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Abstract Systemic lupus erythematosus (SLE) is a chronic and systemic autoimmune disease characterized by dysregulation in both innate and adaptive immunity. Polarization of macrophages into M1/M2 macrophages affects the development of lupus. Exosomes-miRNA plays a crucial role in disease progression. This study aims to explore the mechanism of circulating exosomes participating in the pathogenesis of SLE and seek new therapeutic targets. Plasma derived-exosomes from SLE patients accelerated the disease progression and polarization of macrophages of the kidney in MRL/lpr mice. Exosomes were taken up by macrophages and stimulated macrophage polarization in vitro. MiRNA-sequence analysis revealed that plasma-derived exosomal miR-151a-5p, miR-1180a-5p, miR-1246 and miR-122-5p were abnormal. Of them, the expression of miR-122-5p was significantly upregulated in SLE exosomes, and positively correlated with systemic lupus erythematosus disease activity index (SLEDAI) and the dsDNA levels. Compared with SLE exosomes, inhibition of circulating exosomal miR-122-5p from SLE patients relieved lupus clinical aspects and polarization of macrophage. SLE exosomal miR-122-5p motivated M1 macrophage polarization by targeting FOXO3/NF-κB signaling pathway. Based on these findings, we conclude that SLE exosomal miR-122-5p can promote M1 macrophage polarization via targeting FOXO3/NF-κB signaling pathway and participate in pathogenesis of SLE. Collectively, plasma-derived exosomal miR-122-5p is a promising and effective target for treating SLE. Graphical Abstract

Abstract Accumulating evidence has shown that tRNA-derived small RNAs (tsRNAs) play crucial roles in malignant tumor development. However, whether serum tsRNAs can act as potential biological markers for hepatocellular carcinoma (HCC) are still largely unknown. In the current study, a novel tsRNA, namely tsRNA-Thr-5-0015, was prominently elevated in the sera of HCC patients than that of hepatitis cases and healthy check-ups, and it was related with TNM stage and lymphatic metastasis of HCC patients. Moreover, methodological evaluation confirmed that tsRNA-Thr-5-0015 had excellent stability, precision, accuracy and linear range. Additionally, the combined detection of serum tsRNA-Thr-5-0015 with AFP as well as PIVKA-II improved the diagnostic sensitivity for HCC. Furthermore, dynamic monitoring found that the serum tsRNA-Thr-5-0015 was drastically decreased in the postoperative HCC patients. Besides, Kaplan–Meier analysis displayed that patients with high level of serum tsRNA-Thr-5-0015 had shorter overall survival than that of the low level ones. In addition, bioinformatic prediction unveiled that the downstream targets of tsRNA-Thr-5-0015 were enriched in several signaling pathways, such as MAPK, PI3K-Akt, etc. In summary, tsRNA-Thr-5-0015 may be a promising biomarker for HCC diagnosis, therapeutic effect assessment and prognosis judgement. Especially, the combination with serum tsRNA-Thr-5-0015, AFP and PIVKA-II can enhance the diagnostic efficiency for HCC.

BackgroundThe Omicron variant’s high transmissibility has made it the most widespread novel coronavirus variant. Elevated serum β2-MG levels from viral infections and EOS’ role in viral clearance have garnered attention. However, their predictive value for Omicron’s severity and prognosis needs further exploration.MethodsThis retrospective study included 424 patients with confirmed COVID-19 Omicron variant admitted to the Second Hospital of Jilin University in Changchun, China, of whom 128 experienced in-hospital mortality. Patients were divided into high and low groups according to β2-MG and EOS levels; the relationship between disease severity and patient prognosis was analyzed.ResultsOur findings showed that severe-to-critical Omicron patients had higher β2-MG levels than mild-normal patients. Conversely, EOS levels were higher in mild-moderate cases. Both β2-MG and EOS levels normalized when Omicron patients tested negative for nucleic acid. Deceased Omicron patients had significantly lower pre-mortem EOS levels. Elevated β2-MG and lower EOS levels correlated with reduced overall survival. Multivariate COX regression analysis indicated that elevated β2-MG was an independent adverse prognostic factor for Omicron patients.ConclusionHigh serum β2-MG levels and low eosinophil levels upon admission correlate with omicron variant severity and prognosis. β2-MG is an independent risk factor for poor outcomes in omicron patients.

[Introduction] With the large-scale application of new energy, the challenges faced by the grid connection of new energy power generation are growing, and the importance of energy storage system is increasing. carbon dioxide energy storage (CES) technology is a kind of compressed gas energy storage technology emerging in recent years, with the advantages of high energy storage density, long service life and high design flexibility. For liquid carbon dioxide energy storage (LCES) technology, CO2 is stored as liquid phase in both HP and LP sides of the system, which has high energy storage density and strong operation stability. [Method] Firstly, the operation principle and key technical indicators of the LCES system was introduced and the importance of carbon dioxide liquefaction and common liquefaction processes were clarified. Then, the research status of CO2 liquefaction on the LP side of the LCES system was introduced, including the use of mixed energy storage working medium, self-condensation, the LNG cold energy, and the regenerator. The characteristics of each method were analyzed in detail. [Result] The research indicates that the application of regenerator is the most effective method. It is necessary to further analyze the challenges faced by current cold storage liquefaction technology and its development direction. [Conclusion] The research could provide guidance for the further development of CO2 liquefaction technology for the LCES system.

Abstract Idiopathic pulmonary fibrosis (IPF) is a globally prevalent, progressive disease with limited treatment options and poor prognosis. Because of its irreversible disease progression, IPF affects the quality and length of life of patients and imposes a significant burden on their families and social healthcare services. The use of the antifibrotic drugs pirfenidone and nintedanib can slow the progression of the disease to some extent, but it does not have a reverse effect on the prognosis. The option of lung transplantion is also limited owing to contraindications to transplantation, possible complications after transplantation, and the risk of death. Therefore, the discovery of new, effective treatment methods is an urgent need. Over recent years, various studies have been undertaken to investigate the relationship between interstitial pneumonia and lung cancer, suggesting that some immune checkpoints in IPF are similar to those in tumors. Immune checkpoints are a class of immunosuppressive molecules that are essential for maintaining autoimmune tolerance and regulating the duration and magnitude of immune responses in peripheral tissues. They can prevent normal tissues from being damaged and destroyed by the immune response. While current studies have focused on PD-1/PD-L1 and CTLA-4, PD-1/PD-L1 may be the only effective immune checkpoint IPF treatment. This review discusses the application of PD-1/PD-L1 checkpoint in IPF, with the aim of finding a new direction for IPF treatment.

The heating source temperature of the vacuum belt system (VBD) is an important factor affecting the drying rate and the material quality. However, it has problems with large fluctuation, instability, and hysteresis due to interference from various factors, which increases the drying time and energy consumption. To address these issues, this study proposes fuzzy control and integral control synergistic (FCICS) control to realize temperature regulation of the VBD system, enhancing the performance and stability of the heating source. Simulations were conducted in Simulink, and an experimental verification was carried out based on the constructed experimental system. The results show that the FCICS control outperforms the conventional PID control in terms of material warming rate, temperature stability, and energy consumption, and the transient and stable state performance is improved. Specifically, the material warming rate increased by 15%, temperature stability improved by 20%, and energy consumption decreased by more than 1.74% with the FCICS control strategy.

BackgroundIn recent years, the Chinese government has placed growing emphasis on environmental development. The implementation of effective waste separation practices in schools is crucial for establishing an ecological civilization in China.ObjectiveThe present study aimed to assess the knowledge, attitude, and practice (KAP) of waste separation among Chinese university students and to understand the demographic factors influencing the KAP of the interviewed students. These sociodemographic factors include gender, age, education, and family environment.MethodsBased on the KAP theoretical model and the Lewin behavioral model (LBM), this study developed its questionnaire on college students’ KAP of rubbish sorting. A survey was conducted on 1,282 college students from five colleges and universities in Beijing. A one-way ANOVA, Pearson’s correlation analysis, and multiple linear stepwise regression analyzes were employed to explore the factors influencing college students’ KAP scores on waste sorting. The questionnaire’s reliability and validity were effectively verified through two rounds of Delphi expert consultation.ResultsThe scores for KAP dimensions were 55.64, 69.18, and 54.8%, respectively. The overall KAP score of university students in waste classification was 46.93 ± 9.93, with a percentage score of 62.57%. More than half of the college students lack a clear understanding of waste classification. Grade, gender, major, highest family education, and family economic status all influence college students’ KAP scores on waste classification. There is a notable deficiency in school education regarding waste classification, with only 30.7% reporting having received such education.ConclusionThis study unveils the overall KAP score of waste separation among Chinese college students, which is marginally acceptable. The interviewed students exhibit a positive attitude and a willingness to participate in waste separation. However, there is room for improvement in both knowledge and practices. A lack of knowledge about waste sorting emerges as the primary influence on individual-level practices. Consideration should be given to enhancing education and management of waste separation among college students, emphasizing the cultivation of an eco-conscious culture, and guiding students to establish correct ecological values.

PurposeComparing the outcomes of video-laryngoscopy and flexible fiberoptic bronchoscopy for endotracheal intubation in patients with cervical spine immobilization.MethodsAll of the comparative studies published in the PubMed, Cochrane Library, Medline, Web of Science, and EMBASE databases as of 8 Jan 2024 were included. All outcomes were analyzed using Review Manager 5.4. The primary outcomes were the successful first-attempt intubation rate, intubation time, heart rate after intubation, mean arterial pressure after intubation, overall intubation success rate, risk of tissue damage and sore throat.ResultsThe meta-analysis included six randomized controlled studies with a total of 694 patients. The outcomes of the meta-analysis revealed that the use of video laryngoscopy was better than flexible fiberoptic bronchoscopy in terms of the successful first-attempt intubation rate (P0.05) between the video laryngoscopy and flexible fiberoptic bronchoscopy groups.ConclusionsCompared with flexible fiberoptic bronchoscopy, video laryngoscopy has superior tracheal intubation performance in terms of the first-attempt success rate and intubation speed. This finding was observed in patients with cervical spine immobilization who utilized a cervical collar to simulate a difficult airway. Additionally, both types of scopes demonstrated similar complication rates. Current evidence suggests that video laryngoscopy is better suited than flexible fiberoptic bronchoscopy for endotracheal intubation in patients immobilized with a cervical collar.Trial registrationSystematic review protocol: CRD42024499868.

Abstract Effective drugs with broad spectrum safety profile to all people are highly expected to combat COVID-19 caused by SARS-CoV-2. Here we report that nelfinavir, an FDA approved drug for the treatment of HIV infection, is effective against SARS-CoV-2 and COVID-19. Preincubation of nelfinavir could inhibit the activity of the main protease of the SARS-CoV-2 (IC50 = 8.26 μM), while its antiviral activity in Vero E6 cells against a clinical isolate of SARS-CoV-2 was determined to be 2.93 μM (EC50). In comparison with vehicle-treated animals, rhesus macaque prophylactically treated with nelfinavir had significantly lower temperature and significantly reduced virus loads in the nasal and anal swabs of the animals. At necropsy, nelfinavir-treated animals had a significant reduction of the viral replication in the lungs by nearly three orders of magnitude. A prospective clinic study with 37 enrolled treatment-naive patients at Shanghai Public Health Clinical Center, which were randomized (1:1) to nelfinavir and control groups, showed that the nelfinavir treatment could shorten the duration of viral shedding by 5.5 days (9.0 vs. 14.5 days, P = 0.055) and the duration of fever time by 3.8 days (2.8 vs. 6.6 days, P = 0.014) in mild/moderate COVID-19 patients. The antiviral efficiency and clinical benefits in rhesus macaque model and in COVID-19 patients, together with its well-established good safety profile in almost all ages and during pregnancy, indicated that nelfinavir is a highly promising medication with the potential of preventative effect for the treatment of COVID-19.

Excessive light exposure can damage photoreceptors and lead to blindness. Oxidative stress serves a key role in photo-induced retinal damage. Free radical scavengers have been proven to protect against photo-damaged retinal degeneration. Fullerol, a potent antioxidant, has the potential to protect against ultraviolet-B (UVB)-induced cornea injury by activating the endogenous stem cells. However, its effects on cell fate determination of Müller glia (MG) between gliosis and de-differentiation remain unclear. Therefore, we established a MG lineage-tracing mouse model of light-induced retinal damage to examine the therapeutic effects of fullerol. Fullerol exhibited superior protection against light-induced retinal injury compared to glutathione (GSH) and reduced oxidative stress levels, inhibited gliosis by suppressing the TGF-β pathway, and enhanced the de-differentiation of MG cells. RNA sequencing revealed that transcription candidate pathways, including Nrf2 and Wnt10a pathways, were involved in fullerol-induced neuroprotection. Fullerol-mediated transcriptional changes were validated by qPCR, Western blotting, and immunostaining using mouse retinas and human-derived Müller cell lines MIO-M1 cells, confirming that fullerol possibly modulated the Nrf2, Wnt10a, and TGF-β pathways in MG, which suppressed gliosis and promoted the de-differentiation of MG in light-induced retinal degeneration, indicating its potential in treating retinal diseases.

Abstract Chronic pain has attracted wide interest because it is a major obstacle affecting the quality of life. Consequently, safe, efficient, and low‐addictive drugs are highly desirable. Nanoparticles (NPs) with robust anti‐oxidative stress and anti‐inflammatory properties possess therapeutic possibilities for inflammatory pain. Herein, a bioactive zeolitic imidazolate framework (ZIF)‐8‐capped superoxide dismutase (SOD) and Fe3O4 NPs (SOD&Fe3O4@ZIF‐8, SFZ) is developed to achieve enhanced catalytic, antioxidative activities, and inflammatory environment selectivity, ultimately improving analgesic efficacy. SFZ NPs reduce tert‐butyl hydroperoxide (t‐BOOH)‐induced reactive oxygen species (ROS) overproduction, thereby depressing the oxidative stress and inhibiting the lipopolysaccharide (LPS)‐induced inflammatory response in microglia. After intrathecal injection, SFZ NPs efficiently accumulate at the lumbar enlargement of the spinal cord and significantly relieve complete Freund's adjuvant (CFA)‐induced inflammatory pain in mice. Moreover, the detailed mechanism of inflammatory pain therapy via SFZ NPs is further studied, where SFZ NPs inhibit the activation of the mitogen‐activated protein kinase (MAPK)/p‐65 signaling pathway, leading to reductions in phosphorylated protein levels (p‐65, p‐ERK, p‐JNK, and p‐p38) and inflammatory factors (tumor necrosis factor [TNF]‐α, interleukin [IL]‐6, and IL‐1β), thereby preventing microglia and astrocyte activation for acesodyne. This study provides a new cascade nanoenzyme for antioxidant treatments and explores its potential applications as non‐opioid analgesics.

PurposeDiabetes mellitus is a systemic metabolic disorder which may target the lungs and lead to interstitial lung disease. The clinical characteristics and mechanisms of type 2 diabetes mellitus (T2DM) complicated with interstitial lung disease (ILD) have been studied. However, little work has been done to assess genetic contributions to the development of T2DM complicated with ILD.MethodA pedigree of T2DM complicated with ILD was investigated, and the whole genome re-sequencing was performed to identify the genetic variations in the pedigree. According to the literature, the most valuable genetic contributors to the pathogenesis of T2DM complicated with ILD were screened out, and the related cellular functional experiments were also performed.ResultsA large number of SNPs, InDels, SVs and CNVs were identified in eight subjects including two diabetic patients with ILD, two diabetic patients without ILD, and four healthy subjects from the pedigree. After data analysis according to the literature, MUC5B SNP rs2943512 (A > C) was considered to be an important potentially pathogenic gene mutation associated with the pathogenesis of ILD in T2DM patients. In vitro experiments showed that the expression of MUC5B in BEAS-2B cells was significantly up-regulated by high glucose stimulation, accompanied by the activation of ERK1/2 and the increase of IL-1β and IL-6. When silencing MUC5B by RNA interference, the levels of p-ERK1/2 as well as IL-1β and IL-6 in BEAS-2B cells were all significantly decreased.ConclusionThe identification of these genetic variants in the pedigree enriches our understanding of the potential genetic contributions to T2DM complicated with ILD. MUC5B SNP rs2943512 (A > C) or the up-regulated MUC5B in bronchial epithelial cells may be an important factor in promoting ILD inT2DM patients, laying a foundation for future exploration about the pathogenesis of T2DM complicated with ILD.

In order to study effects of macrophage-derived inflammatory mediators associated with systemic inflammation on brain endothelial cells, we have established a co-culture system consisting of bEnd.3 cells and LPS-activated Raw 264.7 cells and performed its cytokine profiling. The cytokine profile of the co-culture model was compared to that of mice treated with intraperitoneal LPS injection. We found that, among cytokines profiled, eight cytokines/chemokines were similarly upregulated in both in vivo mouse and in vitro co-culture model. In contrast to the co-culture model, the cytokine profile of a common mono-culture system consisting of only LPS-activated bEnd.3 cells had little similarity to that of the in vivo mouse model. These results indicate that the co-culture of bEnd.3 cells with LPS-activated Raw 264.7 cells is a better model than the common mono-culture of LPS-activated bEnd.3 cells to investigate the molecular mechanism in endothelial cells, by which systemic inflammation induces neuroinflammation. Moreover, fibrinogen adherence both to bEnd.3 cells in the co-culture and to brain blood vessels in a LPS-treated animal model of Alzheimer's disease increased. To the best of our knowledge, this is the first to utilize bEnd.3 cells co-cultured with LPS-activated Raw 264.7 cells as an in vitro model to investigate the consequence of macrophage-derived inflammatory mediators on brain endothelial cells.

Acute lung injury (ALI) is a common critical disease of the respiratory system that progresses into acute respiratory distress syndrome (ARDS), with high mortality, mainly related to pulmonary oxidative stress imbalance and severe inflammation. However, there are no clear and effective treatment strategies at present. Nuclear factor erythroid 2-related factor 2(Nrf2) is a transcription factor that interacts with multiple signaling pathways and regulates the activity of multiple oxidases (NOX, NOS, XO, CYP) related to inflammation and apoptosis, and exhibits antioxidant and anti-inflammatory roles in ALI. Recently, several studies have reported that the active ingredients of natural medicines show protective effects on ALI via the Nrf2 signaling pathway. In addition, they are cheap, naturally available, and possess minimal toxicity, thereby having good clinical research and application value. Herein, we summarized various studies on the protective effects of natural pharmaceutical components such as polyphenols, flavonoids, terpenoids, alkaloids, and polysaccharides on ALI through the Nrf2 signaling pathway and demonstrated existing gaps as well as future perspectives.

Bisphenols, including Bisphenol A (BPA), Tetrabromobisphenol A (TBBPA), and Tetrabromobisphenol S (TBBPS), have been widely applied in the production of polycarbonate plastics and epoxy resins and have been detected in the environment worldwide. The frequent detection of bisphenols in maternal and fetal samples has raised concerns about their toxic effects on human embryonic development, especially on the development of the central nervous system. However, the effect of bisphenols on human retinal development is still unknown. In this study, to evaluate the toxicity of bisphenols on early retinal development, human embryonic stem cells were induced to differentiate into retinal organoids that responded to BPA, TBBPA, and TBBPS, at human exposure relevant concentrations. The global gene expression of retinal organoids was analyzed by RNA sequencing (RNA-seq). A set of retinal development-related biological processes, including neuron differentiation, phototransduction, axon guidance, and retina layer formation, were identified in retinal organoids corresponding to different developmental stages. The RNA-seq data also showed that BPA, TBBPA, and TBBPS influenced retinal development by interfering with the Cytokine-cytokine receptor interaction pathway. HSPA6, HIF1A-AS3, CDC20B, IL19, OAS1, HSPA7, and RN7SK were dysregulated by these chemicals. Additionally, BPA, TBBPA, and TBBPS exhibited different toxic effects on neural retina development, with TBBPA appearing to exert more toxicity than BPA and TBBPS. Furthermore, three bisphenols exhibited different effects at different stages of neural retina development. The sensitivity of retinal development to bisphenols depends on their developmental stage. This study provides new insights into the deep dissection of retinotoxicity after prenatal bisphenol exposure.

The ultimate goal of PPP-RTK is to achieve rapid ambiguity resolution, which is influenced by the prior precision of the external ionospheric information. This study proposes a method for determining the precision of ionospheric corrections for each satellite. In this method, an 8 min piece-wise function linearly related to the spatial three-direction distance components (SDC) within the geocentric coordinate system is constructed. By exploiting the SDC model, the user can calculate the precision of the ionospheric corrections satellite by satellite. Using the German and French stations, we validate this method experimentally and compare it to a method with an 8 min piece-wise function constructed by the baseline length (BLL). The SDC model provides an accuracy better than 10 mm in modeling ionospheric correction precision for each GPS satellite, with an average improvement of 43% compared to the BLL model. In addition, the SDC model offers an accuracy of approximately 5 mm in the reference network with an inter-station distance of less than 100 km, which is about 15% better than that of the BLL model during the active ionospheric period. The SDC model exhibits advantages over ionospheric correction precision modeling, with an average improvement of 73.5% for a reference network with station spacing of 125–155 km. By adopting the adaptive ionospheric precision derived from the SDC model, the GPS/GPS + Galileo PPP-RTK achieves a horizontal error of 50 mm and a vertical error of 100 mm within an average of three to four epochs. Notably, the convergence time is significantly enhanced by 30% in reference networks with inter-station distances of 125–155 km, compared to that of the PPP-RTK solution generated with dynamic ionospheric correction precision from the BLL model for all observed satellites.

Due to the combined pressures of energy shortage and environmental degradation, bio-liquid fuels have been widely studied as a green, environmentally friendly, renewable petroleum alternative. This article summarizes the various technologies of three generations of biomass feedstocks (especially the second-generation, biomass lignin, and the third-generation, algae raw materials) used to convert liquid fuels (bioethanol, biodiesel, and bio-jet fuel) and analyzes their advantages and disadvantages. In addition, this article details the latest research progress in biomass liquid fuel production, summarizes the list of raw materials, products and conversion processes, and provides personal opinions on its future development. The aim is to provide a theoretical basis and reference for the optimization of existing technology and future research and development of biomass liquid fuels.

The eyes are highly susceptible to the oxidative stress induced by ultraviolet B (UVB, wavelength between 280 ∼ 320 nm), which could cause severe damage to the cornea. Fullerenols are effective antioxidants to alleviate UVB-induced injury, while their application for the eyes is still rare. In present study, we investigated the protective performance and mechanism of fullerenols on cornea under UVB radiation in vivo and in vitro. The synthesized fullerenols exhibited broad-spectrum free radical scavenging properties (applicable to both reactive oxygen species (ROS) and reactive nitrogen species (RNS)) and photo-stability. When compared with another widely used antioxidant glutathione (GSH), the administration of fullerenols markedly decreased the injured area, corneal edema, cell death, and increased the cell proliferation in UVB-induced rat cornea. The effects of fullerenols were confirmed in UVB-exposed human corneal epithelial cells (hCECs), where elevated cell viability and proliferation, decreased oxidative free radical production, repaired mitochondrial dysfunction and DNA lesions were observed. RNA sequencing (RNA-Seq) analysis demonstrated that fullerenol alleviated UVB-induced corneal injury through down-regulation of oxidative stress-related genes and up-regulation of proliferation-associated genes. Our results demonstrate the suitability of fullerenols as a potential exogenous treatment in ameliorating UVB-induced cornea damage.

Nanotechnology has been developed rapidly in recent decades and widely applied in ocular disease therapy. Nano-drug delivery systems overcome the bottlenecks of current ophthalmic drug delivery and are characterized with strong biocompatibility, stability, efficiency, sustainability, controllability, and few side effects. Nanoparticles have been identified as a promising and generally safe ophthalmic drug-delivery system based on the toxicity assessment in animals. Previous studies have found that common nanoparticles can be toxic to the cornea, conjunctiva, and retina under certain conditions. Because of the species differences between humans and animals, advanced in vitro cell culture techniques, such as human organoids, can mimic the human organism to a certain extent, bringing nanoparticle toxicity assessment to a new stage. This review summarizes the advanced application of nanoparticles in ocular drug delivery and the potential toxicity, as well as some of the current challenges and future opportunities in nanotoxicological evaluation.

Increasing evidence in animal models has suggested that polybrominated diphenyl ethers (PBDEs), a class of brominated flame retardants, can cause retinotoxicity. However, data on the influence of PBDE treatment on human retinal development are scarce due to the lack of appropriate models. In the present study, we report the utilization of human embryonic stem cell-derived retinal organoids (hESC-ROs) for toxicity assessment of the most common PBDE congener (BDE-47) during the early stages of retinal development. Exposure to BDE-47 decreased the thickness and area of the neural retina (NR) of hESC-ROs in a dose- and time-dependent manner. Abnormal retinal cell distributions, disordered NR structures, and neural rosette-like structures were found on hESC-ROs after low-level BDE-47 exposure. Moreover, BDE-47 exposure decreased cell proliferation, promoted cell apoptosis, and caused abnormal differentiation. Transcriptomic analysis demonstrated that differentially expressed genes, caused by BDE-47, were enriched in extracellular matrix organization. Metabolomic studies of hESC-ROs revealed significant changes in the metabolism of purine and glutathione after BDE-47 exposure for five weeks. This study clarifies the retinotoxicity of low-level BDE-47 treatment and highlights the powerfulness of the hESC-RO model, deepening our understanding of BDE-47-driven human early retina developmental toxicity.

Abstract Background To explore the modulatory effects and mechanism of secretory clusterin (sCLU) on cancer stem cell (CSC) properties in hepatocellular carcinoma (HCC). Methods The effects of sCLU repression or overexpression on chemoresistance, migration, invasion, and tumor growth were detected by MTT, wound healing, transwell assays, and xenograft assay, respectively. The tumor sphere assay was performed to evaluate the self-renewal ability of HCC cells. In addition, the molecular regulation between sCLU and AKT/GSK-3β/β-catenin axis in HCC cells were discovered by western blotting, quantitative real-time PCR (qRT-PCR), and immunofluorescence. The expression status of sCLU and β-catenin in HCC tissues were investigated by immunohistochemistry. Results Knockdown or overexpressing sCLU remarkably inhibited or promoted the chemoresistance against sorafenib/doxorubicin, metastasis, and tumor growth of HCC cells, respectively. HepG2 and HCCLM3-derived spheroids showed higher expression of sCLU than that in attached cells. Additionally, repressing sCLU impaired the self-renewal capacity of HCC cells and CSC-related chemoresistance while overexpression of sCLU enhanced these CSC properties. Knockdown or overexpression of sCLU inhibited or increased the expressions of β-catenin, cyclinD1, MMP-2 and MMP-9, and the phosphorylation of AKT or GSK3β signaling, respectively. However, LiCl or LY294002 abrogated the effects mediated by sCLU silencing or overexpression on chemoresistance, metastasis, and CSC phenotype. Furthermore, co-expression of sCLU and β-catenin in HCC tissues indicated poor prognosis of HCC patients. Conclusions Taken together, the oncogenic sCLU might promote CSC phenotype via activating AKT/GSK3β/β-catenin axis, suggesting that sCLU was a potential molecular-target for HCC therapy.

Abstract Background Emerging evidence suggests that neural crest-derived cells (NCCs) present important functions in peripheral nerve regeneration to correct the insufficiency of autogenous Schwann cells. Postmigratory NCCs have been successfully isolated from adult rat bone marrow in our previous work. In this study, we aim to provide neural crest-derived Schwann cell precursors (SCPs) for repair of nerve defects in adult rats, and partially reveal the mechanisms involved in neuroregeneration of cell therapy. Methods A clonal cell line of neural crest precursors of rat bone marrow origin (rBM-NCPs) with SCP identity was expanded in adherent monolayer culture to ensure the stable cell viability of NCPs and potentiate the repair of nerve defects after rBM-NCPs implantation based on tissue engineering nerve grafts (TENG). Here the behavioral, morphological, and electrophysiological detection was performed to evaluate the therapy efficacy. We further investigated the treatment with NCP-conditioned medium (NCP-CM) to sensory neurons after exposure to oxygen-glucose-deprivation (OGD) and partially compared the expression of trophic factor genes in rBM-NCPs with that in mesenchymal stem cells of bone marrow origin (rBM-MSCs). Results It was showed that the constructed TENG with rBM-NCPs loaded into silk fibroin fiber scaffolds/chitosan conduits repaired 10-mm long sciatic nerve defects more efficiently than conduits alone. The axonal regrowth, remyelination promoted the reinnervation of the denervated hind limb muscle and skin and thereby alleviated muscle atrophy and facilitated the rehabilitation of motor and sensory function. Moreover, it was demonstrated that treatment with NCP-CM could restore the cultured primary sensory neurons after OGD through trophic factors including epidermal growth factor (EGF), platelet-derived growth factor alpha (PDGFα), ciliary neurotrophic factor (CNTF), and vascular endothelial growth factor alpha (VEGFα). Conclusions In summary, our findings indicated that monolayer-cultured rBM-NCPs cell-based therapy might effectively repair peripheral nerve defects partially through secreted trophic factors, which represented the secretome of rBM-NCPs differing from that of rBM-MSCs.

Managing the dysregulated host response to infection remains a major challenge in sepsis care. Chinese treatment guideline recommends adding XueBiJing, a five-herb medicine, to antibiotic-based sepsis care. Although adding XueBiJing further reduced 28-day mortality via modulating the host response, pharmacokinetic herb–drug interaction is a widely recognized issue that needs to be studied. Building on our earlier systematic chemical and human pharmacokinetic investigations of XueBiJing, we evaluated the degree of pharmacokinetic compatibility for XueBiJing/antibiotic combination based on mechanistic evidence of interaction risk. Considering both XueBiJing‒antibiotic and antibiotic‒XueBiJing interaction potential, we integrated informatics-based approach with experimental approach and developed a compound pair-based method for data processing. To reflect clinical reality, we selected for study XueBiJing compounds bioavailable for drug interactions and 45 antibiotics commonly used in sepsis care in China. Based on the data of interacting with drug metabolizing enzymes and transporters, no XueBiJing compound could pair, as perpetrator, with the antibiotics. Although some antibiotics could, due to their inhibition of uridine 5′-diphosphoglucuronosyltransferase 2B15, organic anion transporters 1/2 and/or organic anion-transporting polypeptide 1B3, pair with senkyunolide I, tanshinol and salvianolic acid B, the potential interactions (resulting in increased exposure) are likely desirable due to these XueBiJing compounds' low baseline exposure levels. Inhibition of aldehyde dehydrogenase by 7 antibiotics probably results in undesirable reduction of exposure to protocatechuic acid from XueBiJing. Collectively, XueBiJing/antibiotic combination exhibited a high degree of pharmacokinetic compatibility at clinically relevant doses. The methodology developed can be applied to investigate other drug combinations. Key Words: XueBiJing, Antibiotic, Combination drug therapy, Sepsis, Pharmacokinetic compatibility, Herb‒drug interaction

Objectives: A novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is causing the worldwide coronavirus disease 2019 (COVID-19) outbreak with high mortality. A unique finding among COVID-19 patients was a decline of eosinophil levels (eosinopenia). However, results from previous studies on the relationship between eosinopenia and disease severity were inconsistent. The objective of this study is to determine the relationship between eosinopenia and COVID-19 mortality as well as the clinical conditions that could potentially lead to mortality. Methods: One hundred ninety patients diagnosed as moderate, severe, or critical COVID-19 at hospital admission were enrolled. Data collected from patients’ medical records on the second day after hospital admission included medical histories, clinical symptoms, chest images of computed tomography (CT), laboratory examinations, and outcomes. Results: Eosinophil levels were significantly lower in patients with critical disease, when compared to those with moderate and severe diseases. After controlled for confounding factors, ie, age, gender, hypertension, coronary heart disease, diabetes, and chronic lung disease, a progressive decline of eosinophil levels was independently associated with mortality. Moreover, eosinophil levels significantly and positively correlated with platelet and D-dimer levels but significantly and inversely correlated with serum levels of urea, creatinine, aspartate aminotransferase, lactate dehydrogenase, and creatine kinase. Conclusions: Eosinopenia, if progressively worsening, indicates that COVID-19 patients may progress to critical disease and have a significantly higher chance of mortality. Additionally, eosinopenia correlates with biomarkers of coagulation disorder and those of tissue damage in kidney, liver, and other tissues.

Amyloid plaques, mainly composed of abnormally aggregated amyloid β-protein (Aβ) in the brain parenchyma, and neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau protein aggregates in neurons, are two pathological hallmarks of Alzheimer's disease (AD). Aβ fibrils and tau aggregates in the brain are closely associated with neuroinflammation and synapse loss, characterized by activated microglia and dystrophic neurites. Genome-wide genetic association studies revealed important roles of innate immune cells in the pathogenesis of late-onset AD by recognizing a dozen genetic risk loci that modulate innate immune activities. Furthermore, microglia, brain resident innate immune cells, have been increasingly recognized to play key, opposing roles in AD pathogenesis by either eliminating toxic Aβ aggregates and enhancing neuronal plasticity or producing proinflammatory cytokines, reactive oxygen species, and synaptotoxicity. Aggregated Aβ binds to toll-like receptor 4 (TLR4) and activates microglia, resulting in increased phagocytosis and cytokine production. Complement components are associated with amyloid plaques and NFTs. Aggregated Aβ can activate complement, leading to synapse pruning and loss by microglial phagocytosis. Systemic inflammation can activate microglial TLR4, NLRP3 inflammasome, and complement in the brain, leading to neuroinflammation, Aβ accumulation, synapse loss and neurodegeneration. The host immune response has been shown to function through complex crosstalk between the TLR, complement and inflammasome signaling pathways. Accordingly, targeting the molecular mechanisms underlying the TLR-complement-NLRP3 inflammasome signaling pathways can be a preventive and therapeutic approach for AD.

Abstract Background As the development of urbanization in China, the morbidity of allergic disease rise up prominently even in children, which may be partially associated with the excessively clean environment. It has been reported that common microorganism in rural environment shows protective effects on allergic disease by modulating TLRs-Tregs/Th cell axis. But the mechanism of this protection still needs to be elucidated in detail. We investigated the effects of maternal exposure to farming environment on the neonatal innate immune system, especially on the TLR-Treg-Th (Th1, Th2, Th9, and Th17) axis, in the Jilin province of China. Methods Eighty-four non-farming and 42 farming pregnant women were recruited. Endotoxins and glucans in dust from the living rooms of the pregnant mothers were measured. Cord blood mononuclear cells were challenged with phytohemagglutinin, lipopolysaccharide, or peptidoglycan. Proliferative response of lymphocyte was measured by 3H-TdR incorporation methods, CD4 + CD25 + FOXP3 + T cells percentage was assessed with flow cytometry, Tregs specific genes (FOXP3, LAG3, GITR, CTLA-4 and TGF-β) and TLR2, TLR4 genes expression were detected by RT-PCR, specific cytokines of Th1, Th2, Th9, Th17 and Tregs were measured with flow cytometer, suppressive capacity of Tregs was tested by culturing with effector cells in vitro, and TLR2/4 gene polymorphism was detected. Results Higher endotoxin content was observed in the living rooms of the farming mothers. Compared with that in the non-farming group, in farming neonatal CBMCs, lymphocyte proliferation declined; the IFN-γ/IL-13 ratio increased; and the quantity of Tregs and gene expression of FOXP3, GITR, CTLA4 and TLR2 increased significantly (P

Inspired by the superhydrophobic properties of some plants and animals with special structures, such as self-cleaning, water repellent, and drag reduction, the research on the basic theory and practical applications of superhydrophobic surfaces is increasing. In this paper, the characteristics of superhydrophobic surfaces and the preparation methods of superhydrophobic surfaces are briefly reviewed. The mechanisms of drag reduction on superhydrophobic surfaces and the effects of parameters such as flow rate, fluid viscosity, wettability, and surface morphology on drag reduction are discussed, as well as the applications of superhydrophobic surfaces in boiling heat transfer and condensation heat transfer. Finally, the limitations of adapting superhydrophobic surfaces to industrial applications are discussed. The possibility of applying superhydrophobic surfaces to highly viscous fluids for heat transfer to reduce flow resistance and improve heat transfer efficiency is introduced as a topic for further research in the future.

Obesity significantly increases the risk of developing type 2 diabetes mellitus and other metabolic diseases. Obesity is associated with chronic low-grade inflammation in white adipose tissues, which is thought to play an essential role in developing insulin resistance. Many lines of evidence indicate that toll-like receptors (TLRs) and their downstream signaling pathways are involved in development of chronic low-grade inflammation and insulin resistance, which are associated with obesity. Mice lacking molecules positively involved in the TLR signaling pathways are generally protected from high-fat diet-induced inflammation and insulin resistance. In this study, we have determined the effects of genetic deficiency of toll/interleukin-1 receptor-domain-containing adaptor-inducing interferon-β (TRIF) on food intake, bodyweight, glucose metabolism, adipose tissue macrophage polarization, and insulin signaling in normal chow diet-fed mice to investigate the role of the TRIF-dependent TLR signaling in adipose tissue metabolism and inflammation. TRIF deficiency (TRIF−/−) increased food intake and bodyweight. The significant increase in bodyweight in TRIF−/− mice was discernible as early as 24 weeks of age and sustained thereafter. TRIF−/− mice showed impaired glucose tolerance in glucose tolerance tests, but their insulin tolerance tests were similar to those in TRIF+/+ mice. Although no difference was found in the epididymal adipose mass between the two groups, the percentage of CD206+ M2 macrophages in epididymal adipose tissue decreased in TRIF−/− mice compared with those in TRIF+/+ mice. Furthermore, activation of epididymal adipose AKT in response to insulin stimulation was remarkably diminished in TRIF−/− mice compared with TRIF+/+ mice. Our results indicate that the TRIF-dependent TLR signaling contributes to maintaining insulin/AKT signaling and M2 macrophages in epididymal adipose tissue under a normal chow diet and provide new evidence that TLR4-targeted therapies for type 2 diabetes require caution.

Biofilm formation, one of the most important virulence factors of pathogenic bacteria, protects bacteria against desiccation, antibiotics, phages and host immune responses. However, phage-derived depolymerases show antibiofilm activity and demonstrate great potential to treat infections caused by biofilm-forming bacteria. In this study, the Escherichia coli phage vB_EcoM_ECOO78 was isolated and characterised, and we observed its ability to lyse five out of 34 tested E. coli clinical isolates. The highest phage titre was observed at a multiplicity of infection of 10-5 and a burst size of approximately 74 plaque forming units (PFU)/infection. Electron micrographs indicated that vB_EcoM_ECOO78 belongs to the family Myoviridae. The presence of increasing halos surrounding the lysis plaques formed by vB_EcoM_ECOO78 indicated that this phage may encode a depolymerase. Based on a sequencing analysis, the complete genome of vB_EcoM_ECOO78 was found to be 41,289 bp in size, with a GC content of 53.07%. Additionally, vB_EcoM_ECOO78 has 56 predicted open reading frames, 51 (91.07%) of which are assumed to be functional. A BLAST analysis indicated that ORF42 of vB_EcoM_ECOO78 (Dpo42) has low identity with other reported phage-associated depolymerases. Dpo42 was expressed and purified as a soluble protein using E. coli BL21. The biofilm formation ability of E. coli isolates and the antibiofilm activity of Dpo42 were tested by performing spot assays and using a 96-well micro-titre plate method. Dpo42 degraded the capsular polysaccharides surrounding E. coli and exhibited dose-dependent biofilm-formation prevention activity. Based on these results, Dpo42 appears to be a novel phage-derived depolymerase that represents a new potential strategy for preventing E. coli biofilm formation.

Diabetic cardiomyopathy (DCM) is a common and severe complication of diabetes and results in high mortality. It is therefore imperative to develop novel therapeutics for the prevention or inhibition of the progression of DCM. Oxidative stress is a key mechanism by which diabetes induces DCM. Hence, targeting of oxidative stress-related processes in DCM could be a promising therapeutic strategy. To date, a number of studies have shown beneficial effects of several natural products on the attenuation of DCM via an antioxidative mechanism of action. The aim of the present review is to provide a comprehensive and concise overview of the previously reported antioxidant natural products in the inhibition of DCM progression. Clinical trials of the antioxidative natural products in the management of DCM are included. In addition, discussion and perspectives are further provided in the present review.

Hypoxemia is a common complication of the diseases associated with the central nervous system, and neurons are highly sensitive to the availability of oxygen. Neuroplasticity is an important property of the neural system controlling breathing, memory, and cognitive ability. However, the underlying mechanism has not yet been clearly elucidated. In recent years, several pieces of evidence have highlighted the effect of hypoxic injury on neuronal plasticity in the pathogenesis and treatment of mood disorder. Therefore, the present study reviewed the relevant articles regarding hypoxic injury and neuronal plasticity and discussed the pathological changes and physiological functions of neurons in hypoxemia in order to provide a translational perspective to the relevance of hypoxic injury and mood disorder.