The associations between common neuroimaging parameters of Progressive Supranuclear Palsy in magnetic resonance imaging and non-specific inflammatory factors - pilot study.

Progressive Supranuclear Palsy is an atypical parkinsonism based on tauopathic pathology. Growing interest is associated with the pathomechanism of this disease. Among theories analyzing this issue can be mentioned the one highlighting the significance of inflammation. In this study authors examined 14 patients with PSP-Richardson syndrome (PSP-RS) and 13 healthy volunteers using laboratory testing based on the analysis of interleukins 1 and 6 (IL-1 and IL-6), tau in the cerebrospinal fluid (CSF) and non-specific parameters of peripheral inflammation in the serum (IL-1, IL-6, neutrophils, lymphocytes, monocytes, platelets and the ratios based on the factors). All of the patients underwent neuroimaging using magnetic resonance imaging using 3 Tesla. The serum levels of IL-1 were positively correlated with the area of the mesencephalon, suggesting that higher levels of IL-1 are not linked with atrophic changes in this region, whereas serum levels IL-6 was positively correlated with frontal horn width and negatively correlated with superior cerebellar area. Additionally IL-6 in the serum was found to be correlated with neutrophil-to-high density lipoprotein ratio. The observations were not confirmed in the analysis of the levels of interleukins in the CSF. To the best of our knowledge this work is one of the first analyzing this issue. The outcome of the work shows that the role of interleukins associated with microglial activation may possibly differ in the context of neurodegenerative changes, moreover the role of peripheral inflammation in PSP requires further analysis.

The potential significance of hepcidin evaluation in progressive supranuclear palsy.

INTRODUCTION: Hepcidin is a peptide associated with controlling the distribution of iron in tissues. Growing interest is linked with its impact on neurodegenerative diseases, as disruption of the iron regulation may be considered an initiatory element of pathological protein accumulation. The possible impact of hepcidin was not previously sufficiently explored in progressive supranuclear palsy (PSP). METHODS: Twelve patients with PSP-Richardson's syndrome (PSP-RS), 12 with PSP-Parkinsonism Predominant (PSP-P), and 12 controls were examined using Unified Parkinson's Disease Rating Scale-III part (UPDRS-III) in OFF stage and analyzed in the context of hepcidin levels in the serum. RESULTS: The work revealed increased levels of hepcidin in PSP-RS when compared to PSP-P and controls. Moreover, hepcidin was found to be negatively correlated with UPDRS-III results in PSP-RS, whereas positively in PSP-P. CONCLUSION: The work may suggest a possible impact of hepcidin in PSP, possibly differing depending on its subtype.

Routine end-ischemic hypothermic machine perfusion in liver transplantation from donors after brain death: results of two-year follow-up of a randomized controlled trial.

BACKGROUND: Data on routine hypothermic machine perfusion of livers procured from donors after brain death (DBD) are scarce, and the benefits of the method have only been demonstrated in extended criteria grafts. The aim of this study was to assess if end-ischemic dual hypothermic oxygenated machine perfusion (dHOPE) is superior to static cold storage (SCS) in preservation of livers procured from DBD donors with respect to long-term outcomes. Existing data on short-term outcomes favours dHOPE in patients receiving high-risk grafts. METHODS: This prospective randomized controlled trial included 104 recipients of DBD livers randomly assigned to static cold storage arm (78 patients) and dHOPE arm (26 patients). Endpoints of interest were occurrence of biliary complications (biliary fistula, anastomotic, and nonanastomotic strictures) and overall patient (OS) and graft survival (GS) during two-year follow-up. RESULTS: A total of 36 patients developed biliary complications (at least one event) - 6 events in dHOPE arm and 30 in SCS arm. There was no significant difference in biliary complications between groups (23.7% vs. 43.4% [P=0.11]). No differences were found significant with respect to anastomotic (19.9% vs. 33.7% [P=0.20]) and non-anastomotic strictures (0% vs. 11.1% [P=0.10]) as well as biliary fistulas (11.7% vs. 12.2% [P=0.93]). Survival analysis did not show significantly different result in the study population - OS: 92.3% in dHOPE and 83.9% in SCS (P=0.35), and GS: 92.3% and 81.4% (P=0.23), respectively. However, significant difference in GS was noted in recipients of high-risk grafts - 100% in dHOPE and 73.1% in SCS, respectively (P=0.038). CONCLUSIONS: The long-term outcome data suggest that the routine use of dHOPE may be beneficial for recipients of high-risk grafts from DBD donors. The present study does not provide any evidence for benefits of dHOPE in low-risk grafts.

Synthesis and Biological Evaluation of New Compounds with Nitroimidazole Moiety.

Heterocyclic compounds, particularly those containing azole rings, have shown extensive biological activity, including anticancer, antibacterial, and antifungal properties. Among these, the imidazole ring stands out due to its diverse therapeutic potential. In the presented study, we designed and synthesized a series of imidazole derivatives to identify compounds with high biological potential. We focused on two groups: thiosemicarbazide derivatives and hydrazone derivatives. We synthesized these compounds using conventional methods and confirmed their structures via nuclear magnetic resonance spectroscopy (NMR), MS, and elemental analysis, and then assessed their antibacterial and antifungal activities in vitro using the broth microdilution method against Gram-positive and Gram-negative bacteria, as well as Candida spp. strains. Our results showed that thiosemicarbazide derivatives exhibited varied activity against Gram-positive bacteria, with MIC values ranging from 31.25 to 1000 µg/mL. The hydrazone derivatives, however, did not display significant antibacterial activity. These findings suggest that structural modifications can significantly influence the antimicrobial efficacy of imidazole derivatives, highlighting the potential of thiosemicarbazide derivatives as promising candidates for further development in antibacterial therapies. Additionally, the cytotoxic activity against four cancer cell lines was evaluated. Two derivatives of hydrazide-hydrazone showed moderate anticancer activity.

Novel Combretastatin A-4 Analogs-Design, Synthesis, and Antiproliferative and Anti-Tubulin Activity.

Combretastatins isolated from the Combretum caffrum tree belong to a group of closely related stilbenes. They are colchicine binding site inhibitors which disrupt the polymerization process of microtubules in tubulins, causing mitotic arrest. In vitro and in vivo studies have proven that some combretastatins exhibit antitumor properties, and among them, combretastatin A-4 is the most active mitotic inhibitor. In this study, a series of novel combretastatin A-4 analogs containing carboxylic acid, ester, and amide moieties were synthesized and their cytotoxic activity against six tumor cell lines was determined using sulforhodamine B assay. For the most cytotoxic compounds (8 and 20), further studies were performed. These compounds were shown to induce G0/G1 cell cycle arrest in MDA and A549 cells, in a concentration-dependent manner. Moreover, in vitro tubulin polymerization assays showed that both compounds are tubulin polymerization enhancers. Additionally, computational analysis of the binding modes and binding energies of the compounds with respect to the key human tubulin isotypes was performed. We have obtained a satisfactory correlation of the binding energies with the IC50 values when weighted averages of the binding energies accounting for the abundance of tubulin isotypes in specific cancer cell lines were computed.

Novel Tetracyclic Azaphenothiazines with the Quinoline Ring as New Anticancer and Antibacterial Derivatives of Chlorpromazine.

Phenothiazine derivatives are widely studied in various fields such as biology, chemistry, and medicine research because of their pharmaceutical effects. The first compound used successfully in the treatment of psychosis was a phenthiazine derivative, chlorpromazine. Apart from its activity in neurons, chlorpromazine has also been reported to display anticancer and antibacterial properties. In this study, we present the synthesis and research on the activity of A549, MDA, MiaPaCa, PC3, and HCT116 cancer cell lines and of S. aureus, S. epidermidis, E. coli, and P. aeruginosa bacterial strains against a series of new tetracyclic chlorpromazine analogues containing a quinoline scaffold in their structure instead of the benzene ring and various substituents at the thiazine nitrogen. The structure of these novel molecules has been determined by 1H NMR, 13C NMR, and HRMS spectral techniques. The seven most active of the twenty-four new chlorpromazine analogues tested were selected to study the mechanism of cytotoxic action. Their ability to induce apoptosis or necrosis in cancer cells was assessed by flow cytometry analysis. The results obtained confirmed the proapoptotic activity of selected compounds, especially in terms of inducing late apoptosis or necrosis in cancer cell lines A549, MiaPaCa-2, and HCT-116. Furthermore, studies on the induction of cell cycle arrest suggest that the new chlorpromazine analogues exert antiproliferative effects by inducing cell cycle arrest in the S phase and, consequently, apoptosis.

New Thiosemicarbazide Derivatives with Multidirectional Biological Action.

Over the years, several new medicinal substances have been introduced for the treatment of diseases caused by bacteria and parasites. Unfortunately, due to the production of numerous defense mechanisms by microorganisms and parasites, they still pose a serious threat to humanity around the world. Therefore, laboratories all over the world are still working on finding new, effective methods of pharmacotherapy. This research work aimed to synthesize new compounds derived from 3-trifluoromethylbenzoic acid hydrazide and to determine their biological activity. The first stage of the research was to obtain seven new compounds, including six linear compounds and one derivative of 1,2,4-triazole. The PASS software was used to estimate the potential probabilities of biological activity of the newly obtained derivatives. Next, studies were carried out to determine the nematocidal potential of the compounds with the use of nematodes of the genus Rhabditis sp. and antibacterial activity using the ACCT standard strains. To determine the lack of cytotoxicity, tests were performed on two cell lines. Additionally, an antioxidant activity test was performed due to the importance of scavenging free radicals in infections with pathogenic microorganisms. The conducted research proved the anthelmintic and antibacterial potential of the newly obtained compounds. The most effective were two compounds with a 3-chlorophenyl substituent, both linear and cyclic derivatives. They demonstrated higher efficacy than the drugs used in treatment.

The significance of glial cell line-derived neurotrophic factor analysis in Progressive Supranuclear Palsy.

Progressive Supranuclear Palsy (PSP) is an atypical parkinsonism. Major subtypes of the disease: PSP-Richardson's Syndrome (PSP-RS) and PSP Parkinsonism Predominant (PSP-P) vary in clinical features, the pathomechanism remains unexplored. The aim of this work is to analyze the relevance of glial cell line-derived neurotrophic factor (GDNF) evaluation in the serum and cerebrospinal fluid (CSF) in PSP subtypes and to verify its significance as a possible factor in the in vivo examination. Authors assessed the concentration of GDNF in the serum and CSF of 12 patients with PSP-RS, 12 with PSP-P and 12 controls. Additionally authors evaluated patients using Unified Parkinson's Disease Rating Scale-III part (UPDRS-III), Frontal Assessment Battery (FAB) and Magnetic Resonance Imaging (MRI). The evaluation revealed significantly increased concentrations of GDNF in the CSF among PSP-RS patients and substantially increased concentrations of GDNF in the serum in PSP-P. Though the GDNF concentrations differentiated PSP subtypes, no correlations between with clinical factors were observed however certain correlations with atrophic changes in MRI were detected. GDNF is a factor which may impact the pathogenesis of PSP. Possible implementation of GDNF as a therapeutic factor could be a perspective in the search for therapy in this currently incurable disease.

Glucose Metabolism and Cognitive Decline in Progressive Supranuclear Palsy and Corticobasal Syndrome: A Preliminary Study.

Multiple studies have analyzed the possible correlations between diabetes and Alzheimer's disease. Less is known about the context of cognitive deterioration among patients with atypical Parkinsonian syndromes and glucose metabolism impairment. The aim of this study was to evaluate the association between the impaired glucose metabolism and cognitive decline among patients with progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). The study included 22 patients with PSP and CBS with disease durations varying from 3 to 6 years. The levels of glycated hemoglobin (HbA1C), fasting blood glucose, fasting C-peptide and the presence of microalbuminuria were evaluated, and oral glucose tolerance tests (OGTT) were performed. Based on the OGTT results, the glycemic variability, mean glycemia, glycemia standard deviation (SD) and coefficient of variation (%CV) were calculated. All patients underwent a three-Tesla brain magnetic resonance (MRI) examination and neuropsychological cognitive assessment with the use of standardized scales: Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB). A statistical analysis revealed that poor control of glycemia with high glycemic variability and increased atrophy of the medial temporal lobe among patients with PSP and CBS correlated with worse cognitive performance independent of age or sex, even among patients who did not fulfill the criteria for diabetes. The study results indicate the importance of glucose metabolism control and optimal treatment in the context of cognition maintenance among patients with PSP and CBS. Due to the relatively small number of analyzed patients, the issue requires further assessment. To the best of our knowledge, this is the first study discussing the role of glycemic variability in atypical Parkinsonian syndromes.