Xenobiotica最新文献

Liver ischemia-reperfusion injury (IRI) is a common complication during liver transplantation and surgery, characterised by oxidative stress, inflammation, and apoptosis, which contribute to hepatocyte damage and impaired liver function. Safflower, known for its antioxidant and anti-inflammatory properties, has not been fully explored for its potential to alleviate liver IRI.This study aims to investigate the effects of safflower components on oxidative stress and cell apoptosis in liver IRI. A microfluidic liver cell ischemia-reperfusion model was employed to screen safflower components for their protective effects against oxidative stress and apoptosis. The effects of HSYA and other compounds were assessed by measuring cell viability, ROS levels, apoptosis, DNA damage (8-oxo-dG), lipid peroxidation (MDA), and inflammatory cytokine production (TNF-α, IL-1β, IL-6). HSYA exhibited superior protective effects, significantly reducing ROS, apoptosis, DNA damage, and lipid peroxidation. It also decreased pro-inflammatory cytokine levels, underscoring its antioxidant and anti-inflammatory properties.These findings suggest that HSYA effectively mitigates oxidative stress, inflammation, and apoptosis in liver IRI, positioning it as a promising candidate for therapeutic liver protection.

The aim of this study was to observe the sensitivity of the resistant strains to gemcitabine by interfering with the LCN2.An AsPC-1 gemcitabine-resistant cell line (GEM-R) was generated. Based on GEM-R, a lentivirus-infected shRNA-transfected LCN2 cell line was established. The proliferation of LCN2-regulated GEM-R cells was evaluated using the CCK-8 test and the mRNA expression of Ki-67. The apoptosis level of each drug-resistant strain was detected by flow cytometry. The expression of Bax, Bcl-2, Akt, E-cadherin and Vimentin were detected by western blotting.A gemcitabine-resistant strain of AsPC-1 was successfully induced and constructed as an shRNA LCN2 strain based on GEM-R. The interference of LCN2 expression enhanced the tumour inhibition and pro-apoptotic level of gemcitabine, increased the Bax/Bcl-2 value, and decreased p-Akt/Akt value. Meanwhile, the expression of E-cadherin was enhanced while the expression of Vimentin was decreased.This study confirmed that LCN2 affects gemcitabine sensitivity by participating in apoptosis and EMT processes, which may provide potential for overcoming gemcitabine resistance.

With the increasing prevalence and escalating complexity of mental disorders, precise medication has become critically important. This necessitates an efficient, accurate, and convenient method for drug concentration monitoring to support laboratory personnel and clinicians. In this study, three liquid chromatography-tandem mass spectrometry methods were developed and validated for simultaneously determining and quantifying 27 antipsychotics and related metabolites in human plasma. The plasma samples were subjected to protein precipitation using methanol, with isotope-labelled internal standards (ISs), followed by separation via isocratic elution on a BEH C18 column. Mass spectrometric analysis was performed using electrospray ionisation in positive ionisation mode with multiple reaction monitoring for quantitative detection. The analytes demonstrated high separation efficiency, with a single sample run time of 3.0 min. The method exhibited a wide linear range with excellent linearity across the concentration range. The intra- and inter-batch precision were ≤10.00%, the accuracy was 88.67-113.29%. Accurate quantification of antipsychotics remained unaffected under various storage conditions: 72 h at room temperature, 7 d at 4 °C refrigeration, and 14 d at -80 °C freezing. This validated methodology has been successfully applied to plasma samples from patients with psychiatric disorders, demonstrating its practical utility for accurate quantification of antipsychotics in large-scale and complex matrices containing multiple analytes.

The research aims to develop and validate a stability-indicating reverse phase high-performance liquid chromatography (RP-HPLC) method for Lurasidone hydrochloride, an antipsychotic drug derived from benzisothiazole derivatives.A Binary Gradient HPLC System with a PDA detector, C18 column (4.6 x 100 mm, 2.5 mm), and a Shimadzu 8040 series triple quadrupole mass analyzer with an electron spray ionizer was used for the LC-MS/MS analysis.The method was linear in the concentration range of 10-50 μg/mL with a correlation coefficient (r²) of 0.999. The limit of detection (LOD) and limit of quantification (LOQ) were 0.091 μg/mL and 0.275 μg/mL, respectively. Validation included accuracy, percentage recovery, robustness, system suitability, and interday and intraday precision. Forced degradation studies were conducted in acid, alkali, oxidative, neutral, and photolytic conditions after 1, 2, and 6 hours, and in oxidative conditions for 24 hours. Degraded products were evaluated on LC-MS (100 m/z to 550 m/z). Lurasidone was more susceptible to alkali hydrolysis, with fragmentation peaks at 109, 166, 220, and 317 m/z. and possible fragmentation pattern was also evaluated.This method is used for routine quality control analysis as a stability-indicating method of Lurasidone hydrochloride in pharmaceuticals, and the LC-MS data is used for evaluating stability and identifying drug intermediates.

Rapamycin has been shown to be effective in the treatment of a variety of neurological disorders, including epilepsy. Intranasal drug administration is a novel mode of drug delivery that bypasses the blood-brain barrier and numerous biological effects thereby entering the central nervous system directly. Thus, the objective of this study was to investigate the brain entrance efficacy of rapamycin following intranasal administration of rapamycin.First, we found that acute high-dose administration with a total dose of 0.326 mg of rapamycin in a novel dosage form produced few side effects on body weight, various organs, and nasal mucosa in rats. Then, we examined the distribution of drug concentrations in the brain, nasal mucosa, and blood using the above dosage form administered intranasally to rats at 0.04 mg/kg. We found that intranasal administration was significantly more efficacious than oral administration for rapamycin brain delivery. We also discovered gender differences in drug absorption following intranasal administration of rapamycin, wherein rapamycin exhibited faster systemic absorption in female rats compared to males. Our study demonstrated that intranasal administration of rapamycin is highly effective and low toxic, which may provide a new delivery option for rapamycin therapy in brain diseases.

The Nrf2 signalling pathway is crucial for cellular defense against oxidative stress and xenobiotic toxicity, highlighting its importance in both human health and environmental responses.This review focuses on the dual role of Drosophila melanogaster in Nrf2 research: we utilised the PubMed database to collect and summarised research articles on fruit fly Nrf2 studies published in the past decade, using keywords such as 'Nrf2', 'CncC', and 'Drosophila'.We found that Drosophila melanogaster, as a classical model organism for studying human diseases such as neurodegenerative disorders, cancers, and diabetes, and as an insect model for investigating xenobiotic responses and pesticide resistance, is particularly well-suited for exploring the diverse and complex functions of Nrf2 pathway.Additionally, Natural products such as curcumin and quercetin can modulate Nrf2 activity for cytoprotection. Utilising D. melanogaster's genetic tools and short life cycles, researchers can discover new therapeutics and study their mechanisms.This twofold exploration not only advances our understanding of Nrf2 in human health but also provides insights into pest control strategies through enhanced insect resistance mechanisms. Continued research in this area is essential for developing innovative treatments and effective pest management approaches.

The goal of current investigation was to develop eugenol-fortified fisetin nano-invasomes. Fisetin-loaded invasomes were prepared using thin film hydration procedure and evaluated for various parameters. Additionally, the optimised fisetin invasomes formulation (F5) was converted to fisetin invasomes gel using Carbopol^® as gelling agent and evaluated for pH, spreadability, homogeneity, drug content, in vitro fisetin release, antioxidant activity and stability study.Prepared optimised fisetin invasomes formulation (F5) demonstrated vesicles size, PDI, zeta potential and entrapment efficiency of 153.85 ± 14.32 nm, 0.208 ± 0.042, -12.67 ± 1.08 mV and 72.10 ± 6.36%. The TEM image indicated that the prepared invasomes vesicles are intact, spherical and found in the range of nanosized scale. Prepared fisetin invasomes gel showed better spreadability and in vitro fisetin released in contrast to fisetin control gel. Substantial improvement in the DPPH radical scavenging activity of fisetin invasomes gel 44.70% (3.1 µM) and 83.94% (50 µM), was noted as compared to the control gel at 39.47% (3.1 µM) and 79.10% at (50 µM). The prepared fisetin invasomes gel formulation was found stable at 4 °C.Based on the results, prepared invasomes gel formulation was found as a viable method for better delivery of bioactive compound(s) including fisetin.

Yes-associated protein (YAP) is a core effector molecule in the Hippo signalling pathway, but its role in antituberculosis drug-induced liver injury (ADLI) is unclear. We aimed to explore the regulatory effects of YAP on the NLRP3 inflammasome in ADLI and its potential hepatoprotective effects.An ADLI animal model was established. Various indicators of experimental animals were detected at 0, 7, 14, and 21 days. On day 7, HE staining observed liver tissue, and liver index, ALT, and AST levels confirmed the ADLI model. YAP's mRNA and protein levels were examined, YAP inhibitor effects were observed, and NLRP3 inflammasome, inflammation, and oxidative stress indicators were analysed.It was found that the mRNA and protein levels of YAP increased during ADLI and then decreased due to the action of YAP inhibitors. YAP caused an elevation in NLRP3 inflammasome indicators, as well as increased expression of inflammation and oxidative stress. After feeding with YAP inhibitors, these indicators were reduced.The results suggest that targeting YAP may be a novel therapeutic strategy for alleviating antituberculosis drug-induced liver injury.

17ɑ-methyl-19-nortestosterone (MNT), a steroid prohibited in sport, has been marketed since the 1990s, however their use is increasingly, mainly because it is contained in nutritional supplements. The study of the metabolism of the prohibited substances for athletes allows to identify new metabolites that could increase the veracity of the results. This work studied preliminary the in-vivo metabolism of MNT.The study was conducted after a single oral administration dose using the simple quadrupole mass spectrometry coupled to gas chromatography and considering the steroids classic metabolic reactions.Nine MNT metabolites were detected in urine. Mass spectra and fragmentation patterns were proposed for each metabolite. In addition to MNT, the detection of four metabolites corroborated what is described in the specialised literature. However, to our knowledge, four other metabolites have not been explicitly described. According to the time-course, three metabolites were still detected at 96-, 84- and 72-hours port-administration. These detection windows can increase by using other instrumentations such as a triple quadrupole mass spectrometer with multiple reaction monitoring acquisition mode.

Phthalates, widely utilised as plasticisers to enhance the flexibility of rigid materials like polyvinyl chloride, are known for their endocrine-disrupting properties and cytotoxic effects.This study investigated the impact of Diisononyl phthalate (DINP) and Diethyl-hexyl terephthalate (DEHT) on human endothelial cells (EA.hy926).The assessment focused on cell viability, reactive oxygen species (ROS) production, and the antioxidant-responsive genes expression (NFE2L2, SOD1, TXN, and TXNRD2) following exposure to varying 1, 10, and 100 µg/mL of DINP or DEHT.Cell viability was determined using MTT and lactate dehydrogenase (LDH) release assays. ROS were measured using the DCFDA assay.Gene expression analysis was conducted via qRT-PCR after 48 h of exposure. Results revealed that DINP 100 µg/mL significantly reduced cell viability at 11 and 17% at 48 and 72 h, respectively, whereas increased LDH release by 69% at 48 h. ROS levels also rose by 19-30%, accompanied by down-regulation of NFE2L2, TXN, and TXNRD2.Conversely, DEHT had no adverse effect on cell viability or LDH levels but elevated ROS production (11-14%) and induced up-regulation of antioxidant genes, including SOD1.The findings indicate that DINP exposure could negatively affect the cellular antioxidant response, whereas DEHT leads to up-regulation of antioxidant genes without detrimental effects on viability.