For the occurrence of PPCPs from source to tap: A novel approach modified in terms of sample preservation and SPE cartridge to monitor PPCPs in our water supply.

BACKGROUND: The ongoing infusion of pharmaceutical and personal care products (PPCPs) into ecosystems sustains a perpetual life cycle and leads to multi-generational exposures. Limited understanding of their environmental impact and their intrinsic ability to induce physiological effect in humans, even at low doses, pose great risks to human health. Few scholarly works have conducted systematic research into the occurrence of PPCPs within potable water systems. Concurrently, the associated monitoring techniques have not been comprehensively examined with regards to the specific nature of drinking water, namely whether the significant presence of disinfectants may influence the detection of PPCPs. RESULTS: A modified approach in terms of detailed investigation of sample preservation and optimization of an in-lab fabricated solid phase extraction (SPE) cartridge filled with DVB-VP and PS-DVB sorbent was proposed. Favorable methodological parameters were achieved, with correlation coefficients spanning from 0.9866 to 0.9998. The LODs of the PPCPs fluctuated from 0.001 to 2 µg L-1, while the LOQs varied from 0.002 to 5 µg L-1. The analysis of spiked samples disclosed a methodological precision of 2.31-9.86 % and a recovery of 52.4-119 %. We utilized the established method for analyzing 14 water samples of three categories (source water, finished water and tap water) from five centralized water supply plants. A total of 24 categories encompassing 72 PPCPs were detected, with the concentrations of PPCPs manifested a marked decrease from source water to finished water and finally to tap water. SIGNIFICANCE: Our research meticulously examined the enhancement and purification effects of widely used commercial SPE cartridges and suggested the use of in-lab fabricated SPE cartridges packed with DVB-VP and PS-DVB adsorbents. We also conducted a systematic evaluation of the need to incorporate ascorbic acid and sodium thiosulfate as preservatives for PPCP measurement, in consideration of the unique characteristics of drinking water matrices, specifically, the significant concentration levels of disinfectants. Furthermore, the proposed method was effectively employed to study the presence of PPCPs in source water, finished water, and tap water collected from centralized water supply plants.

Chitooligosaccharide reconstitutes intestinal mucus layer to improve oral absorption of water-soluble drugs.

Intestinal mucus is a complex natural hydrogel barrier with unique physical properties that impede the absorption of various oral drugs. Both washout from the upper water layer and the physical resistance of the mucus layer particularly affect bioavailability of, especially, highly water-soluble molecules. One potential strategy for designing pharmaceutical formulations is to add absorption enhancers (AEs). However, there are few reports of AEs that work on mucus and their underlying mechanisms, leading to imprecise application. In this study, we investigated chitooligosaccharide (COS) as a safe, low-cost, and effective oral drug AE. We revealed the hydrodynamic law of interaction between COS and the intestinal mucus layer, which was associated with absorption benefiting mucus structural reconstruction. Based on this, we designed a translational strategy to improve the bioavailability of a group of soluble oral drugs by drinking COS solution before administration. Moreover, this research is expected to expand its application scenario by reducing drug dosage such as avoiding gastro-intestinal irritation and slowing veterinary antibiotic resistance.

[Determination of five amanita peptide toxins in poisonous mushrooms by ultra performance liquid chromatography-quadrupole electrostatic field orbitrap high resolution mass spectrometry].

Food poisoning by toxic mushrooms occurs frequently worldwide. It is one of the most common food poisoning events and the main cause of death. Amanita peptide toxins are the most common lethal toxins in poisonous mushrooms. Presently, a novel method based on ultra performance liquid chromatography-quadrupole electrostatic field orbitrap high resolution mass spectrometry (UPLC-Q/Orbitrap HRMS) was developed for the determination of five amanitapeptide toxins (α-amanitin, ß-amanitin, γ-amanitin, phalloidin, and phallacidin). Because the isotope summit of α-amanitin affects the detection of ß-amanitin, it cannot be distinguished by low resolution mass spectrometry. Therefore, experimental conditions including chromatography and mass spectrometry were explored in detail. The five peptide toxins were extracted from poisonous mushrooms with pure water and filtered through a 0.22 µm teflon microporous membrane. The procedure was rapid, simple, and environmentally friendly. Chromatographic separation was performed on a strong polarity HSS T3 column (100 mm×2.0 mm, 2.1 µm) with gradient elution using acetonitrile and 5 mmol/L ammonium acetate containing 0.1% (v/v) formic acid as mobile phases at a flow rate of 0.3 mL/min. The column temperature was set to 40 ℃. The analytes were ionized using a heating electrospray ionization source and collected in positive ion mode. Full scanning/data-dependent secondary mass spectrometry (Full mass-ddMS2) mode was used for qualitative analysis of the targets within 10 min. The target ion selective scan (Targeted-SIM) mode was used for quantification by external standard calibration. The measured and theoretical values of the exact mass and the MS2 fragment ions of the five compounds were within an error of 5×10-6. Method validation was performed according to the criteria recommended by the Chinese National Standard. All the compounds showed an excellent linear relationship in the range of 1.0-20.0 µg/L. The correlation coefficients (r) ranged from 0.9974 to 0.9989. The limit of detection was 0.006 mg/kg for all five compounds. Recoveries ranged from 81.8% to 102.4%. There was no matrix effect in the blank mushroom sample for the five compounds, and the relative standard deviations ranged from 3.2% to 8.3%. This method provides abundant compound characteristic mass information, such as retention time, exact mass, fragment ions, and other information. The data can be used to identify suspected compounds based on the extracted ion flow diagram and isotope distribution information. Comparison between the actual exact mass and the theoretical exact mass, combined with the fragment ions enables identification of the structures of unknown compounds and collision methods, which can be confirmed in the absence of standard materials. In this study, the isomer of γ-amanitin was identified as amaninamide. The novel method is simple, accurate, specific, and sensitive. The method permits the rapid qualitative and quantitative detection of compound in public health emergency settings and will provide reliable technical support for the rapid screening of such toxic compounds and the structural locking of unknown toxins in the future.

Time Rules the Efficacy of Immune Checkpoint Inhibitors in Photodynamic Therapy.

Lack of adequate effector T cells infiltrated in tumor is one of the main problems in the failure of immune checkpoint blockade therapy (ICBT). Photodynamic therapy (PDT) induced acute inflammation can sensitize tumors and activate T cells, thus assisting immune checkpoint inhibitors (ICI) against tumor growth and metastasis. T cells maturation and activation lag 3 to 7 days behind PDT. However, such timing in the combination therapy of ICI and PDT is commonly ignored in designing numerous multi-functional integrated nanomedicines. Herein, the authors illustrate that intervention timing of ICI after PDT affects the anti-tumor efficacy. A tumor-targeting nanomedicine is prepared by encapsulating indocyanine green into CD44 specifically binding material, a hyaluronic acid conjugated lipid poly(ethylene glycol). The PDT nanomedicine is designed to induce a robust immune response in tumor. The optimal group (Combo-STAR), ICI gave 5 days after PDT, significantly suppresses local tumor growth and eliminates metastasis. What should be highlighted is the time point of administration because if ICI is given too early, T cells are immature, otherwise, T cells are exhausted if ICI is given too late. This work presents theoretical guidance for raising awareness of intervention timing when augmenting ICBT with immune response inducers in clinic.

Altered expression levels of miR-144-3p and ATP1B2 are associated with schizophrenia.

Objectives: Schizophrenia is a devastating mental disease. Various microRNAs were proven to be associated with schizophrenia. Altered microRNA-144-3p (miR-144-3p) levels were found in various neurological and psychotic disorders. Beta2-subunit of Na(+)/K(+)-ATPase (ATP1B2) regulates neuronal migration and cell growth during brain development through the PI3K/Akt/mTOR pathway. The present study explored the associations of miR-144-3p and ATP1B2 with schizophrenia and their mutual interaction.Methods: A schizophrenic animal model employing repeated MK-801 administration was established and 293 T cells over-expressing miR-144-3p were constructed by lentivirus. The in vitro and in vivo levels of miR-144-3p, ATP1B2, and the PI3K/Akt/mTOR pathway were examined by qRT-PCR and Western Blots. The interaction between miR-144-3p and ATP1B2 was predicted and assessed by using bioinformatic methods and a luciferase reporter gene assay, respectively.Results: MiR-144-3p expression was elevated in the schizophrenic rat hippocampus. ATP1B2 was down-regulated in schizophrenic patients by analysing GEO datasets. Additionally, miR-144-3p can directly bind with ATP1B2. Furthermore, the ATP1B2 expression and PI3K/Akt/mTOR phosphorylation levels were down-regulated in the 293 T cells over-expressing miR-144-3p and schizophrenic rat hippocampus, which could be reversed by risperidone.Conclusions: This study revealed that up-regulated miR-144-3p might be associated with schizophrenia through down-regulating ATP1B2, implicating new targets of schizophrenia treatment.