Table 2.
Significant pathways identified by IPA bioinformatic software after 4 days LIM treatment with the p values and associated genes, that were in agreement to previous -omics studies. The p-value was calculated with the Fischer’s exact test and z-score represents activation or suppression of the corresponding pathway. NaN represents unpredicted.
| No | Pathway Name | p Value | Z Score | Molecules | Evidence from Gene Expression | Evidence from Protein Expression |
|---|---|---|---|---|---|---|
| 1 | Phototransduction Pathway | 0.000 | NaN | PRKACB, GNB1, RGS9BP, GRK1, PDE6B, PRKAR1A, RCVRN | [60] (Tkatchenko et al., 2019) [61] (Tkatchenko et al., 2018) | [45] (Shan et al., 2018) |
| 2 | Oxidative Phosphorylation | 0.000 | NaN | SDHA, ATP5B, COX5B, COX7A2, ATPAF2, CYB5A, NDUFAB1, NDUFB10 | [61] (Tkatchenko et al., 2018) [62] (Giummarra et al., 2018) | N/A |
| 3 | Mitochondrial Dysfunction | 0.000 | NaN | SDHA, ATP5B, COX5B, COX7A2, MAPK9, ATPAF2, CYB5A, NDUFAB1, NDUFB10 | [61] (Tkatchenko et al., 2018) [63] (Riddell and Crewther, 2017) | N/A |
| 4 | IL-1 Signaling | 0.000 | NaN | PRKACB, GNB1, MAPK9, GNG13, GNG3, PRKAR1A | [60] (Tkatchenko et al., 2019) | N/A |
| 5 | Huntington’s Disease Signaling | 0.000 | NaN | GNB1, SDHA, ATP5B, MAPK9, GNG13, DLG4, GNG3, AP2A2, SNAP25 | [60] (Tkatchenko et al., 2019) [62] (Giummarra et al., 2018) | N/A |
| 6 | Tight Junction Signaling | 0.001 | NaN | PRKACB, EPB41, TJP2, PPP2R2A, SNAP25, ACTA1, PRKAR1A | [60] (Tkatchenko et al., 2019) [64] (Zhang et al., 2010) | N/A |
| 7 | Tec Kinase Signaling | 0.001 | 1.000 | GNB1, RHOC, PAK2, MAPK9, GNG13, GNG3, ACTA1 | [60] (Tkatchenko et al., 2019) | N/A |
| 8 | Germ Cell-Sertoli Cell Junction Signaling | 0.001 | NaN | EPN1, RHOC, PAK2, ILK, MAPK9, ACTN4, ACTA1 | [60] (Tkatchenko et al., 2019) | N/A |
| 9 | Calcium Signaling | 0.001 | 1.000 | PRKACB, CAMK2A, CAMK2D, ATP2B3, TPM3, ACTA1, PRKAR1A | [60] (Tkatchenko et al., 2019) [61] (Tkatchenko et al., 2018) | N/A |
| 10 | α-Adrenergic Signaling | 0.001 | NaN | PRKACB, GNB1, GNG13, GNG3, PRKAR1A | [60] (Tkatchenko et al., 2019) [61] (Tkatchenko et al., 2018) | N/A |
| 11 | G Beta Gamma Signaling | 0.001 | 0.447 | PRKACB, GNB1, GNG13, GNG3, PRKAR1A | [60] (Tkatchenko et al., 2019) | N/A |
| 12 | TCA Cycle II (Eukaryotic) | 0.001 | NaN | SDHA, IDH3G, DLST | [62] (Giummarra et al., 2018) | N/A |
| 13 | CREB Signaling in Neurons | 0.001 | 1.000 | PRKACB, GNB1, CAMK2A, CAMK2D, GNG13, GNG3, PRKAR1A | [60] (Tkatchenko et al., 2019) [61] (Tkatchenko et al., 2018) | N/A |
| 14 | CDP-diacylglycerol Biosynthesis I | 0.001 | NaN | CDS1, AGPAT1, LPGAT1 | [60] (Tkatchenko et al., 2019) | N/A |
| 15 | Phosphatidylglycerol Biosynthesis II (Non-plastidic) | 0.001 | NaN | CDS1, AGPAT1, LPGAT1 | [60] (Tkatchenko et al., 2019) | N/A |
| 16 | Relaxin Signaling | 0.002 | NaN | PRKACB, GNB1, GNG13, GNG3, PDE6B, PRKAR1A | [60] (Tkatchenko et al., 2019) | N/A |
| 17 | Gαs Signaling | 0.003 | NaN | PRKACB, GNB1, GNG13, GNG3, PRKAR1A | [60] (Tkatchenko et al., 2019) [61] (Tkatchenko et al., 2018) | N/A |
| 18 | G Protein Signaling Mediated by Tubby | 0.003 | NaN | GNB1, GNG13, GNG3 | [60] (Tkatchenko et al., 2019) | N/A |
| 19 | Androgen Signaling | 0.003 | NaN | PRKACB, GNB1, GNG13, GNG3, PRKAR1A | [61] (Tkatchenko et al., 2018) | N/A |
| 20 | CXCR4 Signaling | 0.003 | 1.000 | GNB1, RHOC, PAK2, MAPK9, GNG13, GNG3 | [60] (Tkatchenko et al., 2019) | N/A |
| 21 | Melatonin Signaling | 0.003 | −1.000 | PRKACB, CAMK2A, CAMK2D, PRKAR1A | [60] (Tkatchenko et al., 2019) | [65] (Rada and Wiechmann, 2006) |
| 22 | Ephrin B Signaling | 0.004 | NaN | GNB1, EPHB2, GNG13, GNG3 | [61] (Tkatchenko et al., 2018) | N/A |
| 23 | Gαi Signaling | 0.004 | NaN | PRKACB, GNB1, GNG13, GNG3, PRKAR1A | [60] (Tkatchenko et al., 2019) [66] (Srinivasalu et al., 2018) | N/A |
| 24 | Purine Nucleotides De Novo Biosynthesis II | 0.004 | NaN | ADSS, PAICS | [60] (Tkatchenko et al., 2019) | N/A |
| 25 | RhoGDI Signaling | 0.004 | NaN | GNB1, RHOC, PAK2, GNG13, GNG3, ACTA1 | [60] (Tkatchenko et al., 2019) | N/A |
| 26 | Gustation Pathway | 0.004 | NaN | PRKACB, GNB1, GNG13, PDE6B, PRKAR1A | [61] (Tkatchenko et al., 2018) | N/A |
| 27 | Oleate Biosynthesis II (Animals) | 0.005 | NaN | SCD5, CYB5A | [60] (Tkatchenko et al., 2019) | N/A |
| 28 | Signaling by Rho Family GTPases | 0.005 | 1.000 | GNB1, RHOC, PAK2, MAPK9, GNG13, GNG3, ACTA1 | [60] (Tkatchenko et al., 2019) | N/A |
| 29 | P2Y Purigenic Receptor Signaling Pathway | 0.006 | NaN | PRKACB, GNB1, GNG13, GNG3, PRKAR1A | [60] (Tkatchenko et al., 2019) | N/A |
| 30 | Protein Kinase A Signaling | 0.007 | 1.633 | PRKACB, GNB1, CAMK2A, CAMK2D, GNG13, GNG3, GRK1, PDE6B, PRKAR1A | [60] (Tkatchenko et al., 2019)[61] (Tkatchenko et al., 2018) | N/A |
| 31 | ILK Signaling | 0.007 | 0.816 | PPP2R2A, RHOC, ILK, MAPK9, ACTN4, ACTA1 | [60] (Tkatchenko et al., 2019)[67] (Wu et al., 2018) | N/A |
| 32 | IL-8 Signaling | 0.007 | 1.000 | GNB1, RHOC, PAK2, MAPK9, GNG13, GNG3 | [60] (Tkatchenko et al., 2019) | N/A |
| 33 | Clathrin-mediated Endocytosis Signaling | 0.007 | NaN | EPN1, SYNJ1, RAB11B, EPHB2, AP2A2, ACTA1 | [60] (Tkatchenko et al., 2019) | N/A |
| 34 | D-myo-inositol (1,4,5)-trisphosphate Degradation | 0.010 | NaN | SYNJ1, BPNT1 | [60] (Tkatchenko et al., 2019) | N/A |
| 35 | CDK5 Signaling | 0.010 | −1.000 | PRKACB, PPP2R2A, MAPK9, PRKAR1A | [60] (Tkatchenko et al., 2019) | N/A |
| 36 | Regulation of eIF4 and p70S6K Signaling | 0.011 | NaN | RPS7, EIF4EBP2, PPP2R2A, EIF2B2, EIF3M | [60] (Tkatchenko et al., 2019)[61] (Tkatchenko et al., 2018) [68] (Zelinka et al., 2016) | N/A |
| 37 | EIF2 Signaling | 0.012 | NaN | RPS7, RPL8, EIF2B2, ACTA1, RPLP0, EIF3M | [60] (Tkatchenko et al., 2019) [61] (Tkatchenko et al., 2018) [ [69](Yang et al., 2015) [67] (Wu et al., 2018) | N/A |
| 38 | Spermine Biosynthesis | 0.017 | NaN | SMS | [61] (Tkatchenko et al., 2018) | |
| 39 | Ephrin Receptor Signaling | 0.017 | NaN | GNB1, EPHB2, PAK2, GNG13, GNG3 | [60] (Tkatchenko et al., 2019)[61] (Tkatchenko et al., 2018) | N/A |
| 40 | Super-pathway of D-myo-inositol (1,4,5)-trisphosphate Metabolism | 0.018 | NaN | SYNJ1, BPNT1 | [60] (Tkatchenko et al., 2019) | N/A |
| 41 | Synaptic Long Term Potentiation | 0.020 | 1.000 | PRKACB, CAMK2A, CAMK2D, PRKAR1A | [60] (Tkatchenko et al., 2019) [61] (Tkatchenko et al., 2018) | N/A |
| 42 | RAR Activation | 0.024 | NaN | PRKACB, SRA1, MAPK9, CRABP1, PRKAR1A | [60] (Tkatchenko et al., 2019) [70] (Huang et al., 2011) | [70] (Huang et al., 2011) [71] (Huo et al., 2013) |
| 43 | S-methyl-5-thio-α-D-ribose 1-phosphate Degradation | 0.026 | NaN | APIP | [61] (Tkatchenko et al., 2018) | N/A |
| 44 | Inosine-5’-phosphate Biosynthesis II | 0.026 | NaN | PAICS | [60] (Tkatchenko et al., 2019) | N/A |
| 45 | NRF2-mediated Oxidative Stress Response | 0.026 | NaN | AKR1A1, MAPK9, DNAJA1, MGST3, ACTA1 | [60] (Tkatchenko et al., 2019) [67] (Wu et al., 2018) | N/A |
| 46 | Antiproliferative Role of Somatostatin Receptor 2 | 0.027 | NaN | GNB1, GNG13, GNG3 | [60] (Tkatchenko et al., 2019)[61] (Tkatchenko et al., 2018) | N/A |
| 47 | BMP signaling pathway | 0.028 | NaN | PRKACB, MAPK9, PRKAR1A | [72] (Li et al., 2015) | [73] (Li et al., 2016) |
| 48 | Dopamine Receptor Signaling | 0.028 | NaN | PRKACB, PPP2R2A, PRKAR1A | [60] (Tkatchenko et al., 2019) [61] (Tkatchenko et al., 2018) | [74] (Feldkaemper and Schaeffel, 2013) [75] (Chen et al., 2017) [76] (Zhou et al., 2017) |
| 49 | Insulin Receptor Signaling | 0.033 | 0.000 | PRKACB, SYNJ1, EIF2B2, PRKAR1A | [60] (Tkatchenko et al., 2019) [77] (He et al., 2014) [78] (Penha et al., 2011) | [79] (Ritchey et al., 2012) |
| 50 | Xenobiotic Metabolism Signaling | 0.037 | NaN | SRA1, CAMK2A, CAMK2D, PPP2R2A, MAPK9, MGST3 | [60] (Tkatchenko et al., 2019) | N/A |
| 51 | HIPPO signaling | 0.039 | NaN | TJP2, PPP2R2A, DLG4 | [60] (Tkatchenko et al., 2019) [61] (Tkatchenko et al., 2018) | N/A |
| 52 | Integrin Signaling | 0.041 | −0.447 | RHOC, PAK2, ILK, ACTN4, ACTA1 | [60] (Tkatchenko et al., 2019)[61] (Tkatchenko et al., 2018) [80] (Tian et al., 2013) | N/A |
| 53 | cAMP-mediated signaling | 0.044 | 0.447 | PRKACB, CAMK2A, CAMK2D, PDE6B, PRKAR1A | [61] (Tkatchenko et al., 2018) [81] (Tao et al., 2013) | [82](Chun et al., 2015) |
| 54 | Regulation of Actin-based Motility by Rho | 0.044 | NaN | RHOC, PAK2, ACTA1 | [60] (Tkatchenko et al., 2019) [40] (Wu et al., 2018a) | N/A |
| 55 | Netrin Signaling | 0.044 | NaN | PRKACB, PRKAR1A | [60] (Tkatchenko et al., 2019) | N/A |
| 56 | Gαq Signaling | 0.049 | NaN | GNB1, RHOC, GNG13, GNG3 | [60] (Tkatchenko et al., 2019) | N/A |