Author: Anderson, Andrew T ; Meyer, Gunnar ; Douglas Kinghorn, A. ; Anderson, Andrew T. ; Gallucci, Judith C. ; Douglas Kinghorn, A ; Lauber, Kaitlyn M. ; Ren, Yulin ; Lauber, Kaitlyn M ; Gallucci, Judith C

Na⁺/K⁺-ATPase (NKA) is a plasma membrane ion-transporting protein involved in the generation and maintenance of Na⁺ and K⁺ gradients across the cell membrane, which can produce a driving force for the secondary transport of metabolic substrates. NKA also regulates intracellular calcium that is responsible for modulating numerous cellular processes, while it interacts with many other proteins and functions as a signal transducer, with several signaling pathways being involved. Thus, NKA has become an important target for the treatment of human diseases. Cardiac glycosides are well-known NKA inhibitors, of which (+)-digoxin or digoxin has been long used for the treatment of congestive heart failure. Also, digoxin has exhibited potential antitumor activity, by targeting directly HIF-1α, NKA, and NF-κB. Thus, the function of NKA in human cardiovascular diseases and cancer and the therapeutic effects of digoxin on these diseases are summarized in the present review, with the correlations among digoxin, NKA, cardiovascular diseases, and cancer being discussed. Presented herein are also the antitumor potential of monosaccharide cardiac glycoside analogues of digoxin, including (-)-cryptanoside A, (-)-oleandrin, (-)-ouabain, and (+)-strebloside. It is hoped that this contribution will provide some helpful information for the design and discovery of new cardiac glycoside-type therapeutic agents for the treatment of cardiovascular diseases and cancer.

01 Oct 2024·Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology

Function and regulation of the insect NaCCC2 sodium transport proteins

Article

Author: Gillen, Christopher M ; Piermarini, Peter M ; Romero, Michael F ; Song, Maria Hemmi ; Yarcusko, Ryan S ; Neuger, Grace C

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 Oct 2024·Biomedicine & Pharmacotherapy

Intratympanic injection of MSC-derived small extracellular vesicles protects spiral ganglion neurons from degeneration

Article

Author: Lin, Yongdong ; Chen, Anning ; Tian, Xuexin ; You, Yunyou ; Zhang, Hongzheng ; Shu, Fan ; Qu, Jiaxi ; Luo, Yanjing ; Tang, Jie ; Scheper, Verena ; Pan, Jing

Sensorineural hearing loss is one of the most prevalent sensory deficits. Spiral ganglion neurons (SGNs) exhibit very limited regeneration capacity and their degeneration leads to profound hearing loss. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have been demonstrated to repair tissue damage in various degenerative diseases. However, the effects of MSC-sEV on SGN degeneration remain unclear. In this study, we investigated the efficacy of MSC-sEV for protection against ouabain-induced SGN degeneration. MSC-sEV were derived from rat bone marrow and their components related to neuron growth were determined by proteomic analysis. In primary culture SGNs, MSC-sEV significantly promoted neurite growth and growth cone development. The RNA-Seq analysis of SGNs showed that enriched pathways include neuron development and axon regeneration, consistent with proteomics. In ouabain induced SGN degeneration rat model, MSC-sEV administration via intratympanic injection significantly enhanced SGN survival and mitigated hearing loss. Furthermore, after ouabain treatment, SGNs displayed evident signs of apoptosis, including nuclei condensation and fragmentation, with numerous cells exhibiting TUNEL-positive. However, administration of MSC-sEV effectively decreased the number of TUNEL-positive cells and reduced caspase-3 activation. In conclusion, our findings demonstrate the potential of MSC-sEV in preventing SGN degeneration and promoting neural growth, suggesting intratympanic injection of MSC-sEV is a specific and efficient strategy for neural hearing loss.

100 Deals associated with Ouabain

External Link

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	-	-	-

Clinical Result

Indication

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASN2018	Not Applicable	Renal Cell Carcinoma	-	Ouabain	pgblewdqrh(thdkqrsbxs) = xfyrllszsn xczibqbkja (srartodtsg )	-	23 Oct 2018
ASN2016	Not Applicable	Diabetic Nephropathies	-	Ouabain	bdahkgaxdy(xxmjpaadjl) = lqmllanjmp svqgochqsv (wpyqtjgdvv, 4.1)	Positive	15 Nov 2016
				Ouabain 5nM	bdahkgaxdy(xxmjpaadjl) = kvcvsajtgq svqgochqsv (wpyqtjgdvv, 1.3)
ASN2014	Not Applicable	Hypertension serum uric acid \| endogenous ouabain \| ATP-binding cassette B1 gene	222	Ouabain	tvvihskbxz(ycjmzoahyg) = ifzjtcocxq njccwwykdx (engvtkfipq )	-	11 Nov 2014
ASN2014	Not Applicable	Proteinuria ouabain	-	Rostafuroxin 100 µg/kg/day	(sxkawxcrnh) = tsfgxshuom sangofbvte (qlieapicmn ) View more	Positive	11 Nov 2014
				Ouabain	(sxkawxcrnh) = zefrjoijpk sangofbvte (qlieapicmn ) View more
ASN2012	Not Applicable	Dysentery, Bacillary Stx2 \| Gb3 receptors \| Bax ... View more	-	Ouabain/Na,K-ATPase	lbgwthrega(zlkaegekgs) = khijqsgtgb vxctvwflty (qvtlnpimtx ) View more	Positive	30 Oct 2012
				Ouabain	lbgwthrega(zlkaegekgs) = gdwpjbwgnc vxctvwflty (qvtlnpimtx ) View more
ASN2010	Not Applicable	Hypertension Na-K ATPase \| NHE-1	-	Ouabain	(lsataelrjy) = kmztaizrqb qmvxxibbds (xagfxalkxl, 3.26)	Positive	16 Nov 2010
				Vehicle	(lsataelrjy) = mvykqkaofo qmvxxibbds (xagfxalkxl, 5.32)
ARVO2008	Not Applicable	-	-	Ouabain 30 nM	lvgqdqomll(rftgkfyuyk) = flqxfivcft awtxfmzgjl (mbaogixzsl )	-	01 May 2008
				Ouabain	lvgqdqomll(rftgkfyuyk) = nzfmqoatmm awtxfmzgjl (mbaogixzsl )
ARVO2005	Not Applicable	Iris Pigment Epithelium Anomalies	-	Ouabain	wqkazmpmoi(iuahfpwayw) = ouabain did enhance BKCa-channel activity without a change in single-channel amplitude rpcrqbbvru (poamalrsts )	-	01 May 2005

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