Advances in protein chemistry and structural biology最新文献

Studies focusing on characterizing circRNAs with the potential to translate into peptides are quickly advancing. It is helping to elucidate the roles played by circRNAs in several biological processes, especially in the emergence and development of diseases. While various tools are accessible for predicting coding regions within linear sequences, none have demonstrated accurate open reading frame detection in circular sequences, such as circRNAs. Here, we present cirCodAn, a novel tool designed to predict coding regions in circRNAs. We evaluated the performance of cirCodAn using datasets of circRNAs with strong translation evidence and showed that cirCodAn outperformed the other tools available to perform a similar task. Our findings demonstrate the applicability of cirCodAn to identify coding regions in circRNAs, which reveals the potential of use of cirCodAn in future research focusing on elucidating the biological roles of circRNAs and their encoded proteins. cirCodAn is freely available at https://github.com/denilsonfbar/cirCodAn.

The role of motor proteins in supporting intracellular transports of vesicles and organelles in mammalian cells has been known for decades. On the other hand, the function of motor proteins that support spermatogenesis is also well established since the deletion of motor protein genes leads to subfertility and/or infertility. Furthermore, mutations and genetic variations of motor protein genes affect fertility in men, but also a wide range of developmental defects in humans including multiple organs besides the testis. In this review, we seek to provide a summary of microtubule and actin-dependent motor proteins based on earlier and recent findings in the field. Since these two cytoskeletons are polarized structures, different motor proteins are being used to transport cargoes to different ends of these cytoskeletons. However, their involvement in germ cell transport across the blood-testis barrier (BTB) and the epithelium of the seminiferous tubules remains relatively unknown. It is based on recent findings in the field, we have provided a hypothetical model by which motor proteins are being used to support germ cell transport across the BTB and the seminiferous epithelium during the epithelial cycle of spermatogenesis. In our discussion, we have highlighted the areas of research that deserve attention to bridge the gap of research in relating the function of motor proteins to spermatogenesis.

Alzheimer's disease is progressive neurodegenerative disease characterize by the presence of extracellular accumulation of amyloid-β plaques and intracellular deposits of neurofibrillary tangles of Tau. Apart from axonal depositions pathological aggregated Tau protein is known to secrete into extracellular spaces and propagate through seeding mechanism. Microglia, the immune cells of the brain display modest ability to internalize the extracellular Tau and degrade it through endolysosomal pathway. However, the excessive burden of pathoproteins weakens the phagocytic ability of microglia. Extracellular supplementation of omega-3 fatty acids (n-3) may regulate the phagocytosis of microglia as they mediate the anti-inflammatory polarization of microglia through membrane lipid compositions changes. The internalization of extracellular Tau in the microglia is regulated by cortical membrane-associated actin remodeling driven by interplay of actin-binding proteins. On the other hand, Tau display capability bind and interact with various actin-binding protein owing to the presence of proline-rich domain in the structure and regulate their activation. In this study, we hypothesize that internalization of Tau in the presence of omega-3 fatty acids would propagate the Tau-mediated activation of actin-binding proteins as well as extracellular matrix and in turn modulate cortical actin remodeling for phagocytosis.

There are many things that can be used to characterize a protein. Size, isoelectric point, hydrophobicity, structure (primary to quaternary), and subcellular location are just a few parameters that are used. The most important feature of a protein, however, is its function. While there are many experiments that can indicate a protein's role, identifying the molecules it interacts with is probably the most definitive way of determining its function. Owing to technology limitations, protein interactions have historically been identified on a one molecule per experiment basis. The advent of high throughput multiplexed proteomic technologies in the 1990s, however, made identifying hundreds and thousands of proteins interactions within single experiments feasible. These proteomic technologies have dramatically increased the rate at which protein-protein interactions (PPIs) are discovered. While the improvement in mass spectrometry technology was an early driving force in the rapid pace of identifying PPIs, advances in sample preparation and chromatography have recently been propelling the field. In this chapter, we will discuss the importance of identifying PPIs and describe current state-of-the-art technologies that demonstrate what is currently possible in this important area of biological research.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor derived from parafollicular thyroid gland cells. In both hereditary MTC and sporadic forms, genetic changes result in fundamental changes, and prognosis and mutational status are highly correlated. In this work, biomarker genes (DEGs and DEmiRNAs) for MTC will be computationally identified in order to help in their diagnosis and treatment. The gene expression profiles of two different types of studies, namely without-treatment (wo-trt) and with-treatment (w-trt), are considered for discovering biomarkers. The datasets were retrieved from the GEO database, and the DEGs and DEmiRNAs were analyzed using ExpressAnalyst and GEO2R. The functional analysis of DEGs and DEmiRNAs was performed, and most of the pathways enriched related to thyroid oncological pathways such as MAPK pathway,mTOR pathway, and PI3K-AKT Signaling pathway. Through this conclusion, the RET gene was upregulated wo-trt; the dinaciclib treatment RET gene was down-regulated computationally. To optimize the therapeutic targeting of RET, greater research into the mechanisms regulating RET transcription is necessary.

Melatonin is an indolamine secreted to circulation by the pineal gland according to a circadian rhythm. Melatonin levels are higher during nighttime, and the principal function of this hormone is to organize the temporal night and day distribution of physiological adaptive processes. Besides hormonal pineal production, melatonin is synthesized in various organs and tissues like the ovaries or the placenta for local utilization. In addition to its function as a circadian messenger, melatonin is also associated with many physiological functions. For example, melatonin has antioxidant properties and is involved in the regulation of energy and bone metabolism, and reproduction. Melatonin impacts several stages of reproduction and the action across the hypothalamus-pituitary-gonadal axis is well described. However, it is not well understood how those actions impact the female reproductive hormones secretion nor the consequent physiological outcomes. Thus, the first part of this chapter describes the regulation of female reproductive hormone synthesis by melatonin. Moreover, melatonin and female reproductive hormones have coincident physiological functions. Life stages like pregnancy or menopause are characterized by alterations in the reproductive hormones secretion that may be associated with certain physiological stages. Therefore, the second part discusses whether melatonin fluctuations could have an overlapping role with reproductive hormones in contributing to clinical outcomes associated with pregnancy and menopause.

Immunosenescence is a pertinent factor in the mortality rate caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The changes in the immune system are strongly associated with age and provoke the deterioration of the individual's health. Traditional medical practices in ancient India effectively deal with COVID-19 by boosting natural immunity through medicinal plants. The anti-inflammatory and antiviral properties of Glycyrrhiza glabra are potent in fighting against COVID-19 and promote immunity boost against the severity of the infection. Athimadhura Chooranam, a polyherbal formulation containing Glycyrrhiza glabra as the main ingredient, is recommended as an antiviral Siddha herb by the Ministry of AYUSH. This paper is intended to identify the phytoconstituents of Glycyrrhiza glabra that are actively involved in preventing individuals from COVID-19 transmission. The modulated pathways, enrichment study, and drug-likeness are calculated from the target proteins of the phytoconstituents at the pharmacological activity (Pa) of more than 0.7. Liquiritigenin and Isoliquiritin, the natural compounds in Glycyrrhiza glabra, belong to the flavonoid class and exhibit ameliorative effects against COVID-19. The latter compound displays a higher protein interaction to a maximum of six, out of which HMOX1, PLAU, and PGR are top-hub genes. ADMET screening further confirms the significance of the abovementioned components containing better drug-likeness. The molecular docking and molecular dynamics method identified liquiritigenin as a possible lead molecule capable of inhibiting the activity of the major protease protein of SARS-CoV-2. The findings emphasize the importance of in silico network pharmacological assessments in delivering cost-effective, time-bound clinical drugs.

RSPO2 protein may provide valuable insights into the mechanism underlying various types of tumorigenesis. The role of RSPO2 in pan-cancer has not been reported so far. Therefore, this study aimed to provide a comprehensive analysis of RSPO2 from a pan-cancer perspective employing multiomics data. The expression profile and function of RSPO2 across different tumors were investigated using various web-based tools UALCAN, GEPIA, TIMER, Human Protein Atlas, cBioPortal, TISIDB, STRING, and Metascape to interpret the expression profile, promoter methylation status, genomic alterations, survival analysis, protein-protein interaction, correlation with immune cell subtypes, tumor immune microenvironment and enrichment analysis. Comprehensive pan-cancer analysis indicated that RSPO2 was significantly downregulated in eleven and upregulated in five tumor types compared to normal tissues, validation results further suggest RSPO2 was downregulated in most of the tumors. The protein level expression of RSPO2 was mostly low in malignant tissues. We found that RSPO2 was significantly related to individual pathological stages in BLCA, COAD, LUAD and LUSC. Prognostic analysis indicates that the high RSPO2 expression was significantly correlated with the poor prognosis in BRCA, KICH, KIRP, READ, and UCES. Furthermore, RSPO2 is frequently amplified, exhibits hypermethylated promoter in most cancers, and is associated with immune subtypes, molecular subtypes and immune cell infiltration. Finally, enrichment analysis showed that RSPO2 is involved in the regulation of the canonical Wnt pathway and neuronal development. The overall comprehensive pan-cancer analysis affirms that RSPO2 could be a promising diagnostic and prognostic biomarker and latent therapy target in the future.

Hormones play a crucial role in maintaining the normal human physiology. By acting as chemical messengers that facilitate the communication between different organs, tissues and cells of the body hormones assist in responding appropriately to external and internal stimuli that trigger growth, development and metabolic activities of the body. Any abnormalities in the hormonal composition and balance can lead to devastating health consequences. Hormones have been important therapeutic agents since the early 20th century, when it was realized that their exogenous supply could serve as a functional substitution for those hormones which are not produced enough or are completely lacking, endogenously. Insulin, the pivotal anabolic hormone in the body, was used for the treatment of diabetes mellitus, a metabolic disorder due to the absence or intolerance towards insulin, since 1921 and is the trailblazer in hormone therapeutics. At present the largest market share for therapeutic hormones is held by insulin. Many other hormones were introduced into clinical practice following the success with insulin. However, for the six decades following the introduction the first therapeutic hormone, there was no reliable method for producing human hormones. The most common source for hormones were animals, although semisynthetic and synthetic hormones were also developed. However, none of these were optimal because of their allergenicity, immunogenicity, lack of consistency in purity and most importantly, scalability. The advent of recombinant DNA technology was a game changer for hormone therapeutics. This revolutionary molecular biology tool made it possible to synthesize human hormones in microbial cell factories. The approach allowed for the synthesis of highly pure hormones which were structurally and biochemically identical to the human hormones. Further, the fermentation techniques utilized to produce recombinant hormones were highly scalable. Moreover, by employing tools such as site directed mutagenesis along with recombinant DNA technology, it became possible to amend the molecular structure of the hormones to achieve better efficacy and mimic the exact physiology of the endogenous hormone. The first recombinant hormone to be deployed in clinical practice was insulin. It was called biosynthetic human insulin to reflect the biological route of production. Subsequently, the biochemistry of recombinant insulin was modified using the possibilities of recombinant DNA technology and genetic engineering to produce analogues that better mimic physiological insulin. These analogues were tailored to exhibit pharmacokinetic and pharmacodynamic properties of the prandial and basal human insulins to achieve better glycemic control. The present chapter explores the principles of genetic engineering applied to therapeutic hormones by reviewing the evolution of therapeutic insulin and its analogues. It also focuses on how recombinant analogues account for the better

Recent advances in genome-wide studies have revealed numerous epigenetic regulations brought about by genes involved in cellular metabolism. Isocitrate dehydrogenase (IDH), an essential enzyme, that converts isocitrate into -ketoglutarate (KG) predominantly in the tricarboxylic acid (TCA) cycle, has gained particular importance due to its cardinal role in the metabolic pathway in cells. IDH1, IDH2, and IDH3 are the three isomeric IDH enzymes that have been shown to regulate cellular metabolism. Of particular importance, IDH2 genes are associated with several cancers, including gliomas, oligodendroglioma, and astrocytomas. These mutations lead to the production of oncometabolite D-2-hydroxyglutarate (D-2-HG), which accumulates in cells promoting tumor growth. The enhanced levels of D-2-HG competitively inhibit α-KG dependent enzymes, inhibiting cell TCA cycle, upregulating the cell growth and survival relevant HIF-1α pathway, promoting DNA hypermethylation related epigenetic activity, all of which synergistically contribute to carcinogenesis. The present review discusses epigenetic mechanisms inIDH2 regulation in cells and further its clinical implications.