Oridonin: A small molecule inhibitor of cystic fibrosis transmembrane conductance regulator (CFTR) isolated from traditional Chinese medicine

Luan, Jian; Zhang, Yaofang; Yang, Shuang; Xue, Wei; B, Yu; Yang, Hong

doi:10.1016/j.fitote.2014.11.001

Cited by 8 publications

(6 citation statements)

References 21 publications

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“…Oridonin (Orid, C 20 H 28 O 6 ) is a bioactive natural substance isolated from the Chinese herb Rabdosia Rubescens [8]. It is also known as rubesecensin A, and its main constituent is 7, 20-epoxy-ent-kauranes [9].…”

Section: Introductionmentioning

confidence: 99%

Oridonin relieves hypoxia-evoked apoptosis and autophagy via modulating microRNA-214 in H9c2 cells

Gong

Zhang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Oridonin (Orid) has been diffusely applied to remedy dissimilar cancers. Howbeit, the influence of Orid in ischemic heart disease (IHD) remains imprecise. The current study uncovered the functions of Orid in hypoxia-caused apoptosis and autophagy in H9c2 cells. H9c2 cells received hypoxia and Orid manipulation, cell viability, apoptosis, apoptosis-interrelated factors and autophagy-correlative factors were appraised. After the extraordinary vectors transfections, the impacts of miR-214 inhibition on hypoxia-triggered apoptosis and autophagy were investigated. Further, dual luciferase reporter assay was enforced for ascertaining the pertinence between miR-214 and PTEN. PI3K/AKT/mTOR pathway was finally determined using western blot. We found that, Orid significantly alleviated hypoxia-induced apoptosis and autophagy through regulation their associated proteins in H9c2 cells. Up-regulation of miR-214 was found in hypoxia and Orid co-managed cells, meanwhile, repression of miR-214 obviously annulled the modulatory functions of Orid in hypoxia-evoked apoptosis and autophagy. Additionally, PTEN was forecasted to be a firsthand target of miR-214. Besides, we observed that Orid evoked PI3K/ AKT/mTOR activation through elevation of miR-214 in hypoxia-managed H9c2 cells. In conclusion, the amusing results corroborated that Orid relieved hypoxia-caused apoptosis and autophagy via adjusting PI3K/AKT/mTOR pathway through enhancement of miR-214 in H9c2 cells.

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Section: Introductionmentioning

confidence: 99%

Oridonin relieves hypoxia-evoked apoptosis and autophagy via modulating microRNA-214 in H9c2 cells

Gong

Zhang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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“…Thiazolidinones are also potential development candidates, although their IC 50 values for CFTR inhibition are much greater than that of (R)‐BPO‐27 (21). There are also natural‐product preparations (41, 42) and purified compounds (43, 44) with reported CFTR inhibition activity, although their potencies are low (IC 50. 20 μM) or their active components have not been identified.…”

Section: Discussionmentioning

confidence: 99%

Benzopyrimido‐pyrrolo‐oxazine‐dione CFTR inhibitor (R)‐BPO‐27 for antisecretory therapy of diarrheas caused by bacterial enterotoxins

et al. 2016

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Secretory diarrheas caused by bacterial enterotoxins, including cholera and traveler's diarrhea, remain a major global health problem. Inappropriate activation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel occurs in these diarrheas. We previously reported that the benzopyrimido-pyrrolo-oxazinedione (R)-BPO-27 inhibits CFTR chloride conductance with low-nanomolar potency. Here, we demonstrate using experimental mouse models and human enterocyte cultures the potential utility of (R)-BPO-27 for treatment of secretory diarrheas caused by cholera and Escherichia coli enterotoxins. (R)-BPO-27 fully blocked CFTR chloride conductance in epithelial cell cultures and intestine after cAMP agonists, cholera toxin, or heat-stable enterotoxin of E. coli (STa toxin), with IC down to ∼5 nM. (R)-BPO-27 prevented cholera toxin and STa toxin-induced fluid accumulation in small intestinal loops, with IC down to 0.1 mg/kg. (R)-BPO-27 did not impair intestinal fluid absorption or inhibit other major intestinal transporters. Pharmacokinetics in mice showed >90% oral bioavailability with sustained therapeutic serum levels for >4 h without the significant toxicity seen with 7-d administration at 5 mg/kg/d. As evidence to support efficacy in human diarrheas, (R)-BPO-27 blocked fluid secretion in primary cultures of enteroids from human small intestine and anion current in enteroid monolayers. These studies support the potential utility of (R)-BPO-27 for therapy of CFTR-mediated secretory diarrheas.-Cil, O., Phuan, P.-W., Gillespie, A. M., Lee, S., Tradtrantip, L., Yin, J., Tse, M., Zachos, N. C., Lin, R., Donowitz, M., Verkman, A. S. Benzopyrimido-pyrrolo-oxazine-dione CFTR inhibitor (R)-BPO-27 for antisecretory therapy of diarrheas caused by bacterial enterotoxins.

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“…Closed-loop studies were conducted similarly to previously published methods with minor modifications. 41,42 Prior to the study initiation, mice were deprived of food for 18 h with free access to water. Mice were given Rimadyl (7.5 mg/kg, subcutaneously (SC)) 2 h prior to surgery to ameliorate post-operative pain.…”

Section: Closed-loop Studiesmentioning

confidence: 99%

Prevention and treatment of secretory diarrhea by the lysophosphatidic acid analog Rx100

Thompson

Ray

Alli

et al. 2018

Exp Biol Med (Maywood)

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Diarrheal disease is a severe global health problem. It is estimated that secretory diarrhea causes 2.5 million deaths annually among children under the age of five in the developing world. A critical barrier in treating diarrheal disease is lack of easy-to-use effective treatments. While antibiotics may shorten the length and severity of diarrhea, oral rehydration remains the primary approach in managing secretory diarrhea. Existing treatments mostly depend on reconstituting medicines with water that is often contaminated which can be an unresolved problem in the developing world. Standard treatments for secretory diarrhea also include drugs that decrease intestinal motility. This approach is less than ideal because in cases where infection is the cause, this can increase the incidence of bacterial translocation and the potential for sepsis. Our goal is to develop a safe, effective, easy-to-use, and inexpensive treatment to reduce fluid loss in secretory diarrhea. We have developed Rx100, which is a metabolically stable analog of lysophosphatidic acid. We tested the hypothesis that Rx100, similarly to lysophosphatidic acid, inhibits the activation of the cystic fibrosis transmembrane regulator Cl− channel and also reduces barrier permeability resulting in the decrease of fluid loss in multiple etiologies of secretory diarrhea. Here we have established the bioavailability and efficacy of Rx100 in cholera toxin-induced secretory diarrhea models. We have demonstrated the feasibility of Rx100 as an effective treatment for Citrobacter rodentium infection-induced secretory diarrhea. Using both the open- and closed-loop mouse models, we have optimized the dosing regimen and time line of delivery for Rx100 via oral and parenteral delivery. Impact statement A critical barrier in treating diarrheal disease is easy-to-use effective treatments. Rx100 is a first in class, novel small molecule that has shown efficacy after both subcutaneous and oral administration in a mouse cholera-toxin- and Citrobacter rodentium infection-induced diarrhea models. Our findings indicate that Rx100 a metabolically stable analog of the lipid mediator lysophosphatidic acid blocks activation of CFTR-mediated secretion responsible for fluid discharge in secretory diarrhea. Rx100 represents a new treatment modality which does not directly block CFTR but attenuates its activation by bacterial toxins. Our results provide proof-of-principle that Rx100 can be developed for use as an effective oral or injectable easy-to-use drug for secretory diarrhea which could significantly improve care by eliminating the need for severely ill patients to regularly consume large quantities of oral rehydration therapies and offering options for pediatric patients.

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Oridonin: A small molecule inhibitor of cystic fibrosis transmembrane conductance regulator (CFTR) isolated from traditional Chinese medicine

Cited by 8 publications

References 21 publications

Oridonin relieves hypoxia-evoked apoptosis and autophagy via modulating microRNA-214 in H9c2 cells

Oridonin relieves hypoxia-evoked apoptosis and autophagy via modulating microRNA-214 in H9c2 cells

Benzopyrimido‐pyrrolo‐oxazine‐dione CFTR inhibitor (R)‐BPO‐27 for antisecretory therapy of diarrheas caused by bacterial enterotoxins

Prevention and treatment of secretory diarrhea by the lysophosphatidic acid analog Rx100

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