Saikosaponin F ameliorates depression-associated dry eye disease by inhibiting TRIM8-induced TAK1 ubiquitination.

AIMS: Saikosaponin F (SsF) is one of the major active ingredients of Radix Bupleuri, an herb widely used in the treatment of depression. Studies have shown that dry eye disease often occurs together with depression. The aim of this study is to investigate whether SsF can improve depression-associated dry eye disease and explore the underlying mechanism. METHODS: Behavioral test was used to verify the effect of SsF on CUMS-induced depression-like behaviors in mice. Corneal fluorescein staining, phenol red cotton thread test and periodic acid-Schiff (PAS) staining were used to observe the effect of SsF on depression-associated dry eye disease. Western blot (WB) was performed to observe the expression of TAK1 protein and key proteins of NF-κB and MAPK (P38) inflammatory pathways in the hippocampus and cornea. Immunohistochemical staining was used to observe the expression of microglia, and immunoprecipitation was used to observe K63-linked TAK1 ubiquitination. Subsequently, we constructed a viral vector sh-TAK1 to silence TAK1 protein to verify whether SsF exerted its therapeutic effect based on TAK1. The expression of inflammatory factors such as IL-1ß, TNF-α and IL-18 in hippocampus and cornea were detected by ELISA. Overexpression of TRIM8 (OE-TRIM8) by viral vector was used to verify whether SsF improved depression-associated dry eye disease based on TRIM8. RESULTS: SsF treatment significantly improved the depression-like behavior, increased tear production and restored corneal injury in depression-related dry eye model mice. SsF treatment downregulated TAK1 expression and TRIM8-induced K63-linked TAK1 polyubiquitination, while inhibiting the activation of NF-κB and MAPK (P38) inflammatory pathways and microglial expression. In addition, selective inhibition of TAK1 expression ameliorated depression-associated dry eye disease, while overexpression of TRIM8 attenuated the therapeutic effect of SsF on depression-associated dry eye disease. CONCLUSION: SsF inhibited the polyubiquitination of TAK1 by acting on TRIM8, resulting in the downregulation of TAK1 expression, inhibition of inflammatory response, and improvement of CUMS-induced depression-associated dry eye disease.

Symptom structure of posttraumatic stress disorder in workplace trauma: A "distraction-avoidance" pattern.

BACKGROUND: Individuals who experience a workplace trauma are at a high risk of developing posttraumatic stress disorder (PTSD). Most of these people return to work soon after the trauma (i.e., experience early-stage natural exposure). This study aims to explore the response pattern of workers who have experienced a workplace trauma and early-stage natural exposure through network analysis and provide insights into the potential impact of early-stage natural exposure. METHODS: Our study included 278 workers directly experiencing the workplace explosion in the Tianjin Economic and Technological Development Zone. A partial correlation network analysis was used to explore the PTSD symptoms relationship and identify central symptoms. RESULTS: The results suggest that emotional numbness, difficulty in concentration, re-experiencing symptoms, and avoidance of thoughts are the most central symptoms, reflecting a "distraction-avoidance" pattern. CONCLUSIONS: The current study found that workers who experienced workplace trauma exhibited a "distraction-avoidance" pattern, which helps deepen our understanding of the PTSD network and leads to some suggestions on intervention measures.

A 3D-Printed Ferromagnetic Liquid Crystal Elastomer with Programmed Dual-Anisotropy and Multi-Responsiveness.

Liquid crystal elastomers (LCE) and magnetic soft materials are promising active materials in many emerging fields, such as soft robotics. Despite the high demand for developing active materials that combine the advantages of LCE and magnetic actuation, the lack of independent programming of the LCE nematic order and magnetization in a single material still hinders the desired multi-responsiveness. In this study, a ferromagnetic LCE (magLCE) ink with nematic order and magnetization is developed that can be independently programmed to be anisotropic, referred to as "dual anisotropy", via a customized 3D-printing platform. The magLCE ink is fabricated by dispersing ferromagnetic microparticles in the LCE matrix, and a 3D-printing platform is created by integrating a magnet with 3-DoF motion into an extrusion-based 3D printer. In addition to magnetic fields, magLCEs can also be actuated by heating sources (either environmental heating or photo-heating of the embedded ferromagnetic microparticles) with a high energy density and tunable actuation temperature. A programmed magLCE strip robot is demonstrated with enhanced adaptability to complex environments (different terrains, magnetic fields, and temperatures) using a multi-actuation strategy. The magLCE also has potential applications in mechanical memory, as demonstrated by the multistable mechanical metastructure array with remote writability and stable memory.

Mechanisms of Wuyao (Linderae Radix) in treating chronic pelvic inflammatory disease based on network pharmacology and animal experiments / 数字中医药（英文）

@#【Objective】  To predict the active components and action targets of Wuyao (Linderae Radix) in the treatment of chronic pelvic inflammatory disease (CPID) based on network pharmacology, explore possible mechanisms of the treatment through animal experiments, and provide a scientific basis for clinical applications of Wuyao (Linderae Radix). 【Methods】  Possible active components and targets of Wuyao (Linderae Radix) in the treatment of CPID were obtained applying network pharmacology and molecular docking technology. CPID rat models were established using the mixed Escherichia coli, Staphylococcus aureus, and Ureaplasma urealyticum plus the performance of mechanical injury. Hematoxylineosin (HE) staining was applied to observe the pathological changes in the uterus, fallopian tube, and spleens of rat models. The contents of nitric oxide (NO), superoxide dismutase (SOD), and malondialdehyde (MDA) in the serum of rats were determined with the use of corresponding detection kits. Enzyme-linked immunosorbent assay (ELISA) test was used to measure the expression of interleukin (IL)-6 and IL-10 in the serum of rat models. Flow cytometry was used to determine the percentage of CD4+ and CD8a+ T cells as well as CD4+ CD25+ regulatory T cells (Tregs) in the spleen of rat models. 【Results】  A total of nine potential active components and four core therapeutic targets related to inflammatory response in Wuyao (Linderae Radix) were obtained. The animal experiments showed that Wuyao (Linderae Radix) markedly inhibited uterus swelling, regulated morphological changes in the fallopian tube and spleen,  effectively reduced inflammatory infiltration and injuries in the uterus and fallopian tube, and improved spleen functions in CPID rats. Moreover, Wuyao (Linderae Radix) markedly reduced the levels of NO, IL-6, and MDA, and increased the levels of IL-10 and SOD in the serum of rats. Wuyao (Linderae Radix) also elevated the percentage of CD4+T cells and the CD4+ T/CD8a+ T cell ratio, reduced the percentage of CD8a+ T cells, and raised the percentage of CD4+ CD25+ Tregs that had been abnormally decreased in rat models (P < 0.05). 【Conclusion】  Wuyao (Linderae Radix) could have therapeutic effects on CPID rats by relieving oxidative stress, mitigating inflammatory levels, and regulating the immuno-function of T cell subgroups to improve the pathological changes in CPID rats. It is a medicinal herb worth being further explored for its clinical values.

Application of BMP in Bone Tissue Engineering.

At present, bone nonunion and delayed union are still difficult problems in orthopaedics. Since the discovery of bone morphogenetic protein (BMP), it has been widely used in various studies due to its powerful role in promoting osteogenesis and chondrogenesis. Current results show that BMPs can promote healing of bone defects and reduce the occurrence of complications. However, the mechanism of BMP in vivo still needs to be explored, and application of BMP alone to a bone defect site cannot achieve good therapeutic effects. It is particularly important to modify implants to carry BMP to achieve slow and sustained release effects by taking advantage of the nature of the implant. This review aims to explain the mechanism of BMP action in vivo, its biological function, and how BMP can be applied to orthopaedic implants to effectively stimulate bone healing in the long term. Notably, implantation of a system that allows sustained release of BMP can provide an effective method to treat bone nonunion and delayed bone healing in the clinic.

Sustained Release of VEGF to Promote Angiogenesis and Osteointegration of Three-Dimensional Printed Biomimetic Titanium Alloy Implants.

Tumor resection and treatment of trauma-related regional large bone defects have major challenges in the field of orthopedics. Scaffolds that treat bone defects are the focus of bone tissue engineering. 3D printing porous titanium alloy scaffolds, prepared via electron beam melting technology, possess customized structure and strength. The addition of a growth factor coating to the scaffold introduces a specific form of biological activation. Vascular endothelial growth factor (VEGF) is key to angiogenesis and osteogenesis in vivo. We designed a porous titanium alloy scaffold/thermosensitive collagen hydrogel system, equipped with VEGF, to promote local osseointegration and angiogenesis. We also verified the VEGF release via thermosensitive collagen and proliferation and induction of the human umbilical vein endothelial cells (HUVECs) via the composite system in vitro. In vivo, using microscopic computed tomography (Micro-CT), histology, and immunohistochemistry analysis, we confirmed that the composite scaffold aids in angiogenesis-mediated bone regeneration, and promotes significantly more bone integration. We also discovered that the composite scaffold has excellent biocompatibility, provides bioactive VEGF for angiogenesis and osteointegration, and provides an important theoretical basis for the restoration of local blood supply and strengthening of bone integration.

Investigation on Protic Ionic Liquids as Physical Solvents for Absorption of NO at Low Pressures.

Nitric oxide (NO) absorption in ionic liquids (ILs) is an interesting issue, but little attention has been focused on the removal of NO at low partial pressures. Herein, a series of protic ionic liquids (PILs) based on polyamines as the cation and hydroxybenzenes as the anion were prepared for capturing low-concentration NO (0-0.6 bar). Triethylenetetramine phenolate ([TETAH][PhO]) showed an excellent absorption performance, with low viscosity, fast absorption rate, and high absorption capacity. The experimental solubility data were fitted by the Krichevsky-Kasarnovsky (K-K) equation, and the absorption enthalpy (ΔH) of NO in [TETAH][PhO] was thus calculated to be -43.60 kJ/mol. Density functional theory calculations were further performed to better understand the interaction of [TETAH][PhO] with NO on the molecular level, and the results suggest that the weak interaction of NO with the PIL was induced by the presence of H protons. It is believed that this work may provide a new method for the efficient and reversible absorption of low-concentration NO.

New Insight of Circular RNAs in Human Musculoskeletal Diseases.

Circular RNAs (circRNAs), a novel group of noncoding RNAs, are present in most eukaryotic cells. Different from messenger RNAs, circRNAs have a covalently closed single-stranded stable structure and often act in cell type and tissue-specific manners, indicating that they can be used as biomarkers. With the advance of high-throughput RNA sequencing technology and bioinformatics, a large number of circRNAs have been identified in association with musculoskeletal diseases, but the functions of most circRNAs have not been clarified. circRNAs regulate biological processes by adsorbing microRNA as "sponges," binding to proteins, acting as transcriptional regulators, and participating in translation of proteins. In this study, we discuss the latest understanding of biogenesis and gene regulatory mechanisms of circRNAs with special emphasis on new targets for musculoskeletal disease diagnosis and clinical treatment.

Identification of biomarkers associated with synovitis in rheumatoid arthritis by bioinformatics analyses.

OBJECTIVES: Rheumatoid arthritis (RA) is the most common inflammatory arthritis in the world, but its underlying mechanism is still unclear. The present study aims to screen and verify the potential biomarkers of RA. METHODS: We searched the Gene Expression Omnibus (GEO) database for synovial expression profiling from different RA microarray studies to perform a systematic analysis. Functional annotation of differentially expressed genes (DEGs) was conducted, including GO enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The protein-protein interaction (PPI) networks of the DEGs were constructed based on data from the STRING database. The expression levels of the hub genes in normal membranes and RA synovium were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot system. RESULTS: A total of 444 differential expression genes were identified, including 172 up-regulated and 272 down-regulated genes in RA synovium compared with normal controls. The top ten hub genes; protein tyrosine phosphatase receptor type C (PTPRC), LCK proto-oncogene (LCK), cell division cycle 20 (CDC20), Jun proto-oncogene (JUN), cyclin-dependent kinase 1 (CDK1), kinesin family member 11 (KIF11), epidermal growth factor receptor (epidermal growth factor receptor (EGFR), vascular endothelial growth factor A (VEGFA), mitotic arrest deficient 2 like 1 (MAD2L1), and signal transducer and activator of transcription 1 (STAT1) were identified from the PPI network, and the expression level of VEGFA and EGFR was significantly increased in RA membranes (P<0.05). CONCLUSION: Our results indicate that the hub genes VEGFA and EGFR may have essential effects during the development of RA and can be used as potential biomarkers of RA.

Study of Osteoarthritis-Related Hub Genes Based on Bioinformatics Analysis.

Osteoarthritis (OA) is a common cause of morbidity and disability worldwide. However, the pathogenesis of OA is unclear. Therefore, this study was conducted to characterize the pathogenesis and implicated genes of OA. The gene expression profiles of GSE82107 and GSE55235 were downloaded from the Gene Expression Omnibus database. Altogether, 173 differentially expressed genes including 68 upregulated genes and 105 downregulated genes in patients with OA were selected based on the criteria of ∣log fold-change | >1 and an adjusted p value < 0.05. Protein-protein interaction network analysis showed that FN1, COL1A1, IGF1, SPP1, TIMP1, BGN, COL5A1, MMP13, CLU, and SDC1 are the top ten genes most closely related to OA. Quantitative reverse transcription-polymerase chain reaction showed that the expression levels of COL1A1, COL5A1, TIMP1, MMP13, and SDC1 were significantly increased in OA. This study provides clues for the molecular mechanism and specific biomarkers of OA.

Lixisenatide attenuates advanced glycation end products (AGEs)-induced degradation of extracellular matrix in human primary chondrocytes.

Osteoarthritis (OA) poses a growing threat to the health of the global population. Accumulation of advanced glycation end-products (AGEs) has been shown to upregulate expression of degradative enzymes such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) in chondrocytes, which leads to excessive degradation of type II collagen and aggrecan in the articular extracellular matrix (ECM). In the present study we investigated the effects of the GLP-1 agonist lixisenatide, a widely used type II diabetes medication, on AGEs-induced decreased mitochondrial membrane potential (MMP), degradation of ECM, oxidative stress, expression of cytokines including interleukin (IL)-1ß and IL-6, and activation of nuclear factor kappa B (NF-κB). Our findings indicate that lixisenatide significantly ameliorated the deleterious effects of AGEs in a dose-dependent manner. Thus, lixisenatide has potential as a safe and effective treatment for OA and other AGEs-induced inflammatory diseases.

Fungal Endophytic Communities of Two Wild Rosa Varieties With Different Powdery Mildew Susceptibilities.

Powdery mildew (PM) is one of the most devastating and wide spread fungal diseases of rose, which seriously decrease its productivity and commercial value. In the present study, the endophytic fungal communities of two wild Rosa varieties (Rosa multiflora Thunb and R. multiflora var. carnea Redouté and Thory) with different PM susceptibilities were studied through Illumina MiSeq sequencer. A total of 14,000,424 raw reads were obtained from 60 samples, and 6,862,953 tags were produced after merging paired-end reads. 4462 distinct OTUs were generated at a 97% similarity level. It was found that only 34.2% of OTUs shared between two plant varieties. All of the OTUs were assigned into four fungal phyla, 17 classes, 43 orders, 86 families, 157 genera, and 208 species. Members of Ascomycota were found to be the most common fungal endophytes (EF) among all plant samples (93.7% relative abundance), followed by Basidiomycota (4.7% relative abundance), while Zygomycota and Glomeromycota were found to be rare and incidental. At each developmental stage of plants, the diversity and community structure of EF between two Rosa varieties showed significant differences. Both PCoA plots and PERMANOVA analyses indicated that developmental stage was the major factor contributing to the difference between the Rosa varieties (R 2 = 0.348, p < 0.001). In addition, plant varieties and tissues were also important factors contributing to the difference (R 2 = 0.031, p < 0.05; R 2 = 0.029, p < 0.05). Moreover, Neofusicoccum, Rhodosporidium, and Podosphaera, etc., were found to be significantly different between two Rosa varieties, and some of the endophytes may play a role in PM resistance. These finding are encouraging to testify the potential use of these fungi in the biocontrol of PM in future studies.