Shikonin Inhibits Intestinal Calcium-Activated Chloride Channels and Prevents Rotaviral Diarrhea

Jiang, Yu; B, Yu; Yang, Hong; Ma, Tiantian

doi:10.3389/fphar.2016.00270

Cited by 38 publications

(31 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although the role of CLCs in renal physiology is not clear (97), excessive amounts of chlorine aggravate cell damage. The shikonin in the herbal medicine is said to be a CLC inhibitor (98). In the current study, one of the flavonoids, troxerutin, had rescue effects on OTA-induced CLC activation.…”

Section: Discussionsupporting

confidence: 48%

Precision toxicology shows that troxerutin alleviates ochratoxin A–induced renal lipotoxicity

Yang

Huang

et al. 2018

FASEB j.

View full text Add to dashboard Cite

Lipotoxicity is the most common cause of severe kidney disease, with few treatment options available today. Precision toxicology can improve detection of subtle intracellular changes in response to exogenous substrates; thus, it facilitates in‐depth research on bioactive molecules that may interfere with the onset of certain diseases. In the current study, troxerutin significantly relieved nephrotoxicity, increased endurance, and improved systemic energy metabolism and renal inflammation in OTA‐induced nephrotic mice. Lipidomics showed that troxerutin effectively reduced the levels of triglycerides, phosphatidylcholines, and phosphatidylethanolamines in nephropathy. The mechanism was partly attributable to troxerutin in alleviating the aberrantly up‐regulated expression of sphingomyelinase, the cystic fibrosis transmembrane conductance regulator, and chloride channel 2. Renal tubular epithelial cells, the main site of toxin‐induced accumulation of lipids in the kidney, were subjected to transcriptomic profiling, which uncovered several metabolic factors relevant to aberrant lipid and lipoprotein metabolism. Our work provides new insights into the molecular features of toxin‐induced lipotoxicity in renal tubular epithelial cells in vivo and demonstrates the function of troxerutin in alleviating OTA‐induced nephrosis and associated systemic energy metabolism disorders.—Yang, X., Xu, W., Huang, K., Zhang, B., Wang, H., Zhang, X., Gong, L., Luo, Y., He, X. Precision toxicology shows that troxerutin alleviates ochratoxin A‐induced renal lipotoxicity. FASEB J. 33, 2212–2227 (2019). http://www.fasebj.org

show abstract

Section: Discussionsupporting

confidence: 48%

Precision toxicology shows that troxerutin alleviates ochratoxin A–induced renal lipotoxicity

Yang

Huang

et al. 2018

FASEB j.

View full text Add to dashboard Cite

show abstract

“…Inhibition of saliva production and dry mouth may occur mediation with TMEM16A-inhibitors (Ousingsawat et al, 2009; Catalan et al, 2015). Inhibition of TMEM16A may also attenuate intestinal contraction and abdominal peristalsis (Sanders et al, 2012; Singh et al, 2014), and therefore could have antidiarrheal effects (Tradtrantip et al, 2010; Namkung et al, 2011b; Jiang et al, 2016). Finally, inhibition of renal TMEM16A could potentially lead to proteinuria and acidosis (Faria et al, 2014; Schenk et al, 2018).…”

Section: Biological Effects Of Inhibitors and Activators Of Tmem16amentioning

confidence: 99%

TMEM16A in Cystic Fibrosis: Activating or Inhibiting?

et al. 2019

View full text Add to dashboard Cite

The inflammatory airway disease cystic fibrosis (CF) is characterized by airway obstruction due to mucus hypersecretion, airway plugging, and bronchoconstriction. The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is dysfunctional in CF, leading to defects in epithelial transport. Although CF pathogenesis is still disputed, activation of alternative Cl− channels is assumed to improve lung function in CF. Two suitable non-CFTR Cl− channels are present in the airway epithelium, the Ca2+ activated channel TMEM16A and SLC26A9. Activation of these channels is thought to be feasible to improve hydration of the airway mucus and to increase mucociliary clearance. Interestingly, both channels are upregulated during inflammatory lung disease. They are assumed to support fluid secretion, necessary to hydrate excess mucus and to maintain mucus clearance. During inflammation, however, TMEM16A is upregulated particularly in mucus producing cells, with only little expression in ciliated cells. Recently it was shown that knockout of TMEM16A in ciliated cells strongly compromises Cl− conductance and attenuated mucus secretion, but does not lead to a CF-like lung disease and airway plugging. Along this line, activation of TMEM16A by denufosol, a stable purinergic ligand, failed to demonstrate any benefit to CF patients in earlier studies. It rather induced adverse effects such as cough. A number of studies suggest that TMEM16A is essential for mucus secretion and possibly also for mucus production. Evidence is now provided for a crucial role of TMEM16A in fusion of mucus-filled granules with the apical plasma membrane and cellular exocytosis. This is probably due to local Ca2+ signals facilitated by TMEM16A. Taken together, TMEM16A supports fluid secretion by ciliated airway epithelial cells, but also maintains excessive mucus secretion during inflammatory airway disease. Because TMEM16A also supports airway smooth muscle contraction, inhibition rather than activation of TMEM16A might be the appropriate treatment for CF lung disease, asthma and COPD. As a number of FDA-approved and well-tolerated drugs have been shown to inhibit TMEM16A, evaluation in clinical trials appears timely.

show abstract

“…This multi-faceted control of Ca 2+ signalling suggests a crucial role for Ca 2+ channels in the pathophysiology of RV. In this regard, it was shown that the blockade of CaCCs, including TMEM16A, reduces intestinal motility and fluid loss in vivo with no direct effects on the levels of virus infection [74].…”

Section: Viral Channelopathies and Ca 2+ Channelsmentioning

confidence: 99%

Ion Channels as Therapeutic Targets for Viral Infections: Further Discoveries and Future Perspectives

Charlton

Pearson

Hover

et al. 2020

Viruses

View full text Add to dashboard Cite

Ion channels play key roles in almost all facets of cellular physiology and have emerged as key host cell factors for a multitude of viral infections. A catalogue of ion channel-blocking drugs have been shown to possess antiviral activity, some of which are in widespread human usage for ion channel-related diseases, highlighting new potential for drug repurposing. The emergence of ion channel–virus interactions has also revealed the intriguing possibility that channelopathies may explain some commonly observed virus induced pathologies. This field is rapidly evolving and an up-to-date summary of new discoveries can inform future perspectives. We herein discuss the role of ion channels during viral lifecycles, describe the recently identified ion channel drugs that can inhibit viral infections, and highlight the potential contribution of ion channels to virus-mediated disease.

show abstract

Shikonin Inhibits Intestinal Calcium-Activated Chloride Channels and Prevents Rotaviral Diarrhea

Cited by 38 publications

References 36 publications

Precision toxicology shows that troxerutin alleviates ochratoxin A–induced renal lipotoxicity

Precision toxicology shows that troxerutin alleviates ochratoxin A–induced renal lipotoxicity

TMEM16A in Cystic Fibrosis: Activating or Inhibiting?

Ion Channels as Therapeutic Targets for Viral Infections: Further Discoveries and Future Perspectives

Contact Info

Product

Resources

About