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6:2 fluorotelomer carboxylic acid (6:2 FTCA) is a perfluorooctanoic acid (PFOA) substitute, which is supposedly less accumulative and toxic than PFOA. However, 6:2 FTCA is structurally similar to PFOA, and there had already been reports about its toxicities comparable to PFOA. The aim of the current study is to assess potential effects of developmental exposure to 6:2 FTCA on the development of kidney in chicken embryo and to investigate underlying mechanism. Fertile chicken eggs were exposed to 1.25â¯mg/kg, 2.5â¯mg/kg or 5â¯mg/kg doses of 6:2 FTCA, or 2â¯mg/kg PFOA, then incubated to hatch. Serum and kidney of hatchling chickens were collected. Blood urea nitrogen (BUN) and creatinine (Cre) levels were measured with commercially available kits. Morphology of kidney was assessed with histopathology. To further reveal molecular mechanism of observed endpoints, IGF signaling molecules were assessed in the kidney samples with qRT-PCR, results indicated that IGFBP3 is a potentially crucial molecule. Lentiviruses overexpressing or silencing IGFBP3 were designed and applied to enhance/suppress the expression of IGFBP3 in developing chicken embryo for further verification of its role in the observed effects. Disrupted nephron formation, in the manifestation of decreased glomeruli number/area and increased serum BUN/Cre levels, was observed in the animals developmentally exposed to 6:2 FTCA. Correspondingly, IGF signaling molecules (IGF1, IGF1R and IGFBP3) were affected by 6:2 FTCA exposure. Meanwhile, overexpression of IGFBP3 effectively alleviated such changes, while silencing of IGFBP3 mimicked observed effects. In conclusion, developmental exposure to 6:2 FTCA is associated with disrupted chicken embryo renal development, in which IGFBP3 seems to be a remarkable contributor, suggesting potential health risks for human and other species. Further risk assessments and mechanistic works are necessary.
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The role and mechanisms of DEP exposure on thyroid injury are not yet clear. This study explores thyroid damage induced by in vivo DEP exposure using a mouse model. This study has observed alterations in thyroid follicular architecture, including rupture, colloid overflow, and the formation of voids. Additionally, there was a significant decrease in the expression levels of proteins involved in thyroid hormone synthesis, such as thyroid peroxidase and thyroglobulin, their trend of change is consistent with the damage to the thyroid structure. Serum levels of triiodothyronine and tetraiodothyronine were raise. However, the decrease in TSH expression suggests that the function of the HPT axis is unaffected. To delve deeper into the intrinsic mechanisms of thyroid injury, we performed KEGG pathway enrichment analysis, which revealed notable alterations in the cell adhesion signaling pathway. Our immunofluorescence results show that DEP exposure impairs thyroid adhesion, and integrin α3ß1 plays an important role. CD151 binds to α3ß1, promoting multimolecular complex formation and activating adhesion-dependent small GTPases. Our in vitro model has confirmed the pivotal role of integrin α3ß1 in thyroid cell adhesion, which may be mediated by the CD151/α3ß1/Rac1 pathway. In summary, exposure to DEP disrupts the structure and function of the thyroid, a process that likely involves the regulation of cell adhesion through the CD151/α3ß1/Rac1 pathway, leading to glandular damage.
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Integrina alfa3beta1 , Glándula Tiroides , Emisiones de Vehículos , Animales , Ratones , Glándula Tiroides/efectos de los fármacos , Emisiones de Vehículos/toxicidad , Integrina alfa3beta1/metabolismo , Adhesión Celular/efectos de los fármacos , Contaminantes Atmosféricos/toxicidad , Material Particulado/toxicidad , Células Epiteliales Tiroideas/efectos de los fármacos , Células Epiteliales Tiroideas/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Hexafluoropropylene oxide trimer acid (HFPO-TA), a perfluorooctanoic acid (PFOA) substitute, exhibited strong affinity and capability to activate peroxisome proliferator activated receptor gamma (PPARγ), a lipid metabolism regulator, suggesting potential to induce metabolic toxicities. METHODS: Fertile chicken eggs were exposed to 0, 0.5, 1 or 2 mg/kg (egg weight) HFPO-TA and incubated until hatch. Serum from 0- and 3- month-old chickens were subjected to liquid chromatography ultra-high resolution mass spectrometry for HFPO-TA concentration, while liver, pancreas and adipose tissue samples were collected for histopathological assessments. In ovo PPARγ reporter and silencing system were established with lentivirus microinjection. qRT-PCR and immunohistochemistry were utilized to evaluate the expression levels of PPARγ downstream genes. RESULTS: In 3-month-old animals developmentally exposed to HFPO-TA, adipose tissue hyperplasia, hepatic steatosis, pancreas islet hypertrophy and elevated serum free fatty acid / insulin levels were observed. Results of reporter assay and qRT-PCR indicated HFPO-TA-mediated PPARγ transactivation in chicken embryo. Silencing of PPARγ alleviated HFPO-TA-induced changes, while PPARγ agonist rosiglitazone mimicked HFPO-TA-induced effects. qRT-PCR and immunohistochemistry revealed that FASN and GPD1 were upregulated following developmental exposure to HFPO-TA in 3-month-old animals. CONCLUSIONS: Developmental exposure to HFPO-TA induced persistent metabolic toxicities in chickens, in which PPARγ played a central role.
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Fluorocarburos , PPAR gamma , Animales , PPAR gamma/genética , PPAR gamma/metabolismo , Fluorocarburos/toxicidad , Embrión de Pollo , Hígado/efectos de los fármacos , Hígado/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Pollos , Páncreas/efectos de los fármacos , Páncreas/metabolismoRESUMEN
OBJECTIVE: The effects of air pollution on metabolism have become a popular research topic, and a large number of studies had confirmed that air pollution exposure could induce insulin resistance (IR) to varying degrees, but the results were inconsistent, especially for the long-term exposures. The aim of the current study was to further investigate the potential effects of air pollution on IR. METHODS: A systematic review and meta-analysis of four electronic databases, including PubMed, Embase, Web of Science and Cochrane were conducted, searching for relevant studies published before June 10, 2023, in order to explore the potential relationships between long-term exposure to air pollution and IR. A total of 10 studies were included for data analysis, including seven cohort studies and three cross-sectional studies. Four major components of air pollution, including PM2.5 (particulate matter with an aerodynamic diameter of 2.5 µm or less), PM10 (particulate matter with an aerodynamic diameter of 10 µm or less), NO2, and SO2 were selected, and each analyzed for the potential impacts on insulin resistance, in the form of adjusted percentage changes in the homeostasis assessment model of insulin resistance (HOMA-IR). RESULTS: This systematic review and meta-analysis showed that for every 1 µg/m³ increase in the concentration of selected air pollutants, PM2.5 induced a 0.40% change in HOMA-IR (95%CI: -0.03, 0.84; I2 =67.4%, p = 0.009), while PM10 induced a 1.61% change (95%CI: 0.243, 2.968; I2 =49.1%, p = 0.001). Meanwhile, the change in HOMA-IR due to increased NO2 or SO2 exposure concentration was only 0.09% (95%CI: -0.01, 0.19; I2 =83.2%, p = 0.002) or 0.01% (95%CI: -0.04, 0.06; I2 =0.0%, p = 0.638), respectively. CONCLUSIONS: Long-term exposures to PM2.5, PM10, NO2 or SO2 are indeed associated with the odds of IR. Among the analyzed pollutants, inhalable particulate matters appear to exert greater impacts on IR.
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Contaminantes Atmosféricos , Contaminación del Aire , Resistencia a la Insulina , Humanos , Dióxido de Nitrógeno/análisis , Estudios Transversales , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Contaminantes Atmosféricos/toxicidad , Contaminantes Atmosféricos/análisis , Material Particulado/toxicidad , Material Particulado/análisisRESUMEN
Hexafluoropropylene oxide tetramer acid (HFPO-TeA) is an emerging environmental contaminant, with environmental presence but limited toxicological information. To investigate its potential developmental toxicities, various doses of HFPO-TeA exposure were achieved in chicken embryos via air cell injection, and the exposed embryos were incubated until hatch. Within 24 h of hatch, the hatchling chickens were assessed with electrocardiography and histopathology for toxicological evaluation. For mechanistic investigation, in ovo silencing of PPARα was achieved via lentivirus microinjection, then the morphological/functional endpoints along with protein expression levels of PPARα-regulated genes were assessed. HFPO-TeA exposure in chicken embryo resulted in developmental cardiotoxicity and hepatotoxicity. Specifically, decreased right ventricular wall thickness, increased heart rate and hepatic steatosis were observed, whereas silencing of PPARα resulted in alleviation of observed toxicities. Western blotting for EHHADH and FABPs suggested that developmental exposure to HFPO-TeA effectively increased the expression levels of both targets in hatchling chicken heart and liver tissue samples, while PPARα silencing prevented such changes, suggesting that PPARα and its downstream genes are playing critical roles in HFPO-TeA induced developmental toxicities.
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Pollos , Fluorocarburos , Embrión de Pollo , Animales , Pollos/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Fluorocarburos/toxicidad , Corazón , Hígado/metabolismoRESUMEN
BACKGROUND: Vascular toxicity induced by particulate matter (PM) exposure exacerbates the onset and development of cardiovascular diseases; however, its detailed mechanism remains unclear. Platelet-derived growth factor receptor ß (PDGFRß) acts as a mitogen for vascular smooth muscle cells (VSMCs) and is therefore essential for normal vasoformation. However, the potential effects of PDGFRß on VSMCs in PM-induced vascular toxicity have not yet been elucidated. METHODS: To reveal the potential roles of PDGFRß signalling in vascular toxicity, individually ventilated cage (IVC)-based real-ambient PM exposure system mouse models and PDGFRß overexpression mouse models were established in vivo, along with in vitro VSMCs models. RESULTS: Vascular hypertrophy was observed following PM-induced PDGFRß activation in C57/B6 mice, and the regulation of hypertrophy-related genes led to vascular wall thickening. Enhanced PDGFRß expression in VSMCs aggravated PM-induced smooth muscle hypertrophy, which was attenuated by inhibiting the PDGFRß and janus kinase 2 /signal transducer and activator of transcription 3 (JAK2/STAT3) pathways. CONCLUSION: Our study identified the PDGFRß gene as a potential biomarker of PM-induced vascular toxicity. PDGFRß induced hypertrophic effects through the activation of the JAK2/STAT3 pathway, which may be a biological target for the vascular toxic effects caused by PM exposure.
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Músculo Liso Vascular , Transducción de Señal , Animales , Ratones , Hipertrofia/metabolismo , Músculo Liso Vascular/metabolismo , Material Particulado/metabolismo , Receptor beta de Factor de Crecimiento Derivado de PlaquetasRESUMEN
Perfluorooctanoic acid (PFOA) is a widespread persistent organic pollutant. Fertile chicken eggs were exposed to PFOA and incubated to hatch. At three time points post hatch (0-, 1- and 3-months old), chickens were subjected to electrocardiography and sacrificed. Serum was subjected to LC-MS/MS for PFOA concentration, and organs were subjected to histopathological assessments. Additionally, PPARα-silencing lentivirus was co-applied with PFOA exposure, and the corresponding phenotypes were evaluated. Western blotting was performed to assess expressions of FABPs and pSMAD2 in heart and liver samples. Considerable amount of PFOA were detected in hatchling chicken serum, but not in one-month-old or three-month-old chicken serum. PFOA exposure resulted in developmental cardiotoxicity and hepatotoxicity in hatchling chickens. Meanwhile, one-month-old chickens still exhibited elevated heart rate, but classical cardiac remodeling (thicker right ventricular wall) were observed in exposed animals. Three-month-old chickens exhibited similar results as one-month-old ones. PPARα silencing only had partial protective effects in hatchling chickens, but the protective effects seemed to increase as chickens aged. Western blotting results indicated that L-FABP was involved in PFOA-induced hepatotoxicity, while pSMAD2 was involved in PFOA-induced cardiotoxicity. In summary, developmental exposure to PFOA resulted in persistent cardiotoxicity, but not hepatotoxicity. PPARα participates in both cardiotoxicity and hepatotoxicity.
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Pollos , Fluorocarburos , Animales , Pollos/metabolismo , Cardiotoxicidad , PPAR alfa/genética , PPAR alfa/metabolismo , Cromatografía Liquida , Peroxisomas/metabolismo , Espectrometría de Masas en Tándem , Caprilatos/toxicidad , Caprilatos/metabolismo , Fluorocarburos/toxicidad , Fluorocarburos/metabolismo , Proliferación Celular , Hígado/metabolismoRESUMEN
Perfluorooctanoic acid (PFOA) could induce developmental toxicities, affecting various organs, including the heart. Although peroxisome-proliferation activated receptor alpha (PPARα) had been identified as a major target of PFOA, PPARα-independent effects are frequently reported. To further elucidate the mechanism of toxicity in PFOA-induced developmental cardiotoxicity, RNA-seq analysis was performed in hatchling chicken hearts developmentally exposed to vehicle or 2 mg/kg (egg weight) PFOA. RT-PCR and western blotting were then performed to confirm the identified potential targets. Furthermore, lentivirus was designed to overexpress and silence identified target miRNA in developing chicken embryo, and the resulting phenotypes were investigated. 21 miRNAs and 1142 mRNAs were identified to be affected by developmental exposure to PFOA in chicken embryo hearts. Among the identified differentially expressed miRNAs, miR-490-5p was confirmed to be significantly affected by PFOA exposure, along with its downstream targets, Synaptosome associated protein 91 (SNAP91) and LY6/PLAUR domain containing 6 (LYPD6), as indicated by RT-PCR and western blotting results. Lentivirus overexpressing miR-490-5p mimicked the phenotype induced by PFOA exposure, while lentivirus silencing miR-490-5p alleviated PFOA-induced changes. Similar patterns were also observed in the expression of downstream target genes, SNAP91 and LYPD6. In summary, miR-490-5p and its downstream genes, SNAP91 and LYPD6 are associated with PFOA-induced developmental cardiotoxicity in chicken embryo, which might help to further elucidate the mechanism of PFOA-induced developmental cardiotoxicity.
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Fluorocarburos , MicroARNs , Animales , Caprilatos , Cardiotoxicidad , Embrión de Pollo , Pollos/metabolismo , Fluorocarburos/metabolismo , Fluorocarburos/toxicidad , MicroARNs/genética , MicroARNs/metabolismo , PPAR alfa/metabolismoRESUMEN
Aminopeptidase N (APN, CD13) is closely associated with the development and progression of cancer. Previous studies suggested APN as a biomarker for cancer stem cells. APN inhibitors have been intensively evaluated as chemosensitizers for cancer treatments. In the present study, tetrahydro-ß-carboline scaffold was introduced to the structure of APN inhibitors. The synthesized compounds showed potent enzyme inhibitory activities compared with Bestatin, an approved APN inhibitor, in cell-based enzymatic assay. In combination with chemotherapeutic drugs, representative APN inhibitor molecules D12, D14 and D16 significantly improved the antiproliferative potency of anticancer drugs in the in vitro tests. Further mechanistic studies revealed that the anticancer effects of these drug combinations are correlated with decreased APN expression, increased ROS level, and induction of cell apoptosis. The spheroid-formation assay and colony-formation assay results showed effectiveness of Paclitaxel-APN inhibitor combination against breast cancer stem cell growth. The combined drug treatment led to reduced mRNA expression of OCT-4, SOX-2 and Nanog in the cancer stem cells tested, suggesting the reduced stemness of the cells. In the in vivo study, the selected APN inhibitors, especially D12, exhibited improved anticancer activity in combination with Paclitaxel compared with Bestatin. Collectively, potent APN inhibitors were discovered, which could be used as lead compounds for tumor chemo-sensitization and cancer stem cell-based therapies.
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A growing body of evidence associated particulate matter (PM) exposure with lipid metabolism disorders, yet, the underlying mechanism remains to be elucidated. Among the major lipid metabolism modulators, peroxisome proliferator-activated receptor (PPAR) alpha plays an important role. In the current study, an individually ventilated cage (IVC) system was used to expose C57/B6 mice to real-ambient PM for six weeks, with or without co-treatment of PPAR alpha agonist WY14,643. The general parameters, liver and adipose tissue pathology, serum lipids, metal deposition and lipid profile of liver were assessed. The results indicated that six weeks of real-ambient PM exposure induced dyslipidemia, including increased serum triglycerides (TG) and decreased high density lipoprotein cholesterol (HDL-C) level, along with steatosis in liver, increased size of adipocytes in white adipose tissue (WAT) and whitening of brown adipose tissue (BAT). ICP-MS results indicated increased Cr and As deposition in liver. Lipidomics analysis revealed that glycerophospholipids and cytochrome P450 pathway were most significantly affected by PM exposure. Several lipid metabolism-related genes, including CYP4A14 in liver and UCP1 in BAT were downregulated following PM exposure. WY14,643 treatment alleviated PM-induced dyslipidemia, liver steatosis and whitening of BAT, while enhancing CD36, SLC27A1, CYP4A14 and UCP1 expression. In conclusion, PPAR alpha pathway participates in PM-induced lipid metabolism disorder, PPAR alpha agonist WY14,643 treatment exerted protective effects on PM-induced dyslipidemia, liver steatosis and whitening of BAT, but not on increased adipocyte size of WAT.
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Trastornos del Metabolismo de los Lípidos , PPAR alfa , Tejido Adiposo Pardo/metabolismo , Animales , Metabolismo de los Lípidos , Trastornos del Metabolismo de los Lípidos/metabolismo , Ratones , PPAR alfa/genética , PPAR alfa/metabolismo , Material Particulado/metabolismo , Proliferadores de Peroxisomas/metabolismo , Proliferadores de Peroxisomas/farmacologíaRESUMEN
Hexafluoropropylene oxide dimer acid (HFPO-DA) is a perfluorooctanoic acid (PFOA) substitute. In the current study, potential developmental cardiotoxicity and hepatotoxicity following HFPO-DA exposure in chicken embryo has been investigated, focusing on the roles of peroxisome proliferator activated receptor alpha (PPARα), the major molecular target in PFOA-induced toxicities. HFPO-DA was exposed to fertile chicken eggs via air cell injection, morphology and function of the target organs (heart and liver) in hatchlings were investigated with histopathology and electrocardiography, and the serum levels of HFPO-DA had been measured with quadrupole-time of flight liquid chromatograph-mass spectrometer (Q-TOF LC/MS). Additionally, lentivirus-mediated in ovo PPARα silencing was used to assess the roles of PPARα in HFPO-DA induced developmental toxicities. The results indicated that developmental exposure to HFPO-DA induced developmental cardiotoxicity, including thinned right ventricular wall and elevated heart rates, similar to those observed with PFOA exposure, as well as developmental hepatotoxicity in the form of steatosis. Silencing of PPARα alleviated such effects, suggesting participation of PPARα in HFPO-DA induced developmental toxicities in chicken embryo. Moreover, enhanced expression of PPARα downstream genes, cluster of differentiation 36 (CD36) and enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (EHHADH), were observed in HFPO-DA exposed animal heart tissues, which can be abolished by PPARα silencing. On the other hand, liver-type fatty acid binding protein (L-FABP) and CD36 expression were effectively enhanced in exposed liver tissues, but not EHHADH, suggesting differential mechanism of toxicity in heart and liver tissues. In summary, developmental exposure to HFPO-DA induced developmental cardiotoxicity and hepatotoxicity in hatchling chickens similar to PFOA, and PPARα still participates in such toxicities, with some differential downstream gene regulations in different organs. Further investigation on HFPO-DA-induced developmental toxicities is guaranteed.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Fluorocarburos , Animales , Cardiotoxicidad , Embrión de Pollo , Pollos , Fluorocarburos/toxicidad , Hígado , Óxidos , PPAR alfa/genéticaRESUMEN
Particulate matter (PM) had been associated with cardiotoxicity, while the mechanism of toxicity has yet to be elucidated, with mitochondria dysfunction as a potential candidate. To investigate the potential cardiotoxic effects of ambient PM exposure and assess the damage to cardiac mitochondria, C57/B6 mice were exposed to filtered air or real ambient PM for three or six weeks. Furthermore, to reveal the role of peroxisome proliferators-activated receptor alpha (PPAR alpha) in PM exposure induced cardiotoxicity/mitochondria damage, animals were also co-treated with PPAR alpha agonist WY 14,643 or PPAR alpha antagonist GW 6471. Cardiotoxicity was assessed with echocardiography and histopathology, while mitochondria damage was evaluated with mitochondria membrane potential measurement and transmission electron microscopy. Potential impacts of PM exposure to PPAR alpha signaling were detected with co-immunoprecipitation and western blotting. The results indicated that exposure to ambient PM exposure induced cardiotoxicity in C57/B6 mice, including altered cardiac functional parameters and morphology. Cardiac mitochondria damage is detected, in the form of compromised mitochondria membrane potential and morphology. Molecular investigations revealed disruption of PPAR alpha interaction with peroxisome proliferator-activated receptor gamma coactivator-1A (PGC-1a) as well as altered expression levels of PPAR alpha downstream genes. Co-treatment with WY 14,643 alleviated the observed toxicities, while co-treatment with GW 6471 had mixed results, exaggerating most cardiotoxicity and mitochondrial damage endpoints but alleviating some cardiac functional parameters. Interestingly, WY 14,643 and GW 6471 co-treatment seemed to exhibit similar regulative effects towards PPAR alpha signaling in animals exposed to PM. In conclusion, ambient PM exposure indeed induced cardiotoxicity in C57/B6 mice, in which cardiac mitochondria damage and disrupted PPAR alpha signaling are contributors.
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PPAR alfa , Material Particulado , Animales , Cardiotoxicidad , Ratones , Mitocondrias , PPAR alfa/genética , Material Particulado/toxicidad , Transducción de SeñalRESUMEN
To assess the toxicities of gas/aerosol, inhalation exposure model is necessary. Especially important is the inhalation exposure early in life. Traditional inhalation exposure method requires specific instruments and may have to imitate the exposure either days before or after birth. Here, a new inhalation exposure method is introduced, which may be performed without any specific instruments and effectively expose late stage chicken embryos to gas/aerosol very early-in-life by inhalation. This method may facilitate the risk assessment and mechanistic studies regarding the early-in-life effects of gas/aerosol exposure.
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Aerosoles/efectos adversos , Embrión de Pollo/efectos de los fármacos , Gases/efectos adversos , Exposición por Inhalación/efectos adversos , Aerosoles/toxicidad , Animales , Pollos , Gases/toxicidad , Pruebas de Toxicidad/métodosRESUMEN
Chicken embryos are a classical model in developmental studies. During the development of chicken embryos, the time window of heart development is well-defined, and it is relatively easy to achieve precise and timely exposure via multiple methods. Moreover, the process of heart development in chicken embryos is similar to mammals, also resulting in a four-chambered heart, making it a valuable alternative model in the assessment of developmental cardiotoxicities. In our lab, the chicken embryo model is routinely used in the assessment of developmental cardiotoxicities following exposure to various environmental pollutants, including per- and polyfluoroalkyl substances (PFAS), particulate matter (PMs), diesel exhaust (DE) and nano materials. The exposure time can be freely selected based on the need, from the beginning of development (embryonic day 0, ED0) all the way to the day prior to hatch. The major exposure methods include air-cell injection, direct microinjection, and air-cell inhalation (originally developed in our lab), and the currently available endpoints include cardiac function (electrocardiography), morphology (histological assessments) and molecular biological assessments (immunohistochemistry, qRT-PCR, western blotting, etc.). Of course, the chicken embryo model has its own limitations, such as limited availability of antibodies. Nevertheless, with more laboratories starting to utilize this model, it can be used to make significant contributions to the study of developmental cardiotoxicities.
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Cardiotoxicidad/fisiopatología , Animales , Embrión de Pollo , PollosRESUMEN
Short-and long-term exposure to particulate matter (PM) has been associated with cardiovascular disease (CVD). It is well recognized that oxidative stress is a potential major mechanism in PM-induced vascular injuries, in which the nuclear factor E2-related factor 2 (Nrf2) signaling pathway plays a critical role. In the current study, a Nrf2 knockout mouse model was used in combination with an individual ventilated cage (IVC)-based real-ambient PM exposure system to assess the potential vascular injury and the potential role of Nrf2 in the angiotensin II (Ang II)-associated vascular injury. After 6-or 11-week exposure to PM, the histopathology assay revealed that PM exposure resulted in the thickening of the walls of vascular. After 6 weeks exposure to PM, the ELISA assay revealed that PM exposure resulted in the elevated plasma concentration of Ang II. The expression levels of genes of interest were then further investigated with quantitative real-time PCR. Notably, the results showed that Angiotensinogen (AGT), Angiotensin converting enzyme (ACE) and Angiotensin type I receptor (AT1R) were involved in PM-induced pathological changes. Western blotting for ACE showed similar results. Moreover, the extent of vascular thickening and the Ang II elevation was most prominent in the Nrf2 gene knockout PM exposure group (KOE). Furthermore, the expression of Nrf2 downstream relevant genes (HO1, Nqo1, Gclc, Gsta4) were significantly enhanced in the wildtype PM exposure group (WTE), while those were remarkably suppressed in the Nrf2 gene knockout groups. The ELISA result of monocyte chemoattractant protein-1 (MCP-1) serum levels in the KOE group was significantly higher in relation to that in the Nrf2 knockout control group (KOC). In summary, PM exposure is associated with thickening of vascular wall, while Nrf2 knockout may further enhance this effect. A potential mechanistic contributor of such effects is the activation of ACE/ANGII/AT1R axis, in which Nrf2 played a regulatory role.
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In discovery of HDAC inhibitors (HDACIs) with improved anticancer potency, structural modification was performed on the previous derived indole-3-butyric acid derivative. Among all the synthesised compounds, molecule I13 exhibited high HDAC inhibitory and antiproliferative potencies in the in vitro investigations. The IC50 values of I13 against HDAC1, HDAC3, and HDAC6 were 13.9, 12.1, and 7.71 nM, respectively. In the cancer cell based screening, molecule I13 showed increased antiproliferative activities in the inhibition of U937, U266, HepG2, A2780, and PNAC-1 cells compared with SAHA. In the HepG2 xenograft model, 50 mg/kg/d of I13 could inhibit tumour growth in athymic mice compared with 100 mg/kg/d of SAHA. Induction of apoptosis was revealed to play an important role in the anticancer potency of molecule I13. Collectively, a HDACI (I13) with high anticancer activity was discovered which can be utilised as a lead compound for further HDACI design.
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Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Indoles/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Indoles/síntesis química , Indoles/química , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Masculino , Ratones , Ratones Desnudos , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Particulate matter poses health risk to developing organisms. To investigate particulate matters with a diameter smaller than 2.5 um (PM2.5)-induced developmental cardiotoxicity, fertile chicken eggs were exposed to PM2.5 via air cell injection at doses of 0.05, 0.2, 0.5, 2, and 5 mg/egg kg. Morphological changes in the embryonic day four (ED4) and hatchling hearts were assessed with histological techniques. Heart rates of hatchling chickens were measured with electrocardiography. The protein expression levels of nuclear factor kappa-light-chain-enhancer of activated B cells p65 (NF-kb p65), inducible nitric oxide synthase (iNOS), and matrix metallopeptidase 9 (MMP9) were assessed with immunohistochemistry or western blotting in hatchling hearts. PM2.5 exposure elevated areas of heart in ED4 embryo, increased heart rate, and thickened right ventricular wall thickness in hatchling chickens. Immunohistochemistry revealed enhanced NF-kb p65 expression in hatchling hearts. Western blotting results indicated that both iNOS and MMP9 expression were enhanced by lower doses of PM2.5 exposure (0.2 and 0.5 mg/kg) but not 2 mg/kg. In summary, developmental exposure to PM2.5 induced developmental cardiotoxicity in chicken embryo and hatchling chickens, which is associated with NF-kb p65, iNOS, and MMP9.
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[This corrects the article on p. 1047 in vol. 5, PMID: 26045985.].
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Diesel exhaust (DE) had been associated with cardiopulmonary toxicity and developmental toxicity. However, neonatal very early-in-life exposure had not been extensively studied previously. To investigate the potential effects of neonatal very early-in-life exposure to DE, a brand-new chicken embryo in ovo exposure model had been established, with which the cardiopulmonary effects of DE exposure via air cell infusion at embryonic day 18/19 (ED18/19) were assessed in hatchling chicks post-hatch 0-, 1-, or 2-weeks. Heart rates were assessed with electrocardiography. Cardiac and pulmonary morphologies were investigated with histopathological methods. Cardiopulmonary effects were explored with immunohistochemistry for alpha smooth muscle actin (alpha-SMA). In further investigations, the expression levels of phosphorylated AhR, serum levels of TGF-ß1, phosphorylated SMAD2/3 and phosphorylated p38MAPK were assessed in the lung tissues. Significantly elevated heart rates, increased right ventricular wall thickness and cardiac collagen deposition were observed in the hearts of exposed hatchling chicks. Significantly increased collagen deposition as well as increased vascular alpha-SMA layer thickness/decreased cavity area were observed in exposed animal lungs. These effects persisted up to two weeks post-hatch. Mechanistic studies revealed elevated phosphorylated AhR expression levels in 0-week and 1-week chicken lungs, while phosphorylated SMAD2/3 levels significantly increased in 0-week chicken lungs but decreased in 2-week chicken lungs following DE exposure. Phosphorylation of p38MAPK did not remarkably increase until 2-week post-hatch. In summary, the novel chicken neonatal very early-in-life exposure model effectively exposed the chicken embryos during the neonatal initial breathing, resulting in cardiopulmonary toxicity, which is associated with AHR, TGF-ß1 and MAPK signaling.