Unraveling olanzapine toxicity in planarian: Multi-omics reveals mechanisms of behavioral and regenerative deficits.

The aim of the present study was to predict olanzapine (OLZ) exposure in individual patients using physiologically based pharmacokinetic modelling and simulation (PBPK M&S). A 'bottom-up' PBPK model for OLZ was constructed in Simcyp® (V14.1) and validated against pharmacokinetic studies and data from therapeutic drug monitoring (TDM). The physiological, demographic and genetic attributes of the 'healthy volunteer population' file in Simcyp® were then individualized to create 'virtual twins' of 14 patients. The predicted systemic exposure of OLZ in virtual twins was compared with measured concentration in corresponding patients. Predicted exposures were used to calculate a hypothetical decrease in exposure variability after OLZ dose adjustment. The pharmacokinetic parameters of OLZ from single-dose studies were accurately predicted in healthy Caucasians [mean-fold errors (MFEs) ranged from 0.68 to 1.14], healthy Chinese (MFEs 0.82 to 1.18) and geriatric Caucasians (MFEs 0.55 to 1.30). Cumulative frequency plots of trough OLZ concentration were comparable between the virtual population and patients in a TDM database. After creating virtual twins in Simcyp®, the R2 values for predicted vs. observed trough OLZ concentrations were 0.833 for the full cohort of 14 patients and 0.884 for the 7 patients who had additional cytochrome P450 2C8 genotyping. The variability in OLZ exposure following hypothetical dose adjustment guided by PBPK M&S was twofold lower compared with a fixed-dose regimen - coefficient of variation values were 0.18 and 0.37, respectively. Olanzapine exposure in individual patients was predicted using PBPK M&S. Repurposing of available PBPK M&S platforms is an option for model-informed precision dosing and requires further study to examine clinical potential.

The antipsychotic drug olanzapine altered lipid metabolism in the common carp (Cyprinus carpio L.): Insight from the gut microbiota-SCFAs-liver axis

Polyhalogenated carbazoles (PHCZs) are emerging environmental contaminants in aquatic ecosystems. Despite their reported endocrine-disrupting potential, the adverse effects of PHCZs on aquatic organisms and their underlying mechanisms remain poorly understood. In this study, we employed 2,7-dibromocarbazole (2,7-DBCZ) as a representative PHCZ to evaluate its detrimental effects on zebrafish and reveal the underlying mechanisms. Exposure to 2,7-DBCZ led to inhibited locomotor activity in zebrafish larvae. Mechanistically, 2,7-DBCZ significantly elevated embryonic estrogen (E2) and triiodothyronine (T3) levels, disrupting the normal transcription of E2-related genes. Moreover, 2,7-DBCZ disrupted energy expenditure homeostasis by affecting energy metabolism-related metabolites, particularly carbohydrates (glucose 1-phosphate and fructose 6-phosphate) and amino acids (glutamine and serine). These findings suggest that the suppression of locomotor behavior in zebrafish larvae induced by 2,7-DBCZ could be attributed to its endocrine-disrupting potential, which triggers disturbances in energy metabolism. The data provide a comprehensive understanding of the ecological risks posed by PHCZs, supporting regulatory decisions regarding these emerging contaminants.

The increasing prevalence of pharmaceutical contaminants in aquatic ecosystems poses profound challenges for both environmental sustainability and public health. Addressing this pressing issue requires the development of innovative, cost-effective, and efficient remediation approaches. Here we report the synthesis of WO3/diatomite composites and their photocatalytic degradation in conjunction with potassium peroxymonosulfate (PMS) activation. By leveraging the synergistic effects, we observe a remarkable degradation of tetracycline, a significant pharmaceutical contaminant, under visible light. Analytically, we have elucidated the driving factors for the enhanced performance, emphasizing the optimal amount of WO3 (10%) in the composite and PMS concentration (3 mM). Specifically, the WO3/diatomite catalyst presents a degradation rate of 80.75% tetracycline (40 mg L-1) after 180 min of visible light irradiation. Also, we elucidate the primary roles of ˙SO4 - radicals in driving the photocatalytic reaction using free radical trapping studies. Our approach not only offers a direct solution to controlling pharmaceutical contamination but also opens new possibilities for advancing the design of composite-based photocatalysts by taking advantage of nature-derived materials.

Açaí (Euterpe oleracea Mart), a Brazilian fruit, is considered a "superfruit" due its energetic properties and bioactive compounds. The açai's anti-inflammatory effects could attenuate the undesirable metabolic and pro-inflammatory side effects triggered by some antipsychotic drugs, such as Olanzapine (OLZ). It is possible to infer that açai supplement could potentially minimize the adverse effects of OLZ. Aim. This study tested the potential in vitro effects of açai hydroalcoholic extract on the inflammatory activation of the RAW 264.7 macrophage line triggered by OLZ antipsychotic drugs. An in vitro protocol was performed using commercial RAW 264.7 macrophages, cultured under sterile conditions at 37°C with 5% CO2 saturation. Initially, a pharmacological curve was defined to determine the concentration of Olanzapine to be used. After this, the cells were supplemented with different concentrations of hydroalcoholic extract of açaí, which had been previously chemically characterized. After 24 and 72 hours of treatment, oxidative and inflammatory tests were performed. Therefore, the aim of this study was to verify whether the hydroalcoholic extract of açaí can modulate the oxy-inflammatory response of olanzapine in vitro. From a preliminary analysis, the açai extract at 5 mg/mL presented higher activity against inflammation triggered by OLZ (0.03 μg/mL). At this concentration, açai was able to reduce several oxidative and inflammatory markers triggered by OLZ (0.03 μg/mL) exposure, such as nitric oxide (NO), reactive oxygen species (ROS), and pro-inflammatory cytokine levels (IL-1b, IL-6, TNF-a, IFN-g) caused by OLZ (0.03 μg/mL). Moreover, açaí reverted the levels of anti-inflammatory cytokine IL-10 that had been dropped by OLZ exposure to their pre-exposure treatments. The results suggest that açai extract could be useful in attenuating the peripheral inflammatory states triggered by OLZ. Additional pre-clinical and clinical investigations could be useful in testing therapeutic açai extract supplements.

Aquatic ecosystems around the world are contaminated with a wide range of anthropogenic chemicals, including metals and organic pollutants, that originate from point and nonpoint sources. Many of these chemical contaminants have complex environmental cycles, are persistent and bioavailable, can be incorporated into aquatic food webs, and pose a threat to the health of wildlife and humans. Identifying appropriate sentinels that reflect bioavailability is critical to assessing and managing aquatic ecosystems impacted by contaminants. The objective of the present study is to review research on riparian spiders as sentinels of persistent and bioavailable chemical contaminants in aquatic ecosystems. Our review of the literature on riparian spiders as sentinels suggests that significant progress has been made during the last two decades of research. We identified 55 published studies conducted around the world in which riparian spiders (primarily of the families Tetragnathidae, Araneidae, Lycosidae, and Pisauridae) were used as sentinels of chemical contamination of lotic, lentic, and estuarine systems. For several contaminants, such as polychlorinated biphenyls (PCBs), Hg, and Se, it is now clear that riparian spiders are appropriate sentinels. However, many contaminants and factors that could impact chemical concentrations in riparian spiders have not been well characterized. Further study of riparian spiders and their potential role as sentinels is critical because it would allow for development of national-scale programs that utilize riparian spiders as sentinels to monitor chemical contaminants in aquatic ecosystems. A riparian spider sentinel program in the United States would be complementary to existing national sentinel programs, including those for fish and immature dragonflies. Environ Toxicol Chem 2022;41:499-514. © 2021 SETAC.

Olanzapine (OLZ), a second‐generation antipsychotic drug, is effective in the treatment of acute psychosis, schizophrenia, agitation, bipolar mania, and other psychiatric problems. Antipsychotics are prescribed drugs, which lead the drug abuser to illegal methods of access. This behavior also demonstrates the association of OLZ with criminal involvement, commonly observed at forensic crime scenes. The acute toxicity and even death resulting from OLZ exposure have been highlighted in numerous studies. Therefore, developing analytical techniques to detect OLZ is essential for forensic toxicology. This study aimed to develop a specific and reliable LC–MS/MS method for OLZ detection and quantification in hair samples. The method was validated in terms of selectivity, linearity, limit of detection (LOD), limit of quantification (LOQ), trueness, precision, and uncertainty. The range of linearity was between 0.1–100 ng/mg, with LOD and LOQ values established at 0.036 ng/mg and 0.1 ng/mg, respectively. All validation results are within acceptable parameters. The validated method has been applied to authentic hair samples. The variation of OLZ concentrations in 12 hair segments (2 from Case 1 and 10 from Case 2) from two drug‐positive patients, ranging from 0.131 to 0.460 ng/mg, is presented in this study. Although several studies have been conducted to determine OLZ in hair samples using segmental analysis via hair solubilization, this study is the first to determine OLZ in hair samples after “digestion” with comparative parameters prior to chromatographic analysis.

Regulation of obesity-associated metabolic disturbance by the antipsychotic drug olanzapine: Role of the autophagy-lysosome pathway

In psychiatric patients, haloperidol (HAL) induces a number of adverse extrapyramidal and cognitive symptoms, which appear to be less problematic with olanzapine (OLZ). In animals, HAL may initiate a number of harmful effects on central nervous system neurons, including damage to cholinergic pathways - an effect that could be especially deleterious to those experiencing memory dysfunction. The identification of the neurobiological substrates of such effects in animal models may help to improve the algorithms used for proper drug selection especially for long-term neuroleptic use. The aim of this study was to compare the effects of chronic (45-day and 90-day), continuous oral exposure to HAL with OLZ for effects on cognitive performance and cholinergic markers in rats. After chronic neuroleptic exposure (and a 4-day washout) spatial memory performance was measured in a water maze task, and choline acetyltransferase (ChAT) immunoreactivity was assessed with immunofluorescence staining. In water maze experiments, HAL and OLZ (relative to vehicle) administered for 90 days (but not 45 days) significantly impaired learning performance (i.e., higher mean latencies across several trials to reach a hidden platform). HAL administered for 90 days was associated with impairment across a greater number of trials than OLZ and it also impaired probe trial performance, as indicated by a reduced number of crossings over the previous platform area (when compared with OLZ or vehicle). Both 45 days and 90 days of HAL treatment reduced ChAT staining in the cortex and hippocampus when compared with OLZ or vehicle. The results in the rat suggest that OLZ (relative to HAL) may be more desirable as an antipsychotic for patients suffering from memory dysfunction especially for those in which cholinergic deficits may already be present.

Olanzapine exposure disordered lipid metabolism, gut microbiota and behavior in zebrafish (Danio rerio).

Olanzapine (OLZ), an effective treatment of schizophrenia and other disorders, causes weight gain and metabolic syndrome. Most studies to date have focused on the potential effects of OLZ on the central nervous system's mediation of weight; however, peripheral changes in liver or other key metabolic organs may also play a role in the systemic effects of OLZ. Thus, the purpose of this study was to investigate the effects of OLZ on hepatic metabolism in a mouse model of OLZ exposure. Female C57Bl/6J mice were administered OLZ (8 mg/kg per day) or vehicle subcutaneously by osmotic minipumps for 28 days. Liver and plasma were taken at sacrifice for biochemical analyses and for comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry metabolomics analysis. OLZ increased body weight, fat pad mass, and liver-to-body weight ratio without commensurate increase in food consumption, indicating that OLZ altered energy expenditure. Expression and biochemical analyses indicated that OLZ induced anaerobic glycolysis and caused a pseudo-fasted state, which depleted hepatic glycogen reserves. OLZ caused similar effects in cultured HepG2 cells, as determined by Seahorse analysis. Metabolomic analysis indicated that OLZ increased hepatic concentrations of amino acids that can alter metabolism via the mTOR pathway; indeed, hepatic mTOR signaling was robustly increased by OLZ. Interestingly, OLZ concomitantly activated AMP-activated protein kinase (AMPK) signaling. Taken together, these data suggest that disturbances in glucose and lipid metabolism caused by OLZ in liver may be mediated, at least in part, via simultaneous activation of both catabolic (AMPK) and anabolic (mammalian target of rapamycin) pathways, which yields new insight into the metabolic side effects of this drug.

Mechanistic insights into the effects of Fluoxetine in Mytilus galloprovincialis using in vivo and in vitro approaches.

Design of TiO2/Ag3BiO3 n-n heterojunction for enhanced degradation of tetracycline hydrochloride under visible-light irradiation

Exclusive enteral nutrition (EEN) is a first-line therapeutic approach for inducing remission in Crohn's disease. However, the underlying mechanisms of its action remain poorly understood. This study aims to investigate the effects of EEN on the gut microbiome and metabolome of CD patients and to elucidate the mechanisms responsible for EEN-induced remission. Fecal and blood samples were collected from treatment-naïve CD patients (n = 25) both before and after 8 weeks of EEN therapy, as well as from healthy control subjects (n = 25). The composition of the gut microbiome was analyzed through 16S rRNA gene sequencing, while metabolomic profiling was conducted using liquid chromatography-mass spectrometry (LC-MS). Functional analysis of microbial pathways was performed utilizing the KEGG Orthology (KO) and MetaCyc databases. EEN therapy induced significant structural shifts in the gut microbiome, including a reduction in the abundance of pro-inflammatory bacteria such as Fusobacterium and Veillonella. Metabolomic profiling revealed stage-specific metabolic reprogramming, with notable alterations in phenazine biosynthesis, indole diterpene alkaloid biosynthesis, and sphingolipid metabolism. Functional analyses indicated the activation of energy metabolism pathways and the suppression of pro-inflammatory metabolic pathways. Importantly, EEN therapy was associated with a reduction in oxidative stress and an improvement in gut barrier function. This study comprehensively integrates microbiome and metabolome analyses, providing new insights into the mechanism of action of EEN therapy in CD. EEN exerts therapeutic effects by restoring metabolic balance and enhancing the integrity of the intestinal barrier, which may be achieved by reducing pro-inflammatory bacteria and activating antioxidant and energy metabolism pathways.

Chapter 2 - Transport, fate, and toxicity of the emerging and nanomaterial contaminants in aquatic ecosystems: Removal by natural processes