Evaluation of Ouabain's Tissue Distribution in C57/Black Mice Following Intraperitoneal Injection, Using Chromatography and Mass Spectrometry.

Cardiotonic steroids (CTSs), such as digoxin, are used for heart failure treatment. However, digoxin permeates the brain-blood barrier (BBB), affecting central nervous system (CNS) functions. Finding a CTS that does not pass through the BBB would increase CTSs' applicability in the clinic and decrease the risk of side effects on the CNS. This study aimed to investigate the tissue distribution of the CTS ouabain following intraperitoneal injection and whether ouabain passes through the BBB. After intraperitoneal injection (1.25 mg/kg), ouabain concentrations were measured at 5 min, 15 min, 30 min, 1 h, 3 h, 6 h, and 24 h using HPLC-MS in brain, heart, liver, and kidney tissues and blood plasma in C57/black mice. Ouabain was undetectable in the brain tissue. Plasma: Cmax = 882.88 ± 21.82 ng/g; Tmax = 0.08 ± 0.01 h; T1/2 = 0.15 ± 0.02 h; MRT = 0.26 ± 0.01. Cardiac tissue: Cmax = 145.24 ± 44.03 ng/g (undetectable at 60 min); Tmax = 0.08 ± 0.02 h; T1/2 = 0.23 ± 0.09 h; MRT = 0.38 ± 0.14 h. Kidney tissue: Cmax = 1072.3 ± 260.8 ng/g; Tmax = 0.35 ± 0.19 h; T1/2 = 1.32 ± 0.76 h; MRT = 1.41 ± 0.71 h. Liver tissue: Cmax = 2558.0 ± 382.4 ng/g; Tmax = 0.35 ± 0.13 h; T1/2 = 1.24 ± 0.7 h; MRT = 0.98 ± 0.33 h. Unlike digoxin, ouabain does not cross the BBB and is eliminated quicker from all the analyzed tissues, giving it a potential advantage over digoxin in systemic administration. However, the inability of ouabain to pass though the BBB necessitates intracerebral administration when used to investigate its effects on the CNS.

Plasma oxylipin profiles reflect Parkinson's disease stage.

Derivatives of polyunsaturated fatty acids (PUFAs), also known as oxylipins, are key participants in regulating inflammation. Neuroinflammation is involved in many neurodegenerative diseases, including Parkinson's disease. The development of ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) facilitated the study of oxylipins on a system level, i.e., the analysis of oxylipin profiles. We analyzed oxylipin profiles in the blood plasma of 36 healthy volunteers (HC) and 73 patients with Parkinson's disease (PD), divided into early (L\M, 29 patients) or advanced (H, 44 patients) stages based on the Hoehn and Yahr scale. Among the 40 oxylipins detected, we observed a decrease in the concentration of arachidonic acid (AA) and AA derivatives, including anandamide (AEA) and Leukotriene E4 (LTE4), and an increase in the concentration of hydroxyeicosatetraenoic acids 19-HETE and 12-HETE (PD vs HC). Correlation analysis of gender, age of PD onset, and disease stages revealed 20 compounds the concentration of which changed depending on disease stage. Comparison of the acquired oxylipin profiles to openly available PD patient brain transcriptome datasets showed that plasma oxylipins do not appear to directly reflect changes in brain metabolism at different disease stages. However, both the L\M and H stages are characterized by their own oxylipin profiles - in patients with the H stage oxylipin synthesis is increased, while in patients with L\M stages oxylipin synthesis decreases compared to HC. This suggests that different therapeutic approaches may be more effective for patients at early versus late stages of PD.

Prevalence and risk factors for dysphagia in older adults after thyroid and parathyroid surgery.

BACKGROUND: We aimed to determine the prevalence and risk factors for dysphagia in adults 65 years and older before and after thyroidectomy or parathyroidectomy. METHODS: We performed a longitudinal prospective cohort study of older adults undergoing initial thyroidectomy or parathyroidectomy. We administered the Dysphagia Handicap Index questionnaire preoperatively and 1, 3, and 6 months postoperatively. We compared preoperative and postoperative total and domain-specific scores using paired t tests and identified risk factors for worse postoperative scores using multivariable logistic regression. RESULTS: Of the 175 patients evaluated, the mean age was 71.1 years (range = 65-94), 73.7% were female, 40.6% underwent thyroidectomy, 57% underwent bilateral procedures, and 21.1% had malignant diagnoses. Preoperative swallowing dysfunction was reported by 77.7%, with the prevalence 22.4% greater in frail than robust patients (P = .013). Compared to preoperative scores, 43.4% and 49.1% had worse scores at 3 and 6 months postoperatively. Mean functional domain scores increased by 62.3% at 3 months postoperatively (P = .007). Preoperative swallowing dysfunction was associated with a 3.07-fold increased likelihood of worse functional scores at 3 months. Whereas frailty was associated with preoperative dysphagia, there was no association between worse postoperative score and age, sex, race, frailty, body mass index, smoking status, gastroesophageal reflux disease, comorbidity index, malignancy, surgical extent, or type of surgery. CONCLUSION: Adults 65 years and older commonly report swallowing impairment preoperatively, which is associated with a 3.07-fold increased likelihood of worsened dysphagia after thyroid and parathyroid surgery that may persist up to 6 months postoperatively.

Impact of manganese accumulation on Na,K-ATPase expression and function in the cerebellum and striatum of C57Bl/6 mice.

Overexposure to Mn causes a neurological disorder-manganism-with motor symptoms that overlap closely with disorders associated with haploinsufficiency in the gene encoding for α3 isoform of Na+,K+-ATPase (NKA). The present study was designed to test the hypothesis that behavioral changes in the mouse model of manganism may be associated with changes in the expression and activity of α3 NKA in the cerebellum (CB) and striatum (STR)-the key brain structures responsible for motor control in adult mice. C57Bl/6 mice were exposed to MnCl2 at 0.5 g/L (in drinking water) for up to eight weeks. After four weeks of Mn consumption, Mn levels were increased in the CB only. Behavioral tests demonstrated decreased performance of Mn-treated mice in the shuttle box test (third through sixth weeks), and the inclined grid walking test (first through sixth weeks), suggesting the development of learning impairment, decreased locomotion, and motor discoordination. The activity of NKA significantly decreased, and the expression of α1-α3 isoforms of NKA increased in the second week in the CB only. Thus, signs of learning and motor disturbances developing in this model of manganism are unlikely to be directly linked to disturbances in the expression or activity of NKA in the CB or STR. Whether these early changes may contribute to the pathogenesis of later behavioral deficits remains to be determined.

Na+,K+-ATPase and Cardiotonic Steroids in Models of Dopaminergic System Pathologies.

In recent years, enough evidence has accumulated to assert that cardiotonic steroids, Na+,K+-ATPase ligands, play an integral role in the physiological and pathophysiological processes in the body. However, little is known about the function of these compounds in the central nervous system. Endogenous cardiotonic steroids are involved in the pathogenesis of affective disorders, including depression and bipolar disorder, which are linked to dopaminergic system dysfunction. Animal models have shown that the cardiotonic steroid ouabain induces mania-like behavior through dopamine-dependent intracellular signaling pathways. In addition, mutations in the alpha subunit of Na+,K+-ATPase lead to the development of neurological pathologies. Evidence from animal models confirms the neurological consequences of mutations in the Na+,K+-ATPase alpha subunit. This review is dedicated to discussing the role of cardiotonic steroids and Na+,K+-ATPase in dopaminergic system pathologies-both the evidence supporting their involvement and potential pathways along which they may exert their effects are evaluated. Since there is an association between affective disorders accompanied by functional alterations in the dopaminergic system and neurological disorders such as Parkinson's disease, we extend our discussion to the role of Na+,K+-ATPase and cardiotonic steroids in neurodegenerative diseases as well.

Neuroprotective Efficacy of a Nanomicellar Complex of Carnosine and Lipoic Acid in a Rat Model of Rotenone-Induced Parkinson's Disease.

Oxidative stress, accompanied by mitochondrial dysfunction, is a key mechanism involved in the pathogenesis of Parkinson's disease (PD). Both carnosine and lipoic acid are potent antioxidants, the applicability of which in therapy is hindered by their limited bioavailability. This study aimed to evaluate the neuroprotective properties of a nanomicellar complex of carnosine and lipoic acid (CLA) in a rotenone-induced rat model of PD. Parkinsonism was induced via the administration of 2 mg/kg rotenone over the course of 18 days. Two doses of intraperitoneal CLA (25 mg/kg and 50 mg/kg) were administered alongside rotenone to assess its neuroprotective effect. At 25 mg/kg CLA decreased muscle rigidity and partially restored locomotor activity in animals that received rotenone. Furthermore, it caused an overall increase in brain tissue antioxidant activity, accompanied by a 19% increase in neuron density in the substantia nigra and increased dopamine levels in the striatum relative to animals that only received rotenone. Based on the acquired results, it may be concluded that CLA have neuroprotective properties and could potentially be beneficial in PD treatment when used in conjunction with the base therapy.

Changing profile of infective endocarditis during a 20-year observation period.

BACKGROUND: Infective endocarditis (IE) is most often caused by bacteria. OBJECTIVES: The aim of this work is the research of the dynamics of the clinical laboratory and instrumental methods of the diagnostics during the period of two decades. METHODS: The data of 241 patients with infective endocarditis (IE) who were treated at the State Clinical Hospital named after Botkin S.P. was included in the research. 121 patients were observed from 2011 till 2020 (the first group) and 120 patients - from 1997 to 2004 (the second test group). These data included age and social structure of pathology, peculiarities of clinical picture, laboratory, and instrumental methods of research, as well as the outcome of the disease. We studied the concentrations of procalcitonin and presepsin in patients hospitalized after 2011. We observed pathomorphism of the modern IE. RESULTS: To discover the bacteriological origin of the disease, we found the diagnostic evaluation of inflammation, procalcitonin, and presepsin activities, using C-reactive protein, important. We observed decrease in the number of general and hospital deaths. CONCLUSIONS: The knowledge of the IE peculiarities during the IE progression is essential for timely diagnosis and more accurate pathology prediction (Fig. 5, Ref. 38). Text in PDF www.elis.sk Keywords: infectious endocarditis, valve apparatus disease, thromboembolic complications, immunocomplex complications, procalcitonin, presepsin.

Hysteroscopic injections of autologous endometrial cells and platelet-rich plasma in patients with thin endometrium: a pilot randomized study.

The aim of this study was to evaluate the efficacy of hysteroscopically controlled injections of autologous platelet-rich plasma (PRP) and autologous endometrial cells as a treatment for infertile women with thin endometrium. The study enrolled 115 patients with thin endometrium (< 7 mm at implantation window) and infertility, who were divided into groups: Group 1 (the control) underwent conservative therapy; Group 2 received intraendometrial PRP injections instead of the conservative therapy; Group 3 received identical injections after conservative therapy; Group 4 received injections of the autologous endometrial cells suspended in PRP. A single injection dose of PRP contained 0.6-0.7 × 1011 of platelets. The levels of PDGF-BB and VEGF in PRP were increased compared with ordinary plasma. The autologous endometrial cells, obtained from pipelle biopsies, constituted heterogeneous cell populations containing stromal and epithelial cells. Intraendometrial PRP injections had significant impact on endometrial thickness and local microcirculation in Group 2 and Group 3. In Group 4, injections of PRP reinforced with endometrial cells also facilitated a significant increase in endometrial thickness. This work describes a novel approach for infertility treatment in patients with refractory thin endometrium. PRP injections and injections of the endometrial cells suspended in PRP into endometrium enhanced cell proliferation and angiogenesis.

Secondary Hyperparathyroidism and Cognitive Decline.

Purpose of Review: Secondary hyperparathyroidism (SHPT) likely contributes to the high prevalence of cognitive decline found among individuals with end-stage kidney disease (ESKD). Our objective is to critically evaluate the recent literature regarding the association between SHPT and cognitive decline and identify potential mechanisms. Recent Findings: Nine studies assessing the relationship between SHPT and cognition have been published in the last two decades, each showing that elevated parathyroid hormone (PTH) levels were associated with cognitive decline. One also found structural changes within the brain related to SHPT. Additionally, two found that SHPT treatment decreases the risk of cognitive decline in ESKD patients. Summary: SHPT is associated with cognitive impairment. However, the severity of SHPT associated with these changes and the specific cognitive domains affected remain unclear. Future studies are needed to focus on specific cognitive domains, the trajectory of cognitive decline, and optimal treatment strategies including the impact of kidney transplant and tertiary hyperparathyroidism.

Time Course of Neurobehavioral Disruptions and Regional Brain Metabolism Changes in the Rotenone Mice Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by slow progression with a long prodromal stage and the gradual evolution of both neuropsychological symptoms and subtle motor changes, preceding motor dysfunction. Thus, in order for animal models of PD to be valid, they should reproduce these characteristics of the disease. One of such models, in which neuropathology is induced by chronic injections of low doses of mitochondrial toxin rotenone, is well established in rats. However, data on this model adapted to mice remain controversial. We have designed the study to describe the timecourse of motor and non-motor symptoms during chronic subcutaneous administration of rotenone (4 mg/kg daily for 35 days) in C57BL/6 mice. We characterize the underlying neuropathological processes (dopaminergic neuron degeneration, regional brain metabolism, monoamine neurotransmitter and lipid peroxidation changes) at different timepoints: 1 day, 2 weeks and 5 weeks of daily rotenone exposure. Based on the behavioral data, we can describe three stages of pathology: cognitive changes from week 2 of rotenone exposure, subtle motor changes in week 3-4 and motor dysfunction starting roughly from week 4. Neuropathological changes in this model include a general decrease in COX activity in different areas of the brain (acute effect of rotenone) and a more specific decrease in midbrain (chronic effect), followed by significant neurodegeneration in SNpc but not VTA by the 5th week of rotenone exposure. However, we were unable to find changes in the level of monoamine neurotransmitters neither in the striatum nor in the cortex, nor in the level of lipid peroxidation in the brainstem. Thus, the gradual progression of pathology in this model is linked with metabolic changes, rather than with oxidative stress or tonic neurotransmitter release levels. Overall, this study supports the idea that a low-dose rotenone mouse model can also reproduce different stages of PD as well as rats.

The Normohormonal Primary Hyperparathyroidism; a surgical dilemma pre and intra-operatively.

INTRODUCTION: Normohormonal Primary Hyperparathyroidism (NPHPT), poses a dilemma for surgeons; first in deciding when to operate where the PTH is normal and second at what level should the drop in intra-operative PTH (ioPTH) be considered a successful operation. MATERIALS & METHODS: A retrospective evaluation of all parathyroidectomies performed by a single surgeon from 2009 to 2019 was conducted. RESULTS: In 33 of 349 (9%) parathyroidectomies the indication was NPHPT. Negative pre-operative nuclear localization was found in 17(52%) patients. Intra-operative findings were: 27(82%) single-adenoma, 3(9%) double-adenomas and 3(9%) hyperplasia. In patients with single-adenomas the ioPTH dropped from 57 ± 8 to 23 ± 10 pg./ml. The average size of the adenomas was 403 ± 360 mg. CONCLUSION: NPHPT is uncommon where the disease is diagnosed in its early stages. Over 50% has negative pre-operative nuclear localization test requiring 4-gland surgical exploration. The intra-operative drop in PTH below 30 pg./ml can be utilized as an indicator of a successful operation.

An assessment of the transport mechanism and intraneuronal stability of L-carnosine.

L-Carnosine (ß-alanyl-L-histidine) is a well-known antioxidant and neuroprotector in various models on animals and cell cultures. However, while there is a plethora of data demonstrating its efficiency as a neuroprotector, there is a distinct lack of data regarding the mechanism of its take up by neurons. According to literature, cultures of rat astrocytes, SKPT cells and rat choroid plexus epithelial cells take up carnosine via the H+-coupled PEPT2 membrane transporter. We've assessed the effectiveness and mechanism of carnosine transport, and its stability in primary rat cortical culture neurons. We demonstrated that neurons take up carnosine via active transport with Km = 119 µM and a maximum velocity of 0.289 nmol/mg (prot)/min. Passive transport speed constituted 0.21∙10-4 nmol/mg (prot)/min (with 119 µM concentration in the medium)-significantly less than active transport speed. However, carnosine concentrations over 12.5 mM led to passive transport speed becoming greater than active transport speed. Using PEPT2 inhibitor zofenopril, we demonstrated that PEPT2-dependent transport is one of the main modes of carnosine take up by neurons. Our experiments demonstrated that incubation with carnosine does not affect PEPT2 amount present in culture. At the same time, after removing carnosine from the medium, its elimination speed by culture cells reached 0.035 nmol/mg (prot)/min, which led to a decrease in carnosine quantity to control levels in culture within 1 h. Thus, carnosine is taken up by neurons with an effectiveness comparable to that of other PEPT2 substrates, but its elimination rate suggests that for effective use as a neuroprotector it's necessary to either maintain a high concentration in brain tissue, or increase the effectiveness of glial cell synthesis of endogenous carnosine and its shuttling into neurons, or use more stable chemical modifications of carnosine.

Modulation of the Primary Astrocyte-Enriched Cultures' Oxylipin Profiles Reduces Neurotoxicity.

Recently, manipulations with reactive astrocytes have been viewed as a new therapeutic approach that will enable the development of treatments for acute brain injuries and neurodegenerative diseases. Astrocytes can release several substances, which may exert neurotoxic or neuroprotective effects, but the nature of these substances is still largely unknown. In the present work, we tested the hypothesis that these effects may be attributed to oxylipins, which are synthesized from n-3 or n-6 polyunsaturated fatty acids (PUFAs). We used astrocyte-enriched cultures and found that: (1) lipid fractions secreted by lipopolysaccharide (LPS)-stimulated rat primary astrocyte-enriched cultures-possessed neurotoxic activity in rat primary neuronal cultures; (2) both of the tested oxylipin synthesis inhibitors, ML355 and Zileuton, reduce the LPS-stimulated release of interleukin 6 (IL-6) by astrocyte cultures, but only ML355 can change lipid fractions from neurotoxic to non-toxic; and (3) oxylipin profiles, measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) from neurotoxic and non-toxic lipid fractions, reveal a group of n-3 docosahexaenoic acid derivatives, hydroxydocosahexaenoic acids (HdoHEs)-4-HdoHE, 8-HdoHE, and 17-HdoHE, which may reflect the neuroprotective features of lipid fractions. Regulating the composition of astrocyte oxylipin profiles may be suggested as an approach for regulation of neurotoxicity in inflammatory processes.

Efficacy and Safety of Divaza for the Correction of Oxidative Disturbances in Patients with Cerebral Atherosclerosis: A Randomized Controlled Trial.

OBJECTIVE: The objective of this study was to determine if Divaza, a drug with nootropic and antioxidant effects, was safe and effective for the correction of oxidative disturbances and to stabilize cognitive impairment in patients with cerebral atherosclerosis. STUDY DESIGN: The study design consisted of a 12-week multicenter, randomized, double-blind, placebo-controlled, prospective trial in parallel groups. SETTING: The setting in which the study was conducted comprised 10 clinical centers across the Russian Federation. INTERVENTIONS: Patients were randomized into 2 groups and instructed to take either 2 tablets of the study drug or a placebo 3 times per day in conjunction with basic therapy. OUTCOMES: The primary outcome was a change in the average endogenous antioxidant potential after the completion of the study. The blood indicators of the oxidative stress (OS) were analyzed at the baseline and then after 12 weeks of therapy using iron-induced chemiluminescence analysis. The Montreal cognitive assessment test was used as a secondary outcome measure to evaluate cognitive impairment at the end of the study. RESULTS: 124 outpatients with a mean age of 60.7 ± 7.6 years were enrolled and randomly assigned to receive Divaza (n = 65) or a placebo (n = 59). An improvement of cognitive function was observed in all patients of the Divaza group at the end of the treatment; this was significantly better than the placebo group (100 [100] vs. 89.5 [89.1]%, respectively, p = 0.0272 [p = 0.0128]). The administration of Divaza restored the activity of the endogenous antioxidant system. The change in the average level of lipoprotein resistance to oxidation after 12 weeks of therapy, compared to the baseline, was significantly higher in the Divaza group (14.8 ± 14.7 [14.8 ± 14.7] seconds latent period vs. 6.4 ± 16.9 [6.9 ± 16.7] seconds in the placebo group (p = 0.007 [p = 0.0107]). CONCLUSIONS: Divaza is a safe and effective therapeutic option for attenuating OS and recovery of cognitive impairment in patients with cerebral atherosclerosis.

Relation between lignin molecular profile and fungal exo-proteome during kraft lignin modification by Trametes hirsuta LE-BIN 072.

The process of kraft lignin modification by the white-rot fungus Trametes hirsuta was investigated using electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI FT-ICR MS), and groups of systematically changing compounds were delineated. In the course of cultivation, fungus tended to degrade progressively more reduced compounds and produced more oxidized ones. However, this process was not gradual - the substantial discontinuity was observed between 6th and 10th days of cultivation. Simultaneously, the secretion of ligninolytic peroxidases by the fungus was changing in a cascade manner - new isoenzymes were added to the mixture of the already secreted ones, and once new isoenzyme appeared both its relative quantity and number of isoforms increased as cultivation proceeded. It was proposed, that the later secreted peroxidases (MnP7 and MnP1) possess higher substrate affinity for some phenolic compounds and act in more specialized manner than the early secreted ones (MnP5 and VP2).

The dynamics of nigrostriatal system damage and neurobehavioral changes in the rotenone rat model of Parkinson's disease.

Subcutaneous administration of rotenone to rats is currently a widely used method of reproducing Parkinson's disease (PD) symptoms, due to its convenience and effectiveness. Despite this, its influence on the temporal dynamics of parkinsonism development has yet to be investigated. The present study characterizes behavioral and neurochemical disruptancies underlying the dynamics of parkinsonism development in rats, induced by chronic subcutaneous administration of 2 mg/kg rotenone over the course of 18 days. In this article, the presence of two stages of pathology development in the model in question - the premotor and motor disability stages - are illustrated through a complex assessment of animal behavior, the development of an original neurological symptoms scale, and the establishment of the dynamics of histological and neurochemical changes in the brain. The premotor stage was observed up to 3 days of rotenone administration, and was characterized by a decrease in the motivational component of behavior, shown both in the food-getting task and in the "sucrose preference" test. A 30 % decrease in the number of cells in the substantia nigra pars compacta by the 3rd day of rotenone administration was also shown during the premotor stage. No changes in the metabolism of dopamine and other monoamine mediators were observed at this time. At the same time, acute administration of rotenone caused an increase in the GSH / GSSG ratio by 69 %. The motor stage developed after a decrease in the number of cells in the SNpc by more than 30 %, and was characterized by changes in the dopaminergic system, leading up to a 71 % reduction in dopamine levels in the striatum. It was shown that starting from 4 to 6 days of rotenone injection, experimental group animals begin to develop motor symptoms of Parkinson's disease, including bradykinesia, rigidity and postural instability. The development of motor impairment in all rats of this group was accompanied by significantly reduced activity of the antioxidant system in brain frontal lobe tissue homogenates, as compared to intact rats. Thus, in the used model of rotenone-induced parkinsonism, the dynamics of neuropathology development are described and the premotor stage of the disease is highlighted, which allows future using of this model in developing new approaches for treatment of parkinsonism at an early stage.

Ouabain-Induced Gene Expression Changes in Human iPSC-Derived Neuron Culture Expressing Dopamine and cAMP-Regulated Phosphoprotein 32 and GABA Receptors.

Cardiotonic steroids (CTS) are specific inhibitors and endogenous ligands of a key enzyme in the CNS-the Na+, K+-ATPase, which maintains and creates an ion gradient on the plasma membrane of neurons. CTS cause the activation of various signaling cascades and changes in gene expression in neurons and other cell types. It is known that intracerebroventricular injection of cardiotonic steroid ouabain causes mania-like behavior in rodents, in part due to activation of dopamine-related signaling cascades in the dopamine and cAMP-regulated phosphoprotein 32 (DARPP-32) expressing medium spiny neurons in the striatum. Dopaminergic projections in the striatum innervate these GABAergic medium spiny neurons. The objective of this study was to assess changes in the expression of all genes in human iPSC-derived expressing DARPP-32 and GABA receptors neurons under the influence of ouabain. We noted a large number of statistically significant upregulated and downregulated genes after a 16-h incubation with non-toxic concentration (30 nM) of ouabain. These changes in the transcriptional activity were accomplished with activation of MAP-kinase ERK1/2 and transcriptional factor cAMP response element-binding protein (CREB). Thus, it can be concluded that 30 nM ouabain incubated for 16 h with human iPSC-derived expressing DARPP-32 and GABA receptors neurons activates genes associated with neuronal maturation and synapse formation, by increasing the expression of genes associated with translation, vesicular transport, and increased electron transport chain function. At the same time, the expression of genes associated with proliferation, migration, and early development of neurons decreases. These data indicate that non-toxic concentrations of ouabain may induce neuronal maturation, neurite growth, and increased synaptogenesis in dopamine-receptive GABAergic neurons, suggesting formation of plasticity and the establishment of new neuronal junctions.

Changes in COX histochemistry in the brain of mice and rats exposed to chronic subcutaneous rotenone.

Exposure of experimental animals to the mitochondrial toxin rotenone is considered to be a model of environmental progression of Parkinson's disease (PD). We investigated the differential vulnerability of various brain regions to generalized inhibition of complex I, induced by subcutaneous rotenone injections for the duration of 1, 3 and 7 days in both rats (2 mg/kg dosage) and mice (4 mg/kg dosage). To examine patterns of metabolic activity changes in the brain, histochemical evaluation of cytochrome C oxidase (COX) activity was performed in post mortem brain sections. Animals displayed a similar time course of neuronal loss in substantia nigra pars compacta (SNpc), reaching 44 % in mice and 42 % in rats by the 7th day. The pattern of COX activity changes, however, was different for the two species. In both experiments, metabolic changes were evident not only in the substantia nigra, but also in non-specific structures (cortex and hippocampus). In mice, a decrease in COX activity was shown mostly for the non-specific areas (V1 cortex and ventral hippocampus) after the single exposure to rotenone. Data from the experiment conducted on rats demonstrated both an acute metabolic decrease in mesencephalic structures (SNpc and nucleus ruber) after a single injection of rotenone and secondary changes in cortical structures (S1 cortex and dorsal hippocampus) after chronic 7 day exposure. These changes reflect the general effect of rotenone on neuronal metabolic rate.

An overview of the pathogenic mechanisms involved in severe cases of COVID-19 infection, and the proposal of salicyl-carnosine as a potential drug for its treatment.

Multiple organ failure in COVID-19 patients is a serious problem which can result in a fatal outcome. Damage to organs and tissues, including general lung dysfunction, develops as a consequence of ischemia, which, in turn, is caused by thrombosis in small blood vessels and hypoxia, leading to oxidative stress and inflammation. Currently, research is underway to screen existing drugs for antioxidant, antiplatelet and anti-inflammatory properties. Having studied the available publications concerning the mechanisms of damage to tissues and organs of patients with COVID-19, as well as the available treatment strategies, we propose to investigate salicyl-carnosine as a potential drug for treating COVID-19 patients. In a recent study, we described the drug's synthesis procedure, and showed that salicyl-carnosine possesses antioxidant, anti-inflammatory, and antiplatelet effects. Therefore, it can simultaneously act on the three pathogenetic factors involved in tissue and organ damage in COVID-19. Thus, we propose to consider salicyl-carnosine as a potential drug for the treatment of patients with severe cases of COVID-19 infection.

Oxylipin Profiles in Plasma of Patients with Wilson's Disease.

Wilson's disease (WD) is a rare autosomal recessive metabolic disorder resulting from mutations in the copper-transporting, P-type ATPase gene ATP7B gene, but influences of epigenetics, environment, age, and sex-related factors on the WD phenotype complicate diagnosis and clinical manifestations. Oxylipins, derivatives of omega-3, and omega-6 polyunsaturated fatty acids (PUFAs) are signaling mediators that are deeply involved in innate immunity responses; the regulation of inflammatory responses, including acute and chronic inflammation; and other disturbances related to any system diseases. Therefore, oxylipin profile tests are attractive for the diagnosis of WD. With UPLC-MS/MS lipidomics analysis, we detected 43 oxylipins in the plasma profiles of 39 patients with various clinical manifestations of WD compared with 16 healthy controls (HCs). Analyzing the similarity matrix of oxylipin profiles allowed us to cluster patients into three groups. Analysis of the data by VolcanoPlot and partial least square discriminant analysis (PLS-DA) showed that eight oxylipins and lipids stand for the variance between WD and HCs: eicosapentaenoic acid EPA, oleoylethanolamide OEA, octadecadienoic acids 9-HODE, 9-KODE, 12-hydroxyheptadecatrenoic acid 12-HHT, prostaglandins PGD2, PGE2, and 14,15-dihydroxyeicosatrienoic acids 14,15-DHET. The compounds indicate the involvement of oxidative stress damage, inflammatory processes, and peroxisome proliferator-activated receptor (PPAR) signaling pathways in this disease. The data reveal novel possible therapeutic targets and intervention strategies for treating WD.