Identification of New Hepatic Metabolites of Miconazole by Biological and Electrochemical Methods Using Ultra-High-Performance Liquid Chromatography Combined with High-Resolution Mass Spectrometry.

The main objective of this study was to investigate the metabolism of miconazole, an azole antifungal drug. Miconazole was subjected to incubation with human liver microsomes (HLM) to mimic phase I metabolism reactions for the first time. Employing a combination of an HLM assay and UHPLC-HRMS analysis enabled the identification of seven metabolites of miconazole, undescribed so far. Throughout the incubation with HLM, miconazole underwent biotransformation reactions including hydroxylation of the benzene ring and oxidation of the imidazole moiety, along with its subsequent degradation. Additionally, based on the obtained results, screen-printed electrodes (SPEs) were optimized to simulate the same biotransformation reactions, by the use of a simple, fast, and cheap electrochemical method. The potential toxicity of the identified metabolites was assessed using various in silico models.

Antifungal drugs in the aquatic environment: A review on sources, occurrence, toxicity, health effects, removal strategies and future challenges.

Fungal infections pose a significant global health burden, resulting in millions of severe cases and deaths annually. The escalating demand for effective antifungal treatments has led to a rise in the wholesale distribution of antifungal drugs, which consequently has led to their release into the environment, posing a threat to ecosystems and human health. This article aims to provide a comprehensive review of the presence and distribution of antifungal drugs in the environment, evaluate their potential ecological and health risks, and assess current methods for their removal. Reviewed studies from 2010 to 2023 period have revealed the widespread occurrence of 19 various antifungals in natural waters and other matrices at alarmingly high concentrations. Due to the inefficiency of conventional water treatment in removing these compounds, advanced oxidation processes, membrane filtration, and adsorption techniques have been developed as promising decontamination methods.In conclusion, this review emphasizes the urgent need for a comprehensive understanding of the presence, fate, and removal of antifungal drugs in the environment. By addressing the current knowledge gaps and exploring future prospects, this study contributes to the development of strategies for mitigating the environmental impact of antifungal drugs and protecting ecosystems and human health.

Analysis of the Efficacy of Diet and Short-Term Probiotic Intervention on Depressive Symptoms in Patients after Bariatric Surgery: A Randomized Double-Blind Placebo Controlled Pilot Study.

(1) Background: studies have shown that some patients experience mental deterioration after bariatric surgery. (2) Methods: We examined whether the use of probiotics and improved eating habits can improve the mental health of people who suffered from mood disorders after bariatric surgery. We also analyzed patients' mental states, eating habits and microbiota. (3) Results: Depressive symptoms were observed in 45% of 200 bariatric patients. After 5 weeks, we noted an improvement in patients' mental functioning (reduction in BDI and HRSD), but it was not related to the probiotic used. The consumption of vegetables and whole grain cereals increased (DQI-I adequacy), the consumption of simple sugars and SFA decreased (moderation DQI-I), and the consumption of monounsaturated fatty acids increased it. In the feces of patients after RYGB, there was a significantly higher abundance of two members of the Muribaculaceae family, namely Veillonella and Roseburia, while those after SG had more Christensenellaceae R-7 group, Subdoligranulum, Oscillibacter, and UCG-005. (4) Conclusions: the noted differences in the composition of the gut microbiota (RYGB vs. SG) may be one of the determinants of the proper functioning of the gut-brain microbiota axis, although there is currently a need for further research into this topic using a larger group of patients and different probiotic doses.

Electrochemical Simulation of Phase I Hepatic Metabolism of Voriconazole Using a Screen-Printed Iron(II) Phthalocyanine Electrode.

Understanding the metabolism of pharmaceutical compounds is a fundamental prerequisite for ensuring their safety and efficacy in clinical use. However, conventional methods for monitoring drug metabolism often come with the drawbacks of being time-consuming and costly. In an ongoing quest for innovative approaches, the application of electrochemistry in metabolism studies has gained prominence as a promising approach for the synthesis and analysis of drug transformation products. In this study, we investigated the hepatic metabolism of voriconazole, an antifungal medication, by utilizing human liver microsomes (HLM) assay coupled with LC-MS. Based on the obtained results, the electrochemical parameters were optimized to simulate the biotransformation reactions. Among the various electrodes tested, the chemometric analysis revealed that the iron(II) phthalocyanine electrode was the most effective in catalyzing the formation of all hepatic voriconazole metabolites. These findings exemplify the potential of phthalocyanine electrodes as an efficient and cost-effective tool for simulating the intricate metabolic processes involved in drug biotransformation, offering new possibilities in the field of pharmaceutical research. Additionally, in silico analysis showed that two detected metabolites may exhibit significantly higher acute toxicity and mutagenic potential than the parent compound.

Multivariate Chemometric Comparison of Forced Degradation and Electrochemical Oxidation LC-MS Profiles of Maraviroc.

In this study, nine forced degradation products of maraviroc were found using chemometric analysis. This antiretroviral drug was subjected to photolytic, oxidative, as well as neutral, basic and acidic hydrolysis stress conditions. Additionally, its electrochemical transformation on platinum, gold and glassy carbon screen-printed electrodes was examined. This study showed that maraviroc is especially susceptible to UVA, H2O2 and electrochemical degradation, while being resistant to neutral and acidic hydrolysis. A cluster analysis showed that the electrochemical transformation, with particular reference to the platinum electrode, is able to partially simulate the forced degradation processes, especially in the context of redox reactions. These findings indicate that the electrochemical methods can be considered as quick and relatively low-cost supplements to the commonly applied forced degradation procedures.

Association between Fecal Microbiota, SCFA, Gut Integrity Markers and Depressive Symptoms in Patients Treated in the Past with Bariatric Surgery-The Cross-Sectional Study.

(1) Background: Depressive symptoms often appear after surgical treatment. (2) Methods: We involved 41 adults who underwent bariatric surgery a minimum of 6 months before the study and had the Beck scale ≥12. We analysed patients' mental state, gut barrier markers, faecal short chain fatty acids, and microbiota. (3) Results: Gut microbiota composition differed significantly among patients undergoing two different types of surgery (F = 1.64, p = 0.00002). Additionally, we discovered an association between short chain fatty acids and the Beck scale (F = 1.22, p = 0.058). The rearrangement of bacterial metabolites may be due to the patients' use of increased dietary protein, with insufficient intake of products containing vegetable fiber (Diet Quality Index (DQI-I )adequacy 22.55 (±3.46) points). (4) Conclusions: Bariatric surgery affects the gut microbiota, which may play an important role in the development of depressive and gastrointestinal symptoms in patients after bariatric surgery. Low fiber consumption and increased levels of faecal isobutyric acid may lead to intestinal inflammation. There is a need for further research on this topic including a larger sample size.

Deficit Symptomatology of Schizophrenia Is Associated with Attenuated Taste Identification: Findings from a Cross-Sectional Study.

Schizophrenia is the subject of many studies. There have been reports of taste disturbances in mental disorders. We found a possible relationship between deficit symptoms of schizophrenia and the dysgeusia of monosodium glutamate (MSG). Dysgeusia is a disorder that distorts the sense of taste. People describe all foods as tasting sweet, sour, bitter, or metallic. We aimed to verify whether the level of MSG taste perception may be related to the severity of deficit symptoms. MSG detection threshold was assessed via sublingual administration of three fluid samples containing MSG or water. The MSG samples had different concentrations in each sample. The task was to indicate which of the samples contained MSG, determine the intensity of the taste, and assess the taste as pleasant, unpleasant, or neutral. The study group included 200 patients diagnosed with paranoid schizophrenia according to ICD-10. We found a significant negative correlation between mean intensity of taste and the number of deficit symptoms. The symptoms of taste disturbances reported by the patient should be monitored by clinicians and differentiated between the actual deficits in the field of taste perception and the taste hallucinations as a symptom of psychosis. It is important to continue research in this area.

Efficient removal of anti-HIV drug - maraviroc from natural water by peroxymonosulfate and TiO2 photocatalytic oxidation: Kinetic studies and identification of transformation products.

In this study photochemical transformation of the antiretroviral pharmaceutical maraviroc under the simulated UV-Vis radiation was presented. The drug was shown to be extremely photo-resistant, with a half-life over 250 h, which is particularly significant, considering its presence in the aquatic environments. Addition of the natural river water matrix substantially increased the degradation rate, albeit the process led to formation of numerous phototransformation products. Due to high photostability and presumable environmental persistence of maraviroc, a photocatalytic method of its elimination was proposed. Although titanium dioxide alone presented acceptable results, its combination with peroxymonosulfate enormously accelerated the degradation process, increasing it over 67 000 times in comparison with the direct photolysis. Substitution of ultrapure water with river water resulted in inhibition of the PMS-driven processes, however the decomposition efficiency was still very high. Noteworthy, majority of the identified photoproducts were still present after termination of irradiation in all the experiments, which may indicate necessity of ecotoxicological assessment of those compounds.

NanoForms: an integrated server for processing, analysis and assembly of raw sequencing data of microbial genomes, from Oxford Nanopore technology.

Background: Next Generation Sequencing (NGS) techniques dominate today's landscape of genetics and genomics research. Though Illumina still dominates worldwide sequencing, Oxford Nanopore is one of the leading technologies currently being used by biologists, medics and geneticists across various applications. Oxford Nanopore is automated and relatively simple for conducting experiments, but generates gigabytes of raw data, to be processed by often ambiguous set of alternative bioinformatics command-line tools, and genomics frameworks which require a knowledge of bioinformatics to run. Results: We established an inter-collegiate collaboration across experimentalists and bioinformaticians in order to provide a novel bioinformatics tool, free for academics. This tool allows people without extensive bioinformatics knowledge to simply process their raw genome sequencing data. Currently, due to ICT resources' maintenance reasons, our server is only capable of handling small genomes (up to 15 Mb). In this paper, we introduce our tool, NanoForms: an intuitive and integrated web server for the processing and analysis of raw prokaryotic genome data, coming from Oxford Nanopore. NanoForms is freely available for academics at the following locations: http://nanoforms.tech (webserver) and https://github.com/czmilanna/nanoforms (GitHub source repository).

Identification of the New Metabolite of Nebivolol Using Liquid Chromatography Coupled with High-Resolution Mass Spectrometry and Chemometrics.

In this study, the phase I hepatic metabolism pathway of a cardiovascular drug nebivolol was proposed on the basis of a human liver microsomes assay with the use of LC-HR-MS coupled with the chemometric method. Six biotransformation products were found with the assistance of chemometric analysis. Five of them were identified as the previously reported products of alicyclic hydroxylation and dihydroxylation, aromatic hydroxylation, as well as alicyclic oxidation of the parent compound. Moreover, one metabolite, not reported so far, was found to be a product of N-dealkylation of nebivolol-2-amino-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)ethan-1-ol. The novel metabolite was submitted to an in silico toxicity analysis to assess its biological properties. The applied computational methods indicated a significantly elevated risk of its mutagenic activity, compared to the parent molecule. Several metabolites of the nebivolol described in the literature were not detected in this study, indicating their non-hepatic origin.

Multimodal longitudinal respiratory function assessment in very low birth weight 7-year-old children.

PURPOSE: Preterm birth is associated with adverse pulmonary outcomes. We aimed to evaluate respiratory morbidities and lung function of very low birth weight (VLBW) Polish children followed up at the age of 7 years old, and to compare with electrical impedance segmentography (EIS) results recorded at 4 years of age. MATERIALS AND METHODS: VLBW children were compared with term controls using impulse oscillometry and spirometry. Perinatal data and current respiratory morbidities were analyzed and pulmonary function test results were compared with previous EIS results. RESULTS: We included 40 VLBW children and 30 controls in the analysis. Elevated total airway resistance and forced expiratory volume in the first second below the lower limit of normal were more prevalent in VLBW children compared with term controls (15 vs 0%; 18 vs 0%). A positive bronchodilator response was more common in VLBW children (R5 Hz: 46 vs 13.3%; R5-20 â€‹Hz: 65 vs 36.7%). Children with bronchopulmonary dysplasia (BPD) had higher total airway resistance (R5 Hz/R5 Hz pred: 1.35 vs 0.95; p â€‹< â€‹0.001), large airway resistance (R20 Hz/R20 Hz pred: 0.89 vs 0.66; p â€‹= â€‹0.001), small airway resistance (R5-20 â€‹Hz: 0.57 vs 0.34 â€‹kPa â€‹L-1 â€‹s-1; p â€‹= â€‹0.009), than controls. Strong correlation between BDR in EIS and R5 Hz/R5 Hz pred was observed in children with BPD (r â€‹= â€‹0.7). CONCLUSION: VLBW school-aged children with BPD presented with substantial respiratory morbidity and persistent reduction of lung function, affecting small and large airways and lung parenchyma. EIS may be an alternative tool for lung function assessment in children with BPD.

Analysis of gut microbiota and intestinal integrity markers of inpatients with major depressive disorder.

Previous studies have reported on the relationship between gut microbiota and major depressive disorder (MDD). However, there remain gaps in literature concerning the role of the intestinal barrier and microflora in the pathogenesis of depression. This study analyzes the potential causative relationship between gut microbiota and inflammatory and gut integrity markers and clinical symptoms in inpatients with depressive episodes. Sixteen inpatients (50% females) being treated with escitalopram (5-20 mg daily) in standardized conditions were included in the study. The composition of fecal microbiota was evaluated at baseline and endpoint using 16S rRNA sequencing. A significant correlation between depression severity was found, as measured with HDRS24 (Hamilton Depression Rating Scale-24 item), and the following abundance in bacteria: positive correlation with Paraprevotella (r = 0.80, q = 0.012), strong, negative correlations with Clostridiales (r = -0.70, q = 0.016), Clostridia (r = -0.71, q = 0.026), Firmicutes (r = -0.67. q = 0.032), and the RF32 order (r = -0.70, p = 0.016) in the Alphaproteobacteria (r = -0.66, q = 0.031). After six weeks of treatment, clinical outcomes were found to have a negative correlation with levels of plasma intestinal fatty acid-binding protein (IFABP) at the beginning of the study. Still they had a positive correlation with changes in fecal calprotectin during hospitalization. In conclusion, gut microbiota was associated with the severity of depressive symptoms. However, these findings do not serve as predictors of symptomatic improvement during antidepressant treatment in inpatient treatment for MDD. In turn, intestinal integrity and inflammation markers were associated with the response to treatment of patients with MDD and symptom severity. Additional studies are needed to confirm and extend these findings.

Depressive Disorders and Sleeping Disturbances-Surveys Study of 923 Participants on the Pol'and'Rock Festival, Kostrzyn, Poland 2019.

Depressive disorders are common among young people and can decrease social competences and thus the quality of life. There is a relationship between the occurrence of depressive disorders and insomnia. The aim of the study was to determine the prevalence of insomnia and depressive behavior and assess the relationship between these among participants of the Pol'and'Rock Festival, Kostrzyn, Poland 2019. The study used the Athens Insomnia Scale (AIS) and the Beck Inventory II Scale (BDI-II). The study group consisted of 923 people, with the majority of women (n = 500; 54.2%). A total of 297 persons (32.2%) reported varying severity of depressive symptoms. Insomnia was observed in 261 (28.28%) respondents. Sleeping disturbances were observed more frequently in females. Persons with insomnia had a significantly higher BDI-II score. A strong positive correlation (r = 0.65) between the number of points obtained on the Beck and AIS scales was observed. Insomnia and depressive behavior are prevalent in the Polish population. Due to long-term social and economic consequences, special attention should be paid to the prevention, early detection and treatment of both disorders.

Association between DRD2 and ANKK1 polymorphisms with the deficit syndrome in schizophrenia.

BACKGROUND: The clinical course of schizophrenia varies among patients and is difficult to predict. Some patient populations present persistent negative symptoms, referred to as the deficit syndrome. Compared to relatives of non-deficit schizophrenia patients, family members of this patient population are at an increased risk of developing schizophrenia. Therefore, the aim of this study was to search for genetic underpinnings of the deficit syndrome in schizophrenia. METHODS: Three SNPs, i.e., rs1799732 and rs6276 located within DRD2, and rs1800497 within ANKK1, were identified in the DNA samples of 198 schizophrenia probands, including 103 patients with deficit (DS) and 95 patients with non-deficit schizophrenia (NDS). Results: No significant differences concerning any of the analyzed polymorphisms were found between DS and NDS patients. However, significant links were observed between family history of schizophrenia and the deficit syndrome, G/G genotype and rs6276 G allele. In a separate analysis, we identified significant differences in frequencies of rs6276 G allele between DS and NDS patients with family history of schizophrenia. No significant associations were found between DRD2 and ANKK1 SNPs and the age of onset or schizophrenia symptom severity. CONCLUSIONS: The results of our preliminary study fail to provide evidence of associations between DRD2 and ANKK1 polymorphisms with the deficit syndrome or schizophrenia symptom severity, but suggest potential links between rs6276 in DRD2 and the deficit syndrome in patients with hereditary susceptibility to schizophrenia. However, further studies are necessary to confirm this observation.

Analysis of Gut Microbiota and Their Metabolic Potential in Patients with Schizophrenia Treated with Olanzapine: Results from a Six-Week Observational Prospective Cohort Study.

Accumulating evidence indicates the potential effect of microbiota on the pathogenesis and course of schizophrenia. However, the effects of olanzapine, second-generation antipsychotics, on gut microbiota have not been investigated in humans. This study aimed to analyze fecal microbiota in schizophrenia patients treated with olanzapine during six weeks of their hospital stay. After a seven-day washout from all psychotropic medications, microbiota compositions were evaluated at baseline and after six weeks of hospitalization using 16S rRNA sequencing. The study was conducted in 20 inpatients, who followed the same hospital routine and received 5-20 mg daily doses of olanzapine. Olanzapine treatment was associated with clinical improvements in all patients and significant increases in body mass index in females, but not changes in gut microbiota compositions and predicted function. The severity of symptoms at the beginning of treatment varied in accordance with the predicted metabolic activity of the bacteria. The present findings indicate that the microbiota of schizophrenia patients is highly individual and has different taxonomical (Type 1, with a predominance of Prevotella, and Type 2 with a higher abundance of Bacteroides, Blautia and Clostridium) and functional clusters, and it does not change following six weeks of olanzapine therapy; in addition, the microbiota is not associated with either the weight gain observed in women or the effectiveness of olanzapine therapy.

Fecal Microbiota Analysis in Patients Going through a Depressive Episode during Treatment in a Psychiatric Hospital Setting.

RATIONALE: There is a worldwide prevalence of generalized anxiety and major depressive disorders (MDD). Gut⁻brain axis dysfunction, antibacterial activity, and modulatory effects of antidepressants toward intestinal bacteria have been shown both in vitro and in vivo. OBJECTIVES: In this study, we aimed to investigate the effects of hospital stay, including escitalopram administration, on gut microbiota in patients with depressive episodes. METHODS: After admission to the hospital and 7-days washout from all medications the composition of fecal microbiota samples was evaluated at baseline (W0) and after 6 weeks (W6), using 16S rRNA sequencing. The study was conducted on 17 inpatients (52.9% females), who followed the same daily hospital routine, including a standard diet and received 5⁻20 mg daily doses of escitalopram. RESULTS: At the end of treatment (W6), no change was observed in the Chao1 index. However, Shannon (median (Q1⁻Q3): W0 2.78 (2.67⁻3.02) vs. W6 3.11 (2.80⁻3.30)), and inverse Simpson (median (Q1⁻Q3): W0 9.26 (7.26⁻13.76) vs. W6 12.13 (9.17⁻15.73)) indices increased significantly compared to baseline values (False Discovery Rate p (q) = 0.031 and q = 0.011, respectively). We also found that between-subject W0 Bray⁻Curtis dissimilarities were significantly higher than W0⁻W6 within-subject dissimilarities (median (Q1⁻Q3): 0.68 (0.56⁻0.77) vs. 0.38 (0.35⁻0.52), two sided Mann⁻Whitney test p < 0.00001. The within-subject dissimilarities did not depend on sex, age, BMI, illness duration and a daily dose of escitalopram. No significant differences between taxa levels, at the studied time points, were observed when adjusted for multiple hypotheses testing procedures. CONCLUSIONS: We conclude that a six-week treatment in a psychiatric hospital setting resulted in increased alpha biodiversity in fecal microbiota, however its causal relationship with patients' mental health was not proved. We have also found that individual microbiome stability was not affected by hospitalization.

Coping styles and symptomatic manifestation of first-episode psychosis: Focus on cognitive performance.

Cognitive deficits are widely observed in patients with psychosis and represent one of most important determinants of functional outcomes. It has been shown that patients with psychosis prefer maladaptive coping strategies over active coping styles. However, it remains unknown whether cognitive impairments are related to coping styles in psychotic disorders. Therefore, the aim of this study was to assess whether cognitive deficits observed in patients with first-episode psychosis (FEP) might impact the use of specific coping strategies. We recruited 40 FEP patients and 35 healthy controls. In our study, FEP patients were more likely to use maladaptive coping styles after adjustment for education level and medication effects. The use of maladaptive coping strategies was associated with greater impairments of visuospatial/constructional abilities and language skills in FEP patients. In addition, lower odds of using adaptive coping were related to higher levels of depressive symptoms in the group of patients. Adaptive coping was associated with better global cognitive performance in healthy controls. Our results indicate that cognitive impairments, especially worse performance of visuospatial/constructional abilities and language skills, might be related to the preference of maladaptive coping strategies. Lower odds of using adaptive coping styles might be associated with more severe depressive symptomatology.

Assessment of the Association Between Cigarette Smoking and Cognitive Performance in Patients With Schizophrenia-Spectrum Disorders: A Case-Control Study.

The prevalence of cigarette smoking is significantly higher in patients with schizophrenia compared to the general population. Schizophrenia is also characterized by cognitive impairments that can be detected in the premorbid phase of illness. However, studies addressing the association between cigarette smoking and cognition in patients with psychosis have provided mixed findings. Therefore, the aim of this study was to assess the relationship between tobacco smoking and cognitive performance in patients with schizophrenia. In this case-control study, we recruited 67 inpatients with schizophrenia (34 cigarette smokers) and 62 healthy controls (30 cigarette smokers) at two clinical sites (Wroclaw and Szczecin, Poland). Cognitive performance was examined using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Smoking dependence was determined using the Fagerström Test for Nicotine Dependence (FTND) and the pack-year index. Results show that, after adjustment for potential confounders, smokers with schizophrenia presented significantly lower scores on delayed memory tests compared to non-smokers with schizophrenia (F = 11.07, p = 0.002). In healthy controls, after adjustment for age, sex, and education level, smokers had significantly lower scores in immediate memory (47.1 ± 6.4 vs. 52.0 ± 4.0, F = 11.64, p = 0.001), visuospatial/constructional functions (34.8 ± 3.8 vs. 37.7 ± 1.8, F = 12.86, p = 0.001) and global cognition (177.0 ± 15.7 vs. 191.2 ± 14.0, F = 12.63, p = 0.001) compared to non-smokers. There were no significant correlations between FTND scores or pack-year index and cognitive performance neither in patient nor control group. Our results show that cigarette smoking is related to worse delayed memory performance in schizophrenia patients as well as deficits of immediate memory, visuospatial/constructional functions, and global cognition in controls. Longitudinal studies are required to establish causal interference between smoking and cognition in patients with schizophrenia.

Decreased use of active coping styles contributes to elevated allostatic load index in first-episode psychosis.

Accumulating evidence indicates that stress plays an important role in the development of psychotic disorders. Recent studies have revealed that patients with first-episode psychosis (FEP) present systemic biological dysregulations related to stress-exposure in terms of elevated allostatic load (AL) index. However, the mechanisms underlying this observation remain unknown. Therefore, in this study we aimed to investigate the AL index with respect to stress coping strategies in 36 FEP patients and 31 matched controls. We found significantly higher AL index in FEP patients compared to controls after co-varying for potential confounding factors. Patients with FEP were less likely to use active and task-focused coping. Lower odds of using these coping styles, planning as well as positive reinterpretation and growth were related to higher AL index in FEP patients, but not in controls. Depressive symptoms were associated with lower likelihood of using task-focused coping as well as positive reinterpretation and growth. Additionally, depressive symptoms were related to higher AL index. Finally, depressive symptoms mediated the effects of task-focused coping as well as positive reinterpretation and growth on the AL index. Our results confirm systemic biological dysregulation indexed as AL in FEP patients. Lower odds of using active coping styles might contribute to higher AL index via the mediating effect of depressive symptoms in patients with FEP. Longitudinal studies are required to establish causal inferences between coping styles, depressive symptoms and the AL index in early psychosis.