The Mechanism of "Treating Different Diseases with the Same Treatment" by Qiangji Jianpi Decoction in Ankylosing Spondylitis Combined with Inflammatory Bowel Disease: A Comprehensive Analysis of Multiple Methods.

Background: Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) are prevalent autoimmune disorders that often co-occur, posing significant treatment challenges. This investigation adopts a multidisciplinary strategy, integrating bioinformatics, network pharmacology, molecular docking, and Mendelian randomization, to elucidate the relationship between AS and IBD and to investigate the potential mechanisms of traditional Chinese medicine formulations, represented by Qiangji Jianpi (QJJP) decoction, in treating these comorbid conditions. Methods: We utilized databases to pinpoint common targets among AS, IBD, and QJJP decoction's active compounds through intersection analysis. Through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, we mapped a network in Cytoscape, isolating critical targets. Molecular docking with AutoDock validated the affinity between targets and compounds. ROC analysis and dataset validation assessed diagnostic performance, while Gene Set Enrichment Analysis (GSEA) offered pathway insights. Mendelian randomization explored the AS-IBD causal relationship. Results: Screening identified 105 targets for QJJP decoction, 414 for AS, and 2420 for IBD, with 85 overlapping. These targets predominantly participate in organismal responses and DNA transcription factor binding, with a significant cellular presence in the endoplasmic reticulum and vesicle lumen. Molecular docking, facilitated by Cytoscape, confirmed IL1A, IFNG, TGFB1, and EDN1 as critical targets, with IFNG demonstrating diagnostic potential through GEO dataset validation. The integration of GSEA with network pharmacology highlighted the therapeutic significance of the relaxin, osteoclast differentiation, HIF-1, and AGE-RAGE signaling pathways in QJJP decoction's action. Mendelian randomization analysis indicated a positive causal relationship between IBD and AS, pinpointing rs2193041 as a key SNP influencing IFNG. Conclusion: Based on the principle of "treating different diseases with the same method" in traditional Chinese medicine theory, we explored the intricate mechanisms through which QJJP decoction addresses AS and IBD comorbidity. Our research spotlighted the pivotal role of the IFNG gene. IFNG emerges not only as a key therapeutic target but also assumes significance as a potential diagnostic biomarker through its genetic underpinnings. This investigation establishes a solid base for subsequent experimental inquiries. Our findings introduce novel approaches for incorporating traditional Chinese medicine into the treatment of AS-IBD comorbidity, setting the stage for groundbreaking research directions.

A validated LC-MS/MS method for determination of six Anti-SARS-CoV-2 drugs in plasma and its application for a pharmacokinetic study in rats.

Antiviral treatment for COVID-19 is considered an effective tool in reducing the rate of severe cases and deaths. As of June 2023, a total of six small molecule antiviral drugs have been conditionally approved for marketing by the National Medical Products Administration (NMPA) within China. In this study, a method of HPLC-MS/MS was established and validated for the determination of six small molecule antiviral drugs in plasma using Lamivudine as an internal standard. The chromatographic separation was performed using gradient elution with an ACE 3 C18-PFP column (3.0 mm × 150 mm, 3 µm), and the mobile phase consisted of deionized water and acetonitrile/water (90:10, v/v), both with 10 mmol/L of ammonium acetate and 0.1 % ammonium hydroxide added. Quantitative analysis of the six small molecule drugs was carried out through selective reaction monitoring based on the positive ion spray ionization mode. The method exhibited excellent precision, accuracy, recovery, and linearity, and it was used to determine the pharmacokinetic characteristics in rats. Our work not only established a bioanalytical method for six small molecule antiviral drugs but also provided scientific references for clinical pharmacokinetic studies.

Polystyrene microplastics exposure aggravates acute liver injury by promoting Kupffer cell pyroptosis.

OBJECTIVE: To investigate the long-term effects of polystyrene (PS) exposure on acute liver injury. METHODS: The carbon tetrachloride-induced acute injury mouse model was subjected to long-term PS exposure. Pyroptosis was inhibited by knocking out Gsdmd in mice or treating with the Gsdmd inhibitor necrosulfonamide (NSA) to evaluate the effect of PS on liver injury. Kupffer cells were used as a cellular model to examine the effects of PS on cell pyroptosis, lactate dehydrogenase release rate, structural integrity (propidium iodide staining), and inflammatory factor levels. RESULTS: In mice, PS exposure exacerbated acute liver injury, which was mitigated upon Gsdmd knockout (KO) or NSA treatment along with the downregulation of tissue inflammatory response. In vitro studies demonstrated that PS promoted Kupffer cell pyroptosis, which was suppressed upon Gsdmd KO or NSA treatment along with the alleviation of inflammation. CONCLUSION: These results suggest that long-term PS exposure exacerbates acute liver injury by promoting Kupffer cell pyroptosis, which is one of the hepatotoxic mechanisms of PS.

Clinical and magnetic resonance imaging features predict microvascular invasion in intrahepatic cholangiocarcinoma.

Introduction: Clinical features and magnetic resonance imaging (MRI)-related data are commonly employed in clinical settings and can be used to predict the microvascular invasion (MVI) status of intrahepatic cholangiocarcinoma (ICC) patients. Aim: To generate a clinical and MRI-based model capable of predicting the MVI status of ICC patients. Material and methods: Consecutive ICC patients evaluated from June 2015 to December 2018 were retrospectively enrolled in a training group to establish a predictive clinical MRI model. Consecutive ICC patients evaluated from January 2019 to June 2019 were prospectively enrolled in a validation group to test the reliability of this model. Results: In total, 143 patients were enrolled in the training group, of whom 46 (32.2%) and 96 (67.8%) were MVI-positive and MVI-negative, respectively. Logistics analyses revealed larger tumour size (p = 0.008) and intrahepatic duct dilatation (p = 0.01) to be predictive of MVI positivity, enabling the establishment of the following predictive model: -2.468 + 0.024 × tumour size + 1.094 × intrahepatic duct dilatation. The area under the receiver operating characteristic (ROC) curve (AUC) for this model was 0.738 (p < 0.001). An optimal cut-off value of -1.0184 was selected to maximize sensitivity (71.7%) and specificity (61.9%). When the data from the validation group were incorporated into the predictive model, the AUC value was 0.716 (p = 0.009). Conclusions: Both larger tumour size and intrahepatic duct dilatation were predictive of MVI positivity in patients diagnosed with ICC, and the predictive model developed based on these variables can offer quantitative guidance for assessing the risk of MVI.

Comparison of Contributors to Mortality Differences in SLE Patients with Different Initial Disease Activity: A Larger Multicenter Cohort Study.

To explore the etiology of risk factors and quantify the mortality differences in systemic lupus erythematosus (SLE) patients with different initial disease activity. The Jiangsu Lupus database was established by collecting medical records from first-hospitalized SLE patients during 1999-2009 from 26 centers in Jiangsu province, China, and their survival status every five years. The initial SLEDAI scores [high (>12) vs. low-moderate (≤12)] differences in mortality attributable to risk factors were quantified using population attributable fraction (PAF), relative attributable risk (RAR) and adjusted relative risk (ARR). Among 2446 SLE patients, 83 and 176 deaths were observed in the low-moderate and high activity groups, with mortality rates of 7.7 and 14.0 per 1000 person years, respectively. Anemia was the leading contributor to mortality, with PAFs of 40.4 and 37.5 in the low-moderate and high activity groups, respectively, and explained 23.2% of the mortality differences with an ARR of 1.66 between the two groups. Cardiopulmonary involvement caused the highest PAFs in the low-moderate (20.5%) and high activity (13.6%) groups, explaining 18.3% of the mortality differences. The combination of anemia and cardiopulmonary involvement had the highest RAR, causing 39.8% of the mortality differences (ARR = 1.52) between the two groups. In addition, hypoalbuminemia and a decrease in the creatinine clearance rate accounted for 20-30% of deaths and explained 10-20% of the mortality differences between the two groups, while antimalarial drug nonuse accounted for about 35% of deaths and explained 3.6% of the mortality differences. Anemia, cardiopulmonary involvement and hypoalbuminemia may cause substantial mortality differences across disease activity states, suggesting additional strategies beyond disease activity assessment to monitor SLE outcomes.

The neurotoxicity and mechanism of TBBPA-DHEE exposure in mature zebrafish (Danio rerio).

Tetrabromobisphenol A-bis (2-hydroxyethyl) ether (TBBPA-DHEE) has been detected in various environmental media and organisms, and its ecological risks and health hazards have attracted great attention, but sufficient toxicological data have not proved the toxic effects of TBBPA-DHEE exposure on aquatic organism. In this study, the neurotoxicity and mechanism of zebrafish (3-month-old) exposed to TBBPA-DHEE (0.86 µg/L, 12.9 µg/L, 193.5 µg/L) were studied. Furthermore, the neurotoxicity susceptibility of different sexes of zebrafish was revealed. Behavioral studies revealed that TBBPA-DHEE exposure has significant differences in average speed, duration of mania, the distance between objects, and ATP content between male and female zebrafish. Slight damage in brain tissue of male zebrafish was found. The transcriptome analysis revealed that the molecular mechanism of neurotoxicity in mature female and male zebrafish is different. For mature female zebrafish, TBBPA-DHEE significantly affected the expression of genes related to behavior and development, and its mechanism may be that it can produce neurotoxicity by affecting related genes in the hormone, synapse, and Ca2+ signaling pathway. For mature male zebrafish, TBBPA-DHEE can significantly affect their behavior and expression of nerve-related genes. Results from the transcriptomic analysis suggests that the possible molecular mechanism may be through the inhibition of Ca2+ signal transmission and produce neurotoxicity by affecting the expression of related genes in neural synapses, Ca2+ signal, and MAPK signal in brain tissue of zebrafish. The results suggested that exposure to low-dose TBBPA-DHEE could induce neurotoxicity in zebrafish, and female and male zebrafish showed different toxic effects and molecular mechanisms.

Pharmacokinetic study on the effect of ligustrazine-tangeretin co-administration on the pharmacokinetics of ligustrazine and its potential mechanism in rats.

Both ligustrazine and tangeretin are usually prescribed in the treatment of cardiovascular diseases, which makes their co-administration possible. The investigation of the interaction between ligustrazine and tangeretin is necessary for the clinical compatibility of their source herbs. This study aimed to investigate the interaction of ligustrazine and tangeretin during their co-administration. The pharmacokinetics of ligustrazine (15 mg/kg) was investigated in the presence of 50, 100, and 150 mg/kg tangeretin in rats with six of each. A single dose of ligustrazine was set as the control. The effect of tangeretin on the in vitro metabolic stability of ligustrazine was also investigated in rat liver microsomes. Tangeretin significantly reduced the system exposure of ligustrazine under all experimental concentrations. Specifically, tangeretin reduced the AUC (from 48.86 ± 12.57 to 41.02 ± 4.85 (50 mg/kg tangeretin), 31.47 ± 5.26 (100 mg/kg tangeretin), and 27.55 ± 9.60 (150 mg/kg) µg/mL × h), MRT (from 7.05 ± 0.26 to 6.33 ± 0.48, 5.53 ± 0.68, and 5.21 ± 1.31 h), Cmax (from 7.45 ± 0.44 to 6.03 ± 0.44, 5.24 ± 0.47, and 5.02 ± 0.56 µg/mL), and t1/2 (from 5.90 ± 1.27 to 4.84 ± 1.19, 3.48 ± 1.33, 3.09 ± 0.62 h) in rats. In vitro, tangeretin also reduced the metabolic stability of ligustrazine behaved as the decreased half-life and increased intrinsic clearance rate. Co-consumption of ligustrazine with tangeretin induced interactions, which shortens the system exposure of ligustrazine. This study provides theoretical guidance for the clinical prescription of ligustrazine- and tangeretin-containing herbs.

Bioinformatics Analysis of Immune Cell Infiltration and Diagnostic Biomarkers between Ankylosing Spondylitis and Inflammatory Bowel Disease.

Background: Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) are both autoimmune diseases, and they often occur together in clinical practice, but the pathogenesis is unclear. This study is aimed at identifying the hub genes and explore the related immune molecular mechanisms between AS and IBD by bioinformatics analysis. Methods: From the public Gene Expression Omnibus (GEO) database, the AS and IBD datasets (GSE73754, GSE59071, GSE25101, and GSE36807) were obtained. The immune cell infiltration in the peripheral blood tissues of GSE73754 and GSE59071 was assessed using the CIBERSORT algorithm. Then, we used the Weighted Gene Coexpression Network Analysis (WGCNA) to identify the Differentially Expressed Genes (DEGs) related to AS and IBD. Then, the immune genes from the ImmPort database intersected with the DEGs to obtain hub genes. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyzed the functional correlation of hub genes. Then, hub genes were verified in GSE25101 and GSE36807. The clusterProfiler software and Gene Set Enrichment Analysis (GSEA) were used to conduct functional enrichment and pathway enrichment studies. Finally, the diagnostic efficacy was assessed using Receiver Operating Characteristic (ROC) curve analysis. Results: The analysis of immune characteristics showed that both AS and IBD were related to immunity, and neutrophils were positively correlated in both diseases. Nine coexpressed genes, including FCGRT, S100A11, IFNGR1, NFKBIZ, JAK2, LYN, PLAUR, ADM, and IL1RN, were linked to immune cells. The GO and KEGG analyses results showed that enrichment analysis was mainly related to cell transport and migration. Finally, the ROC curve was verified with the validation set, and it was found that PLAUR has clinical diagnostic significance and the most excellent specificity and sensitivity, respectively. Conclusions: PLAUR (uPAR) is a promising biomarker and will be an underlying genetic biomarker for diagnosing AS comorbid IBD. Inflammation and immunological modulation mediated by neutrophil infiltration were important in the development of AS and IBD and may be diagnostic and therapeutic targets.

A transcriptomic-based analysis predicts the neuroendocrine disrupting effect on adult male and female zebrafish (Danio rerio) following long-term exposure to tetrabromobisphenol A bis(2-hydroxyethyl) ether.

Endocrine-disrupting chemicals (EDCs) are now ubiquitously distributed in the environment. Tetrabromobisphenol A bis(2-hydroxyethyl) ether (TBBPA-DHEE) pollution in environment media poses a significant threat to humans and aquatic organisms as a result of its potential neurotoxicity and endocrine-disrupting effect. The endocrine-disrupting effects of TBBPA-DHEE on aquatic organisms, however, have received limited attention. In this study, the neurotoxicity and reproductive endocrine-disruptive effect of TBBPA-DHEE was evaluated by observing the neurobehavioral changes, vitellogenin (VTG), testosterone, 17ß-estradiol and gene expression levels in adult male and female zebrafish exposed to TBBPA-DHEE (0.05, 0.2 and 0.3 mg/L) for 100 days. Furthermore, transcriptomic analysis was conducted to unravel other potential neuroendocrine-disrupting mechanism. Our result showed TBBPA-DHEE significantly (p < 0.05) altered the locomotor behavior and motor coordination abilities in both sexes. Steroid hormone and VTG levels were also altered indicating the neuroendocrine-disrupting effect of TBBPA-DHEE on the hypothalamic-pituitary-gonadal-axis. A total of 1568 genes were upregulated and 542 genes downregulated in males, whereas, 1265 upregulated and 535 downregulated genes were observed in females. The KEGG enrichment analysis showed that cell cycle and p55 signaling pathways were significantly enriched due to TBBPA-DHEE exposure. These pathways and its component genes are potential target of EDCs. The significant upregulation of genes in these pathways could partly explain the neuroendocrine disrupting effect of TBBPA-DHEE. The observed toxic effects of TBBPA-DHEE observed in this study is confirmation of the endocrine-disrupting toxicity of this chemical which would be valuable in biosafety evaluation and biomonitoring of TBBPA-DHEE for public health purposes.

Transcriptomic profiling reveals the neuroendocrine-disrupting effect and toxicity mechanism of TBBPA-DHEE exposure in zebrafish (Danio rerio) during sexual development.

TBBPA bis(2-hydroxyethyl) ether (TBBPA-DHEE) pollution in the environment has raised serious public health concerns due to its potential neuroendocrine-disrupting effects. The neuroendocrine-disrupting effects of TBBPA-DHEE on marine spices, on the other hand, have received little attention. The behavioral, neuroendocrine-disrupting, and possible reproductive toxicity of TBBPA-DHEE were assessed in sexual developing zebrafish treated for 40 days by examining locomotor activity, Gonadotrophin releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels, and quantifying gene expression. In addition, transcriptome profiling was carried out to explore the possible mechanisms. According to our findings, TBBPA-DHEE treated zebrafish showed altered locomotor activity, a potential neuroendocrine-disrupting effect via the toxic effect on the hypothalamus and pituitary gland, which is evident in decreased levels of GnRH, FSH, and LH, according to our findings. The transcriptomic profiling reveals that a total of 216 DEGs were detected (5 upregulated and 211 down-regulated). Transcriptomic analysis shows that TBBPA-DHEE exposure caused decreased transcript levels of genes (cyp11a1, ccna1, ccnb2, ccnb1, cpeb1b, wee2) involved in cell cycle oocyte meiosis, progesterone mediated oocyte maturation, and ovarian steroidogenesis, which are known reproduction-related pathways. Overall, these findings add to our understanding of the impact of TBBPA-DHEE and biomonitoring in the maritime environment.

Intrathecal or Intraventricular Tigecycline Therapy for Central Nervous System Infection Associated with Carbapenem-Resistant Klebsiella pneumoniae.

Purpose: Infection with carbapenem-resistant Klebsiella pneumoniae (CRKP) is a great challenge. Central nervous system (CNS) infection caused by CRKP is rarely reported, and effective treatment is limited. Thus, this study aimed to assess intrathecal (IT) or intraventricular (IVT) injection of tigecycline for clearing infection with CRKP in CNS. Patients and Methods: Two patients who had intracranial infection with CRKP after craniotomy were treated in our institution and analyzed retrospectively, summarizing their therapeutic schedules. Results: They all had a fever with the positive results of cerebrospinal fluid (CSF) test, and CSF culture showed positive for CPKP, which was sensitive only to tigecycline. In addition, the MIC of polymyxin B was not tested due to the limited laboratory conditions. After IT or IVT injection of tigecycline treatment, the temperature of the patients became normal in 3 days, with normal levels of white blood cells, protein, glucose and chlorine concentrations in the CSF. Crucially, twice CSF cultures also became negative with no clinical symptoms of intracranial infection after IT or IVT injection of tigecycline treatment. Moreover, there were no adverse drug reactions observed. Conclusion: IT or IVT injection of tigecycline may be a bright choice to control intracranial infection with CRKP.

Multitarget and Multipathway Regulation of Zhenqi Fuzheng Granule against Non-Small Cell Lung Cancer Based On Network Pharmacology and Molecular Docking.

Background and Objective. The morbidity and mortality rates of non-small cell lung cancer (NSCLC) remain high. Zhenqi Fuzheng (ZQFZ) granule, which consists of Astragali Radix and Ligustri Lucidi Fructus, is commonly used to improve the immunity of cancer patients. However, the mechanism of ZQFZ granule against NSCLC is still unclear. In this study, the network pharmacology and molecular docking approaches were used to investigate the potential mechanism of ZQFZ granule on NSCLC. Methods. The ingredients in the ZQFZ granule were considered in one study based on UPLC, and the potential targets were predicted in the SwissTargetPrediction database. NSCLC targets were gathered from GeneCards, OMIM, and TTD databases. The ingredient-target-NSCLC network was drawn by Cytoscape. The protein-protein interaction was obtained from the STRING database, and the gene function and biological pathways were analyzed by Metascape. AutoDock Vina was used to verify the molecular docking between the key compounds and core targets, and PyMol visualized the results. Results. 244 targets were related to 13 candidate compounds and 1904 targets were related to NSCLC, of which a total of 106 anti-NSCLC targets were predicted. The compound-target-NSCLC network indicated that sinapinic acid, ferulic acid, asiatic acid, pratensein, and glycitein might be the key components for treating NSCLC. The 41 vital targets (out of 106 targets) above the median calculated by PPI degree were selected for bioinformatics analysis. The top 10 targets out of 41 ranked by MCC were IL-6, SRC, CTNNB1, STAT3, CASP3, TNF, EGFR, MAPK8, HSP90AA1, and PTGS2. ZQFZ granule treatment for NSCLC involved many pathways through KEGG analyses, which included pathways in cancer (hsa05200), proteoglycans in cancer (hsa05205), endocrine resistance (hsa01522), microRNAs in cancer (hsa05206), PI3K-Akt signaling pathway (hsa04151), and IL-17 signaling pathway (hsa04657). Molecular docking studies revealed that sinapinic acid, ferulic acid, asiatic acid, pratensein, and glycitein had good infinity with most core targets. Conclusions. This study indicated that ZQFZ granule with multicompounds could treat NSCLC through multitargets and multipathways.

Transcriptomic sequencing reveals the potential molecular mechanism by which Tetrabromobisphenol A bis (2-hydroxyethyl ether) exposure exerts developmental neurotoxicity in developing zebrafish (Danio rerio).

Tetrabromobisphenol A bis (2-hydroxyethyl ether) (TBBPA-DHEE) is a derivative of Tetrabromobisphenol A (TBBPA) used as an intermediate flame retardant in engineering polymers. The mechanism of neurodevelopmental toxicity of TBBPA-DHEE remains unclear due to limited toxicological data. We performed behavioral and transcriptomic analyses to assess the neurodevelopmental effects of TBBPA-DHEE on developing zebrafish and potential toxicity mechanisms. Our result shows that exposure to TBBPA-DHEE significantly increased mortality, deformity rate, and reduction in hatch rate, hatchability, and body length relative to the DMSO control. The behavior analysis indicates that TBBPA-DHEE significantly reduced the spontaneous movement of larva compared to the control. The TSH and GH levels were significantly reduced in all the exposure groups in a concentration-dependent manner relative to the DMSO control. TBBPA-DHEE exhibited a significant reduction in locomotor activity across all the exposure groups in the light/dark locomotion test. The transcriptomic analysis result shows that 579 genes were differentially expressed. KEGG analysis shows the enrichment of complement cascade, JAK-STAT signaling pathway, cytokine-cytokine interaction, and phototransduction pathway resulting in a change in mRNA expression of their genes. These observed changes in developmental endpoints, hormonal level, and alteration in mRNA expression of component genes involved in neurodevelopmental pathways could be part of the possible mechanism of the observed toxic effects of TBBPA-DHEE exposure on zebrafish. This study could reveal the possible neurodevelopmental toxicity of TBBPA-DHEE to aquatic species, which could help uncover the health implications of emerging environmental contaminants.

Development and Verify of Survival Analysis Models for Chinese Patients With Systemic Lupus Erythematosus.

Background: The aim of this study is to develop survival analysis models of hospitalized systemic lupus erythematosus (h-SLE) patients in Jiangsu province using data mining techniques to predict patient survival outcomes and survival status. Methods: In this study, based on 1999-2009 survival data of 2453 hospitalized SLE (h-SLE) patients in Jiangsu Province, we not only used the Cox proportional hazards model to analyze patients' survival factors, but also used neural network models to predict survival outcomes. We used semi-supervised learning to label the censored data and introduced cost-sensitivity to achieve data augmentation, addressing category imbalance and pseudo label credibility. In addition, the risk score model was developed by logistic regression. Results: The overall accuracy of the survival outcome prediction model exceeded 0.7, and the sensitivity was close to 0.8, and through the comparative analysis of multiple indicators, our model outperformed traditional classifiers. The developed survival risk assessment model based on logistic regression found that there was a clear threshold, i.e., a survival threshold indicating the survival risk of patients, and cardiopulmonary and neuropsychiatric involvement, abnormal blood urea nitrogen levels and alanine aminotransferase level had the greatest impact on patient survival time. In addition, the study developed a graphical user interface (GUI) integrating survival analysis models to assist physicians in diagnosis and treatment. Conclusions: The proposed survival analysis scheme identifies disease-related pathogenic and prognosis factors, and has the potential to improve the effectiveness of clinical interventions.

Predictors of improvement in disease activity in first hospitalized patients with systemic lupus erythematosus: a multicenter retrospective study of a Chinese cohort.

OBJECTIVES: To analyze the relative factors of improvement in disease activity (IDA) after first hospitalized treatment based on the systemic lupus erythematosus disease activity index (SLEDAI). METHODS: A total of 1069 adult systemic lupus erythematosus (SLE) patients who were hospitalized for the first time in 26 hospitals in Jiangsu Province from 1999 to 2009 were retrospectively analyzed. SLEDAI decrease ≥ 4 during hospitalization was identified as IDA. Relative factors of IDA were assessed by univariate and multivariate logistic regression. RESULTS: A total of 783 (73.2%) adult SLE patients showed IDA after the first hospitalization, while the remaining patients (n = 286) were in the non-IDA group. The IDA group had higher SLEDAI at admission; fewer patients had SLICC/ACR damage index (SDI) ≥ 1, comorbidities at admission, especially Sjögren's syndrome, abnormal serum creatinine, and glomerular filtration rate. More patients had mucocutaneous and musculoskeletal involvements, leukopenia, increased C-reactive protein, anti-dsDNA antibody positive, and hypocomplementemia at admission and were treated with methotrexate and leflunomide during hospitalization. After multivariate logistic regression analysis, SDI ≥ 1 (P = 0.005) and combined with Sjögren's syndrome (P < 0.001) at admission had negative association with IDA. Musculoskeletal involvement (P < 0.001), anti-dsDNA antibody positive (P = 0.012), hypocomplementemia (P = 0.001), and use of leflunomide (P = 0.030) were significantly related with IDA. CONCLUSION: Organ damage or comorbidities at admission were adverse to SLE improvement. Anti-dsDNA antibody positive, hypocomplementemia, musculoskeletal involvements, and leflunomide treatment had positive association with IDA of SLE. Key Points • Organ damage or comorbidities at admission were negatively correlated with SLE improvement. • Anti-dsDNA antibody positivity, hypocomplementemia, musculoskeletal involvements, and leflunomide treatment were positively associated with SLE improvement.

Human liver microsomes study on the inhibitory effect of plantainoside D on the activity of cytochrome P450 activity.

BACKGROUND: Plantainoside D is widely existed in the herbs and possesses various pharmacological activities, making it possible to co-administrate with other herbs. Its effect on cytochrome P450 enzymes (P450) is a risk factor for inducing adverse drug-drug interactions. To assess the effect of plantainoside D on the activity of major P450 isoenzymes in human liver microsomes. METHODS: The Cocktail method was conducted in human liver microsomes in the presence of probe substrates. The activity of P450 isoenzymes was evaluated by the production of corresponding metabolites. The concentration-dependent and time-dependent inhibition assays were performed in the presence of 0, 2.5, 5, 10, 25, 50, and 100 µM plantainoside D to characterize the inhibitory effect of plantainoside D. RESULTS: Significant inhibition was observed in the activity of CYP1A2, 2D6, and 3A, which was concentration-dependent with the IC50 values of 12.83, 8.39, and 14.66 µM, respectively. The non-competitive manner and competitive manner were observed in the CYP3A inhibition (Ki = 7.16 µM) and CYP1A2 (Ki = 6.26 µM) and 2D6 inhibition (Ki = 4.54 µM), respectively. Additionally, the inhibition of CYP3A was found to be time-dependent with the KI of 1.28 µM-1 and Kinact of 0.039 min-1. CONCLUSIONS: Weak inhibitory effects of plantainoside D on the activity of CYP1A2, 2D6, and 3A were revealed in vitro, implying its potential of inducing interactions with CYP1A2-, 2D6-, and 3A-metabolized drugs. Although further in vivo validations are needed, the feasibility of the Cocktail method in evaluating P450 activity has been verified.

Clinical and laboratorial outcome of different age-onset systemic lupus erythematosus patients in Jiangsu, China: a multicentre retrospective study.

Studies on clinical features of systemic lupus erythematosus among different age-onset patients are lacking in China. This multicentre study aimed to systemically compare clinical manifestations, comorbidities, organ involvement, and laboratory findings among 797 Chinese juvenile-onset, adult-onset, and late-onset SLE (JSLE, ASLE, and LSLE) patients. They were classified into JSLE, ASLE, and LSLE groups if first diagnosed at < 18, 18-50, and > 50 years old, respectively. Chi-square test and analysis of variance were employed for categorical and continuous variables respectively. In younger-onset patients, the SLE Disease Activity Index 2000 score was significantly higher (JSLE vs. ASLE vs. LSLE = 17.43 ± 9.139 vs. 16.34 ± 8.163 vs. 14.08 ± 6.474, p = 0.031). Mucocutaneous symptoms (79.5% vs. 73.4% vs. 62.0%, p = 0.042), especially malar rash (76.1% vs. 66.1% vs. 53.5%, p = 0.011) occurred more frequently, and proteinuria rate was higher (54.5% vs. 56.3% vs. 36.6%, p = 0.007). In later-onset patients, cardiopulmonary involvement increased (11.4% vs. 24.3% vs. 29.6%, p = 0.012). In ASLE, hypoalbuminemia rate elevated (46.6% vs. 59.9% vs. 47.9%, p = 0.015). Our study demonstrated in a Chinese population that JSLE may be more active and suffer mucocutaneous disorders, while LSLE tended to suffer cardiopulmonary involvement at-onset. These findings may help identify treatment priorities when facing different age-onset SLE patients.

Transcriptomic profiling and differential analysis revealed the neurodevelopmental toxicity mechanisms of zebrafish (Danio rerio) larvae in response to tetrabromobisphenol A bis(2-hydroxyethyl) ether (TBBPA-DHEE) exposure.

Tetrabromobisphenol A bis(2-hydroxyetyl) ether (TBBPA-DHEE) is among the main derivatives of Tetrabromobisphenol A (TBBPA). Result from previous study showed that TBBPA-DHEE can cause neurotoxicity in rat. In this study, zebrafish larvae were used for evaluation of TBBPA-DHEE-induced developmental toxicity, apoptosis, oxidative stress and the potential molecular mechanisms of action. Our result showed that TBBPA-DHEE exposure caused a significant concentration-dependent developmental toxicity endpoints like death rate, malformation rate, growth rate. TBBPA-DHEE altered locomotor and enzymes activities of larvae and caused apoptosis within the brain indicating the potential TBBPA-DHEE-induced cardiac, brain impairment in the zebrafish larvae. Our transcriptomic analysis shows that 691 genes were differentially expressed (DEGs) (539 upregulated, 152 downregulated). The KEGG and GO enrichment pathway analysis shows that the DEGs were involved in development, immunity, enzyme activity. Our study provides novel evidence on the neurodevelopmental toxicity and toxicity mechanism of TBBPA-DHEE which are vital for assessment of the environmental toxicity and risk assessment of the chemical.

Low dosage use of cyclophosphamide improves the survival of patients with systemic lupus erythematosus.

OBJECTIVE: To investigate the effect of cyclophosphamide (CYC) on organ involvement and SLE patients' overall and cause-specific mortality. METHODS: Information about CYC prescription was taken from the Jiangsu Lupus database, which was set up to collect medical records from SLE patients since their first admission during 1999-2009 in Jiangsu province, China. Follow-up studies were carried out in 2010 and 2015 to check the survival status of the patients. Cox regression models were used to estimate the hazard ratio (HR) and 95% CI. Kaplan-Meier model was used to assess the effect of CYC on mortality between organ involvement and non-involvement. RESULTS: There were 221 deaths observed out of 2446 SLE patients. CYC users decreased overall mortality of SLE (8.4%) with adjusted HR (95% CI) of 0.74 (0.56-0.97), as compared to non-users. A decrease in overall mortality of SLE was found in the low dosage (< 600 mg) of CYC users, with adjusted HR (95% CI) of 0.54 (0.36-0.81). The protection of CYC on mortality of SLE was further observed in subgroups, such as female; SLEDAI score ≥ 15 group; and those with neuropsychiatric, renal, and hematological involvements, and low serum C3. In addition, CYC could eliminate the differences in mortality between organ involvement and non-involvement, including renal, neuropsychiatric, cardiopulmonary, gastrointestinal, and hematological involvement, but not for mucocutaneous and musculoskeletal involvement. CONCLUSION: Low dosage use of CYC decreased the risk of overall mortality of SLE. CYC might improve the survival of SLE patients with renal, neuropsychiatric, cardiopulmonary, gastrointestinal, and hematological involvements. Key Points • Cyclophosphamide decreases overall mortality of SLE patients. • Decreased mortality is mainly observed from low dosage use of cyclophosphamide. • Cyclophosphamide improves the survival of SLE patients when major systems such as renal, neuropsychiatric, cardiopulmonary, gastrointestinal, and hematological are involved.

Gold-Specific Biosensor for Monitoring Wastewater Using Genetically Engineered Cupriavidus metallidurans CH34.

Transcription factor-based whole-cell biosensors have recently become promising alternatives to conventional analytical methods due to their advantage of simplicity, cost-effectiveness, and environmental friendliness. In this study, we used genetic engineering to develop a whole-cell biosensor based on the activation of promoters by CupR via interactions with gold ions, leading to the expression of reporter genes that yield output signals. Altering the promoter sequences was shown to significantly improve the performance of the biosensor strain in terms of gold-specificity. The detection sensitivity of our engineered strains was 42-fold higher than that of wild-type strains. The linear range of the purposed sensor was 125-1000 nM with a limit of detection at 46.5 nM. The effectiveness of the sensor strain was verified in wastewater samples.