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Pulmonary Proteome and Protein Networks in Response to the Herbicide Paraquat in Rats.

Cho IK, Jeong M, You AS, Park KH, Li QX - J Proteomics Bioinform (2015)

Bottom Line: The effects of PQ on cellular processes and biological pathways were investigated by analyzing proteome in the lung tissues in comparison with the control.Under-represented proteins occurred in the p53 signaling pathway, mitogen-activated protein kinase signaling pathway, cartilage development and angiogenesis inhibition in the PQ-treated lungs.The results suggest that PQ may generate reactive oxygen species, impair the MAPK/p53 signaling pathway, activate angiogenesis and depress apoptosis in the lungs.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI 96822, USA.

ABSTRACT

Paraquat (PQ) has been one of the most widely used herbicides in the world. PQ, when ingested, is toxic to humans and may cause acute respiratory distress syndrome. To investigate molecular perturbation in lung tissues caused by PQ, Sprague Dawley male rats were fed with PQ at a dose of 25 mg/kg body weight for 20 times in four weeks. The effects of PQ on cellular processes and biological pathways were investigated by analyzing proteome in the lung tissues in comparison with the control. Among the detected proteins, 321 and 254 proteins were over-represented and under-represented, respectively, in the PQ-exposed rat lung tissues in comparison with the no PQ control. All over- and under-represented proteins were subjected to Ingenuity Pathway Analysis to create 25 biological networks and 38 pathways of interacting protein clusters. Over-represented proteins were involved in the C-jun-amino-terminal kinase pathway, caveolae-mediated endocytosis signaling, cardiovascular-cancer-respiratory pathway, regulation of clathrin-mediated endocytosis, non-small cell lung cancer signaling, pulmonary hypertension, glutamate receptor, immune response and angiogenesis. Under-represented proteins occurred in the p53 signaling pathway, mitogen-activated protein kinase signaling pathway, cartilage development and angiogenesis inhibition in the PQ-treated lungs. The results suggest that PQ may generate reactive oxygen species, impair the MAPK/p53 signaling pathway, activate angiogenesis and depress apoptosis in the lungs.

No MeSH data available.


Related in: MedlinePlus

Canonical pathway and gene network analysis of the 26 identifiers that were expressed in the lungs of PQ-treated rats. The 26 identifiers were analyzed using IPA and the identifiers were grouped to 14 canonical biological process pathways. The synaptic long term depression, glutamate receptor signaling, SAPK/JNK signaling, neuropathic pain signaling in dorsal horn neurons and synaptic long term potentiation were found to be the dominant canonical pathways represented by the identifiers. A representative protein network of the dominant canonical pathways was then generated. The network was obtained by merging the 2 highest scored networks into one overall network; cell-to-signaling and interaction, nervous system development and function, cell cycle. C1orf38 was not involved in the highest scored network. Solid grey lines and dotted grey lines indicated direct and indirect interactions, respectively. Arrow-headed lines and simple lines without arrows indicated ‘acts on’ and ‘binding only’, respectively. Solid orange lines and dotted orange lines indicated highlighted direct and indirect interactions, respectively.
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Figure 6: Canonical pathway and gene network analysis of the 26 identifiers that were expressed in the lungs of PQ-treated rats. The 26 identifiers were analyzed using IPA and the identifiers were grouped to 14 canonical biological process pathways. The synaptic long term depression, glutamate receptor signaling, SAPK/JNK signaling, neuropathic pain signaling in dorsal horn neurons and synaptic long term potentiation were found to be the dominant canonical pathways represented by the identifiers. A representative protein network of the dominant canonical pathways was then generated. The network was obtained by merging the 2 highest scored networks into one overall network; cell-to-signaling and interaction, nervous system development and function, cell cycle. C1orf38 was not involved in the highest scored network. Solid grey lines and dotted grey lines indicated direct and indirect interactions, respectively. Arrow-headed lines and simple lines without arrows indicated ‘acts on’ and ‘binding only’, respectively. Solid orange lines and dotted orange lines indicated highlighted direct and indirect interactions, respectively.

Mentions: Synaptic long term depression was the strongest functional association identified for this set of 28 identifiers (p=1×10−5, Fischer’s exact test). The 26 identifiers that were detected in the PQ-treated rat lungs, but not in the PQ-free rat lungs (Table 2) were grouped to 14 canonical biological pathways. The dominant canonical pathways were the synaptic long term depression, glutamate receptor signaling, SAPK/c-Jun N-terminal kinase (JNK) signaling, neuropathic pain signaling in dorsal horn neurons, synaptic long term potentiating. One overall network was merged from the 2 highest scored (38, 25) networks (cell-to-cell signaling and interaction; cell cycle, cell-to-cell signaling and interaction) (Figure 6). Cell cycle was the highest network that was created with 26 identifiers. Among the 26 identifiers, protein THEMIS2 (C1orf38) has not been involved in the scored (38 and 25) networks since the Clorf38 belongs to the cellular development (score, 2). The pathway was activated with glutamate receptors (GRIA1, GRM1 and GRM5) and nitric oxide synthase 3 (NOS3) (Figure 6), which these proteins are involved in glutamate receptor signaling, neuropathic pain signaling in dorsal horn neurons and CREB signaling in neurons [52]. Huang et al. [55] reported that the activation of rat p38 MAPK protein increased the long term depression of synapse, which is dependent on rat GRM5 protein that was over-presented (Figure 6). Some of the expressed proteins in the network (Figure 6) were involved in the JNK pathway (DUSP10, MAPK8IP2, MAP3K1 and CASR), innate immune response (MARCO, NLRX1, FAIM3, Cd55/Daf2, BCL3 and RNF125), the macrophage inflammatory response (C1orf38) and angiogenesis (ROBO4, ELK3, COL4A2 and NOS3). The finding indicates that PQ induces oxidative stress, activation of antioxidant defense system and immune responses, and then leads to apoptotic death of neuronal cells in PQ-exposed lungs. The B-cell lymphoma 3-encoded protein homolog (BCL3) is related to T-helper 1 type immune response in nucleus as a transcriptional activator that promotes transcription of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) target genes. The NF-kB, controlling the transcription of DNA, is involved in cellular responses to stimuli and plays a key role in regulating the immune response to infection [56]. AP2-associated protein kinase 1 (AAK1) and NOS3 were related to the clathrin-mediated endocytosis and cardiovascular-cancer-respiratory pathway, respectively. In particular, the NOS3 pathway induces pulmonary hypertension, oxidation stress of heart. Regulation of clathrin-mediated endocytosis by AAK1 presents cell death of epithelia cell lines, cell death of kidney cell lines and cell death of embryonic cell lines [57]. CDKN2A-interacting protein (CDKN2AIP) is associated with the activation of TP53/p53 that can be induced by CDKN2Adependent and CDKN2A-independent pathways.


Pulmonary Proteome and Protein Networks in Response to the Herbicide Paraquat in Rats.

Cho IK, Jeong M, You AS, Park KH, Li QX - J Proteomics Bioinform (2015)

Canonical pathway and gene network analysis of the 26 identifiers that were expressed in the lungs of PQ-treated rats. The 26 identifiers were analyzed using IPA and the identifiers were grouped to 14 canonical biological process pathways. The synaptic long term depression, glutamate receptor signaling, SAPK/JNK signaling, neuropathic pain signaling in dorsal horn neurons and synaptic long term potentiation were found to be the dominant canonical pathways represented by the identifiers. A representative protein network of the dominant canonical pathways was then generated. The network was obtained by merging the 2 highest scored networks into one overall network; cell-to-signaling and interaction, nervous system development and function, cell cycle. C1orf38 was not involved in the highest scored network. Solid grey lines and dotted grey lines indicated direct and indirect interactions, respectively. Arrow-headed lines and simple lines without arrows indicated ‘acts on’ and ‘binding only’, respectively. Solid orange lines and dotted orange lines indicated highlighted direct and indirect interactions, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 6: Canonical pathway and gene network analysis of the 26 identifiers that were expressed in the lungs of PQ-treated rats. The 26 identifiers were analyzed using IPA and the identifiers were grouped to 14 canonical biological process pathways. The synaptic long term depression, glutamate receptor signaling, SAPK/JNK signaling, neuropathic pain signaling in dorsal horn neurons and synaptic long term potentiation were found to be the dominant canonical pathways represented by the identifiers. A representative protein network of the dominant canonical pathways was then generated. The network was obtained by merging the 2 highest scored networks into one overall network; cell-to-signaling and interaction, nervous system development and function, cell cycle. C1orf38 was not involved in the highest scored network. Solid grey lines and dotted grey lines indicated direct and indirect interactions, respectively. Arrow-headed lines and simple lines without arrows indicated ‘acts on’ and ‘binding only’, respectively. Solid orange lines and dotted orange lines indicated highlighted direct and indirect interactions, respectively.
Mentions: Synaptic long term depression was the strongest functional association identified for this set of 28 identifiers (p=1×10−5, Fischer’s exact test). The 26 identifiers that were detected in the PQ-treated rat lungs, but not in the PQ-free rat lungs (Table 2) were grouped to 14 canonical biological pathways. The dominant canonical pathways were the synaptic long term depression, glutamate receptor signaling, SAPK/c-Jun N-terminal kinase (JNK) signaling, neuropathic pain signaling in dorsal horn neurons, synaptic long term potentiating. One overall network was merged from the 2 highest scored (38, 25) networks (cell-to-cell signaling and interaction; cell cycle, cell-to-cell signaling and interaction) (Figure 6). Cell cycle was the highest network that was created with 26 identifiers. Among the 26 identifiers, protein THEMIS2 (C1orf38) has not been involved in the scored (38 and 25) networks since the Clorf38 belongs to the cellular development (score, 2). The pathway was activated with glutamate receptors (GRIA1, GRM1 and GRM5) and nitric oxide synthase 3 (NOS3) (Figure 6), which these proteins are involved in glutamate receptor signaling, neuropathic pain signaling in dorsal horn neurons and CREB signaling in neurons [52]. Huang et al. [55] reported that the activation of rat p38 MAPK protein increased the long term depression of synapse, which is dependent on rat GRM5 protein that was over-presented (Figure 6). Some of the expressed proteins in the network (Figure 6) were involved in the JNK pathway (DUSP10, MAPK8IP2, MAP3K1 and CASR), innate immune response (MARCO, NLRX1, FAIM3, Cd55/Daf2, BCL3 and RNF125), the macrophage inflammatory response (C1orf38) and angiogenesis (ROBO4, ELK3, COL4A2 and NOS3). The finding indicates that PQ induces oxidative stress, activation of antioxidant defense system and immune responses, and then leads to apoptotic death of neuronal cells in PQ-exposed lungs. The B-cell lymphoma 3-encoded protein homolog (BCL3) is related to T-helper 1 type immune response in nucleus as a transcriptional activator that promotes transcription of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) target genes. The NF-kB, controlling the transcription of DNA, is involved in cellular responses to stimuli and plays a key role in regulating the immune response to infection [56]. AP2-associated protein kinase 1 (AAK1) and NOS3 were related to the clathrin-mediated endocytosis and cardiovascular-cancer-respiratory pathway, respectively. In particular, the NOS3 pathway induces pulmonary hypertension, oxidation stress of heart. Regulation of clathrin-mediated endocytosis by AAK1 presents cell death of epithelia cell lines, cell death of kidney cell lines and cell death of embryonic cell lines [57]. CDKN2A-interacting protein (CDKN2AIP) is associated with the activation of TP53/p53 that can be induced by CDKN2Adependent and CDKN2A-independent pathways.

Bottom Line: The effects of PQ on cellular processes and biological pathways were investigated by analyzing proteome in the lung tissues in comparison with the control.Under-represented proteins occurred in the p53 signaling pathway, mitogen-activated protein kinase signaling pathway, cartilage development and angiogenesis inhibition in the PQ-treated lungs.The results suggest that PQ may generate reactive oxygen species, impair the MAPK/p53 signaling pathway, activate angiogenesis and depress apoptosis in the lungs.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI 96822, USA.

ABSTRACT

Paraquat (PQ) has been one of the most widely used herbicides in the world. PQ, when ingested, is toxic to humans and may cause acute respiratory distress syndrome. To investigate molecular perturbation in lung tissues caused by PQ, Sprague Dawley male rats were fed with PQ at a dose of 25 mg/kg body weight for 20 times in four weeks. The effects of PQ on cellular processes and biological pathways were investigated by analyzing proteome in the lung tissues in comparison with the control. Among the detected proteins, 321 and 254 proteins were over-represented and under-represented, respectively, in the PQ-exposed rat lung tissues in comparison with the no PQ control. All over- and under-represented proteins were subjected to Ingenuity Pathway Analysis to create 25 biological networks and 38 pathways of interacting protein clusters. Over-represented proteins were involved in the C-jun-amino-terminal kinase pathway, caveolae-mediated endocytosis signaling, cardiovascular-cancer-respiratory pathway, regulation of clathrin-mediated endocytosis, non-small cell lung cancer signaling, pulmonary hypertension, glutamate receptor, immune response and angiogenesis. Under-represented proteins occurred in the p53 signaling pathway, mitogen-activated protein kinase signaling pathway, cartilage development and angiogenesis inhibition in the PQ-treated lungs. The results suggest that PQ may generate reactive oxygen species, impair the MAPK/p53 signaling pathway, activate angiogenesis and depress apoptosis in the lungs.

No MeSH data available.


Related in: MedlinePlus