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Examines the existence of hepatic stem cells (HSC) in the spleens of mice. Replacement demands of cellular losses; Role of HSC in hepatocarcinogenesis; Preparation of donor cells.

Receptor activator of NF-κB ligand (RANKL) is essential for osteoclastogenesis. Targeting RANKL signaling pathways has been an encouraging strategy for treating lytic bone diseases such as osteoporosis and rheumatoid arthritis (RA). Sinomenine (SIN), derived from Chinese medicinal plant Sinomenioum acutum, is an active compound to treat RA, but its effect on osteoclasts has been hitherto unknown. In the present study, SIN was found to ameliorate M. tuberculosis H37Ra (Mt)-induced bone loss in rats with a decreased serum level of TRACP5b and RANKL, and an increased level of osteoprotegerin (OPG). In vitro study also showed that SIN could inhibit RANKL-induced osteoclast formation and bone resorption. The osteoclastic specific marker genes induced by RANKL including c-Src, MMP-9, TRACP were inhibited by SIN in a dose dependent manner. Signal transduction studies showed that SIN could obviously reduce the expression of RANK adaptor molecule TRAF6 and down-regulate RANKL-induced NF-κB activation. It decreased the RANKL-induced p38, JNK posphorylation but not ERK1/2 posphorylation. SIN could also reduce RANKL-mediated calcium influx which is associated with TRAF6/c-Src complex. Finally, SIN suppressed RANKL induced AP-1 and NFAT transcription, as well as the gene expression of NFATc1 and AP-1 components (Fra-1, Fra-2, c-Fos). The protein expression of c-Fos and TRAF6 were also inhibited by SIN after RANKL stimulation. Taken together, SIN could attenuate osteoclast formation and Mt-induced bone loss by mediating RANKL signaling pathways. [ABSTRACT FROM AUTHOR]

Abstract: The abnormal proliferation and polarization of Th17/Th1 subsets are believed to contribute to the progression of multiple sclerosis. We demonstrated that neural stem cells (NSCs) could inhibit CD4+T cells from mice of experimental autoimmune encephalomyelitis to proliferate and polarize into Th17 but promote their apoptosis and to generate regulatory T cells in response to myelin antigen via releasing prostaglandin E2 by activated Th1-derived IFN-γ. The study indicated that NSCs play a negatively regulatory role in T cell responses and provided novel evidence for the therapeutic mechanisms underlying the usage of NSCs to treat autoimmune diseases of central nervous system. [Copyright &y& Elsevier]

• A novel AgVO 3 /Mo-BiVO 4 photoanode is firstly fabricated. • The as-obtained photoanode achieves excellent photoelectrochemical performance. • p-n heterojunction and Mo dopant can meliorate the intrinsic deficiency of BiVO 4. • The huge potential of AgVO 3 in PEC water splitting is unraveled. BiVO 4 is largely restricted by its intrinsic poor electron mobility and sluggish surface reaction. Aiming at eliminating the deficiency of BiVO 4 , we assemble a novel composite photoanode through simultaneous bulk and surface modification. In detail, controllable Mo doping is manipulated through a spin-coating method, and AgVO 3 nanoparticles are loaded by successive ionic layer adsorption and reaction (SILAR) process. The as-prepared photoanode boosts the photocurrent density by 7 folds at 1.23 V vs. RHE and moves the onset potential negatively by 387 mV compared to the bare BiVO 4. Furthermore, the charge injection efficiency is substantially boosted to 49% at 1.23 V RHE , nearly 5 times as that of pure BiVO 4. With detailed physical and electrochemical characterization, we reveal the essential reason for the boosted photoelectrochemical activity. Appropriate Mo doping can simultaneously enhance the carrier density and electron mobility of BiVO 4. Specifically, more (0 4 0) facet are exposed for retarding charge recombination and increasing photocatalytic reaction sites. Then the simple SILAR process grows AgVO 3 nanoparticles homogeneously with uniform diameter of 3–5 nm on BiVO 4 , forming p-n heterojunction to accelerate charge separation, and abundant oxygen vacancy emerged on the surface, which has been demonstrated as active sites for water oxidation reaction. [ABSTRACT FROM AUTHOR]

• Encapsulating the FeVO 4 -passivated layer on ZnO nanorod as PEC photoanode. • Heterojunction and surface passivated layer promote charge separation/transfer ability. • The optimized photoelectrode acquires superior water splitting performance and photostability characteristic. Among many novel and promising semiconductors, the triclinic iron vanadate (FeVO 4) has been rarely applied in the field of solar water splitting due to its poor charge carrier separation ability. In this work, we prepared FeVO 4 -passivated ZnO heterojunction nanorods (FVO/ZnO NRs) photoanodes by simple spin-coating and calcination method for the first time. The optimal photoanode exibihits stable and effective PEC water oxidation performance, compared to pristine ZnO, affording 130 mV negative shift in onset potential and 2.4 folds augment in photocurrent density. Particularly, X-ray photoelectron spectroscopy and Mott-Schottky test reveal the establishment of heterojunction, which subdue photo-induced carriers bulk recombination and improve the charge separation efficiency. Open-circuit photovoltage and electrochemical impedance spectroscopy were recorded to further clarify that the FeVO 4 -passivated layer eliminates the surface trapping state, thus increasing the photovoltage and promoting the interface charge transfer kinetics. These demonstrations are expected to provide new thread for the rational application of new photoanode candidates and to optimize PEC performance. [ABSTRACT FROM AUTHOR]

Background: Keloid is a disease characterized by proliferation of fibrous tissue after the healing of skin tissue, which seriously affects the daily life of patients. However, the clinical treatment of keloids still has limitations, that is, it is not effective in controlling keloids, resulting in a high recurrence rate. Thus, it is urgent to identify new signatures to improve the diagnosis and treatment of keloids., Method: Bulk RNA seq and scRNA seq data were downloaded from the GEO database. First, we used WGCNA and MEGENA to co-identify keloid/immune-related DEGs. Subsequently, we used three machine learning algorithms (Randomforest, SVM-RFE, and LASSO) to identify hub immune-related genes of keloid (KHIGs) and investigated the heterogeneous expression of KHIGs during fibroblast subpopulation differentiation using scRNA-seq. Finally, we used HE and Masson staining, quantitative reverse transcription-PCR, western blotting, immunohistochemical, and Immunofluorescent assay to investigate the dysregulated expression and the mechanism of retinoic acid in keloids., Results: In the present study, we identified PTGFR, RBP5, and LIF as KHIGs and validated their diagnostic performance. Subsequently, we constructed a novel artificial neural network molecular diagnostic model based on the transcriptome pattern of KHIGs, which is expected to break through the current dilemma faced by molecular diagnosis of keloids in the clinic. Meanwhile, the constructed IG score can also effectively predict keloid risk, which provides a new strategy for keloid prevention. Additionally, we observed that KHIGs were also heterogeneously expressed in the constructed differentiation trajectories of fibroblast subtypes, which may affect the differentiation of fibroblast subtypes and thus lead to dysregulation of the immune microenvironment in keloids. Finally, we found that retinoic acid may treat or alleviate keloids by inhibiting RBP5 to differentiate pro-inflammatory fibroblasts (PIF) to mesenchymal fibroblasts (MF), which further reduces collagen secretion., Conclusion: In summary, the present study provides novel immune signatures (PTGFR, RBP5, and LIF) for keloid diagnosis and treatment, and identifies retinoic acid as potential anti-keloid drugs. More importantly, we provide a new perspective for understanding the interactions between different fibroblast subtypes in keloids and the remodeling of their immune microenvironment., (© 2024. The Author(s).)

The pathogenesis of rheumatoid arthritis (RA) remains elusive. The initiation of joint degeneration is characterized by the loss of self-tolerance in peripheral joints. Ferroptosis, a form of regulated cell death, holds significant importance in the pathophysiology of inflammatory arthritis, primarily due to iron accumulation and the subsequent lipid peroxidation. The present study investigated the association between synovial lesions and ferroptosis-related genes using previously published data from rheumatoid patients. Transcriptome differential gene analysis was employed to identify ferroptosis-related differentially expressed genes (FRDEGs). To validate FRDEGs and screen hub genes, we used weighted gene co-expression network analysis (WGCNA) and receiver operating characteristic (ROC) curves. Subsequently, immune infiltration analysis and single cell analysis were conducted to investigate the relationship between various synovial tissues cells and FRDEGs. The findings were further confirmed through reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunohistochemical staining, and immunofluorescence techniques. Upon intersecting DEGs with ferroptosis-related genes, we identified a total of 104 FRDEGs. Through the construction of a protein-protein interaction (PPI) network, we pinpointed the top 20 most highly concentrated genes as hub genes. Subsequent analyses using ROC curve and WGCNA validated eight FRDEGs: TIMP1, JUN, EGFR, SREBF1, ADIPOQ, SCD, AR, and FABP4. Immuno-infiltration analyses revealed significant infiltration of immune cell in RA synovial tissues and their correlations with the FRDEGs. Notably, TIMP1 demonstrated a positive correlation with various immune cell populations. Single-cell sequencing date of RA synovial tissue revealed predominant expression of TIMP1 is in fibroblasts. RT-qPCR, immunohistochemistry, and immunofluorescence analyses confirmed significant upregulation of TIMP1 at both mRNA and protein levels in RA synovial tissues and fibroblast-like synoviocytes (FLS). The findings provide novel insights into pathophysiology of peripheral immune tolerance deficiency in RA. The dysregulation of TIMP1, a gene associated with ferroptosis, was significantly observed in RA patients, suggesting its potential as a promising biomarker and therapeutic target., Competing Interests: 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., (© 2024 The Authors.)

Background: This meta-analysis investigated the influence of exercise on cognitive function in people living with diabetes., Methods: Stringent criteria for literature inclusion and exclusion were defined. Searches were conducted across four English databases to gather randomized controlled trials investigating exercise interventions for cognitive function in people living with diabetes. Outcome indicators from 1193 subjects across 12 articles were analyzed using RevMan 5.4 software., Results: Exercise intervention demonstrated the ability to mitigate cognitive decline in people living with diabetes, with a combined effect size (standardized mean difference) of 0.91, 95% CI: 0.28, 1.54, P < 0.00001. The intervention effect showed significant modulation by intervention content (I2 = 95%), intervention duration (I2 = 95%), intervention frequency (I2 = 95%), and intervention cycle (I2 = 96%). Among these factors, multi-component exercise, sessions >40 minutes, exercise frequency >4 times per week, and sustained exercise for >6 months were paramount, all with P < 0.05., Conclusion: Exercise intervention emerges as a viable strategy for delaying cognitive decline in people living with diabetes. Its efficacy is subject to modulation by various variables. Optimal intervention includes multi-component exercise, individual sessions lasting 40-60 minutes, exercising >4 times a week, and continuous exercise for over 6 months., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Based on the land economic density of 892 town units, the spatial pattern of the land economic density in Zhejiang Province is analyzed using the coefficient of variation, spatial classification, and spatial correlation methods, and the influencing factors are analyzed using a spatial regression model. The results are as follows: (1) The coefficients of variation were 2.6 and 3.1 in 2014 and 2019, respectively, indicating that the degree of imbalance of the town's industrial economy at the county level increased. (2) The distribution of the high-level agglomeration areas was characterized by one core area and two sub-core areas. The main core area was located at the junction of Hangzhou City, Shaoxing City, and Jiaxing City, and the two sub-core areas were located in Yuyao City and the main urban area of Ningbo City. In addition, several small-scale agglomeration areas composed of medium and high-level units were distributed in Wenzhou City. (3) The high-value agglomeration and low-value agglomeration distribution in the spatial correlation patterns was identified using the spatial auto-correlation method. The hot spots and sub-hot spots were distributed in Northern Zhejiang, and the cold spots formed a large-scale agglomeration in Quzhou City, Lishui City, Taizhou City, and several other cities in Southern Zhejiang. (4) Compared with the county scale, the spatial scope of the high-level areas in Northern Zhejiang shrunk significantly at the township scale, and the high-level agglomeration areas along the southeast coast changed into a cluster of several townships. (5) According to the geographically weighted regression (GWR) model, the importance of influencing factors is as follows: population density > regional area > industrial output value per capita > total population > proportion of secondary and tertiary personnel > total employees., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Developing a highly active, durable, and low-platinum-based electrocatalyst for the cathodic oxygen reduction reaction (ORR) is for breaking the bottleneck of large-scale applications of proton exchange membrane fuel cells (PEMFCs). Herein, ultrafine PtZn intermetallic nanoparticles with low Pt-loading and trace germanium (Ge) involvement confined in the nitrogen-doped porous carbon (Ge-L 10 -PtZn@N-C) are reported. The Ge-L 10 -PtZn@N-C exhibit superior ORR activity with a mass activity of 3.04 A mg -1 Pt and specific activity of 4.69 mA cm -2 , ≈12.2- and 10.2-times improvement compared to the commercial Pt/C (20%) at 0.90 V in 0.1 m KOH. The cathodic catalyst Ge-L 10 -PtZn@N-C assembled in the PEMFC shows encouraging peak power densities of 316.5 (at 0.86 V) and 417.2 mW cm -2 (at 0.91 V) in alkaline and acidic fuel-cell, respectively. The combination of experiment and density functional theory calculations (DFT) results robustly reveal that the participation of trace Ge can not only trigger a "growth site locking effect" to effectively inhibit nanoparticle growth, bring miniature nanoparticles, enhance dispersion uniformity, and achieve the exposure of the more electrochemical active site, but also effectively modulates the electronic structure, hence optimizing the adsorption/desorption of the oxygen intermediates., (© 2023 Wiley‐VCH GmbH.)

Tumor metastasis involves cells migrating directionally in response to external chemical signals. Reactive oxygen species (ROS) in the form of H 2 O 2 has been demonstrated as a chemoattractant for neutrophils but its spatial characteristics in tumor microenvironment and potential role in tumor cell dissemination remain unknown. Here we investigate the spatial ROS distribution in 3D tumor spheroids and identify a ROS concentration gradient in spheroid periphery, which projects into a H 2 O 2 gradient in tumor microenvironment. We further reveal the role of H 2 O 2 gradient to induce chemotaxis of tumor cells by activating Src and subsequently inhibiting RhoA. Finally, we observe that the absence of mitochondria cristae remodeling proteins including the mitochondria-localized actin motor Myosin 19 (Myo19) enhances ROS gradient and promotes tumor dissemination. Myo19 downregulation is seen in many tumors, and Myo19 expression is negatively associated with tumor metastasis in vivo. Together, our study reveals the chemoattractant role of tumor microenvironmental ROS and implies the potential impact of mitochondria cristae disorganization on tumor invasion and metastasis., (© 2024. The Author(s).)

Two-dimensional (2D) PdSe 2 film has the characteristics of adjustable bandgap, high carrier mobility, and high stability. Photodetector (PD) based on 2D PdSe 2 exhibits wide spectral self-driving features, demonstrating enormous potential in the field of optical detection. Here, we design and fabricate PdSe 2 /Si heterojunction PDs with various thicknesses of the PdSe 2 films from 10 to 35 nm. Due to the enhancement of light absorption capacity and built-in electric field of heterojunction, the photodetector with thicker PdSe 2 film can generate more photo-generated carriers and effectively separate them to form a large photocurrent, thus showing more excellent photodetection performance. The responsivity and specific detectivity of the PdSe 2 /Si PDs with 10 nm, 20 nm, and 35 nm PdSe 2 films are 2.12 A W -1 and 6.72 × 10 9 Jones, 6.17 A W -1 and 1.95 × 10 10 Jones, and 8.02 A W -1 and 2.54 × 10 10 Jones, respectively (808 nm illumination). The PD with 35 nm PdSe 2 film exhibits better performance than the other two PDs, with the rise/fall times of 15.8 μ s/138.9 μ s at f = 1 kHz and the cut-off frequency of 8.6 kHz. Furthermore, we demonstrate that the properties of PdSe 2 /Si PD array have excellent uniformity and stability at room temperature and shows potential for image sensing in the UV-vis-NIR wavelength range., (© 2023 IOP Publishing Ltd.)

Background: Smad7 is protective in a mouse model of rheumatoid arthritis. Here we investigated whether Smad7-expressing CD4 + T cells and the methylation of Smad7 gene in CD4 + T cells contribute to the disease activity of RA in patients., Methods: Peripheral CD4 + T cells were collected from 35 healthy controls and 57 RA patients. Smad7 expression by CD4 + T cells were determined and correlated with the clinical parameters of RA including RA score and serum levels of IL-6, CRP, ESR, DAS28-CRP, DAS28-ESR, Swollen joints and Tender joints. Bisulfite sequencing (BSP-seq) was used to determine the DNA methylation in Smad7 promoter (-1000 to +2000) region in CD4 + T cells. In addition, a DNA methylation inhibitor, 5-Azacytidine (5-AzaC), was added to CD4 + T cells to examine the possible role of Smad7 methylation in CD4 + T cell differentiation and functional activity., Results: Compared to the heath controls, Smad7 expression was significantly decreased in CD4 + T cells from RA patients and inversely correlated with the RA activity score and serum levels of IL-6 and CRP. Importantly, loss of Smad7 in CD4 + T cell was associated with the alteration of Th17/Treg balance by increasing Th17 over the Treg population. BSP-seq detected that DNA hypermethylation occurred in the Smad7 promoter region of CD4 + T cells obtained from RA patients. Mechanistically, we found that the DNA hypermethylation in the Smad7 promoter of CD4 + T cells was associated with decreased Smad7 expression in RA patients. This was associated with overreactive DNA methyltransferase (DMNT1) and downregulation of the methyl-CpG binding domain proteins (MBD4). Inhibition of DNA methylation by treating CD4 + T cells from RA patients with 5-AzaC significantly increased Smad7 mRNA expression along with the increased MBD4 but reduced DNMT1 expression, which was associated with the rebalance in the Th17/Treg response., Conclusion: DNA hypermethylation at the Smad7 promoter regions may cause a loss of Smad7 in CD4 + T cells of RA patients, which may contribute to the RA activity by disrupting the Th17/Treg balance., 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 Hu, Xu, He, Shan, Zhou, Wang, Bai, Shang, Nie, Pan, Lan and Wang.)

The massive use of fossil fuels releases a great amount of CO 2 , which substantially contributes to the global warming. For the global goal of putting CO 2 emission under control, effective utilization of CO 2 is particularly meaningful. Electrocatalytic CO 2 reduction reaction (eCO 2 RR) has great potential in CO 2 utilization, because it can convert CO 2 into valuable carbon-containing chemicals and feedstock using renewable electricity. The catalyst design for eCO 2 RR is a key challenge to achieving efficient conversion of CO 2 to fuels and useful chemicals. For a typical heterogeneous catalyst, surface and interface engineering is an effective approach to enhance reaction activity. Herein, the development and research progress in CO 2 catalysts with focus on surface and interface engineering are reviewed. First, the fundaments of eCO 2 RR is briefly discussed from the reaction mechanism to performance evaluation methods, introducing the role of the surface and interface engineering of electrocatalyst in eCO 2 RR. Then, several routes to optimize the surface and interface of CO 2 electrocatalysts, including morphology, dopants, atomic vacancies, grain boundaries, surface modification, etc., are reviewed and representative examples are given. At the end of this review, we share our personal views in future research of eCO 2 RR., (© 2022 Wiley-VCH GmbH.)

The intracellular triterpene yield from Ganoderma atrum was enhanced by optimization based on single-factor experiments, Plackett-Burman experimental design (PBED) and response surface methodology (RSM) under liquid fermentation conditions. The optimal medium composition (g·L-1) was glucose (46.0), bean cake powder (30.2), KH2PO4 (2.0), CaCl2 (3.0), MgSO4 (1.5), FeSO4 (0.2), and pH 6.0. Under the optimal conditions, the highest triterpene yield of 0.527 g·L-1 was obtained, which was 4.705-fold higher than before optimization. The fermented powder that was collected from the optimal medium was subjected to simulated gastrointestinal digestion, with differences resulting from extraction in different digestive juices (purified water, simulated gastric digestive juice, simulated gastrointestinal digestive juice). The content of triterpenes and polysaccharides increased, except for total phenol content. In terms of the antioxidant activity, the 1,1-diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH+⋅) scavenging activity gradually decreased whereas the 2, 2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+⋅) scavenging activity first decreased and then increased. In terms of enzyme viability, the activity of α-amylase (α-AL) and α-glucosidase (α-GC) in the digestive juices decreased dramatically. The main bioactive components of G. atrum and their bioactivity in digestive juices were evaluated, providing a reference for the effective use of fermented power from G. atrum.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease. We previously revealed that the natural compound artemisitene (ATT) exhibits excellent broad anticancer activities without toxicity on normal tissues. Nevertheless, the effect of ATT on RA is undiscovered. Herein, we aim to study the effect and potential mechanism of ATT on RA management., Methods: A collagen-induced arthritis (CIA) mouse model was employed to confirm the anti-RA potential of ATT. Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays, cell cycle and apoptosis analysis, immunofluorescence, migration and invasion assays, quantitative real-time PCR (RT-qPCR), Western blot, RNA-sequencing (RNA-seq) analysis, plasmid construction and lentivirus infection, and methylated RNA immunoprecipitation and chromatin immunoprecipitation assays, were carried out to confirm the effect and potential mechanism of ATT on RA management., Results: ATT relieved CIA in mice. ATT inhibited proliferation and induced apoptosis of RA-fibroblast-like synoviocytes (FLSs). ATT restrained RA-FLSs migration and invasion via suppressing epithelial-mesenchymal transition. RNA-sequencing analysis and bioinformatics analysis identified intercellular adhesion molecule 2 (ICAM2) as a promoter of RA progression in RA-FLSs. ATT inhibits RA progression by suppressing ICAM2/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/p300 pathway in RA-FLSs. Moreover, ATT inhibited methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine methylation of ICAM2 mRNA in RA-FLSs. Interestingly, p300 directly facilitated METTL3 transcription, which could be restrained by ATT in RA-FLSs. Importantly, METTL3, ICAM2 and p300 expressions in synovium tissues of RA patients were related to clinical characteristics and therapy response., Conclusions: We provided strong evidence that ATT has therapeutic potential for RA management by suppressing proliferation, migration and invasion, in addition to inducing apoptosis of RA-FLSs through modulating METTL3/ICAM2/PI3K/AKT/p300 feedback loop, supplying the fundamental basis for the clinical application of ATT in RA therapy. Moreover, METTL3, ICAM2 and p300 might serve as biomarkers for the therapy response of RA patients., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Objective: To investigate the effects of shikonin (SKN) on M1 and M2 polarization of macrophages both and ., Methods: Collagen-induced arthritis (CIA) in male DBA/1 mice were treated with a dose of 4 mg/kg/day of SKN for 23 d ( = 6/group). The histopathology of inflamed joints in CIA mice was evaluated to test the anti-arthritic effect of SKN. M1/M2 polarization of macrophages induced by lipopolysaccharide (LPS) and interferon (IFN)-γ or interleukin (IL)-4 and IL-13, were used to assess the effect of SKN (0.05, 0.1, and 0.2 μM). The effect of SKN on the protein expression of nitric oxide synthase, arginase, CD68, and CD206 was evaluated using western blot analysis., Results: The results of this study revealed that SKN delayed the arthritis feet symptom score, reduced the incidence rate of arthritis, and relieved the inflammation of joints in CIA mice. SKN inhibited M1 macrophage polarization but did not affect M2 macrophage polarization in the joints of CIA mice. Moreover, SKN inhibited M1 polarization induced by LPS and IFN-γ, but did not affect M2 polarization induced by IL-4 and IL-13., Conclusion: These findings suggest that SKN alleviated CIA through inhibiting M1 macrophage polarization and has great potential as a new drug for RA treatment.

Rheumatoid arthritis (RA) is a common disease worldwide and is treated commonly with methotrexate (MTX). CS12192 is a novel JAK3 inhibitor discovered by Chipscreen Biosciences for the treatment of autoimmune diseases. In the present study, we examined the therapeutic effect of CS12192 against RA and explored if the combinational therapy of CS12192 and MTX produced a synergistic effect against RA in rat collagen-induced arthritis (CIA). Arthritis was induced in male Sprague-Dawley rats by two intradermal injections of bovine type II collagen (CII) and treated with MTX, CS12192, or the combination of CS12192 and MTX daily for two weeks. Effects of different treatments on arthritis score, X-ray score, pathology, and expression of inflammatory cytokines and biomarkers were examined. We found that treatment with either CS12192 or MTX produced a comparable therapeutic effect on CIA including: (1) significantly lowering the arthritis score, X-ray score, serum levels of rheumatic factor (RF), C-reactive protein (CRP), and anti-nuclear antibodies (ANA); (2) largely alleviating histopathological damage, reducing infiltration of Th17 cells while promoting Treg cells; (3) inhibiting the expression of inflammatory cytokines and chemokines such as IL-1β, TNF-α, IL-6, CCL2, and CXCL1. All these inhibitory effects were further improved by the combinational therapy with MTX and CS12192. Of importance, the combinational treatment also resulted in a marked switching of the Th17 to Treg and the M1 to M2 immune responses in synovial tissues of CIA. Thus, when compared to the monotherapy, the combination treatment with CS12192 and MTX produces a better therapeutic effect against CIA with a greater suppressive effect on T cells and macrophage-mediated joint inflammation.

Background Artificial forest can have great potential in serving as habitat to wildlife, depending on different management methods. As the state-owned forest farms now play a new role in ecological conservation in China, the biological richness of this kind of land-use type is understudied. Once owned by a mining company, a largest state-owned forest farm, Jingxi Forest Farm, has been reformed to be a state-owned forest farm with the purpose of conservation since 2017. Although this 116.4 km 2 forest farm holds a near-healthy montaine ecosystem very representative in North China, a large proportion of artificial coniferous forest in the forest farm has been proven to hold less biodiversity than natural vegetation. This situation, however, provides a great opportunity for ecological restoration and biodiversity conservation. Therefore, from November 2019 to December 2020, we conducted a set of biodiversity surveys, whose results will serve as a baseline for further restoration and conservation. New information Here, we report the result of a multi-taxa fauna diversity survey conducted in Jingxi Forest Farm mainly in year 2020 with explicit spatial information. It is the first survey of its kind conducted in this area, revealing a total of 19 species of mammals, 86 birds, four reptiles, two amphibians and one fish species, as well as 101 species of insects. Four species of mammals are identified as data-poor species as they have less than 100 occurrence records with coordination in the GBIF database. One species of insect, representing one new provincial record genus of Beijing, is reported., (Xiangying Shi, Ge Sun, Xinyu Yang, Junhong Gao, Lingdi Tan, Yuexin Song, Yiping Hu, Zunxiu Zhou, Huibin Zhao, Zhihai Hu, Shunwan Zhu, Yufan Cao, Rui Liao, Wei Chen, Zhehao Wu, Xiangyu Guan, Xiaotong Ren, Shen Zhang.)

Insulin is produced and secreted by pancreatic β cells in the pancreas, which plays a key role in maintaining euglycemia. Insufficient secretion or deficient usage of insulin is the main cause of diabetes mellitus (DM). Drug therapy and islets transplantation are classical treatments for DM. Pancreatic β cell replacement therapy could help patients to get rid of drugs and alleviate the problem of lacking in transplantable donors. Pancreatic β-like cells can be acquired by cell reprogramming techniques or directed induction of stem cell differentiation. These cells are proved to be functional both in vitro and in vivo . Some hospitals have already performed clinical trials for pancreatic β cell replacement therapy. Functional pancreatic β-like cells, which obtained from in vitro pathway, could be a reliable source of cell therapy for treating DM. In this review, the approaches of obtaining pancreatic β cells are summarized and the remaining problems are discussed. Some thoughts are provided for further acquisition and application of pancreatic β cells.

Background: Atrial fibrillation is a well-documented complication following cardiac surgery. It is associated with increased inpatient and long-term mortality. There have been few prior studies on perioperative atrial fibrillation following burn surgery in severely burned patients. The purpose of this study was to identify the incidence, predictors, and prognosis of perioperative atrial fibrillation after burn surgery in severely burned patients., Methods: Patients aged older than 18 years with 30% burned total body surface area (TBSA) were enrolled in this study. Patients who had a previous history of atrial fibrillation or atrial fibrillation on the preoperative electrocardiogram were excluded. We reviewed medical records retrospectively, and the data of 214 patients were studied., Results: A total of 214 critically ill burned patients and 1132 operations were available for analysis during the 5-year study period; 12 (1.1%) patients were diagnosed with newly developed atrial fibrillation after a burn operation, of whom 4 patients showed paroxysmal atrial fibrillation (all related to surgical stimulation) and none changed to persistent atrial fibrillation. The incidence of perioperative atrial fibrillation was associated with TBSA%, full-thickness TBSA%, and hypertension. Multiple logistic regression analysis indicated that TBSA% (OR=13.851, P < 0.001) and full-thickness TBSA% (OR=15.223, P = 0.018) were independent predictors for developing perioperative atrial fibrillation. All of our patients had at least one risk factor, with blood volume variation or burn sepsis occurring most commonly. Perioperative atrial fibrillation developed after a median of 0 days after burn surgery. Three patients died, and the causes of death were noncardiovascular events such as sepsis and multiple organ failure., Conclusion: Atrial fibrillation was a relatively rare complication among severely burned patients admitted to surgery and was associated with TBSA% and full thickness TBSA%. All of our patients exhibited at least one of the modifiable risk factors for atrial fibrillation, confirming the importance of optimization of electrolytes and fluid status and limitation of sympathetic activation., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: To evaluate the difference of the lens nuclear density measured before and after mydriasis by using the IOLMaster 700 (Carl Zeiss Meditec AG, Jena, Germany) and the Pentacam Scheimpflug imaging (Pentacam HR, Oculus Incorporation, Wetzlar, Germany) and investigate the relationship between the measurement data and the phacoemulsification parameters. Methods: Patients with age-related nuclear cataracts diagnosed on the slit-lamp examination were enrolled in the age range of 53-76 years. No patient had a history of ocular surgery, laser treatment, or general disorders affecting vision. The mean optical density (OD) was measured by the IOLMaster 700 by using the Image-Pro ® Plus software before and after mydriasis. The Pentacam nucleus densitometry (PND) was obtained automatically from the Pentacam Scheimpflug imaging and compared with OD. The correlation between OD and effective phacoemulsification time (EPT), PND, and EPT were analyzed, respectively. Results: In this study, 53 eyes of 52 patients were evaluated. Before and after mydriasis, the mean OD values were 64.34 ± 23.31 and 63.81 ± 23.21 pixel units, respectively; the mean PND values were 28.51 ± 11.42 and 25.41 ± 11.31, respectively; and the mean EPT value was 6.24 ± 3.49. The Bland-Altman analysis showed that the lens nuclear densities of the two devices were highly consistent. There was no significant difference in the OD values ( t = 0.455, p > 0.05) before and after mydriasis, but the difference has existed in the PND values ( t = 2.509, p < 0.05). The OD and PND values were positively correlated with EPT before and after mydriasis ( r OD-Before = 0.604, r OD-After = 0.593, r PND-Before = 0.701, and r PND-After = 0.891, p < 0.01). Conclusion: The combination of the IOLMaster 700 and the Image-Pro ® Plus software can quantitatively evaluate the degree of the cataract lens opacification. It has good consistency with the Pentacam and is positively correlated with the phacoemulsification parameters. It is expected to become a new method to predict the phacoemulsification parameters before and during cataract surgery., 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 © 2021 Li, Liu, Hu and Shi.)

Background: Rheumatoid arthritis is a progressive and systemic autoimmune disease seriously compromises human health. Fibroblast like synoviocytes are the major effectors of proliferation and inflammation in rheumatoid arthritis synovial tissue. Shikonin has anti-inflammatory and immunomodulatory activities. But, its role on synovitis of rheumatoid arthritis is unknown., Methods: The DBA/1 male mice were randomly divided into the following three groups (n = 6): (1) the normal control group of mice, (2) the CIA (collagen-induced arthritis) group in which mice suffered from arthritis induced by collagen, (3) the SKN (shikonin) group of mice which got arthritis and given intragastrically with shikonin 4 mg/kg per day continuously for 20 days,(4) the MTX (methotrexate) group of mice which got arthritis and orally administration with shikonin 0.5  mg/kg once two days continuously for 20 days. The therapeutic effect of shikonin on collagen induced arthritis mice was tested by arthritis incidence rate, arthritis score and inflammatory joint histopathology. The invasion, adhesion and migration of fibroblast like synoviocytes induced by tumor necrosis factor-α were applied to measure the anti-synovitis role of shikonin. The effect of shikonin on expression of interleukin-6, interleukin-1β and tumor necrosis factor-α was measured by enzyme linked immunosorbent assay. The interaction between shikonin and suppressor of cytokine signaling 1 was verified by molecular docking. The signaling pathways activated by shikonin were measured by western blot., Results: Shikonin decreased the arthritis score and arthritis incidence, and inhibited inflammation of inflamed joints in collagen induced arthritis mice. And shikonin reduced the number of vimentin + cells in collagen induced arthritis mice inflamed joints. Meanwhile, shikonin suppressed tumor necrosis factor-α-induced invasion, adhesion and migration of fibroblast like synoviocytes and reduced the expression of interleukin-6, interleukin-1β and tumor necrosis factor-α. And we found that shikonin targeted suppressor of cytokine signaling 1. More interestingly, shikonin blocked the phosphorylation of Janus kinase 1/signal transducer andactivator of transcription 1/signal transducer andactivator of transcription 6 in synovial tissues and in fibroblast like synoviocytes., Conclusion: Shikonin represents a promising new anti-rheumatoid arthritis drug candidate that has anti-synovitis effect in collagen induced arthritis mice and inhibits tumor necrosis factor-α-induced fibroblast like synoviocytes by targeting suppressor of cytokine signaling 1/ Janus kinase/signal transducer andactivator of transcription signaling pathway. These findings demonstrate that shikonin has anti-synovitis effect and has great potential to be a new drug for the treatment of rheumatoid arthritis., (© 2021. The Author(s).)

Transforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7., (© 2021. The Author(s).)

Objective: The purpose of this study was to evaluate the therapeutic effects and mechanism of Qufeng Zhitong (QFZT)capsule for the treatment of osteoarthritis (OA) in a rat model., Methods: 8-10-week-old male Sprague-Dawley rats were randomly divided into the sham group (vehicle-treated), OA group (vehicle-treated), high-dose, middle-dose, low-dose of QFZT capsule -treated groups. OA was induced by transecting the medial collateral ligament and the medial meniscus in the right limb. The Sprague-Dawley rats were treated daily for 12 weeks with different concentrations of QFZT capsule : low (QFZT-L, 128 ​mg/kg), medium (QFZT-M, 256.5 ​mg/kg), and high (QFZT-H, 513 ​mg/kg) by gavage administration for a period of 4 and 12 weeks respectively. Vehicle-treated rats served as controls and administered 0.5% Carboxymethyl Cellulose Sodium (CMC-Na) by gavage on the same schedule. Weekly measurement of dynamic weight-bearing capacity, grip strength, joint swelling was were performed to monitor the progression of disease for 3 weeks. After euthanasia, the knee joints were articular cartilage changes. Pro-inflammatory gene expression in synovial joints was examined to assess the bone and cartilage changes. Gene expression of pro-inflammatory cytokines in synovial joints was measured to determine the therapeutic effect of QFZT., Results: 2 weeks after the treatment, the grip strength and weight-bearing capacity were significantly increased in the QFZT-M and QFZT-H groups, compared with the OA group. The joint widths were decreased significantly in the QFZT-L and QFZT- H groups, compared with the OA group as well. The mRNA level in the articular cartilage of knee joint of IL-1β in the QFZT-L group and IL-6 in the QFZT-H group was significantly suppressed at week 4, compared with the OA group. The radiology score was significantly decreased in the QFZT-H group compared with the OA group 12 weeks after treatment. Furthermore, the rats on QFZT treatment decreased the progression of OA, which was characterised by decreased cartilage degradation. However, the bone changes were no different in OA group and QFZT groups., Conclusion: In a rat model of OA, QFZT capsule shows the tendency to reduce the destruction of cartilage, joint swelling and bone erosion which provides new evidence for the therapeutic potential of QFZT capsule in the treatment of OA in clinics., The Translational Potential of This Article: The QFZT capsule can improve the symptoms of the OA in rodent animal rats by attenuating pain and retarding cartilage damage. This study indicated that the QFZT capsule has the potential clinical application of in OA therapy., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (© 2021 The Authors.)

Based on the analysis of the theoretical calculation model of axial resolution of optical coherence tomograph for the posterior segment of the human eye, a set of testing device for measuring its axial resolution is designed and developed. In view of a commercial ophthalmic optical coherence tomograph in clinical use, its axial resolution is calculated to be 5.07 μm theoretically, and the actual measurement value is 5.45 μm. The uncertainty of the detection device is evaluated and the result is (5.45±0.10) μm. The measurement error introduced by the testing device is very small. Meanwhile, the axial resolution measured by the testing device meets the requirements of the instrument(≤ 6 μm).

Rheumatoid arthritis (RA) is the most common type of autoimmune arthritis. Hypoxia-inducible factor-1α (HIF-1α) as a transcription factor in response to hypoxia suggests that it could be a potential therapeutic target for the treatment of RA. In this study, we assessed whether the HIF pathway blockade attenuates the manifestations of RA in the collagen-induced arthritis (CIA) rat model. We constructed a short hairpin RNA (shRNA) lentiviral expression vector targeting HIF-1α (pLVX-shRNA-HIF-1α) and to achieve HIF-1α RNA interference. Quantitative RT-PCR, immunofluorescence staining, and western blot were used to detect the expressions of HIF-1α, vascular endothelial growth factor (VEGF), phsopho (p)-p65, and p-IКBɑ mRNA and protein, respectively. Micro-computed tomography was used to investigate joint morphology at different time points after CIA induction. Moreover, enzyme-linked immunosorbent assay (ELISA) was used to monitor the expression of inflammatory cytokines. In vitro analyses revealed that pLVX-shRNA-HIF-1α effectively inhibited the expression of HIF-1α and VEGF and led to the activation of p-65 and p-IКBɑ, as well as decreased proinflammatory cytokine expression in cell culture. Inhibition of HIF-1α in rats decreased signs of a systemic inflammatory condition, together with decreased pathological changes of RA. Moreover, downregulation of HIF-1α expression markedly reduced the synovitis and angiogenesis. In conclusion, we have shown that pharmacological inhibition of HIF-1 may improve the clinical manifestations of RA., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: To evaluate the effects of anterior capsular opening size on deviation from predicted refraction and the effective position of the intraocular lens (ELP) in cataract surgery., Methods: Nonrandomized clinical trial. Eighty patients (80 eyes) with simple age-related cataracts were treated from May 2018 to September 2018 at the Fourth Affiliated Hospital of China Medical University. All patients undergoing phacoemulsification received intraocular lens based on the voluntary principle. Forty eyes were implanted with the C-loop haptic intraocular lens (AMO Tecnis ZCB00) while the other 40 eyes were implanted with the plate haptic intraocular lens (CT ASPHINA 509 M). Follow-up visits were conducted postoperatively at 1 week, 1 month, and 3 months during which patients underwent refraction and data collection after pupil dilation, which included anterior segment photography and Scheimpflug imaging by Pentacam. The area, horizontal and vertical diameter of the capsulorrhexis, circularity, decentration, and package were analysed using the image analysis software Image-Pro-Plus 6.0,then evaluated the relationship between the different shapes of capsulorrhexis with deviation from predicted refraction and ELP in cataract surgery., Results: Deviation from predicted refraction and all of the parameters of capsulorrhexis were not correlative in the 509 M IOL group, however, in the Tecnis IOL group, while the deviation from predicted refraction and all of the capsulorrhexis parameters were not correlative at 1 week, the deviation from predicted refraction did correlate with capsulorrhexis area, horizontal diameter at 1 month (P = 0.029, P = 0.048), and with capsulorrhexis area, vertical diameter at 3 months (P = 0.03, P = 0.017). The ELP correlated with package in both groups postoperatively (r > 0, P < 0.05), but there is no other capsulorrhexis parameters correlated with ELP in the 509 M IOL group (all P > 0.05). For the Tecnis IOL group, the ELP and capsulorrhexis area were correlated at 1 week and 1 month, while the ELP and horizontal diameter, the ELP and vertical diameter were correlated at 1 week, but did not correlate with the other capsulorrhexis parameters in the Tecnis IOL group (all P > 0.05)., Conclusions: The shape of the capsulorrhexis has an effect on postoperative refractive outcomes and the effective position of the intraocular lens in cataract surgery, and plate haptic intraocular lenses have better refractive stability than C-loop haptic intraocular lenses., Trial Registration: ChiCTR1800015638 ,2018-04-12.

Based on the Gullstrand I model eye, a simplified model eye for testing fundus imaging device is designed. The model eye can reach the following requirements:(1) The refractive characteristics of the ocular refractive tissue are simulated, and the equivalent focal length in air is 17 mm; (2) The differences between relative refractive index differences of the adjacent materials of the simplified model eye and relative refractive index differences of any adjacent two layers (cornea and aqueous humor, aqueous humor and lens, lens and vitreous body) of the Gullstrand I model eye are not more than 1%; (3) In the case of the incident aperture diameter of 3 mm, the differences of radii of the diffuse spots formed by the paraxial light and the axial light are not more than 15%; (4) The differences of angles of chief ray and tangent line of the fundus are not more than 1°; (5) In the case of the incident aperture diameter of 3 mm, the differences of MTF values of the near axis light are not more than 0.1. The simplified model eye can be expected to be used for testing fundus imaging device instead of the test method in ISO 10940:2009 Ophthalmic instruments-Fundus cameras.

Background: This work aimed to evaluate the effects of genistein treatment in Collagen Induced Arthritis (CIA) mouse model., Methods: CIA was elicited in DBA/1 Mice by an intradermal injection of 100 μL of an emulsion of bovine type II collagen (CII) in isovolumic incomplete Freund's adjuvant (IFA) at the base of the tail. Twenty-one days later, a second injection of CII in IFA was administered at the base of the tail. After the symptoms of arthritis showed in mouse model, we divided animals into two groups according to their clinical symptom scores. The treatment group was intraperitoneally injected daily with genistein (based on the pre-experiment data and literature reported, 5 mg/kg dose was selected and tested) for 12 days, while the control group was injected with phosphate buffered saline. Inflammatory cytokines titer, radiological, and histological observations were completed at different time's points after treatment. CT analysis was conducted 3 months after the treatment to observe the articular structures. Immunohistochemical analysis was performed to investigate the expression and distribution of VEGF in joint tissues., Results: Genistein suppressed the expressions of IL-1β, IL-6 and TNF-α in the serum. Radiological results showed that bone degradation was inhibited by the treatment. Moreover, hematoxylin and eosin staining showed that the degree of inflammation was relieved. In the cartilage area, TRAP stain-positive cells were detected, which was notably reduced in the treatment group compared to the control group. Micro-CT 3D images clearly exhibited that the joint adhered and structures destroyed in the control group with less destruction in the treatment group. Furthermore, genistein suppressed VEGF expression, and blocked angiogenesis in the synovial tissue., Conclusion: Our work provides further data regarding the effects of genistein as a potential treatment drug for RA, as well as the role of genistein in the anti-inflammatory pathway in RA therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: GTS-21, a selective α7 nicotinic acetylcholine receptor agonist, has recently been established as a promising treatment for inflammation. However, the detailed molecular mechanism of GTS-21 in suppressing pro-inflammatory cytokine production is only partially explored. The study aimed to analyze cytokine expression suppressed by GTS-21 with lipopolysaccharide (LPS)-induced inflammation in vitro and to gain insights into the role of Akt/NF-κB signaling pathway in this process., Materials and Methods: Cell Counting Kit-8 (CCK-8) assay was performed to detect drug cytotoxicity. RAW 264.7 cells were stimulated with LPS and treated with GTS-21. Interleukin (IL)-1β, IL-6, or tumor necrosis factor (TNF)-α production was detected using enzyme-linked immunosorbent assay. Western blot was used to assess the expression patterns of signal transduction protein. Nuclear translocation of nuclear factor (NF)-κB was analyzed by confocal fluorescence microscopy. In addition, α7 nicotinic acetylcholine receptors (α7 nAChR) were detected on RAW264.7, and the α7 nAChR-specific antagonist was adopted to verify whether the effect of GTS-21 was mediated by α7 nAChR., Results: The CCK-8 assay showed that GTS-21 did not significantly affect cell proliferation. The production of IL-1β, IL-6, and TNF-α decreased after being treated with GTS-21 in LPS-stimulated RAW 264.7 cells. GTS-21 also suppressed LPS-induced phosphorylation of NF-κBp65, IKKα/β, IκBα, and Akt, as well as NF-κB p65 nuclear translocation. Moreover, α7 nAChR was expressed on the surfaces of RAW264.7 cells, and the α7 nAChR-specific antagonist almost completely prohibited the inhibitory effect of GTS-21 on NF-κB activation., Conclusion: These findings indicate that GTS-21 suppresses LPS-induced inflammation by inhibiting the Akt/NF-κB signal pathway through α7 nAChR. GTS-21 has a potential application in inflammatory disease therapy., (Copyright © 2015. Published by Elsevier B.V.)

Different from the previous knowledge regarding reactive oxygen species (ROS), recent research suggests that ROS play essential roles in initiating cascade reaction of wound healing. During wound healing, ROS can serve as the second messenger to regulate signal transduction and gene expression. In this paper, we review the mechanism of generation of cyclooxygenase 2-prostaglandin E2 induced by ROS, which regulates the early inflammatory response and subsequent healing after injury.

Objective: To observe if VIR576, an 20-mer peptide derived from the C-proximal subfragment of a1-antitrypsin (a1-AT) which inhibits human immunodeficiency virus type 1 (HIV-1) entry into the target cells by interacting with fusion peptide (FP), can also directly inhibit CD4(+) T cell activation in vitro., Methods: Splenocytes isolated from DO11.10 OVA Tg mice were stimulated with ovalbumin or concanavalin A to test the effects of VIR576 on antigen-specific or non-antigen-specific T cell activation. Both primary CD4(+)CD25(-) T cells from DO11.10 mice and CD4(+) T cell line A2b were activated with specific antigens to evaluate the effects of VIR576., Results: VIR576 inhibited antigen-specific splenocyte activation but had no significant effect on non-antigen-specific T-cell activation, which bypassed the crosstalk between the CD3-signaling complex and TCR. We furthermore observed that VIR576 could also down-regulate antigen-specific CD4(+) T-cell activation., Conclusions: Given the high susceptibility of activated CD4(+) T cells in the mucosa to HIV-1 infection, the inhibitory effects of VIR576 on both HIV entry into the target cells and CD4(+) T-cell activation suggest the potential of VIR576 as a microbicide for prevention of sexual transmission of HIV.

Aims: Genistein, an isoflavone derivative found in soy, is known as a promising treatment for rheumatoid arthritis (RA). However, the detailed molecular mechanism of genistein in suppression of proinflammatory cytokine production remains ambiguous. The aim of this work was to evaluate the signal pathway by which genistein modulates inflammatory cytokine expression., Materials and Methods: MH7A cells were stimulated with tumor necrosis factor (TNF)-α and incubated with genistein, and interleukin (IL)-1β, IL-6, and IL-8 production was measured by enzyme-linked immunosorbent assay. Nuclear translocation of nuclear factor (NF)-κB was measured by a confocal fluorescence microscopy. The intracellular accumulation of reactive oxygen species (ROS) was monitored using the fluorescent probe 5-6-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate. Signal-transduction protein expression was measured by Western blot., Results: Genistein decreased the secretion of IL-1β, IL-6, and IL-8 from TNF-α-stimulated MH7A cells in a dose-dependent manner. Genistein prevented TNF-α-induced NF-κB translocation as well as phosphorylation of IκB kinase-α/β and IκBα, and also suppressed TNF-α-induced AMPK inhibition. The production of IL-1β, IL-6, and IL-8 induced by TNF-α was decreased by the phosphatidylinositol-3 kinase inhibitor LY294002, suggesting that inhibition of Akt activation might inhibit IL-1β, IL-6, and IL-8 production induced by TNF-α. In addition, we also found that pretreatment with the adenosine monophosphate-activated protein kinase (AMPK) agonist 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside obviously inhibited TNF-α-induced proinflammatory cytokine production. These observations suggest that the inhibitory effect of genistein on TNF-α-induced proinflammatory cytokine production is dependent on AMPK activation., Conclusion: These findings indicate that genistein suppressed TNF-α-induced inflammation by inhibiting the ROS/Akt/NF-κB pathway and promoting AMPK activation in MH7A cells.

The abnormal proliferation and polarization of Th17/Th1 subsets are believed to contribute to the progression of multiple sclerosis. We demonstrated that neural stem cells (NSCs) could inhibit CD4(+)T cells from mice of experimental autoimmune encephalomyelitis to proliferate and polarize into Th17 but promote their apoptosis and to generate regulatory T cells in response to myelin antigen via releasing prostaglandin E2 by activated Th1-derived IFN-γ. The study indicated that NSCs play a negatively regulatory role in T cell responses and provided novel evidence for the therapeutic mechanisms underlying the usage of NSCs to treat autoimmune diseases of central nervous system., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Tetracyclines have been widely used in bone histomorphometry to label new bone formation and apposition rate. However, most studies of tetracyclines have also shown their strong inhibitory action on osteoclasts and their effects on osteoblast activities as well. To even obtain the in-depth understanding on this issue, we have reviewed related studies in "Pubmed" by searching the keywords "tetracyclines and osteoclast", "tetracyclines and osteoblast", which retrieved 118 and 162 related documents, respectively. Among these papers, some described the application of tetracyclines as fluorescent marker in bone histomorphometry, while others discussed their role in protection of bone metabolism partly through inhibiting osteoclastogenesis or bone resorption and through enhancing osteogenesis. Based on the above mentioned, it seems that tetracyclines used as bone labeling markers may affect the results of bone histomorphometry to some extent. To even confirm the effect of tetracyclines on bones cells (osteoblast, osteoclast) and in vivo bone remodeling, related research work has been performed in our research team which indicated quite different results in vivo and in vitro. Therefore, the influence of tetracyclines on bones may differ in terms of different conditions which need to be further elucidated.

Background & Aims: Hepatocyte-like cells can be derived from pluripotent stem cells such as embryonic stem (ES) cells, but ES cell-derived hepatic cells with extensive capacity to repopulate liver have not been identified. We aimed to identify and purify ES cell-derived hepatoblast-like progenitor cells and to explore their capacity for liver repopulation in mice after in vitro expansion., Methods: Unmanipulated mouse ES cells were cultured under defined conditions and allowed to undergo stepwise hepatic differentiation. The derived hepatic cells were examined by morphologic, fluorescence-activated cell sorting, gene expression, and clonal expansion analyses. The capacities of ES cell-derived hepatic progenitor cells to repopulate liver were investigated in mice that were deficient in fumarylacetoacetate hydrolase (Fah) (a model of liver injury)., Results: Mouse ES cells were induced to differentiate into a population that contained hepatic progenitor cells; this population included cells that expressed epithelial cell adhesion molecule (EpCAM) but did not express c-Kit. Clonal hepatic progenitors that arose from single c-Kit(-)EpCAM(+) cells could undergo long-term expansion and maintain hepatoblast-like characteristics. Enriched c-Kit(-)EpCAM(+) cells and clonally expanded hepatic progenitor cells repopulated the livers of Fah-deficient mice without inducing tumorigenesis., Conclusions: ES cell-derived c-Kit(-)EpCAM(+) cells contain a population of hepatoblast-like progenitor cells that can repopulate livers of mice., (Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Functional human hepatocytes xeno-engrafted in mouse liver can be used as a model system to study hepatitis virus infection and vaccine efficacy. Significant liver xeno-repopulation has been reported in two kinds of genetically modified mice that have both immune deficiency and liver injury-induced donor hepatocyte selection: the uPA/SCID mice and Fah(-/-) Rag2(-/-)Il2rg(-/-) mice. The lack of hardy breeding and the overly elaborated technique in these two models may hinder the potential future application of these models to hepatitis virus infection and vaccination studies. Improving the transplantation protocol for liver xeno-repopulation from human hepatocytes will increase the model efficiency and application. In this study, we successfully apply immunosuppressive drug treatments of anti-asialo GM1 and FK506 in Fah(-/-)Rag2(-/-) mice, resulting in significant liver xeno-repopulation from human hepatocytes and human fetal liver cells. This methodology decreases the risk of animal mortality during breeding and surgery. When infected with hepatitis B virus (HBV) sera, Fah(-/-)Rag2(-/-) mice with liver xeno-repopulation from human hepatocytes accumulate significant levels of HBV DNA and HBV proteins. Our new protocol for humanized liver could be applied in the study of human hepatitis virus infection in vivo, as well as the pharmacokinetics and efficacy of potential vaccines.

To elucidate the effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles (NPs), rhodamine B (RhB) labeled carboxymethyl chitosan grafted NPs (RhB-CMCNP) and chitosan hydrochloride grafted NPs (RhB-CHNP) were developed as the model negatively and positively charged polymeric NPs, respectively. These NPs owned well defined particle sizes (150-500 nm) and Zeta potentials (-40 mV - +35 mV). FITC labeled protamine sulfate (FITC-PS) loaded RhB-CMCNP and camptothecin (CPT) loaded RhB-CHNP with high encapsulation efficiency were prepared. The fluorescence stability in plasma and towards I(-) was investigated, and the result indicated it was sufficient for qualitative and quantitative analysis. NPs with high surface charge and large particle size were phagocytized more efficiently by murine macrophage. Slight particle size and surface charge differences and different cell lines had significant implications in the cellular uptake of NPs, and various mechanisms were involved in the uptake process. In vivo biodistribution suggested that NPs with slight negative charges and particle size of 150 nm were tended to accumulate in tumor more efficiently. These results could serve as a guideline in the rational design of drug nanocarriers with maximized therapeutic efficacy and predictable in vivo properties, in which the control of particle size and surface charge was of significance., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The development of hippocampal circuitry depends on the proper assembly of correctly specified and fully differentiated hippocampal neurons. Little is known about factors that control the hippocampal specification. Here, we show that zinc finger protein Zbtb20 is essential for the specification of hippocampal CA1 field identity. We found that Zbtb20 expression was initially activated in the hippocampal anlage at the onset of corticogenesis, and persisted in immature hippocampal neurons. Targeted deletion of Zbtb20 in mice did not compromise the progenitor proliferation in the hippocampal and adjacent transitional ventricular zone, but led to the transformation of the hippocampal CA1 field into a transitional neocortex-like structure, as evidenced by cytoarchitectural, neuronal migration, and gene expression phenotypes. Correspondingly, the subiculum was ectopically located adjacent to the CA3 in mutant. Although the field identities of the mutant CA3 and dentate gyrus (DG) were largely maintained, their projections were severely impaired. The hippocampus of Zbtb20 null mice was reduced in size, and exhibited increased apoptotic cell death during postnatal development. Our data establish an essential role of Zbtb20 in the specification of CA1 field identity by repressing adjacent transitional neocortex-specific fate determination.

Highly specific amplification of complex DNA pools without bias or template-independent products (TIPs) remains a challenge. We have developed a method using phi29 DNA polymerase and trehalose and optimized control of amplification to create micrograms of specific amplicons without TIPs from down to subfemtograms of DNA. With an input of as little as 0.5-2.5 ng of human gDNA or a few cells, the product could be close to native DNA in locus representation. The amplicons from 5 and 0.5 ng of DNA faithfully demonstrated all previously known heterozygous segmental duplications and deletions (3 Mb to 18 kb) located on chromosome 22 and even a homozygous deletion smaller than 1 kb with high-resolution chromosome-wide comparative genomic hybridization. With 550k Infinium BeadChip SNP typing, the >99.7% accuracy was compared favorably with results on unamplified DNA. Importantly, underrepresentation of chromosome termini that occurred with GenomiPhi v2 was greatly rescued with the present procedure, and the call rate and accuracy of SNP typing were also improved for the amplicons with a 0.5-ng, partially degraded DNA input. In addition, the amplification proceeded logarithmically in terms of total yield before saturation; the intact cells was amplified >50 times more efficiently than an equivalent amount of extracted DNA; and the locus imbalance for amplicons with 0.1 ng or lower input of DNA was variable, whereas for higher input it was largely reproducible. This procedure facilitates genomic analysis with single cells or other traces of DNA, and generates products suitable for analysis by massively parallel sequencing as well as microarray hybridization.