INTRODUCTION: A variable proportion of non-responders to cardiac resynchronization therapy (CRT) warrants the search for new approaches to optimize the position of the left ventricular (LV) lead and the CRT device programming. CineECG is a novel ECG modality proposed for the spatial visualization and quantification of myocardial depolarization and repolarization sequences. OBJECTIVE: The present study aimed to evaluate CineECG-derived parameters in different pacing modes and to test their associations with acute hemodynamic responses in CRT patients. METHODS AND RESULTS: CineECG was used to construct the average electrical path within the cardiac anatomy from the 12-lead ECG. CineECG and LV dP/dt max were tested in 15 patients with nonischemic dilated cardiomyopathy and left bundle branch block (QRS: 170 ± 17 ms; LVEF: 26 ± 5.5%) under pacing protocols with different LV lead localizations. The CineECG-derived path directions were computed for the QRS and ST-T intervals for the anteroposterior (Xh), interventricular (Yh), and apicobasal (Zh) axes. In a multivariate linear regression analysis with adjustment for the pacing protocol type, the ST-T path direction Yh was independently associated with the increase in dP/dt max during CRT, [regression coefficient 639.4 (95% confidence interval: 187.9-1090.9), p = 0.006]. In ROC curve analysis, the ST-T path direction Yh was associated with the achievement of a 10% increase in dP/dt max (AUC: 0.779, p = 0.002) with the optimal cut-off > 0.084 (left-to-right direction) with sensitivity 0.67 and specificity 0.92. CONCLUSION: The acute hemodynamic response in CRT patients was associated with specific CineECG repolarization sequence parameters, warranting their further testing as potential predictors of clinical outcomes.

• MeSH
• akční potenciály MeSH
• blokáda Tawarova raménka * patofyziologie   terapie   diagnóza   MeSH
• časové faktory MeSH
• dilatační kardiomyopatie patofyziologie   terapie   diagnóza   MeSH
• elektrokardiografie * MeSH
• funkce levé komory srdeční * MeSH
• hemodynamika * MeSH
• lidé středního věku MeSH
• lidé MeSH
• prediktivní hodnota testů * MeSH
• prostředky srdeční resynchronizační terapie MeSH
• senioři MeSH
• srdeční frekvence MeSH
• srdeční resynchronizační terapie * MeSH
• srdeční selhání patofyziologie   terapie   diagnóza   MeSH
• tepový objem MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Despite the availability of new drugs on the clinics in recent years, drug-resistant epilepsy remains an unresolved challenge for healthcare, and one-third of epilepsy patients remain refractory to anti-seizure medications. Gene therapy in experimental models has emerged as effective treatment targeting specific neuronal populations in the epileptogenic focus. When combined with an external chemical activator using chemogenetics, it also becomes an "on-demand" treatment. Here, we evaluate a targeted and specific chemogenetic therapy, the PSAM/PSEM system, which holds promise as a potential candidate for clinical application in treating drug-resistant epilepsy. We show that the inert ligand uPSEM817, which selectively activates the chloride-permeable channel PSAM4-GlyR, effectively reduces the number of depolarization-induced action potentials in vitro. This effect is likely due to the shunting of depolarizing currents, as evidenced by decreased membrane resistance in these cells. In organotypic slices, uPSEM817 decreased the number of bursts and peak amplitude of events of spontaneous epileptiform activity. Although administration of uPSEM817 in vivo did not significantly alter electrographic seizures in a male mouse model of temporal lobe epilepsy, it did demonstrate a strong trend toward reducing the frequency of interictal epileptiform discharges. These findings indicate that PSAM4-GlyR-based chemogenetics holds potential as an anti-seizure strategy, although further refinement is necessary to enhance its efficacy.

• MeSH
• akční potenciály účinky léků   MeSH
• epilepsie patofyziologie   genetika   farmakoterapie   terapie   metabolismus   MeSH
• genetická terapie metody   MeSH
• hipokampus * metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Diabetes mellitus (DM) causes myocardial electrical remodeling and promotes ventricular tachycardia and/or fibrillation (VT/VF). However, experimental studies have been frequently unsuccessful in developing a DM model with the expected high level of arrhythmic outcomes. The present study aims at evaluating cardiac electrophysiological properties in the rats with different Type 1 DM (T1DM) durations and identifying an electrophysiological phenotype associated with the high incidence of VT/VF. METHODS: The experiments were performed in 109 male Wistar rats (6-10 weeks old), subdivided into the groups of control, 4-weeks and 8-weeks T1DM (streptozotocin model). The animals were studied with epicardial electrophysiological mapping, whole-cell patch-clamp and histological examination. The VT/VF susceptibility was tested in ischemia/reperfusion induced in the anesthetized animals. RESULTS: In the 4-weeks T1DM group, we observed the increase in the incidence of reperfusion VT/VF, collagen deposition and dispersion of repolarization, slowed longitudinal and transverse conduction velocity, prolonged action potential duration, increased INa and ICaL currents, nonchanged Ito and IK1 currents. In the 8-weeks T1DM group, the VT/VF incidence, dispersion of repolarization, INa and Ito currents decreased. Other parameters persisted unchanged as compared to the 4-weeks T1DM group. CONCLUSIONS: Relatively early (4 weeks) diabetic electrical remodeling was proarrhythmic and included augmentation of sodium and calcium currents in the presence of fibrosis and slowed conduction and increased dispersion of repolarization. An unexpected finding was that diabetic arrhythmogenesis was associated with the increase in depolarizing transmembrane currents. Further research is warranted to elucidate molecular mechanisms and test the potential for the control of observed changes.

• MeSH
• diabetes mellitus 1. typu * komplikace   patofyziologie   MeSH
• experimentální diabetes mellitus patofyziologie   komplikace   MeSH
• fibrilace komor patofyziologie   MeSH
• komorová tachykardie patofyziologie   etiologie   MeSH
• krysa rodu rattus MeSH
• modely nemocí na zvířatech MeSH
• potkani Wistar * MeSH
• remodelace komor MeSH
• srdeční arytmie patofyziologie   etiologie   MeSH
• srdeční komory patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Electrical stimulation involving temporal interference of two different kHz frequency sinusoidal electric fields (temporal interference (TI)) enables non-invasive deep brain stimulation, by creating an electric field that is amplitude modulated at the slow difference frequency (within the neural range), at the target brain region. OBJECTIVE: Here, we investigate temporal interference neural stimulation using square, rather than sinusoidal, electric fields that create an electric field that is pulse-width, but not amplitude, modulated at the difference frequency (pulse-width modulated temporal interference, (PWM-TI)). METHODS/RESULTS: We show, using ex-vivo single-cell recordings and in-vivo calcium imaging, that PWM-TI effectively stimulates neural activity at the difference frequency at a similar efficiency to traditional TI. We then demonstrate, using computational modelling, that the PWM stimulation waveform induces amplitude-modulated membrane potential depolarization due to the membrane's intrinsic low-pass filtering property. CONCLUSIONS: PWM-TI can effectively drive neural activity at the difference frequency. The PWM-TI mechanism involves converting an envelope amplitude-fixed PWM field to an amplitude-modulated membrane potential via the low-pass filtering of the passive neural membrane. Unveiling the biophysics underpinning the neural response to complex electric fields may facilitate the development of new brain stimulation strategies with improved precision and efficiency.

• MeSH
• elektrická stimulace MeSH
• mozek * MeSH
• počítačová simulace MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Extracellular potassium concentration might modify electrophysiological properties in the border zone of ischemic myocardium. We evaluated the depolarization and repolarization characteristics across the ischemic-normal border under [K+] variation. Sixty-four-lead epicardial mapping was performed in 26 rats ([K+] 2.3-6.4 mM) in a model of acute ischemia/reperfusion. The animals with [K+] < 4.7 mM (low-normal potassium) had an ischemic zone with ST-segment elevation and activation delay, a border zone with ST-segment elevation and no activation delay, and a normal zone without electrophysiological abnormalities. The animals with [K+] >4.7 mM (normal-high potassium) had only the ischemic and normal zones and no transitional area. Activation-repolarization intervals and local conduction velocities were inversely associated with [K+] in linear regression analysis with adjustment for the zone of myocardium. The reperfusion extrasystolic burden (ESB) was greater in the low-normal as compared to normal-high potassium animals. Ventricular tachycardia/fibrillation incidence did not differ between the groups. In patch-clamp experiments, hypoxia shortened action potential duration at 5.4 mM but not at 1.3 mM of [K+]. IK(ATP) current was lower at 1.3 mM than at 5.4 mM of [K+]. We conclude that the border zone formation in low-normal [K+] was associated with attenuation of IK(ATP) response to hypoxia and increased reperfusion ESB.

• MeSH
• akční potenciály * fyziologie   MeSH
• draslík * krev   metabolismus   MeSH
• ischemická choroba srdeční * patofyziologie   krev   metabolismus   MeSH
• krysa rodu rattus MeSH
• potkani Wistar MeSH
• reperfuzní poškození myokardu krev   patofyziologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Starting from benzyl 30-oxobetulinate and 30-oxobetulin diacetate, substituted dienes were synthesized and subjected to Diels-Alder reaction, yielding a variety of triterpenoid phthalates, phthalimides, and related derivatives. A total of 55 new compounds were prepared and tested for in vitro cytotoxic activity against eight cancer cell lines and two non-cancerous cell lines. Four compounds with IC50 values of 5 μM or lower were selected for further investigation. These compounds induced apoptosis in CCRF-CEM cells in a concentration-dependent manner, accompanied by mitochondrial depolarization and altered expression of key proteins involved in mitochondrial apoptosis. The compounds also disrupted DNA replication and transcriptional activity. Modulation of key proliferation pathways, including PI3K/Akt and STAT3, further supported the antiproliferative potential of these derivatives. Considering their high cytotoxicity and antiproliferative activity in CCRF-CEM cells, compounds 19, 26, 28, and 30 have been identified as promising candidates for further development.

• MeSH
• apoptóza * účinky léků   MeSH
• ftalimidy * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• mitochondrie * účinky léků   metabolismus   MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk * účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv * MeSH
• triterpeny * farmakologie   chemie   chemická syntéza   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Hypoxic pulmonary vasoconstriction (HPV) rapidly and reversibly matches lung ventilation (V) and perfusion (Q), optimizing oxygen uptake and systemic oxygen delivery. HPV occurs in small pulmonary arteries (PA), which uniquely constrict to hypoxia. Although HPV is modulated by the endothelium the core mechanism of HPV resides in PA smooth muscle cells (PASMC). The PASMC's mitochondrial oxygen sensor lies within the electron transport chain (ETC) and includes NDUFS2 in ETC Complex-I. PASMC mitochondria respond to hypoxia by varying production of reactive oxygen species (ROS) and hydrogen peroxide in proportion to alveolar oxygen tension. Hypoxic ROS inhibition results in a state of reduction which triggers a redox-mediated inhibition of oxygen-sensitive, voltage-gated, potassium channels, including Kv1.5 and Kv2.1. Kv channel inhibition depolarizes the PASMC, opening of large-conductance calcium channels (CaL), elevating cytosolic calcium and activating the contractile apparatus. HPV is strongest in small PAs where sensors (hypoxia-responsive mitochondria) and effectors (oxygen-sensitive K+ channels) are enriched. Oxygenation at birth reverses fetal HPV, contributing to the rapid neonatal drop in pulmonary vascular resistance (PVR). A similar mitochon-drial-K+ channel sensor-effector mechanism exists in the ductus arteriosus (DA), however in DASMC it is oxygen-induced increases in mitochondrial ROS that inhibit DASMC K+ channels, causing DA constriction. Atelectasis and pneumonia elicit HPV, which optimises V/Q matching, increasing systemic oxygenation. Whilst HPV in response to localized hypoxia in a single lung lobe does not increase PA pressure; global airway hypoxia, as occurs with altitude or sleep apnea, causes pulmonary hypertension. HPV can be inhibited by drugs, including calcium channel blockers, or used to maintain a dry operative field during single lung anesthesia for lung surgery. HPV does not normally cause lung edema but excessive, heterogenous HPV contributes to high altitude pulmonary edema. HPV is suppressed in COVID-19 pneumonia by a SARS-CoV-2 mitochondriopathy. HPV is a component of the body's homeostatic oxygen sensing system. Keywords: Ductus arteriosus, Redox, NDUFS2, Oxygen sensitive potassium, Channels, High altitude pulmonary edema (HAPE), Mitochondrial electron transport chain, COVID-19 pneumonia, Atelectasis.

• MeSH
• arteria pulmonalis metabolismus   MeSH
• COVID-19 metabolismus   komplikace   MeSH
• homeostáza * fyziologie   MeSH
• hypoxie * metabolismus   patofyziologie   MeSH
• kyslík * metabolismus   MeSH
• lidé MeSH
• vazokonstrikce * fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: The ventricular trabeculae play a role, among others, in the impulse spreading in ectothermic hearts. Despite the morphological similarity with the early developing hearts of endotherms, this trabecular function in mammalian and avian embryos was poorly addressed. RESULTS: We simulated impulse propagation inside the looping ventricle and revealed delayed apical activation in the heart with inhibited trabecular growth. This finding was corroborated by direct imaging of the endocardial surface showing early activation within the trabeculae implying preferential spreading of depolarization along with them. Targeting two crucial pathways of trabecular formation (Neuregulin/ErbB and Nkx2.5), we showed that trabecular development is also essential for proper conduction patterning. Persistence of the slow isotropic conduction likely contributed to the pumping failure in the trabeculae-deficient hearts. CONCLUSIONS: Our results showed the essential role of trabeculae in intraventricular impulse spreading and conduction patterning in the early endothermic heart. Lack of trabeculae leads to the failure of conduction parameters differentiation resulting in primitive ventricular activation with consequent impact on the cardiac pumping function.

• MeSH
• neureguliny MeSH
• savci MeSH
• srdce * MeSH
• srdeční komory * MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Mutations in DNA polymerase gamma (POLG) are known as the predominant cause of inherited mitochondrial disorders. But how these POLG mutations disturb mitochondrial function remains to be determined. Furthermore, no effective therapy, to date, has been reported for POLG diseases. Using differentiated SH-SY5Y cells, a human neuronal model cell line, the current study investigated whether the novel POLG variant p.A962T impairs mitochondrial function. This involved quantifying mitochondrial DNA (mtDNA) content using PCR and assessing the expression levels of the subunits of complex IV (COXI-IV), a complex I subunit NDUFV1 and Cytochrome C (Cyto C) release using Western blotting. Activities of mitochondrial complex I, II, and IV were measured using colorimetric assays. Mitochondrial membrane potential (delta Psim) and ATP were evaluated using fluorescence assays and luminescent assays, respectively. In addition, we investigated whether mitochondrial transplantation (MT) using Pep-1-conjugated mitochondria could compensate for mitochondrial defects caused by the variant in cells carrying mutant POLG. The results of this study showed that POLG p.A962T mutation resulted in mitochondrial defects, including mitochondrial DNA (mtDNA) depletion, membrane potential (delta Psim) depolarization and adenosine triphosphate (ATP) reduction. Mechanistically, POLG mutation-caused mtDNA depletion led to the loss of mtDNA-encoded subunits of complex I and IV and thus compromised their activities. POLG p.A962T mutation is a pathogenic mutation leading to mitochondrial malfunction and mtDNA depletion in neurons. Cell-penetrating peptide Pep-1-mediated MT treatment compensated for mitochondrial defects induced by these POLG variants, suggesting the therapeutic application of this method in POLG diseases.

• MeSH
• DNA polymeráza gama * genetika   metabolismus   MeSH
• DNA-dependentní DNA-polymerasy genetika   metabolismus   MeSH
• lidé MeSH
• membránový potenciál mitochondrií MeSH
• mitochondriální DNA genetika   MeSH
• mitochondriální nemoci genetika   metabolismus   MeSH
• mitochondrie * metabolismus   MeSH
• mutace * MeSH
• nádorové buněčné linie MeSH
• neurony * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The transient receptor potential canonical (TRPC) channels are a group of highly homologous nonselective cation channels from the larger TRP channel family. They have the ability to form homo- and heteromers with varying degrees of calcium (Ca2+) permeability and signalling properties. TRPC5 is the one cold-sensitive among them and likewise facilitates the influx of extracellular Ca2+ into cells to modulate neuronal depolarization and integrate various intracellular signalling pathways. Recent research with cryo-electron microscopy revealed its structure, along with clear insight into downstream signalling and protein-protein interaction sites. Investigations using global and conditional deficient mice revealed the involvement of TRPC5 in metabolic diseases, energy balance, thermosensation and conditions such as osteoarthritis, rheumatoid arthritis, and inflammatory pain including opioid-induced hyperalgesia and hyperalgesia following tooth decay and pulpitis. This review provides an update on recent advances in our understanding of the role of TRPC5 with focus on metabolic diseases and pain.

• MeSH
• bolest * farmakoterapie   metabolismus   MeSH
• kationtové kanály TRPC * metabolismus   MeSH
• lidé MeSH
• metabolické nemoci * farmakoterapie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH