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Cardiotonic Steroids: From Toxins to Hormones

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 33161

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Special Issue Editors

Dr. Alexei Y. Bagrov

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Guest Editor

Padakonn Pharma, 20309 Narva, Estonia
Interests: salt-sensitive hypertension; preeclampsia; chronic renal failure; Na/K-ATPase inhibitors; endogenous cardiotonic steroids; marinobufagenin; antibody to marinobufagenin; immunotherapy: gene expression; fibrosis
Special Issues, Collections and Topics in MDPI journals

Dr. Olga V. Fedorova

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Guest Editor

Laboratory of Cardiovascular Science, National Institute on Aging, NIH, 251 Bayview Blvd, Baltimore, MD 21224, USA
Interests: cardiotonic steroids; Na/K-ATPase inhibitors; marinobufagenin; gene expression; growth factors; arterial wall diseases; fibrosis; vascular dementia; Alzheimer’s disease; amyloidosis; salt-sensitive hypertension; chronic kidney disease; aging
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Cardiotonic steroids (CS), obtained from plants such as Digitalis purpurea and Strophanthus, and animals like toad Bufo Marinus, were once widely used components of traditional medicine. The use of CS ouabain by Skou in the discovery of Na/K-ATPase consolidated the function of CS as inhibitors and regulators of Na/K-ATPase, opening a new era in the studies of these steroidal agents. Several decades later, the endogenous forms of CS were discovered in mammals, specifically in humans and rodents. Numerous important findings and discoveries have been made since then. While our understanding of the CT function is still incomplete, the importance of this class of hormones is considerable. Endogenous CS were found to be mostly presented by cardenolides, like ouabain, and bufadienolides, such as marinobufagenin and telocinobufagin. CS functions include not only the inhibition of Na/K-ATPase, and regulation of the monovalent ions balance and cell homeostasis, but also the initiation of multisignal cascade transduction pathways. By binding to the Na pump ,CS can affect cell growth and differentiation, apoptosis and proliferation, glucose metabolism, and control of central nervous functions. Dysregulation of CS plays an important role in multiple diseases, including chronic kidney disease, cancer, preeclampsia, hypertension, and other cardiovascular disorders. The understanding of this class of hormones will lead to the discovery of the novel therapeutic strategies in the regulation of physiological functions and in curing diseases. The present Special Issue on “Cardiotonic Steroids” is dedicated to the recent findings related to a multifaceted role of these incredible molecules in health and disease.

Dr. Alexei Y. Bagrov
Dr. Olga Fedorova
Guest Editors

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Keywords

cardiotonic steroids
biosynthesis
physiological and pathological function
immunoregulation

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Cardiotonic Steroids: From Toxins to Hormones 2.0 in International Journal of Molecular Sciences (21 articles)

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18 pages, 3692 KiB

Open AccessArticle

Chronic Ouabain Prevents Na,K-ATPase Dysfunction and Targets AMPK and IL-6 in Disused Rat Soleus Muscle

by Violetta V. Kravtsova, Inna I. Paramonova, Natalia A. Vilchinskaya, Maria V. Tishkova, Vladimir V. Matchkov, Boris S. Shenkman and Igor I. Krivoi

Int. J. Mol. Sci. 2021, 22(8), 3920; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083920 - 10 Apr 2021

Cited by 8 | Viewed by 2235

Abstract

Sustained sarcolemma depolarization due to loss of the Na,K-ATPase function is characteristic for skeletal muscle motor dysfunction. Ouabain, a specific ligand of the Na,K-ATPase, has a circulating endogenous analogue. We hypothesized that the Na,K-ATPase targeted by the elevated level of circulating ouabain modulates skeletal muscle electrogenesis and prevents its disuse-induced disturbances. Isolated soleus muscles from rats intraperitoneally injected with ouabain alone or subsequently exposed to muscle disuse by 6-h hindlimb suspension (HS) were studied. Conventional electrophysiology, Western blotting, and confocal microscopy with cytochemistry were used. Acutely applied 10 nM ouabain hyperpolarized the membrane. However, a single injection of ouabain (1 µg/kg) prior HS was unable to prevent the HS-induced membrane depolarization. Chronic administration of ouabain for four days did not change the α1 and α2 Na,K-ATPase protein content, however it partially prevented the HS-induced loss of the Na,K-ATPase electrogenic activity and sarcolemma depolarization. These changes were associated with increased phosphorylation levels of AMP-activated protein kinase (AMPK), its substrate acetyl-CoA carboxylase and p70 protein, accompanied with increased mRNA expression of interleikin-6 (IL-6) and IL-6 receptor. Considering the role of AMPK in regulation of the Na,K-ATPase, we suggest an IL-6/AMPK contribution to prevent the effects of chronic ouabain under skeletal muscle disuse. Full article

(This article belongs to the Special Issue Cardiotonic Steroids: From Toxins to Hormones)

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17 pages, 5500 KiB

Open AccessArticle

Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na/K-ATPase α1^s/sα2^s/s Mouse Model of High Affinity for Cardiotonic Steroids

by Pauline V. Marck, Marco T. Pessoa, Yunhui Xu, Laura C. Kutz, Dominic M. Collins, Yanling Yan, Cierra King, Xiaoliang Wang, Qiming Duan, Liquan Cai, Jeffrey X. Xie, Jerry B. Lingrel, Zijian Xie, Jiang Tian and Sandrine V. Pierre

Int. J. Mol. Sci. 2021, 22(7), 3462; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073462 - 27 Mar 2021

Cited by 9 | Viewed by 2385

Abstract

The Na/K-ATPase is the specific receptor for cardiotonic steroids (CTS) such as ouabain and digoxin. At pharmacological concentrations used in the treatment of cardiac conditions, CTS inhibit the ion-pumping function of Na/K-ATPase. At much lower concentrations, in the range of those reported for endogenous CTS in the blood, they stimulate hypertrophic growth of cultured cardiac myocytes through initiation of a Na/K-ATPase-mediated and reactive oxygen species (ROS)-dependent signaling. To examine a possible effect of endogenous concentrations of CTS on cardiac structure and function in vivo, we compared mice expressing the naturally resistant Na/K-ATPase α1 and age-matched mice genetically engineered to express a mutated Na/K-ATPase α1 with high affinity for CTS. In this model, total cardiac Na/K-ATPase activity, α1, α2, and β1 protein content remained unchanged, and the cardiac Na/K-ATPase dose–response curve to ouabain shifted to the left as expected. In males aged 3–6 months, increased α1 sensitivity to CTS resulted in a significant increase in cardiac carbonylated protein content, suggesting that ROS production was elevated. A moderate but significant increase of about 15% of the heart-weight-to-tibia-length ratio accompanied by an increase in the myocyte cross-sectional area was detected. Echocardiographic analyses did not reveal any change in cardiac function, and there was no fibrosis or re-expression of the fetal gene program. RNA sequencing analysis indicated that pathways related to energy metabolism were upregulated, while those related to extracellular matrix organization were downregulated. Consistent with a functional role of the latter, an angiotensin-II challenge that triggered fibrosis in the α1^r/rα2^s/s mouse failed to do so in the α1^s/sα2^s/s. Taken together, these results are indicative of a link between circulating CTS, Na/K-ATPase α1, ROS, and physiological cardiac hypertrophy in mice under baseline laboratory conditions. Full article

(This article belongs to the Special Issue Cardiotonic Steroids: From Toxins to Hormones)

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17 pages, 6699 KiB

Open AccessArticle

Model of Chronic Thromboembolic Pulmonary Hypertension in Rats Caused by Repeated Intravenous Administration of Partially Biodegradable Sodium Alginate Microspheres

by Andrei A. Karpov, Nikita A. Anikin, Aleksandra M. Mihailova, Sergey S. Smirnov, Dariya D. Vaulina, Leonid A. Shilenko, Dmitry Yu. Ivkin, Alexei Y. Bagrov, Olga M. Moiseeva and Michael M. Galagudza

Int. J. Mol. Sci. 2021, 22(3), 1149; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031149 - 24 Jan 2021

Cited by 7 | Viewed by 2525

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and life-threatening complication of pulmonary embolism. As existing animal models of CTEPH do not fully recapitulate complex disease pathophysiology, we report a new rat model for CTEPH evoked by repetitive embolization of the distal pulmonary artery branches with partially biodegradable alginate microspheres (MSs). MSs (180 ± 28 μm) were intravenously administered eight times at 4-day intervals; control animals received saline. The validity of the model was confirmed using transthoracic echocardiography, exercise testing, catheterization of the right ventricle, and histological examination of the lung and heart. The animals in the CTEPH group demonstrated a stable increase in right ventricular systolic pressure (RVSP) and decreased exercise tolerance. Histopathological examination revealed advanced medial hypertrophy in the small pulmonary arteries associated with fibrosis. The diameter of the main pulmonary artery was significantly larger in the CTEPH group than in the control group. Marinobufagenin and endothelin-1 serum levels were significantly elevated in rats with CTEPH. In conclusion, repetitive administration of alginate MSs in rats resulted in CTEPH development characterized by specific lung vasculature remodeling, reduced exercise tolerance, and a persistent rise in RVSP. The developed model can be used for pre-clinical testing of promising drug candidates. Full article

(This article belongs to the Special Issue Cardiotonic Steroids: From Toxins to Hormones)

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18 pages, 2959 KiB

Open AccessArticle

Ouabain Promotes Gap Junctional Intercellular Communication in Cancer Cells

by Mauricio Serrano-Rubi, Lidia Jimenez, Jacqueline Martinez-Rendon, Marcelino Cereijido and Arturo Ponce

Int. J. Mol. Sci. 2021, 22(1), 358; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010358 - 31 Dec 2020

Cited by 1 | Viewed by 2150

Abstract

Gap junctions are molecular structures that allow communication between neighboring cells. It has been shown that gap junctional intercellular communication (GJIC) is notoriously reduced in cancer cells compared to their normal counterparts. Ouabain, a plant derived substance, widely known for its therapeutic properties on the heart, has been shown to play a role in several types of cancer, although its mechanism of action is not yet fully understood. Since we have previously shown that ouabain enhances GJIC in epithelial cells (MDCK), here we probed whether ouabain affects GJIC in a variety of cancer cell lines, including cervico-uterine (CasKi, SiHa and Hela), breast (MDA-MB-321 and MCF7), lung (A549), colon (SW480) and pancreas (HPAF-II). For this purpose, we conducted dye transfer assays to measure and compare GJIC in monolayers of cells with and without treatment with ouabain (0.1, 1, 10, 50 and 500 nM). We found that ouabain induces a statistically significant enhancement of GJIC in all of these cancer cell lines, albeit with distinct sensitivity. Additionally, we show that synthesis of new nucleotides or protein subunits is not required, and that Csrc, ErK1/2 and ROCK-Rho mediate the signaling mechanisms. These results may contribute to explaining how ouabain influences cancer. Full article

(This article belongs to the Special Issue Cardiotonic Steroids: From Toxins to Hormones)

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19 pages, 2558 KiB

Open AccessArticle

Transcriptomic Changes in Endothelial Cells Triggered by Na,K-ATPase Inhibition: A Search for Upstream Na⁺_i/K⁺_i Sensitive Genes

by Elizaveta A. Klimanova, Svetlana V. Sidorenko, Polina A. Abramicheva, Artem M. Tverskoi, Sergei N. Orlov and Olga D. Lopina

Int. J. Mol. Sci. 2020, 21(21), 7992; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217992 - 27 Oct 2020

Cited by 4 | Viewed by 2064

Abstract

Stimulus-dependent elevation of intracellular Ca²⁺ affects gene expression via well-documented calmodulin-mediated signaling pathways. Recently, we found that the addition of extra- and intracellular Ca²⁺ chelators increased, rather than decreased, the number of genes expressed, and that this is affected by the elevation of [Na⁺]_i/[K⁺]_i-ratio. This assumes the existence of a novel Na⁺_i/K⁺_i-mediated Ca²⁺_i-independent mechanism of excitation-transcription coupling. To identify upstream Na⁺_i/K⁺_i-sensitive genes, we examined the kinetics of transcriptomic changes in human umbilical vein endothelial cells (HUVEC) subjected to Na,K-ATPase inhibition by ouabain or K⁺-free medium. According to our data, microRNAs, transcription factors, and proteins involved in immune response and inflammation might be considered as key components of Na⁺_i/K⁺_i-mediated excitation-transcription coupling. Special attention was focused on the FOS gene and the possible mechanism of transcription regulation via G-quadruplexes, non-canonical secondary structures of nucleic acids, whose stability depends on [Na⁺]_i/[K⁺]_i-ratio. Verification of the [Na⁺]_i/[K⁺]_i-sensitive transcription regulation mechanism should be continued in forthcoming studies. Full article

(This article belongs to the Special Issue Cardiotonic Steroids: From Toxins to Hormones)

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20 pages, 2239 KiB

Open AccessArticle

Predicting Nonalcoholic Fatty Liver Disease through a Panel of Plasma Biomarkers and MicroRNAs in Female West Virginia Population

by Sneha S. Pillai, Hari Vishal Lakhani, Mishghan Zehra, Jiayan Wang, Anum Dilip, Nitin Puri, Kathleen O’Hanlon and Komal Sodhi

Int. J. Mol. Sci. 2020, 21(18), 6698; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186698 - 13 Sep 2020

Cited by 19 | Viewed by 3347

Abstract

(1) Background: Nonalcoholic fatty liver disease (NAFLD) is primarily characterized by the presence of fatty liver, hepatic inflammation and fibrogenesis eventually leading to nonalcoholic steatohepatitis (NASH) or cirrhosis. Obesity and diabetes are common risk factors associated with the development and progression of NAFLD, with one of the highest prevalence of these diseased conditions in the West Virginia population. Currently, the diagnosis of NAFLD is limited to radiologic studies and biopsies, which are not cost-effective and highly invasive. Hence, this study aimed to develop a panel and assess the progressive levels of circulatory biomarkers and miRNA expression in patients at risk for progression to NASH to allow early intervention strategies. (2) Methods: In total, 62 female patients were enrolled and blood samples were collected after 8–10 h of fasting. Computed tomography was performed on abdomen/pelvis following IV contrast administration. The patients were divided into the following groups: Healthy subjects with normal BMI and normal fasting blood glucose (Control, n = 20), Obese with high BMI and normal fasting blood glucose (Obese, n = 20) and Obese with high fasting blood glucose (Obese + DM, n = 22). Based on findings from CT, another subset was created from Obese + DM group with patients who showed signs of fatty liver infiltration (Obese + DM(FI), n = 10). ELISA was performed for measurement of plasma biomarkers and RT-PCR was performed for circulating miRNA expression. (3) Results: Our results show significantly increased levels of plasma IL-6, Leptin and FABP-1, while significantly decreased level of adiponectin in Obese, Obese + DM and Obese + DM(FI) group, as compared to healthy controls. The level of CK-18 was significantly increased in Obese + DM(FI) group as compared to control. Subsequently, the expression of miR-122, miR-34a, miR-375, miR-16 and miR-21 was significantly increased in Obese + DM and Obese + DM(FI) group as compared to healthy control. Our results also show distinct correlation of IL-6, FABP-1 and adiponectin levels with the expression of miRNAs in relation to the extent of NAFLD progression. (4) Conclusion: Our results support the clinical application of these biomarkers and miRNAs in monitoring the progression of NAFLD, suggesting a more advanced diagnostic potential of this panel than conventional methods. This panel may provide an appropriate method for early prognosis and management of NAFLD and subsequent adverse hepatic pathophysiology, potentially reducing the disease burden on the West Virginia population. Full article

(This article belongs to the Special Issue Cardiotonic Steroids: From Toxins to Hormones)

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25 pages, 9171 KiB

Open AccessArticle

Oxidant-Induced Alterations in the Adipocyte Transcriptome: Role of the Na,K-ATPase Oxidant Amplification Loop

by Komal Sodhi, James Denvir, Jiang Liu, Juan R. Sanabria, Yiliang Chen, Roy Silverstein, Zijian Xie, Nader G. Abraham and Joseph I. Shapiro

Int. J. Mol. Sci. 2020, 21(16), 5923; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165923 - 18 Aug 2020

Cited by 7 | Viewed by 2330

Abstract

(1) Background: Recently we have noted that adipocyte specific expression of the peptide, NaKtide, which was developed to attenuate the Na,K-ATPase oxidant amplification loop, could ameliorate the phenotypical features of uremic cardiomyopathy. We performed this study to better characterize the cellular transcriptomes that are involved in various biological pathways associated with adipocyte function occurring with renal failure. (2) Methods: RNAseq was performed on the visceral adipose tissue of animals subjected to partial nephrectomy. Specific expression of NaKtide in adipocytes was achieved using an adiponectin promoter. To better understand the cause of gene expression changes in vivo, 3T3L1 adipocytes were exposed to indoxyl sulfate (IS) or oxidized low density lipoprotein (oxLDL), with and without pNaKtide (the cell permeant form of NaKtide). RNAseq was also performed on these samples. (3) Results: We noted a large number of adipocyte genes were altered in experimental renal failure. Adipocyte specific NaKtide expression reversed most of these abnormalities. High correlation with some cardiac specific phenotypical features was noted amongst groups of these genes. In the murine adipocytes, both IS and oxLDL induced similar pathway changes as were noted in vivo, and pNaKtide appeared to reverse these changes. Network analysis demonstrated tremendous similarities between the network revealed by gene expression analysis with IS compared with oxLDL, and the combined in vitro dataset was noted to also have considerable similarity to that seen in vivo with experimental renal failure. (4) Conclusions: This study suggests that the myriad of phenotypical features seen with experimental renal failure may be fundamentally linked to oxidant stress within adipocytes. Full article

(This article belongs to the Special Issue Cardiotonic Steroids: From Toxins to Hormones)

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16 pages, 2427 KiB

Open AccessArticle

Na⁺, K⁺-ATPase α Isoforms and Endogenous Cardiac Steroids in Prefrontal Cortex of Bipolar Patients and Controls

by Shiv Vardan Singh, Olga V. Fedorova, Wen Wei, Haim Rosen, Noa Horesh, Asher Ilani and David Lichtstein

Int. J. Mol. Sci. 2020, 21(16), 5912; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165912 - 17 Aug 2020

Cited by 8 | Viewed by 2816

Abstract

Bipolar disorder is a chronic multifactorial psychiatric illness that affects the mood, cognition, and functioning of about 1–2% of the world’s population. Its biological basis is unknown, and its treatment is unsatisfactory. The α1, α2, and α3 isoforms of the Na⁺, K⁺-ATPase, an essential membrane transporter, are vital for neuronal and glial function. The enzyme and its regulators, endogenous cardiac steroids like ouabain and marinobufagenin, are implicated in neuropsychiatric disorders, bipolar disorder in particular. Here, we address the hypothesis that the α isoforms of the Na⁺, K⁺-ATPase and its regulators are altered in the prefrontal cortex of bipolar disease patients. The α isoforms were determined by Western blot and ouabain and marinobufagenin by specific and sensitive immunoassays. We found that the α2 and α3 isoforms were significantly higher and marinobufagenin levels were significantly lower in the prefrontal cortex of the bipolar disease patients compared with those in the control. A positive correlation was found between the levels of the three α isoforms in all samples and between the α1 isoform and ouabain levels in the controls. These results are in accordance with the notion that the Na⁺, K⁺-ATPase-endogenous cardiac steroids system is involved in bipolar disease and suggest that it may be used as a target for drug development. Full article

(This article belongs to the Special Issue Cardiotonic Steroids: From Toxins to Hormones)

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16 pages, 2792 KiB

Open AccessArticle

Circulating Ouabain Modulates Expression of Claudins in Rat Intestine and Cerebral Blood Vessels

by Alexander G. Markov, Arina A. Fedorova, Violetta V. Kravtsova, Anastasia E. Bikmurzina, Larisa S. Okorokova, Vladimir V. Matchkov, Valeria Cornelius, Salah Amasheh and Igor I. Krivoi

Int. J. Mol. Sci. 2020, 21(14), 5067; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145067 - 17 Jul 2020

Cited by 14 | Viewed by 2647

Abstract

The ability of exogenous low ouabain concentrations to affect claudin expression and therefore epithelial barrier properties was demonstrated previously in cultured cell studies. We hypothesized that chronic elevation of circulating ouabain in vivo can affect the expression of claudins and tight junction permeability in different tissues. We tested this hypothesis in rats intraperitoneally injected with ouabain (1 μg/kg) for 4 days. Rat jejunum, colon and brain frontal lobes, which are variable in the expressed claudins and tight junction permeability, were examined. Moreover, the porcine jejunum cell line IPEC-J2 was studied. In IPEC-J2-cells, ouabain (10 nM, 19 days of incubation) stimulated epithelial barrier formation, increased transepithelial resistance and the level of cSrc-kinase activation by phosphorylation, accompanied with an increased expression of claudin-1, -5 and down-regulation of claudin-12; the expression of claudin-3, -4, -8 and tricellulin was not changed. In the jejunum, chronic ouabain increased the expression of claudin-1, -3 and -5 without an effect on claudin-2 and -4 expression. In the colon, only down-regulation of claudin-3 was observed. Chronic ouabain protected the intestine transepithelial resistance against functional injury induced by lipopolysaccharide treatment or by modeled acute microgravity; this regulation was most pronounced in the jejunum. Claudin-1 was also up-regulated in cerebral blood vessels. This was associated with reduction of claudin-3 expression while the expression of claudin-5 and occludin was not affected. Altogether, our results confirm that circulating ouabain can functionally and tissue-specifically affect barrier properties of epithelial and endothelial tissues via Na,K-ATPase-mediated modulation of claudins expression. Full article

(This article belongs to the Special Issue Cardiotonic Steroids: From Toxins to Hormones)

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15 pages, 2402 KiB

Open AccessArticle

Skeletal Muscle Na,K-ATPase as a Target for Circulating Ouabain

by Violetta V. Kravtsova, Elena V. Bouzinova, Vladimir V. Matchkov and Igor I. Krivoi

Int. J. Mol. Sci. 2020, 21(8), 2875; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082875 - 20 Apr 2020

Cited by 10 | Viewed by 2827

Abstract

While the role of circulating ouabain-like compounds in the cardiovascular and central nervous systems, kidney and other tissues in health and disease is well documented, little is known about its effects in skeletal muscle. In this study, rats were intraperitoneally injected with ouabain (0.1–10 µg/kg for 4 days) alone or with subsequent injections of lipopolysaccharide (1 mg/kg). Some rats were also subjected to disuse for 6 h by hindlimb suspension. In the diaphragm muscle, chronic ouabain (1 µg/kg) hyperpolarized resting potential of extrajunctional membrane due to specific increase in electrogenic transport activity of the α2 Na,K-ATPase isozyme and without changes in α1 and α2 Na,K-ATPase protein content. Ouabain (10–20 nM), acutely applied to isolated intact diaphragm muscle from not injected rats, hyperpolarized the membrane to a similar extent. Chronic ouabain administration prevented lipopolysaccharide-induced (diaphragm muscle) or disuse-induced (soleus muscle) depolarization of the extrajunctional membrane. No stimulation of the α1 Na,K-ATPase activity in human red blood cells, purified lamb kidney and Torpedo membrane preparations by low ouabain concentrations was observed. Our results suggest that skeletal muscle electrogenesis is subjected to regulation by circulating ouabain via the α2 Na,K-ATPase isozyme that could be important for adaptation of this tissue to functional impairment. Full article

(This article belongs to the Special Issue Cardiotonic Steroids: From Toxins to Hormones)

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Review

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13 pages, 6223 KiB

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Preeclampsia: Cardiotonic Steroids, Fibrosis, Fli1 and Hint to Carcinogenesis

by Natalia I. Agalakova, Nikolai I. Kolodkin, C. David Adair, Alexander P. Trashkov and Alexei Y. Bagrov

Int. J. Mol. Sci. 2021, 22(4), 1941; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041941 - 16 Feb 2021

Cited by 9 | Viewed by 2477

Abstract

Despite prophylaxis and attempts to select a therapy, the frequency of preeclampsia does not decrease and it still takes the leading position in the structure of maternal mortality and morbidity worldwide. In this review, we present a new theory of the etiology and pathogenesis of preeclampsia that is based on the interaction of Na/K-ATPase and its endogenous ligands including marinobufagenin. The signaling pathway of marinobufagenin involves an inhibition of transcriptional factor Fli1, a negative regulator of collagen synthesis, followed by the deposition of collagen in the vascular tissues and altered vascular functions. Moreover, in vitro and in vivo neutralization of marinobufagenin is associated with the restoration of Fli1. The inverse relationship between marinobufagenin and Fli1 opens new possibilities in the treatment of cancer; as Fli1 is a proto-oncogene, a hypothesis on the suppression of Fli1 by cardiotonic steroids as a potential anti-tumor therapeutic strategy is discussed as well. We propose a novel therapy of preeclampsia that is based on immunoneutralization of the marinobufagenin by monoclonal antibodies, which is capable of impairing marinobufagenin-Na/K-ATPase interactions. Full article

(This article belongs to the Special Issue Cardiotonic Steroids: From Toxins to Hormones)

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17 pages, 1691 KiB

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Elucidating Potential Profibrotic Mechanisms of Emerging Biomarkers for Early Prognosis of Hepatic Fibrosis

by Mishghan Zehra, James C. Curry, Sneha S. Pillai, Hari Vishal Lakhani, Cory E. Edwards and Komal Sodhi

Int. J. Mol. Sci. 2020, 21(13), 4737; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134737 - 03 Jul 2020

Cited by 10 | Viewed by 4467

Abstract

Hepatic fibrosis has been associated with a series of pathophysiological processes causing excessive accumulation of extracellular matrix proteins. Several cellular processes and molecular mechanisms have been implicated in the diseased liver that augments fibrogenesis, fibrogenic cytokines and associated liver complications. Liver biopsy remains an essential diagnostic tool for histological evaluation of hepatic fibrosis to establish a prognosis. In addition to being invasive, this methodology presents with several limitations including poor cost-effectiveness, prolonged hospitalizations, and risks of peritoneal bleeding, while the clinical use of this method does not reveal underlying pathogenic mechanisms. Several alternate noninvasive diagnostic strategies have been developed, to determine the extent of hepatic fibrosis, including the use of direct and indirect biomarkers. Immediate diagnosis of hepatic fibrosis by noninvasive means would be more palatable than a biopsy and could assist clinicians in taking early interventions timely, avoiding fatal complications, and improving prognosis. Therefore, we sought to review some common biomarkers of liver fibrosis along with some emerging candidates, including the oxidative stress-mediated biomarkers, epigenetic and genetic markers, exosomes, and miRNAs that needs further evaluation and would have better sensitivity and specificity. We also aim to elucidate the potential role of cardiotonic steroids (CTS) and evaluate the pro-inflammatory and profibrotic effects of CTS in exacerbating hepatic fibrosis. By understanding the underlying pathogenic processes, the efficacy of these biomarkers could allow for early diagnosis and treatment of hepatic fibrosis in chronic liver diseases, once validated. Full article

(This article belongs to the Special Issue Cardiotonic Steroids: From Toxins to Hormones)

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