine and phosphatidylethanolamine, and sphingolipids such as hexosylceramide. In addition, saturated, monounsaturated, and polyunsaturated fatty acids were enriched within brain lipid species. To understand the source of the brain lipidomic alterations, the blood and liver lipidomes and the cecal microbiome were evaluated. The liver and blood demonstrated changes amongst multiple lipid classes, including triacylglycerol suppression, as well as altered esterified fatty acid content. Significant alterations were also detected in the cecal microbiome, with decreases in the Firmicutes to Bacteriodetes ratio, changes in beta diversity, and pathway alterations associated with metabolic pathways and amino acid biosynthesis. These data demonstrate that HBCD can induce lipidomic alterations across brain regions and organs and supports a potential role of the microbiome in these alterations.
RESUMEN
Recognition of pathogen-associated molecular patterns by innate immune receptors is essential for host defense responses. Although extracellular stress proteins are considered as indicators of the stressful conditions (e.g., infection or cell injury), the exact roles of these molecules in the extracellular milieu remain less defined. We found that glucose-regulated protein 170 (Grp170), the largest stress protein and molecular chaperone, is highly efficient in binding CpG oligodeoxynucleotides (CpG-ODN), the microbial DNA mimetic sensed by toll-like receptor 9 (TLR9). Extracellular Grp170 markedly potentiates the endocytosis and internalization of CpG-ODN by mouse bone marrow-derived macrophages and directly interacts with endosomal TLR9 on cell entry. These molecular collaborations result in the synergistic activation of the MyD88-dependent signaling and enhanced production of proinflammatory cytokines and nitric oxide in mouse primary macrophages as well as human THP-1 monocyte-derived macrophages, suggesting that Grp170 released from injured cells facilitates the sensing of pathogen-associated "danger" signals by intracellular receptors. This CpG-ODN chaperone complex-promoted innate immunity confers increased resistance in mice to infection of Listeria monocytogenes compared with CpG-ODN treatment alone. Our studies reveal a previously unrecognized attribute of Grp170 as a superior DNA-binding chaperone capable of amplifying TLR9 activation on pathogen recognition, which provides a conceptual advance in understanding the dynamics of ancient chaperoning functions inside and outside the cell.
Asunto(s)
Glicoproteínas/inmunología , Proteínas HSP70 de Choque Térmico/inmunología , Inmunidad Innata/inmunología , Macrófagos/inmunología , Chaperonas Moleculares/inmunología , Animales , Endocitosis/inmunología , Endosomas/metabolismo , Glicoproteínas/genética , Proteínas HSP70 de Choque Térmico/genética , Humanos , Listeria monocytogenes/inmunología , Macrófagos/citología , Ratones , Ratones Endogámicos , Chaperonas Moleculares/genética , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Oligodesoxirribonucleótidos/inmunología , Receptor Toll-Like 9/inmunologíaRESUMEN
New pH-sensitive lipids were synthesized and utilized in formulations of liposomes suitable for controlled drug release. These liposomes contain various amounts of NaCl in the internal aqueous compartments. The release of the drug model is triggered by an application of HCl cotransporter and exogenous physiologically relevant NaCl solution. HCl cotransporter allows an uptake of HCl by liposomes to the extent of their being proportional to the transmembrane Cl(-) gradient. Therefore, each set of liposomes undergoes internal acidification, which, ultimately, leads to the hydrolysis of the pH-sensitive lipids and content release at the desired time. The developed system releases the drug model in a stepwise fashion, with the release stages separated by periods of low activity. These liposomes were found to be insensitive to physiological concentrations of human serum albumin and to be nontoxic to cells at concentrations exceeding pharmacological relevance. These results render this new drug-release model potentially suitable for in vivo applications.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Lípidos/química , Liposomas/administración & dosificación , Cloruro de Sodio/química , Línea Celular Tumoral/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada , Humanos , Concentración de Iones de Hidrógeno , Lípidos/síntesis química , Liposomas/efectos adversos , Liposomas/química , Simportadores del Cloruro de Sodio/administración & dosificación , Simportadores del Cloruro de Sodio/química , Soluciones/administración & dosificación , Soluciones/químicaRESUMEN
AIMS: Cellulose nanofibrils (CNF, or NFC), cellulose nanocrystals (CNC, or NCC), and Tempo (2,2,6,6-tetramethylpiperidine-1-oxyl radical) oxidized CNF (Tempo-CNF) were compared for the short-term effect on mice fed with a high-fat and high-sugar (Western diet, WD) to investigate their effect when combined with a sub-optimal diet. SCOPE: Thirty C57B/C female mice (10 weeks old; 5-6 mice/group) were given water, cellulose, or three types of nanocellulose once daily in a dose of 30 mg/kg body weight by oral gavage. After six weeks, weight changes, fecal output, glucose homeostasis, and gut permeability showed no significant among groups. Serum analysis including triglycerides, cholesterol and total bile acids and small intestinal morphology including villus length, villus width, crypt depth, goblet cell count and goblet cell density were no difference for all groups. Only CNC group had higher excretion of bile acids in the feces. CONCLUSIONS: These results suggest that current treated dose using three types of nanocellulose had no detrimental effects on blood lipid level and small intestinal morphology.
Asunto(s)
Nanopartículas , Femenino , Animales , Ratones , Nanopartículas/química , Celulosa/farmacología , Celulosa/química , Lípidos , Óxidos N-Cíclicos/farmacología , Óxidos N-Cíclicos/química , ReologíaRESUMEN
AIMS: To determine if cellulose nanofibrils (CNF) have potential applications as food additives. MATERIALS AND METHODS: Male C57BL/6 mice on a Western diet were exposed to CNF for one month at a dose of 30 mg/kg by gavage. Male NOD mice, a model for type 1 diabetes (T1D), were used in a six-month study. KEY FINDINGS: Sequencing analysis of 16S rRNA genes suggested significant changes in gut microbiome of male C57BL/6 mice exposed to CNF. Analysis of functional metagenomics indicated that many of the functional contents that might be altered following CNF ingestion were associated with lipid and carbohydrate processing. Further studies in NOD mice suggested that there were some decreases in the blood glucose levels during the insulin tolerance test and glucose tolerance test following CNF treatment. However, these small decreases were not considered biologically meaningful as there were no significant changes in either the area under the curve or the first-order rate constant for glucose disappearance. Moreover, serum concentrations of cytokines/chemokines including IL-3, IL-12(p70) and the keratinocyte chemoattractant were increased following chronic exposure to CNF. In addition, behavioral studies suggested that the percentage of immobility time during the tail-suspension test was significantly increased following six months of exposure to CNF in NOD mice, signifying an increase in depression-related behavior. SIGNIFICANCE: Collectively, long-term CNF consumption was associated with changes in the ecology of the gut microbiome, immune homeostasis, and possibly energy metabolism and mental health in male NOD mice on a Western diet.
Asunto(s)
Microbioma Gastrointestinal , Masculino , Animales , Ratones , Ratones Endogámicos NOD , Dieta Occidental/efectos adversos , ARN Ribosómico 16S/genética , Depresión , Ratones Endogámicos C57BLRESUMEN
Transient activation of p38 through anisomycin is demonstrated to precondition the heart against myocardial injury. However, it remains unknown whether specific TNF-α receptor (TNFR) p55/p75 and Nox2, a subunit of NADPH oxidase, are involved in this event. We sought to investigate whether the genetic disruption of TNFRp55/p75 and Nox2 eliminated cardioprotection elicited by anisomycin and whether p38-dependent activation of Nox2 stimulated TNFR to ultimately achieve protective effects. Adult wild-type and TNFR p55/p75(-/-) and Nox2(-/-) mice received intraperitoneal injections of anisomycin (0.1 mg/kg), a potent activator of p38. The hearts were subjected to 30 min myocardial ischemia/30 min reperfusion in the Langendorff perfused heart after 24 h. Left ventricular function was measured, and infarct size was determined. Myocardial TNF-α protein, Nox2, and superoxides releases were detected. Gel kinase assay was employed to detect the effect of p38 on Nox2 phosphorylation. Activation of p38 through anisomycin produces marked improvements in left ventricular functional recovery, and the reduction of myocardial infarction, which were abrogated by disruption of Nox2 and TNFR p55/p75. Disruption of Nox2 and TNFR p55/p75 abolished the effect of anisomycin-induced reduction of infarct size. Anisomycin induced the production of TNF-α, which was abrogated in Nox2(-/-) mice and by treatment with SB203580, but not by disruption of p55/p75. Anisomycin treatment resulted in an increase in Nox2 protein and the phosphorylation of Nox2, which was blocked by inhibition of p38. Taken together, these results indicate that stimulation of the Nox2 and TNFR p55/p75 pathway is a novel approach to anisomycin-induced cardioprotection.