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Computational characterization and integrative analysis of proteins involved in spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
Pranitha Jenardhanan, Manivel Panneerselvam, Premendu P. Mathur
The combined expression profiling of both miRNA and their target mRNAs in normal versus impaired sperm donors was performed by Zhuang et al. In their study,37 they collected the testes from normal, obstructive azoospermia, and nonobstructive azoospermic patients. The differential expression of the miRNAs and mRNAs obtained was studied and results found that about 93 miRNAs and 4172 mRNAs were differentially expressed in obstructive azoospermia and nonobstructive azoospermic patients. Functional classification of these miRNA/mRNA pairs revealed that they are highly associated with spermatogenesis, cell meiosis, cell cycle, and development of secondary sexual characteristics. Interestingly, identified miRNAs were found to target multiple genes such as hsa-miR-199a-5p that targets spermatid-associated protein (SPERT), SPACA4, actin-like protein 7A (ACTL7A), testis-specific serine kinase 6 (TSSK6), and UBQLN3. Of these, the functional role of TSSK6 and UBQLN3 has been well studied. TSSK6 belongs to the testis-specific serine/threonine kinase family, and the downregulation associated with TSSK6 is observed to result in production of abnormal sperm morphology and is also associated with affecting sperm-egg fusion.38,39 UBQLN3, on the other hand, belongs to the family of ubiquitin-like proteins, and is a testis-specific gene essential for sperm function.40
Epigenetic Modifications of Histones
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
George Rasti, Alejandro Vaquero
Histones lysine residues can also be modified by addition of nine kDa proteins, the most relevant being ubiquitin. Ubiquitination associates with gene expression or repression (11). For instance, H2AK119 ubiquitination leads to polycomb-associated silencing, whereas mono-ubiquitination of histone H2B in p21 gene associates with p53-dependent transcriptional (12). Lysines can also undergo addition of SUMO1-3, ubiquitin-like proteins associated with gene activation and gene silencing (13).
Host and Pathogen-Specific Drug Targets in COVID-19
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Bruce D. Uhal, David Connolly, Farzaneh Darbeheshti, Yong-Hui Zheng, Ifeanyichukwu E. Eke, Yutein Chung, Lobelia Samavati
Besides being a viral protease, PLpro has been shown to exert its effects on the host antiviral immunity. It was discovered that PLpro functions as a deubiquitinating agent (DUB). This was further validated since both GRL0617 and Z93, another potential inhibitor for PLpro, were used as inhibitors for human ubiquitin carboxyl-terminal hydrolase 2 (USP)-2 [57]. However, PLpro shows more homology to the USP18 and its primary target is the host Ubiquitin-Like Protein interferon stimulated gene ISG15. ISG15 is induced by type I interferon (IFN-I) signaling via interferon-response factor (IRF) and functions like ubiquitination processing K48 [58], a process known as ISGlylation [59]. ISGlylation has two major antiviral functions. It can be directed to viral transcriptases/replicases to inhibit viral protein synthesis. Examples of that are seen for the influenza virus, where ISGylation of the replication complex protein NS1 shuts down virion production [59]. ISGlylation of host viral RNA sensors RIG-1 and MDA5 provides positive feedback of IFN-I responses as well as directly inhibits viral replication [60]. PLpro has been demonstrated to be a de-ISGlylation agent which directly cleaves ISG15 [61] (Figure 10.1). The role of PLpro and how it downregulates ISG15 was starting to merge, as a protease beside cleaving viral polyprotein, alternatively it antagonizes IFN-1-induced antiviral activities [58, 62, 63]. This implies that targeted drugs that inhibit PLpro are very important, as they are not only controlling viral replication but also restoring host responses to viral infections. Currently, it is not clear whether ISGlylation occurs directly at the SARS-CoV-2 RTC complex. Nevertheless, the role of PLpro and its antagonism on ISGlylation needs to be further studied.
A serum miRNAs signature for early diagnosis of bladder cancer
Published in Annals of Medicine, 2023
Zuhu Yu, Chong Lu, Yongqing Lai
The function annotation of the target genes was analyzed with Enrichr database and illustrated in Figure 5. Go analysis revealed that these genes were mostly enriched in intracellular membrane-bounded organelle, nucleus, intracellular vesicle, cyclin/CDK positive transcription elongation factor complex, serine/threonine kinase complex. Molecular function of the target genes was enriched in regulation of transcription, cellular response to transforming growth factor beta stimulus. Biological process of the target genes involved was enriched in sequence-specific DNA binding, protein serine/threonine kinase activator activity, cyclin-dependent protein serine/threonine kinase activator activity, ubiquitin-like protein ligase binding. KEGG pathway analysis indicated the target genes enriched in FOXO signaling pathway, MAPK signaling pathway, Relaxin signaling pathway, Hepatocellular carcinoma, pathways in cancer. The functional annotation implied that target genes of the three miRNAs may be involved in proliferation and progression of bladder cancer.
The therapeutic prospect of zinc oxide nanoparticles in experimentally induced diabetic nephropathy
Published in Tissue Barriers, 2023
Samia A. Abd El-Baset, Nehad F. Mazen, Rehab S. Abdul-Maksoud, Asmaa A. A. Kattaia
Although oxidative stress is an important factor during pathogenesis of DN,14 other pathways are also involved in autophagy.15 Hyperglycemia induced impaired podocyte autophagic activity through activation of mechanistic target of rapamycin (mTOR).16 mTOR is encoded by mTOR gene and related to the phosphatidylinositol kinase family proteins. It controls metabolism, growth and survival of the cells, and is regulated by hormones, growth factors and stressful conditions.17 In the same context, beclin-1 is an essential element in activating autophagy. It becomes a part of the autophagosome membrane and promotes autophagy nucleation.18 Microtubule-associated protein 1 light chain 3 (LC3) is a ubiquitin-like protein that is involved in autophagy. LC3 is cut to liberate the cytosolic LC3-I, which is transformed to the membrane-bound LC3-II that is then incorporated into autophagosomes. The increase of LC3-II signifies the number of autophagosomes.19 LC3 buildup is either due to enhanced autophagosome formation or decreased autophagosome-lysosome fusion. To differentiate between the two probabilities, p62 could be examined, its accumulation indicates blockage of autophagosome clearance. P62 protein acts as a receptor for ubiquitinated proteins, binds LC3-II followed by degradation in autolysosomes.20
Global proteomics of fibroblast cells treated with bacterial cyclic dinucleotides, c-di-GMP and c-di-AMP
Published in Journal of Oral Microbiology, 2022
Kenneth I. Onyedibe, Samira Elmanfi, Uma K. Aryal, Eija Könönen, Ulvi Kahraman Gürsoy, Herman O. Sintim
Accumulating evidences indicate that beyond upregulating the expression of interferons and cytokines via the STING pathway, CDNs also affect other non-STING pathways in a differential manner. For example, Woodward et al. demonstrated that c-di-AMP but not cGAMP binds to the oxidoreductase, RECON to regulate NF-kB [12]. cGAMP has also been shown to regulate ULK1 kinase via AMPK [13]. Using label-free quantitative proteomics, we previously demonstrated that c-di-GMP and 2ʹ3’cGAMP differentially affect pathways in macrophages [14]. As would be expected in macrophages, many of the proteins upregulated by the CDNs were related to cytokine signaling and interferon production including interferon-induced proteins 47, 202 and 204 (IFI47, IFI202, IFI204) and interferon-induced protein with tetratricopeptide repeats 1, 2 or 3 (IFIT1, IFIT2, IFIT3) [14]. Ubiquitin-like protein ISG15 (ISG15) was also significantly upregulated by cyclic dinucleotides [14]. The modulations of other processes by CDNs, other than inflammatory pathways, have not been fully characterized and this work aimed to fill this gap in knowledge, using fibroblast cell as a model.