scholarly journals Pharmacologic rescue of circadian β-cell failure through P2Y1 purinergic receptor identified by small-molecule screen

2021 ◽  
Author(s):  
Joseph Bass ◽  
Biliana Marcheva ◽  
Benjamin J Weidemann ◽  
Akihiko Taguchi ◽  
Mark Perelis ◽  
...  
Keyword(s):  
Beta Cells ◽  
Purinergic Receptor ◽  
Luciferase Reporter ◽  
Chemical Genetic ◽  
Primary Mouse ◽  
Small Molecule Screen ◽  
Pharmacologically Active ◽  
And Behavior ◽  
Pharmacologically Active Compounds ◽  
Peripheral Cells

The mammalian circadian clock drives daily oscillations in physiology and behavior through an autoregulatory transcription feedback loop present in central and peripheral cells. Ablation of the core clock within the endocrine pancreas of adult animals impairs the transcription and splicing of genes involved in hormone exocytosis and causes hypoinsulinemic diabetes. However, identification of druggable proteins and pathways to ameliorate the burden of circadian metabolic disease remains a challenge. Here, we generated beta cells expressing a nano-luciferase reporter within the proinsulin polypeptide to screen 2,640 pharmacologically-active compounds and identify insulinotropic molecules that bypass the secretory defect in clock mutant beta cells. We validated lead compounds in primary mouse islets and identified known modulators of ligand-gated ion channels and G-protein coupled receptors, including the antihelmintic ivermectin. Single-cell electrophysiology in circadian mutant mouse and human cadaveric islets validated ivermectin as a glucose-dependent secretagogue. Genetic, genomic, and pharmacologic analyses established that the molecular clock controls the expression of the purinergic P2Y1 receptor to mediate the insulinotropic activity of ivermectin. These findings identify the P2Y1 purinergic receptor as a target to rescue circadian beta-cell failure and establish a chemical genetic screen for endocrine therapeutics.

scholarly journals Podophyllotoxin: History, Recent Advances and Future Prospects

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 603
Author(s):  
Zinnia Shah ◽  
Umar Farooq Gohar ◽  
Iffat Jamshed ◽  
Aamir Mushtaq ◽  
Hamid Mukhtar ◽  
...  
Keyword(s):  
Structure Optimization ◽  
Cytokine Storm ◽  
Chemotherapeutic Drug ◽  
Future Prospects ◽  
Naturally Occurring ◽  
Pharmacologically Active ◽  
Almost All ◽  
Pharmacologically Active Compounds ◽  
Synthetic Derivatives ◽  
Related Compounds

Podophyllotoxin, along with its various derivatives and congeners are widely recognized as broad-spectrum pharmacologically active compounds. Etoposide, for instance, is the frontline chemotherapeutic drug used against various cancers due to its superior anticancer activity. It has recently been redeveloped for the purpose of treating cytokine storm in COVID-19 patients. Podophyllotoxin and its naturally occurring congeners have low bioavailability and almost all these initially discovered compounds cause systemic toxicity and development of drug resistance. Moreover, the production of synthetic derivatives that could suffice for the clinical limitations of these naturally occurring compounds is not economically feasible. These challenges demanded continuous devotions towards improving the druggability of these drugs and continue to seek structure-optimization strategies. The discovery of renewable sources including microbial origin for podophyllotoxin is another possible approach. This review focuses on the exigency of innovation and research required in the global R&D and pharmaceutical industry for podophyllotoxin and related compounds based on recent scientific findings and market predictions.

scholarly journals Development of A Continuous Fluorescence-Based Assay for N-Terminal Acetyltransferase D

2021 ◽  
Vol 22 (2) ◽  
pp. 594
Author(s):  
Yi-Hsun Ho ◽  
Lan Chen ◽  
Rong Huang
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
High Throughput Screening ◽  
Coenzyme A ◽  
Therapeutic Potential ◽  
Biological Functions ◽  
Histone H4 ◽  
Fluorescent Signal ◽  
Pharmacologically Active ◽  
Pharmacologically Active Compounds

N-terminal acetylation catalyzed by N-terminal acetyltransferases (NATs) has various biological functions in protein regulation. N-terminal acetyltransferase D (NatD) is one of the most specific NAT with only histone H4 and H2A proteins as the known substrates. Dysregulation of NatD has been implicated in colorectal and lung cancer progression, implying its therapeutic potential in cancers. However, there is no reported inhibitor for NatD yet. To facilitate the discovery of small-molecule NatD inhibitors, we report the development of a fluorescence-based acetyltransferase assay in 384-well high-throughput screening (HTS) format through monitoring the formation of coenzyme A. The fluorescent signal is generated from the adduct in the reaction between coenzyme A and fluorescent probe ThioGlo4. The assay exhibited a Z′-factor of 0.77 and a coefficient of variation of 6%, indicating it is a robust assay for HTS. A pilot screen of 1280 pharmacologically active compounds and subsequent validation identified two hits, confirming the application of this fluorescence assay in HTS.

scholarly journals Marine-Derived Compounds with Anti-Alzheimer’s Disease Activities

Marine Drugs ◽  
2021 ◽  
Vol 19 (8) ◽  
pp. 410
Author(s):  
Salar Hafez Ghoran ◽  
Anake Kijjoa
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Thinking Skills ◽  
Mechanisms Of Action ◽  
Brain Disorder ◽  
Brain Functioning ◽  
Pharmacologically Active ◽  
Pharmacologically Active Compounds

Alzheimer’s disease (AD) is an irreversible and progressive brain disorder that slowly destroys memory and thinking skills, and, eventually, the ability to perform simple tasks. As the aging population continues to increase exponentially, AD has become a big concern for society. Therefore, neuroprotective compounds are in the spotlight, as a means to tackle this problem. On the other hand, since it is believed—in many cultures—that marine organisms in an individual diet cannot only improve brain functioning, but also slow down its dysfunction, many researchers have focused on identifying neuroprotective compounds from marine resources. The fact that the marine environment is a rich source of structurally unique and biologically and pharmacologically active compounds, with unprecedented mechanisms of action, marine macroorganisms, such as tunicates, corals, sponges, algae, as well as microorganisms, such as marine-derived bacteria, actinomycetes, and fungi, have been the target sources of these compounds. Therefore, this literature review summarizes and categorizes various classes of marine-derived compounds that are able to inhibit key enzymes involved in AD, including acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase (BACE-1), and different kinases, together with the related pathways involved in the pathogenesis of AD. The compounds discussed herein are emerging as promising anti-AD activities for further in-depth in vitro and in vivo investigations, to gain more insight of their mechanisms of action and for the development of potential anti-AD drug leads.

scholarly journals PPARγ inhibits airway epithelial cell inflammatory response through a MUC1-dependent mechanism

2012 ◽  
Vol 302 (7) ◽  
pp. L679-L687 ◽  
Author(s):  
Yong Sung Park ◽  
Erik P. Lillehoj ◽  
Kosuke Kato ◽  
Choon Sik Park ◽  
Kwang Chul Kim
Keyword(s):  
Epithelial Cells ◽  
Culture Media ◽  
A549 Cells ◽  
Luciferase Reporter ◽  
Muc1 Expression ◽  
Mrna Levels ◽  
Airway Epithelial ◽  
Pparγ Agonist ◽  
Tnf Α ◽  
Primary Mouse

This study was conducted to examine the relationship between the peroxisome proliferator-associated receptor-γ (PPARγ) and MUC1 mucin, two anti-inflammatory molecules expressed in the airways. Treatment of A549 lung epithelial cells or primary mouse tracheal surface epithelial (MTSE) cells with phorbol 12-myristate 13-acetate (PMA) increased the levels of tumor necrosis factor (TNF)-α in cell culture media compared with cells treated with vehicle alone. Overexpression of MUC1 in A549 cells decreased PMA-stimulated TNF-α levels, whereas deficiency of Muc1 expression in MTSE cells from Muc1 null mice increased PMA-induced TNF-α levels. Treatment of A549 or MTSE cells with the PPARγ agonist troglitazone (TGN) blocked the ability of PMA to stimulate TNF-α levels. However, the effect of TGN required the presence of MUC1/Muc1, since no differences in TNF-α levels were seen between PMA and PMA plus TGN in MUC1/Muc1-deficient cells. Similarly, whereas TGN decreased interleukin-8 (IL-8) levels in culture media of MUC1-expressing A549 cells treated with Pseudomonas aeruginosa strain K (PAK), no differences in IL-8 levels were seen between PAK and PAK plus TGN in MUC1-nonexpressing cells. EMSA confirmed the presence of a PPARγ-binding element in the MUC1 gene promoter. Finally, TGN treatment of A549 cells increased MUC1 promoter activity measured using a MUC1-luciferase reporter gene, augmented MUC1 mRNA levels by quantitative RT-PCR, and enhanced MUC1 protein expression by Western blot analysis. These combined data are consistent with the hypothesis that PPARγ stimulates MUC1/Muc1 expression, thereby blocking PMA/PAK-induced TNF-α/IL-8 production by airway epithelial cells.

ChemInform Abstract: SEARCH FOR PHARMACOLOGICALLY ACTIVE COMPOUNDS IN A SERIES OF AMINOMETHYL DERIVATIVES OF 5-HYDROXYBENZOFURAN

1979 ◽  
Vol 10 (29) ◽  
Author(s):  
A. N. GRINEV ◽  
N. V. ARKHANGEL'SKAYA ◽  
G. YA. URETSKAYA ◽  
A. A. STOLYARCHUK ◽  
P. A. GALENKO-YAROSHEVSKII
Keyword(s):  
Active Compounds ◽  
Aminomethyl Derivatives ◽  
Pharmacologically Active ◽  
Pharmacologically Active Compounds ◽  
Derivatives Of

scholarly journals NEW PHARMACOLOGICALLY ACTIVE COMPOUNDS BASED ON 5-HYDROXY-7-METHOXY-2-PHENYLCHROMAN-4-ONE

2021 ◽  
Vol 3 ◽  
pp. 119-127
Author(s):  
G.M. Baisarov ◽  
◽  
S.M. Adekenov ◽  
Keyword(s):  
Nmr Spectroscopy ◽  
13C Nmr ◽  
Potassium Carbonate ◽  
13C Nmr Spectroscopy ◽  
1H And 13C Nmr ◽  
Pharmacologically Active ◽  
Pharmacologically Active Compounds ◽  
First Time

The reaction of 5-hydroxy-7-methoxy-2-phenylchroman-4-one with dibromoalkanes in acetone in the presence of potassium carbonate proceeds according to the Michael’s retro-reaction O-alkylation and leads to the formation of the corresponding 2-(bromo-alkoxy) chalcones. The structure of the synthesized compounds was confirmed by IR-, 1H- and 13C-NMR spectroscopy. The cytotoxic, hepatoprotective and anti-inflammatory effects of chalcone derivatives (2-3) were studied for the first time in vitro and in vivo.

scholarly journals Propofol Ameliorates Microglia Activation by Targeting MicroRNA-221/222-IRF2 Axis

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Xi Xiao ◽  
Yuanyuan Hou ◽  
Wei Yu ◽  
Sihua Qi
Keyword(s):  
Molecular Mechanism ◽  
Neuroprotective Effect ◽  
Ectopic Expression ◽  
Microglia Activation ◽  
Luciferase Reporter ◽  
Enzyme Linked Immunosorbent Assay ◽  
Loss Of Function ◽  
Critical Function ◽  
Bv2 Cells ◽  
Primary Mouse

Background. Propofol is a widely used intravenous anesthetic drug with potential neuroprotective effect in diverse diseases of neuronal injuries such as traumatic brain injury and ischemic stroke. However, the underlying molecular mechanism remains largely unknown. Methods. Real-time qPCR, enzyme-linked immunosorbent assay, and Western blotting were used to identify the expression pattern of miR-221/222, inflammatory genes, cytokines, and IRF2. The biological roles and mechanisms of propofol in microglia activation were determined in BV2 cells and primary microglia. Bioinformatic analysis and luciferase reporter assay were used to confirm the regulatory role of miR-221/222 in Irf2 expression. Results. We found that miR-221 and miR-222 were downstream targets of propofol and were consistently upregulated in lipopolysaccharide- (LPS-) primed BV2 cells. Gain- and loss-of-function studies revealed that miR-221 and miR-222 were profoundly implicated in microglia activation. Then, interferon regulatory factor 2 (Irf2) was identified as a direct target gene of miR-221/222. IRF2 protein levels were reduced by miR-221/222 and increased by propofol treatment. Ectopic expression of IRF2 attenuated the proinflammatory roles induced by LPS in BV2 cells. More importantly, the suppressive effects of propofol on LPS-primed activation of BV2 cells or primary mouse microglia involved the inhibition of miR-221/222-IRF2 axis. Conclusions. Our study highlights the critical function of miR-221/222, which inhibited Irf2 translation, in the anti-inflammatory effects of propofol, and provides a new perspective for the molecular mechanism of propofol-mediated neuroprotective effect.

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