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9 pages, 986 KiB

Open AccessArticle

Drug Repurposing in Dentistry: Towards Application of Small Molecules in Dentin Repair

by Anahid A. Birjandi, Fernanda R. Suzano and Paul T. Sharpe

Int. J. Mol. Sci. 2020, 21(17), 6394; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176394 - 02 Sep 2020

Cited by 11 | Viewed by 3199

One of the main goals of dentistry is the natural preservation of the tooth structure following damage. This is particularly implicated in deep dental cavities affecting dentin and pulp, where odontoblast survival is jeopardized. This activates pulp stem cells and differentiation of new [...] Read more.

One of the main goals of dentistry is the natural preservation of the tooth structure following damage. This is particularly implicated in deep dental cavities affecting dentin and pulp, where odontoblast survival is jeopardized. This activates pulp stem cells and differentiation of new odontoblast-like cells, accompanied by increased Wnt signaling. Our group has shown that delivery of small molecule inhibitors of GSK3 stimulates Wnt/β-catenin signaling in the tooth cavity with pulp exposure and results in effective promotion of dentin repair. Small molecules are a good therapeutic option due to their ability to pass across cell membranes and reach target. Here, we investigate a range of non-GSK3 target small molecules that are currently used for treatment of various medical conditions based on other kinase inhibitory properties. We analyzed the ability of these drugs to stimulate Wnt signaling activity by off-target inhibition of GSK3. Our results show that a c-Met inhibitor, has the ability to stimulate Wnt/β-catenin pathway in dental pulp cells in vitro at low concentrations. This work is an example of drug repurposing for dentistry and suggests a candidate drug to be tested in vivo for natural dentin repair. This approach bypasses the high level of economical and time investment that are usually required in novel drug discoveries. Full article

(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways)

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24 pages, 2763 KiB

Open AccessArticle

The Polymorphic PolyQ Tail Protein of the Mediator Complex, Med15, Regulates the Variable Response to Diverse Stresses

by Jennifer E.G. Gallagher, Suk Lan Ser, Michael C. Ayers, Casey Nassif and Amaury Pupo

Int. J. Mol. Sci. 2020, 21(5), 1894; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051894 - 10 Mar 2020

Cited by 7 | Viewed by 4125

Abstract

The Mediator is composed of multiple subunits conserved from yeast to humans and plays a central role in transcription. The tail components are not required for basal transcription but are required for responses to different stresses. While some stresses are familiar, such as [...] Read more.

The Mediator is composed of multiple subunits conserved from yeast to humans and plays a central role in transcription. The tail components are not required for basal transcription but are required for responses to different stresses. While some stresses are familiar, such as heat, desiccation, and starvation, others are exotic, yet yeast can elicit a successful stress response. 4-Methylcyclohexane methanol (MCHM) is a hydrotrope that induces growth arrest in yeast. We found that a naturally occurring variation in the Med15 allele, a component of the Mediator tail, altered the stress response to many chemicals in addition to MCHM. Med15 contains two polyglutamine repeats (polyQ) of variable lengths that change the gene expression of diverse pathways. The Med15 protein existed in multiple isoforms and its stability was dependent on Ydj1, a protein chaperone. The protein level of Med15 with longer polyQ tracts was lower and turned over faster than the allele with shorter polyQ repeats. MCHM sensitivity via variation of Med15 was regulated by Snf1 in a Myc-tag-dependent manner. Tagging Med15 with Myc altered its function in response to stress. Genetic variation in transcriptional regulators magnified genetic differences in response to environmental changes. These polymorphic control genes were master variators. Full article

(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways)

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12 pages, 306 KiB

Open AccessReview

The Role of DAMPS in Burns and Hemorrhagic Shock Immune Response: Pathophysiology and Clinical Issues. Review

by Desirè Pantalone, Carlo Bergamini, Jacopo Martellucci, Giovanni Alemanno, Alessandro Bruscino, Gherardo Maltinti, Maximilian Sheiterle, Riccardo Viligiardi, Roberto Panconesi, Tommaso Guagni and Paolo Prosperi

Int. J. Mol. Sci. 2021, 22(13), 7020; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137020 - 29 Jun 2021

Cited by 17 | Viewed by 3010

Abstract

Severe or major burns induce a pathophysiological, immune, and inflammatory response that can persist for a long time and affect morbidity and mortality. Severe burns are followed by a “hypermetabolic response”, an inflammatory process that can be extensive and become uncontrolled, leading to [...] Read more.

Severe or major burns induce a pathophysiological, immune, and inflammatory response that can persist for a long time and affect morbidity and mortality. Severe burns are followed by a “hypermetabolic response”, an inflammatory process that can be extensive and become uncontrolled, leading to a generalized catabolic state and delayed healing. Catabolism causes the upregulation of inflammatory cells and innate immune markers in various organs, which may lead to multiorgan failure and death. Burns activate immune cells and cytokine production regulated by damage-associated molecular patterns (DAMPs). Trauma has similar injury-related immune responses, whereby DAMPs are massively released in musculoskeletal injuries and elicit widespread systemic inflammation. Hemorrhagic shock is the main cause of death in trauma. It is hypovolemic, and the consequence of volume loss and the speed of blood loss manifest immediately after injury. In burns, the shock becomes evident within the first 24 h and is hypovolemic-distributive due to the severely compromised regulation of tissue perfusion and oxygen delivery caused by capillary leakage, whereby fluids shift from the intravascular to the interstitial space. In this review, we compare the pathophysiological responses to burns and trauma including their associated clinical patterns. Full article

(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways)

16 pages, 2210 KiB

Open AccessReview

Applications of Metabolomics in Forensic Toxicology and Forensic Medicine

by Michal Szeremeta, Karolina Pietrowska, Anna Niemcunowicz-Janica, Adam Kretowski and Michal Ciborowski

Int. J. Mol. Sci. 2021, 22(6), 3010; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063010 - 16 Mar 2021

Cited by 30 | Viewed by 6820

Abstract

Forensic toxicology and forensic medicine are unique among all other medical fields because of their essential legal impact, especially in civil and criminal cases. New high-throughput technologies, borrowed from chemistry and physics, have proven that metabolomics, the youngest of the “omics sciences”, could [...] Read more.

Forensic toxicology and forensic medicine are unique among all other medical fields because of their essential legal impact, especially in civil and criminal cases. New high-throughput technologies, borrowed from chemistry and physics, have proven that metabolomics, the youngest of the “omics sciences”, could be one of the most powerful tools for monitoring changes in forensic disciplines. Metabolomics is a particular method that allows for the measurement of metabolic changes in a multicellular system using two different approaches: targeted and untargeted. Targeted studies are focused on a known number of defined metabolites. Untargeted metabolomics aims to capture all metabolites present in a sample. Different statistical approaches (e.g., uni- or multivariate statistics, machine learning) can be applied to extract useful and important information in both cases. This review aims to describe the role of metabolomics in forensic toxicology and in forensic medicine. Full article

(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways)

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23 pages, 2679 KiB

Open AccessReview

Impact of SMTP Targeting Plasminogen and Soluble Epoxide Hydrolase on Thrombolysis, Inflammation, and Ischemic Stroke

by Keiji Hasumi and Eriko Suzuki

Int. J. Mol. Sci. 2021, 22(2), 954; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020954 - 19 Jan 2021

Cited by 24 | Viewed by 4143

Abstract

Stachybotrys microspora triprenyl phenol (SMTP) is a large family of small molecules derived from the fungus S. microspora. SMTP acts as a zymogen modulator (specifically, plasminogen modulator) that alters plasminogen conformation to enhance its binding to fibrin and subsequent fibrinolysis. Certain SMTP [...] Read more.

Stachybotrys microspora triprenyl phenol (SMTP) is a large family of small molecules derived from the fungus S. microspora. SMTP acts as a zymogen modulator (specifically, plasminogen modulator) that alters plasminogen conformation to enhance its binding to fibrin and subsequent fibrinolysis. Certain SMTP congeners exert anti-inflammatory effects by targeting soluble epoxide hydrolase. SMTP congeners with both plasminogen modulation activity and anti-inflammatory activity ameliorate various aspects of ischemic stroke in rodents and primates. A remarkable feature of SMTP efficacy is the suppression of hemorrhagic transformation, which is exacerbated by conventional thrombolytic treatments. No drug with such properties has been developed yet, and SMTP would be the first to promote thrombolysis but suppress disease-associated bleeding. On the basis of these findings, one SMTP congener is under clinical study and development. This review summarizes the discovery, mechanism of action, pharmacological activities, and development of SMTP. Full article

(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways)

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15 pages, 587 KiB

Open AccessReview

Mapping TRPM7 Function by NS8593

by Vladimir Chubanov and Thomas Gudermann

Int. J. Mol. Sci. 2020, 21(19), 7017; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197017 - 23 Sep 2020

Cited by 19 | Viewed by 3779

Abstract

The transient receptor potential cation channel, subfamily M, member 7 (TRPM7) is a ubiquitously expressed membrane protein, which forms a channel linked to a cytosolic protein kinase. Genetic inactivation of TRPM7 in animal models uncovered the critical role of TRPM7 in early embryonic [...] Read more.

The transient receptor potential cation channel, subfamily M, member 7 (TRPM7) is a ubiquitously expressed membrane protein, which forms a channel linked to a cytosolic protein kinase. Genetic inactivation of TRPM7 in animal models uncovered the critical role of TRPM7 in early embryonic development, immune responses, and the organismal balance of Zn²⁺, Mg²⁺, and Ca²⁺. TRPM7 emerged as a new therapeutic target because malfunctions of TRPM7 have been associated with anoxic neuronal death, tissue fibrosis, tumour progression, and giant platelet disorder. Recently, several laboratories have identified pharmacological compounds allowing to modulate either channel or kinase activity of TRPM7. Among other small molecules, NS8593 has been defined as a potent negative gating regulator of the TRPM7 channel. Consequently, several groups applied NS8593 to investigate cellular pathways regulated by TRPM7. Here, we summarize the progress in this research area. In particular, two notable milestones have been reached in the assessment of TRPM7 druggability. Firstly, several laboratories demonstrated that NS8593 treatment reliably mirrors prominent phenotypes of cells manipulated by genetic inactivation of TRPM7. Secondly, it has been shown that NS8593 allows us to probe the therapeutic potential of TRPM7 in animal models of human diseases. Collectively, these studies employing NS8593 may serve as a blueprint for the preclinical assessment of TRPM7-targeting drugs. Full article

(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways)

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20 pages, 2148 KiB

Open AccessReview

Small Molecules and Peptides Targeting Glial Cell Line-Derived Neurotrophic Factor Receptors for the Treatment of Neurodegeneration

by Yulia A. Sidorova and Mart Saarma

Int. J. Mol. Sci. 2020, 21(18), 6575; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186575 - 08 Sep 2020

Cited by 9 | Viewed by 3796

Abstract

Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are able to promote the survival of multiple neuronal populations in the body and, therefore, hold considerable promise for disease-modifying treatments of diseases and conditions caused by neurodegeneration. Available data reveal the potential of [...] Read more.

Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are able to promote the survival of multiple neuronal populations in the body and, therefore, hold considerable promise for disease-modifying treatments of diseases and conditions caused by neurodegeneration. Available data reveal the potential of GFLs for the therapy of Parkinson’s disease, neuropathic pain and diseases caused by retinal degeneration but, also, amyotrophic lateral sclerosis and, possibly, Alzheimer’s disease. Despite promising data collected in preclinical models, clinical translation of GFLs is yet to be conducted. The main reasons for the limited success of GFLs clinical development are the poor pharmacological characteristics of GFL proteins, such as the inability of GFLs to cross tissue barriers, poor diffusion in tissues, biphasic dose-response and activation of several receptors in the organism in different cell types, along with ethical limitations on patients’ selection in clinical trials. The development of small molecules selectively targeting particular GFL receptors with improved pharmacokinetic properties can overcome many of the difficulties and limitations associated with the clinical use of GFL proteins. The current review lists several strategies to target the GFL receptor complex with drug-like molecules, discusses their advantages, provides an overview of available chemical scaffolds and peptides able to activate GFL receptors and describes the effects of these molecules in cultured cells and animal models. Full article

(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways)

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18 pages, 3141 KiB

Open AccessReview

Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery

by Qingxin Li and CongBao Kang

Int. J. Mol. Sci. 2020, 21(15), 5262; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155262 - 24 Jul 2020

Cited by 39 | Viewed by 6928

Abstract

Small-molecule drugs are organic compounds affecting molecular pathways by targeting important proteins. These compounds have a low molecular weight, making them penetrate cells easily. Small-molecule drugs can be developed from leads derived from rational drug design or isolated from natural resources. A target-based [...] Read more.

Small-molecule drugs are organic compounds affecting molecular pathways by targeting important proteins. These compounds have a low molecular weight, making them penetrate cells easily. Small-molecule drugs can be developed from leads derived from rational drug design or isolated from natural resources. A target-based drug discovery project usually includes target identification, target validation, hit identification, hit to lead and lead optimization. Understanding molecular interactions between small molecules and their targets is critical in drug discovery. Although many biophysical and biochemical methods are able to elucidate molecular interactions of small molecules with their targets, structural biology is the most powerful tool to determine the mechanisms of action for both targets and the developed compounds. Herein, we reviewed the application of structural biology to investigate binding modes of orthosteric and allosteric inhibitors. It is exemplified that structural biology provides a clear view of the binding modes of protease inhibitors and phosphatase inhibitors. We also demonstrate that structural biology provides insights into the function of a target and identifies a druggable site for rational drug design. Full article

(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways)

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