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1
Telling, Glenn. "Protein-based PCR for prion diseases?" Nature Medicine 7, no. 7 (July 2001): 778–79. http://dx.doi.org/10.1038/89895.
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Li, Yan, Yi Jia, Xiao-Lin Wang, Hai Shang, and Yu Tian. "Protein-Targeted Degradation Agents Based on Natural Products." Pharmaceuticals 16, no. 1 (December 28, 2022): 46. http://dx.doi.org/10.3390/ph16010046.
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Natural products are an important source of drug lead compounds, and natural products with significant biological activity are constantly being discovered and used in clinical practice. At present, natural products play an important role in the targeted therapy of cancer, cardiovascular and cerebrovascular diseases, nervous system diseases, and autoimmune diseases. Meanwhile, in recent years, the rise of protein-targeted degradation technologies, such as proteolysis-targeting chimeras (PROTACs) and molecular glues, has provided a new solution for drug resistance caused by clinical molecular-targeting drugs. It is noteworthy that natural products and their derivatives, as important components of PROTACs and molecular glues, play an important role in the development of protein-targeting drugs. Hence, this review summarized the protein-targeted degradation agents based on natural products, such as PROTACs and molecular glues. More natural products with the potential to be used in the development of PROTACs and molecular glues as targeted protein degradation agents are still being investigated.
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Yadav, Kusum, Anurag Yadav, Priyanka Vashistha, Veda P. Pandey, and Upendra N. Dwivedi. "Protein Misfolding Diseases and Therapeutic Approaches." Current Protein & Peptide Science 20, no. 12 (December 16, 2019): 1226–45. http://dx.doi.org/10.2174/1389203720666190610092840.
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Protein folding is the process by which a polypeptide chain acquires its functional, native 3D structure. Protein misfolding, on the other hand, is a process in which protein fails to fold into its native functional conformation. This misfolding of proteins may lead to precipitation of a number of serious diseases such as Cystic Fibrosis (CF), Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Amyotrophic Lateral Sclerosis (ALS) etc. Protein Quality-control (PQC) systems, consisting of molecular chaperones, proteases and regulatory factors, help in protein folding and prevent its aggregation. At the same time, PQC systems also do sorting and removal of improperly folded polypeptides. Among the major types of PQC systems involved in protein homeostasis are cytosolic, Endoplasmic Reticulum (ER) and mitochondrial ones. The cytosol PQC system includes a large number of component chaperones, such as Nascent-polypeptide-associated Complex (NAC), Hsp40, Hsp70, prefoldin and T Complex Protein-1 (TCP-1) Ring Complex (TRiC). Protein misfolding diseases caused due to defective cytosolic PQC system include diseases involving keratin/collagen proteins, cardiomyopathies, phenylketonuria, PD and ALS. The components of PQC system of Endoplasmic Reticulum (ER) include Binding immunoglobulin Protein (BiP), Calnexin (CNX), Calreticulin (CRT), Glucose-regulated Protein GRP94, the thiol-disulphide oxidoreductases, Protein Disulphide Isomerase (PDI) and ERp57. ER-linked misfolding diseases include CF and Familial Neurohypophyseal Diabetes Insipidus (FNDI). The components of mitochondrial PQC system include mitochondrial chaperones such as the Hsp70, the Hsp60/Hsp10 and a set of proteases having AAA+ domains similar to the proteasome that are situated in the matrix or the inner membrane. Protein misfolding diseases caused due to defective mitochondrial PQC system include medium-chain acyl-CoA dehydrogenase (MCAD)/Short-chain Acyl-CoA Dehydrogenase (SCAD) deficiency diseases, hereditary spastic paraplegia. Among therapeutic approaches towards the treatment of various protein misfolding diseases, chaperones have been suggested as potential therapeutic molecules for target based treatment. Chaperones have been advantageous because of their efficient entry and distribution inside the cells, including specific cellular compartments, in therapeutic concentrations. Based on the chemical nature of the chaperones used for therapeutic purposes, molecular, chemical and pharmacological classes of chaperones have been discussed.
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Teribele Venturin, Gianina, and Zhen Cheng. "Small Peptide and Protein-based Molecular Probes for Imaging Neurological Diseases." Current Protein & Peptide Science 17, no. 6 (July 15, 2016): 543–58. http://dx.doi.org/10.2174/1389203717666160101123500.
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Chaudhuri, Tapan K., and Subhankar Paul. "Protein-misfolding diseases and chaperone-based therapeutic approaches." FEBS Journal 273, no. 7 (April 2006): 1331–49. http://dx.doi.org/10.1111/j.1742-4658.2006.05181.x.
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Lorenzo-Pouso, Alejandro I., Mario Pérez-Sayáns, Susana B. Bravo, Pía López-Jornet, María García-Vence, Manuela Alonso-Sampedro, Javier Carballo, and Abel García-García. "Protein-Based Salivary Profiles as Novel Biomarkers for Oral Diseases." Disease Markers 2018 (November 7, 2018): 1–22. http://dx.doi.org/10.1155/2018/6141845.
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The Global Burden of Oral Diseases affects 3.5 billion people worldwide, representing the number of people affected by the burden of untreated dental caries, severe periodontal disease, and edentulism. Thus, much more efforts in terms of diagnostics and treatments must be provided in the fight of these outcomes. In this sense, recently, the study of saliva as biological matrix has been identified as a new landmark initiative in the search of novel and useful biomarkers to prevent and diagnose these conditions. Specifically, saliva is a rich reservoir of different proteins and peptides and accessible due to recent advances in molecular biology and specially in targeted and unbiased proteomics technologies. Nonetheless, emerging barriers are an obstacle to the study of the salivary proteome in an effective way. This review aims at giving an overall perspective of salivary biomarkers identified in several oral diseases by means of molecular biology approaches.
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Pang, Yihe, and Bin Liu. "DMFpred: Predicting protein disorder molecular functions based on protein cubic language model." PLOS Computational Biology 18, no. 10 (October 31, 2022): e1010668. http://dx.doi.org/10.1371/journal.pcbi.1010668.
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Intrinsically disordered proteins and regions (IDP/IDRs) are widespread in living organisms and perform various essential molecular functions. These functions are summarized as six general categories, including entropic chain, assembler, scavenger, effector, display site, and chaperone. The alteration of IDP functions is responsible for many human diseases. Therefore, identifying the function of disordered proteins is helpful for the studies of drug target discovery and rational drug design. Experimental identification of the molecular functions of IDP in the wet lab is an expensive and laborious procedure that is not applicable on a large scale. Some computational methods have been proposed and mainly focus on predicting the entropic chain function of IDRs, while the computational predictive methods for the remaining five important categories of disordered molecular functions are desired. Motivated by the growing numbers of experimental annotated functional sequences and the need to expand the coverage of disordered protein function predictors, we proposed DMFpred for disordered molecular functions prediction, covering disordered assembler, scavenger, effector, display site and chaperone. DMFpred employs the Protein Cubic Language Model (PCLM), which incorporates three protein language models for characterizing sequences, structural and functional features of proteins, and attention-based alignment for understanding the relationship among three captured features and generating a joint representation of proteins. The PCLM was pre-trained with large-scaled IDR sequences and fine-tuned with functional annotation sequences for molecular function prediction. The predictive performance evaluation on five categories of functional and multi-functional residues suggested that DMFpred provides high-quality predictions. The web-server of DMFpred can be freely accessed from http://bliulab.net/DMFpred/.
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Kovacs, Gabor G. "Molecular pathology of neurodegenerative diseases: principles and practice." Journal of Clinical Pathology 72, no. 11 (August 8, 2019): 725–35. http://dx.doi.org/10.1136/jclinpath-2019-205952.
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Neurodegenerative diseases are characterised by selective dysfunction and progressive loss of synapses and neurons associated with pathologically altered proteins that deposit primarily in the human brain and spinal cord. Recent discoveries have identified a spectrum of distinct immunohistochemically and biochemically detectable proteins, which serve as a basis for protein-based disease classification. Diagnostic criteria have been updated and disease staging procedures have been proposed. These are based on novel concepts which recognise that (1) most of these proteins follow a sequential distribution pattern in the brain suggesting a seeding mechanism and cell-to-cell propagation; (2) some of the neurodegeneration-associated proteins can be detected in peripheral organs; and (3) concomitant presence of neurodegeneration-associated proteins is more the rule than the exception. These concepts, together with the fact that the clinical symptoms do not unequivocally reflect the molecular pathological background, place the neuropathological examination at the centre of requirements for an accurate diagnosis. The need for quality control in biomarker development, clinical and neuroimaging studies, and evaluation of therapy trials, as well as an increasing demand for the general public to better understand human brain disorders, underlines the importance for a renaissance of postmortem neuropathological studies at this time. This review summarises recent advances in neuropathological diagnosis and reports novel aspects of relevance for general pathological practice.
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Gul, Irfan, Amreena Hassan, Ehtishamul Haq, Syed Mudasir Ahmad, Riaz Ahmad Shah, Nazir Ahmad Ganai, Naveed Anjum Chikan, Mohamed Faizal Abdul-Careem, and Nadeem Shabir. "An Investigation of the Antiviral Potential of Phytocompounds against Avian Infectious Bronchitis Virus through Template-Based Molecular Docking and Molecular Dynamics Simulation Analysis." Viruses 15, no. 4 (March 26, 2023): 847. http://dx.doi.org/10.3390/v15040847.
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Vaccination is widely used to control Infectious Bronchitis in poultry; however, the limited cross-protection and safety issues associated with these vaccines can lead to vaccination failures. Keeping these limitations in mind, the current study explored the antiviral potential of phytocompounds against the Infectious Bronchitis virus using in silico approaches. A total of 1300 phytocompounds derived from fourteen botanicals were screened for their potential ability to inhibit the main protease, papain-like protease or RNA-dependent RNA–polymerase of the virus. The study identified Methyl Rosmarinate, Cianidanol, Royleanone, and 6,7-Dehydroroyleanone as dual-target inhibitors against any two of the key proteins. At the same time, 7-alpha-Acetoxyroyleanone from Rosmarinus officinalis was found to be a multi-target protein inhibitor against all three proteins. The potential multi-target inhibitor was subjected to molecular dynamics simulations to assess the stability of the protein–ligand complexes along with the corresponding reference ligands. The findings specified stable interactions of 7-alpha-Acetoxyroyleanone with the protein targets. The results based on the in silico study indicate that the phytocompounds can potentially inhibit the essential proteins of the Infectious Bronchitis virus; however, in vitro and in vivo studies are required for validation. Nevertheless, this study is a significant step in exploring the use of botanicals in feed to control Infectious Bronchitis infections in poultry.
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Mishra and Dey. "Molecular Docking Studies of a Cyclic Octapeptide-Cyclosaplin from Sandalwood." Biomolecules 9, no. 11 (November 15, 2019): 740. http://dx.doi.org/10.3390/biom9110740.
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Natural products from plants, such as chemopreventive agents, attract huge attention because of their low toxicity and high specificity. The rational drug design in combination with structure-based modeling and rapid screening methods offer significant potential for identifying and developing lead anticancer molecules. Thus, the molecular docking method plays an important role in screening a large set of molecules based on their free binding energies and proposes structural hypotheses of how the molecules can inhibit the target. Several peptide-based therapeutics have been developed to combat several health disorders, including cancers, metabolic disorders, heart-related diseases, and infectious diseases. Despite the discovery of hundreds of such therapeutic peptides however, only few peptide-based drugs have made it to the market. Moreover, the in silico activities of cyclic peptides towards molecular targets, such as protein kinases, proteases, and apoptosis related proteins have not been extensively investigated. In this study, we explored the in silico kinase and protease inhibitor potentials of cyclosaplin, and studied the interactions of cyclosaplin with other apoptosis-related proteins. Previously, the structure of cyclosaplin was elucidated by molecular modeling associated with dynamics that were used in the current study as well. Docking studies showed strong affinity of cyclosaplin towards cancer-related proteins. The binding affinity closer to 10 kcal/mol indicated efficient binding. Cyclosaplin showed strong binding affinities towards protein kinases such as EGFR, VEGFR2, PKB, and p38, indicating its potential role in protein kinase inhibition. Moreover, it displayed strong binding affinity to apoptosis-related proteins and revealed the possible role of cyclosaplin in apoptotic cell death. The protein–ligand interactions using LigPlot displayed some similar interactions between cyclosaplin and peptide-based ligands, especially in case of protein kinases and a few apoptosis related proteins. Thus, the in silico analyses gave the insights of cyclosaplin being a potential apoptosis inducer and protein kinase inhibitor.
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Rajesh, Netra Unni, and Anam Qudrat. "Protein Chimera-based Ca2+ Rewiring as a Treatment Modality for Neurodegeneration." Current Psychopharmacology 8, no. 1 (March 18, 2019): 27–40. http://dx.doi.org/10.2174/2211556007666181001102702.
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Calcium is a versatile signaling molecule; a key regulator of an array of diverse cellular processes ranging from transcription to motility to apoptosis. It plays a critical role in neuronal signal transmission and energy metabolism through specialized mechanisms. Dysregulation of the Ca2+ signaling pathways has been linked to major psychiatric diseases. Here, we focus on molecular psychiatry, exploring the role of calcium signaling in neurological disease development and aggravation, specifically in Alzheimer’s and Huntington’s diseases. Understanding the molecular underpinnings helps us first to identify common mechanistic patterns, and second to develop targeted therapeutics for symptom alleviation. Specifically, we propose potential protein-level hallmarks of dysregulation that can be targeted using calcium-based chimeras (synthetic fusions of unrelated modular proteins) for localized pharmacotherapy.
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Ohue, Masahito, Yuki Kojima, and Takatsugu Kosugi. "Generating Potential Protein-Protein Interaction Inhibitor Molecules Based on Physicochemical Properties." Molecules 28, no. 15 (July 26, 2023): 5652. http://dx.doi.org/10.3390/molecules28155652.
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Protein-protein interactions (PPIs) are associated with various diseases; hence, they are important targets in drug discovery. However, the physicochemical empirical properties of PPI-targeted drugs are distinct from those of conventional small molecule oral pharmaceuticals, which adhere to the ”rule of five (RO5)”. Therefore, developing PPI-targeted drugs using conventional methods, such as molecular generation models, is challenging. In this study, we propose a molecular generation model based on deep reinforcement learning that is specialized for the production of PPI inhibitors. By introducing a scoring function that can represent the properties of PPI inhibitors, we successfully generated potential PPI inhibitor compounds. These newly constructed virtual compounds possess the desired properties for PPI inhibitors, and they show similarity to commercially available PPI libraries. The virtual compounds are freely available as a virtual library.
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Suratanee, Apichat, and Kitiporn Plaimas. "Reverse Nearest Neighbor Search on a Protein-Protein Interaction Network to Infer Protein-Disease Associations." Bioinformatics and Biology Insights 11 (January 1, 2017): 117793221772040. http://dx.doi.org/10.1177/1177932217720405.
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The associations between proteins and diseases are crucial information for investigating pathological mechanisms. However, the number of known and reliable protein-disease associations is quite small. In this study, an analysis framework to infer associations between proteins and diseases was developed based on a large data set of a human protein-protein interaction network integrating an effective network search, namely, the reverse k-nearest neighbor (R kNN) search. The R kNN search was used to identify an impact of a protein on other proteins. Then, associations between proteins and diseases were inferred statistically. The method using the R kNN search yielded a much higher precision than a random selection, standard nearest neighbor search, or when applying the method to a random protein-protein interaction network. All protein-disease pair candidates were verified by a literature search. Supporting evidence for 596 pairs was identified. In addition, cluster analysis of these candidates revealed 10 promising groups of diseases to be further investigated experimentally. This method can be used to identify novel associations to better understand complex relationships between proteins and diseases.
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Rochet, Jean-Christophe. "Novel therapeutic strategies for the treatment of protein-misfolding diseases." Expert Reviews in Molecular Medicine 9, no. 17 (June 2007): 1–34. http://dx.doi.org/10.1017/s1462399407000385.
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Most proteins in the cell adopt a compact, globular fold that determines their stability and function. Partial protein unfolding under conditions of cellular stress results in the exposure of hydrophobic regions normally buried in the interior of the native structure. Interactions involving the exposed hydrophobic surfaces of misfolded protein conformers lead to the formation of toxic aggregates, including oligomers, protofibrils and amyloid fibrils. A significant number of human disorders (e.g. Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and type II diabetes) are characterised by protein misfolding and aggregation. Over the past five years, outstanding progress has been made in the development of therapeutic strategies targeting these diseases. Three promising approaches include: (1) inhibiting protein aggregation with peptides or small molecules identified via structure-based drug design or high-throughput screening; (2) interfering with post-translational modifications that stimulate protein misfolding and aggregation; and (3) upregulating molecular chaperones or aggregate-clearance mechanisms. Ultimately, drug combinations that capitalise on more than one therapeutic strategy will constitute the most effective treatment for patients with these devastating illnesses.
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Singh, Om V. "Protein-misfolding diseases and the paradigm of proteomics-based therapeutic targets." Expert Review of Proteomics 7, no. 4 (August 2010): 463–64. http://dx.doi.org/10.1586/epr.10.71.
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Al-Suhaimi, Ebtesam, Vijaya Ravinayagam, B. Rabindran Jermy, Tarhini Mohamad, and Abdelhamid Elaissari. "Protein/ Hormone Based Nanoparticles as Carriers for Drugs Targeting Protein-Protein Interactions." Current Topics in Medicinal Chemistry 19, no. 6 (May 2, 2019): 444–56. http://dx.doi.org/10.2174/1568026619666190304152320.
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Background: In this review, protein-protein interactions (PPIs) were defined, and their behaviors in normal in disease conditions are discussed. Their status at nuclear, molecular and cellular level was underscored, as for their interference in many diseases. Finally, the use of protein nanoscale structures as possible carriers for drugs targeting PPIs was highlighted. Objective: The objective of this review is to suggest a novel approach for targeting PPIs. By using protein nanospheres and nanocapsules, a promising field of study can be emerged. Methods: To solidify this argument, PPIs and their biological significance was discussed, same as their role in hormone signaling. Results: We shed the light on the drugs that targets PPI and we suggested the use of nanovectors to encapsulate these drugs to possibly achieve better results. Conclusion: Protein based nanoparticles, due to their advantages, can be suitable carriers for drugs targeting PPIs. This can open a new opportunity in the emerging field of multifunctional therapeutics.
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Peng, Yunhui, Emil Alexov, and Sankar Basu. "Structural Perspective on Revealing and Altering Molecular Functions of Genetic Variants Linked with Diseases." International Journal of Molecular Sciences 20, no. 3 (January 28, 2019): 548. http://dx.doi.org/10.3390/ijms20030548.
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Structural information of biological macromolecules is crucial and necessary to deliver predictions about the effects of mutations—whether polymorphic or deleterious (i.e., disease causing), wherein, thermodynamic parameters, namely, folding and binding free energies potentially serve as effective biomarkers. It may be emphasized that the effect of a mutation depends on various factors, including the type of protein (globular, membrane or intrinsically disordered protein) and the structural context in which it occurs. Such information may positively aid drug-design. Furthermore, due to the intrinsic plasticity of proteins, even mutations involving radical change of the structural and physico–chemical properties of the amino acids (native vs. mutant) can still have minimal effects on protein thermodynamics. However, if a mutation causes significant perturbation by either folding or binding free energies, it is quite likely to be deleterious. Mitigating such effects is a promising alternative to the traditional approaches of designing inhibitors. This can be done by structure-based in silico screening of small molecules for which binding to the dysfunctional protein restores its wild type thermodynamics. In this review we emphasize the effects of mutations on two important biophysical properties, stability and binding affinity, and how structures can be used for structure-based drug design to mitigate the effects of disease-causing variants on the above biophysical properties.
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Tang, Yi-Wei, Gary W. Procop, and David H. Persing. "Molecular diagnostics of infectious diseases." Clinical Chemistry 43, no. 11 (November 1, 1997): 2021–38. http://dx.doi.org/10.1093/clinchem/43.11.2021.
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Abstract Over the past several years, the development and application of molecular diagnostic techniques has initiated a revolution in the diagnosis and monitoring of infectious diseases. Microbial phenotypic characteristics, such as protein, bacteriophage, and chromatographic profiles, as well as biotyping and susceptibility testing, are used in most routine laboratories for identification and differentiation. Nucleic acid techniques, such as plasmid profiling, various methods for generating restriction fragment length polymorphisms, and the polymerase chain reaction (PCR), are making increasing inroads into clinical laboratories. PCR-based systems to detect the etiologic agents of disease directly from clinical samples, without the need for culture, have been useful in rapid detection of unculturable or fastidious microorganisms. Additionally, sequence analysis of amplified microbial DNA allows for identification and better characterization of the pathogen. Subspecies variation, identified by various techniques, has been shown to be important in the prognosis of certain diseases. Other important advances include the determination of viral load and the direct detection of genes or gene mutations responsible for drug resistance. Increased use of automation and user-friendly software makes these technologies more widely available. In all, the detection of infectious agents at the nucleic acid level represents a true synthesis of clinical chemistry and clinical microbiology techniques.
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Sitkov, N. O., T. M. Zimina, V. V. Luchinin, A. A. Kolobov, A. A. Romanov, Yu D. Orekhov, A. V. Korlyakov, A. A. Ryabko, O. A. Naretskaya, and M. I. Kiseleva. "Hybrid-Integrated Biosensor for Express Determination of Protein Markers of Diseases based on Molecular Recognition and Direct Fluorimetric Detection." Nano- i Mikrosistemnaya Tehnika 23, no. 6 (December 23, 2021): 326–32. http://dx.doi.org/10.17587/nmst.23.326-332.
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Ways of creating new generation biosensors for multiparametric express diagnostics based on molecular recognition and direct fluorimetric registration of a peptide aptamer — protein marker complex were considered. The biosensor platform comprises a microfluidic channel for delivery sample solutions, coupled with flow-through zones containing covalently attached arrays of peptide probes — aptamers. An outer glass window of the biochip assembly contains a layer of luminophore ZnS:Cu, bound on it via an acrylic lacquer and intended for the re-emitting native fluorescence of bound proteins into the longer wavelength range, more efficient in registering signals with CMOS sensors. The aptamers were designed using "Protein 3D" program for analysis of spatial complementarity of protein structures. The peptide, complementary to Troponin T, was modified by replacement of aromatic amino acid residue while maintaining the spatial configuration. The complementarity of peptide and Troponin T was confirmed using a capillary electrophoresis-on-a-chip. Biosensors are manufactured using thick-film technology and photolithography. The fluorescence of marker proteins was excited using UV-LED with a radiation wavelength of 275 nm. The limit of detection achieved for Troponin T was 6 ng/ml.
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Ramly, Balqis, Nor Afiqah-Aleng, and Zeti-Azura Mohamed-Hussein. "Protein–Protein Interaction Network Analysis Reveals Several Diseases Highly Associated with Polycystic Ovarian Syndrome." International Journal of Molecular Sciences 20, no. 12 (June 18, 2019): 2959. http://dx.doi.org/10.3390/ijms20122959.
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Based on clinical observations, women with polycystic ovarian syndrome (PCOS) are prone to developing several other diseases, such as metabolic and cardiovascular diseases. However, the molecular association between PCOS and these diseases remains poorly understood. Recent studies showed that the information from protein–protein interaction (PPI) network analysis are useful in understanding the disease association in detail. This study utilized this approach to deepen the knowledge on the association between PCOS and other diseases. A PPI network for PCOS was constructed using PCOS-related proteins (PCOSrp) obtained from PCOSBase. MCODE was used to identify highly connected regions in the PCOS network, known as subnetworks. These subnetworks represent protein families, where their molecular information is used to explain the association between PCOS and other diseases. Fisher’s exact test and comorbidity data were used to identify PCOS–disease subnetworks. Pathway enrichment analysis was performed on the PCOS–disease subnetworks to identify significant pathways that are highly involved in the PCOS–disease associations. Migraine, schizophrenia, depressive disorder, obesity, and hypertension, along with twelve other diseases, were identified to be highly associated with PCOS. The identification of significant pathways, such as ribosome biogenesis, antigen processing and presentation, and mitophagy, suggest their involvement in the association between PCOS and migraine, schizophrenia, and hypertension.
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Kirkegaard, Thomas. "Development of heat shock protein based therapies for lysosomal diseases." Molecular Genetics and Metabolism 117, no. 2 (February 2016): S68. http://dx.doi.org/10.1016/j.ymgme.2015.12.322.
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Lindquist, Susan, Sylvia Krobitsch, Liming Li, and Neal Sondheimer. "Investigating protein conformation–based inheritance and disease in yeast." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 356, no. 1406 (February 28, 2001): 169–76. http://dx.doi.org/10.1098/rstb.2000.0762.
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Our work supports the hypothesis that a protein can serve as an element of genetic inheritance. This protein–only mechanism of inheritance is propagated in much the same way as hypothesized for the transmission of the protein–only infectious agent in the spongiform encephalopathies; hence these protein factors have been called yeast prions. Our work has focused on [ PSI + ], a dominant cytoplasmically inherited factor that alters translational fidelity.This change in translation is produced by a self–perpetuating change in the conformation of the translation–termination factor, Sup35. Most recently, we have determined that new elements of genetic inheritance can be created by deliberate genetic engineering, opening prospects for new methods of manipulating heredity. We have also uncovered evidence that other previously unknown elements of protein–based inheritance are encoded in the yeast genome. Finally, we have begun to use yeast as a model system for studying human protein folding diseases, such as Huntington's disease. Proteins responsible for some of these diseases have properties uncannily similar to those that produce protein–based mechanisms of inheritance.
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Nguyen, Thanh-Phuong, Laura Caberlotto, Melissa J. Morine, and Corrado Priami. "Network Analysis of Neurodegenerative Disease Highlights a Role of Toll-Like Receptor Signaling." BioMed Research International 2014 (2014): 1–16. http://dx.doi.org/10.1155/2014/686505.
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Despite significant advances in the study of the molecular mechanisms altered in the development and progression of neurodegenerative diseases (NDs), the etiology is still enigmatic and the distinctions between diseases are not always entirely clear. We present an efficient computational method based on protein-protein interaction network (PPI) to model the functional network of NDs. The aim of this work is fourfold: (i) reconstruction of a PPI network relating to the NDs, (ii) construction of an association network between diseases based on proximity in the disease PPI network, (iii) quantification of disease associations, and (iv) inference of potential molecular mechanism involved in the diseases. The functional links of diseases not only showed overlap with the traditional classification in clinical settings, but also offered new insight into connections between diseases with limited clinical overlap. To gain an expanded view of the molecular mechanisms involved in NDs, both direct and indirect connector proteins were investigated. The method uncovered molecular relationships that are in common apparently distinct diseases and provided important insight into the molecular networks implicated in disease pathogenesis. In particular, the current analysis highlighted the Toll-like receptor signaling pathway as a potential candidate pathway to be targeted by therapy in neurodegeneration.
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Sahu, Itishri, A. K. M. Ashiqul Haque, Brian Weidensee, Petra Weinmann, and Michael S. D. Kormann. "Recent Developments in mRNA-Based Protein Supplementation Therapy to Target Lung Diseases." Molecular Therapy 27, no. 4 (April 2019): 803–23. http://dx.doi.org/10.1016/j.ymthe.2019.02.019.
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Le, Vu Anh, Cam Quyen Thi Phan, and Thuy Huong Nguyen. "Data mining in mass spectrometry-based proteomics studies." Science & Technology Development Journal - Engineering and Technology 2, no. 4 (March 24, 2020): 258–76. http://dx.doi.org/10.32508/stdjet.v2i4.483.
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The post-genomic era consists of experimental and computational efforts to meet the challenge of clarifying and understanding the function of genes and their products. Proteomic studies play a key role in this endeavour by complementing other functional genomics approaches, encompasses the large-scale analysis of complex mixtures, including the identification and quantification of proteins expressed under different conditions, the determination of their properties, modifications and functions. Understanding how biological processes are regulated at the protein level is crucial to understanding the molecular basis of diseases and often highlights the prevention, diagnosis and treatment of diseases. High-throughput technologies are widely used in proteomics to perform the analysis of thousands of proteins. Specifically, mass spectrometry (MS) is an analytical technique for characterizing biological samples and is increasingly used in protein studies because of its targeted, nontargeted, and high performance abilities. However, as large data sets are created, computational methods such as data mining techniques are required to analyze and interpret the relevant data. More specifically, the application of data mining techniques in large proteomic data sets can assist in many interpretations of data; it can reveal protein-protein interactions, improve protein identification, evaluate the experimental methods used and facilitate the diagnosis and biomarker discovery. With the rapid advances in mass spectrometry devices and experimental methodologies, MS-based proteomics has become a reliable and necessary tool for elucidating biological processes at the protein level. Over the past decade, we have witnessed a great expansion of our knowledge of human diseases with the adoption of proteomic technologies based on MS, which leads to many interesting discoveries. Here, we review recent advances of data mining in MS-based proteomics in biomedical research. Recent research in many fields shows that proteomics goes beyond the simple classification of proteins in biological systems and finally reaches its initial potential – as an essential tool to aid related disciplines, notably biomedical research. From here, there is great potential for data mining in MS-based proteomics to move beyond basic research, into clinical research and diagnostics.
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Noelker, Carmen, Harald Hampel, and Richard Dodel. "Blood-Based Protein Biomarkers for Diagnosis and Classification of Neurodegenerative Diseases." Molecular Diagnosis & Therapy 15, no. 2 (April 2011): 83–102. http://dx.doi.org/10.1007/bf03256398.
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Rao, V. Srinivasa, K. Srinivas, G. N. Sujini, and G. N. Sunand Kumar. "Protein-Protein Interaction Detection: Methods and Analysis." International Journal of Proteomics 2014 (February 17, 2014): 1–12. http://dx.doi.org/10.1155/2014/147648.
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Protein-protein interaction plays key role in predicting the protein function of target protein and drug ability of molecules. The majority of genes and proteins realize resulting phenotype functions as a set of interactions. The in vitro and in vivo methods like affinity purification, Y2H (yeast 2 hybrid), TAP (tandem affinity purification), and so forth have their own limitations like cost, time, and so forth, and the resultant data sets are noisy and have more false positives to annotate the function of drug molecules. Thus, in silico methods which include sequence-based approaches, structure-based approaches, chromosome proximity, gene fusion, in silico 2 hybrid, phylogenetic tree, phylogenetic profile, and gene expression-based approaches were developed. Elucidation of protein interaction networks also contributes greatly to the analysis of signal transduction pathways. Recent developments have also led to the construction of networks having all the protein-protein interactions using computational methods for signaling pathways and protein complex identification in specific diseases.
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Yang, Qiya, Xi Zhang, Dhanasekaran Solairaj, Rouling Lin, Kaili Wang, and Hongyin Zhang. "TMT-Based Proteomic Analysis of Hannaella sinensis-Induced Apple Resistance-Related Proteins." Foods 12, no. 14 (July 8, 2023): 2637. http://dx.doi.org/10.3390/foods12142637.
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Studies on the molecular mechanism of antagonistic yeasts to control apple postharvest diseases are not comprehensive enough. Our preliminary investigations screened the biocontrol effect of Hannaella sinensis, an antagonistic yeast, and discovered its control efficacy on apple blue mold decay. However, the molecular mechanism of H. sinensis-induced resistance in apple has not been studied. In this study, proteins from apple treated with H. sinensis and sterile saline were analyzed using TMT proteomics technology. It was found that H. sinensis treatment induced the expressions of apple resistance-related proteins. Among the proteins in H. sinensis-induced apple, proteins related to plant defense mechanisms, such as reactive oxygen species scavenging, improvement of plant resistance and synthesis of resistant substances, improvement of plant disease resistance, the degradation of the pathogen cell wall, cell signaling, antibacterial activity, transport of defense-related substances, and protein processing, were differentially regulated. The results of this study revealed the underlying molecular mechanisms of H. sinensis-induced apple resistance at the protein level; the results also provided a theoretical basis for the commercial application of H. sinensis.
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Zhao, Jian-Hua, Hsuan-Liang Liu, Hsin-Yi Lin, Chih-Hung Huang, Hsu-Wei Fang, Shiao-Shing Chen, Yih Ho, Wei-Bor Tsai, and Wen-Yih Chen. "Chemical Chaperone and Inhibitor Discovery: Potential Treatments for Protein Conformational Diseases." Perspectives in Medicinal Chemistry 1 (January 2007): PMC.S212. http://dx.doi.org/10.4137/pmc.s212.
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Protein misfolding and aggregation cause a large number of neurodegenerative diseases in humans due to (i) gain of function as observed in Alzheimer's disease, Huntington's disease, Parkinson's disease, and Prion's disease or (ii) loss of function as observed in cystic fibrosis and α1-antitrypsin deficiency. These misfolded proteins could either lead to the formation of harmful amyloids that become toxic for the cells or to be recognized and prematurely degraded by the protein quality control system. An increasing number of studies has indicated that some low-molecular-weight compounds named as chemical chaperones can reverse the mislocalization and/or aggregation of proteins associated with human conformational diseases. These small molecules are thought to non-selectively stabilize proteins and facilitate their folding. In this review, we summarize the probable mechanisms of protein conformational diseases in humans and the use of chemical chaperones and inhibitors as potential therapeutic agents against these diseases. Furthermore, recent advanced experimental and theoretical approaches underlying the detailed mechanisms of protein conformational changes and current structure-based drug designs towards protein conformational diseases are also discussed. It is believed that a better understanding of the mechanisms of conformational changes as well as the biological functions of these proteins will lead to the development and design of potential interfering compounds against amyloid formation associated with protein conformational diseases.
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Wang, Li, and Nanbert Zhong. "Application of the ProteomeLab™ PF2D protein fractionation system in proteomic analysis for human genetic diseases." Open Chemistry 10, no. 3 (June 1, 2012): 836–43. http://dx.doi.org/10.2478/s11532-012-0033-2.
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AbstractProteomic analysis has been widely used in elucidating the mechanism of diseases. As a classical proteomic approach, two-dimensional gel electrophoresis (2DGE) has been commonly applied in finding differentially expressed proteins through a first dimension of separation by the isoelectric point (pI) of proteins and a second dimension of separation according to the molecular weight (MW) of proteins. Compared to 2DGE, a recently developed commercial system from Beckman Coulter, the two-dimensional protein fractionation (PF2D), separates proteins according to the pI of proteins in the first dimension followed by a second dimension of separation according to the degree of protein hydrophobicity. As a liquid-based fractionation system, PF2D could facilitate the extraction and separation of broader protein categories and improve reproducibility and quantification as well as be less labor-intensive, which are usually identified as limitations of a gel-based 2DGE platform. This review evaluates the applications of the PF2D system and discusses the perspectives and advantages of PF2D in the investigation of cancer and genetic disorders and in protein mapping in human biological fluids and cell cultures.
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Amano, Atsuo, Takayuki Nakamura, Shigenobu Kimura, Ichijiro Morisaki, Ichiro Nakagawa, Shigetada Kawabata, and Shigeyuki Hamada. "Molecular Interactions of Porphyromonas gingivalisFimbriae with Host Proteins: Kinetic Analyses Based on Surface Plasmon Resonance." Infection and Immunity 67, no. 5 (May 1, 1999): 2399–405. http://dx.doi.org/10.1128/iai.67.5.2399-2405.1999.
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ABSTRACT Fimbriae of Porphyromonas gingivalis are thought to play an important role in the colonization and invasion of periodontal tissues. In this study, we analyzed the interactions of P. gingivalis fimbriae with human hemoglobin, fibrinogen, and salivary components (i.e., proline-rich protein [PRP], proline-rich glycoprotein [PRG], and statherin) based on surface plasmon resonance (SPR) spectroscopy with a biomolecular interaction analyzing system (BIAcore). The real-time observation showed that the fimbriae interacted more quickly with hemoglobin and PRG than with other proteins and more intensely with fibrinogen. The significant association constant (k a) values obtained by BIAcore demonstrated that the interactions between fimbriae and these host proteins are specific. These estimated K avalues were not too different; however, the K avalues for hemoglobin (2.43 × 106) and fibrinogen (2.16 × 106) were statistically greater than those for the salivary proteins (1.48 × 106 to 1.63 × 106). The K a value of anti-fimbriae immunoglobulin G for fimbriae was estimated to be 1.22 × 107, which was 6.55-fold higher than the meanK a value of the host proteins. Peptide PRP-C, a potent inhibitor of PRP-fimbriae interaction, dramatically inhibited fimbrial association to PRP and PRG and was also inhibitory against other host proteins by BIAcore. The binding of fimbriae to these proteins was also evaluated by other methods with hydroxyapatite beads or polystyrene microtiter plates. The estimated binding abilities differed considerably, depending on the assay method that was used. It was noted that the binding capacity of PRP was strongly diminished by immobilization on a polystyrene surface. Taken together, these findings suggest that P. gingivalis fimbriae possess a strong ability to interact with the host proteins which promote bacterial adherence to the oral cavity and that SPR spectroscopy is a useful method for analyzing specific protein-fimbriae interactions.
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Dzieciatkowska, Monika, Guihong Qi, Jinsam You, Kerry G. Bemis, Heather Sahm, Howard M. Lederman, Thomas O. Crawford, Lawrence M. Gelbert, Cynthia Rothblum-Oviatt, and Mu Wang. "Proteomic Characterization of Cerebrospinal Fluid from Ataxia-Telangiectasia (A-T) Patients Using a LC/MS-Based Label-Free Protein Quantification Technology." International Journal of Proteomics 2011 (June 23, 2011): 1–13. http://dx.doi.org/10.1155/2011/578903.
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Cerebrospinal fluid (CSF) has been used for biomarker discovery of neurodegenerative diseases in humans since biological changes in the brain can be seen in this biofluid. Inactivation of A-T-mutated protein (ATM), a multifunctional protein kinase, is responsible for A-T, yet biochemical studies have not succeeded in conclusively identifying the molecular mechanism(s) underlying the neurodegeneration seen in A-T patients or the proteins that can be used as biomarkers for neurologic assessment of A-T or as potential therapeutic targets. In this study, we applied a high-throughput LC/MS-based label-free protein quantification technology to quantitatively characterize the proteins in CSF samples in order to identify differentially expressed proteins that can serve as potential biomarker candidates for A-T. Among 204 identified CSF proteins with high peptide-identification confidence, thirteen showed significant protein expression changes. Bioinformatic analysis revealed that these 13 proteins are either involved in neurodegenerative disorders or cancer. Future molecular and functional characterization of these proteins would provide more insights into the potential therapeutic targets for the treatment of A-T and the biomarkers that can be used to monitor or predict A-T disease progression. Clinical validation studies are required before any of these proteins can be developed into clinically useful biomarkers.
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Espay, Alberto J., Joaquin A. Vizcarra, Luca Marsili, Anthony E. Lang, David K. Simon, Aristide Merola, Keith A. Josephs, et al. "Revisiting protein aggregation as pathogenic in sporadic Parkinson and Alzheimer diseases." Neurology 92, no. 7 (February 11, 2019): 329–37. http://dx.doi.org/10.1212/wnl.0000000000006926.
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The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in SNCA gene multiplication or aggregated β-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic–molecular cohorts.
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Li, Xue, Lifeng Yang, Xiaopan Zhang, and Xiong Jiao. "Prediction of Protein-Protein Interactions Based on Domain." Computational and Mathematical Methods in Medicine 2019 (August 21, 2019): 1–7. http://dx.doi.org/10.1155/2019/5238406.
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Protein-protein interactions (PPIs) play a crucial role in various biological processes. To better comprehend the pathogenesis and treatments of various diseases, it is necessary to learn the detail of these interactions. However, the current experimental method still has many false-positive and false-negative problems. Computational prediction of protein-protein interaction has become a more important prediction method which can overcome the obstacles of the experimental method. In this work, we proposed a novel computational domain-based method for PPI prediction, and an SVM model for the prediction was built based on the physicochemical property of the domain. The outcomes of SVM and the domain-domain score were used to construct the prediction model for protein-protein interaction. The predicted results demonstrated the domain-based research can enhance the ability to predict protein interactions.
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Kumaran, Poojitha. "Molecular docking analysis of Indole based oxadiazoles with the H-binding protein from Treponema denticola." Bioinformation 19, no. 1 (January 31, 2023): 79–84. http://dx.doi.org/10.6026/97320630019084.
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Treponema denticola is a gram-negative bacteria that is associated with periodontal diseases. Literature derived, six indole based oxadiazole derivatives are docked with the target Factor H binding protein (fHbp) protein. Results show better docking interaction compared to clinically proven drugs and all compounds obey Lipinski’s rule of five. Hence, the compounds were inferred to be potential inhibitors for factor H binding protein of Treponema denticola.
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Gadhave, Kundlik, Prateek Kumar, Shivani Kapuganti, Vladimir Uversky, and Rajanish Giri. "Unstructured Biology of Proteins from Ubiquitin-Proteasome System: Roles in Cancer and Neurodegenerative Diseases." Biomolecules 10, no. 5 (May 21, 2020): 796. http://dx.doi.org/10.3390/biom10050796.
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The 26S proteasome is a large (~2.5 MDa) protein complex consisting of at least 33 different subunits and many other components, which form the ubiquitin proteasomal system (UPS), an ATP-dependent protein degradation system in the cell. UPS serves as an essential component of the cellular protein surveillance machinery, and its dysfunction leads to cancer, neurodegenerative and immunological disorders. Importantly, the functions and regulations of proteins are governed by the combination of ordered regions, intrinsically disordered protein regions (IDPRs) and molecular recognition features (MoRFs). The structure–function relationships of UPS components have not been identified completely; therefore, in this study, we have carried out the functional intrinsic disorder and MoRF analysis for potential neurodegenerative disease and anti-cancer targets of this pathway. Our report represents the presence of significant intrinsic disorder and disorder-based binding regions in several UPS proteins, such as extraproteasomal polyubiquitin receptors (UBQLN1 and UBQLN2), proteasome-associated polyubiquitin receptors (ADRM1 and PSMD4), deubiquitinating enzymes (DUBs) (ATXN3 and USP14), and ubiquitinating enzymes (E2 (UBE2R2) and E3 (STUB1) enzyme). We believe this study will have implications for the conformation-specific roles of different regions of these proteins. This will lead to a better understanding of the molecular basis of UPS-associated diseases.
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Sedov, Igor, and Diliara Khaibrakhmanova. "Molecular Mechanisms of Inhibition of Protein Amyloid Fibril Formation: Evidence and Perspectives Based on Kinetic Models." International Journal of Molecular Sciences 23, no. 21 (November 3, 2022): 13428. http://dx.doi.org/10.3390/ijms232113428.
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Inhibition of fibril formation is considered a possible treatment strategy for amyloid-related diseases. Understanding the molecular nature of inhibitor action is crucial for the design of drug candidates. In the present review, we describe the common kinetic models of fibril formation and classify known inhibitors by the mechanism of their interactions with the aggregating protein and its oligomers. This mechanism determines the step or steps of the aggregation process that become inhibited and the observed changes in kinetics and equilibrium of fibril formation. The results of numerous studies indicate that possible approaches to antiamyloid inhibitor discovery include the search for the strong binders of protein monomers, cappers blocking the ends of the growing fibril, or the species absorbing on the surface of oligomers preventing nucleation. Strongly binding inhibitors stabilizing the native state can be promising for the structured proteins while designing the drug candidates targeting disordered proteins is challenging.
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Opo, F. A. Dain Md, Saleh Alkarim, Ghadeer I. Alrefaei, Mohammad Habibur Rahman Molla, Nouf H. Alsubhi, Faisal Alzahrani, and Foysal Ahammad. "Pharmacophore-Model-Based Virtual-Screening Approaches Identified Novel Natural Molecular Candidates for Treating Human Neuroblastoma." Current Issues in Molecular Biology 44, no. 10 (October 13, 2022): 4838–58. http://dx.doi.org/10.3390/cimb44100329.
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The mortality of cancer patients with neuroblastoma is increasing due to the limited availability of specific treatment options. Few drug candidates for combating neuroblastoma have been developed, and identifying novel therapeutic candidates against the disease is an urgent issue. It has been found that muc-N protein is amplified in one-third of human neuroblastomas and expressed as an attractive drug target against the disease. The myc-N protein interferes with the bromodomain and extraterminal (BET) family proteins. Pharmacologically inhibition of the protein potently depletes MYCN in neuroblastoma cells. BET inhibitors target MYCN transcription and show therapeutic efficacy against neuroblastoma. Therefore, the study aimed to identify potential inhibitors against the BET family protein, specifically Brd4 (brodamine-containing protein 4), to hinder the activity of neuroblastoma cells. To identify effective molecular candidates against the disease, a structure-based pharmacophore model was created for the binding site of the Brd4 protein. The pharmacophore model generated from the protein Brd4 was validated to screen potential natural active compounds. The compounds identified through the pharmacophore-model-based virtual-screening process were further screened through molecular docking, ADME (absorption, distribution, metabolism, and excretion), toxicity, and molecular dynamics (MD) simulation approach. The pharmacophore-model-based screening process initially identified 136 compounds, further evaluated based on molecular docking, ADME analysis, and toxicity approaches, identifying four compounds with good binding affinity and lower side effects. The stability of the selected compounds was also confirmed by dynamic simulation and molecular mechanics with generalized Born and surface area solvation (MM-GBSA) methods. Finally, the study identified four natural lead compounds, ZINC2509501, ZINC2566088, ZINC1615112, and ZINC4104882, that will potentially inhibit the activity of the desired protein and help to fight against neuroblastoma and related diseases. However, further evaluations through in vitro and in vivo assays are suggested to identify their efficacy against the desired protein and disease.
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Tiwari, Kunal, Rahul Saxena, and Dr Sarika Saxena. "MOLECULAR TECHNIQUES ADOPTED AGAINST SARS-COV-2 IN VACCINE DEVELOPMENT." International Journal of Engineering Applied Sciences and Technology 6, no. 6 (October 1, 2021): 197–206. http://dx.doi.org/10.33564/ijeast.2021.v06i06.028.
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In this review, we attempted to highlight the uniqueness and difference among vaccines. Vaccine is a biological preparation that improves immunity to diseases and protect us from Covid 19. The term vaccine applies to all biological preparations produced by the living organisms, that enhance immunity against disease and the techniques used for the development of vaccines were reverse vaccinology, structural vaccinology, synthetic biology, and vaccine adjuvants. Besides these mRNA vaccines, we will also highlight the Protein subunit vaccines, which include separated proteins from viral or bacterial diseases, vaccines improve the immune system's "memorization" of the pathogen by imitating a milder form of disease, might provide a viable alternative to the mRNA-based coronavirus vaccines and discuss their advantages and disadvantages over the mRNA-based vaccines.
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Ali, Yasir, Hina Imtiaz, Muhammad Mutaal Tahir, Fouzia Gul, Umair Ali Khan Saddozai, Ashfaq ur Rehman, Zhi-Guang Ren, Saadullah Khattak, and Xin-Ying Ji. "Fragment-Based Approaches Identified Tecovirimat-Competitive Novel Drug Candidate for Targeting the F13 Protein of the Monkeypox Virus." Viruses 15, no. 2 (February 19, 2023): 570. http://dx.doi.org/10.3390/v15020570.
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Monkeypox is a serious public health issue in tropical and subtropical areas. Antivirals that target monkeypox proteins might lead to more effective and efficient therapy. The F13 protein is essential for the growth and maturation of the monkeypox virus. F13 inhibition might be a viable therapeutic target for monkeypox. The in silico fragment-based drug discovery method for developing antivirals may provide novel therapeutic options. In this study, we generated 800 compounds based on tecovirimat, an FDA-approved drug that is efficacious at nanomolar quantities against monkeypox. These compounds were evaluated to identify the most promising fragments based on binding affinity and pharmacological characteristics. The top hits from the chemical screening were docked into the active site of the F13 protein. Molecular dynamics simulations were performed on the top two probable new candidates from molecular docking. The ligand–enzyme interaction analysis revealed that the C2 ligand had lower binding free energy than the standard ligand tecovirimat. Water bridges, among other interactions, were shown to stabilize the C2 molecule. Conformational transitions and secondary structure changes in F13 protein upon C2 binding show more native three-dimensional folding of the protein. Prediction of pharmacological properties revealed that compound C2 may be promising as a drug candidate for monkeypox fever. However, additional in vitro and in vivo testing is required for validation.
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Mazanetz, Michael P., Ian M. Withers, Charles A. Laughton, and Peter M. Fischer. "Exploiting glycogen synthase kinase 3β flexibility in molecular recognition." Biochemical Society Transactions 36, no. 1 (January 22, 2008): 55–58. http://dx.doi.org/10.1042/bst0360055.
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GSK3β (glycogen synthase kinase 3β) is involved in the phosphorylation of various important regulatory proteins. Pharmacological inhibition of this enzyme could yield treatments for a variety of diseases including diabetes and Alzheimer's disease. The understanding of events involved in the molecular recognition of inhibitors by the active site of this enzyme is key in structure-based design strategies. The present study deals with the dynamic nature of GSK3β and highlights the importance of studying protein plasticity in structure-based drug design, exemplified by our method called ASP (active-site pressurization).
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Barresi, Vincenza, Camillo Musmeci, Alessandro Rinaldi, and Daniele Filippo Condorelli. "Transcript-Targeted Therapy Based on RNA Interference and Antisense Oligonucleotides: Current Applications and Novel Molecular Targets." International Journal of Molecular Sciences 23, no. 16 (August 9, 2022): 8875. http://dx.doi.org/10.3390/ijms23168875.
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The development of novel target therapies based on the use of RNA interference (RNAi) and antisense oligonucleotides (ASOs) is growing in an exponential way, challenging the chance for the treatment of the genetic diseases and cancer by hitting selectively targeted RNA in a sequence-dependent manner. Multiple opportunities are taking shape, able to remove defective protein by silencing RNA (e.g., Inclisiran targets mRNA of protein PCSK9, permitting a longer half-life of LDL receptors in heterozygous familial hypercholesteremia), by arresting mRNA translation (i.e., Fomivirsen that binds to UL123-RNA and blocks the translation into IE2 protein in CMV-retinitis), or by reactivating modified functional protein (e.g., Eteplirsen able to restore a functional shorter dystrophin by skipping the exon 51 in Duchenne muscular dystrophy) or a not very functional protein. In this last case, the use of ASOs permits modifying the expression of specific proteins by modulating splicing of specific pre-RNAs (e.g., Nusinersen acts on the splicing of exon 7 in SMN2 mRNA normally not expressed; it is used for spinal muscular atrophy) or by downregulation of transcript levels (e.g., Inotersen acts on the transthryretin mRNA to reduce its expression; it is prescribed for the treatment of hereditary transthyretin amyloidosis) in order to restore the biochemical/physiological condition and ameliorate quality of life. In the era of precision medicine, recently, an experimental splice-modulating antisense oligonucleotide, Milasen, was designed and used to treat an 8-year-old girl affected by a rare, fatal, progressive form of neurodegenerative disease leading to death during adolescence. In this review, we summarize the main transcriptional therapeutic drugs approved to date for the treatment of genetic diseases by principal regulatory government agencies and recent clinical trials aimed at the treatment of cancer. Their mechanism of action, chemical structure, administration, and biomedical performance are predominantly discussed.
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Xiao, Maolin, Jianjun Li, Qingyuan Liu, Xiangbiao He, Zongke Yang, and Delin Wang. "Expression and Role of TRIM2 in Human Diseases." BioMed Research International 2022 (August 23, 2022): 1–14. http://dx.doi.org/10.1155/2022/9430509.
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Tripartite motif (TRIM) protein family proteins contain more than 80 members in humans, and most of these proteins exhibit E3 ubiquitin ligase activity mediated through a RING finger domain. Their biological functions are very complex, and they perform diverse functions in cell evolution processes, such as intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy, and carcinogenesis. Tripartite motif-containing protein 2 (TRIM2), a member of the TRIM superfamily, is an 81 kDa multidomain protein, also known as CMT2R or RNF86, located at 4q31.3. TRIM2 functions as an E3 ubiquitin ligase. Current studies have shown that TRIM2 can play roles in neuroprotection, neuronal rapid ischemic tolerance, antiviral responses, neurological diseases, etc. Moreover, based on some studies in tumors, TRIM2 regulates tumor proliferation, migration, invasion, apoptosis, and drug resistance through different mechanisms and plays a critical role in tumor occurrence and development. This review is aimed at providing a systematic and comprehensive summary of research on TRIM2 and at exploring the potential role of TRIM2 as a biomarker and therapeutic target in many kinds of human diseases.
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Kim, Yoonbee, Jong-Hoon Park, and Young-Rae Cho. "Network-Based Approaches for Disease-Gene Association Prediction Using Protein-Protein Interaction Networks." International Journal of Molecular Sciences 23, no. 13 (July 3, 2022): 7411. http://dx.doi.org/10.3390/ijms23137411.
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Genome-wide association studies (GWAS) can be used to infer genome intervals that are involved in genetic diseases. However, investigating a large number of putative mutations for GWAS is resource- and time-intensive. Network-based computational approaches are being used for efficient disease-gene association prediction. Network-based methods are based on the underlying assumption that the genes causing the same diseases are located close to each other in a molecular network, such as a protein-protein interaction (PPI) network. In this survey, we provide an overview of network-based disease-gene association prediction methods based on three categories: graph-theoretic algorithms, machine learning algorithms, and an integration of these two. We experimented with six selected methods to compare their prediction performance using a heterogeneous network constructed by combining a genome-wide weighted PPI network, an ontology-based disease network, and disease-gene associations. The experiment was conducted in two different settings according to the presence and absence of known disease-associated genes. The results revealed that HerGePred, an integrative method, outperformed in the presence of known disease-associated genes, whereas PRINCE, which adopted a network propagation algorithm, was the most competitive in the absence of known disease-associated genes. Overall, the results demonstrated that the integrative methods performed better than the methods using graph-theory only, and the methods using a heterogeneous network performed better than those using a homogeneous PPI network only.
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Кандалова, О. В., Д. Е. Ключникова, and И. В. Елистратова. "Zinc-based treatment of atopic dermatitis and other skin diseases." Nauchno-prakticheskii zhurnal «Patogenez», no. 4 (January 24, 2022): 67–74. http://dx.doi.org/10.25557/2310-0435.2021.04.67-74.
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Цель работы - изучить влияние препаратов цинка на уровень экспрессии белков, ассоциированных со стрессом, в лимфоцитах крови больных атопическим дерматитом (АД) в зависимости от уровня цинка в сыворотке крови. Методы. Кровь брали натощак. Определяли концентрацию цинка в сыворотке крови методом абсобрционной спектроскопии. Лимфоциты выделяли на гралиенте плотности Фиколла-Верографина и окрашивали моноклональными антителами ко внутриклеточным белкам. Интенсивность флуоресценции измеряли на проточном цитометре FACSCalibur по программе SimulSet. Статистический анализ проводили по программе «Биостатистика». Результаты. Показано влияние исходной концентрации цинка в сыворотке крови на показатели сигнальных белков в лимфоцитах. При дефиците цинка уровень ингибитора клеточного цикла р21 в лимфоцитах повышен, а терапия цинк пиритионом снижает уровень экспрессии р21. При дефиците цинка в сыворотке крови больных АД уровень экспрессии белков киназ р38 и JNK был повышен по сравнению с показателями лиц без дефицита цинка, и снижался после применения цинк пиритиона у больных АД. При дефиците цинка у больных АД была повышена экспрессия молекулярных шаперонов DNAJA3, DNAJB6 и DNAJC15 в лимфоцитах. Применение цинк пиритиона снижает экспрессию этих стрессовых белков. Заключение. Дефицит цинка в сыворотке крови больных АД сопряжен с развитием стресса в лимфоцитах периферической крови больных. Добавление цинк пиритиона снижает уровень экспрессии стресс-зависимых белков в лимфоцитах крови больных АД. The aim of the work was to study the effect of zinc pyrithione and zinc oxide on stress-associated protein expression in blood lymphocytes of patients with atopic dermatitis (AD) depending on the serum concentration of zinc. Methods. Blood was collected in fasting state. Blood concentration of zinc was determined by absorption spectroscopy. Lymphocytes were isolated by the Ficoll/verografin density gradient centrifugation and stained with monoclonal antibodies to intracellular proteins. The fluorescence intensity was measured on a FACSCalibur flow cytometer using the SimulSet software. Statistical analysis was performed using the Biostatistic software. Results. The study showed the effect of zinc serum concentration at baseline on stress-dependent proteins in lymphocytes. In zinc deficiency, the content of cell cycle inhibitor p21 in lymphocytes was increased whereas the zinc pyrithione treatment reduced the p21 expression. Serum zinc deficiency in patients with AD was associated with increased expression of kinase proteins p38 and JNK compared to patients without zinc deficiency; in patients with AD, the kinase protein expression decreased after administration of zinc pyrithione. In AD patients with zinc deficiency, the lymphocyte expression of the DNAJA3, DNAJB6 and DNAJC15 molecular chaperones was increased. The zinc pyrithione treatment restricted the expression of these stress proteins. Conclusions. Serum zinc deficiency in patients with AD is associated with the development of stress in peripheral blood lymphocytes. The zinc pyrithione treatment restricts the expression of stress-dependent proteins in lymphocytes of patients with AD.
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Chen, Mingzhu, Yizi Zhu, Huajun Li, Yubo Zhang, and Mei Han. "A Quantitative Proteomic Approach Explores the Possible Mechanisms by Which the Small Molecule Stemazole Promotes the Survival of Human Neural Stem Cells." Brain Sciences 12, no. 6 (May 25, 2022): 690. http://dx.doi.org/10.3390/brainsci12060690.
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Neurodegenerative disorders have become a serious healthcare problem worldwide and there is no efficacious cure. However, regulating the fate of stem cells is an effective way to treat these neurological diseases. In previous work, stemazole was reported to maintain the survival of human neural stem cells in the absence of growth factors and to have therapeutic effects on neurodegenerative diseases. However, although it is a promising small molecule, the molecular mechanisms against apoptosis are ambiguous. In this study, tandem mass tag (TMT)-based proteomics were performed to obtain whole protein expression profiles of human neural stem cells in different groups under extreme conditions. Bioinformatics analysis based on protein–protein interaction (PPI) network construction, gene ontology (GO) and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis were adopted to explore crucial proteins and possible pharmacological mechanisms. A total of 77 differentially expressed proteins were identified, comprising 38 upregulated proteins and 39 downregulated proteins. Combined with a diseases database of Alzheimer’s disease (AD), caspase-2 (CASP2), PKA C-alpha (PRKACA), fibronectin (FN1), large neutral amino acid transporter small subunit 1 (SLC7A5), which are involved in cell proliferation and apoptosis, this was further validated by enzyme activity assay and molecular docking, and regarded as putative targets regulated by stemazole. The present results give an insight into this small molecule and a better understanding for further elucidating the underlying mechanisms in the treatment of stem cells and neurodegenerative diseases.
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Berdnikova, Daria V., Paolo Carloni, Sybille Krauß, and Giulia Rossetti. "Role and Perspective of Molecular Simulation-Based Investigation of RNA–Ligand Interaction: From Small Molecules and Peptides to Photoswitchable RNA Binding." Molecules 26, no. 11 (June 3, 2021): 3384. http://dx.doi.org/10.3390/molecules26113384.
Full textAbstract:
Aberrant RNA–protein complexes are formed in a variety of diseases. Identifying the ligands that interfere with their formation is a valuable therapeutic strategy. Molecular simulation, validated against experimental data, has recently emerged as a powerful tool to predict both the pose and energetics of such ligands. Thus, the use of molecular simulation may provide insight into aberrant molecular interactions in diseases and, from a drug design perspective, may allow for the employment of less wet lab resources than traditional in vitro compound screening approaches. With regard to basic research questions, molecular simulation can support the understanding of the exact molecular interaction and binding mode. Here, we focus on examples targeting RNA–protein complexes in neurodegenerative diseases and viral infections. These examples illustrate that the strategy is rather general and could be applied to different pharmacologically relevant approaches. We close this study by outlining one of these approaches, namely the light-controllable association of small molecules with RNA, as an emerging approach in RNA-targeting therapy.
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Bertsch, Uwe, Konstanze F. Winklhofer, Thomas Hirschberger, Jan Bieschke, Petra Weber, F. Ulrich Hartl, Paul Tavan, Jörg Tatzelt, Hans A. Kretzschmar, and Armin Giese. "Systematic Identification of Antiprion Drugs by High-Throughput Screening Based on Scanning for Intensely Fluorescent Targets." Journal of Virology 79, no. 12 (June 15, 2005): 7785–91. http://dx.doi.org/10.1128/jvi.79.12.7785-7791.2005.
Full textAbstract:
ABSTRACT Conformational changes and aggregation of specific proteins are hallmarks of a number of diseases, like Alzheimer's disease, Parkinson's disease, and prion diseases. In the case of prion diseases, the prion protein (PrP), a neuronal glycoprotein, undergoes a conformational change from the normal, mainly alpha-helical conformation to a disease-associated, mainly beta-sheeted scrapie isoform (PrPSc), which forms amyloid aggregates. This conversion, which is crucial for disease progression, depends on direct PrPC/PrPSc interaction. We developed a high-throughput assay based on scanning for intensely fluorescent targets (SIFT) for the identification of drugs which interfere with this interaction at the molecular level. Screening of a library of 10,000 drug-like compounds yielded 256 primary hits, 80 of which were confirmed by dose response curves with half-maximal inhibitory effects ranging from 0.3 to 60 μM. Among these, six compounds displayed an inhibitory effect on PrPSc propagation in scrapie-infected N2a cells. Four of these candidate drugs share an N′-benzylidene-benzohydrazide core structure. Thus, the combination of high-throughput in vitro assay with the established cell culture system provides a rapid and efficient method to identify new antiprion drugs, which corroborates that interaction of PrPC and PrPSc is a crucial molecular step in the propagation of prions. Moreover, SIFT-based screening may facilitate the search for drugs against other diseases linked to protein aggregation.
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Kim, Sung-Jae, Van-Giap Nguyen, Thi-My-Le Huynh, Yong-Ho Park, Bong-Kyun Park, and Hee-Chun Chung. "Molecular Characterization of Porcine Epidemic Diarrhea Virus and Its New Genetic Classification Based on the Nucleocapsid Gene." Viruses 12, no. 8 (July 23, 2020): 790. http://dx.doi.org/10.3390/v12080790.
Full textAbstract:
Porcine epidemic diarrhea virus (PEDV) causes continuous, significant damage to the swine industry worldwide. By RT-PCR-based methods, this study demonstrated the ongoing presence of PEDV in pigs of all ages in Korea at the average detection rate of 9.92%. By the application of Bayesian phylogenetic analysis, it was found that the nucleocapsid (N) gene of PEDV could evolve at similar rates to the spike (S) gene at the order of 10−4 substitutions/site/year. Based on branching patterns of PEDV strains, three main N gene-base genogroups (N1, N2, and N3) and two sub-genogroups (N3a, N3b) were proposed in this study. By analyzing the antigenic index, possible antigenic differences also emerged in both the spike and nucleocapsid proteins between the three genogroups. The antigenic indexes of genogroup N3 strains were significantly lower compared with those of genogroups N1 and N2 strains in the B-cell epitope of the nucleocapsid protein. Similarly, significantly lower antigenic indexes in some parts of the B-cell epitope sequences of the spike protein (COE, S1D, and 2C10) were also identified. PEDV mutants derived from genetic mutations of the S and N genes may cause severe damage to swine farms by evading established host immunities.
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Tabeshmehr, Parisa, and Eftekhar Eftekharpour. "Tau; One Protein, So Many Diseases." Biology 12, no. 2 (February 3, 2023): 244. http://dx.doi.org/10.3390/biology12020244.
Full textAbstract:
Tau, a member of the microtubule-associated proteins, is a known component of the neuronal cytoskeleton; however, in the brain tissue, it is involved in other vital functions beyond maintaining the cellular architecture. The pathologic tau forms aggregates inside the neurons and ultimately forms the neurofibrillary tangles. Intracellular and extracellular accumulation of different tau isoforms, including dimers, oligomers, paired helical filaments and tangles, lead to a highly heterogenous group of diseases named “Tauopathies”. About twenty-six different types of tauopathy diseases have been identified that have different clinical phenotypes or pathophysiological characteristics. Although all these diseases are identified by tau aggregation, they are distinguishable based on the specific tau isoforms, the affected cell types and the brain regions. The neuropathological and phenotypical heterogeneity of these diseases impose significant challenges for discovering new diagnostic and therapeutic strategies. Here, we review the recent literature on tau protein and the pathophysiological mechanisms of tauopathies. This article mainly focuses on physiologic and pathologic tau and aims to summarize the upstream and downstream events and discuss the current diagnostic approaches and therapeutic strategies.