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Proteomics study of the antifibrotic effects of α-mangostin in a rat model of renal fibrosis

Thana Chaeyklinthes
Thana Chaeyklinthes
, 
Vilailak Tiyao
Vilailak Tiyao
, 
Sittiruk Roytrakul
Sittiruk Roytrakul
, 
Narumon Phaonakrop
Narumon Phaonakrop
, 
Udomsri Showpittapornchai
Udomsri Showpittapornchai
 and 
Wisuit Pradidarcheep
Wisuit Pradidarcheep
   | Sep 25, 2019
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Article Category: Original article
Published Online: Sep 25, 2019
Page range: 149 - 160
DOI: https://doi.org/10.1515/abm-2019-0015
Keywords
© 2018 Thana Chaeyklinthes et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

Figure 1

Brief summary of GeLC-MS/MS and bioinformatics methodology. GeLC-MS/MS, gel liquid chromatography-tandem mass spectrometry
Brief summary of GeLC-MS/MS and bioinformatics methodology. GeLC-MS/MS, gel liquid chromatography-tandem mass spectrometry

Figure 2

Sirius Red staining of (A) control, (B) TAA, (C) TAA + AM groups and their respective threshold image for the quantification of percent area stained red. AM, α-mangostin; TAA, thioacetamide. Scale bars in blue and red represent 100 μm
Sirius Red staining of (A) control, (B) TAA, (C) TAA + AM groups and their respective threshold image for the quantification of percent area stained red. AM, α-mangostin; TAA, thioacetamide. Scale bars in blue and red represent 100 μm

Figure 3

Automated quantification of Sirius Red staining using ImageJ across the 3 experimental groups plotted as relative area (%) stained red. Bars indicate the means and error bars represent standard deviation (SD). ***P < 0.001 when the TAA group (mean ± SD; 4.86 ± 0.56%) was compared with the control (1.37 ± 0.55%) and TAA + AM group (2.50 ± 0.81%). **P < 0.01 (= 0.002) when the TAA + AM group (2.50 ± 0.81%) was compared with the control group AM, α-mangostin; TAA, thioacetamide
Automated quantification of Sirius Red staining using ImageJ across the 3 experimental groups plotted as relative area (%) stained red. Bars indicate the means and error bars represent standard deviation (SD). ***P < 0.001 when the TAA group (mean ± SD; 4.86 ± 0.56%) was compared with the control (1.37 ± 0.55%) and TAA + AM group (2.50 ± 0.81%). **P < 0.01 (= 0.002) when the TAA + AM group (2.50 ± 0.81%) was compared with the control group AM, α-mangostin; TAA, thioacetamide

Figure 4

Cflar protein (red node) and its functional partners upon analysis by STITCH 5.0. Analysis of the KEGG identified that Cflar is directly involved pathways corresponding to apoptosis, TNF signaling, NK-κB signaling, and Chagas disease (American trypanosomiasis). Uniprot accession: C0H5Y5, Mass: 55,059 Da, Cellular location: Cytosol. Cflar, CASP8 and FADD-like apoptosis regulator; KEGG, Kyoto Encyclopedia of Genes and Genomes; TNF, tumor necrosis factor
Cflar protein (red node) and its functional partners upon analysis by STITCH 5.0. Analysis of the KEGG identified that Cflar is directly involved pathways corresponding to apoptosis, TNF signaling, NK-κB signaling, and Chagas disease (American trypanosomiasis). Uniprot accession: C0H5Y5, Mass: 55,059 Da, Cellular location: Cytosol. Cflar, CASP8 and FADD-like apoptosis regulator; KEGG, Kyoto Encyclopedia of Genes and Genomes; TNF, tumor necrosis factor

Figure 5

Lamtor3 protein (red node) and its functional partners upon analysis by STITCH 5.0. Analysis of KEGG identified that Lamtor3 is directly involved in the MAPK signaling pathway, but may interface with other pathways including VEGF signaling and tumor formation such as those occurring in thyroid cancer, bladder cancer, endometrial cancer, glioma, non-small cell lung cancer, renal cell carcinoma, and melanoma through its interaction with Mapk1, Map2k1, Mapk3, Map2k2. Uniprot accession: Q5U204, Mass: 13,580 Da, Cellular location: Endosome. Lamtor3, Ragulator complex protein LAMTOR3; KEGG, Kyoto Encyclopedia of Genes and Genomes; VEGF, vascular endothelial growth factor
Lamtor3 protein (red node) and its functional partners upon analysis by STITCH 5.0. Analysis of KEGG identified that Lamtor3 is directly involved in the MAPK signaling pathway, but may interface with other pathways including VEGF signaling and tumor formation such as those occurring in thyroid cancer, bladder cancer, endometrial cancer, glioma, non-small cell lung cancer, renal cell carcinoma, and melanoma through its interaction with Mapk1, Map2k1, Mapk3, Map2k2. Uniprot accession: Q5U204, Mass: 13,580 Da, Cellular location: Endosome. Lamtor3, Ragulator complex protein LAMTOR3; KEGG, Kyoto Encyclopedia of Genes and Genomes; VEGF, vascular endothelial growth factor

Figure 6

Map3k14 protein (red node) and its functional partners upon analysis by STITCH 5.0. Analysis of KEGG identified that Map3k14 is directly involved in NF-κB signaling, Epstein–Barr virus infection, TNF signaling, and MAPK signaling, and apoptosis. Uniprot accession: D3ZTD1, Mass: 103,584 Da, Cellular location: Cytosol and Nucleus. KEGG, Kyoto Encyclopedia of Genes and Genomes; Map3k14, Mitogen-activated protein kinase kinase kinase 14; TNF, tumor necrosis factor
Map3k14 protein (red node) and its functional partners upon analysis by STITCH 5.0. Analysis of KEGG identified that Map3k14 is directly involved in NF-κB signaling, Epstein–Barr virus infection, TNF signaling, and MAPK signaling, and apoptosis. Uniprot accession: D3ZTD1, Mass: 103,584 Da, Cellular location: Cytosol and Nucleus. KEGG, Kyoto Encyclopedia of Genes and Genomes; Map3k14, Mitogen-activated protein kinase kinase kinase 14; TNF, tumor necrosis factor

Figure 7

Mapk8ip3 protein (red node) and its functional partners upon analysis by STITCH 5.0. Analysis of KEGG identified that Mapk8ip3 is directly involved in the MAPK signaling pathway. Mapk8ip3 may interface with activities that involve the JNK cascade because of its interaction with Mapk8, Mapk10, and Mapk9, which play important roles in apoptosis, inflammation, cytokine production, and metabolism activated in response to environmental stress. Uniprot accession: B0VXR4, Mass: 145,619 Da, Cellular location: Endoplasmic reticulum and Golgi apparatus. KEGG, Kyoto Encyclopedia of Genes and Genomes; JNK, c-Jun N-terminal kinase; Mapk8ip3, C-Jun-amino-terminal kinaseinteracting protein 3
Mapk8ip3 protein (red node) and its functional partners upon analysis by STITCH 5.0. Analysis of KEGG identified that Mapk8ip3 is directly involved in the MAPK signaling pathway. Mapk8ip3 may interface with activities that involve the JNK cascade because of its interaction with Mapk8, Mapk10, and Mapk9, which play important roles in apoptosis, inflammation, cytokine production, and metabolism activated in response to environmental stress. Uniprot accession: B0VXR4, Mass: 145,619 Da, Cellular location: Endoplasmic reticulum and Golgi apparatus. KEGG, Kyoto Encyclopedia of Genes and Genomes; JNK, c-Jun N-terminal kinase; Mapk8ip3, C-Jun-amino-terminal kinaseinteracting protein 3

Figure 8

Summarized hypothesized activities of AM and its related pathways. AM, α-mangostin; EMT, epithelial–mesenchymal transition; ERK, extracellular signal–regulated kinase; FAK, focal adhesion kinase; c-FLIP, Cflar also known as cellular FADD-like IL-1β-converting enzyme (FLICE)-inhibitory protein; IkB, inhibitors of NF-κB; IKKα, JNK, Mapk8ip3 also known as C-Jun N-terminal kinase; JIP3, JNK-interacting protein 3; JSAP, JNK-stress-activated protein kinase-associated protein 1; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; MP1, Lamtor3 also known as MEK partner 1; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; NIK, Map3k14 also known as NF-κB-inducing kinase; Raf, Rapidly accelerated fibrosarcoma proto-oncogene serine/threonine-protein kinase; Ras, rat sarcoma small GTPase; TGF-β, transforming growth factor-β; TNFR, Tumor necrosis factor receptor
Summarized hypothesized activities of AM and its related pathways. AM, α-mangostin; EMT, epithelial–mesenchymal transition; ERK, extracellular signal–regulated kinase; FAK, focal adhesion kinase; c-FLIP, Cflar also known as cellular FADD-like IL-1β-converting enzyme (FLICE)-inhibitory protein; IkB, inhibitors of NF-κB; IKKα, JNK, Mapk8ip3 also known as C-Jun N-terminal kinase; JIP3, JNK-interacting protein 3; JSAP, JNK-stress-activated protein kinase-associated protein 1; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; MP1, Lamtor3 also known as MEK partner 1; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; NIK, Map3k14 also known as NF-κB-inducing kinase; Raf, Rapidly accelerated fibrosarcoma proto-oncogene serine/threonine-protein kinase; Ras, rat sarcoma small GTPase; TGF-β, transforming growth factor-β; TNFR, Tumor necrosis factor receptor

Proteins correlated with quantified Sirius Red collagen staining identified by using the self-organizing tree algorithm of Mev software (version 4.6.1). We identified 68 proteins. Accession numbers searchable on NCBI and their identity details are tabulated. P-values from t tests are also tabulated to indicate the confidence of identification using Mascot software. The numbers in the column for each group represent the log2 ion peak intensity for each species.

NCBI accessionIdentity details†PControlTAATAA+AM
NP_036894.2Caspase-17.17E–031.59E+011.62E+011.55E+01
NP_001100608.1Protein strawberry notch homolog 14.09E–040.00E+001.74E+010.00E+00
NP_001005905.1T-complex protein 1 subunit beta5.40E–030.00E+001.75E+010.00E+00
NP_001020151.1Ankyrin repeat domain-containing protein 34A3.69E–031.67E+011.73E+011.65E+01
AAB82191.1Anti-fluorescein monoclonal IgM heavy chain5.22E–071.59E+011.67E+011.49E+01
NP_037081.2Beta-enolase6.56E–032.05E+012.12E+011.95E+01
NP_113948.1Bile salt export pump5.84E–031.91E+011.96E+011.76E+01
AAI66492.1Bms1 protein6.05E–031.59E+011.62E+011.55E+01
NP_058801.1Bone morphogenetic protein 3 precursor7.67E–031.95E+012.16E+011.86E+01
AAH98803.1C1r protein8.13E–041.82E+011.95E+011.85E+01
NP_001029036.1Cflar isoform 1‡1.38E–062.06E+012.06E+012.05E+01
NP_001099374.1CD209a molecule6.01E–031.34E+011.61E+011.43E+01
NP_001102339.1Cell death activator CIDE-B8.09E–030.00E+001.92E+010.00E+00
NP_001094143.1Mapk8ip3‡1.61E–041.64E+011.67E+011.54E+01
AAL86014.1Co-activator/regulatory zinc-finger protein NIF2.32E–031.85E+011.92E+011.80E+01
NP_690059.1Coagulation factor VII precursor3.99E–031.88E+011.97E+011.85E+01
NP_001137368.1Coiled-coil domain-containing protein 1376.79E–041.89E+011.95E+011.88E+01
NP_001004262.1Conserved oligomeric Golgi complex subunit 67.10E–031.85E+011.96E+011.76E+01
NP_598218.1CX3C chemokine receptor 18.30E–031.71E+011.83E+011.73E+01
NP_001013155.1C-X-C motif chemokine 14 precursor3.64E–031.66E+011.81E+011.69E+01
NP_001013201.1Cytosolic Fe-S cluster assembly factor NARFL2.90E–031.44E+011.68E+011.45E+01
NP_001129274.1Disks large-associated protein 58.75E–031.52E+011.63E+011.51E+01
NP_001102999.1DNA/RNA-binding protein KIN177.11E–031.98E+012.08E+011.85E+01
NP_064311.2E3 ubiquitin-protein ligase ARIH15.07E–031.59E+011.63E+011.49E+01
NP_620252.1Gamma-aminobutyric acid receptor subunit rho-3 precursor2.44E–031.40E+011.58E+011.40E+01
NP_036702.1Glutamate dehydrogenase 1, mitochondrial precursor4.81E–031.64E+011.85E+011.71E+01
NP_899653.2Glutathione peroxidase 27.58E–030.00E+001.64E+010.00E+00
NP_001007636.2GTPase activating protein testicular GAP13.01E–031.19E+011.28E+011.04E+01
NP_001101888.1HEAT repeat-containing protein 15.38E–031.82E+012.04E+011.84E+01
NP_001099862.1Heparan sulfate glucosamine 3-O-sulfotransferase 53.94E–031.65E+011.85E+011.66E+01
NP_001099302.1Homeobox protein DLX-3a7.95E–041.67E+011.79E+011.67E+01
NP_001102748.1Iron-sulfur cluster assembly 2 homolog, mitochondrial precursor1.56E–041.57E+011.72E+011.47E+01
ACX55121.1Jarid1d protein9.36E–031.43E+011.67E+011.41E+01
NP_001102270.1Krueppel-like factor 76.68E–041.62E+011.76E+011.66E+01
NP_001101180.1Leucine-rich repeats and immunoglobulin-like domains protein 2 precursor2.94E–041.87E+011.93E+011.81E+01
CAA62024.1Mature alpha chain of major histocompatibility complex class I antigen2.91E–031.67E+011.76E+011.58E+01
AFD32168.1Mitogen-activated protein kinase kinase kinase 15.26E–031.51E+011.66E+011.50E+01
NP_001101771.1Map3k14‡9.93E–040.00E+002.12E+010.00E+00
AAN86532.1Multidrug resistance-associated protein 12.53E–061.53E+011.60E+011.44E+01
NP_446266.2Myosin phosphatase Rho-interacting protein isoform 11.34E–041.36E+011.62E+011.45E+01
NP_663707.1N-acetyllactosaminide alpha-1,3-galactosyltransferase5.28E–031.84E+011.93E+011.87E+01
NP_001000033.1Olfactory receptor Olr15074.95E–031.65E+011.66E+011.61E+01
NP_001000682.1Olfactory receptor Olr4866.49E–041.64E+011.66E+011.59E+01
NP_001005384.1Oncostatin-M-specific receptor subunit beta precursor2.38E–041.76E+011.92E+011.61E+01
AAI69002.1Phosphatase, orphan 17.90E–031.92E+012.08E+011.94E+01
NP_114007.1Protocadherin Fat 1 precursor4.82E–040.00E+001.71E+010.00E+00
NP_536320.1Puromycin-sensitive aminopeptidase precursor7.38E–051.56E+011.71E+011.60E+01
NP_001008376.1Lamtor3‡3.60E–041.58E+011.64E+011.50E+01
NP_001103357.1Receptor-type tyrosine-protein phosphatase C isoform 3 precursor1.62E–031.72E+011.94E+011.65E+01
P38650.1Cytoplasmic dynein 1 heavy chain 16.45E–031.76E+011.92E+011.77E+01
AGG39759.1Rh-associated glycoprotein, partial1.93E–031.63E+011.67E+011.63E+01
NP_001161999.1Selenocysteine insertion sequence-binding protein 2-like7.31E–031.52E+011.63E+011.55E+01
NP_579826.1Seminal vesicle antigen-like 1 precursor1.50E–041.96E+011.99E+011.87E+01
NP_954526.1Seminal vesicle secretory protein 1 precursor3.13E–041.57E+011.60E+011.55E+01
AAL77056.1SH2 phosphatase 14.31E–031.88E+012.01E+011.93E+01
NP_001041645.1SH2B adapter protein 1 isoform 25.69E–041.79E+011.85E+011.81E+01
EDM04919.1Similar to G protein pathway suppressor 2, isoform CRA_d2.32E–031.60E+011.81E+011.61E+01
EDM18475.1Similar to RIKEN cDNA 1810020D17, isoform CRA_c6.74E–030.00E+001.74E+010.00E+00
NP_113871.1Structural maintenance of chromosomes protein 1A5.12E–031.76E+011.84E+011.73E+01
CAA33552.1Sucrase isomaltase, partial6.23E–031.61E+011.66E+011.62E+01
CAC37104.1TA1 KET beta protein7.79E–031.68E+011.76E+011.63E+01
BAH79733.1Tensin31.82E–031.63E+011.68E+011.65E+01
AAI60846.1Terf2 protein4.22E–050.00E+001.78E+010.00E+00
NP_001258196.1Transcription factor SOX-52.84E–041.59E+011.61E+011.55E+01
NP_620221.2Translation initiation factor eIF-2B subunit epsilon4.87E–051.42E+011.45E+011.36E+01
NP_001102110.2Tubulin monoglycylase TTLL32.82E–070.00E+001.68E+010.00E+00
NP_001100418.1Ubiquitin carboxyl-terminal hydrolase 268.37E–031.78E+011.86E+011.80E+01
NP_598280.1UDP-glucose:glycoprotein glucosyltransferase 1 precursor8.43E–031.95E+012.00E+011.84E+01
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