Engineering metabolite-responsive transcriptional factors to sense small molecules in eukaryotes: current state and perspectives

The homeobox (HOX) genes encoding an evolutionarily highly conserved family of homeodomain-containing transcriptional factors are essential for embryogenesis and tumorigenesis. HOX genes are involved in cell identity determination during early embryonic development and postnatal processes. The deregulation of HOX genes is closely associated with numerous human malignancies, highlighting the indispensable involvement in mortal cancer development. Since most HOX genes behave as oncogenes or tumor suppressors in human cancer, a better comprehension of their upstream regulators and downstream targets contributes to elucidating the function of HOX genes in cancer development. In addition, targeting HOX genes may imply therapeutic potential. Recently, novel therapies such as monoclonal antibodies targeting tyrosine receptor kinases, small molecular chemical inhibitors, and small interfering RNA strategies, are difficult to implement for targeting transcriptional factors on account of the dual function and pleiotropic nature of HOX genes-related molecular networks. This paper summarizes the current state of knowledge on the roles of HOX genes in human cancer and emphasizes the emerging importance of HOX genes as potential therapeutic targets to overcome the limitations of present cancer therapy.

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Metabolomics in Central Sensitivity Syndromes

Metabolites ◽

10.3390/metabo10040164 ◽

2020 ◽

Vol 10 (4) ◽

pp. 164 ◽

Cited By ~ 1

Author(s):

Joseph S. Miller ◽

Luis Rodriguez-Saona ◽

Kevin V. Hackshaw

Keyword(s):

Small Molecules ◽

Central Sensitization ◽

Metabolic Pathways ◽

Treatment Options ◽

Case Series ◽

Opiate Abuse ◽

Current State ◽

Increased Risk ◽

Adults And Children

Central sensitization syndromes are a collection of frequently painful disorders that contribute to decreased quality of life and increased risk of opiate abuse. Although these disorders cause significant morbidity, they frequently lack reliable diagnostic tests. As such, technologies that can identify key moieties in central sensitization disorders may contribute to the identification of novel therapeutic targets and more precise treatment options. The analysis of small molecules in biological samples through metabolomics has improved greatly and may be the technology needed to identify key moieties in difficult to diagnose diseases. In this review, we discuss the current state of metabolomics as it relates to central sensitization disorders. From initial literature review until Feb 2020, PubMed, Embase, and Scopus were searched for applicable studies. We included cohort studies, case series, and interventional studies of both adults and children affected by central sensitivity syndromes. The majority of metabolomic studies addressing a CSS found significantly altered metabolites that allowed for differentiation of CSS patients from healthy controls. Therefore, the published literature overwhelmingly supports the use of metabolomics in CSS. Further research into these altered metabolites and their respective metabolic pathways may provide more reliable and effective therapeutics for these syndromes.

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Connectivity Mapping: Methods and Applications

Annual Review of Biomedical Data Science ◽

10.1146/annurev-biodatasci-072018-021211 ◽

2019 ◽

Vol 2 (1) ◽

pp. 69-92 ◽

Cited By ~ 6

Author(s):

Alexandra B. Keenan ◽

Megan L. Wojciechowicz ◽

Zichen Wang ◽

Kathleen M. Jagodnik ◽

Sherry L. Jenkins ◽

...

Keyword(s):

Small Molecules ◽

Small Molecule ◽

Historical Perspective ◽

Disease Gene ◽

Cellular Tissue ◽

Hypothesis Generation ◽

Connectivity Mapping ◽

Current State ◽

Global View

Connectivity mapping resources consist of signatures representing changes in cellular state following systematic small-molecule, disease, gene, or other form of perturbations. Such resources enable the characterization of signatures from novel perturbations based on similarity; provide a global view of the space of many themed perturbations; and allow the ability to predict cellular, tissue, and organismal phenotypes for perturbagens. A signature search engine enables hypothesis generation by finding connections between query signatures and the database of signatures. This framework has been used to identify connections between small molecules and their targets, to discover cell-specific responses to perturbations and ways to reverse disease expression states with small molecules, and to predict small-molecule mimickers for existing drugs. This review provides a historical perspective and the current state of connectivity mapping resources with a focus on both methodology and community implementations.

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Targeting uPAR in diabetic vascular pathologies*

Postępy Higieny i Medycyny Doświadczalnej ◽

10.5604/01.3001.0013.6909 ◽

2019 ◽

Vol 73 ◽

pp. 803-808

Author(s):

Martyna Durak-Kozica ◽

Francisco J. Enguita ◽

Ewa Stępień

Keyword(s):

Cell Proliferation ◽

Small Molecules ◽

Cell Invasion ◽

Biological Processes ◽

Effective Inhibitor ◽

Current State

The uPAR protein is one of the most important elements in fibrinolysis. uPAR is associated with many biological processes, such as cell invasion, angiogenesis and cell proliferation. Because of its multifunctional character, it is difficult to produce an effective inhibitor of uPA-uPAR interactions. The present paper shows the current state of knowledge about the contribution of uPA-uPAR complex in many biological processes and the application of uPAR inhibitors (antibodies, small-molecules, peptides), which might be potentially useful in the treatment of vascular pathologies.

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MALAT1 Long Non-Coding RNA: Functional Implications

Non-Coding RNA ◽

10.3390/ncrna6020022 ◽

2020 ◽

Vol 6 (2) ◽

pp. 22 ◽

Cited By ~ 5

Author(s):

Gayatri Arun ◽

Disha Aggarwal ◽

David L. Spector

Keyword(s):

Small Molecules ◽

Functional Significance ◽

Antisense Oligonucleotides ◽

Normal Development ◽

Mammalian Genome ◽

Dependent Manner ◽

Current State ◽

Non Coding Rna ◽

Functional Implications ◽

Long Non Coding Rna

The mammalian genome is pervasively transcribed and the functional significance of many long non-coding RNA (lncRNA) transcripts are gradually being elucidated. Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is one of the most well-studied lncRNAs. MALAT1 is a highly conserved nuclear retained lncRNA that is abundantly expressed in cells and tissues and has been shown to play a role in regulating genes at both the transcriptional and post-transcriptional levels in a context-dependent manner. However, Malat1 has been shown to be dispensable for normal development and viability in mice. Interestingly, accumulating evidence suggests that MALAT1 plays an important role in numerous diseases including cancer. Here, we discuss the current state-of-knowledge in regard to MALAT1 with respect to its function, role in diseases, and the potential therapeutic opportunities for targeting MALAT1 using antisense oligonucleotides and small molecules.

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The current state of the art for biological therapies and new small molecules in inflammatory bowel disease

Mucosal Immunology ◽

10.1038/s41385-018-0050-3 ◽

2018 ◽

Vol 11 (6) ◽

pp. 1558-1570 ◽

Cited By ~ 28

Author(s):

Sudarshan Paramsothy ◽

Adam K. Rosenstein ◽

Saurabh Mehandru ◽

Jean-Frederic Colombel

Keyword(s):

Inflammatory Bowel Disease ◽

Small Molecules ◽

Bowel Disease ◽

State Of The Art ◽

Biological Therapies ◽

Current State ◽

Inflammatory Bowel

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Pharmacological Interventions That Target Biological Aging

Innovation in Aging ◽

10.1093/geroni/igaa057.2980 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 818-818

Author(s):

Matt Kaeberlein

Keyword(s):

Small Molecules ◽

Mtor Inhibitors ◽

Mechanisms Of Action ◽

Laboratory Animals ◽

Biological Aging ◽

Pharmacological Interventions ◽

Current State ◽

Age Related ◽

Disease Risks ◽

High Level

Abstract There is a high level of interest in drugs that may delay or even reverse the functional declines and disease risks that accompany biological aging. Several interventions have been shown to improve age-related outcomes and increase lifespan in laboratory animals by targeting the hallmarks of aging. A number of these small molecules are being clinically evaluated for age-related indications, including mTOR inhibitors such as rapamycin, the anti-diabetic drug metformin, and senescent-cell clearing senolytics. Others are being marketed to consumers outside of the federal regulatory process as “anti-aging” natural products with little information about safety or efficacy. Here I will provide an overview of the current state of “anti-aging drugs” with an emphasis on potential mechanisms of action and evaluation of the existing pre-clinical and clinical data.

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Probing ubiquitin and SUMO conjugation and deconjugation

Biochemical Society Transactions ◽

10.1042/bst20170086 ◽

2018 ◽

Vol 46 (2) ◽

pp. 423-436 ◽

Cited By ~ 12

Author(s):

Huib Ovaa ◽

Alfred C.O. Vertegaal

Keyword(s):

Signal Transduction ◽

Small Molecules ◽

State Of The Art ◽

New Drugs ◽

Chemical Probes ◽

Probe Signal ◽

Sumo Conjugation ◽

Small Proteins ◽

Current State ◽

Covalently Linked

Ubiquitin (Ub) and ubiquitin-like (Ubl) proteins including small Ubl modifier (SUMO) are small proteins which are covalently linked to target proteins to regulate their functions. In this review, we discuss the current state of the art and point out what we feel this field urgently needs in order to delineate the wiring of the system. We discuss what is needed to unravel the connections between different components of the conjugation machineries for ubiquitylation and SUMOylation, and to unravel the connections between the conjugation machineries and their substrates. Chemical probes are key tools to probe signal transduction by these small proteins that may help understand their action. This rapidly moving field has resulted in various small molecules that will help us to further understand Ub and SUMO function and that may lead to the development of new drugs.

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From Small Molecules toward Whole Cells Detection: Application of Electrochemical Aptasensors in Modern Medical Diagnostics

Sensors ◽

10.3390/s21030724 ◽

2021 ◽

Vol 21 (3) ◽

pp. 724

Author(s):

Robert Ziółkowski ◽

Marta Jarczewska ◽

Łukasz Górski ◽

Elżbieta Malinowska

Keyword(s):

Small Molecules ◽

Medical Diagnostics ◽

Future Trends ◽

Future Perspectives ◽

Whole Cells ◽

Current State ◽

Medical Instruments ◽

Medical Diagnostic ◽

Abused Drugs ◽

User Friendly

This paper focuses on the current state of art as well as on future trends in electrochemical aptasensors application in medical diagnostics. The origin of aptamers is presented along with the description of the process known as SELEX. This is followed by the description of the broad spectrum of aptamer-based sensors for the electrochemical detection of various diagnostically relevant analytes, including metal cations, abused drugs, neurotransmitters, cancer, cardiac and coagulation biomarkers, circulating tumor cells, and viruses. We described also possible future perspectives of aptasensors development. This concerns (i) the approaches to lowering the detection limit and improvement of the electrochemical aptasensors selectivity by application of the hybrid aptamer–antibody receptor layers and/or nanomaterials; and (ii) electrochemical aptasensors integration with more advanced microfluidic devices as user-friendly medical instruments for medical diagnostic of the future.

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