NaCCC2 transport proteins, including those from Drosophila melanogaster (Ncc83) and Aedes aegypti (aeCCC2), are an insect-specific clade with sequence similarity to Na⁺-K⁺-2Cl^- cotransporters. Whereas the Na⁺-K⁺-2Cl^- cotransporters and other cation-chloride cotransporters are electroneutral, recent work indicates that Ncc83 and aeCCC2 carry charge across membranes. Here, we further characterize the regulation and transport properties of Ncc83 and aeCCC2 expressed in Xenopus oocytes. In cation uptake experiments, Li⁺ was used as a tracer for Na⁺ and Rb⁺ was used as a tracer for K⁺. Li⁺ uptake of oocytes expressing either aeCCC2 or Ncc83 was greater than uptake in water-injected controls, activated by hypotonic swelling, and not inhibited by ouabain or ethyl cinnamate. Rb⁺ uptake of oocytes expressing either aeCCC2 or Ncc83 was not different than water injected controls. In oocytes expressing either aeCCC2 or Ncc83, Li⁺ uptake plateaued with increasing Li⁺ concentrations, with apparent K_m values in the range of 10 to 20 mM. Following exposure to ouabain, intracellular [Na⁺] was greater in oocytes expressing aeCCC2 than in controls. Elevating intracellular cAMP (via 8-bromo-cAMP) in Ncc83 oocytes significantly stimulated both Li⁺ uptake and membrane conductances. Elevating intracellular cAMP in aeCCC2 oocytes did not affect Li⁺ uptake, but stimulated membrane conductances. Overall, these results confirm that the NaCCC2s resemble other cation-chloride cotransporters in their regulation and some transport properties. However, unlike other cation-chloride cotransporters, they carry charge across membranes.

01 Sep 2024·Archives of Biochemistry and Biophysics

Evaluation of the activity of cardiac glycosides on RORγ and RORγT nuclear receptors

Article

Author: Sałkowska, Anna ; Ratajewski, Marcin ; Pastwińska, Joanna ; Karwaciak, Iwona ; Bachorz, Rafał A

Cardiac glycosides, derived from plants and animals, have been recognized since ancient times. These substances hinder the function of the sodium-potassium pump within eukaryotic cells. Many reports have shown that these compounds influence the activity of nuclear receptors. Thus, we assessed the effects of various cardiac glycosides at nontoxic concentrations on RORγ and RORγT. RORγT is a crucial protein involved in the differentiation of Th17 lymphocytes. Sixteen analyzed cardiac glycosides exhibited varying toxicities in HepG2 cells, all of which demonstrated agonistic effects on RORγ, as confirmed in the RORγ-HepG2 reporter cell line. The overexpression of both the RORγ and RORγT isoforms intensified the effects of these compounds. Additionally, these glycosides induced the expression of G6PC, a gene regulated by RORγ, in HepG2 cells. Subsequently, the effects of two endogenous cardiac glycosides (marinobufagenin and ouabain) and the three most potent glycosides (bufalin, oleandrin, and telecinobufagenin) were evaluated in Th17 primary lymphocytes. All of these compounds increased the expression of the IL17A, IL17F, IFNG, and CXCL10 genes, but they exhibited varying effects on GZMB and CCL20 expression. Molecular docking analysis revealed the robust binding affinity of cardiac glycosides for the ligand binding domain of the RORγ/RORγT receptors. Thus, we demonstrated that at nontoxic concentrations, cardiac glycosides have agonistic effects on RORγ/RORγT nuclear receptors, augmenting their activity. This potential can be harnessed to modulate the phenotype of IL17-expressing cells (e.g., Th17 or Tc17 lymphocytes) in adoptive therapy for combating various types of cancer.

01 Aug 2024·International Journal for Parasitology: Drugs and Drug Resistance

Ouabain, ATPase inhibitor, potentially enhances the effect of polyhexamethylene biguanide on Acanthamoeba castellanii

Article

Author: Shih, Kuang-Yi ; Chang, Yao-Tsung ; Huang, Jian-Ming ; Wang, Yu-Jen

Acanthamoeba, a free-living amoeba, is commonly found in various natural environments, such as rivers and soil, as well as in public baths, swimming pools, and sewers. Acanthamoeba can cause severe illness such as granulomatous amoebic encephalitis and Acanthamoeba keratitis (AK) in humans. AK, the most recognized disease, can cause permanent visual impairment or blindness by affecting the cornea. AK commonly affects contact lens wearers who neglect proper cleaning habits. The symptoms of AK include epithelial and stromal destruction, corneal infiltrate, and intense ocular pain, occasionally necessitating surgical removal of the entire eyeball. Current AK treatment involves the hourly application of eye drops containing polyhexamethylene biocide (PHMB). However, studies have revealed their ineffectiveness against drug-resistant strains. Acanthamoeba can form cysts as a survival mechanism in adverse environments, though the exact mechanism remains unknown. Our experiments revealed that sodium P-type ATPase (ACA1_065450) is closely linked to encystation. In addition, various encystation buffers, such as MgCl₂ or NaCl, induced the expression of P-type ATPase. Furthermore, we used ouabain, an ATPase inhibitor, to inhibit the Na⁺/K⁺ ion pump, consequently decreasing the encystation rate of Acanthamoeba. Our primary objective is to develop an advanced treatment for AK. We anticipate that the combination of ouabain and PHMB may serve as an effective therapeutic approach against AK in the future.

100 Deals associated with Ouabain

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KEGG	Wiki	ATC	Drug Bank
D00112	Ouabain	C01AC01	DB01092

R&D Status

10 top approved records.

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Indication	Country/Location	Organization	Date
Heart Failure	-	-	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ERA2023	Not Applicable	Acute Kidney Injury \| Sepsis	177	ENDOGENOUS OUABAIN (Patients diagnosed with sepsis or septic shock)	ckapvpzgrw(abnimivjry) = rxgjgnbylg fsjbznfgui (mcviakblgu ) View more	-	15 Jun 2023
ASN2018	Not Applicable	Renal Cell Carcinoma	-	Ouabain	xndhavnyct(vpsfjifdub) = ryzuleqfdu qyrkhnrsin (lfnbjyarwx )	-	23 Oct 2018
ASN2016	Not Applicable	Diabetic Nephropathies	-	Ouabain	pfahquehwh(awdtatjlhi) = gbwdydrqjn vyenyzldnu (uwdctmtkew, 4.1)	Positive	15 Nov 2016
				Ouabain 5nM	pfahquehwh(awdtatjlhi) = hmhtuwkyzi vyenyzldnu (uwdctmtkew, 1.3)
ASN2014	Not Applicable	Proteinuria ouabain	-	Rostafuroxin 100 µg/kg/day	(jrjpuaixpw) = eybrrbriwu kkgxjomcbu (gtypwlbyzp ) View more	Positive	11 Nov 2014
				Ouabain	(jrjpuaixpw) = tlvtlzkwlr kkgxjomcbu (gtypwlbyzp ) View more
ASN2014	Not Applicable	Hypertension serum uric acid \| endogenous ouabain \| ATP-binding cassette B1 gene	222	Ouabain	gaasykjzvt(znfwgltejx) = dubomujgpv zdjkocndya (erryfxbxcf )	-	11 Nov 2014
ASN2012	Not Applicable	Dysentery, Bacillary Stx2 \| Gb3 receptors \| Bax ... View more	-	Ouabain/Na,K-ATPase	geoqifmphz(cmurfnmelq) = sofohssksn eekbnsigfo (mtpawzduot ) View more	Positive	30 Oct 2012
				Ouabain	geoqifmphz(cmurfnmelq) = pvbetmyhwy eekbnsigfo (mtpawzduot ) View more
ASN2010	Not Applicable	Hypertension Na-K ATPase \| NHE-1	-	Ouabain	(puzphpdzej) = ibgradrwov xokaajtsoz (dbrhnmucir, 3.26)	Positive	16 Nov 2010
				Vehicle	(puzphpdzej) = yxplgmmgek xokaajtsoz (dbrhnmucir, 5.32)
ARVO2008	Not Applicable	-	-	Ouabain 30 nM	ervxdqooer(xcduhglgkr) = hfxsrlfjxu arwvppktpi (mqhictjdju )	-	01 May 2008
				Ouabain	ervxdqooer(xcduhglgkr) = jcwurgpseg arwvppktpi (mqhictjdju )
ARVO2005	Not Applicable	Iris Pigment Epithelium Anomalies	-	Ouabain	scdupozxvs(xngpzrajsu) = ouabain did enhance BKCa-channel activity without a change in single-channel amplitude bejbkigxfz (svkzhhnmmz )	-	01 May 2005

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