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Determining the Individual Theta Frequency for Associative Memory Targeted Personalized Transcranial Brain Stimulation
Get PDFNon-invasive brain stimulation (NIBS) methods have gained increased interest in research and therapy of associative memory (AM) and its impairments. However, the one-size-fits-all approach yields inconsistent findings, thus putting forward the need for electroencephalography (EEG)-guided personalized frequency-modulated NIBS protocols to increase the focality and the effectiveness of the interventions. Still, extraction of individual frequency, especially in the theta band, turned out to be a challenging task. Here we present an approach to extracting the individual theta-band frequency (ITF) from EEG signals recorded during the AM task. The method showed a 93% success rate, good reliability, and the full range of variability of the extracted ITFs. This paper provides a rationale behind the adopted approach and critically evaluates it in comparison to the alternative methods that have been reported in the literature. Finally, we discuss how it could be used as an input parameter for personalized frequency-modulated NIBS approaches—transcranial alternating current stimulation (tACS) and transcranial oscillatory current stimulation (otDCS) directed at AM neuromodulation
P1002: Anti-fibrotic activity of BMP2 in bone marrow-derived mesenchymal stromal cells of myeloproliferative neoplasms
No full textBackground: Myeloproliferative neoplasms (MPN) are clonal hematopoietic disorders that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Bone marrow fibrosis (BMF) is a shared feature of all MPN, although it is most pronounced in PMF and represents a major diagnostic criteria. Studies suggest a correlation between the grade of BMF and prognosis of MPN, with more fibrosis associated with worse outcome. A large body of evidence has suggested that transforming growth factor beta (TGF-β) is among the most prominent inducers of fibrotic processes. Bone morphogenetic proteins (BMPs) are major regulators of cell fate in tissue homeostasis. In MPN, bone marrow-derived mesenchymal stromal cells (BM-MSC) are identified as a major cellular source of fibrosis, but exact molecular mechanism involved have not been identified so far. Aims: In addition to apoptosis and prolifration, we analyzed the effect of BMP2 and TGF- β / SMAD signaling pathway on the fibrotic phenotype of BM-MSC isolated from MPN patients and healthy donors. Methods: Bone marrow aspirates from 5 newly diagnosed MPN patients (3 PMF and 2 PV patients) and 3 healthy donors were analyzed by immunofluorescence expression of fibronectin and alpha smooth muscle Actin (αSMA), after treatment with TGF-β and / or BMP2. Using immunocytochemistry, we analyzed HEL 92.1.7 cells with a homozygous expression of JAK2V617F for proliferation (Ki67) and apoptosis (ssDNA) during exposure to BMP2 and selective BMP signaling inhibitor LDN-193189. Results: Our results showed that TGF-β significantly increased fibronectin expression, in contrast to BMP2, in BM-MSC of healthy donors. Also, the joint treatment of TGF-β and BMP2 reduced the level of fibronectin expression relative to TGF-β. In addition, TGF-β increased αSMA expression in BM-MSC from healthy donors. In contrast, BMP2 reduces the expression of αSMA and fibronectin in BM-MSC of healthy donors.BMP2 significantly reduced fibronectin expression in BM-MSC compared to untreated cells of patients with MPN. BMP2 dose dependently and significantly (p<0.01) increased the proliferation of HEL 92.1.7 cells, while the BMP signaling inhibitor LDN-193189 also demonstrated dose dependence in stimulation of proliferation (p<0.001). Apoptosis of HEL 92.1.7 cells was slightly affected by BMP2 and LDN-193189. Summary/Conclusion: Our results show that BMP2 has anti-fibrotic activity that is antagonistic to TGF-β. This indicate that BMP2 may modify the TGF-β signaling pathway
P1.09 Dynamic proteome profiling of myoblasts from FSHD patients and their unaffected siblings
No full textWe used stable isotope (deuterium oxide; D2O) labelling and peptide mass spectrometry to investigate the abundance and turnover rates of proteins in cultured muscle cells from 2 FSHD patients and their unaffected siblings (UASb). Our analysis encompassed 4,485 proteins and highlighted 41 significant (P<0.01) differences in abundance between FSHD and UASb groups. FSHD cells were enriched in inhibitors of muscle development including LIM and cysteine rich domains protein 1 (2.4-fold) and TGF-β receptor type 2 (2.2-fold), whereas heterogeneous and small nuclear ribonucleoproteins were significantly less abundant in FSHD myoblasts. Average protein turnover was not different between groups, but there were differences in protein-specific turnover rates. In growth media, 12 proteins exhibited differences (P<0.01); e.g., the turnover of protein kinase MRCKA was 13-fold less in FSHD, whereas the turnover of laminin β-1 was 2.9-fold greater compared to UASb cells. Under differentiation conditions, 13 proteins exhibited differences (P<0.01) in turnover rate. FSHD myoblasts had a 14-fold greater turnover of FK506-binding protein 15 and a 2.7-fold greater turnover of ATP-dependent RNA helicase A, whereas the turnover of COP9 signalosome complex subunit 4 was 4.9-fold less, and defender against cell death 1 (DAD1) was 14-fold less in FSHD myoblasts. These data represent the first large-scale study of proteostasis in FSHD, and provide new insight and a resource for exploring new therapeutic targets
Role of Corticosteroids in Drug-Induced Liver Injury. A Systematic Review
Get PDFIntroduction: Apart from cessation of the implicated agent leading to drug-induced liver injury (DILI), there is no standard therapy for DILI. Corticosteroids have been used in DILI, although their efficacy is unclear. Published data showed either beneficial effects or no improvement associated with steroid therapy. The aim of the current study was to perform a systematic review of the role of corticosteroids in the treatment of DILI. Methods: A search was performed in PubMed, searching for the terms: “corticosteroids” and “drug-induced liver injury”. Observation studies were included, but case reports excluded. Results: A total of 24 papers were retrieved. Most of these were observational studies on the effects of corticosteroids in moderate/severe DILI (n = 8), reports on the corticosteroid treatment in patients with drug-induced autoimmune hepatitis (DI-AIH) (n = 5), and effects of corticosteroids in drug-induced fulminant acute liver failure (ALF, n = 2). Furthermore, treatment of corticosteroids in patients with liver injury due to check point inhibitors (CPIs) was addressed in nine studies. In moderate/severe DILI, six out of eight studies suggested steroid treatment to be beneficial, whereas two studies showed negative results. All five observational studies on the effects of corticosteroids in DI-AIH showed good therapeutic response with rapid and long lasting effects after discontinuation of corticosteroids and without evidence of relapse. Steroid therapy was not associated with improved overall survival in patients with drug-induced fulminant ALF. CPIs-induced liver injury was found to improve spontaneously in 33–50% without corticosteroids, and the rate of patients who were treated responded to steroids in 33–100% (mean 72%). Conclusions: The majority of studies analyzing the effects of corticosteroids in moderate/severe DILI have demonstrated beneficial effects. However, this was not the case in drug-induced fulminant ALF. Patients with DI-AIH had an excellent response to corticosteroids. The majority of those with CPIs-induced liver injury responded to corticosteroids; however, patients without treatment usually recovered spontaneously. The observational design and comparison with historical controls in these studies makes it very difficult to draw conclusions on the efficacy of corticosteroids in DILI. Therefore, there is a strong need for a randomized controlled trial to properly assess the role of corticosteroids in DILI
Gait alterations in Parkinson’s disease at the stage of hemiparkinsonism—A longitudinal study
Get PDFBackground Progressive gait impairment in Parkinson’s disease (PD) leads to significant disability. Quantitative gait parameters analysis provides valuable information about fine gait alterations. Objectives To analyse change of gait parameters in patients with early PD at the stage of hemiparkinsonism and after 1 year of follow up, taking into account clinical asymmetry. Methods Consecutive early PD outpatients with strictly unilateral motor features underwent clinical and neuropsychological assessment at the study entry and after 1 year of follow up. Gait was assessed with GAITRite walkway using dual-task methodology. Spatiotemporal gait parameters (step time and length, swing time and double support time) and their coefficients of variation (CV), gait velocity and heel-to-heel base support were evaluated. Results We included 42 PD patients with disease duration of 1.3 years (±1.13). Progression of motor and non-motor symptoms, without significant cognitive worsening, was observed after 1 year of follow up. Significant shortening of the swing time, prolongation of the double support and increase of their CVs were observed during all task conditions similarly for most parameters on symptomatic and asymptomatic bodysides, except for CV for the swing time under the combined task. Conclusion Alterations of the swing time and double support time are already present even at the asymptomatic body side, and progress similarly, or even at faster pace, at this side, despite dopaminergic treatment These parameters deserve further investigation in larger, prospective studies to address their potential to serve as markers of progression in interventional disease modifying trials with early PD patients. © 2022 Marković et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
In Vivo and in vitro antitumor activity of tomatine in hepatocellular carcinoma
Get PDFBackground: There is abundant ethnopharmacological evidence the uses of regarding Solanum species as antitumor and anticancer agents. Glycoalkaloids are among the molecules with antiproliferative activity reported in these species. Purpose: To evaluate the anticancer effect of the Solanum glycoalkaloid tomatine in hepatocellular carcinoma (HCC) in vitro (HepG2 cells) and in vivo models. Methods: The resazurin reduction assay was performed to detect the effect of tomatine on cell viability in human HepG2 cell lines. Programmed cell death was investigated by means of cellular apoptosis assays using Annexin V. The expression of cancer related proteins was detected by Western blotting (WB). Reactive oxygen species (ROS) and calcium were determined by 2,7-dichlorodihydrofluorescein diacetate and Fluo-4, respectively. Intrahepatic HepG2 xenograft mouse model was used to elucidate the effect of tomatine on tumor growth in vivo. Results and Discussion: Tomatine reduced HepG2 cell viability and induced the early apoptosis phase of cell death, consistently with caspase-3, -7, Bcl-2 family, and P53 proteins activation. Furthermore, tomatine increased intracellular ROS and cytosolic Ca+2 levels. Moreover, the NSG mouse xenograft model showed that treating mice with tomatine inhibited HepG2 tumor growth. Conclusion: Tomatine inhibits in vitro and in vivo HCC tumorigenesis in part via modulation of p53, Ca+2, and ROS signalling. Thus, the results suggest the potential cancer therapeutic use of tomatine in HCC patients
Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation
Get PDFAbstract Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery of potent HDAC inhibitors, with 1-benzhydryl piperazine as a surface recognition group, that differ in hydrocarbon linker. In vitro HDAC screening identified two selective HDAC6 inhibitors with nanomolar IC50 values, as well as two non-selective nanomolar HDAC inhibitors. Structure-based molecular modeling was employed to study the influence of linker chemistry of synthesized inhibitors on HDAC6 potency. The breast cancer cell lines (MDA-MB-231 and MCF-7) were used to evaluate compound-mediated in vitro anti-cancer, anti-migratory, and anti-invasive activities. Experiments on the zebrafish MDA-MB-231 xenograft model revealed that a novel non-selective HDAC inhibitor with a seven-carbon-atom linker exhibits potent anti-tumor, anti-metastatic, and anti-angiogenic effects when tested at low micromolar concentrations
P1: Black currants and cornelian cherry juices prevent body characteristics and plasma lipid disturbance in high-fat high-fructose fed rats
No full textMetabolic syndrome (MetS) is a cluster of conditions- visceral obesity, high fasting glucose, high triglyceride, low HDL-cholesterol, high blood pressure -that increases the risk of cardiovascular disease and type 2 diabetes. Polyphenols from natural sources have an ameliorating effect on obesity-related metabolic disorders, and cardiovascular disease. This study was aimed to test the effects of polyphenol rich black currants (Ribes nigrum) and cornelian cherry (Cornus mas) juices on the body characteristics and plasma biochemistry parameters associated with MetS development in high-fat high-fructose (HFHF) fed rats. Male 4-month-old Wistar rats were divided into four groups (n=8): Control fed with standard chow diet +drinking water; HFHF fed with HFHF diet (standard chow diet with 25% sunflower oil, 20% fructose, 1% cholic acid) +drinking water; BC-HFHF fed with HFHF diet +25% black currants juice in drinking water; CC-HFHF fed with HFHF diet +25% cornelian cherry juice in drinking water. After 10 weeks of the dietary treatment, an increase of body fat (27,89±5,76 vs 14,97±2,85g), systolic (153,57±11 vs 128,33±12 mmHg) and diastolic (117,25±12 vs 100±12 mmHg) blood pressure, plasma glucose (6,36 ±0,72 vs 5,26 ±0,28 mmol/l), total (1,65±0,13 vs 1,41±0.10 mmol/l) and LDL-cholesterol (0,45±0,15 vs 0,24±0,16 mmol/l), and triglycerides (0,80±0,14 vs 0,64±0,12 mmol/l) was detected in HFHF group in comparison with Control, while HDLcholesterol was decreased (0,71±0,09 vs 0,97±0,14 mmol/l). Parallel treatment with black currants juice resulted in reduced body (391±35 vs 42±20g), fat (20,46±3,88 vs 14,97±2,85g) and liver mass (9,06±0,72 vs 10,23±1,29g), as well as in decreased glucose level (5,20±0,43 vs 6,36±0,72 mmol/l), total cholesterol (1,13±0,18 vs 1,65±0,13 mmol/l), triglycerides (0,51±0,21 vs 0,80±0,14 mmol/l) and liver enzymes AST (99,15±19 vs 193,68±70 IU/l) and ALT (35,20±3,5 vs 53,23±14 IU/l) in BC-HFHF when compared to HFHF group. Similarly, the lower total cholesterol (1,30±0,14 vs 1,65±0,13 mmol/l), triglycerides (0,58±0,16 vs 0,80±0,14 mmol/l), AST (110,30±60 vs 193,68±70 IU/l) and systolic blood pressure (141,17±9 vs 153,57±11 mmHg) were observed in CC-HFHF when compared with HFHF group. Obtained results have shown that polyphenol rich black currants and cornelian cherry juices have beneficial effect on the prevention of body characteristics and plasma biochemistry, particularly plasma lipid disturbance during dietary-induced MetS development
Uticaj različitih uslova mikrosredine na terapijski potencijal mezenhimskih matičnih ćelija zubnih tkiva
No full textPrema najnovijim istraživanjima mikrookruženje ćelija predstavlja značajan faktor koji moduliše fizičke funkcije, patološke promene, kao i terapijske efekte matičnih ćelija. Kada se uporede regenerativna svojstva različitih tipova matičnih ćelija koje se koriste u citoterapiji i tkivnom inženjeringu, mezenhimske matične ćelije (MMĆ) su trenutno najatraktivniji izvor ćelija za regeneraciju kostiju i zuba zbog njihovog diferencijacionog i imunomodulatornog potencijala i nedostatka etičkih pitanja povezanih sa njihovom upotrebom. Dentalne MĆ su lako dostupan izvor MĆ kroz neizvazivne stomatološke procedure i jednostavne metode izolacije iz različitih dentalnih tkiva. Međutim, neki od podataka vezani za regenerativni potencijal istog tipa ćelija su oprečni pa je važno istaći da biologija dentalnih MMĆ još nije u potpunosti istražena. Dodatno, mikrookruženje donora i primalaca koji učestvuju u citoterapiji igra ključnu ulogu u regenerativnom potencijalu transplantiranih MMĆ, što pokazuje da su interakcije ćelija sa njihovim mikrookruženjem neophodne u MMĆ posredovanoj regeneraciji kostiju i zuba. Imajući ovo u vidu a s obzirom da su različite populacije MMĆ dobijene iz različitih delova zuba i potpornih tkiva zuba, postizanje uspešnog terapijskog efekta u obolelom mikrookruženju predstavlja najveći izazov. Takođe, razumevanje uticaja mikrookruženja obolelog tkiva na regenerativni potencijal MMĆ bi pomoglo kako bi se ove ćelije mogle primeniti u procesu zarastanja