3D printing of interferon γ-preconditioned NSC-derived exosomes/collagen/chitosan biological scaffolds for neurological recovery after TBI.

The reconstruction of neural function and recovery of chronic damage following traumatic brain injury (TBI) remain significant clinical challenges. Exosomes derived from neural stem cells (NSCs) offer various benefits in TBI treatment. Numerous studies confirmed that appropriate preconditioning methods enhanced the targeted efficacy of exosome therapy. Interferon-gamma (IFN-γ) possesses immunomodulatory capabilities and is widely involved in neurological disorders. In this study, IFN-γ was employed for preconditioning NSCs to enhance the efficacy of exosome (IFN-Exo, IE) for TBI. miRNA sequencing revealed the potential of IFN-Exo in promoting neural differentiation and modulating inflammatory responses. Through low-temperature 3D printing, IFN-Exo was combined with collagen/chitosan (3D-CC-IE) to preserve the biological activity of the exosome. The delivery of exosomes via biomaterial scaffolds benefited the retention and therapeutic potential of exosomes, ensuring that they could exert long-term effects at the injury site. The 3D-CC-IE scaffold exhibited excellent biocompatibility and mechanical properties. Subsequently, 3D-CC-IE scaffold significantly improved impaired motor and cognitive functions after TBI in rat. Histological results showed that 3D-CC-IE scaffold markedly facilitated the reconstruction of damaged neural tissue and promoted endogenous neurogenesis. Further mechanistic validation suggested that IFN-Exo alleviated neuroinflammation by modulating the MAPK/mTOR signaling pathway. In summary, the results of this study indicated that 3D-CC-IE scaffold engaged in long-term pathophysiological processes, fostering neural function recovery after TBI, offering a promising regenerative therapy avenue.

Ziprasidone population pharmacokinetics and co-medication effects in Chinese patients.

Ziprasidone is widely used in the treatment of psychiatric disorders. Despite its prevalence, there is a notable lack of population pharmacokinetics (PPK) studies on ziprasidone in serum, both domestically and internationally. This study aimed to comprehensively investigate the various factors influencing the PPK characteristics of Ziprasidone, thereby providing a scientific basis for personalized treatment strategies in clinical settings. This is a retrospective study. A non-linear mixed-effects modeling method was used for data analysis, with the ziprasidone PPK model established using the Phoenix NLME 8.1 software. Model evaluation employed goodness-of-fit plots, visual predictive checks, and Bootstrap methods to ensure reliability and accuracy. To further validate the model's applicability, data from an additional 30 patients meeting the same inclusion criteria but not included in the final model were collected for external validation. Simulations were performed to explore the personalized dosage regimens. This retrospective analysis collected 547 drug concentration data points from 185 psychiatric disorder patients, along with related medical records. The data included detailed demographic information (such as age, gender, weight), dosing regimens, laboratory test results, and concomitant medication details. In the final model, Ka was fixed at 0.5 h-1 based on literature, and the population typical values for ziprasidone clearance (CL) and volume of distribution (V) were 18.74 L/h and 110.24 L, respectively. Co-administration of lorazepam and valproic acid significantly influenced the clearance of ziprasidone. Moreover, the model evaluation indicated good stability and predictive accuracy. A simple to use dosage regimen table was derived based on the results of simulations. This study successfully established and validated a PPK model for ziprasidone in Chinese patients with psychiatric disorders. The model provides a scientific reference for individualized dosing of ziprasidone and holds the potential to optimize treatment strategies, thereby enhancing therapeutic efficacy and safety.

Low-intensity ultrasound ameliorates brain organoid integration and rescues microcephaly deficits.

Human brain organoids represent a remarkable platform for modeling neurological disorders and a promising brain repair approach. However, the effects of physical stimulation on their development and integration remain unclear. Here, we report that low-intensity ultrasound significantly increases neural progenitor cell proliferation and neuronal maturation in cortical organoids. Histological assays and single-cell gene expression analyses reveal that low-intensity ultrasound improves the neural development in cortical organoids. Following organoid grafts transplantation into the injured somatosensory cortices of adult mice, longitudinal electrophysiological recordings and histological assays reveal that ultrasound-treated organoid grafts undergo advanced maturation. They also exhibit enhanced pain-related gamma-band activity and more disseminated projections into the host brain than the untreated groups. Finally, low-intensity ultrasound ameliorates neuropathological deficits in a microcephaly brain organoid model. Hence, low-intensity ultrasound stimulation advances the development and integration of brain organoids, providing a strategy for treating neurodevelopmental disorders and repairing cortical damage.

[Source Apportionment of Ambient VOCs in Qingdao Based on Photochemical Loss Correction].

Ozone was one of the major pollutants affecting the environmental air quality in China. The accurate apportionment of key sources and their contributions of ambient ozone and its precursor VOCs played an important role in the effective prevention and control of ozone pollution. Therefore, this study utilized the photochemical-age-based parameterization method to estimate the initial concentrations of ambient VOCs data collected from January 1 to February 28, 2021 in Jiaozhou, Qingdao and corrected the photochemical losses of ambient VOC species. The positive matrix factorization(PMF) and ozone formation potential(OFP) models were used to conduct source apportionment of ambient VOCs and their OFPs so as to provide data support for the prevention and control of ozone pollution in Qingdao. The results showed that the average values of ambient ρ(TVOCs) and OFP in Qingdao during the study period were 65.9 µg·m-3 and 176.7 µg·m-3, respectively. Propane had the highest concentration(12.4 µg·m-3) and percentage(18.9%), whereas m/p-xylene had the highest OFP(24.6 µg·m-3) and percentage(13.9%). The mean initial concentration of TVOCs during the study was 153.1 µg·m-3, and its photochemical loss rate reached 63.8%. Alkenes were the VOC species with the highest photochemical loss rate(92.1%), and the photochemical loss rate of isoprene reached 98.6%, which was substantially higher than that of other VOC species. According to the source apportionment results of initial concentrations(IC-PMF), liquefied petroleum gas(24.2%), solvent use(17.8%), natural gas and petrochemical-related enterprises(16.6%), gasoline volatilization(13.2%), combustion and gasoline vehicle emissions(12.2%), biogenic emissions(8.6%), and diesel vehicle emissions(7.4%) were the main contributing sources of the ambient VOCs in Jiaozhou. Compared with the apportioned results of IC-PMF, the contribution of biogenic emissions was underestimated by 38.9% in the apportioned results based on observed concentrations(OC-PMF), and the contribution of natural gas and petrochemical-related enterprises was underestimated by 28.5%, and the underestimations of their contributions were substantially higher than those of other sources. Compared with that before the Spring Festival, the contribution of gasoline volatilization to ambient VOCs increased markedly during the Spring Festival, whereas the contributions of solvent use, combustion, and gasoline vehicle emissions to ambient VOCs increased most significantly after the Spring Festival. The main contributing sources of ambient ozone during the study period were solvent use(31.3%), natural gas and petrochemical-related enterprises(16.1%), biogenic emissions(14.5%), and combustion and gasoline vehicle emissions(13.2%). The primary contributors of ambient ozone in different Spring Festival periods showed substantial differences. Before the Spring Festival, solvent use had the highest contribution(71.1 µg·m-3), and gasoline volatilization was the highest contributor during the Spring Festival(34.4 µg·m-3), whereas biogenic emissions after the Spring Festival were the highest contributor(39.1 µg·m-3).

Which can Predict the Outcome of Antidepressants: Metabolic Genes or Pharmacodynamic Genes?

Drug therapy is the primary modality for depression; however, its outcome is often unpredictable, ranging from beneficial effects to serious adverse effects. Genetic variations in drug metabolizing enzymes and pharmacodynamic molecules are responsible for a considerable proportion of interindividual differences in the effectiveness and toxicity of antidepressants. For the improvement in the use of antidepressants, the focus is mainly on personalized treatment emphasizing interindividual differences in genes. This study provides a comprehensive review of the literature on the clinical applications of pharmacogenomics for antidepressant therapy. The polymorphisms of metabolizing enzymes (CYP2D6, CYP2C19, and others) governing the pharmacokinetic behavior of drugs are potential predictors of side effects or treatment failure with medications and there are good pharmacogenetic clinical recommendations for a wide selection of psychopharmacological agents based on functional diplotypes of CYP2C19 and CYP2D6. The relationship between pharmacodynamic genes, including FKBP5, SLC6A4, BDNF, ABCB1, HTR1A, and HTR2A, and clinical outcomes varies in different races. Receptors that are currently used as drug targets for antidepressant drugs are evolutionarily conserved to a higher extent than genes encoding drug metabolism, and the actionability of pharmacodynamic-related genotyping is currently still questionable. The limited availability of largescale, long-term clinical studies on different races and medications currently impedes the implementation of pharmacogenomics in antidepressant treatment. The use of pharmacokinetic and pharmacodynamic modeling, and therapeutic drug monitoring combined with genetic, somatic, dietary, and environmental factors represents a promising avenue for improving the precision and effectiveness of antidepressant therapy.

[Chemical Characteristics and Source Apportionment for VOCs During the Ozone Pollution Episodes and Non-ozone Pollution Periods in Qingdao].

The ambient concentration of ozone is high in Qingdao, and ozone pollution episodes occur frequently in summer. The refined source apportionment of ambient volatile organic compounds (VOCs) and their ozone formation potential (OFP) during ozone pollution episodes and non-ozone pollution periods can play an important role in effectively reducing air ozone pollution in coastal cities and continuously improving ambient air quality. Therefore, this study applied the online VOCs monitoring data with hourly resolution in summer (from June to August) in 2020 in Qingdao to analyze the chemical characteristics of ambient VOCs during the ozone pollution episodes and non-ozone pollution periods and conducted the refined source apportionment of ambient VOCs and their OFP using a positive matrix factorization (PMF) model. The results showed that the average mass concentration of ambient VOCs in Qingdao in summer was 93.8 µg·m-3, and compared with that during the non-ozone pollution period, the mass concentration of ambient VOCs during the ozone pollution episodes increased by 49.3%, and the mass concentration of aromatic hydrocarbons increased by 59.7%. The total OFP of ambient VOCs in summer was 246.3 µg·m-3. Compared with that in the non-ozone pollution period, the total OFP of ambient VOCs in the ozone pollution episodes increased by 43.1%; that of alkanes increased the most, reaching 58.8%. M-ethyltoluene and 2,3-dimethylpentane were the species with the largest increase in OFP and its proportion during the ozone pollution episodes. The main contributors of ambient VOCs in Qingdao in summer were diesel vehicles (11.2%), solvent use (4.7%), liquefied petroleum gas and natural gas (LPG/NG) (27.5%), gasoline vehicles (8.9%), gasoline volatilization (26.6%), emissions of combustion- and petrochemical-related enterprises (16.4%), and plant emissions (4.8%). Compared with that in the non-ozone pollution period, the contribution concentration of LPG/NG in the ozone pollution episodes increased by 16.4 µg·m-3, which was the source category with the largest increase. The contribution concentration of plant emissions increased by 88.6% in the ozone pollution episodes, which was the source category with the highest increase rate. In addition, emissions from combustion- and petrochemical-related enterprises were the largest contributor to the OFP of ambient VOCs in summer in Qingdao, with its OFP and contribution proportion being 38.0 µg·m-3and 24.5%, respectively, followed by that of LPG/NG and gasoline volatilization. Compared with the non-ozone pollution period, the total contributions of LPG/NG, gasoline volatilization, and solvent use to the increase in OFP for ambient VOCs in the ozone pollution episodes were 74.1%, which were the main contribution source categories.

Isolation and identification of high-yielding alkaline phosphatase strain: a novel mutagenesis technique and optimization of fermentation conditions.

Isolating and screening enzyme-producing strains from microorganisms and the commercial production of ALPs from microorganisms are of increasing interest. In this work, isolation and identification of high-yielding alkaline phosphatase strain were carried out using atmospheric and room temperature plasma mutagenesis (ARTP) for optimization of fermentation conditions. A strain of alkaline phosphatase-producing bacteria was screened from soil and identified by 16S rRNA gene sequencing as Bacillus amyloliquefaciens and named S-1. This strain had an alkaline phosphatase activity of 2594.73 U/L. Later, mutagenesis breeding of the alkaline phosphatase-producing S-1 strain was conducted using (ARTP), from which a higher alkaline phosphatase-producing positive mutant strain S-52 was screened. A central combination of five factors, including corn starch, yeast extract, metal ions, fermentation temperature and inoculum ratio, was then used to influence the activity of alkaline phosphatase. Results from the response surface methodology showed that the maximum enzyme activity of alkaline phosphatase was 12,110.6 U/L at corn starch, yeast extract and magnesium ions concentrations of 17.48 g/L, 18.052 g/L and 0.744 g/L, respectively; fermentation temperature of 37.192 °C; and inoculation ratio of 5.59%. This study is important for further exploring ARTP mutagenesis in B. amyloliquefaciens and the commercialization of ALPs.

Hepatitis B virus X protein promotes podocyte pyroptosis in hepatitis B virus-associated glomerulonephritis by down-regulating microRNA -223 targeting NLRP3 inflammasome / 中华肝脏病杂志

Objective: To investigate the potential function and related mechanism of microRNA-223 (miRNA-223) in the podocyte pyroptosis of hepatitis B virus (HBV)-associated glomerulonephritis induced by HBV X protein (HBx). Methods: HBx-overexpressing lentivirus was transfected into human renal podocytes to mimic the pathogenesis of HBV-GN. Real-time fluorescence quantitative PCR and Western blotting experiments were used to detect the mRNA and protein expression of pyroptosis-related proteins [nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1], and inflammatory factors (interleukin-1β and interleukin-18), respectively.TUNEL staining and flow cytometry were used to detect the number of pyroptosis cells. Immunofluorescence staining was used to detect the expression of podocytes biomarkers desmin and nephrin; Hoechst 33342 staining was used to observe the morphological and quantitative changes of podocyte nuclei. Enzyme-linked immunosorbent assay was used to measure caspase-1 activity. The dual luciferase reporter gene assay was used to verify the downstream target of miRNA-223. Podocytes were divided into the following nine groups: control group (no special treatment), empty plasmid group (transfected with empty plasmid), HBx overexpression group (transfected with HBx overexpression lentivirus), HBx overexpression+miRNA-223 mimic group (transfected with HBx overexpression lentivirus and miRNA-223 mimic), HBx overexpression+miRNA-223 inhibitor group (transfected with HBx overexpression lentivirus and miRNA-223 inhibitor), HBx overexpression+miRNA-223 mimic+NLRP3 group (transfected with HBx overexpression lentivirus, miRNA-223 mimic and NLRP3 overexpression plasmid), HBx overexpression+miRNA-223 mimic+ NLRP3 siRNA group (transfected with HBx overexpression lentivirus, miRNA-223 mimic and NLRP3 siRNA), HBx overexpression+miRNA-223 inhibitor+NLRP3 group (transfected with HBx overexpression lentivirus, miRNA-223 inhibitor and NLRP3 overexpression plasmid), HBx overexpression+miRNA-223 inhibitor+NLRP3 siRNA group (transfected with HBx overexpression lentivirus, miRNA-223 inhibitor and NLRP3 siRNA). Results: miRNA-223 was down-regulated in HBx overexpression group compared with the control group (P < 0.05). TUNEL and immunofluorescence staining showed that NLRP3 knockdown attenuated podocyte injury and pyroptosis induced by HBx overexpression (P < 0.05). Dual luciferase reporter gene assay demonstrated that NLRP3 was one of the downstream targets of miRNA-223. Rescue experiments revealed that NLRP3 overexpression weakened the protective effect of miRNA-223 in podocyte injury (P < 0.05). The addition of miRNA-223 mimic and NLRP3 siRNA decreased the expression of NLRP3 inflammasome and cytokines, and reduced the number of pyroptosis cells induced by HBx overexpression (all P < 0.05); The addition of miRNA-223 inhibitor and NLRP3 overexpression plasmid significantly increased the expression of NLRP3 inflammasome and cytokines, caspase-1 activity, and the number of pyroptosis cells (all P < 0.05). Conclusion: HBx may promote podocyte pyroptosis of HBV-GN via downregulating miRNA-223 targeting NLRP3 inflammasome, suggesting that miRNA-223 is expected to be a potential target for the treatment of HBV-GN.

Short-term outcomes of near-infrared imaging using indocyanine green in laparoscopic lateral pelvic lymph node dissection for middle-lower rectal cancer: A propensity score-matched cohort analysis.

Laparoscopic lateral pelvic lymph node dissection (LPND) is limited by complex neurovascular bundles in the narrow pelvic sidewall and various post-operative complications. Indocyanine green (ICG) has been applied to increase the number of harvested lymph nodes and reduce the injury of irrelevant vessels in patients with rectal cancer. However, few studies on the recurrence rate of ICG fluorescence imaging-guided laparoscopic LPND were reported. This retrospective study enrolled 50 middle- low rectal cancer patients who were treated by LPND. After propensity score matching, 20 patients were matched in each of the indocyanine green (ICG) guided imaging group (ICG group) and non-ICG guided imaging group (non-ICG group). The average follow-up time was 13.5 months (12-15 months). Our results showed that the total number of harvested lymph nodes in the ICG group was significantly higher than that in the non-ICG group (P < 0.05), and intraoperative blood loss and post-operative hospital stay times in the ICG group were less than those in the non-ICG group (P < 0.05). After 12 months of follow-up, no residual lymph node and local tumor recurrence were found for patients in the ICG group. Four patients in the non-ICG group detected residual lymph nodes at the 3-month visit. Our findings highlighted the importance of ICG fluorescence-guided imaging in LPND because it has unique advantages in improving the number of lymph node dissections, surgical accuracy, and decreasing the residual lymph nodes and local tumor recurrence. In addition, ICG fluorescence guidance technology can effectively shorten the operation time, and it is simple to operate, which is worth popularizing.

Population pharmacokinetics of valproic acid in adult Chinese patients with bipolar disorder.

PURPOSE: To develop and validate a population pharmacokinetic (PPK) model of valproic acid (VPA) in adult Chinese patients with bipolar disorder, and provide guidance for individualized therapy in this population. METHODS: A total of 1104 serum concentrations from 272 patients were collected in this study. The data analysis was performed using a nonlinear mixed-effects modeling approach. Covariates included demographic parameters, biological characteristics, and concomitant medications. Bootstrap validation (1000 runs), normalized prediction distribution error (NPDE), and external validation of 50 patients were employed to evaluate the final model. RESULTS: A one-compartment model with first-order absorption and elimination was developed for VPA extended-release tablets. VPA clearance was significantly influenced by three variables: sex (12% higher in male patients), daily dose (increasing with the 0.13 exponent), and body weight (increasing with the 0.56 exponent). Typical values for the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) for a female patient weighing 70 kg administered VPA 1000 mg/day were 0.18 h-1, 0.46 L/h, and 12.84 L, respectively. The results of model evaluation indicated a good stable and precise performance of the final model. CONCLUSIONS: A qualified PPK model of VPA was developed in Chinese patients with bipolar disorder. This model could be used as a suitable tool for the personalization of VPA dosing for bipolar patients.

[Characteristics of Ozone and Source Apportionment of the Precursor VOCs in Tianjin Suburbs in Summer].

From June to August 2018, a 1-hr resolution concentration dataset of ozone and its gaseous precursors (volatile organic compounds(VOCs) and NOx), and meteorological parameters were synchronously monitored by online instruments of the Nankai University Air Quality Research Supersite. The relationships and variation characteristics between ozone and its precursors were analyzed. According to the photochemical age, the initial concentrations of VOCs were calculated, and the photochemical loss of the concentration of VOCs during the daytime (06:00-24:00) was corrected. The initial and directly monitored concentrations of VOCs were incorporated into the PMF model for source apportionment. The results indicated that the mean concentration of O3 in Tianjin in summer was (41.3±25.7)×10-9, while that of VOCs was (13.9±12.3)×10-9. The average concentration of alkane (7.0±6.8)×10-9 was clearly higher than that of other VOC species. The species with high concentrations of alkanes were propane and ethane, accounting for 47% of the total alkane concentration. The average ozone formation potential (OFP) in summer was 52.1×10-9, and the OFP value of alkene was the highest and its contribution reached 57%. During the daytime, alkene loss accounted for 75% of the total VOC loss. The major sources of VOCs that were calculated based on the initial concentration data were the chemical industry and solvent usage (25%), automobile exhaust (22%), combustion source (19%), LPG/NG (19%), and gasoline volatilization (15%), respectively. Compared with the apportionment results based on directly monitored concentrations, the contribution of the chemical industry and solvent usage decreased by 4%, while automobile exhaust decreased by 5%. By combining the results of PMF apportionment and the OFP model to analyze the relative contributions of emission sources to ozone formation, and we found that the highest contribution source of ozone was the chemical industry and solvent usage (26%) in summer. Compared with the analysis results based on the directly monitored concentrations, the OFP values of the chemical industry and solvent usage decreased by 7%, while that of NG/LPG apparently decreased by 13%.

Pre- and Post-treatment Levels of Plasma Metabolites in Patients With Bipolar Depression.

Background: Bipolar disorder (BD) is a serious mental disease with complex clinical manifestations and high recurrence rate. The purpose of this study was to detect metabolites related to the diagnosis and efficacy evaluation of bipolar depression in plasma samples by metabolomics. Methods: Thirty-one bipolar depression patients were recruited and completed 8 weeks medication and a matched group of 47 healthy controls (HCs) was recruited. Nuclear magnetic resonance spectroscopy was used to profile plasma samples of bipolar depression patients at baseline and after 8 weeks medication, and HCs. Then Multivariate statistical analysis was performed to analyze differences of plasma metabolites among the three groups. Results: We detected seven specific differential metabolites in bipolar depression. Six of the metabolites were returned to the normal levels in different degrees after 8 weeks medication, only Glycine continuously decreased in the acute and significant improvement stages of bipolar depression (VIP > 1 and p < 0.05). These differential metabolites involved several metabolic pathways. Limitations: The small sample size was one of the most prominent limitations. Each BD patient was given an individualized medication regimen according to the clinical guidelines. Conclusion: There were metabolites changes before and after 8 weeks medication. Glycine may be a characteristic marker of bipolar depression and does not change with the improvement of bipolar depression, while other 6 differential metabolites may be biomarkers associated with the pathological development or the improvement of bipolar depression. And, these differential metabolites mainly related to energy metabolism, amino acid metabolism and gut microbiota metabolism.

Effects of triclosan on the RedoximiRs/Sirtuin/Nrf2/ARE signaling pathway in mosquitofish (Gambusia affinis).

Triclosan (TCS) has been widely used in daily life for its broad-spectrum antibacterial property and subsequently detected frequently in aquatic waterborne. Environmental relevant concentrations of TCS in water (ng-µg/L) may pose potential unexpected impact on non-target aquatic organisms. In the present work, we investigated the transcriptional responses of Nrf2 as well as its downstream genes, sirtuins and redox-sensitive microRNAs (RedoximiRs) in livers of the small freshwater fish mosquitofish (Gambusia affinis) which were exposed to environmental relevant concentrations of TCS (0.05 µg/L, 0.5 µg/L and 5 µg/L for 24 h and 168 h). Results showed there were similar up-regulations in Nrf2 and its target genes (e. g. NQO1, CAT and SOD) at transcriptional, enzymatic and protein levels, reflecting oxidative stress of TCS to mosquitofish. Meanwhile, up-regulations of Sirt1, Sirt2 and down-regulations of miR-34b, miR-200b-5p and miR-21 could modulate antioxidant system via the Nrf2/ARE signaling pathway by the post-transcriptional regulations. Some oxidative stress-related biomarkers displayed in concentration-dependent manners (e. g. NQO1 mRNA, CAT mRNA) and/or time-dependent manners (e. g. GSH contents). This study indicated that the RedoximiRs/Sirtuin/Nrf2/ARE signaling pathway played a crucial role in mosquitofish exposed to TCS, and there might be potentially profound effects for TCS on the aquatic ecological safety.

Simvastatin affects Nrf2/MAPK signaling pathway and hepatic histological structure change in Gambusia affinis.

Simvastatin (SV) is a typical lipid-lowering agent detected widely in waters, so its latent toxic effects to fish are deserved of concern. The purposes of this study aim at revealing the responses of antioxidant system in mosquitofish (Gambusia affinis) under SV exposure. Transcriptional expressions of oxidative stress-related key transcriptional factor Nrf2 and its downstream genes in mosquitofish were determined under SV exposure for different time. Partly related enzymatic activities, Nrf2 and MAPK protein expressions were also addressed in the same conditions, and histological changes in liver tissues were investigated too. Results showed that Nrf2 mRNA increased with the rising SV concentrations at 3 d and 7 d, displaying typical dose-dependent relationship, and Nrf2 protein by WB showed consistency with transcriptional changes to some degree. Comparatively, responses of gene expressions were more sensitive than enzymatic changes. The histological changes in the mosquitofish liver exposed to SV for 7 d indicated the potential adverse effects of statins. This work demonstrated that SV in aquatic environment could affect the transcriptional expression of antioxidant system, partly related enzymatic activity, and hepatic structure in the mosquitofish, revealing its potential risk on non-target organisms and environmental safety.

Adverse effects in Daphnia magna exposed to e-waste leachate: Assessment based on life trait changes and responses of detoxification-related genes.

The sharp increase in e-waste derived from great consumption of electronic products has become a potential global environmental challenge. Limited information is available about the potential detrimental impact of e-waste on aquatic organisms. The present study investigated the expression of detoxification-related genes and life-history parameter changes in Daphnia magna exposed to e-waste leachate, simultaneously integrating with the chemical analysis of typical pollutants from e-waste leachate. The study aims at assessing impacts of e-waste to aquatic invertebrates and providing insights into its toxic mechanisms. The results showed high concentration of heavy metals like Cu (1657.14 ± 259.3 µg g-1, DW) and persistent organic compounds like polybrominated diphenyl ethers (7831.32 ± 1273.86 ng g-1, DW) in stream sediments near e-waste dismantling areas. Chronic exposure to these pollutants can affect the growth and reproduction of D. magna, resulting in significant development retardation, decreased total egg production per female, and even smaller body size. Expression of some detoxification and reproduction-related genes including DappuHR96, CYP360a, P-gp, EcR, CYP314 and Vtg exhibited different response patterns depending on the e-waste leachate concentration. E-waste leachate may affect the expression of detoxification-related and growth and reproduction-related genes and disrupt the growth and reproduction processes of D. magna.

A randomized phase II trial of best supportive care with or without hyperthermia and vitamin C for heavily pretreated, advanced, refractory non-small-cell lung cancer.

Our previous study indicated that intravenous vitamin C (IVC) treatment concurrent with modulated electrohyperthermia (mEHT) was safe and improved the quality of life (QoL) of non-small-cell lung cancer (NSCLC) patients. The aim of this trial was to further verify the efficacy of the above combination therapy in previously treated patients with refractory advanced (stage IIIb or IV) NSCLC. A total of 97 patients were randomized to receive IVC and mEHT plus best supportive care (BSC) (n = 49 in the active arm, receiving 1 g/kg * d IVC concurrently with mEHT, three times a week for 25 treatments in total) or BSC alone (n = 48 in the control arm). After a median follow-up of 24 months, progression-free survival (PFS) and overall survival (OS) were significantly prolonged by combination therapy compared to BSC alone (PFS: 3 months vs 1.85 months, P < 0.05; OS: 9.4 months vs 5.6 months, P < 0.05). QoL was significantly increased in the active arm despite the advanced stage of disease. The 3-month disease control rate after treatment was 42.9% in the active arm and 16.7% in the control arm (P < 0.05). Overall, IVC and mEHT may have the ability to improve the prognosis of patients with advanced NSCLC.

A Retrospective Study of Gemcitabine and Carboplatin With or Without Intravenous Vitamin C on Patients With Advanced Triple-Negative Breast Cancer.

Background: This is a retrospective study to examine the effect of chemotherapy with or without intravenous vitamin C (IVC) on women with advanced triple-negative breast cancer (TNBC). Methods: From 2008 to 2016, a total of 113 patients with pathologically confirmed TNBC at Clifford Hospital were evaluated, and 70 patients were matched and divided into IVC (treatment group) and non-IVC groups (control group). The match was according to age, menopausal status, and metastatic sites. In the control group, 35 patients received gemcitabine and carboplatin. In the treatment group, 35 patients received the same chemotherapy plus IVC. Results: Baseline characteristics were not significantly different between the 2 groups. According to the criteria of RECIST 1.1 (Response Evaluation Criteria in Solid Tumors), enhanced computed tomography scan was compared after 2 cycles of chemotherapy. In the treatment group, 2/35 cases had a complete remission (CR), 15/35 cases had partial remission (PR), and 13/35 cases had stable disease (SD). The response rate was 48.6%. In the control group, there were no CR cases, 14/35 cases had PR, 14/35 cases had SD, and the response rate was 40.0% (P > .05). The median progression-free survival time and median overall survival time was 7 months (95% confidence interval [CI] =1.5-28.5 months) and 27 months (95% CI = 4-40 months) in the treatment group compared with 4.5 months (95% CI = 1.5-8 months) and 18 months (95% CI = 3-26 months) in the control group (P < .05). All patients experienced diverse reactions in the gastrointestinal tract and myelosuppression. The incidence of adverse reactions in the treatment group was significantly lower than that of the control group (P < .05). Conclusion: IVC may have an effect on improving the prognosis of patients with advanced TNBC.

Responses of the Nrf2/Keap1 signaling pathway in Mugilogobius abei (M. abei) exposed to environmentally relevant concentration aspirin.

Aspirin (ASA) is a widely used non-steroidal anti-inflammatory drug. Its high detection frequency in various waterborne and environmental residues has drawn wide attention. Limited information were provided for the effects of aspirin exposure on oxidative stress signaling pathway in fish, which is closely related to pathological and immunological process of fish. In this study, a small fish - Mugilogobius abei (M. abei) distributing widely in aquatic ecosystems in southern China, was employed as testing organism and the key genes of the detoxification metabolism were cloned for the first time. The responses of Nrf2/Keap1 signaling pathway were investigated under the environmentally relevant concentration aspirin exposure (0.5 µg L-1, 5 µg L-1, and 50 µg L-1) for 24 h, 72 h, and 168 h then. The transcriptional expression of the key genes (Nrf2, Keap1, GCLC, GPx, GST, SOD, CAT, Trx2, and TrxR) as well as the changes of the related enzymatic activities (GPx, GST, SOD, and CAT) and GSH and MDA content were also determined. Results showed that Nrf2 and Keap1 gene expression displayed a negative correlation to some extent under ASA exposure, the transcriptional expressions of the downstream related genes (GCLC, GST, SOD, CAT, Trx2, and TrxR) in Nrf2/Keap1 signaling pathway showed inhibition at 24 h but induction at 72 h and 168 h. At the protein level, ASA exposure can improve the antioxidant capacity by increasing GSH synthesis and enzymatic activity of GPx, GST, SOD, and CAT to reduce the degree of lipid peroxidation. We proposed that ASA exposure may interfere with the redox balance in M. abei at an early stage but sub-chronic ASA exposure can activate the Nrf2 signaling pathway to improve the antioxidant capacity of M. abei.

Metabolic Profiling in Bipolar Disorder Patients During Depressive Episodes.

Bipolar disorder (BD) is a common and debilitating mental disorder. Bipolar depression is the main episode of BD. Furthermore, there are no objective biomarkers available for diagnosing the disorder. In this research, a Nuclear Magnetic Resonance (NMR) spectroscopy based on a metabonomics technique was used to analyze serum samples from 37 patients with bipolar depression and 48 healthy control participants to determine potential biomarkers for bipolar depression. In total, seven different metabolites were identified that could effectively distinguish patients from healthy controls. The metabolites indicated that disturbances of amino acid and energy metabolisms might be involved in the pathogenesis of BD. Finally, a panel consisting of four potential biomarkers (lactate, trimethylamine oxide, N-acetyl glycoprotein, and α-glucose) was identified, which showed a higher combined diagnostic ability with an area under the curve of 0.893. Our findings may contribute to the development of an objective method for diagnosing bipolar depression.

Chang'an II Decoction ( II )-Containing Serum Ameliorates Tumor Necrosis Factor-α-Induced Intestinal Epithelial Barrier Dysfunction via MLCK-MLC Signaling Pathway in Rats.

OBJECTIVE: To investigate the effect of Chang'an II Decoction ( II ))-containing serum on intestinal epithelial barrier dysfunction in rats. METHODS: Tumor necrosis factor (TNF)-α-induced injury of Caco-2 monolayers were established as an inflammatory model of human intestinal epithelium. Caco-2 monolayers were treated with blank serum and Chang'an II Decoction-containing serum that obtained from the rats which were treated with distilled water and Chang'an II Decoction intragastrically at doses of 0.49, 0.98, 1.96 g/(kg·d) for 1 week, respectively. After preparation of containing serum, cells were divided into the normal group, the model group, the Chang'an II-H, M, and L groups (treated with 30 ng/mL TNF-α and medium plus 10% high, middle-, and low-doses Chang'an II serum, respectively). Epithelial barrier function was assessed by transepithelial electrical resistance (TER) and permeability of fluorescein isothiocyanate (FITC)-labeled dextran. Transmission electron microscopy was used to observe the ultrastructure of tight junctions (TJs). Immunofluorescence of zonula occludens-1 (ZO-1), claudin-1 and nuclear transcription factor-kappa p65 (NF-κ Bp65) were measured to determine the protein distribution. The mRNA expression of myosin light chain kinase (MLCK) was measured by real-time polymerase chain reaction. The expression levels of MLCK, myosin light chain (MLC) and p-MLC were determined by Western blot. RESULTS: Chang'an II Decoction-containing serum significantly attenuated the TER and paracellular permeability induced by TNF-α. It alleviated TNF-α-induced morphological alterations in TJ proteins. The increases in MLCK mRNA and MLCK, MLC and p-MLC protein expressions induced by TNF-α were significantly inhibited in the Chang'an II-H group. Additionally, Chang'an II Decoction significantly attenuated translocation of NF-κ Bp65 into the nucleus. CONCLUSION: High-dose Chang'an II-containing serum attenuates TNF-α-induced intestinal barrier dysfunction. The underlying mechanism may be involved in inhibiting the MLCK-MLC phosphorylation signaling pathway mediated by NF-κ Bp65.