Anthraquinones As Pharmacological Tools and Drugs

Malik, Enas M.; Müller, Christian

doi:10.1002/med.21391

Cited by 358 publications

(239 citation statements)

References 259 publications

(556 reference statements)

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“…Additionally, cisplatin mediates CaM crosslinking at methionine residues 43 , which could explain the decrease in FRET. We were unsurprised to observe "frequent hitters" in screens and thiol modifiers, such as Reactive Blue 44 , SCH-202676 45 , cisplatin 46 , aurintricarboxylic acid [47][48][49] , and (6 R)-BH4 50 . Several Hits that induce prominent FRET effects and/or are known functional modulators were further tested in dose-response FRET assays.…”

Section: Hts Performancementioning

confidence: 99%

RyR1-targeted drug discovery pipeline integrating FRET-based high-throughput screening and human myofiber dynamic Ca2+ assays

Rebbeck

Singh

Janicek

et al. 2020

Sci Rep

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Elevated cytoplasmic [Ca 2+ ] is characteristic in severe skeletal and cardiac myopathies, diabetes, and neurodegeneration, and partly results from increased Ca 2+ leak from sarcoplasmic reticulum stores via dysregulated ryanodine receptor (RyR) channels. Consequently, RyR is recognized as a high-value target for drug discovery to treat such pathologies. Using a FRET-based high-throughput screening assay that we previously reported, we identified small-molecule compounds that modulate the skeletal muscle channel isoform (RyR1) interaction with calmodulin and FK506 binding protein 12.6. Two such compounds, chloroxine and myricetin, increase FRET and inhibit [ 3 H]ryanodine binding to RyR1 at nanomolar Ca 2+. Both compounds also decrease RyR1 Ca 2+ leak in human skinned skeletal muscle fibers. Furthermore, we identified compound concentrations that reduced leak by > 50% but only slightly affected Ca 2+ release in excitation-contraction coupling, which is essential for normal muscle contraction. This report demonstrates a pipeline that effectively filters small-molecule RyR1 modulators towards clinical relevance. In striated muscle, contraction requires an intracellular Ca 2+-release event mediated by ryanodine receptors (RyR) that are embedded in the sarcoplasmic reticulum (SR) membrane. Dysregulation of skeletal (RyR1) and cardiac (RyR2) isoforms, via mutations or excess posttranslational modification, has been linked to severe muscle pathologies, including malignant hyperthermia (MH), central core disease, muscular dystrophy (MD), sarcopenia, catecholaminergic polymorphic ventricular tachycardia, heart failure, and more recently RyR2 has been recognized as a potentially significant contributor to diabetes and Alzheimer's disease 1-9. In most of these clinical indications, pathogenesis can be fueled by excess SR Ca 2+ "leak" via RyR under resting cellular conditions, which leads to toxic intracellular basal [Ca 2+ ] and insufficient SR Ca 2+ load. As a result, RyR is intensely studied as a therapeutic target. Indeed, the therapeutic potential of pharmaceutically targeting RyR1-mediated SR Ca 2+ leak in skeletal muscle has been shown in animal models of Duchenne MD, limb-girdle MD, and sarcopenia 5,10,11. The therapeutic potential of targeting RyR2-mediated SR Ca 2+ leak for treating heart failure and arrhythmia is also very well documented 12-16. Additionally, targeting RyR2 (which is abundant in the brain 17,18) may have therapeutic potential for treating neurodegenerative diseases. To introduce a systematic and efficient approach for identifying novel small-molecule chemical scaffolds with potential to mitigate RyR1 dysfunction, we developed and implemented a high-throughput screening (HTS) assay that uses fluorescence lifetime (FLT) detection of FRET 19. This assay was designed to identify compounds that bind to the RyR1 channel complex to allosterically correct its pathologically leaky state (without affecting normal channel function) 19. This FRET-based method is based on monitoring RyR binding of fluorescent...

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Section: Hts Performancementioning

confidence: 99%

RyR1-targeted drug discovery pipeline integrating FRET-based high-throughput screening and human myofiber dynamic Ca2+ assays

Rebbeck

Singh

Janicek

et al. 2020

Sci Rep

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“…Quinones are a class of organic compounds, where 9,10-anthraquinones (9,10 dioxoanthracenes) are an important subgroup [74]. Anthraquinones in Morinda citrifolia are found especially in the roots, and the main compounds with important effects on metabolism are alizarin, lucidin 3- O -β- d -primeveroside, damnacanthol-3- O -β- d -primeveroside, and rubiadin-1-methyl ether [72,73].…”

Section: Morinda Citrifolia Linn (Noni)mentioning

confidence: 99%

Morinda citrifolia Linn. (Noni) and Its Potential in Obesity-Related Metabolic Dysfunction

et al. 2017

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Cultural and economic shifts in the early 19th century led to the rapid development of companies that made good profits from technologically-produced commodities. In this way, some habits changed in society, such as the overconsumption of processed and micronutrient-poor foods and devices that gave rise to a sedentary lifestyle. These factors influenced host-microbiome interactions which, in turn, mediated the etiopathogenesis of “new-era” disorders and diseases, which are closely related, such as obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, hypertension, and inflammatory bowel disease, which are characterized by chronic dysregulation of metabolic and immune processes. These pathological conditions require novel and effective therapeutic approaches. Morinda citrifolia (noni) is well known as a traditional healing plant due to its medicinal properties. Thus, many studies have been conducted to understand its bioactive compounds and their mechanisms of action. However, in obesity and obesity-related metabolic (dysfunction) syndrome, other studies are necessary to better elucidate noni’s mechanisms of action, mainly due to the complexity of the pathophysiology of obesity and its metabolic dysfunction. In this review, we summarize not only the clinical effects, but also important cell signaling pathways in in vivo and in vitro assays of potent bioactive compounds present in the noni plant which have been reported in studies of obesity and obesity-associated metabolic dysfunction.

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“…Studies have shown that AQs and their derivatives induced toxicities to the cells due to the anthracene or quinone moieties, known to be toxic to human mammary epithelial stem cells (De Flora et al, 2006;Kim, Jahan, Kabir, & Brown, 2013;Page et al, 2003). Considerable amount of information has reported that AQs and derivatives induced cytotoxicity, immunotoxicity, and carcinogenesis via alkylation or nucleophilic interaction with important cellular proteins and/or DNA (Bolton, Trush, Penning, Dryhurst, & Monks, 2000;Gorkom & Vries, 1999;Malik & Müller, 2016;Müeller et al, 1999;Müller, Eckert, Lutz, & Stopper, 1996). The studies further showed that AQs induced reactive oxygen species formation due to their highly redox active potential, leading to cellular oxidative stress.…”

Section: Toxicity Of Aqsmentioning

confidence: 99%

Antidiabetic potential of anthraquinones: A review

Mohammed

Ibrahim

Tajuddeen

et al. 2019

Phytotherapy Research

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The present study was designed to review the antidiabetic potential of anthraquinones (AQs) with emphasis on the extent of blood glucose reduction, the half maximal inhibitory concentration values (in vitro studies), the proposed mechanisms of action, and the structure activity relationship studies. We sourced relevant data from the major scientific databases (Pubmed, Science Direct, Medline, and Google Scholar). According to our search, 25 AQs have shown variable antidiabetic potential, whereas one AQ (morindone‐6‐O‐β‐D‐primeveroside) showed no blood glucose‐lowering ability. Emodin and rhein showed the most promising antidiabetic potential in various models. The proposed mechanisms of antidiabetic action include upregulation of insulin receptor substrates‐1, phosphoinositide‐3‐kinase, and Akt‐ser473 expression and elevation of glucagon‐like peptide‐1 level in diabetic animal models linked to the potent protein tyrosine phosphatase 1B and dipeptidyl peptidase‐4 inhibitions. In addition, activation of peroxisome proliferator‐activated receptors gamma and inhibition of α‐glucosidase activity are other possible targets proposed as the mechanism of AQs antidiabetic action. The position and the number of hydroxyl group showed great influence on the overall antidiabetic potential of AQs. AQs hold promising antidiabetic activity despite scanty information. We hope that the present study will serve as a template to further explore the antidiabetic potential of AQs and subsequent antidiabetic drug development.

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Anthraquinones As Pharmacological Tools and Drugs

Cited by 358 publications

References 259 publications

RyR1-targeted drug discovery pipeline integrating FRET-based high-throughput screening and human myofiber dynamic Ca2+ assays

RyR1-targeted drug discovery pipeline integrating FRET-based high-throughput screening and human myofiber dynamic Ca2+ assays

Morinda citrifolia Linn. (Noni) and Its Potential in Obesity-Related Metabolic Dysfunction

Antidiabetic potential of anthraquinones: A review

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