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Nickel-based superalloys have been widely used in the aerospace industry, and regulating the reinforcing phases is the key to improving the high-temperature strength of the alloy. In this study, a series of aging treatments (650 °C, 750 °C, 850 °C and 950 °C for 8 h) were designed to study different thermal deformation behaviors and microstructure evolutions for a novel nickel-based superalloy. Among the aged samples, the 950 °C aged sample achieved the peak stress of ~323 MPa during the thermal deformation and the highest microhardness of ~315 HV after thermal compression, which were the greatest differences compared to before deformation. In addition, the grains of the 950 °C sample exhibit deformed fibrous shapes, and the grain orientation is isotropic, while the other samples exhibited isotropy. In the 850 °C and 950 °C high-temperature aging samples, the γ' precipitate (about 20 nm in size) is gradually precipitated, which inhibits the movement of dislocation in the grain during compression, thus inhibiting the occurrence of dynamic recrystallization and improving the high-temperature mechanical properties of the alloy.
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The prolonged usage of atypical antipsychotic drugs (AAPD) among individuals with schizophrenia often leads to metabolic side effects such as dyslipidemia. These effects not only limit one's selection of AAPD but also significantly reduce compliance and quality of life of patients. Recent studies suggest that bilirubin plays a crucial role in maintaining lipid homeostasis and may be a potential pre-treatment biomarker for individuals with dyslipidemia. The present study included 644 schizophrenia patients from two centers. Demographic and clinical characteristics were collected at baseline and 4 weeks after admission to investigate the correlation between metabolites, episodes, usage of AAPDs, and occurrence of dyslipidemia. Besides, we explored the combined predictive value of genotypes and baseline bilirubin for dyslipidemia by employing multiple PCR targeted capture techniques to sequence two pathways: bilirubin metabolism-related genes and lipid metabolism-related genes. Our results indicated that there existed a negative correlation between the changes in bilirubin levels and triglyceride (TG) levels in patients with schizophrenia. Among three types of bilirubin, direct bilirubin in the baseline (DBIL-bl) proved to be the most effective in predicting dyslipidemia in the ROC analysis (AUC = 0.627, p < 0.001). Furthermore, the odds ratio from multinomial logistic regression analysis showed that UGT1A1*6 was a protective factor for dyslipidemia (ß = -12.868, p < 0.001). The combination of baseline DBIL and UGT1A1*6 significantly improved the performance in predicting dyslipidemia (AUC = 0.939, p < 0.001). Schizophrenia patients with UGT1A1*6 mutation and a certain level of baseline bilirubin may be more resistant to dyslipidemia and have more selections for AAPD than other patients.
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Background: Valproic acid (VPA) stands as one of the most frequently prescribed medications in children with newly diagnosed epilepsy. Despite its infrequent adverse effects within therapeutic range, prolonged VPA usage may result in metabolic disturbances including insulin resistance and dyslipidemia. These metabolic dysregulations in childhood are notably linked to heightened cardiovascular risk in adulthood. Therefore, identification and effective management of dyslipidemia in children hold paramount significance. Methods: In this retrospective cohort study, we explored the potential associations between physiological factors, medication situation, biochemical parameters before the first dose of VPA (baseline) and VPA-induced dyslipidemia (VID) in pediatric patients. Binary logistic regression was utilized to construct a predictive model for blood lipid disorders, aiming to identify independent pre-treatment risk factors. Additionally, The Receiver Operating Characteristic (ROC) curve was used to evaluate the performance of the model. Results: Through binary logistic regression analysis, we identified for the first time that direct bilirubin (DBIL) (odds ratios (OR) = 0.511, p = 0.01), duration of medication (OR = 0.357, p = 0.009), serum albumin (ALB) (OR = 0.913, p = 0.043), BMI (OR = 1.140, p = 0.045), and aspartate aminotransferase (AST) (OR = 1.038, p = 0.026) at baseline were independent risk factors for VID in pediatric patients with epilepsy. Notably, the predictive ability of DBIL (AUC = 0.690, p < 0.0001) surpassed that of other individual factors. Furthermore, when combined into a predictive model, incorporating all five risk factors, the predictive capacity significantly increased (AUC = 0.777, p < 0.0001), enabling the forecast of 77.7% of dyslipidemia events. Conclusion: DBIL emerges as the most potent predictor, and in conjunction with the other four factors, can effectively forecast VID in pediatric patients with epilepsy. This insight can guide the formulation of individualized strategies for the clinical administration of VPA in children.
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Continuous antipsychotic treatment is often recommended to prevent relapse in schizophrenia. However, the efficacy of antipsychotic treatment appears to diminish in patients with relapsed schizophrenia and the underlying mechanisms are still unknown. Moreover, though the findings are inconclusive, several recent studies suggest that intermittent versus continuous treatment may not significantly differ in recurrence risk and therapeutic efficacy but potentially reduce the drug dose and side effects. Notably, disturbances in fatty acid (FA) metabolism are linked to the onset/relapse of schizophrenia, and patients with multi-episode schizophrenia have been reported to have reduced FA biosynthesis. We thus utilized an MK-801-induced animal model of schizophrenia to evaluate whether two treatment strategies of clozapine would affect drug response and FA metabolism differently in the brain. Schizophrenia-related behaviors were assessed through open field test (OFT) and prepulse inhibition (PPI) test, and FA profiles of prefrontal cortex (PFC) and hippocampus were analyzed by gas chromatography-mass spectrometry. Additionally, we measured gene expression levels of enzymes involved in FA synthesis. Both intermittent and continuous clozapine treatment reversed hypermotion and deficits in PPI in mice. Continuous treatment decreased total polyunsaturated fatty acids (PUFAs), saturated fatty acids (SFAs) and FAs in the PFC, whereas the intermittent administration increased n-6 PUFAs, SFAs and FAs compared to continuous administration. Meanwhile, continuous treatment reduced the expression of Fads1 and Elovl2, while intermittent treatment significantly upregulated them. This study discloses the novel findings that there was no significant difference in clozapine efficacy between continuous and intermittent administration, but intermittent treatment showed certain protective effects on phospholipid metabolism in the PFC.
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Antipsicóticos , Clozapina , Modelos Animales de Enfermedad , Maleato de Dizocilpina , Ácidos Grasos , Esquizofrenia , Animales , Clozapina/farmacología , Clozapina/administración & dosificación , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Maleato de Dizocilpina/farmacología , Antipsicóticos/farmacología , Antipsicóticos/administración & dosificación , Ácidos Grasos/metabolismo , Masculino , Ratones , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Inhibición Prepulso/efectos de los fármacos , Ratones Endogámicos C57BL , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Prueba de Campo Abierto/efectos de los fármacosRESUMEN
Although olanzapine (OLZ) remains one of the most efficacious antipsychotic medications for the treatment of schizophrenia, there are significant tolerability issues related to its metabolic profile such as weight gain and dyslipidemia. Our previous studies have demonstrated that progesterone receptor membrane component 1 (PGRMC1) plays a key role in antipsychotic-induced metabolic side effects. Prebiotics showed positive effects on lipid metabolism, however, limited studies focused on their therapeutic potential and mechanisms in treating antipsychotic-induced lipid metabolic disorders. Herein, our study aims to explore the effects of the prebiotic B-GOS on lipid disturbances induced by OLZ and elucidate its underlying mechanisms via PGRMC1 pathway. In an 8-week study, long-term intraperitoneal administration of OLZ at a dosage of 8 mg/kg/day in mice induced lipid disturbances as manifested by significantly increased lipid indexes in plasma and liver. B-GOS effectively alleviated the OLZ-induced abnormal lipid metabolism by enhancing the diversity of the gut microbiota, with a 100-fold increase in Akkermansia abundance and a 10-fold decrease in Faecalibaculum abundance. Followed by the B-GOS related changes of gut microbiota, OLZ-induced substantial hepatic inhibition of PGRMC1, and associated protein factors of Wnt signaling pathway (Wnt3a, ß-catenin, and PPAR-γ) were reversed without affecting plasma levels of short-chain fatty acids. Taken together, prebiotics like B-GOS enriching Akkermansia offer a promising novel approach to alleviate antipsychotic-induced lipid disturbances by modulating the PGRMC1-Wnt signaling pathway.
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Antipsicóticos , Ratones , Animales , Olanzapina/efectos adversos , Antipsicóticos/toxicidad , Vía de Señalización Wnt , Akkermansia , Regulación hacia Arriba , Lípidos , Proteínas de la Membrana , Receptores de ProgesteronaRESUMEN
BACKGROUND: The increasing problem of bacterial resistance, particularly with quinolone-resistant Escherichia coli (QnR eco) poses a serious global health issue. METHODS: We collected data on QnR eco resistance rates and detection frequencies from 2014 to 2021 via the China Antimicrobial Resistance Surveillance System, complemented by meteorological and socioeconomic data from the China Statistical Yearbook and the China Meteorological Data Service Centre (CMDC). Comprehensive nonparametric testing and multivariate regression models were used in the analysis. RESULT: Our analysis revealed significant regional differences in QnR eco resistance and detection rates across China. Along the Hu Huanyong Line, resistance rates varied markedly: 49.35 in the northwest, 54.40 on the line, and 52.30 in the southeast (P = 0.001). Detection rates also showed significant geographical variation, with notable differences between regions (P < 0.001). Climate types influenced these rates, with significant variability observed across different climates (P < 0.001). Our predictive model for resistance rates, integrating climate and healthcare factors, explained 64.1% of the variance (adjusted R-squared = 0.641). For detection rates, the model accounted for 19.2% of the variance, highlighting the impact of environmental and healthcare influences. CONCLUSION: The study found higher resistance rates in warmer, monsoon climates and areas with more public health facilities, but lower rates in cooler, mountainous, or continental climates with more rainfall. This highlights the strong impact of climate on antibiotic resistance. Meanwhile, the predictive model effectively forecasts these resistance rates using China's diverse climate data. This is crucial for public health strategies and helps policymakers and healthcare practitioners tailor their approaches to antibiotic resistance based on local environmental conditions. These insights emphasize the importance of considering regional climates in managing antibiotic resistance.
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Proteínas de Escherichia coli , Quinolonas , Escherichia coli , China/epidemiología , Farmacorresistencia Bacteriana , Antibacterianos/farmacologíaRESUMEN
INTRODUCTION: Progesterone receptor component 1 (PGRMC1) has been identified as a potential target in atypical antipsychotic drug-induced metabolic disturbances as well as neuroprotection in the central nervous system. In our study, we aimed to figure out the essential role of PGRMC1 signaling pathway underlying clozapine-induced cognitive impairment. METHODS: In male SD rats, we utilized recombinant adeno-associated viruses (BBB 2.0) and the specific inhibitor of PGRMC1 (AG205) to regulate the expression of PGRMC1 in the brain, with a special focus on the hippocampus. Treatments of clozapine and AG205 were conducted for 28 days, and subsequent behavioral tests including modified elevated plus maze and Morris water maze were conducted to evaluate the cognitive performance. Hippocampal protein expressions were measured by Western blotting. RESULTS: Our study showed that long-term clozapine administration led to cognitive impairment as confirmed by behavioral tests as well as histopathological examination in the hippocampus. Clozapine inhibited neural survival through the PGRMC1/EGFR/GLP1R-PI3K-Akt signaling pathway, leading to a decrease in the downstream survival factor, brain-derived neurotrophic factor (BDNF), and simultaneously promoted neural apoptosis in the rat hippocampus. Intriguingly, by targeting at the hippocampal PGRMC1, we found that inhibiting PGRMC1 mimics, while its upregulation notably mitigates clozapine-induced cognitive impairment through PGRMC1 and its downstream signaling pathways. CONCLUSION: PGRMC1-overexpression could protect hippocampus-dependent cognitive impairment induced by clozapine. This effect appears to arise, in part, from the upregulated expression of PGRMC1/EGFR/GLP1R and the activation of downstream PI3K-Akt-BDNF and caspase-3 signaling pathways.
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Clozapina , Disfunción Cognitiva , Ratas , Masculino , Animales , Clozapina/efectos adversos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/farmacología , Ratas Sprague-Dawley , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/farmacología , Transducción de Señal , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/metabolismo , Hipocampo , Receptores ErbB/metabolismo , Receptores ErbB/farmacologíaRESUMEN
Schizophrenia (SZ), a complex and debilitating spectrum of psychiatric disorders, is now mainly attributed to multifactorial etiology that includes genetic and environmental factors. Long non-coding RNAs (lncRNAs) are gaining popularity as a way to better understand the comprehensive mechanisms beneath the clinical manifestation of SZ. Only in recent years has it been elucidated that mammalian genomes encode thousands of lncRNAs. Strikingly, roughly 30-40% of these lncRNAs are extensively expressed in different regions across the brain, which may be closely associated with SZ. The therapeutic and adverse effects of atypical antipsychotic drugs (AAPDs) are partially reflected by their role in the regulation of lncRNAs. This begs the question directly, do any lncRNAs exist as biomarkers for AAPDs treatment? Furthermore, we comprehend a range of mechanistic investigations that have revealed the regulatory roles for lncRNAs both involved in the brain and the periphery of SZ. More crucially, we also combine insights from a variety of signaling pathways to argue that lncRNAs probably play critical roles in SZ via their interactive downstream factors. This review provides a thorough understanding regarding dysregulation of lncRNAs, corresponding genetic alternations, as well as their potential regulatory roles in the pathology of SZ, which might help reveal useful therapeutic targets in SZ.
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ARN Largo no Codificante , Esquizofrenia , Animales , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Esquizofrenia/metabolismo , Biomarcadores/metabolismo , Transducción de Señal/genética , Variación Genética , Mamíferos/genética , Mamíferos/metabolismoRESUMEN
BACKGROUND: Accumulating evidence have shown that diet and nutrition play significant roles in mental illness, such as depression, anxiety and bipolar disorder. However, comprehensive evaluation of the relationship between nutrition and schizophrenia is lacking. OBJECTIVE: The present review aims to synthetic elaborate the associations between nutrition and schizophrenia. Relevant studies on dietary patterns, macronutrients, micronutrients were performed through a literature search to synthesize the extracted data. SUMMARY: Dietary interventions may help prevent the occurrence of schizophrenia, or delay symptoms: Healthy diets like nutritious plant-based foods and high-quality protein, have been linked to reducing the risk or symptoms of schizophrenia. Moreover, diet high in saturated fat and sugar is linked to more serious outcomes of schizophrenia. Additionally, when N-acetylcysteine acts as an adjuvant therapy, the overall symptoms of schizophrenia are significantly reduced. Also nascent evidence showed mental disorders may be related to intestinal microbiota dysfunction. Our study offered important insights into the dietary habits of patients with schizophrenia and the potential impact of nutritional factors on the disease. We also emphasized the need for further research, particularly in the form of large randomized double-blind controlled trials, to better understand the effects of nutrients on schizophrenia symptoms in different populations and disease types.
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Clozapine is usually considered as the last resort for treatment-resistant schizophrenia (TRS). However, it shows limited efficacy in cognition improvement. Moreover, the metabolic side effects induced by clozapine can aggravate cognitive impairment, which is closely related to its neurotoxicity. Nevertheless, the mechanisms underlying clozapine's neurotoxicity remain largely elusive. In this study, PC12 cells were simultaneously treated with different concentrations (0 µM, 10 µM, 20 µM, 40 µM and 80 µM) of clozapine and AG205 which functions as a blocking reagent of progesterone receptor membrane component 1 (PGRMC1). In addition, we examined the effect of PGRMC1 in clozapine-induced neurotoxicity through overexpressing or downregulating PGRMC1. Molecular docking and surface plasmon resonance (SPR) analysis indicated that clozapine and AG205 inhibited the binding of endogenous progesterone to PGRMC1. The results showed that high concentration of clozapine and AG205 induced a significant increase in cytotoxicity, reactive oxygen species (ROS) accumulation and mitochondrial membrane potential (MMP) collapse, all of which were worsened as concentration increases, while overexpression of PGRMC1 reverted the above toxic effect of clozapine on PC12 cells. Furthermore, clozapine and AG205 also downregulated the expression of PGRMC1, glucagon-like peptide-1 receptor (GLP-1R) and mitofusin2 (Mfn2). Interestingly, overexpression of PGRMC1 could revert these effects. Our data suggest that overexpression of PGRMC1 in PC12 cells prevents and restores clozapine-induced oxidative and mitochondrial damage. We propose PGRMC1 activation as a promising therapeutic strategy for clozapine-induced neurotoxicity to facilitate the relief of neuronal damage.
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Clozapina , Ratas , Animales , Células PC12 , Clozapina/toxicidad , Receptores de Progesterona/metabolismo , Simulación del Acoplamiento Molecular , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , MitocondriasRESUMEN
As a hydrolysis mediated drug in vivo, the pharmacokinetics of melphalan are highly variable in patients. Few methodologies could simultaneously measure the concentrations of melphalan and its hydrolyzed metabolites in plasma. The aim of this study was to develop a simple, rapid and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of melphalan and its hydrolyzed metabolites, monohydroxy melphalan (MOH melphalan) and dihydroxy melphalan (DOH melphalan). A simple protein precipitation was employed for sample preparation and melphalan-d8 was used as internal standard. Baseline separation of target analytes was achieved using an XSelect HSS T3 column (2.1 × 50 mm, 5 µm) with a gradient elution at a flow rate of 0.5 mL/min in 5 min. The monitored transitions were m/z 305.1 â 287.7 for melphalan, m/z 287.1 â 228.0 for MOH melphalan, m/z 269.3 â 251.8 for DOH melphalan, and m/z 313.1 â 295.7 for melphalan-d8. The method was fully validated in accordance with the FDA guideline. The calibration curves were established over the range of 5.22-5220 ng/mL for melphalan, 7.94-1588 ng/mL for MOH-melphalan, and 15.0-3000 ng/mL for DOH-melphalan with the regression coefficients greater than 0.99. The intra- and inter-day coefficients of variation for the analytes were ≤11.0% and all the biases were less than 8.3%. The method has been successfully applied to the quantification of melphalan and its metabolites in clinical plasma samples obtained from hematopoietic stem cell transplantation patients who received a dose of melphalan for pre-transplant conditioning.
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Melfalán , Espectrometría de Masas en Tándem , Humanos , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Hidrólisis , Reproducibilidad de los Resultados , Cromatografía Líquida de Alta Presión/métodosRESUMEN
Detrimental dietary habits with high-fat food are common in the psychiatric population, leading to higher obesity rate. Olanzapine (OLZ), as one of the mainstream antipsychotic drugs, shows superior efficacy in treating schizophrenia but limited by adverse effects such as obesity, dyslipidemia and liver injury, which are risk factors for the development of nonalcoholic fatty liver disease (NAFLD). Progesterone receptor component 1 (PGRMC1) is a key regulator associated with antipsychotic drug-induced metabolic disorders. Our study aims to investigate whether high-fat supplementation worsens OLZ-induced NAFLD and to validate the potential role of PGRMC1 pathway. In vivo, eight-week OLZ treatment successfully induced hepatic steatosis in female C57BL/6 mice fed with either a high-fat or normal diet, which is independent of body weight gain. Likewise, in vitro, OLZ markedly led to hepatocyte steatosis along with enhanced oxidative stress, which was aggravated by free fatty acids. Moreover, in vivo and in vitro, high-fat supplementation aggravated OLZ-induced hepatic lipid accumulation and oxidative stress via inhibition of hepatic PGRMC1-AMPK-mTORC1/Nrf2 pathways. Inspiringly, PGRMC1 overexpression effectively reversed OLZ-induced hepatocyte steatosis in vitro. Hence, hepatic PGRMC1 is attributable to OLZ-induced NAFLD especially with high-fat supplementation and potentially serves as a novel therapeutic target.
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Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Femenino , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Olanzapina/metabolismo , Olanzapina/uso terapéutico , Ratones Endogámicos C57BL , Hígado/metabolismo , Obesidad/metabolismo , Dieta Alta en Grasa/efectos adversos , Metabolismo de los Lípidos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismoRESUMEN
Second-generation antipsychotics (SGAs) are the mainstay of treatment for schizophrenia and other neuropsychiatric diseases but cause a high risk of disruption to lipid metabolism, which is an intractable therapeutic challenge worldwide. Although the exact mechanisms underlying this lipid disturbance are complex, an increasing body of evidence has suggested the involvement of the gut microbiota in SGA-induced lipid dysregulation since SGA treatment may alter the abundance and composition of the intestinal microflora. The subsequent effects involve the generation of different categories of signaling molecules by gut microbes such as endogenous cannabinoids, cholesterol, short-chain fatty acids (SCFAs), bile acids (BAs), and gut hormones that regulate lipid metabolism. On the one hand, these signaling molecules can directly activate the vagus nerve or be transported into the brain to influence appetite via the gut-brain axis. On the other hand, these molecules can also regulate related lipid metabolism via peripheral signaling pathways. Interestingly, therapeutic strategies directly targeting the gut microbiota and related metabolites seem to have promising efficacy in the treatment of SGA-induced lipid disturbances. Thus, this review provides a comprehensive understanding of how SGAs can induce disturbances in lipid metabolism by altering the gut microbiota.
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At present, receptor tyrosine kinase signaling-related pathways have been successfully mediated to inhibit tumor proliferation and promote anti-angiogenesis effects for cancer therapy. Tyrosine kinase inhibitors (TKIs), a group of novel chemotherapeutic agents, have been applied to treat diverse malignant tumors effectively. However, the latent toxic and side effects of TKIs, such as hepatotoxicity and cardiotoxicity, limit their use in clinical practice. Metabolic activation has the potential to lead to toxic effects. Numerous TKIs have been demonstrated to be transformed into chemically reactive/potentially toxic metabolites following cytochrome P450-catalyzed activation, which causes severe adverse reactions, including hepatotoxicity, cardiotoxicity, skin toxicity, immune injury, mitochondria injury, and cytochrome P450 inactivation. However, the precise mechanisms of how these chemically reactive/potentially toxic species induce toxicity remain poorly understood. In addition, we present our viewpoints that regulating the production of reactive metabolites may decrease the toxicity of TKIs. Exploring this topic will improve understanding of metabolic activation and its underlying mechanisms, promoting the rational use of TKIs. This review summarizes the updated evidence concerning the reactive metabolites of TKIs and the associated toxicities. This paper provides novel insight into the safe use of TKIs and the prevention and treatment of multiple TKIs adverse effects in clinical practice.
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Activación Metabólica , Humanos , Cardiotoxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Inhibidores de Proteínas Quinasas/efectos adversos , /metabolismoRESUMEN
Treatment-resistant schizophrenia (TRS) often results in severe disability and functional impairment. Currently, the diagnosis of TRS is largely exclusionary and emphasizes the improvement of symptoms that may not be detected early and treated according to TRS guideline. As the gold standard, clozapine is the most prescribed selection for TRS. Therefore, how to predict TRS in advance is critical for forming subsequent treatment strategy especially clozapine is used during the early stage of TRS. Although mounting studies have identified certain clinical factors and neuroimaging characteristics associated with treatment response in schizophrenia, the predictors for TRS remain to be explored. Biomarkers, particularly for peripheral biomarkers, show great potential in predicting TRS in view of their predictive validity, noninvasiveness, ease of testing and low cost that would enable their widespread use. Recent evidence supports that the pathogenesis of TRS may be involved in abnormal neurotransmitter systems, inflammation and stress. Due to the heterogeneity of TRS and the lack of consensus in diagnostic criteria, it is difficult to compare extensive results among different studies. Based on the reported neurobiological mechanisms that may be associated with TRS, this paper narratively reviews the updates of peripheral biomarkers of TRS, from genetic and other related perspectives. Although current evidence regarding biomarkers in TRS remains fragmentary, when taken together, it can help to better understand the neurobiological interface of clinical phenotypes and psychiatric symptoms, which will enable individualized prediction and therapy for TRS in the long run.
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Objective: Long-term use of olanzapine can induce various side effects such as lipid metabolic disorders, but the mechanism remains to be elucidated. The gut microbiota-brain axis plays an important role in lipid metabolism, and may be related to the metabolic side effects of olanzapine. Therefore, we explored the mechanism by which olanzapine-induced lipid disturbances through the gut microbiota-brain axis. Methods: Sprague Dawley rats were randomly divided into two groups, which underwent subphrenic vagotomy and sham surgery. Then the two groups were further randomly divided into two subgroups, one was administered olanzapine (10 mg/kg/day) by intragastric administration, and the other was administered normal saline by intragastric administration (4 ml/kg/day) for 2 weeks. The final changes in lipid parameters, gut microbes and their metabolites, and orexin-related neuropeptides in the hypothalamus were investigated among the different groups. Results: Olanzapine induced lipid disturbances as indicated by increased weight gain, elevated ratio of white adipose tissue to brown adipose tissue, as well as increased triglyceride and total cholesterol. Olanzapine also increased the Firmicutes/Bacteroides (F/B) ratio in the gut, which was even aggravated by subphrenic vagotomy. In addition, olanzapine reduced the abundance of short-chain fatty acids (SCFAs) metabolism related microbiome and 5-hydroxytryptamine (5-HT) levels in the rat cecum, and increased the gene and protein expression of the appetite-related neuropeptide Y/agouti-related peptide (NPY/AgRP) in the hypothalamus. Conclusion: The abnormal lipid metabolism caused by olanzapine may be closely related to the vagus nerve-mediated gut microbiota-brain axis.
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There is a paucity of biomarkers for the prediction of treatment response in schizophrenia. In this study, we aimed to investigate whether diminished antipsychotic treatment response in relapsed versus first-episode schizophrenia can be revealed and predicted by a panel of blood-based biomarkers. A cross-sectional cohort consisting of 655 schizophrenia patients at different episodes and 606 healthy controls, and a longitudinal cohort including 52 first-episode antipsychotic-naïve schizophrenia patients treated with the same antipsychotic drugs during the 5-year follow-up of their first three episodes were enrolled. Plasma biomarker changes and symptom improvement were compared between the drug-free phase of psychosis onset and after 4 weeks of atypical antipsychotic drug (AAPD) treatment. In response to treatment, the extent of changes in the biomarkers of bioenergetic, purinergic, phospholipid and neurosteroid metabolisms dwindled down as number of episode and illness duration increased in relapsed schizophrenia. The changes of creatine, inosine, progesterone, allopregnanolone, cortisol and PE(16:0/22:6) were significantly correlated with the improvement of symptomatology. Inosine and progesterone at baseline were shown to be strong predictive biomarkers of treatment response. The results suggest that AAPD treatment response is diminished in the context of relapse, and our findings open new avenues for understanding the pathophysiology of treatment-resistance schizophrenia.
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Antipsicóticos , Esquizofrenia , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Biomarcadores , Estudios Transversales , Humanos , Inosina/uso terapéutico , Estudios Longitudinales , Progesterona , Esquizofrenia/diagnósticoRESUMEN
A ultraperformance liquid chromatography-tandem mass spectrometry method has been developed to determine dihydrocodeine (DHC) and dihydromorphine (DHM) in human plasma using dihydrocodeine-d6 and desomorphine as internal standards (IS). Acetonitrile-water-ammonium format was used as the mobile phase, in gradient elution on a C18 column. The concentration of DHC and DHM was determined in the positive ionization mode of mass spectrometry. The total chromatogram run time was 3.2 min, and the linear ranges of DHC and DHM were 1.000-400.0 ng/mL and 0.050-20.00 ng/mL, respectively. The method was fully validated concerning precision, accuracy, selectivity, linearity, recovery, stability and matrix effect. The method had been successfully applied to the bioequivalence test. In addition, we found that a high-fat diet impacts the Tmax and t1/2 of DHC.