BACKGROUND AND OBJECTIVES: Noninvasive and accurate biomarkers of neurologic Wilson disease (NWD), a rare inherited disorder, could reduce diagnostic error or delay. Excessive subcortical metal deposition seen on susceptibility imaging has suggested a characteristic pattern in NWD. With submillimeter spatial resolution and increased contrast, 7T susceptibility-weighted imaging (SWI) may enable better visualization of metal deposition in NWD. In this study, we sought to identify a distinctive metal deposition pattern in NWD using 7T SWI and investigate its diagnostic value and underlying pathophysiologic mechanism. METHODS: Patients with WD, healthy participants with monoallelic ATP7B variant(s) on a single chromosome, and health controls (HCs) were recruited. NWD and non-NWD (nNWD) were defined according to the presence or absence of neurologic symptoms during investigation. Patients with other diseases with comparable clinical or imaging manifestations, including early-onset Parkinson disease (EOPD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and neurodegeneration with brain iron accumulation (NBIA), were additionally recruited and assessed for exploratory comparative analysis. All participants underwent 7T T1, T2, and high-resolution SWI scanning. Quantitative susceptibility mapping and principal component analysis were performed to illustrate metal distribution. RESULTS: We identified a linear signal intensity change consisting of a hyperintense strip at the lateral border of the globus pallidus in patients with NWD. We termed this feature "hyperintense globus pallidus rim sign." This feature was detected in 38 of 41 patients with NWD and was negative in all 31 nNWD patients, 15 patients with EOPD, 30 patients with MSA, 15 patients with PSP, and 12 patients with NBIA; 22 monoallelic ATP7B variant carriers; and 41 HC. Its sensitivity to differentiate between NWD and HC was 92.7%, and specificity was 100%. Severity of the hyperintense globus pallidus rim sign measured by a semiquantitative scale was positively correlated with neurologic severity (ρ = 0.682, 95% CI 0.467-0.821, p < 0.001). Patients with NWD showed increased susceptibility in the lenticular nucleus with high regional weights in the lateral globus pallidus and medial putamen. DISCUSSION: The hyperintense globus pallidus rim sign showed high sensitivity and excellent specificity for diagnosis and differential diagnosis of NWD. It is related to a special metal deposition pattern in the lenticular nucleus in NWD and can be considered as a novel neuroimaging biomarker of NWD. CLASSIFICATION OF EVIDENCE: The study provides Class II evidence that the hyperintense globus pallidus rim sign on 7T SWI MRI can accurately diagnose neurologic WD.

• MeSH
• Copper-Transporting ATPases metabolism   genetics   MeSH
• Adult MeSH
• Globus Pallidus diagnostic imaging   metabolism   MeSH
• Hepatolenticular Degeneration * diagnostic imaging   metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetic Resonance Imaging * methods   MeSH
• Copper metabolism   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Brain diagnostic imaging   metabolism   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Alternující hemiplegie dětského věku (AHC) je vzácné, geneticky podmíněné neurologické onemocnění, které začíná v kojeneckém věku a je provázeno pestrou neurologickou symptomatikou. Prvními projevy jsou paroxyzmální oční příznaky a tonické nebo dystonické ataky. Posléze se objevují přechodné hemiparézy či hemiplegie, střídající strany, a kvadruplegie, které jsou pro onemocnění charakteristické, stejně jako jejich vymizení během spánku. Dochází k opoždění psychomotorického a mentálního vývoje, přidružují se extrapyramidové, mozečkové příznaky a u poloviny pacientů epileptické záchvaty. Příčinou onemocnění je u většiny pacientů mutace ATP1A3 genu. V diferenciální diagnostice je nutno vyloučit cévní, metabolická a mitochondriální onemocnění. Kauzální léčba není známa, k profylaktické léčbě se používá flunarizin.

Alternating hemiplegia of childhood (AHC) is a rare genetically transmitted neurological disorder that begins in infancy and presents with a wide range of neurologic symptoms. First manifestations are usually paroxysmal ocular signs and tonic/dystonic attacks. Latter, episodes of transient hemiparesis/hemiplegia on either side of body and quadriplegia develop which are typical for the disorder as well as a relief of symptoms with sleep. Delay in psychomotor development and intellectual disability are apparent and accompanied with extrapyramidal and cerebellar signs. In a half of patients seizures are present. AHC is connected with mutations in the ATP1A3 gene in the majority of cases. Differential diagnosis includes vascular, metabolic and mitochondrial disorders. Causal theraphy is not available, flunarizine is used for prophylactic treatment.

• MeSH
• Diagnosis, Differential MeSH
• Child MeSH
• Flunarizine administration & dosage   therapeutic use   MeSH
• Hemiplegia * diagnosis   etiology   drug therapy   complications   physiopathology   MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Sodium-Potassium-Exchanging ATPase genetics   MeSH
• Seizures drug therapy   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

• MeSH
• Potassium * physiology   blood   metabolism   MeSH
• Humans MeSH
• Potassium Deficiency etiology   complications   MeSH
• Sodium-Potassium-Exchanging ATPase MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

PURPOSE: ATP2B2 encodes the variant-constrained plasma-membrane calcium-transporting ATPase-2, expressed in sensory ear cells and specialized neurons. ATP2B2/Atp2b2 variants were previously linked to isolated hearing loss in patients and neurodevelopmental deficits with ataxia in mice. We aimed to establish the association between ATP2B2 and human neurological disorders. METHODS: Multinational case recruitment, scrutiny of trio-based genomics data, in silico analyses, and functional variant characterization were performed. RESULTS: We assembled 7 individuals harboring rare, predicted deleterious heterozygous ATP2B2 variants. The alleles comprised 5 missense substitutions that affected evolutionarily conserved sites and 2 frameshift variants in the penultimate exon. For 6 variants, a de novo status was confirmed. Unlike described patients with hearing loss, the individuals displayed a spectrum of neurological abnormalities, ranging from ataxia with dystonic features to complex neurodevelopmental manifestations with intellectual disability, autism, and seizures. Two cases with recurrent amino-acid variation showed distinctive overlap with cerebellar atrophy-associated ataxia and epilepsy. In cell-based studies, all variants caused significant alterations in cytosolic calcium handling with both loss- and gain-of-function effects. CONCLUSION: Presentations in our series recapitulate key phenotypic aspects of Atp2b2-mouse models and underline the importance of precise calcium regulation for neurodevelopment and cerebellar function. Our study documents a role for ATP2B2 variants in causing heterogeneous neurodevelopmental and movement-disorder syndromes.

• MeSH
• Plasma Membrane Calcium-Transporting ATPases MeSH
• Behavioral Symptoms MeSH
• Cerebellar Ataxia * genetics   MeSH
• Dystonia * genetics   MeSH
• Phenotype MeSH
• Humans MeSH
• Intellectual Disability * genetics   MeSH
• Mice MeSH
• Hearing Loss * MeSH
• Neurodevelopmental Disorders * genetics   MeSH
• Calcium MeSH
• Seizures genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

The human Sec61 complex is a widely distributed and abundant molecular machine. It resides in the membrane of the endoplasmic reticulum to channel two types of cargo: protein substrates and calcium ions. The SEC61A1 gene encodes for the pore-forming Sec61α subunit of the Sec61 complex. Despite their ubiquitous expression, the idiopathic SEC61A1 missense mutations p.V67G and p.T185A trigger a localized disease pattern diagnosed as autosomal dominant tubulointerstitial kidney disease (ADTKD-SEC61A1). Using cellular disease models for ADTKD-SEC61A1, we identified an impaired protein transport of the renal secretory protein renin and a reduced abundance of regulatory calcium transporters, including SERCA2. Treatment with the molecular chaperone phenylbutyrate reversed the defective protein transport of renin and the imbalanced calcium homeostasis. Signal peptide substitution experiments pointed at targeting sequences as the cause for the substrate-specific impairment of protein transport in the presence of the V67G or T185A mutations. Similarly, dominant mutations in the signal peptide of renin also cause ADTKD and point to impaired transport of this renal hormone as important pathogenic feature for ADTKD-SEC61A1 patients as well.

• MeSH
• Endoplasmic Reticulum metabolism   MeSH
• Phenylbutyrates metabolism   pharmacology   MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Mutation, Missense MeSH
• Molecular Chaperones metabolism   MeSH
• Kidney Diseases physiopathology   MeSH
• Polycystic Kidney Diseases MeSH
• Renin genetics   metabolism   MeSH
• Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism   MeSH
• SEC Translocation Channels chemistry   genetics   metabolism   MeSH
• Protein Transport genetics   MeSH
• Calcium metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Drug repositioning is one of the leading strategies in modern therapeutic research. Instead of searching for completely novel substances and demanding studies of their biological effects, much attention has been paid to the evaluation of commonly used drugs, which could be utilized for more distinct indications than they have been approved for. Since treatment approaches for cancer, one of the most extensively studied diseases, have still been very limited, great effort has been made to find or repurpose novel anticancer therapeutics. One of these are cardiac glycosides, substances commonly used to treat congestive heart failure or various arrhythmias. Recently, the antitumor properties of cardiac glycosides have been discovered and, therefore, these compounds are being considered for anticancer therapy. Their mechanism of antitumor action seems to be rather complex and not fully uncovered yet, however, autophagy has been confirmed to play a key role in this process. In this review article, we report on the up-to-date knowledge of the anticancer activity of cardiac glycosides with special attention paid to autophagy induction, the molecular mechanisms of this process, and the potential employment of this phenomenon in clinical practice.

• MeSH
• Apoptosis drug effects   MeSH
• Autophagy * drug effects   MeSH
• Biomarkers metabolism   MeSH
• Models, Biological MeSH
• Humans MeSH
• Sodium-Potassium-Exchanging ATPase metabolism   MeSH
• Cardiac Glycosides pharmacology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Drug repositioning is a successful approach in medicinal research. It significantly simplifies the long-term process of clinical drug evaluation, since the drug being tested has already been approved for another condition. One example of drug repositioning involves cardiac glycosides (CGs), which have, for a long time, been used in heart medicine. Moreover, it has been known for decades that CGs also have great potential in cancer treatment and, thus, many clinical trials now evaluate their anticancer potential. Interestingly, heart failure and cancer are not the only conditions for which CGs could be effectively used. In recent years, the antiviral potential of CGs has been extensively studied, and with the ongoing SARS-CoV-2 pandemic, this interest in CGs has increased even more. Therefore, here, we present CGs as potent and promising antiviral compounds, which can interfere with almost any steps of the viral life cycle, except for the viral attachment to a host cell. In this review article, we summarize the reported data on this hot topic and discuss the mechanisms of antiviral action of CGs, with reference to the particular viral life cycle phase they interfere with.

• MeSH
• Antiviral Agents pharmacology   therapeutic use   MeSH
• COVID-19 MeSH
• Digitoxin MeSH
• Digoxin MeSH
• Virus Internalization drug effects   MeSH
• Humans MeSH
• Neoplasms drug therapy   MeSH
• Ouabain MeSH
• Pandemics MeSH
• Drug Repositioning methods   MeSH
• Virus Replication drug effects   MeSH
• SARS-CoV-2 MeSH
• Sodium-Potassium-Exchanging ATPase MeSH
• Cardiac Glycosides metabolism   therapeutic use   MeSH
• Heart Failure drug therapy   virology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Cardiovascular disease is the main cause of death worldwide, making it crucial to search for new therapies to mitigate major adverse cardiac events (MACEs) after a cardiac ischemic episode. Drugs in the class of the glucagon-like peptide-1 receptor agonists (GLP1Ra) have demonstrated benefits for heart function and reduced the incidence of MACE in patients with diabetes. Previously, we demonstrated that a short-acting GLP1Ra known as DMB (2-quinoxalinamine, 6,7-dichloro-N-[1,1-dimethylethyl]-3-[methylsulfonyl]-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline or compound 2, Sigma) also mitigates adverse postinfarction left ventricular remodeling and cardiac dysfunction in lean mice through activation of parkin-mediated mitophagy following infarction. Here, we combined proteomics with in silico analysis to characterize the range of effects of DMB in vivo throughout the course of early postinfarction remodeling. We demonstrate that the mitochondrion is a key target of DMB and mitochondrial respiration, oxidative phosphorylation and metabolic processes such as glycolysis and fatty acid beta-oxidation are the main biological processes being regulated by this compound in the heart. Moreover, the overexpression of proteins with hub properties identified by protein-protein interaction networks, such as Atp2a2, may also be important to the mechanism of action of DMB. Data are available via ProteomeXchange with identifier PXD027867.

• MeSH
• Quinoxalines administration & dosage   pharmacology   MeSH
• Glycolysis MeSH
• Protein Interaction Maps MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Oxidative Phosphorylation MeSH
• Proteomics methods   MeSH
• Glucagon-Like Peptide-1 Receptor agonists   MeSH
• Ventricular Remodeling drug effects   MeSH
• Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism   MeSH
• Heart Ventricles metabolism   MeSH
• Mitochondria, Heart metabolism   MeSH
• Computational Biology MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Cardiac glycosides (CGs), toxins well-known for numerous human and cattle poisoning, are natural compounds, the biosynthesis of which occurs in various plants and animals as a self-protective mechanism to prevent grazing and predation. Interestingly, some insect species can take advantage of the CG's toxicity and by absorbing them, they are also protected from predation. The mechanism of action of CG's toxicity is inhibition of Na+/K+-ATPase (the sodium-potassium pump, NKA), which disrupts the ionic homeostasis leading to elevated Ca2+ concentration resulting in cell death. Thus, NKA serves as a molecular target for CGs (although it is not the only one) and even though CGs are toxic for humans and some animals, they can also be used as remedies for various diseases, such as cardiovascular ones, and possibly cancer. Although the anticancer mechanism of CGs has not been fully elucidated, yet, it is thought to be connected with the second role of NKA being a receptor that can induce several cell signaling cascades and even serve as a growth factor and, thus, inhibit cancer cell proliferation at low nontoxic concentrations. These growth inhibitory effects are often observed only in cancer cells, thereby, offering a possibility for CGs to be repositioned for cancer treatment serving not only as chemotherapeutic agents but also as immunogenic cell death triggers. Therefore, here, we report on CG's chemical structures, production optimization, and biological activity with possible use in cancer therapy, as well as, discuss their antiviral potential which was discovered quite recently. Special attention has been devoted to digitoxin, digoxin, and ouabain.

• MeSH
• Molecular Targeted Therapy * MeSH
• Digitoxin pharmacology   toxicity   MeSH
• Digoxin pharmacology   toxicity   MeSH
• Humans MeSH
• Neoplasms drug therapy   MeSH
• Ouabain pharmacology   toxicity   MeSH
• Antineoplastic Agents pharmacology   toxicity   MeSH
• Cattle MeSH
• Sodium-Potassium-Exchanging ATPase antagonists & inhibitors   MeSH
• Cardiac Glycosides biosynthesis   pharmacology   toxicity   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Cattle MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Cardiac glycosides (CGs) are natural steroid compounds occurring both in plants and animals. They are known for long as cardiotonic agents commonly used for various cardiac diseases due to inhibition of Na+/K+-ATPase (NKA) pumping activity and modulating heart muscle contractility. However, recent studies show that the portfolio of diseases potentially treatable with CGs is much broader. Currently, CGs are mostly studied as anticancer agents. Their antiproliferative properties are based on the induction of multiple signaling pathways in an NKA signalosome complex. In addition, they are strongly connected to immunogenic cell death, a complex mechanism of induction of anticancer immune response. Moreover, CGs exert various immunomodulatory effects, the foremost of which are connected with suppressing the activity of T-helper cells or modulating transcription of many immune response genes by inhibiting nuclear factor kappa B. The resulting modulations of cytokine and chemokine levels and changes in immune cell ratios could be potentially useful in treating sundry autoimmune and inflammatory diseases. This review aims to summarize current knowledge in the field of immunomodulatory properties of CGs and emphasize the large area of potential clinical use of these compounds.

• MeSH
• Cytokines metabolism   MeSH
• Immunologic Factors pharmacology   therapeutic use   MeSH
• Humans MeSH
• Neoplasms drug therapy   immunology   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Signal Transduction drug effects   MeSH
• Sodium-Potassium-Exchanging ATPase metabolism   MeSH
• Cardiac Glycosides pharmacology   therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH