Search

Using variable separation approach and series solving method of differential equations, analytical solutions for temperature and thermo-mechanical stresses in cross-ply laminated composite cylinder with finite length are presented in this article. The cylinder is assumed to be simply supported at its two ends and is subjected to non-uniform thermal and mechanical loadings on the inner and outer surfaces. As an example, numerical results of temperature distribution, stress fields, and interlayer stresses of a four-layer laminated composite cylinder are graphically presented and briefly discussed. [ABSTRACT FROM AUTHOR]

Brain iron homeostasis plays a vital role in maintaining brain development and controlling neuronal function under physiological conditions. Many studies have shown that the imbalance of brain iron homeostasis is closely related to the pathogenesis of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD). Recent advances have revealed the importance of iron transporters and regulatory molecules in the pathogenesis and treatment of NDs. This review summarizes the research progress on brain iron overload and the aberrant expression of several key iron transporters and regulators in AD and PD, emphasizes the pathological roles of these molecules in the pathogenesis of AD and PD, and highlights the therapeutic prospects of targeting these iron transporters and regulators to restore brain iron homeostasis in the treatment of AD and PD. A comprehensive understanding of the pathophysiological roles of iron, iron transporters and regulators, and their regulations in NDs may provide new therapeutic avenues for more targeted neurotherapeutic strategies for treating these diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objectives: To compare the clinical effect between two acupoint regimens of moxibustion on knee osteoarthritis (KOA), and observe the influences on the serum content of interleukin 1α (IL-1α), interleukin-17A (IL-17A), tumor necrosis factor α (TNF-α), bone gla protein (BGP) and osteoprotegerin (OPG)., Methods: KOA patients were randomly divided into an observation group (40 cases, 2 cases dropped off) and a control group (40 cases, 3 cases dropped off). In the observation group, moxibustion was applied to Xiyan (EX-LE5), Dubi (ST35), Zusanli (ST36), Dazhu (BL11), Xuanzhong (GB39) and Yongquan (KI1) on the affected side. In the control group, EX-LE5, ST35 and ST36 were selected on the affected side. One session of treatment took 30 min in each group, delivered 3 times a week and the duration of treatment was 4 weeks. The scores of Western Ontario and McMaster University (WOMAC) and visual analogue scale (VAS) were observed and the serum content of IL-1α, IL-17A, TNF-α, BGP and OPG of the two groups were measured before and after treatment., Results: Compared with those before treatment, the WOMAC score, VAS score and the serum content of IL-1α, IL-17A and TNF-α were decreased ( P <0.05), and the content of BGP and OPG were increased ( P <0.05) after treatment. Compared with the control group, the WOMAC score, VAS score and the serum content of IL-1α and TNF-α in the observation group were lower ( P <0.05), and the content of BGP and OPG were higher ( P <0.05). The total effective rate of the observation group was 89.5% (34/38), and that of the control group was 83.8% (31/37), with no statistically significant difference., Conclusions: Moxibustion therapy of "nourishing the kidney and benefiting the marrow" can relieve joint pain, improve joint function, reduce the level of inflammatory factors and ameliorate bone metabolic indicators. The effect of the acupoint regimen in this moxibustion therapy is better than that of the local acupoint selection.

The theory of "Developmental Origins of Health and Disease (DOHaD)" espouses that environmental exposures to toxicants during critical developmental stages can affect health outcomes in adulthood. Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer that can be transferred to developing organisms via the placenta and breast milk as an environmental endocrine disruptor. We herein implemented a cross-fostering model to decipher the contributions of prenatal vs. postnatal exposure to low or high dose DEHP (30 or 500 mg/kg-bw•d) on reproductive outcomes in male offspring and the underlying mechanism of action. Unexpectedly, we observed that postnatal DEHP exposure programmed weight gain in a dose-dependent manner, in-utero exposure to high dose DEHP appeared to constitute a significant factor in the weight loss of male offspring. Moreover, in the low dose group, offspring of control that were suckled by DEHP dams (CC-DE) generated a considerable number of adverse reproductive outcomes compared with the offspring of DEHP that were suckled by control dams (DE-CC), based on histopathologic alterations in the testis, blockage of sex hormone secretion, and transcriptional inhibition of steroid-hormone-related factors in the hypothalamic-pituitary-testicular (HPT) axis. However, DE-CC group affected reproductive dysfunction in male offspring more so than CC-DE in the high dose group. Mechanistically, DEHP contributed to the inhibition of steroidogenesis by perturbing the Wnt/β-catenin-signaling pathway. These studies confirm the sensitivity window in which future reproductive outcomes in offspring are influenced following developmental exposure to DEHP at two different dosages, and reveals a critical role for the Wnt/β-catenin signaling pathway in DEHP-induced male reproductive disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aims: Adult hippocampal neurogenesis is an important player in brain homeostasis and its impairment participates in neurological diseases. Iron overload has emerged as an irreversible factor of brain aging, and is also closely related to degenerative disorders, including cognitive dysfunction. However, whether brain iron overload alters hippocampal neurogenesis has not been reported. We investigated the effect of elevated iron content on adult hippocampal neurogenesis and explored the underlying mechanism., Methods: Mouse models with hippocampal iron overload were generated. Neurogenesis in hippocampus and expression levels of related molecules were assessed., Results: Iron accumulation in hippocampus remarkably impaired the differentiation of neural stem cells, resulting in a significant decrease in newborn neurons. The damage was possibly attributed to iron-induced downregulation of proprotein convertase furin and subsequently decreased maturation of brain-derived neurotrophic factor (BDNF), thus contributing to memory decline and anxiety-like behavior of mice. Supportively, knockdown of furin indeed suppressed hippocampal neurogenesis, while furin overexpression restored the impairment., Conclusion: These findings demonstrated that iron overload damaged hippocampal neurogenesis likely via iron-furin-BDNF pathway. This study provides new insights into potential mechanisms on iron-induced neurotoxicity and the causes of neurogenesis injury and renders modulating iron homeostasis and furin expression as novel therapeutic strategies for treatment of neurological diseases., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Aims: Disturbances in the circadian rhythm are positively correlated with the processes of aging and related neurodegenerative diseases, which are also associated with brain iron accumulation. However, the role of brain iron in regulating the biological rhythm is poorly understood. In this study, we investigated the impact of brain iron levels on the spontaneous locomotor activity of mice with altered brain iron levels and further explored the potential mechanisms governing these effects in vitro., Results: Our results revealed that conditional knockout of ferroportin 1 (Fpn1) in cerebral microvascular endothelial cells led to brain iron deficiency, subsequently resulting in enhanced locomotor activity and increased expression of clock genes, including the circadian locomotor output cycles kaput protein (Clock) and brain and muscle ARNT-like 1 (Bmal1). Concomitantly, the levels of period circadian regulator 1 (PER1), which functions as a transcriptional repressor in regulating biological rhythm, were decreased. Conversely, the elevated brain iron levels in APP/PS1 mice inhibited autonomous rhythmic activity. Additionally, our findings demonstrate a significant decrease in serum melatonin levels in Fpn1 cdh5 -CKO mice compared with the Fpn1 flox/flox group. In contrast, APP/PS1 mice with brain iron deposition exhibited higher serum melatonin levels than the WT group. Furthermore, in the human glioma cell line, U251, we observed reduced PER1 expression upon iron limitation by deferoxamine (DFO; iron chelator) or endogenous overexpression of FPN1. When U251 cells were made iron-replete by supplementation with ferric ammonium citrate (FAC) or increased iron import through transferrin receptor 1 (TfR1) overexpression, PER1 protein levels were increased. Additionally, we obtained similar results to U251 cells in mouse cerebellar astrocytes (MA-c), where we collected cells at different time points to investigate the rhythmic expression of core clock genes and the impact of DFO or FAC treatment on PER1 protein levels., Conclusion: These findings collectively suggest that altered iron levels influence the circadian rhythm by regulating PER1 expression and thereby modulating the molecular circadian clock. In conclusion, our study identifies the regulation of brain iron levels as a potential new target for treating age-related disruptions in the circadian rhythm., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Transmembrane serine protease 6 (Tmprss6) has been correlated with the occurrence and progression of tumors, but any specific molecular mechanism linking the enzyme to oncogenesis has remained elusive thus far. In the present study, we found that Tmprss6 markedly inhibited mouse neuroblastoma N2a (neuro-2a) cell proliferation and tumor growth in nude mice. Tmprss6 inhibits Smad1/5/8 phosphorylation by cleaving the bone morphogenetic protein (BMP) co-receptor, hemojuvelin (HJV). Ordinarily, phosphorylated Smad1/5/8 binds to Smad4 for nuclear translocation, which stimulates the expression of hepcidin, ultimately decreasing the export of iron through ferroportin 1 (FPN1). The decrease in cellular iron levels in neuro-2a cells with elevated Tmprss6 expression limited the availability of the metal forribo nucleotide reductase activity, thereby arresting the cell cycle prior to S phase. Interestingly, Smad4 promoted nuclear translocation of activating transcription factor 3 (ATF3) to activate the p38 mitogen-activated protein kinases signaling pathway by binding to ATF3, inducing apoptosis of neuro-2a cells and inhibiting tumor growth. Disruption of ATF3 expression significantly decreased apoptosis in Tmprss6 overexpressed neuro-2a cells. Our study describes a mechanism whereby Tmprss6 regulates the cell cycle and apoptosis. Thus, we propose Tmprss6 as a candidate target for inhibiting neuronal tumor growth., (© 2024. The Author(s).)

Background: Hepcidin is the master regulator of iron homeostasis. Hepcidin downregulation has been demonstrated in the brains of Alzheimer's disease (AD) patients. However, the mechanism underlying the role of hepcidin downregulation in cognitive impairment has not been elucidated., Methods: In the present study, we generated GFAP-Cre-mediated hepcidin conditional knockout mice (Hamp GFAP cKO) to explore the effect of hepcidin deficiency on hippocampal structure and neurocognition., Results: We found that the Hamp GFAP cKO mice developed AD-like brain atrophy and memory deficits. In particular, the weight of the hippocampus and the number of granule neurons in the dentate gyrus were significantly reduced. Further investigation demonstrated that the morphological change in the hippocampus of Hamp GFAP cKO mice was attributed to impaired neurogenesis caused by decreased proliferation of neural stem cells. Regarding the molecular mechanism, increased iron content after depletion of hepcidin followed by an elevated level of the inflammatory factor tumor necrosis factor-α accounted for the impairment of hippocampal neurogenesis in Hamp GFAP cKO mice. These observations were further verified in GFAP promoter-driven hepcidin knockdown mice and in Nestin-Cre-mediated hepcidin conditional knockout mice., Conclusions: The present findings demonstrated a critical role for hepcidin in hippocampal neurogenesis and validated the importance of iron and associated inflammatory cytokines as key modulators of neurodevelopment, providing insights into the potential pathogenesis of cognitive dysfunction and related treatments., (© 2024. The Author(s).)

Creating a personalized implant for cranioplasty can be costly and aesthetically challenging, particularly for comminuted fractures that affect a wide area. Despite significant advances in deep learning techniques for 2D image completion, generating a 3D shape inpainting remains challenging due to the higher dimensionality and computational demands for 3D skull models. Here, we present a practical deep-learning approach to generate implant geometry from defective 3D skull models created from CT scans. Our proposed 3D reconstruction system comprises two neural networks that produce high-quality implant models suitable for clinical use while reducing training time. The first network repairs low-resolution defective models, while the second network enhances the volumetric resolution of the repaired model. We have tested our method in simulations and real-life surgical practices, producing implants that fit naturally and precisely match defect boundaries, particularly for skull defects above the Frankfort horizontal plane., Competing Interests: Author Y-HY was employed by ADLINK Technology, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Yang and Chang.)

Background: The in-hospital mortality of cardiogenic shock (CS) remains high (28% to 45%). As a result, several studies developed prediction models to assess the mortality risk and provide guidance on treatment, including CardShock and IABP-SHOCK II scores, which performed modestly in external validation studies, reflecting the heterogeneity of the CS populations. Few articles established predictive scores of CS based on Asian people with a higher burden of comorbidities than Caucasians. We aimed to describe the clinical characteristics of a contemporary Asian population with CS, identify risk factors, and develop a predictive scoring model., Methods: A retrospective observational study was conducted between 2014 and 2019 to collect the patients who presented with all-cause CS in the emergency department of a single medical center in Taiwan. We divided patients into subgroups of CS related to acute myocardial infarction (AMI-CS) or heart failure (HF-CS). The outcome was all-cause 30-day mortality. We built the prediction model based on the hazard ratio of significant variables, and the cutoff point of each predictor was determined using the Youden index. We also assessed the discrimination ability of the risk score using the area under a receiver operating characteristic curve., Results: We enrolled 225 patients with CS. One hundred and seven patients (47.6%) were due to AMI-CS, and ninety-eight patients among them received reperfusion therapy. Forty-nine patients (21.8%) eventually died within 30 days. Fifty-three patients (23.55%) presented with platelet counts < 155 × 10 3 /μL, which were negatively associated with a 30-day mortality of CS in the restrictive cubic spline plot, even within the normal range of platelet counts. We identified four predictors: platelet counts < 200 × 10 3 /μL (HR 2.574, 95% CI 1.379-4.805, p = 0.003), left ventricular ejection fraction (LVEF) < 40% (HR 2.613, 95% CI 1.020-6.692, p = 0.045), age > 71 years (HR 2.452, 95% CI 1.327-4.531, p = 0.004), and lactate > 2.7 mmol/L (HR 1.967, 95% CI 1.069-3.620, p = 0.030). The risk score ended with a maximum of 5 points and showed an AUC (95% CI) of 0.774 (0.705-0.843) for all patients, 0.781 (0.678-0.883), and 0.759 (0.662-0.855) for AMI-CS and HF-CS sub-groups, respectively, all p < 0.001., Conclusions: Based on four parameters, platelet counts, LVEF, age, and lactate (PEAL), this model showed a good predictive performance for all-cause mortality at 30 days in the all patients, AMI-CS, and HF-CS subgroups. The restrictive cubic spline plot showed a significantly negative correlation between initial platelet counts and 30-day mortality risk in the AMI-CS and HF-CS subgroups.

Iron plays an essential role in various physiological processes. A disruption in iron homeostasis can lead to severe consequences, including impaired neurodevelopment, neurodegenerative disorders, stroke, and cancer. Interestingly, the link between mental health disorders and iron homeostasis has not received significant attention. Therefore, our understanding of iron metabolism in the context of psychological diseases is incomplete. In this review, we aim to discuss the pathologies and potential mechanisms that relate to iron homeostasis in associated mental disorders. We propose the hypothesis that maintaining brain iron homeostasis can support neuronal physiological functions by impacting key enzymatic activities during neurotransmission, redox balance, and myelination. In conclusion, our review highlights the importance of investigating the relationship between trace element nutrition and the pathological process of mental disorders, focusing on iron. This nutritional perspective can offer valuable insights for the clinical treatment of mental disorders.

Objectives: Cerebral venous sinus thrombosis (CVST) can cause sinus obstruction and stenosis, with potentially fatal consequences. High-resolution magnetic resonance imaging (HRMRI) can diagnose CVST qualitatively, although quantitative screening methods are lacking for patients refractory to anticoagulation therapy and who may benefit from endovascular treatment (EVT). Thus, in this study, we used radiomic features (RFs) extracted from HRMRI to build machine learning models to predict response to drug therapy and determine the appropriateness of EVT., Materials and Methods: RFs were extracted from three-dimensional T1-weighted motion-sensitized driven equilibrium (MSDE), T2-weighted MSDE, T1-contrast, and T1-contrast MSDE sequences to build radiomic signatures and support vector machine (SVM) models for predicting the efficacy of standard drug therapy and the necessity of EVT., Results: We retrospectively included 53 patients with CVST in a prospective cohort study, among whom 14 underwent EVT after standard drug therapy failed. Thirteen RFs were selected to construct the RF signature and CVST-SVM models. In the validation dataset, the sensitivity, specificity, and area under the curve performance for the RF signature model were 0.833, 0.937, and 0.977, respectively. The radiomic score was correlated with days from symptom onset, history of dyslipidemia, smoking, fibrin degradation product, and D-dimer levels. The sensitivity, specificity, and area under the curve for the CVST-SVM model in the validation set were 0.917, 0.969, and 0.992, respectively., Conclusions: The CVST-SVM model trained with RFs extracted from HRMRI outperformed the RF signature model and could aid physicians in predicting patient responses to drug treatment and identifying those who may require EVT., (© 2023. The Author(s).)

Background: Mothers of children undergoing surgery for congenital heart disease experience significant stress. Therefore, finding a strategy to decrease this is vital., Aims: To examine whether adding educational digital video discs to routine education can reduce maternal anxiety and depression when their children undergo heart surgery and when surgical or post-surgical complications occur., Study Design: In a teaching hospital, 120 mothers whose children underwent elective heart surgery were randomly and equally divided into two groups: mothers receiving routine education plus a digital video disc before surgery and mothers receiving only routine education. Mothers' anxiety and depression levels were compared before education, after education (before surgery), and on discharge day. The effect of watching the digital video disc on maternal anxiety and depression on discharge day was evaluated for the participants whose children had surgical or post-surgical complications., Results: Compared with only routine education, mothers' anxiety after education and on the discharge day decreased more if digital video disc was added. Depression decreased more after education, but no difference was found on the discharge day. Anxiety levels of mothers whose children had surgical or post-surgical complications on the discharge day decreased more if they watched the digital video disc, compared with those receiving only routine education (Beck anxiety inventory score 3.4 ± 1.9 and 6.1 ± 2.4 respectively; p-value .001)., Conclusions: Compared with only routine education, adding digital video disc could decrease mothers' anxiety, and until the day of discharge. Compared with only routine education, adding digital video disc could decrease mothers' anxiety on the discharge day if their child had surgical or post-surgical complications., Relevance to Clinical Practice: Adding educational digital video disc to routine education could decrease mothers' anxiety until the day of discharge. It could also decrease mothers' anxiety if their child had surgical or post-surgical complications., (© 2022 British Association of Critical Care Nurses.)

This study evaluates the management capacity ability and profitable capacity of eight public-private partnership hospitals in Taiwan from 2015 to 2020. By conducting various ratio analyses of the financial statement, this study found these hospitals have achieved a balance between management efficiency and profitability, thereby confirming the viability of the PPP model for hospital management. In addition, the subject hospitals play a vital role as isolation hospitals during the COVID-19 pandemic. Beyond offering medical assistance to infected individuals, these hospitals contribute to the integrity of Taiwan's medical network, mitigating the impact of the pandemic. Overall, establishing and managing hospitals with PPP partnership is a feasible solution as it alleviates governmental financial burdens related to medical welfare and achieves profitability., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ferroptosis is an iron-dependent, lipid peroxidation-driven cell death pathway, while Parkinson's disease (PD) patients exhibit iron deposition and lipid peroxidation in the brain. Thus, the features of ferroptosis highly overlap with the pathophysiological features of PD. Despite this superficial connection, the possible role(s) of ferroptosis-related (Fr) proteins in dopaminergic neurons and/or glial cells in the substantia nigra (SN) in PD have not been examined in depth. To explore the correlations between the different SN cell types and ferroptosis at the single-cell level in PD patients, and to explore genes that may affect the sensitivity of dopaminergic neurons to ferroptosis, we performed in silico analysis of a single cell RNA sequence (RNA-seq) set (GSE178265) from the Gene Expression Omnibus (GEO) database. We identified differentially expressed genes (DEGs) in the different cell types in the human SN, and proceeded to perform enrichment analysis, constructing a protein-protein interaction network from the DEGs of dopaminergic neurons with the Metascape database. We examined the intersection of Fr genes present in the FerrDb database with DEGs from the GSE178265 set to identify Fr-DEGs in the different brain cells. Further, we identified Fr-DEGs encoding secreted proteins to implicate cell-cell interactions in the potential stimulation of ferroptosis in PD. The Fr-DEGs we identified were verified using the bulk RNA-seq sets (GSE49036 and GSE20164). The number of dopaminergic neurons decreased in the SN of PD patients. Interestingly, non-dopaminergic neurons possessed the fewest DEGs. Enrichment analysis of dopaminergic neurons' DEGs revealed changes in transmission across chemical synapses and ATP metabolic process in PD. The secreted Fr-DEGs identified were ceruloplasmin (CP), high mobility group box 1 (HMGB1) and transferrin (TF). The bulk RNA-seq set from the GEO database demonstrates that CP expression is increased in the PD brain. In conclusion, our results identify CP as a potential therapeutic target to protect dopaminergic neurons by reducing neurons' sensitivity to ferroptosis., (© 2023. Springer Nature Limited.)

Cryptococcal infection is usually diagnosed in immunocompromised individuals and those with meningeal involvement, accounting for most cryptococcosis. Cryptococcemia indicates a poor prognosis and prolongs the course of treatment. We use the scoring systems to predict the mortality risk of cryptococcal fungemia. This was a single hospital-based retrospective study on patients diagnosed with cryptococcal fungemia confirmed by at least one blood culture collected from the emergency department covering January 2012 and December 2020 from electronic medical records in the Taichung Veterans General Hospital. We enrolled 42 patients, including 28 (66.7%) males and 14 (33.3%) females with a mean age of 63.0 ± 19.7 years. The hospital stay ranged from 1 to 170 days (a mean stay of 44.4 days), and the overall mortality rate was 64.3% (27/42). In univariate analysis, the AUC of ROC for MEWS, RAPS, qSOFA, MEWS plus GCS, REMS, NEWS, and MEDS showed 0.833, 0.842, 0.848, 0.846, 0.846, 0.878, and 0.905. In the multivariate Cox regression analysis, all scoring systems, older age, lactate, MAP, and DBP, indicated significant differences between survivor and non-survivor groups. Our results show that all scoring systems could apply in predicting the outcome of patients with cryptococcal fungemia, and the MEDS displays the best performance. We recommend a further large-scale prospective study for patients with cryptococcal fungemia.

Iron is important for life, and iron deficiency impairs development, but whether the iron level regulates neural differentiation remains elusive. In this study, with iron-regulatory proteins (IRPs) knockout embryonic stem cells (ESCs) that showed severe iron deficiency, we found that the Pax6- and Sox2-positive neuronal precursor cells and Tuj1 fibers in IRP1 -/- IRP2 -/- ESCs were significantly decreased after inducing neural differentiation. Consistently, in vivo study showed that the knockdown of IRP1 in IRP2 -/- fetal mice remarkably affected the differentiation of neuronal precursors and the migration of neurons. These findings suggest that low intracellular iron status significantly inhibits neurodifferentiation. When supplementing IRP1 -/- IRP2 -/- ESCs with iron, these ESCs could differentiate normally. Further investigations revealed that the underlying mechanism was associated with an increase in reactive oxygen species (ROS) production caused by the substantially low level of iron and the down-regulation of iron-sulfur cluster protein ISCU, which, in turn, affected the proliferation and differentiation of stem cells. Thus, the appropriate amount of iron is crucial for maintaining normal neural differentiation that is termed ferrodifferentiation., (© 2023. Science China Press.)

Cadmium pollution in Moso bamboo forests poses a potential threat to the sustainable development of the bamboo industry. However, the effects of cadmium toxicity on Moso growth and its mechanisms of adaptation to cadmium stress are poorly understood. In this study, the physiological and transcriptional response of Moso to cadmium stress was investigated in detail using Moso seedlings in a hydroponic system. Cadmium toxicity severely inhibited the growth of roots but had little effect on biomass accumulation in the aerial parts. Cadmium accumulation in roots and aerial parts increased as external cadmium increased, with cadmium mainly localized in the epidermis and pericycle cells in the roots. The uptake and root-to-shoot translocation of cadmium was stimulated, but the photosynthetic process was suppressed under cadmium stress. A total of 3469 differentially expressed genes were identified from the transcriptome profile and those involved in cadmium uptake, transportation and detoxification were analyzed as candidates for having roles in adaptation to cadmium stress. The results suggested that Moso is highly efficient in cadmium uptake, xylem loading and translocation, as well as having a high capacity for cadmium accumulation. This work also provided basic information on physiological and transcriptional responses of Moso to cadmium toxicity., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The incidence of neurological diseases, such as Parkinson's disease, Alzheimer's disease and stroke, is increasing. An increasing number of studies have correlated these diseases with brain iron overload and the resulting oxidative damage. Brain iron deficiency has also been closely linked to neurodevelopment. These neurological disorders seriously affect the physical and mental health of patients and bring heavy economic burdens to families and society. Therefore, it is important to maintain brain iron homeostasis and to understand the mechanism of brain iron disorders affecting reactive oxygen species (ROS) balance, resulting in neural damage, cell death and, ultimately, leading to the development of disease. Evidence has shown that many therapies targeting brain iron and ROS imbalances have good preventive and therapeutic effects on neurological diseases. This review highlights the molecular mechanisms, pathogenesis and treatment strategies of brain iron metabolism disorders in neurological diseases.

Background: Dopamine is a neurotransmitter and has been found to regulate lymphocytes by acting on dopamine receptors (DRs). CD4 + T cells express all the five subtypes of DRs, D1R to D5R. Although CD4 + T cells have been involved in pathogenesis of rheumatoid arthritis (RA), roles of DRs expressed on these cells in RA are poorly understood. This study determined whether D2R expressed on CD4 + T cells regulates inflammatory responses and signs in collagen type II (CII)-induced arthritis (CIA), a mouse model of RA., Methods: DBA/1 mice and C57BL/6 mice with global D1r or D2r deficiency (D1r -/- or D2r -/- ) or CD4 + T cell-specific D2r deletion (D2r fl/fl /CD4 Cre ) were used to prepare CIA model by intradermal injection of CII. D2R agonist sumanirole was intraperitoneally administered in CIA mice. CD4 + T cells obtained from CIA mice were exposed to sumanirole or/and D2R antagonist L-741,626 in vitro. Arthritic symptoms were assessed by clinical arthritis scores. Flow cytometric assay measured frequencies of CD4 + T cell subsets (Th1, Th2, Th17 and Treg cells). Expression of specific transcription factors for the CD4 + T cell subsets was tested by Western blot. Cytokine production was estimated by quantitative PCR and ELISA., Results: CIA mice manifested a bias of CD4 + T cells towards Th1 and Th17 cells. D2r -/- CIA mice showed a stronger bias towards Th1 and Th17 phenotypes than CIA mice, while D1r -/- CIA mice did not show the changes. CD4 + T cell-specific D2r deletion exacerbated both the polarization towards Th1 and Th17 cells and the symptoms of arthritis. Sumanirole administration in CIA mice ameliorated the bias of CD4 + T cells towards Th1 and Th17 phenotypes as well as arthritic symptoms. Sumanirole treatment of in vitro CD4 + T cells obtained from CIA mice promoted the shift to Treg cells, and the effect of sumanirole was blocked by L-741,626., Conclusions: D2R expressed on CD4 + T cells is protective against imbalance between pro-inflammatory and anti-inflammatory T cells and arthritic symptoms in CIA., (© 2023. The Author(s).)

During the COVID-19 pandemic, people voluntarily reduced their necessary healthcare. We examined whether supplying educational digital versatile discs (DVDs) before admission can reduce parental rejection of pediatric cardiac catheterization for congenital heart disease (CHD). Parents of 70 children with CHD selected for cardiac catheterization were randomly allocated to the DVD (received pre-admission DVDs in the outpatient department; 70 parents of 35 children) or non-DVD groups (did not receive the DVDs; 70 parents of 35 children). The parents could reject the admission of their children within 7 days. Cardiac catheterization was rejected by 14 (20.0%) and 26 (37.1%) parents in the DVD and non-DVD groups, respectively ( p = 0.025). Parent Perceptions of Uncertainty Scale scores were lower in the DVD (128.3 ± 8.9 points) than in the non-DVD group (134.1 ± 7.3 points; p < 0.001). Decreased uncertainty due to pre-admission DVD watching could have contributed to the increased parental willingness for cardiac catheterization. The effects of pre-admission educational DVDs were more significant among parents with a lower education, rural residence, with only one child, female child, or younger child. Offering educational DVDs to parents of children selected for cardiac catheterization for CHD may decrease the parental rejection rate of the treatment.

The prophylaxis strategy for hepatitis B virus (HBV) reactivation in kidney transplant recipients (KTRs) with resolved HBV infection remains unclear. In this hospital-based retrospective cohort study, consecutive KTRs with resolved HBV infection were screened from the years 2000 through 2020. After excluding confounding conditions, 212 and 45 patients were respectively recruited into Anti-HBs positive and Anti-HBs negative groups. Cumulative incidences of, and subdistribution hazard ratios (SHRs) for HBV reactivation were analyzed after adjusting the competing risk. During a median 8.3 (mean 8.4 ± 4.9) years of follow-up, the 10-year cumulative incidence of HBV reactivation was significantly higher in Anti-HBs negative group when compared to that in Anti-HBs positive group (15.2%, 95% CI: 3.6-26.7 vs. 1.3%, 95% CI: 0.0-3.0; p < 0.001). In multivariable regression analysis, absence of anti-HBs (SHR 14.2, 95% CI: 3.09-65.2; p < 0.001) and use of high-dose steroids, i.e., steroid dose ≥20 mg/day of prednisolone equivalent over 4 weeks (SHR 8.96, 95% CI: 1.05-76.2; p = 0.045) were independent risk factors related to HBV reactivation. Accordingly, the 10-year cumulative incidence of HBV reactivation occurring in patients with two, one and zero risk factors was 42.7% (95% CI: 0.0-87.1), 7.9% (95% CI: 1.2-14.7) and 0%, respectively ( p < 0.001). In conclusion, the strategy of HBV antiviral prophylaxis may be defined according to the risk stratification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tsai, Wu, Chen, Yang, Huang, Chang, Chang and Lee.)

Ischemic stroke is associated with high mortality and morbidity rates worldwide. However, the molecular mechanisms underlying the neuronal damage incurred by stroke victims remain unclear. It has previously been reported that ischemic stroke can induce an increase in the levels of brain iron, which is an important factor of in the associated brain damage. Ferroportin 1 (FPN1), the only known cellular iron export protein, is found in brain microvascular endothelial cells (BMVECs) at the blood-brain barrier, and is considered the gateway for entry of plasma iron into the central nervous system. Despite the connection of brain iron to neuronal damage, the role of BMVECs FPN1 in ischemic stroke remains unexplored. Herein, we conditionally deleted Fpn1 in mouse endothelial cells (ECs), using VE-cadherin-Cre transgenic mice, and explored the impact on brain iron homeostasis after stroke. Our data demonstrated that Fpn1 knockout in ECs decreased the brain iron levels in mice, attenuated the oxidative stress and inflammatory responses after stroke, and inhibited both ferroptosis and apoptosis, ultimately alleviating neurological impairment and decreasing cerebral infarct volume during the acute phase of ischemic stroke. By contrast, we found that Fpn1 knockout in ECs delayed the recovery of neurological function in mice following ischemic stroke. We also found that ECs Fpn1 knockout decreased the brain iron levels after stroke, exacerbated glial cell proliferation, and inhibited neuronal development, indicating that the diminished brain iron levels hindered the repair of neural injury in mice. In conclusion, our findings reveal a dual consequence of FPN1 deficiency in ECs in the development of ischemic stroke. More specifically, iron deficiency initially exerts a neuroprotective effect during the acute phase of ischemic stroke but inhibits recovery during the later stages. Our findings are important to the development of iron- or FPN1-targeting therapeutics for the treatment of ischemic stroke., (© 2023. The Author(s).)

CHIR99021 is an aminopyrimidine derivative, which can efficiently inhibit the activity of glycogen synthesis kinase 3α (GSK-3α) and GSK-3β. As an essential component of stem cell culture medium, it plays an important role in maintaining cell stemness. However, the mechanism of its role is not fully understood. In the present study, we first found that removal of CHIR99021 from embryonic stem cell culture medium reduced iron storage in mouse embryonic stem cells (mESCs). CHIR99021-treated Neuro-2a cells led to an upregulation of ferritin expression and an increase in intracellular iron levels, along with GSK3β inhibition and Wnt/GSK-3β/β-catenin pathway activation. In addition, iron treatment activated the classical Wnt pathway by affecting the expression of β-catenin in the Neuro-2a cells. Our data link the role of iron in the maintenance of cell stemness via the Wnt/GSK-3β/β-catenin signaling pathway, and identify intermediate molecules, including Steap1, Bola2, and Kdm6bos, which may mediate the upregulation of ferritin expression by CHIR99021. These findings reveal novel mechanisms of the maintenance of cell stemness and differentiation and provide a theoretical basis for the development of new strategies in stem cell treatment in disease.

Proteins do not only serve as nutrients to fulfill the demand for food, but also are used as a source of bioactive proteins/polypeptides for regulating physical functions and promoting physical health. Female breast cancer has the highest incidence in the world and is a serious threat to women's health. Bioactive proteins/polypeptides exert strong anti-tumor effects and exhibit inhibition of multiple breast cancer cells. This review discussed the suppressing effects of bioactive proteins/polypeptides on breast cancer in vitro and in vivo, and their mechanisms of migration and invasion inhibition, apoptosis induction, and cell cycle arrest. This may contribute to providing a basis for the development of bioactive proteins/polypeptides for the treatment of breast cancer., Competing Interests: Conflict of interestThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© The Korean Society of Food Science and Technology 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Ceruloplasmin (CP) plays an important role in maintaining iron homeostasis. Cp gene knockout (Cp -/- ) mice develop a neurodegenerative disease with aging and show iron accumulation in the brain. However, iron deficiency has also been observed in 3 M Cp -/- mice. The use of systemic Cp gene knockout is insufficient to reveal specific functions for CP in the central nervous system. Considering recent discoveries that astrocytes synthetize the majority of brain CP, we generated astrocyte conditional Cp knockout (Cp Gfap cKO) mice, and found that iron contents decreased in the cerebral cortex and hippocampus of young (6 M) and old (18 M) Cp Gfap cKO mice. Further experiments revealed that 6 M Cp Gfap cKO mice exhibited impaired learning and memory function, while 18 M Cp Gfap cKO mice exhibited improved learning and memory function. Our study demonstrates that astrocytic Cp deletion blocks brain iron influx through the blood-brain-barrier, with concomitantly increased iron levels in brain microvascular endothelial cells, resulting in brain iron deficiency and down-regulation of ferritin levels in neurons, astrocytes, microglia and oligodendrocytes. At the young age, the synapse density, synapse-related protein levels, 5-hydroxytryptamine and norepinephrine, hippocampal neurogenesis and myelin formation were all decreased in Cp Gfap cKO mice. These changes affected learning and memory impairment in young Cp Gfap cKO mice. In old Cp Gfap cKO mice, iron accumulation with aging was attenuated, and was accompanied by the alleviation of the ROS-MAPK-apoptosis pathway, Tau phosphorylation and β-amyloid aggregation, thus delaying age-related memory decline. Overall, our results demonstrate that astrocytic Cp deletion has divergent effects on learning and memory function via different regulatory mechanisms induced by decreased iron contents in the brain of mice, which may present strategies for the prevention and treatment of dementia., (© 2022. The Author(s).)

Oxidative stress and deficient bioenergetics are key players in the pathological process of cerebral ischemia reperfusion injury (I/R). As a mitochondrial iron storage protein, mitochondrial ferritin (FtMt) plays a pivotal role in protecting neuronal cells from oxidative damage under stress conditions. However, the effects of FtMt in mitochondrial function and activation of apoptosis under cerebral I/R are barely understood. In the present study, we found that FtMt deficiency exacerbates neuronal apoptosis via classical mitochondria-depedent pathway and the endoplasmic reticulum (ER) stress pathway in brains exposed to I/R. Conversely, FtMt overexpression significantly inhibited oxygen and glucose deprivation and reperfusion (OGD/R)-induced apoptosis and the activation of ER stress response. Meanwhile, FtMt overexpression rescued OGD/R-induced mitochondrial iron overload, mitochondrial dysfunction, the generation of reactive oxygen species (ROS) and increased neuronal GSH content. Using the Seahorse and O2K cellular respiration analyser, we demonstrated that FtMt remarkably improved the ATP content and the spare respiratory capacity under I/R conditions. Importantly, we found that glucose consumption was augmented in FtMt overexpressing cells after OGD/R insult; overexpression of FtMt facilitated the activation of glucose 6-phosphate dehydrogenase and the production of NADPH in cells after OGD/R, indicating that the pentose-phosphate pathway is enhanced in FtMt overexpressing cells, thus strengthening the antioxidant capacity of neuronal cells. In summary, our results reveal that FtMt protects against I/R-induced apoptosis through enhancing mitochondrial bioenergetics and regulating glucose metabolism via the pentose-phosphate pathway, thus preventing ROS overproduction, and preserving energy metabolism., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The functional activities of gold nanoparticles (AuNPs) on biological systems depend on their physical-chemical properties and their surface functionalizations. Within a biological environment and depending on their surface characteristics, NPs can adsorb biomolecules (mostly proteins) present in the microenvironment, thereby forming a dynamic biomolecular corona on the surface. The presence of this biocorona changes the physical-chemical and functional properties of the NPs and how it interacts with cells. Here, we show that primary human epidermal keratinocytes (HEK) exposed in culture to branched polyethyleneimine (BPEI)-AuNPs, but not to lipoic acid (LA)-AuNPs, show potent particle uptake, decreased cell viability and enhanced production of inflammatory factors, while the presence of a human plasma-derived biocorona decreased NPs uptake and rescued cells from BPEI-AuNP-induced cell death. The mechanistic study revealed that the intracellular oxidative level greatly increased after the BPEI-AuNPs treatment, and the transcriptomic analysis showed that the dominant modulated pathways were related to oxidative stress and an antioxidant response. The stress level measured by flow cytometry also showed a significant decrease in the presence of a biocorona. Further anaylsis discovered that nuclear factor erythroid-2 related factor (Nrf2), a major regulator of anti-oxidant and anti-inflammatory genes, as the key factor related to the AuNPs induced oxidative stress and inflammation. This study provides futher understanding into the mechanisms on how NPs-induced cellular stress and reveals the protective effects of a biocorona on inflammatory responses in HEK at the molecular level, which provides important insights into the biological responses of AuNPs and their biocorona., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Glioma is the most common primary malignant brain tumor with high mortality and poor prognosis. Hepcidin is a fascinating iron metabolism regulator. However, the prognostic value of hepcidin HAMP in gliomas and its correlation with immune cell infiltration remain unclear. Here, we comprehensively elucidate the prognostic value and potential role of hepcidin in gliomas., Methods: Hepcidin gene expression and clinical characteristics in glioma were analyzed using the CGGA, TCGA, Rembrandt and Gravendeel glioma databases. A survival analysis was conducted using Kaplan-Meier and Cox regression analyses. A gene set enrichment analysis (GSEA) was conducted to select the pathways significantly enriched for hepcidin associations. The correlations between hepcidin and immune cell infiltration and immunotherapy were analyzed using network platforms such as CIBERSORT and TIMER., Results: In glioma tissues, the expression of hepcidin was significantly increased. High hepcidin expression is related to grade, age, PRS type, IDH mutation, chemotherapy status and 1p19q codeletion status, which significantly indicates the poor prognosis of glioma patients. Hepcidin can be used as an independent prognostic factor for glioma through the multivariate COX regression analysis. The results of Gene Ontology (GO), Kyoto Encyclopedia of Gene and Genome (KEGG) and gene set enrichment analysis (GSEA) indicated that hepcidin was involved in the immune response. In addition, hepcidin expression was positively correlated with the degree of immune cell infiltration, the expression of various immune cell markers and the efficacy of immunotherapy., Conclusion: Our results indicate that hepcidin can be used as a candidate biomarker to judge the prognosis and immune cell invasion of gliomas., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dong, Zhang, Zhang, Wang, Liu, Wang, Hao, Tan and Chang.)

Brain iron overload is positively correlated with the pathogenesis of Alzheimer's disease (AD). However, the role of iron in AD pathology is not completely understood. Furin is the first identified mammalian proprotein convertase that catalyzes the proteolytic maturation of large numbers of prohormones and proproteins. The correlation between altered furin expression and AD pathology has been suggested, but the underlying mechanism remains to be clarified. Here, we found that the expression of furin in the hippocampus of Alzheimer's model APP/PS1 mice was significantly reduced, and we demonstrated that the reduction of furin was directly caused by hippocampal iron overload using wild-type mice with intrahippocampal injection of iron. In cultured neuronal cells, this suppression effect was observed as transcriptional inhibition. Regarding the changes of furin-mediated activities caused by hippocampal iron overload, we found that the maturation of brain-derived neurotrophic factor (BDNF) was impeded and the expression levels of synaptogenesis-related proteins were downregulated, leading to cognitive decline. Furthermore, iron chelation or furin overexpression in the hippocampus of APP/PS1 mice increased furin expression, restored synapse plasticity, and ameliorated cognitive decline. Therefore, the inhibitory effect of hippocampal iron accumulation on furin transcription may be an important pathway involved in iron-mediated synapse damage and memory loss in AD. This study provides new insights into the molecular mechanisms of the toxic effects of iron in neurons and AD pathophysiology and renders furin as a potential target for treatment of iron overload-related neurodegenerative diseases., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The global emergency caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic can only be solved with effective and widespread preventive and therapeutic strategies, and both are still insufficient. Here, we describe an ultrathin two-dimensional CuInP 2 S 6 (CIPS) nanosheet as a new agent against SARS-CoV-2 infection. CIPS exhibits an extremely high and selective binding capacity (dissociation constant (K D ) < 1 pM) for the receptor binding domain of the spike protein of wild-type SARS-CoV-2 and its variants of concern, including Delta and Omicron, inhibiting virus entry and infection in angiotensin converting enzyme 2 (ACE2)-bearing cells, human airway epithelial organoids and human ACE2-transgenic mice. On association with CIPS, the virus is quickly phagocytosed and eliminated by macrophages, suggesting that CIPS could be successfully used to capture and facilitate virus elimination by the host. Thus, we propose CIPS as a promising nanodrug for future safe and effective anti-SARS-CoV-2 therapy, and as a decontamination agent and surface-coating material to reduce SARS-CoV-2 infectivity., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Furin is an important mammalian proprotein convertase that catalyzes the proteolytic maturation of a variety of prohormones and proproteins in the secretory pathway. In the brain, the substrates of furin include the proproteins of growth factors, receptors and enzymes. Emerging evidence, such as reduced FURIN mRNA expression in the brains of Alzheimer's disease patients or schizophrenia patients, has implicated a crucial role of furin in the pathophysiology of neurodegenerative and neuropsychiatric diseases. Currently, compared to cancer and infectious diseases, the aberrant expression of furin and its pharmaceutical potentials in neurological diseases remain poorly understood. In this article, we provide an overview on the physiological roles of furin and its substrates in the brain, summarize the deregulation of furin expression and its effects in neurodegenerative and neuropsychiatric disorders, and discuss the implications and current approaches that target furin for therapeutic interventions. This review may expedite future studies to clarify the molecular mechanisms of furin deregulation and involvement in the pathogenesis of neurodegenerative and neuropsychiatric diseases, and to develop new diagnosis and treatment strategies for these diseases., (© 2022. The Author(s).)

The demand for mobile epidemic prevention medical stations originated from the rapid spread of the COVID-19 pandemic. In order to reduce the infection risk of medical practitioners and provide flexible medical facilities in response to the variable needs of the pandemic, this research aimed to design mobile medical stations for COVID-19 epidemic prevention, the emergence of which began in February 2020. The mobile medical stations include a negative pressure isolation ward, a positive pressure swabbing station, a fever clinic and a laboratory. In Taiwan, many medical institutions used the mobile swabbing station design of this study to practice COVID-19 screening pre-tests. Internationally, this study assisted Palau in setting up medical stations to provide anti-epidemic goods and materials. The design of this study not only provides a highly flexible and safe medical environment but the benefits of screening can also be used as resources for medical research, forming an economic circulation for operation sustainability. In addition, the design of this study can also be used during the non-epidemic period as a healthcare station for rural areas or as a long-term community medical station.

The relationship between cardiovascular diseases and iron disorders has gained increasing attention; however, the effects of hypotensive drugs on iron metabolic alterations in hypertension are not well understood. The purpose of this study was to investigate iron metabolic changes after prazosin treatment of spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. Our second objective was to examine the effects of hypertension and anti-hypertensive drugs on bone formation and resorption. SHRs and WKY rats were randomized into either prazosin-treated groups (WKY + PZ and SHR + PZ) or untreated groups (WKY and SHR). After 7 days of intragastric prazosin administration, the rats were sacrificed for analysis; blood samples and organs (the duodenum, liver, kidneys, spleen, and femur) were collected. Both WKY + PZ and SHR groups exhibited iron deficiency in the serum and liver. Prazosin increased the iron levels in the bone tissue of SHRs. Prazosin stimulated the expression of hepcidin mRNA in the liver of SHRs and inhibited the expression of this iron-regulatory hormone in WKY rats. FPN1 expression in the duodenum was increased significantly in SHRs, however markedly decreased after prazosin treatment. The expression of TLR4 and Ctsk was enhanced in the bone tissue of SHRs, whereas CLC-7 expression was inhibited. Both hypotension and hypertension can lead to iron deficiency. Treatment with prazosin restored iron homeostasis in SHRs. The inverse impacts of prazosin on hepatic hepcidin expression in SHRs versus WKY rats indicates differing iron regulatory mechanisms between hypertensive and normal animals. The osteoclast activity was found to be enhanced in SHRs. Further study is needed to address whether the changes in osteoblast and osteoclast activity in SHRs correlates with the effects on iron metabolism., (© 2022 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Brain iron dysregulation associated with aging is closely related to motor and cognitive impairments in neurodegenerative diseases. The regulation of iron traffic at the blood-brain barrier (BBB) is crucial to maintain brain iron homeostasis. However, the specific mechanism has not been clarified in detail. Using various conditional gene knockout and overexpression mice, as well as cell co-culture of astrocyte and bEND.3 in the transwell, we found that astrocyte hepcidin knockdown increased the expression of ferroportin 1 (FPN1) of brain microvascular endothelial cells (BMVECs), and that it also induced brain iron overload and cognitive decline in mice. Moreover, BMVECs FPN1 knockout decreased iron contents in the cortex and hippocampus. Furthermore, hepcidin regulates the level of FPN1 of BMVECs with conditional gene overexpression in vivo and in vitro. Our results revealed that astrocytes responded to the intracellular high iron level and increased the secretion of hepcidin, which in turn diminished iron uptake at BBB from circulation through directly regulating FPN1 of BMVECs. Our results demonstrate that FPN1 of BMVECs is a gateway for iron transport into the brain from circulation, and the controller of this gateway is hepcidin secreted by astrocyte at its endfeet through physical contact with BMVECs. This regulation is indeed the major checkpoint for iron transport from the blood circulation to the brain. This study delineates the pathway and regulation of iron entry into the brain, providing potential therapeutic targets for iron dysregulation-related neurological diseases., (© 2022. The Author(s).)

For people with habits of chewing betel nuts and smoking, the probability of suffering from oral cancer is ten to a hundred times higher than others. Due to the serious health consequences of areca nut and tobacco, a reliable cessation program is needed. Hair is the best option to document long-term exposure. Unfortunately, the research on betel nut in hair did not attract much attention. In this study, a high-throughput method based on microwave-assisted extraction (MAE) and isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed to measure the four biomarkers of betel nuts and cigarettes, including areca alkaloids (arecoline), tobacco alkaloids (nicotine), and their metabolites (arecaidine and cotinine). The hair sample was washed, cut, weighed, and incubated for 3 min MAE with methanol/trifluoroacetic acid, then evaporated and reconstituted for LC-MS/MS analysis. The total experiment time was 50 min. The lower limits of quantification (LOQ) were 5-10 pg/mg. The intra-day and inter-day precision were 2.2-7.6%. Intra-day and inter-day accuracy were - 6.1-8.2%. The method showed good linearity (r 2 > 0.995) over LOQ - 1000 pg/mg concentration ranges. It was successfully applied to analyze 11 subjects of regular areca nut chewers, also smokers. Eight samples were black hair; three samples were naturally black hair with partially gray hair. Measured concentrations in black hair were in the range 56.9 pg/mg to 3.2 ng/mg for arecoline, 12.8 pg/mg to 222.2 pg/mg for arecaidine, 3.8 ng/mg to 33.4 ng/mg for nicotine and 1.1 ng/mg to 6.1 ng/mg for cotinine. The results showed lower levels in gray hair. This method was utilized successfully to analyze pg/mg levels of arecoline, arecaidine, nicotine, and cotinine, and good recoveries were obtained. The mean concentration of arecaidine and cotinine in hair was 15% and 20% of arecoline and nicotine, respectively. A good positive correlation was found between the concentrations of these compounds and self-report. This method improved extraction speed, concentration, and analysis of samples and is useful for monitoring betel nut and smoking cessation programs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Caffeine is well-known as a psychostimulant, and it can also be beneficial in numerous diseases such as diabetes and different types of cancer. Previous studies have shown that caffeine can have a protective role in bacterial infection-induced inflammation and hyperoxia-mediated pulmonary inflammation. Hepcidin, which is regulated by the IL-6/STAT3 inflammation pathway, is a peptide hormone that maintains systemic iron homeostasis. We hypothesized that caffeine's effects on inflammation may also influence hepcidin production and therefore systemic iron metabolism. To this end, we treated 2-month-old mice with caffeine by daily intragastric administration for 7 days, administering intraperitoneal LPS after the final caffeine treatment. Twelve hours after LPS treatment the mice were euthanized, and tissues were collected. We found that caffeine decreased hepatic hepcidin expression and attenuated LPS-induced hepatic hepcidin overexpression. IL-6 expression and STAT3 phosphorylation were also reduced upon caffeine administration. Additionally, hepatic and splenic FPN1 levels increased after caffeine treatment, leading to lower iron levels in liver and spleen tissues and higher iron levels in serum. Caffeine also prevented the increase in spleen weight and decrease in body weight after LPS treatment. Together, our findings suggest that caffeine decreases hepcidin expression via inhibiting inflammation and the activation of the IL-6/STAT3 pathway, thus presenting an attractive, potential therapeutic for the treatment of anemia of inflammation.

Blood-brain barrier (BBB) breakdown, a characteristic feature of ischemic stroke, contributes to poor patient outcomes. Brain microvascular endothelial cells (BMVECs) are a key component of the BBB and dysfunction or death of these cells following cerebral ischemia reperfusion (I/R) injury can disrupt the BBB, leading to leukocyte infiltration, brain edema and intracerebral hemorrhage. We previously demonstrated that mitochondrial ferritin (FtMt) can alleviate I/R-induced neuronal ferroptosis by inhibiting inflammation-regulated iron deposition. However, whether FtMt is involved in BBB disruption during cerebral I/R is still unknown. In the present study, we found that FtMt expression in BMVECs is upregulated after I/R and overexpression of FtMt attenuates I/R-induced BBB disruption. Mechanistically, we found that FtMt prevents tight junction loss and apoptosis by inhibiting iron dysregulation and reactive oxygen species (ROS) accumulation in I/R-treated BMVECs. Chelating excess iron with deferoxamine alleviates apoptosis in the brain endothelial cell line bEnd.3 under oxygen glucose deprivation followed by reoxygenation (OGD/R) insult. In summary, our data identify a previously unexplored effect for FtMt in the BBB and provide evidence that iron-mediated oxidative stress in BMVECs is an early cause of BMVECs damage and BBB breakdown in ischemic stroke.

A high-throughput method using microwave-assisted extraction, chemical derivatization and liquid chromatography-electrospray tandem mass spectrometry (LC-ESI-MS/MS) was developed for the simultaneous analysis of illicit drugs and their metabolites, including amphetamine (AMP), methamphetamine (MA), methylenedioxy- amphetamine (MDA), methylenedioxy-methamphetamine (MDMA), morphine (MOR), 6-acetylmorphine (6-AM), ketamine (K), and norketamine (NK) in a micro-segment of a single hair (0.4 mm). In order to elevate the throughput and sensitivities of selected compounds, 3 min microwave-assisted extraction and 10 min derivatization with dansyl chloride (DC) were employed. After derivatization, all compounds except ketamine and norketamine were derivatized and enhanced the sensitivities significantly. Derivatives showed intense fragment ions and low background noise on DC-MOR, DC-6-AM, and four DC-amphetamine-type stimulants. The total sample preparation and analysis time was 50 min. The calibration range was from LOQ to 5000 pg/mg, the coefficient of determination was better than 0.997. Intra-assay precision and accuracy were generally less than 15%. Limits of detection ranged from 15 to 50 pg/mg, limits of quantitation ranged between 45 and 125 pg/mg. The matrix effect was better than 90%. The method was successfully applied to the analysis of actual hair samples collected from multi-drug abusers. This advanced method showed practicality in hair analysis and was suitable for the extremely insufficient sample., (Copyright © 2022 Elsevier B.V. All rights reserved.)

As hematopoietic stem cells can differentiate into all hematopoietic lineages, mitigating the damage to hematopoietic stem cells is important for recovery from overdose radiation injury. Cells in bone marrow microenvironment are essential for hematopoietic stem cells maintenance and protection, and many of the paracrine mediators have been discovered in shaping hematopoietic function. Several recent reports support exosomes as effective regulators of hematopoietic stem cells, but the role of osteoblast derived exosomes in hematopoietic stem cells protection is less understood. Here, we investigated that osteoblast derived exosomes could alleviate radiation damage to hematopoietic stem cells. We show that intravenous injection of osteoblast derived exosomes promoted WBC, lymphocyte, monocyte and hematopoietic stem cells recovery after irradiation significantly. By sequencing osteoblast derived exosomes derived miRNAs and verified in vitro , we identified miR-21 is involved in hematopoietic stem cells protection via targeting PDCD4. Collectively, our data demonstrate that osteoblast derived exosomes derived miR-21 is a resultful regulator to radio-protection of hematopoietic stem cells and provide a new strategy for reducing radiation induced hematopoietic injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xue, Du, Ling, Song, Yuan, Liu, Sun, Li, Zhong, Wang, Yuan, Jin, Liu, Zhao, Li, Xing, Fan, Liu, Pan, Zhen, Zhao, Yang, Li, Chang and Li.)

Objective: To evaluate the association between maternal ambient pollutant exposure and neonatal jaundice in multiple pollutant species and examine sex differences., Study Design: Epidemiologic study: Records of 13 297 newborns (6153 male, 7144 female) born in Taichung, Taiwan were obtained from a national database. Average concentrations of prenatal air pollutants 3 months prior to birth were divided into low, middle, and high levels. Neonatal jaundice phototherapy rates between mothers who suffered varying air pollutant levels were compared. Clinical study: Three hundred seventy-six newborns (189 male, 187 female) born and received jaundice treatment with phototherapy in a hospital in Taichung, Taiwan were recruited. The correlation between prenatal exposure to air pollutants 3 months prior to birth, newborn's serum bilirubin, and serum hemoglobin were calculated., Results: Epidemiologic study: Male newborns born to mothers exposed to high carbon monoxide (CO), nitric oxide (NO), nitrogen dioxide (NO 2 ), and methane (CH 4 ) levels had higher phototherapy rates. In female newborns, the same was noted for CO and CH 4 . Clinical study: Male newborns had a positive correlation between CO, ≤2.5 μm diameter particles, ≤10 μm diameter particles, NO, NO 2 , nonmethane hydrocarbon, and CH 4 exposure 3 months prior to birth and serum bilirubin levels. Female newborns had a positive correlation for CH 4 . A positive correlation between CO, ≤2.5 μm diameter particles, ≤10 μm diameter particles, NO 2 , nonmethane hydrocarbon, CH 4 exposure, and serum hemoglobin levels was noted in male newborns., Conclusion: Maternal exposure to air pollutants may increase neonatal jaundice treatment rates for phototherapy and higher neonatal serum total bilirubin level. Higher hemoglobin levels because of higher pollutant exposures may explain our findings. The association was more obvious in male newborns., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The endogenous repair mechanisms play an important role in the recovery of nerve function after stroke, such as gliosis, synaptic plasticity, remyelination and nerve regeneration. Iron is the most abundant trace metal element in the brain and plays a crucial role in the maintenance of normal cerebral function. It is an important coenzyme factor in the process of cell metabolism, DNA synthesis, purine catabolism and neurotransmitter synthesis and decomposition. However, it is unclear what role iron plays in the long-term recovery of neurological function after stroke. In this study, we first observed that changes in iron metabolism occurred during neurological function recovery in the mice with distal middle cerebral artery occlusion (dMCAO). Our data showed that plasticity changes due to endogenous repair mechanisms resulted in improvements in cerebral cortex function. These changes involved gliosis, synaptic function reconstruction, remyelination, and activation of neural stem cells. In order to examine the potential role of iron, we synthesized liposomal-encapsulated deferoxamine (DFO) nanoparticles to further explore the effect and the mechanism of iron on the recovery of neurological function in dMCAO mice. Our results showed that liposome-DFO decreased iron deposition and reversed plasticity changes in cerebral cortex function after stroke, which delayed neurological function recovery. This experiment shows that the increasing iron level promotes endogenous repair in ischemic stroke. Our finding reveals the change regularity of iron and emphasizes the beneficial role of iron in the recovery process of neurological function, which provides an important basis for the prevention and/or treatment of ischemia-reperfusion and recovery after stroke., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We present a 3D deep learning framework that can generate a complete cranial model using a defective one. The Boolean subtraction between these two models generates the geometry of the implant required for surgical reconstruction. There is little or no need for post-processing to eliminate noise in the implant model generated by the proposed approach. The framework can be used to meet the repair needs of cranial imperfections caused by trauma, congenital defects, plastic surgery, or tumor resection. Traditional implant design methods for skull reconstruction rely on the mirror operation. However, these approaches have great limitations when the defect crosses the plane of symmetry or the patient's skull is asymmetrical. The proposed deep learning framework is based on an enhanced three-dimensional autoencoder. Each training sample for the framework is a pair consisting of a cranial model converted from CT images and a corresponding model with simulated defects on it. Our approach can learn the spatial distribution of the upper part of normal cranial bones and use flawed cranial data to predict its complete geometry. Empirical research on simulated defects and actual clinical applications shows that our framework can meet most of the requirements of cranioplasty., (© 2022. The Author(s).)