scholarly journals New Inhibitory Effects of Cilnidipine on Microglial P2X7 Receptors and IL-1β Release: An Involvement in its Alleviating Effect on Neuropathic Pain

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 434
Author(s):  
Tomohiro Yamashita ◽  
Sawako Kamikaseda ◽  
Aya Tanaka ◽  
Hidetoshi Tozaki-Saitoh ◽  
Jose M. M. Caaveiro ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
High Throughput Screening ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Inhibitory Effect ◽  
Intrathecal Administration ◽  
Chemical Library ◽  
P2x7 Receptors ◽  
Approved Drugs ◽  
Cardinal Symptom

P2X7 receptors (P2X7Rs) belong to a family of ATP-gated non-selective cation channels. Microglia represent a major cell type expressing P2X7Rs. The activation of microglial P2X7Rs causes the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β). This response has been implicated in neuroinflammatory states in the central nervous system and in various diseases, including neuropathic pain. Thus, P2X7R may represent a potential therapeutic target. In the present study, we screened a chemical library of clinically approved drugs (1979 compounds) by high-throughput screening and showed that the Ca2+ channel blocker cilnidipine has an inhibitory effect on rodent and human P2X7R. In primary cultured rat microglial cells, cilnidipine inhibited P2X7R-mediated Ca2+ responses and IL-1β release. Moreover, in a rat model of neuropathic pain, the intrathecal administration of cilnidipine produced a reversal of nerve injury-induced mechanical hypersensitivity, a cardinal symptom of neuropathic pain. These results point to a new inhibitory effect of cilnidipine on microglial P2X7R-mediated inflammatory responses and neuropathic pain, proposing its therapeutic potential.

scholarly journals Secondary Metabolites from the Culture of the Marine-derived Fungus Paradendryphiella salina PC 362H and Evaluation of the Anticancer Activity of Its Metabolite Hyalodendrin

Marine Drugs ◽  
2020 ◽  
Vol 18 (4) ◽  
pp. 191
Author(s):  
Ambre Dezaire ◽  
Christophe H. Marchand ◽  
Marine Vallet ◽  
Nathalie Ferrand ◽  
Soraya Chaouch ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cancer Cells ◽  
Crude Extract ◽  
High Throughput Screening ◽  
Therapeutic Potential ◽  
Cancer Cell Line ◽  
Anticancer Activities ◽  
Chemical Library ◽  
Altered Expression ◽  
Cancer Aggressiveness

High-throughput screening assays have been designed to identify compounds capable of inhibiting phenotypes involved in cancer aggressiveness. However, most studies used commercially available chemical libraries. This prompted us to explore natural products isolated from marine-derived fungi as a new source of molecules. In this study, we established a chemical library from 99 strains corresponding to 45 molecular operational taxonomic units and evaluated their anticancer activity against the MCF7 epithelial cancer cell line and its invasive stem cell-like MCF7-Sh-WISP2 counterpart. We identified the marine fungal Paradendryphiella salina PC 362H strain, isolated from the brown alga Pelvetia caniculata (PC), as one of the most promising fungi which produce active compounds. Further chemical and biological characterizations of the culture of the Paradendryphiella salina PC 362H strain identified (-)-hyalodendrin as the active secondary metabolite responsible for the cytotoxic activity of the crude extract. The antitumor activity of (-)-hyalodendrin was not only limited to the MCF7 cell lines, but also prominent on cancer cells with invasive phenotypes including colorectal cancer cells resistant to chemotherapy. Further investigations showed that treatment of MCF7-Sh-WISP2 cells with (-)-hyalodendrin induced changes in the phosphorylation status of p53 and altered expression of HSP60, HSP70 and PRAS40 proteins. Altogether, our study reveals that this uninvestigated marine fungal crude extract possesses a strong therapeutic potential against tumor cells with aggressive phenotypes and confirms that members of the epidithiodioxopiperazines are interesting fungal toxins with anticancer activities.

scholarly journals Canvass: A Crowd-Sourced, Natural Product Screening Library for Exploring Biological Space

2018 ◽  
Author(s):  
Sara E. Kearney ◽  
Gergely Zahoránszky-Kőhalmi ◽  
Kyle R. Brimacombe ◽  
Mark J. Henderson ◽  
Caitlin Lynch ◽  
...  
Keyword(s):  
Natural Products ◽  
High Throughput ◽  
High Throughput Screening ◽  
Therapeutic Potential ◽  
Structural Diversity ◽  
Biological Evaluation ◽  
Structural Class ◽  
Differential Behavior ◽  
Biological Potential ◽  
Approved Drugs

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (–)-2(<i>S</i>)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening.

scholarly journals A New Model of Sensorial Neuron-Like Cells for HTS of Novel Analgesics for Neuropathic Pain

2018 ◽  
Vol 24 (2) ◽  
pp. 158-168 ◽  
Author(s):  
Antón L. Martínez ◽  
José Brea ◽  
Xavier Monroy ◽  
Manuel Merlos ◽  
Javier Burgueño ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Intracellular Calcium ◽  
High Throughput Screening ◽  
Cell Model ◽  
Chemical Library ◽  
Differentiated Cells ◽  
Drg Neuron ◽  
Undifferentiated Cells ◽  
Vitro Model

In this study we developed a new translational phenotypic in vitro model for high-throughput screening (HTS) of novel analgesics for treating neuropathic pain, in order to address the poor translation of traditional recombinant models. The immortalized dorsal root ganglia (DRG) neuron-like F11 cell line was selected based on its phenotype after differentiation. The acquisition of neuronal characteristics was evaluated by measuring the expression of TrkA as a DRG neuron marker ( p < 0.01) as well as by measuring the global neurite length ( p < 0.001). The response of F11 cells to ATP and KCl was obtained by measuring intracellular calcium concentration, dynamic mass redistribution, and membrane potential. A KCl-induced increase of intracellular calcium levels was chosen as the readout because of the better signal quality, higher reproducibility, and greater compatibility with HTS assay requirements compared with other methods. The response to KCl differed significantly between differentiated and undifferentiated cells ( p < 0.05), with an EC50 value of 5 mM in differentiated cells. The model was validated by screening the Prestwick Chemical Library. Five hits already proposed for neuropathic-related pain were identified, with IC50 values between 1 and 7 µM. This cell model provides a new tool for screening novel analgesics for the relief of neuropathic pain.

scholarly journals Canvass: A Crowd-Sourced, Natural Product Screening Library for Exploring Biological Space

2018 ◽  
Author(s):  
Sara E. Kearney ◽  
Gergely Zahoránszky-Kőhalmi ◽  
Kyle R. Brimacombe ◽  
Mark J. Henderson ◽  
Caitlin Lynch ◽  
...  
Keyword(s):  
Natural Products ◽  
High Throughput ◽  
High Throughput Screening ◽  
Therapeutic Potential ◽  
Structural Diversity ◽  
Biological Evaluation ◽  
Structural Class ◽  
Differential Behavior ◽  
Biological Potential ◽  
Approved Drugs

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (–)-2(<i>S</i>)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening.

scholarly journals Canvass: A Crowd-Sourced, Natural Product Screening Library for Exploring Biological Space

2018 ◽  
Author(s):  
Sara E. Kearney ◽  
Gergely Zahoránszky-Kőhalmi ◽  
Kyle R. Brimacombe ◽  
Mark J. Henderson ◽  
Caitlin Lynch ◽  
...  
Keyword(s):  
Natural Products ◽  
High Throughput ◽  
High Throughput Screening ◽  
Therapeutic Potential ◽  
Structural Diversity ◽  
Biological Evaluation ◽  
Structural Class ◽  
Differential Behavior ◽  
Biological Potential ◽  
Approved Drugs

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (–)-2(<i>S</i>)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening.

The Medicinal Chemistry of Therapeutic Peptides: Recent Developments in Synthesis and Design Optimizations

2019 ◽  
Vol 26 (13) ◽  
pp. 2330-2355 ◽  
Author(s):  
Anutthaman Parthasarathy ◽  
Sasikala K. Anandamma ◽  
Karunakaran A. Kalesh
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Therapeutic Potential ◽  
The Past ◽  
Recombinant Production ◽  
Tremendous Progress ◽  
Recent Developments ◽  
Therapeutic Peptides ◽  
Development Processes ◽  
Delivery Strategies

Peptide therapeutics has made tremendous progress in the past decade. Many of the inherent weaknesses of peptides which hampered their development as therapeutics are now more or less effectively tackled with recent scientific and technological advancements in integrated drug discovery settings. These include recent developments in synthetic organic chemistry, high-throughput recombinant production strategies, highresolution analytical methods, high-throughput screening options, ingenious drug delivery strategies and novel formulation preparations. Here, we will briefly describe the key methodologies and strategies used in the therapeutic peptide development processes with selected examples of the most recent developments in the field. The aim of this review is to highlight the viable options a medicinal chemist may consider in order to improve a specific pharmacological property of interest in a peptide lead entity and thereby rationally assess the therapeutic potential this class of molecules possesses while they are traditionally (and incorrectly) considered ‘undruggable’.

The Therapeutic Potential of Chemokines in the Treatment of Chemotherapy- Induced Peripheral Neuropathy

2020 ◽  
Vol 21 (3) ◽  
pp. 288-301 ◽  
Author(s):  
Lin Zhou ◽  
Luyao Ao ◽  
Yunyi Yan ◽  
Wanting Li ◽  
Anqi Ye ◽  
...  
Keyword(s):  
Nervous System ◽  
Neuropathic Pain ◽  
Immune System ◽  
Peripheral Neuropathy ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Chemotherapeutic Agents ◽  
Cell Trafficking ◽  
Mediated Communication ◽  
Novel Therapeutic Strategies

Background: Some of the current challenges and complications of cancer therapy are chemotherapy- induced peripheral neuropathy (CIPN) and the neuropathic pain that are associated with this condition. Many major chemotherapeutic agents can cause neurotoxicity, significantly modulate the immune system and are always accompanied by various adverse effects. Recent evidence suggests that cross-talk occurs between the nervous system and the immune system during treatment with chemotherapeutic agents; thus, an emerging concept is that neuroinflammation is one of the major mechanisms underlying CIPN, as demonstrated by the upregulation of chemokines. Chemokines were originally identified as regulators of peripheral immune cell trafficking, and chemokines are also expressed on neurons and glial cells in the central nervous system. Objective: In this review, we collected evidence demonstrating that chemokines are potential mediators and contributors to pain signalling in CIPN. The expression of chemokines and their receptors, such as CX3CL1/CX3CR1, CCL2/CCR2, CXCL1/CXCR2, CXCL12/CXCR4 and CCL3/CCR5, is altered in the pathological conditions of CIPN, and chemokine receptor antagonists attenuate neuropathic pain behaviour. Conclusion: By understanding the mechanisms of chemokine-mediated communication, we may reveal chemokine targets that can be used as novel therapeutic strategies for the treatment of CIPN.

The Immunomodulatory Role of G2013 (α-L-Guluronic Acid) on the Expression of TLR2 and TLR4 in HT29 cell line

2019 ◽  
Vol 16 (1) ◽  
pp. 91-95 ◽  
Author(s):  
Hamid Farhang ◽  
Laleh Sharifi ◽  
Mohammad Mehdi Soltan Dallal ◽  
Mona Moshiri ◽  
Zahra Norouzbabaie ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Rna Extraction ◽  
Cell Plate ◽  
Inhibitory Effect ◽  
Control Group ◽  
Ht29 Cells ◽  
Guluronic Acid ◽  
Tlr4 Mrna

Background: The non-steroidal anti-inflammatory drugs (NSAIDs) play crucial role in the controlling of inflammatory diseases. Due to the vast side effects of NSAIDs, its use is limited. G2013 or &amp;#945;-L-Guluronic Acid is a new NSAID with immunomodulatory features. Objectives: Considering the leading role of TLRs in inflammatory responses, in this study, we aimed to evaluate G2013 cytotoxicity and its effect on the expression of TLR2 and TLR4 molecules. Methods: HEK293-TLR2 and HEK293-TLR4 cells were cultured and seeded on 96-well cell plate, and MTT assay was performed for detecting the viability of the cells after treatment with different concentrations of G2013. HT29 cells were grown and treated with low and high doses of G2013. After total RNA extraction and cDNA synthesis, quantitative real-time PCR were performed to assess the TLR2 and TLR4 mRNA synthesis. Results: We found that concentrations of ≤125 &amp;#181;g/ml of G2013 had no apparent cytotoxicity effect on the HEK293-TLR2 and -TLR4 cells. Our results indicated that after G2013 treatment (5 &amp;#181;g/ml) in HT29 cells, TLR2 and TLR4 mRNA expression decreased significantly compared with the untreated control group (p=0.02 and p=0.001 respectively). Conclusion: The results of this study revealed that G2013 can down regulate the TLR2 and TLR4 gene expression and exerts its inhibitory effect. Our findings are parallel to our previous finding which showed G2013 ability to down regulate the signaling pathway of TLRs. However, further studies are needed to identify the molecular mechanism of G2013.<p&gt;

scholarly journals Identification of a juvenile-hormone signaling inhibitor via high-throughput screening of a chemical library

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Takumi Kayukawa ◽  
Kenjiro Furuta ◽  
Keisuke Nagamine ◽  
Tetsuro Shinoda ◽  
Kiyoaki Yonesu ◽  
...  
Keyword(s):  
Juvenile Hormone ◽  
Cell Line ◽  
Signaling Pathway ◽  
High Throughput ◽  
High Throughput Screening ◽  
Large Scale ◽  
Ex Vivo ◽  
Agricultural Field ◽  
Chemical Library ◽  
Field Development

Abstract Insecticide resistance has recently become a serious problem in the agricultural field. Development of insecticides with new mechanisms of action is essential to overcome this limitation. Juvenile hormone (JH) is an insect-specific hormone that plays key roles in maintaining the larval stage of insects. Hence, JH signaling pathway is considered a suitable target in the development of novel insecticides; however, only a few JH signaling inhibitors (JHSIs) have been reported, and no practical JHSIs have been developed. Here, we established a high-throughput screening (HTS) system for exploration of novel JHSIs using a Bombyx mori cell line (BmN_JF&AR cells) and carried out a large-scale screening in this cell line using a chemical library. The four-step HTS yielded 69 compounds as candidate JHSIs. Topical application of JHSI48 to B. mori larvae caused precocious metamorphosis. In ex vivo culture of the epidermis, JHSI48 suppressed the expression of the Krüppel homolog 1 gene, which is directly activated by JH-liganded receptor. Moreover, JHSI48 caused a parallel rightward shift in the JH response curve, suggesting that JHSI48 possesses a competitive antagonist-like activity. Thus, large-scale HTS using chemical libraries may have applications in development of future insecticides targeting the JH signaling pathway.

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