RESUMEN
Tumor suppressor cylindromatosis protein (CYLD) regulates NF-κB and JNK signaling pathways by cleaving K63-linked poly-ubiquitin chain from its substrate molecules and thus preventing the progression of tumorigenesis and metastasis of the cancer cells. Mutations in CYLD can cause aberrant structure and abnormal functionality leading to tumor formation. In this study, we utilized several computational tools such as PANTHER, PROVEAN, PredictSNP, PolyPhen-2, PhD-SNP, PON-P2, and SIFT to find out deleterious nsSNPs. We also highlighted the damaging impact of those deleterious nsSNPs on the structure and function of the CYLD utilizing ConSurf, I-Mutant, SDM, Phyre2, HOPE, Swiss-PdbViewer, and Mutation 3D. We shortlisted 18 high-risk nsSNPs from a total of 446 nsSNPs recorded in the NCBI database. Based on the conservation profile, stability status, and structural impact analysis, we finalized 13 nsSNPs. Molecular docking analysis and molecular dynamic simulation concluded the study with the findings of two significant nsSNPs (R830K, H827R) which have a remarkable impact on binding affinity, RMSD, RMSF, radius of gyration, and hydrogen bond formation during CYLD-ubiquitin interaction. The principal component analysis compared native and two mutants R830K and H827R of CYLD that signify structural and energy profile fluctuations during molecular dynamic (MD) simulation. Finally, the protein-protein interaction network showed CYLD interacts with 20 proteins involved in several biological pathways that mutations can impair. Considering all these in silico analyses, our study recommended conducting large-scale association studies of nsSNPs of CYLD with cancer as well as designing precise medications against diseases associated with these polymorphisms.
RESUMEN
Having a previous history of sexually transmitted diseases (STDs) such as gonorrhea and chlamydia increases the chance of developing prostate cancer, the second most frequent malignant cancer among men. However, the molecular functions that cause the development of prostate cancer in persons with gonorrhea and chlamydia are yet unknown. In this study, we studied RNA-seq gene expression profiles using computational biology methods to find out potential biomarkers that could help us in understanding the patho-biological mechanisms of gonorrhea, chlamydia, and prostate cancer. Using statistical methods on the Gene Expression Omnibus (GEO) data sets, it was found that a total of 22 distinct differentially expressed genes were shared among these 3 diseases of which 14 were up-regulated (PGRMC1, TSC22D1, SH3BGRL, NNT, CTSC, FRMD3, CCR2, FAM210B, VCL, PTGS1, SLFN11, SLC40A1, PROS1, and DSE) and the remaining 8 genes were down-regulated (PRNP, HINT3, MARCKSL1, TMED10, SH3KBP1, ENSA, DERL1, and KMT2B). Investigation on these 22 unique dysregulated genes using Gene Ontology, BioCarta, KEGG, and Reactome revealed multiple altered molecular pathways, including regulation of amyloid precursor protein catabolic process, ferroptosis, effects on gene expression of Homo sapiens PPAR pathway, and innate immune system R-HSA-168249. Four significant hub proteins namely VCL, SH3KBP1, PRNP, and PGRMC1 were revealed by protein-protein interaction network analysis. By analyzing gene-transcription factors and gene-miRNAs interactions, significant transcription factors (POU2F2, POU2F1, GATA6, and HIVEP1) and posttranscriptional regulator microRNAs (hsa-miR-7-5p) were also identified. Three potential therapeutic compounds namely INCB3284, CCX915, and MLN-1202 were found to interact with up-regulated protein C-C chemokine receptor type 2 (CCR2) in protein-drug interaction analysis. The proposed biomarkers and therapeutic potential molecules could be investigated for potential pharmacological targets and activity in the fight against in patients with gonorrhea, chlamydia, and prostate cancer.
RESUMEN
Parkinson's disease (PD) is a neurodegenerative disorder responsible for shaking, rigidity, and trouble in walking and patients' coordination ability and physical stability deteriorate day by day. Bipolar disorder (BD) is a psychiatric disorder which is the reason behind extreme shiftiness in mood, and frequent mood inversion may reach too high called mania. People with BD have a greater chance of developing PD during the follow-up period. A lot of work has been done to understand the key factors for developing these 2 diseases. But the molecular functionalities that trigger the development of PD in people with BD are not clear yet. In our study, we are intended to identify the molecular biomarkers and pathways shared between BD and PD. We have investigated the RNA-Seq gene expression data sets of PD and BD. A total of 45 common unique genes (32 up-regulated and 13 down-regulated) abnormally expressed in both PD and BD were identified by applying statistical methods on the GEO data sets. Gene ontology (GO) and BioCarta, KEGG, and Reactome pathways analysis of these 45 common dysregulated genes identified numerous altered molecular pathways such as mineral absorption, Epstein-Barr virus infection, HTLV-I infection, antigen processing, and presentation. Analysis of protein-protein interactions revealed 9 significant hub-proteins, namely RPL21, RPL34, CKS2, B2M, TNFRSF10A, DTX2, HLA-B, ATP2A3, and TAPBP. Significant transcription factors (IRF8, SPI1, RUNX1, and FOXA1) and posttranscriptional regulator microRNAs (hsa-miR-491-3p and hsa-miR-1246) are also found by analyzing gene-transcription factors and gene-miRNAs interactions, respectively. Protein-drug interaction analysis revealed hub-protein B2M's interaction with molecular drug candidates like N-formylmethionine, 3-indolebutyric acid, and doxycycline. Finally, a link between pathological processes of PD and BD is identified at transcriptional level. This study may help us to predict the development of PD among the people suffering from BD and gives some clue to understand significant pathological mechanisms.