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BackgroundStatins, as an important class of lipid-lowering drugs, play a key role in the prevention and treatment of cardiovascular diseases. However, with their widespread use in clinical practice, some adverse events have gradually emerged. In particular, the hepatotoxicity associated with statins use has become one of the clinical concerns that require sufficient attention.MethodsIn this study, we conducted a comprehensive and detailed analysis of the hepatotoxicity of statins based on the data of the US Food and Drug Administration Adverse Event Reporting System database from the first quarter (Q1) of 2004 to the Q1 of 2024 and used Reporting Odds Ratios and Empirical Bayes Geometric Mean to mine the signal of adverse events.ResultsIn this study, hepatic disorder related seven statins all exhibited positive signals. Through signal mining, we identified a total of 14,511 cases of adverse events associated with hepatic disorder caused by these statin drugs, with atorvastatin, simvastatin, and rosuvastatin occurring at a higher rate. A total of 148 positive signals related to adverse events of hepatic disorder were captured. Autoimmune hepatitis and drug-induced liver injury both presented positive signals across multiple statin drugs. Notably, atorvastatin had the most significant signal strength in cholestatic pruritus and bilirubin conjugation abnormal. Fluvastatin also showed notable signal strength in autoimmune hepatitis, while simvastatin had a relatively weaker signal strength for hepatic enzyme increased.ConclusionThis study discovered specific adverse event signal values, revealing potential hepatotoxic risks associated with the use of statin drugs. The results provide an important reference for the safe clinical use of drugs, help to improve the understanding of the safety of statins, and also provide a scientific basis for clinicians to make more accurate and safe decisions when making treatment plans.

BackgroundIFN-γ+CD4+ cells (type 1 helper T cells, Th1) represent a critical component of the inflammatory environment in the lungs of chronic obstructive pulmonary disease (COPD). Identifying influencing factors related to COPD-associated Th1 cells will enhance our understanding of the inflammatory mechanisms involved and facilitate the development of targeted interventions.MethodWe describe T-cell immunoglobulin and mucin-domain containing-3 (Tim3) as a key gene regulating COPD-associated Th1 cells through single-cell sequencing, flow cytometry and knockout mice.ResultsOur findings indicate that Havcr2 expression gradually increases during CD4+ T cell activation in COPD mice, with Tim3 being highly expressed on both CD4+ T cells and Th1 cells. Notably, the knockout of HAVCR2 further promotes the infiltration of CD4+ T cells and the expression of IFN-γ in the lungs, resulting in a more severe emphysema phenotype, although it does not significantly affect TNF-α expression. Additionally, NFIL3, an upstream regulator of Tim3, is also highly expressed in the CD4+ T cells of COPD mice. Mice with NFIL3 knockout exhibit phenotypes similar to those of HAVCR2 knockout mice, along with a significant downregulation of Tim3 expression. In vitro, we simulated the activation process by polarizing primary CD4+ Tn cells from COPD mice and observed that NFIL3/Tim3 expression was significantly upregulated following Th1 polarization.ConclusionOur study demonstrates that the NFIL3/Tim3 axis plays a role in Th1 imbalance in the lungs of COPD by inhibiting Th1 differentiation.

BackgroundChildhood and adolescent cancer represent a significant health burden in the United States. Current and precise epidemiological data are crucial to develop effective cancer control plans and ultimately reduce the burden of childhood and adolescent cancer.MethodsWe analyzed data obtained from cancer registries in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Age-standardized incidence and death rates, assessed using joinpoint analysis, were quantified as annual percentage changes (APC) and average percentage changes (AAPC).ResultsThe overall cancer incidence rate in 2008–2018 was 187.9 per 1,000,000 persons. Cancer incidence rates demonstrated a sustained upward trend, with an APC of 0.8 from 1975 to 2018. Incidence rates during 2008–2018 remained stable among non-Hispanic Black children but increased among other racial and ethnic groups. Leukemias, central nervous system tumors, and lymphomas were the most common cancer groups for patients aged 0–19 years. Cancer death rates decreased among children [AAPC, −1.3 (95% CI, −1.5 to −1.1)] during 2009–2019, while were stable among adolescents during that period.ConclusionsIn this study, we analyzed cancer incidence and mortality rates and trends in children aged 0–19 years in the United States. Our findings revealed an overall increase in cancer incidence rates among children and adolescents, accompanied by a decline in cancer mortality rates over time. These rates and trends varied by age, sex, and particularly race and ethnicity, highlighting the significance of comprehending and addressing disparities and ultimately reducing the disease burden of childhood and adolescent cancer.

IntroductionChina has experienced unprecedented transformations unseen in a century and is gradually progressing toward an emerging superpower. The epidemiological trends of digestive diseases in the United States (the US) have significant prescient effects on China.MethodsWe extracted data on 18 digestive diseases from the Global Burden of Diseases 2019 Data Resource. Linear regression analysis conducted by the JoinPoint software assessed the average annual percentage change of the burden. We performed subgroup analyses based on sex and age group.ResultsIn 2019, there were 836.01 and 180.91 million new cases of digestive diseases in China and the US, causing 1558.01 and 339.54 thousand deaths. The age-standardized incidence rates of digestive diseases in China and the US were 58417.87/100,000 and 55018.65/100,000 respectively, resulting in age-standardized mortality rates of 81.52/100,000 and 60.88/100,000. The rates in China annually decreased by 2.149% for mortality and 2.611% for disability-adjusted life of year (DALY). The mortality and DALY rates of the US, respectively, had average annual percentage changes of −0.219 and −0.251. Enteric infections and cirrhosis and other chronic liver diseases accounted for the highest incidence and prevalence in both counties, respectively. The burden of multiple digestive diseases exhibited notable sex disparities. The middle-old persons had higher age-standardized prevalence rates.ConclusionChina bore a greater burden of digestive diseases, and the evolving patterns were more noticeable. Targeted interventions and urgent measures should be taken in both countries to address the specific burden of digestive diseases based on their different epidemic degree.

IntroductionAlthough carbohydrates and lipids are important energy substances for Chinese mitten crab (Eriocheir sinensis), little is known about their synergistic effect on the growth, energy utilization characteristics and mechanisms involved in this process.MethodsA 58-d feeding experiment was conducted to investigate the effects of dietary carbohydrate to lipid ratio (C/L) on the growth performance, biochemical indices, and metabolism-related differential gene expression of juvenile E. sinensis in both intermolt (InM) and premolt (PrM) stages. Five experimental diets were formulated with increasing dietary C/L (1.34, 2.39, 3.59, 5.52 and 9.42).ResultsThe results showed that the weight growth rate of juvenile E. sinensis was highest in dietary C/L3.59 group, which was significantly higher than that in the other groups. As dietary C/L increased, the hepatic glycogen contents increased, but triglyceride contents decreased in the hepatopancreas of E. sinensis in the InM. In both two molting stages, the activities of glycogen synthase and fatty acid synthase paralleled with their contents, respectively. Crabs in the InM showed higher contents of triglyceride and the activities of glycolytic rate-limiting enzymes but lower contents of hepatic glycogen than those in the PrM, especially in the C/L 1.34 and C/L 3.59 groups. In all dietary groups, the activities and transcription of gluconeogenesis and fatty acid synthesis related enzymes were significantly higher in the InM than those in the PrM. KEGG analysis showed that differential genes were enriched in fatty acid biosynthesis, fatty acid metabolism, oxidative phosphorylation pathway, pentose phosphate pathway, pyruvate metabolism and steroid biosynthesis between different dietary groups and molting stages.DiscussionTo conclude, the optimal dietary C/L was estimated to be 3.59 for juvenile E. sinensis based on the survival and growth performance. Compared to PrM, E. sinensis in the InM was more active in the carbohydrate metabolism (glycolysis and gluconeogenesis) and fatty acid synthesis, with more triglyceride and less glycogen accumulated in the hepatopancreas.This study could contribute to better understanding the carbohydrate and lipid metabolism between different molting stages, and optimizing the precise feed formulation for juvenile E. sinensis.

This study investigated the effects of replacing commercial feeds with fresh black soldier fly larvae (BSFL) on the immune enzyme activities, water quality in the culturing environment, and intestinal microbiota of Pacific white shrimp (Litopenaeus vannamei). Five different feeding regimes were designed, in which 0% (control group), 25%, 50%, 75%, and 100% commercial feeds were replaced with equal wet weight of fresh BSFL, respectively. The experiment lasted for 45 days, and the results showed that the serum T-NOS (total nitric oxide synthase), AKP (alkaline phosphatase), and ACP (acid phosphatase) activity were significantly increased in the BSFL25% group. However, the immune enzymes of the hepatopancreas decreased significantly in all the BSFL-containing groups compared to the control group. Total ammonia nitrogen concentrations throughout the experimental phase and nitrate concentrations in the middle and later phases of the experiment were negatively correlated with the replacement rate of fresh BSFL in the diet, whereas pH was positively correlated with the replacement rate of fresh BSFL in the diet. Proteobacteria and Bacteroidetes were dominant phyla in the intestines of shrimps, but the relative abundances of Proteobacteria and Firmicutes decreased, with those of Bacteroidetes and Planctomycetes increased in the BSFL-containing groups. Among them, higher relative abundances of potential probiotics such as Motilimonas, Shimia, Pseudoalteromonas, and Shewanella and lower relative abundance of genus Vibrio were observed in the fresh BSFL-containing groups. Furthermore, shrimps fed with BSFL-containing diets had higher bacterial richness and diversity in the intestines. In conclusion, a proper replacement of commercial feed with fresh BSFL had a positive effects on the immune-related enzyme activities, water quality, and intestinal health in the L. vannamei.

Inflammatory bowel disease (IBD) has been reported to be associated with NLRP3 inflammasome activation. Therefore inhibiting inflammasome activation could be a new approach to treat IBD. Inflammasome inhibitors NLRP3-IN-2, JC124, and 3,4-methylenedioxy-β-nitrostyrene (MNS) were previously reported to exert anti-inflammatory effects in various disease models but not in the dextran sulfate sodium (DSS)–induced colitis model. Here, we showed that MNS was more efficient in inhibiting the secretion of interleukin-1β (IL-1β) by blocking oligomerization of apoptosis-associated speck-like protein (ASC) than NLRP3-IN-2 and JC124. To investigate the protective effects of MNS on enteritis, we administered intragastric MNS to DSS-induced colitis mice. The results demonstrated that MNS attenuated DSS-induced body weight loss, colon length shortening, and pathological damage. In addition, MNS inhibited the infiltration of macrophages and inflammatory cells and reduced IL-1β and IL-12p40 pro-inflammatory cytokines but had no significant effect on tumor necrosis factor α (TNF-α) and IL-6. Furthermore, we also found that the differentiation of IL-17A+interferon-γ (IFN-γ)+CD4+ T cell was decreased in the colon after MNS treatment, which might be mediated by IL-1β, etc. cytokine release. Taken together, MNS alleviated DSS-induced intestinal inflammation by inhibiting NLRP3 inflammasome activation, which may function as an effective therapeutic for IBD.

ObjectiveIn order to better understand the relative surgical process, this work used a model-based computational analysis on the effectiveness of enhanced recovery after surgery (ERAS) in the operating room with nursing.MethodsA total of 360 surgical patients in the First Affiliated Hospital, Sun Yat-sen University, from the period June 2020 to March 2021, were randomly divided into two groups, namely, observation group and control group, with 180 cases in each group. Routine nursing was used in the control group, while ERAS was implemented in the observation group from the point of view of four aspects, namely, preoperative visit, intraoperative cooperation, postoperative return visit, and psychological intervention.ResultsPostoperative complications, average hospital stay, nursing satisfaction, and postoperative quality of life in the observation group were significantly better than those in the control group (all p

Background and ObjectivesThe study aims to test the hypotheses that a higher burden of cerebral small vascular disease (CSVD) predicts major adverse cardiac and cerebrovascular events (MACCE) in patients with hypertension (HTN) and that abnormal blood pressure variability (BPV) pattern aggravates total CSVD burden.MethodsWe retrospectively reviewed patients with HTN prospectively selected between February 2015 and February 2019 from three participating centers. Patients were included if they had HTN for over 1 year and had at least one MRI feature of CSVD. Independent predictors were found using multivariate logistic regression.ResultsAmong the 908 patients who finally enrolled in the study, the number of CSVD markers (OR = 1.940; 95% CI = 1.393–2.703; P < 0.001) independently predicted MACCE with acceptable predictive value (C-statistic = 0.730; 95% CI = 0.669–0.791; P < 0.001). An abnormal BPV pattern was identified as an independent risk factor for increased CSVD burden. Among them, reverse-dipper subtype demonstrated the most significant relationship (OR = 1.725; 95% CI = 1.129–2.633; P = 0.012).ConclusionTotal CSVD burden predicts an increased risk of composite MACCE independently. An abnormal BPV pattern is associated with a higher burden of CSVD.

The clinical severity of Staphylococcus aureus (S. aureus) respiratory infection correlates with antibacterial gene signature. S. aureus infection induces the expression of an antibacterial gene, as well as a central stress response gene, thus activating transcription factor 3 (ATF3). ATF3-deficient mice have attenuated protection against lethal S. aureus pneumonia and have a higher bacterial load. We tested the hypothesis that ATF3-related protection is based on the increased function of macrophages. Primary marrow-derived macrophages (BMDM) were used in vitro to determine the mechanism through which ATF3 alters the bacterial-killing ability. The expression of ATF3 correlated with the expression of antibacterial genes. Mechanistic studies showed that ATF3 upregulated antibacterial genes, while ATF3-deficient cells and lung tissues had a reduced level of antibacterial genes, which was accompanied by changes in the antibacterial process. We identified multiple ATF3 regulatory elements in the antibacterial gene promoters by chromatin immunoprecipitation analysis. In addition, Wild type (WT) mice had higher F4/80 macrophage migration in the lungs compared to ATF3-null mice, which may correlate with actin filament severing through ATF3-targeted actin-modifying protein gelsolin (GSN) for the macrophage cellular motility. Furthermore, ATF3 positively regulated inflammatory cytokines IL-6 and IL-12p40 might be able to contribute to the infection resolution. These data demonstrate a mechanism utilized by S. aureus to induce ATF3 to regulate antibacterial genes for antimicrobial processes within the cell, and to specifically regulate the actin cytoskeleton of F4/80 macrophages for their migration.

Background: The efficacy and safety of peroral endoscopic myotomy (POEM) in the treatment of sigmoid-type achalasia is unknown. This meta-analysis aims to explore the clinical outcomes of POEM for sigmoid-type achalasia.Method: We searched all relevant studies published up to September 2020 in PubMed, Embase, and Cochrane library databases. Meta-analyses for clinical success, Eckardt score, angle of esophageal tortuosity, diameter of esophagus, lower esophageal sphincter (LES) pressure, integrated relaxation pressure (IRP), adverse events, and gastroesophageal reflux diseases were performed based on random or fixed-effects models as needed.Results: We found a total of eight studies that provided data on 248 patients. Overall, the pooled clinical success was achieved in 211 sigmoid-type achalasia patients [90.4%; 95% confidence interval (CI), 85.5%−93.8%]. The pre- and post-POEM Eckardt scores, angle of esophageal tortuosity, diameter of esophageal, LES pressure, and IRP were significantly improved (All p < 0.05). The pooled adverse events rate was 13.0% (95% CI, 3.6%−37.4%). The pooled objective confirmation of reflux rate was 41.5% (95% CI, 26.5%−58.3%), and symptomatic reflux rate was 12.5% (95% CI, 8.3%−18.4%).Conclusions: Our current evidence indicated that POEM is an effective and safe therapeutic modality for the treatment of sigmoid-type achalasia.

Gastric cancer (GC), a leading cause of cancer-related death, is a heterogeneous disease. We aim to describe clinically relevant molecular classifications of GC that incorporate heterogeneity and provide useful clinical information. We combined different gene expression datasets and filtered a 7-gene signature related to the extracellular matrix (ECM), which also exhibited significant prognostic value in GC patients. Interestingly, putative CCCTC-binding factor (CTCF) regulatory elements were identified within the promoters of these ECM-related genes and were confirmed by chromatin immunoprecipitation sequencing (ChIP-Seq). CTCF binding sites also overlapped with histone activation markers, indicating direct regulation. In addition, CTCF was also correlated with the Wnt signaling pathway. A comparison of human GC cell lines with high or low expression of ECM-related genes revealed different levels of tumor aggressiveness, suggesting the cancer development-promoting functions of ECM-related genes. Furthermore, CTCF regulated COL1A1 and COLA31 expression in vitro. Silencing CTCF or COL1A1/COL1A3 markedly inhibited cell growth and migration in the metastatic GC cell line BGC823. Collectively, this ECM-related 7-gene signature provides a novel insight for survival prediction among GC patients. The zinc finger protein CTCF regulates ECM-related genes, thereby promoting GC cell growth and migration.

Background: The outbreak of coronavirus disease 2019 in Wuhan, Hubei Province, China has seriously affected people's mental health. We aimed to assess the psychological impact of the coronavirus disease 2019 on health care workers and non-health care workers in three different epidemic areas in China and to identify independent risk factors.Methods: We surveyed 1,020 non-health care workers and 480 health care workers in Wuhan, other cities in Hubei except Wuhan and other provinces in China except Hubei.Results: Health care workers in Hubei had higher levels of anxiety and depression than non-health care workers (p < 0.05), but there was no such difference in other provinces in China except Hubei (p > 0.05). Compared with other regions, health care workers in Wuhan was more anxious (p < 0.05), and this anxiety may be caused by concerns about occupational exposure and wearing protective clothing for a long time daily; health care workers in Hubei had more obvious depression (p < 0.05), which may be associated with long days participating in epidemic work and wearing protective clothing for a long time daily. Meanwhile, 62.5% of health care workers were proud of their work. The anxiety and depression of non-health care workers in Wuhan were also the most serious.Conclusions: In Wuhan, where the epidemic is most severe, levels of anxiety and depression seem to be higher, especially among health care workers. This information may help to better prepare for future events.

The biosynthesis of a calcified shell is critical for the development of oyster larvae. This process can be severely inhibited by CO2-induced ocean acidification, causing mass mortality of oyster larvae. However, the underlying molecular mechanism of such process has not been well explored until now. In the present study, a homolog of chitin synthase (named as Cgchs1) and a homolog of chitinase (named as Cgchit4) were identified from the Pacific oyster Crassostrea gigas. The cDNA sequences of Cgchs1 and Cgchit4 were of 813 bp and 2118 bp, encoding a putative polypeptide of 271 amino acids and 706 amino acids, respectively. There were a Chitin_synth_2 domain and a Glyco_18 domain in the inferred amino acid sequences of Cgchs1 and Cgchit4, respectively. Both Cgchs1 and Cgchit4 shared high sequence identity with their homologs in vertebrates. In addition, when oyster larvae were exposed to acidification treatment (pH 7.4), their shell biosynthesis process was seriously restrained. The expression level of Cgchs1 mRNA was significantly suppressed while that of Cgchit4 was dramatically activated upon acidification treatment. Cgchs1 and Cgchit4 are critical enzymes for chitin metabolism, and such changes in their mRNA expression could result in the decrease of chitin content in oyster larvae’s shells, which might lead to the failure of shell formation. Therefore, results in the present study suggested that acidified seawater might inhibit the formation of oyster calcified shell by suppressing the biosynthesis of chitin.

The Chinese mitten crab Eriocheir sinensis lives in saline or fresh water during different life stages and exhibits a complex life history, making it an ideal model to study the salinity adaptation of euryhaline animals. In this study, RNA-seq techniques, and determinations of free amino acids (FAAs), monoamine neurotransmitters, and Na+/K+ pump activity, were employed to understand the osmoregulatory mechanism in Chinese mitten crab. A total of 15,138 differentially expressed genes were obtained from 12 transcriptome libraries. GO enrichment analysis revealed that the mRNA expression profiles were completely remodeled from 12 to 24 h after salinity stress. The neuroendocrine system was activated under stimulation, and the monoamine neurotransmitters including dopamine (DA) and serotonin (5-HT) were released to modulate osmoregulation. Furthermore, the Na+/K+ pump in crab hemocytes was significantly inhibited post salinity stress, resulting in increased intracellular ion concentrations and osmotic pressure to sustain the osmotic balance. Moreover, six key FAAs, including alanine (Ala), proline (Pro), glycine (Gly), glutamate (Glu), arginine (Arg), and aspartate (Asp), were overexpressed to modulate the extracellular osmotic balance during salinity adaptation. Interestingly, the immune genes were not enriched in the GO analysis, implying that the immune system might not contribute fundamentally to the tolerance upon fluctuating ambient salinity in the Chinese mitten crab. These results collectively demonstrated that the Chinese mitten crab had evolved an efficient regulation mechanism by modulating the FAAs production and Na+/K+ pump activity to sustain the osmotic balance independent of the immune system, in which the neuroendocrine modulation, especially generated by the monoamine neurotransmitter, played an indispensable role.

Two of the molecular families closely associated with mediating communication between the brain and immune system are cytokines and the kynurenine metabolites of tryptophan. Both groups regulate neuron and glial activity in the central nervous system (CNS) and leukocyte function in the immune system, although neither group alone completely explains neuroimmune function, disease occurrence or severity. This essay suggests that the two families perform complementary functions generating an integrated network. The kynurenine pathway determines overall neuronal excitability and plasticity by modulating glutamate receptors and GPR35 activity across the CNS, and regulates general features of immune cell status, surveillance and tolerance which often involves the Aryl Hydrocarbon Receptor (AHR). Equally, cytokines and chemokines define and regulate specific populations of neurons, glia or immune system leukocytes, generating more specific responses within restricted CNS regions or leukocyte populations. In addition, as there is a much larger variety of these compounds, their homing properties enable the superimposition of dynamic variations of cell activity upon local, spatially limited, cell populations. This would in principle allow the targeting of potential treatments to restricted regions of the CNS. The proposed synergistic interface of 'tonic' kynurenine pathway affecting baseline activity and the superimposed 'phasic' cytokine system would constitute an integrated network explaining some features of neuroimmune communication. The concept would broaden the scope for the development of new treatments for disorders involving both the CNS and immune systems, with safer and more effective agents targeted to specific CNS regions. [ABSTRACT FROM AUTHOR]

Many invasive micro-organisms produce ‘quorum sensor’ molecules which regulate colony expansion and may modulate host immune responses. We have examined the ability of Pseudomonas Quorum Sensor (PQS) to influence cytokine expression under conditions of inflammatory stress. The administration of PQS in vivo to mice with collagen-induced arthritis (CIA) increased the severity of disease. Blood and inflamed paws from treated mice had fewer regulatory T cells (Tregs) but normal numbers of Th17 cells. However, PQS (1μM) treatment of antigen-stimulated lymph node cells from collagen-immunised mice in vitro inhibited the differentiation of CD4+IFNγ+ cells, with less effect on CD4+IL-17+ cells and no change in CD4+FoxP3+Tregs. PQS also inhibited T cell activation by anti-CD3/anti-CD28 antibodies. PQS reduced murine macrophage polarisation and inhibited expression of IL1B and IL6 genes in murine macrophages and human THP-1 cells. In human monocyte-derived macrophages, IDO1 gene, protein and enzyme activity were all inhibited by exposure to PQS. TNF gene expression was inhibited in THP-1 cells but not murine macrophages, while LPS-induced TNF protein release was increased by high PQS concentrations. PQS is known to have iron scavenging activity and its suppression of cytokine release was abrogated by iron supplementation. Unexpectedly, PQS decreased the expression of indoleamine-2, 3-dioxygenase genes (IDO1 and IDO2), IDO1 protein expression and enzyme activity in mouse and human macrophages. This is consistent with evidence that IDO1 inhibition or deletion exacerbates arthritis, while kynurenine reduces its severity. It is suggested that the inhibition of IDO1 and cytokine expression may contribute to the quorum sensor and invasive actions of PQS. [ABSTRACT FROM AUTHOR]

Background: The lockdown in May 2021 was the first and only lockdown implemented in Taiwan during the COVID-19 pandemic. The epidemic in Taiwan has been maintained under relatively better control and this study aimed to examine the impact of the lockdown on sleep and emotional and behavior disturbances in children and adolescents in Taiwan. Material and methods: Participants over 6 years old were recruited retrospectively from a cohort study, and their parents completed questionnaires including theChildren's SleepHabitsQuestionnaire (CSHQ), the Child Behavior Checklist (CBCL), the Swanson, Nolan and Pelham-IV Teacher and Parent Rating Scale (SNAP-IV), and the function assessment. A total of 217 children and adolescents whose parents completed questionnaires during both the lockdown period and the pre-lockdown period were included. We used paired t-test and independent t test; to analyze the diFFerences between the lockdown and pre-lockdown periods and between diFFerent subgroups. Results: The mean age of all participants was 11.87 ± 3.97 years, with 69.6% male. The results of CSHQ indicated that our participants had significantly increased total sleep time (p = 0.000), more sleep onset delay (p = 0.011), fewer sleep duration problems (p = 0.029), less parasomnia (p = 0.018), fewer sleep breathing problems (p = 0.028), and less daytime sleepiness (p = 0.000) during the lockdown, especially males and children. We observed trends but no significant changes of all participants in CBCL and SNAP during the lockdown. The change of the inattention index reached a significant level between children and adolescents (p² = 0.017). The results of the functional assessment showed more interferences in home living (p = 0.021) of all participants, especially males (p¹ = 0.002). Conclusions: The lockdown significantly impacted children and adolescents' sleep and functioning. We also observed trends of increased emotion, behavior and inattention problems, and significantly increased interference in home living. Male gender and younger age may be associated factors for sleep and functional disturbances of the lockdown. [ABSTRACT FROM AUTHOR]

Pinelliae rhizoma (PR), one kind of commonly-used Chinese herbs, is generally prescribed to treat various respiratory diseases, including acute lung injury (ALI). However, the accurate bioactive ingredients of PR and the underlying pharmacological mechanism have both not been fully elucidated. Therefore, this study aimed to identify the bioactive ingredients that could alleviate lipopolysaccharide (LPS)-induced ALI and explore the possible mechanism involved. Our results confirmed that LPS infection indeed caused acute inflammatory damage in mice lung, accompanying with the enhancement of IL-1β contents and the activation of the NLRP3 inflammasome in lung tissue and macrophagocyte, all of which were remarkably ameliorated by PR treatment. Next, mechanistically, LPS was found to trigger endoplasmic reticulum (ER) stress and downstream cellular calcium ions (Ca2+) release via activating Bip/ATF4/CHOP signaling pathway. Like PR, 4-PBA (a specific inhibitor of ER stress) not only obviously reversed Bip/ATF4/CHOP-mediated ER stress, but also significantly attenuated LPS-induced activation of the NLRP3 inflammasome. Furthermore, the bioactive ingredients of PR, which generated the antiinflammatory effects, were screened by metabolomics and network pharmacology. In vitro experiments showed that chrysin, dihydrocapsaicin, and 7,8-dihydroxyflavone (7,8-DHF) notably suppressed LPS-induced ER stress and following NLRP3 inflammasome activation. In conclusion, our findings suggested that PR alleviated LPS-induced ALI by inhibiting ER stress-mediated NLRP3 inflammasome activation, which is mainly relevant with these three bioactive ingredients. This study provided a theoretical basis for the clinical application of PR to treat ALI, and these bioactive ingredients of PR would be promising therapeutic drugs for the treatment of ALI. [ABSTRACT FROM AUTHOR]

Background: We conducted a five-year prospective follow-up study to track the real-world quality of life of patients with narcolepsy after medication and analyzed predictors. Methods: The study ultimately included 157 participants who completed 5-year follow-up, 111 had type 1 narcolepsy (NT1) and 46 had type 2 narcolepsy (NT2). Polysomnography, multiple sleep latency test, actigraphy and HLA-typing were conducted. The Short Form 36 Health Survey Questionnaire (SF-36), the Stanford Center for Narcolepsy Sleep Inventory, the Epworth Sleepiness Scale (ESS), the visual analog for hypersomnolence (VAS), and Conners' Continuous Performance Test were used. Descriptive statistics, repeated measures, and hierarchical linear models were applied for analysis. Results: Most demographic and clinical data did not significantly differ between groups, but the NT1 group had significantly more overweight, more severe narcoleptic symptoms, more positive HLA typing, shorter mean sleep latency, and more sleep onset rapid eye movement periods. No significant change to the physical domains of SF-36 was found in the total group, but we observed significant changes in emotional role functioning and social function. The NT1 group showed significant improvements in physical role functioning, emotional role functioning, and social function. The NT2 group demonstrated significant improvements in emotional role functioning. At the baseline, the NT2 group had significantly better scores, but there was no significant group difference after treatment, except for physical and social function. ESS and VAS were significantly improved during follow-up. At the baseline, the NT1 group had significantly higher ESS and VAS scores, and continuously significantly higher ESS scores during follow-up. Narcolepsy types, HLA typing, age of onset, symptom severity, attention and vigilance were significantly correlated with SF-36. Conclusion: Symptom control greatly associates with the quality of life in narcoleptic patients, and medication can play the most important role. Management targeting narcoleptic symptoms, attention impairment, and drug adherence should be provided. [ABSTRACT FROM AUTHOR]

The nephrotoxicity of Fructus Psoraleae, an effective traditional Chinese medicine for vitiligo treatment, has been reported. As one of the main toxic components in Fructus Psoraleae, bavachin (BV) was considered to be related to Fructus Psoraleae-caused adverse outcomes, but the direct evidence and molecular mechanism underlying BV-induced nephrotoxicity are not well elucidated. Therefore, this study was designed to confirm whether BV would cause toxic effects on the kidney and explore the possible mode of action. Our results demonstrated that days' treatment with 0.5 µM BV indeed caused obvious renal fibrosis in the zebrafish kidney. The obvious E- to N-cadherin switch and the expressions of proteins promoting epithelial-mesenchymal transition (EMT) were observed in BV-treated human renal tubular epithelial and zebrafish kidneys. In addition, elevated reactive oxygen species (ROS) levels and Bip/eIF2α/CHOP-mediated endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) were caused by BV, both of which could be reversed by ROS scavenger N-acetyl-L-cysteine (NAC). Also, blocking ER stress-caused cytoplasmic Ca2+ overload with 4-PBA notably alleviated BV-induced alterations in key molecular events related to EMT and renal fibrosis. Furthermore, of the natural compounds subjected to screening, ginsenoside Rb1 significantly downregulated BV-induced ER stress by inhibiting ROS generation and following the activation of Bip/eIF2α/CHOP signaling in HK2 cells. Subsequently, BV-triggered EMT and renal fibrosis were both ameliorated by ginsenoside Rb1. In summary, our findings suggested that BV-induced ROS promoted the appearance of EMT and renal fibrosis mainly via Bip/eIF2α/CHOP-mediated ER stress. This ER stress-related toxic pathway might be a potential intervention target for BV-caused renal fibrosis, and ginsenoside Rb1 would be a promising drug against BV- or Fructus Psoraleae-induced nephrotoxicity. [ABSTRACT FROM AUTHOR]

Pepper is an important vegetable in the world. In this work, mRNA and ncRNA transcriptome profiles were applied to understand the heterosis effect on the alteration in the gene expression at the seedling and flowering stages between the hybrid and its parents in Capsicum chinense. Our phenotypic data indicated that the hybrid has dominance in leaf area, plant scope, plant height, and fruit-related traits. Kyoto Encyclopedia of Genes and Genomes analysis showed that nine members of the plant hormone signal transduction pathway were upregulated in the seedling and flowering stages of the hybrid, which was supported by weighted gene coexpression network analysis and that BC332_23046 (auxin response factor 8), BC332_18317 (auxin-responsive protein IAA20), BC332_13398 (ethylene-responsive transcription factor), and BC332_27606 (ethylene-responsive transcription factor WIN1) were candidate hub genes, suggesting the important potential role of the plant hormone signal transduction in pepper heterosis. Furthermore, some transcription factor families, including bHLH, MYB, and HSF were greatly over-dominant. We also identified 2,525 long ncRNAs (lncRNAs), 47 micro RNAs (miRNAs), and 71 circle RNAs (circRNAs) in the hybrid. In particular, downregulation of miR156, miR169, and miR369 in the hybrid suggested their relationship with pepper growth vigor. Moreover, we constructed some lncRNA–miRNA–mRNA regulatory networks that showed a multi-dimension to understand the ncRNA relationship with heterosis. These results will provide guidance for a better understanding of the molecular mechanism involved in pepper heterosis. [ABSTRACT FROM AUTHOR]

EMR2/ADGRE2 is a human myeloid-restricted adhesion G protein-coupled receptor critically implicated in vibratory urticaria, a rare type of allergy caused by vibration-induced mast cell activation. In addition, EMR2 is also highly expressed by monocyte/macrophages and has been linked to neutrophil migration and activation. Despite these findings, little is known of EMR2-mediated signaling and its role in myeloid biology. In this report, we show that activation of EMR2 via a receptor-specific monoclonal antibody promotes the differentiation of human THP-1 monocytic cell line and induces the expression of pro-inflammatory mediators, including IL-8, TNF-α, and MMP-9. Using specific signaling inhibitors and siRNA knockdowns, biochemical and functional analyses reveal that the EMR2-mediated signaling is initiated by Gα16, followed by the subsequent activation of Akt, extracellular signal-regulated kinase, c-Jun N-terminal kinase, and nuclear factor kappa-light-chain-enhancer of activated B cells. Our results demonstrate a functional role for EMR2 in the differentiation and inflammatory activation of human monocytic cells and provide potential targets for myeloid cell-mediated inflammatory disorders. [ABSTRACT FROM AUTHOR]

BackgroundDietary behavior is a main contributing yet modifiable factor to the body weight status of children and may be involved in the pathophysiology of childhood obstructive sleep apnea (OSA). This study aimed to investigate the dietary profile of pediatric OSA patients, effects of educational counseling after adenotonsillectomy, and predictor for disease resolution.MethodsThis observational study included 50 pediatric OSA patients undergoing adenotonsillectomy with routine educational counseling (Group 1), 50 pediatric OSA patients undergoing adenotonsillectomy without formal educational counseling (Group 2), and 303 healthy children without OSA (Control). The three groups were matched by age. The consumption frequency of 25 food items/groups was assessed by the Short Food Frequency Questionnaire. Quality of life was evaluated by the OSA-18 questionnaire. Sleep architecture and OSA severity were measured by standard polysomnography. Between- and within-group comparisons were analyzed by non-parametric approaches and generalized estimating equations. Prediction of disease recovery was performed by multivariable logistic regression models.ResultsGroup 1 children consumed fruit drinks with sugar, vegetables, sweets, chocolate, rice, and noodles more frequently than Control Group children. At baseline, the distributions of sex, weight status, OSA-18 scores, and polysomnographic variables were comparable between Group 1 and Group 2. After a 12-month follow-up, Group 1 had better improvements in physical suffering, caregiver concerns, sleep architecture, and mean peripheral oxygen saturation compared to Group 2. Furthermore, Group 1 no longer had excessive consumption of fruit drinks with sugar, chocolate, and noodles; however, food consumption frequencies did not change significantly. Notably, younger age and reduced intake of butter/margarine on bread and noodles were independent predictors of cured OSA in Group 1.ConclusionThe present study preliminarily characterized an unhealthy dietary profile among pediatric OSA patients and suggested that routine educational counseling in addition to adenotonsillectomy yielded some clinical benefits. Certain items/groups of food frequencies may be associated with disease recovery and further investigations are warranted.

BackgroundObstructive sleep apnea (OSA) is associated with impaired sleep quality and autonomic dysfunction. Adenotonsillectomy significantly improves subjective and objective sleep quality in children with OSA. However, the postoperative changes in heart rate variability (HRV) indices (indicators of cardiac autonomic function) and their importance remain inconclusive in childhood OSA. This retrospective case series aimed to investigate the association of sleep HRV indices, total OSA-18 questionnaire score (a subjective indicator of sleep quality) and polysomnographic parameters (objective indicators of sleep quality), and effects of adenotonsillectomy on HRV indices, total OSA-18 questionnaire score and polysomnographic parameters in children with OSA.MethodsSeventy-six children with OSA were included in baseline analysis, of whom 64 (84%) completed at least 3 months follow-up examinations after adenotonsillectomy and were included in outcome analysis. Associations between baseline variables, and relationships with treatment-related changes were examined.ResultsMultivariable linear regression models in the baseline analysis revealed independent relationships between tonsil size and obstructive apnea-hypopnea index (OAHI), adenoidal-nasopharyngeal ratio and very low frequency (VLF) power of HRV (an indicator of sympathetic activity), and normalized low frequency power (an indicator of sympathetic activity) and OAHI. The outcome analysis showed that adenotonsillectomy significantly improved standard deviation of all normal-to-normal intervals, and high frequency power, QoL (in terms of reduced total OSA-18 questionnaire score), OAHI and hypoxemia. Using a conceptual serial multiple mediation model, % change in OSA-18 questionnaire score and % change in VLF power serially mediated the relationships between change in tonsil size and % change in OAHI.ConclusionsThe improvement in OAHI after adenotonsillectomy was serially mediated by reductions in total OSA-18 questionnaire score and VLF power. These preliminary findings are novel and provide a direction for future research to investigate the effects of VLF power-guided interventions on childhood OSA.

Two of the molecular families closely associated with mediating communication between the brain and immune system are cytokines and the kynurenine metabolites of tryptophan. Both groups regulate neuron and glial activity in the central nervous system (CNS) and leukocyte function in the immune system, although neither group alone completely explains neuroimmune function, disease occurrence or severity. This essay suggests that the two families perform complementary functions generating an integrated network. The kynurenine pathway determines overall neuronal excitability and plasticity by modulating glutamate receptors and GPR35 activity across the CNS, and regulates general features of immune cell status, surveillance and tolerance which often involves the Aryl Hydrocarbon Receptor (AHR). Equally, cytokines and chemokines define and regulate specific populations of neurons, glia or immune system leukocytes, generating more specific responses within restricted CNS regions or leukocyte populations. In addition, as there is a much larger variety of these compounds, their homing properties enable the superimposition of dynamic variations of cell activity upon local, spatially limited, cell populations. This would in principle allow the targeting of potential treatments to restricted regions of the CNS. The proposed synergistic interface of ‘tonic’ kynurenine pathway affecting baseline activity and the superimposed ‘phasic’ cytokine system would constitute an integrated network explaining some features of neuroimmune communication. The concept would broaden the scope for the development of new treatments for disorders involving both the CNS and immune systems, with safer and more effective agents targeted to specific CNS regions.

Many invasive micro-organisms produce ‘quorum sensor’ molecules which regulate colony expansion and may modulate host immune responses. We have examined the ability of Pseudomonas Quorum Sensor (PQS) to influence cytokine expression under conditions of inflammatory stress. The administration of PQS in vivo to mice with collagen-induced arthritis (CIA) increased the severity of disease. Blood and inflamed paws from treated mice had fewer regulatory T cells (Tregs) but normal numbers of Th17 cells. However, PQS (1μM) treatment of antigen-stimulated lymph node cells from collagen-immunised mice in vitro inhibited the differentiation of CD4+IFNγ+ cells, with less effect on CD4+IL-17+ cells and no change in CD4+FoxP3+Tregs. PQS also inhibited T cell activation by anti-CD3/anti-CD28 antibodies. PQS reduced murine macrophage polarisation and inhibited expression of IL1B and IL6 genes in murine macrophages and human THP-1 cells. In human monocyte-derived macrophages, IDO1 gene, protein and enzyme activity were all inhibited by exposure to PQS. TNF gene expression was inhibited in THP-1 cells but not murine macrophages, while LPS-induced TNF protein release was increased by high PQS concentrations. PQS is known to have iron scavenging activity and its suppression of cytokine release was abrogated by iron supplementation. Unexpectedly, PQS decreased the expression of indoleamine-2, 3-dioxygenase genes (IDO1 and IDO2), IDO1 protein expression and enzyme activity in mouse and human macrophages. This is consistent with evidence that IDO1 inhibition or deletion exacerbates arthritis, while kynurenine reduces its severity. It is suggested that the inhibition of IDO1 and cytokine expression may contribute to the quorum sensor and invasive actions of PQS.

ObjectivesPrevious research has shown a possible relationship between endometriosis and autoimmune diseases. However, the relationship between endometriosis and ankylosing spondylitis (AS) is lacking. Therefore, we intended to find possible associations between endometriosis and AS using ICD-9 coding data in a population-based retrospective cohort study in Taiwan.MethodData for this retrospective cohort study were collected from the Taiwan National Health Insurance Research Database (NHIRD) between 2000–2012. We collected 13,145 patients with endometriosis and a 78,870 non-endometriosis comparison cohort. Diagnoses of endometriosis and AS were defined by the International Classification of Diseases-9 (ICD-9-CM) code for at least 3 outpatients or 1 hospitalization. Propensity score matching by comorbidities, corticosteroids, and non-steroidal anti-inflammatory drugs (NSAIDs) usage were done for baseline comparability. Cox proportional hazard models were used to evaluate crude and adjusted hazard ratios.ResultsThe cumulative incidence of AS was higher in patients with endometriosis compared to the non-endometriosis comparison cohort (log-rank test, p = 0.015). The adjusted hazard ratio (aHR) of incidental AS in patients with endometriosis was 1.61 (95% CI = 1.11 to 2.35) in comparison to the non-endometriosis comparison cohort. An increased risk of AS was also observed in subjects with major depressive disorder (aHR = 5.05, 95% CI = 1.85 to 13.78). Stratified analyses of age subgroups showed consistent results. NSAID users had a lower risk of AS than NSAID non-users (aHR 4.57 vs 1.35, p for interaction = 0.031).ConclusionsIn this retrospective population-based cohort study, we found a higher risk of AS in patients with endometriosis. We suggest that clinicians should pay attention to the occurrence of AS in patients with endometriosis.

Failed back surgery syndrome (FBSS) is a highly prevalent condition in patients after spine surgery. Although magnetic resonance imaging (MRI) is the gold standard for the diagnosis of epidural fibrosis, it is sometimes difficult to determine if epidural fibrosis contributes to radiculopathy. Herein, we share our experience in locating radiculopathy lesions using simultaneous positron emission tomography (PET)/MRI. 2-[18F]-FDG (18F-fluorodeoxyglucose) simultaneous PET/MRI maps of body glucose metabolism detected using PET can be used to correlate anatomical details provided by MRI to offer a very clear picture of neural inflammation due to extensive epidural fibrosis. More applications of 2-[18F]-FDG simultaneous PET/MRI in low back pain and other musculoskeletal diseases should be further investigated in the future.

Several serine proteases have been linked to autoimmune disorders and tumour initiation although the mechanisms are not fully understood. Activation of the kynurenine pathway enzyme indoleamine-2,3-dioxygenase (IDO1) modulates cellular activity in the brain, tolerogenesis in the immune system and is a major checkpoint in cancer development. We now report that IDO1 mRNA and IDO1 protein expression (generating kynurenine) are induced in human monocyte-derived macrophages by several chymotryptic serine proteases with direct links to tumorigenesis, including Prostate Specific Antigen (PSA), CD26 (Dipeptidyl-peptidase-4, CD26/DPP-4), High Temperature Requirement protein-A (HtrA), and the bacterial virulence factor subtilisin. These proteases also induce expression of the pro-inflammatory cytokine genes IL1B and IL6. Other serine proteases tested: bacterial glu-C endopeptidase and mammalian Pro-protein Convertase Subtilase-Kexin-3 (PCSK3, furin), urokinase plasminogen activator (uPA), cathepsin G or neutrophil elastase, did not induce IDO1, indicating that the reported effects are not a general property of all serine proteases. The results represent a novel mechanism of activating immunosuppressive IDO1 and inducing kynurenine generation which, together with the production of inflammatory cytokines, would contribute to tumour initiation and progression, providing a new target for drug development. In addition, the proteasomal S20 serine protease inhibitor carfilzomib, used in the treatment of myeloma, prevented the induction of IDO1 and cytokine gene expression, potentially contributing to its clinical anti-cancer activity.

Aristolactam I (ALI) is an active component derived from some Traditional Chinese medicines (TCMs), and also the important metabolite of aristolochic acid. Long-term administration of medicine-containing ALI was reported to be related to aristolochic acid nephropathy (AAN), which was attributed to ALI-induced nephrotoxicity. However, the toxic mechanism of action involved is still unclear. Recently, pathogenic ferroptosis mediated lipid peroxidation was demonstrated to cause kidney injury. Therefore, this study explored the role of ferroptosis induced by mitochondrial iron overload in ALI-induced nephrotoxicity, aiming to identify the possible toxic mechanism of ALI-induced chronic nephropathy. Our results showed that ALI inhibited HK-2 cell activity in a dose-dependent manner and significantly suppressed glutathione (GSH) levels, accompanying by significant increases in intracellular 4-hydroxynonenal (4-HNE) and intracellular iron ions. Moreover, the ALI-mediated cytotoxicity could be reversed by deferoxamine mesylate (DFO). Compared with other inhibitors, Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, obviously alleviated ALI-induced cytotoxicity. Furthermore, we have shown that ALI could remarkably increase the levels of superoxide anion and ferrous ions in mitochondria, and induce mitochondrial damage and condensed mitochondrial membrane density, the morphological characteristics of ferroptosis, all of which could be reversed by DFO. Interestingly, ALI dose-dependently inhibited these protein contents of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4), which could be partly rescued by Tin-protoporphyrin IX (SnPP) and mitoTEMPO co-treatment. In conclusion, our results demonstrated that mitochondrial iron overload-mediated antioxidant system inhibition would assist ALI-induced ferroptosis in renal tubular epithelial cells, and Nrf2-HO-1/GPX4 antioxidative system could be an important intervention target to prevent medicine containing ALI-induced nephropathy.

The importance of the kynurenine pathway in normal immune system function has led to an appreciation of its possible contribution to autoimmune disorders such as rheumatoid arthritis. Indoleamine-2,3-dioxygenase (IDO) activity exerts a protective function, limiting the severity of experimental arthritis, whereas deletion or inhibition exacerbates the symptoms. Other chronic disorder with an inflammatory component, such as atherosclerosis, are also suppressed by IDO activity. It is suggested that this overall anti-inflammatory activity is mediated by a change in the relative production or activity of Th17 and regulatory T cell populations. Kynurenines may play an anti-inflammatory role also in CNS disorders such as Huntington's disease, Alzheimer's disease and multiple sclerosis, in which signs of inflammation and neurodegeneration are involved. The possibility is discussed that in Huntington's disease kynurenines interact with other anti-inflammatory molecules such as Human Lymphocyte Antigen-G which may be relevant in other disorders. Kynurenine involvement may account for the protection afforded to animals with cerebral malaria and trypanosomiasis when they are treated with an inhibitor of kynurenine-3-monoxygenase (KMO). There is some evidence that changes in IL-10 may contribute to this protection and the relationship between kynurenines and IL-10 in arthritis and other inflammatory conditions should be explored. In addition, metabolites of kynurenine downstream of KMO, such as anthranilic acid and 3-hydroxy-anthranilic acid can influence inflammation, and the ratio of these compounds is a valuable biomarker of inflammatory status although the underlying molecular mechanisms of the changes require clarification. Hence it is essential that more effort be expended to identify their sites of action as potential targets for drug development. Finally, we discuss increasing awareness of the epigenetic regulation of IDO, for example by DNA methylation, a phenomenon which may explain differences between individuals in their susceptibility to arthritis and other inflammatory disorders.