Chemical Small Molecules Research Articles

3D Printed Metallic Pillar Nanomechanical Resonators Decorated with TiO2 Nanotubes for Highly Sensitive Environmental Applications

AbstractMicro and nanomechanical devices offer enhanced sensing capabilities for detecting biological and chemical small molecules. However, miniaturization necessitates advanced fabrication processes and complex measurement systems, hindering routine sensor analysis. While alternative methods like 3D printing show promise, challenges such as low device resolution persist due to intrinsic damping of polymer inks. In this study, an array of micrometric pillar resonators is fabricated in Ti6Al4 V alloy using additive manufacturing based on laser powder bed fusion technology. These metallic nanomechanical resonators exhibit a very high quality factor with minimal difference between air and vacuum measurements due to low intrinsic damping. Furthermore, titania nanotubes grown on the pillars via anodic oxidation heighten sensitivity for molecular dye degradation evaluation. Leveraging the weak coupling phenomenon among the pillars in the array, these devices facilitate large‐scale parallelized measurements, here demonstrated with real‐time analysis of dye degradation process. This approach to creating mass sensing devices via metallic additive manufacturing can usher in a new generation of highly performing resonating sensor arrays, offering a cost‐effective and efficient alternative to traditional silicon microfabrication methods.

Investigating Müller glia reprogramming in mice: a retrospective of the last decade, and a look to the future.

Müller glia, as prominent glial cells within the retina, plays a significant role in maintaining retinal homeostasis in both healthy and diseased states. In lower vertebrates like zebrafish, these cells assume responsibility for spontaneous retinal regeneration, wherein endogenous Müller glia undergo proliferation, transform into Müller glia-derived progenitor cells, and subsequently regenerate the entire retina with restored functionality. Conversely, Müller glia in the mouse and human retina exhibit limited neural reprogramming. Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders. Müller glia reprogramming in mice has been accomplished with remarkable success, through various technologies. Advancements in molecular, genetic, epigenetic, morphological, and physiological evaluations have made it easier to document and investigate the Müller glia programming process in mice. Nevertheless, there remain issues that hinder improving reprogramming efficiency and maturity. Thus, understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency, and for developing novel Müller glia reprogramming strategies. This review describes recent progress in relatively successful Müller glia reprogramming strategies. It also provides a basis for developing new Müller glia reprogramming strategies in mice, including epigenetic remodeling, metabolic modulation, immune regulation, chemical small-molecules regulation, extracellular matrix remodeling, and cell-cell fusion, to achieve Müller glia reprogramming in mice.

Drug-Drug Interactions of FXI Inhibitors: Clinical Relevance.

Inhibitors of the factor FXI represent a new class of anticoagulant agents that are facing clinical approval for the treatment of acute coronary syndrome (ACS), venous thromboembolism (VTE), and stroke prevention of atrial fibrillation (AF). These new inhibitors include chemical small molecules (asundexian and milvexian), monoclonal antibodies (abelacimab, osocimab, and xisomab), and antisense oligonucleotides (IONIS-FXIRX and fesomersen), and thus, they have very peculiar and different pharmacokinetic and pharmacodynamic properties. Besides their clinical efficacy and safety, based on their pharmacological heterogeneity, the use of these drugs in patients with comorbidities may undergo drug-drug interactions (DDIs) with other concomitant therapies. Although only little clinical evidence is available, it is possible to predict clinically relevant DDI by taking into consideration their pharmacokinetic properties, such as the CYP450-dependent metabolism, the interaction with drug transporters, and/or the route of elimination. These characteristics may be useful to differentiate their use with the direct oral anticoagulant (DOAC) anti -FXa (rivaroxaban, apixaban, edoxaban) and thrombin (dabigatran), whose pharmacokinetics are strongly dependent from P-gp inhibitors/inducers. In the present review, we summarize the current clinical evidence on DDIs of new anti FXI with CYP450/P-gp inhibitors and inducers and indicate potential differences with DOAC anti FXa.

Construction of a diagnostic model for osteoarthritis based on transcriptomic immune-related genes

BackgroundOsteoarthritis (OA) is a leading cause of disability globally, affecting over 500 million individuals worldwide. However, accurate and early diagnosis of OA is challenging to achieve. Immune-related genes play an essential role in OA development. Therefore, the objective of this study was to develop a diagnostic model for OA based on immune-related genes identified in synovial membrane. MethodsThe gene expression profile of OA were downloaded based on four datasets. The significantly differentially expressed genes (DEGs) between OA and control groups were selected. The differential immune cells were analyzed, followed by immune-related DEGs screening. WGCNA was used to screen module genes and these genes were further selected through optimization algorithm. Then, nomogram model was constructed. Chemical drug small molecule related to OA was predicted. Finally, expression levels of several key genes were validated by qRT-PCR through construction of OA rat models. ResultsThe total 656 DEGs were obtained. Eight immune cells were significantly differential between two groups, and 317 immune-related DEGs were obtained. WGCNA identified three modules. The genes in modules were significantly involved in 15 pathways, involving in 65 genes. Then 12 DEGs were screened as the final optimal combination of DEGs, such as CEBPB, CXCL1, JUND, GABARAPL2 and PDGFC. The Nomogram model was also constructed. Furthermore, the chemical small molecules, such as acetaminophen, aspirin, and caffeine were predicted. The expression levels of CEBPB, CXCL1, GABARAPL2 and PDGFC were validated in OA rat models. ConclusionA diagnostic model based on twelve immune related genes was constructed. These model genes, such as CEBPB, CXCL1, GABARAPL2, and PDGFC, may serve as diagnostic biomarkers and immunotherapeutic targets.

Olfactory Receptors as an Emerging Chemical Sensing Scaffold.

Chemical biosensors are an increasingly ubiquitous part of our lives. Beyond enzyme-coupled assays, recent synthetic biology advances now allow us to hijack more complex biosensing systems to respond to difficult to detect analytes, such as chemical small molecules. Here, we briefly overview recent advances in the biosensing of small molecules, including nucleic acid aptamers, allosteric transcription factors, and two-component systems. We then look more closely at a recently developed chemical sensing system, G protein-coupled receptor (GPCR)-based sensors. Finally, we consider the chemical sensing capabilities of the largest GPCR subfamily, olfactory receptors (ORs). We examine ORs' role in nature, their potential as a biomedical target, and their ability to detect compounds not amenable for detection using other biological scaffolds. We conclude by evaluating the current challenges, opportunities, and future applications of GPCR- and OR-based sensors.

Application and prospects of high-throughput screening for in vitro neurogenesis.

Over the past few decades, high-throughput screening (HTS) has made great contributions to new drug discovery. HTS technology is equipped with higher throughput, minimized platforms, more automated and computerized operating systems, more efficient and sensitive detection devices, and rapid data processing systems. At the same time, in vitro neurogenesis is gradually becoming important in establishing models to investigate the mechanisms of neural disease or deve lopmental processes. However, challenges remain in generating more mature and functional neurons with specific subtypes and in establishing robust and standardized three-dimensional (3D) in vitro models with neural cells cultured in 3D matrices or organoids representing specific brain regions. Here, we review the applications of HTS technologies on in vitro neurogenesis, especially aiming at identifying the essential genes, chemical small molecules and adaptive microenvironments that hold great prospects for generating functional neurons or more reproductive and homogeneous 3D organoids. We also discuss the developmental tendency of HTS technology, e.g., so-called next-generation screening, which utilizes 3D organoid-based screening combined with microfluidic devices to narrow the gap between in vitro models and in vivo situations both physiologically and pathologically.

Real-Time Monitoring of Neurotransmitters in the Brain of Living Animals.

Neurotransmitters, as important chemical small molecules, perform the function of neural signal transmission from cell to cell. Excess concentrations of neurotransmitters are often closely associated with brain diseases, such as Alzheimer's disease, depression, schizophrenia, and Parkinson's disease. On the other hand, the release of neurotransmitters under the induced stimulation indicates the occurrence of reward-related behaviors, including food and drug addiction. Therefore, to understand the physiological and pathological functions of neurotransmitters, especially in complex environments of the living brain, it is urgent to develop effective tools to monitor their dynamics with high sensitivity and specificity. Over the past 30 years, significant advances in electrochemical sensors and optical probes have brought new possibilities for studying neurons and neural circuits by monitoring the changes in neurotransmitters. This Review focuses on the progress in the construction of sensors for in vivo analysis of neurotransmitters in the brain and summarizes current attempts to address key issues in the development of sensors with high selectivity, sensitivity, and stability. Combined with the latest advances in technologies and methods, several strategies for sensor construction are provided for recording chemical signal changes in the complex environment of the brain.

Melittin: A Natural Peptide with Expanded Therapeutic Applications

Background: Apis mellifera, European honey bee venom (BV) is a complex combination of chemical compounds comprising proteins, peptides, enzymes, and other small molecules. Melittin (MEL), which is the key component of BV is considered as an alternative for treatment of various infections. MEL is an amphipathic, cell-penetrating, 26-residue, ahelical anti-hepatoma peptide derived from BV. However, owing to its initial conformational strength and poor stability, melittin is constrained in use as a medication. Objective: The study focused on collective data of therapeutic activities of Bee venom component, MEL. Method: Regardless of its broad variety of biological and possible therapeutic uses, there has been increasing concern in the use of MEL. According to literature, MEL revealed range of activities started from Anti- cancer activity, Anti- microbial activity, Anti- viral activity, Anti-inflammatory activity to Anti- diabetic activity. Present review article summarized therapeutic applications of MEL, their mechanism of action along with recent research progress in field of its delivery. Conclusion: It could be concluded that MEL exerts multiple effects on cellular functions of infected cells.

Chemical and Biological Molecules Involved in Differentiation, Maturation, and Survival of Dopaminergic Neurons in Health and Parkinson's Disease: Physiological Aspects and Clinical Implications.

Parkinson’s disease (PD) is one of the most common neurodegenerative disease characterized by a specific and progressive loss of dopaminergic (DA) neurons and dopamine, causing motor dysfunctions and impaired movements. Unfortunately, available therapies can partially treat the motor symptoms, but they have no effect on non-motor features. In addition, the therapeutic effect reduces gradually, and the prolonged use of drugs leads to a significative increase in the number of adverse events. For these reasons, an alternative approach that allows the replacement or the improved survival of DA neurons is very appealing for the treatment of PD patients and recently the first human clinical trials for DA neurons replacement have been set up. Here, we review the role of chemical and biological molecules that are involved in the development, survival and differentiation of DA neurons. In particular, we review the chemical small molecules used to differentiate different type of stem cells into DA neurons with high efficiency; the role of microRNAs and long non-coding RNAs both in DA neurons development/survival as far as in the pathogenesis of PD; and, finally, we dissect the potential role of exosomes carrying biological molecules as treatment of PD.

A New Metric Quantifying Chemical and Biological Property of Small Molecule Metabolites and Drugs.

One prominent class of drugs is chemical small molecules (CSMs), but the majority of CSMs are of very low druggable potential. Therefore, it is quite important to predict drug-related properties (druggable properties) for candidate CSMs. Currently, a number of druggable properties (e.g., logP and pKa) can be calculated by in silico methods; still the identification of druggable CSMs is a high-risk task, and new quantitative metrics for the druggable potential of CSMs are increasingly needed. Here, we present normalized bond energy (NBE), a new metric for the above purpose. By applying NBE to the DrugBank CSMs whose properties are largely known, we revealed that NBE is able to describe a number of critical druggable properties including logP, pKa, membrane permeability, blood–brain barrier penetration, and human intestinal absorption. Moreover, given that the human endogenous metabolites can serve as important resources for drug discovery, we applied NBE to the metabolites in the Human Metabolome Database. As a result, NBE showed a significant difference in metabolites from various body fluids and was correlated with some important properties, including melting point and water solubility.

Discovery of a fluorescigenic pyrazoline derivative targeting ubiquitin

Despite significant process in ubiquitin modification by using traditional genetic methods, chemical small molecules that directly target and modify ubiquitin are little reported. Here, we find that a fluorescigenic pyrazoline derivative (FPD5) could do so effectively. Molecule docking revealed that lysine 11 of ubiquitin was the key contact residue. FPD5, with stronger fluorescence, elevated the ubiquitination of beclin 1 (BECN1) and promoted autophagy. This study highlights that targeting ubiquitin by chemical small molecules enables us to modulate ubiquitination and the downstream signaling in the ubiquitin system.

Organic and inorganic zinc show similar regulatory effects on the expression of some germ cell specific markers induced in bone marrow mesenchymal stem cells after treatment with retinoic acid

Chemical approaches and small molecules are considered as an inseparable part of regenerative medicine and stem-cell-based therapies. Zinc (Zn) is a well-known trace element essential for normal spermatogenesis and has a regulatory role on the expression of several genes in different tissues of the body. This study determines and compares the effects of organic (acetate, ZnA) and inorganic Zinc (sulfate, ZnS) on the expression of a number of germ cell (GC)-specific genes in retinoic acid (RA)-treated ram bone marrow mesenchymal stem cells (BM-MSCs). First, BM-MSCs were treated with 10 μM RA for 21 days, real-time RT-PCR and immunocytochemistry (ICC) confirmed the expression of the markers in treated cells. Then, in vitro-derived GCs were treated with 1 μM of either ZnS or ZnA for one week. Treatment of in vitro-derived GCs with ZnA significantly downregulated all tested genes. ZnS treatment also induced a significant downregulation in Piwil2 and Vasa, and a moderate decrease in ITG b1 and Oct4 expression levels. Cells treated with ZnS or ZnA showed almost similar gene expression patterns. Zn treatments appeared to make in vitro-derived GCs return to a state similar to the untreated MSCs. We also studied the effects of simultaneous use of RA and one of zinc ions on BM-MSCs. The results showed that presence of organic or inorganic zinc in culture medium containing RA inhibited BM-MSCs to differentiate into GCs. This study showed a new dimension of zinc effect on stem cells which will be really helpful for establishment of novel strategies for Zn applications.

Potential therapeutics of Alzheimer's diseases: New insights into the neuroprotective role of trehalose‐conjugated beta sheet breaker peptides

AbstractAlzheimer's disease (AD) is a progressive neurodegenerative disease with no cure. The conversion of the amyloid‐β (Aβ) peptide into soluble oligomers has recently become recognized as playing a key role in AD pathogenesis. Thus, prevention and therapeutic strategies against AD focus on modulating Aβ levels aiming also at stabilizing Aβ's monomeric status or inhibiting the peptide's self‐assembly. Peptide‐based inhibitors may provide a reasonable alternative to chemical small molecules. We report herein further insights into the neuroprotective action of two trehalose‐conjugated peptides able to counteract the Aβ's oligomers associated neuronal toxicity. In addition, the Trehalose‐Succinyl‐LPFFD‐NH2 (Th‐Succ‐LPFFD‐NH2) and Ac‐LPFFD‐Trehalose (Ac‐LPFFD‐Th) derivatives protect neuronal cells from excitotoxic insult mediated by NMDA and evoke by themselves pro‐survival signal pathways as an additional cell protective action. UHPLC‐HRMS experiments suggest that a possible step associated to the neuroprotective mechanism involves the cell uptake and/or a membrane interaction of the studied peptides.

Recognition of an important G-quadruplex in the HIV-1 promoter with natural small molecules

Targeting a G-quadruplex with chemical small molecules is a useful strategy for gene therapy for disease. The guanine-rich sequence d(5′-TG1G2CCTG3G4G5CG6G7G8ACTG9G10G11-3′) in the HIV-1 promoter can form a G-quadruplex structure. In this study, circular dichroism was performed to study the conformation and thermal stability of the HIV-1 G-quadruplex before and after adding small molecules. A DMS footprinting assay was used to identify which guanosine can be integrated into the G-quadruplex structure. Electrospray ionization mass spectrometry was used to evaluate the binding affinities of the small molecules with the G-quadruplex. Our results showed that G1, G2, G3, G4, G7, G8, G9, and G10 of the above oligonucleotides formed a two G-tetrad antiparallel G-quadrulex, and nitidine chloride was found to have the highest binding affinity toward the HIV-1 G-quadruplex among the eight studied small molecules. The Tm value of the G-quadruplex was enhanced from 56.6 to 63.2 °C when fourfold nitidine chloride was added. This is potentially a novel approach for anti-HIV-1 drug development.

Abstract 3660: Discovery of a small molecule TUBB3/βIII-tubulin modulator in lung cancer

Abstract Background: Non-small Cell Lung Cancer (NSCLC) survival rates are dismal and chemotherapy resistance is a significant clinical problem. βIII-tubulin (encoded by TUBB3 gene) is aberrantly expressed and is associated with chemoresistance and tumor aggressiveness in NSCLC (1), where it has been identified as a bona fide target for chemosensitisation (2,3). In order to understand how TUBB3/βIII-tubulin is regulated in NSCLC cells we sought to identify chemical small molecules that can modulate its expression. Methods: H460 cells expressing a TUBB3 or GAPDH promoter-luciferase reporter construct were generated and used in drug screening and promoter activity testing. To isolate modulators of TUBB3 promoter activity, a cell-based screen of libraries of diverse chemical small molecules (30K) and FDA-approved bioactives (3680) was performed. Cell viability, growth and proliferation were measured using standard methods. Cell cycle was assessed using flow cytometry, and gene and protein expression by RT-PCR and Western blotting, respectively. Microtubule morphology was assessed using immunostaining and confocal microscopy. Drug-treated clonogenic assays were used to quantitate changes in drug sensitivity. Results: Based upon their ability to modulate TUBB3 promoter activity, we identified two hit compounds, CCI01 and CCI02, as well as the bioactive compound, RITA. For all three leads we observed: 1) repression in TUBB3 promoter activity which was not a result of cell cytotoxicity; 2) no effects on cell cycle or viability, but instead cytostatic effects; 3) significantly enhanced TUBB3 expression in a time and dose-dependent manner. TUBB3 gene enhancement was translated at the protein level in CCI01 treated H460, but not in CCI02 or RITA treated cells. Additionally, CCI01 did not alter microtubule morphology but enhanced βIII-tubulin immunostaining in two independent NSCLC cell lines, H460 and H1299, compared to control. Importantly, CCI01 enhanced βIII-tubulin expression was functional and led to a significant decrease in in vitro sensitivity to DNA-damaging and tubulin-binding agents in H460 cells. Conclusion: A novel lead small molecule TUBB3/βIII-tubulin enhancer has been identified that is able to increase expression of βIII-tubulin in NSCLC and significantly reduce sensitivity to tubulin binding and DNA-damaging agents. Implications: Identification of a modulator of TUBB3/βIII-tubulin expression will provide a valuable research tool to probe βIII-tubulin regulation. (1) Kavallaris. Nature Rev Cancer, 10:194-204, 2010 (2) McCarroll et al., Cancer Res 70:4995-5003, 2010 (3) Gan et al., Cancer Res. 67:9356-9363, 2007 Citation Format: Felicity Chao Lin Kao, Tim Failes, Greg M. Arndt, Murray Norris, Maria Kavallaris. Discovery of a small molecule TUBB3/βIII-tubulin modulator in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3660. doi:10.1158/1538-7445.AM2015-3660

Abstract 1834: Targeting ABC transporters in cancer through small molecule inhibitors

Abstract Multidrug resistance is one of the major causes of treatment failure in cancer therapy. While multidrug transporter proteins are known for their contributions to chemoresistance and efflux of anti-cancer drugs from cancer cells, a significant body of evidence points to their fundamental roles in tumour biology (Fletcher et al, Nature Rev Cancer, 10:147-156, 2010). We have investigated the ABCC subfamily of multidrug transporter genes in the highly malignant and aggressive childhood solid tumour, neuroblastoma and found that high levels of ABCC1 and ABCC4 are powerful independent prognostic indicators of clinical outcome. However, the agents used to treat the patients described in these studies are not known substrates of ABCC4 and we have shown that siRNA-mediated knockdown of ABCC4 results in reduced proliferation and enhanced morphological differentiation of neuroblastoma cells, in the absence of any cytotoxic drug treatment (Henderson et al, JNCI, 103;1-16, 2011). The aim of this study is to develop a potential new approach for the treatment of neuroblastoma through the inhibition of ABCC4 using small molecule inhibitors. A cell-based screen of a library of diverse chemical small molecules was used to isolate potent small molecule inhibitors of ABCC4 that were able to sensitize HEK293 cells over-expressing MRP4 to a cytotoxic MRP4 substrate, 6-mercaptopurine (6MP). Filtering of compounds based upon their ability to cause 6MP accumulation, together with focused library screening, have resulted in the identification of several chemical structures able to specifically block MRP4. In addition to reversing drug resistance to 6MP, these compounds cause morphological differentiation and inhibition of cell growth, as seen with MRP4 siRNA, in the BE2C neuroblastoma cell line. Importantly, these compounds significantly potentiate morphological differentiation caused by the established differentiation agent, all-trans retinoic acid. We further show that these inhibitors have potency in other MRP4 expressing cancer cell lines beyond neuroblastoma. These pharmacological inhibitors offer clinical potential for the treatment of neuroblastoma and other MRP4 overexpressing cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1834. doi:1538-7445.AM2012-1834