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High-performance nonlinear-optical (NLO) crystals need to simultaneously meet multiple basic and conflicting performance requirements. Here, by using a partial chemical substitution strategy, the first noncentrosymmetric (NCS) PbBeB2O5crystal with a BeB2O8group was synthesized, exhibiting a two-dimensional [BeB2O5]∞layer constructed by interconnecting BeB2O8groups and bridged PbO4with an active lone pair. The crystal shows a promising UV NLO functional feature, including a strong SHG effect of 3.5 × KDP (KH2PO4), large birefringence realizing phase matchability in the whole transparency region from 246 to 2500 nm, a short UV absorption edge of 246 nm, and single-crystal easy growth. Remarkably, theoretical studies reveal that the BeB2O8group has high nonlinear activity, which could stimulate the discovery of a series of excellent NLO beryllium borates.

Chlorogenic acid (CGA) has been confirmed as a polyphenol, and existing research has suggested the high bioactivity of CGA for therapeutic effects on a wide variety of diseases. Despite the existing reports of anti-inflammatory, antioxidant, and neuroprotective effects of CGA, the role and mechanism of CGA in facilitating the regeneration of peripheral nerve defects have been rarely investigated. Herein, a biodegradable polycaprolactone (PCL) conduit with embedded CGA-releasing GelMA microspheres (CGM/PCL) was successfully prepared and used for repairing a rate model with sciatic nerve defects. CGM and CGM/PCL conduits displayed high in vitrobiocompatibility and can support the growth of cells for nerve regeneration. Furthermore, CGM/PCL conduits displayed high performance which is close to that of autologous nerve grafts in promoting in vivoPNI regeneration, compared with PCL conduits. The sciatic nerve functional index analysis, electrophysiological examination, and immunological analysis performed to evaluate the functional recovery of the injurious sciatic nerve of rats have indeed proved the favorable effects of CGM/PCL conduits. The result of this study not only aimed to explore CGA's contribution to nerve regeneration but also provided a new strategy for designing and preparing functional NGCs for PNI treatment.

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The specific function of long noncoding RNAs (lncRNAs) in systemic lupus erythematosus (SLE) and the mechanism of their involvement in related pathological changes remain to be elucidated, so, in this study, we analyzed the differences in the expression profiles of lncRNAs and their mechanisms of action in SLE using full high-throughput sequencing, bioinformatics, etc. methods. We used high-throughput sequencing to detect differences in the expression profiles of lncRNAs, miRNAs, and mRNAs in PBMCs from patients with SLE at the genome-wide level. Next, we predicted target genes of 30 lincRNAs (long intergenic noncoding RNAs) by constructing a coexpression network of differential lincRNAs and mRNAs and identified the role of lincRNAs. Then, we analyzed the coexpression network of 23 optimized lincRNAs and their corresponding 353 miRNAs, evaluated the cis- and trans-effects of these lincRNAs, and performed GO and KEGG analyses of target genes. We also selected 8 lincRNAs and 2 newly discovered lncRNAs for q-PCR validation and lncRNA–miRNA–mRNA analysis. Finally, we also analyzed respectively the relation between lncRNAs and gender bias in SLE patients using RT-qPCR, the relation between Systemic Lupus Erythematosus Disease Activity Index score and the “IFN signature” using ELISA, and the relation between the differential expression of lncRNAs and a change in the number of a cell type of PBMCs in SLE patients using RT-qPCR. The profiles of 1087 lncRNAs, 102 miRNAs, and 4101 mRNAs in PBMCs significantly differed between patients with SLE and healthy controls. The coexpression network analysis showed that the network contained 23 lincRNAs and 353 mRNAs. The evaluation of the cis- and trans-effects showed that the 23 lincRNAs acted on 704 target genes. GO and KEGG analyses of the target genes predicted the biological functions of the 23 lincRNAs. q-PCR validation showed 7 lincRNAs and 2 novel lncRNAs were identical to the sequencing results. The ceRNA network contained 7 validated lincRNAs, 15 miRNAs, and 155 mRNAs. In addition, the differential expression of lncRNAs may be gender dependent in SLE patients, SLE patients also exhibit a robust “IFN signature,” and PBMCs exhibiting differential expression of lncRNAs may be due to a change in the number of a cell type. This work determined specific lncRNAs that play important biological functions in the pathogenesis of lupus and provided a new direction for diagnosis and treatment of disease.

An anterior cruciate ligament (ACL) injury is one of the most common injuries in sports, and ACL reconstruction with an artificial ligament is a good treatment for quick recovery. However, current artificial ligaments made of polyethylene terephthalate (PET) are still associated with some problems due to the hydrophobic nature and low biological induction activity of PET. Many efforts have been used to improve the biocompatibility of PET in recent years, and our previous work has shown that surface modification is an effective strategy. Here, a hydroxypropylcellulose (HPC) coating was applied on the surface of a PET artificial ligament order to improve its biocompatibility. The effects of the HPC coating on PET artificial ligament graft-bone healing was investigated in vitrousing bone marrow stromal cells (BMSCs), fibroblasts, and RSC-364 cells as well as in vivoin a beagle dog model of ACL reconstruction. HPC was coated successfully on the PET and significantly promoted cell growth, adhesion, and capability of osteogenic differentiation compared to the PET graft without HPC coating. In vivo, the HPC coating significantly enhanced ligament tissue regeneration. Moreover, higher expression of some bone-formation- and ligament-tissue-regeneration-contributing proteins and cell factors, such as COL1, BMP-7, COL3, OCN, RUNX2, TGF-β1, and VEGF, was observed on the HPC-coated PET artificial ligament in comparison with the pure PET artificial ligament. In conclusion, HPC coating can significantly improve the cytocompatibility and graft-to-bone healing of a PET artificial ligament for ACL reconstruction.

Our previous proteomic study indicated that connective tissue growth factor (CTGF) may be a potential biomarker for rheumatoid arthritis (RA) diagnosis. The aim was to assess the performance of CTGF as a biomarker of RA. Serum and synovial fluid CTGF was detected using a direct high sensitivity sandwich ELISA kit. Serum CTGF levels were tested for discriminatory capacity and optimal assay cutoffs determined in a training cohort of 98 cases of RA with 103 healthy controls. The assay performance was then validated in a further cohort of 572 patients (with RA (n= 217), ankylosing spondylitis (n= 92), gout (n= 74), osteoarthritis (n= 52), systemic lupus erythematosus (n= 72), or primary Sjögren’s syndrome (pSS) (n= 65)). Significant elevation of synovial fluid CTGF concentration was found in RA patients, demonstrating excellent diagnostic ability to predict RA (area under the curve (AUC) = 0.97). Similar results were found in serum CTGF detection. At the optimal cutoff value 88.66 pg/mL, the sensitivity, specificity, and the AUC was 0.86, 0.92, and 0.92, respectively, in the training cohort. Similar performance was observed in the validation cohort, with sensitivity, specificity, positive likelihood, and negative likelihood of 0.82, 0.91, 5.74, and 0.12, respectively. Stronger discriminatory capacity was seen with the combination of CTGF and anti-citrullinated protein antibody (ACPA) (AUC = 0.96) than with either ACPA or rheumatoid factor (RF) alone (AUC = 0.80 or 0.79, respectively). The discriminatory performance of serum CTGF was consistent across all inflammatory conditions tested (AUC >0.92 in all cases), with the sole exception of pSS. Serum CTGF did not vary with symptom duration or disease activity. Serum CTGF is a promising diagnostic biomarker for RA, with performance in the current study better than either ACPA or RF.

Our previous proteomic study on fibroblast-like synoviocytes (FLSs) derived from the synovial tissues found that the expression of KIAA1199 was higher in rheumatoid arthritis (RA) patients than in healthy controls. The aim of this study was to examine the biological function of KIAA1199 and evaluate its clinical diagnosis value in RA. The over-expression of KIAA1199 was verified by quantitative real-time polymerase chain reaction (qPCR), Immunohistochemistry, Immunofluorescence and enzyme linked immunosorbent assay (ELISA) in inactive and active RA patients and healthy controls. The effect of KIAA1199 expression on FLSs proliferation, angiogenesis and related pathway were analyzed by MTT, cell migration, tube formation, chorioallantoic membrane (CAM) assay, qPCR and western-blotting after KIAA1199 knockdown and over-expression. The verification results show the up-regulation of KIAA1199 in RA patients at mRNA and protein level as compared to that in healthy controls. ELISA and receiver operator characteristic (ROC) analysis shows that KIAA1199 concentration in serum, synovial fluid and synovial tissues could be used as dependable biomarkers for the diagnosis of active RA, provided an area under roc curve (AUC) of 0.83, 0.92 and 0.92. Sensitivity and specificity, which were determined by cut-off points, reached 72% 84% and 80% in sensitivity and 80%, 93.3%, 93.3% in specificity, respectively. Moreover, KIAA1199 also enhance the proliferation and angiogenesis of synovial membrane, and KIAA1199/ PLXNB3/ SEMA5A/CTGF axis may be a newly found pathway enhancing cell proliferation and angiogenesis. KIAA1199 may be a potential diagnostic biomarker of RA related to angiogenesis.

Aquaporin 1 (AQP1), a member of water channel proteins, functions as a water-selective transporting protein in cell membranes. In recent years, AQP1 has been found to be overexpressed in various tumors. However, the molecular mechanism underlying the biological function of AQP1 in osteosarcoma is still unclear. This study was aimed at elucidating the roles of AQP1 in regulating the biological behavior of osteosarcoma cells. In this study, we found that AQP1 mRNA was elevated in osteosarcoma tissue. High level of AQP1 was associated with poor prognosis in osteosarcoma. Then, we found that knockdown of AQP1 in osteosarcoma cells, U2OS or MG63 cells inhibited cell proliferation and significantly increased cells population in G1 phase. Additionally, suppressing AQP1 expression in osteosarcoma cells dramatically induced cell apoptosis. We also found that down-regulation of AQP1 significantly inhibited cell adhesion and invasion. More importantly, AQP1 knockdown inhibited tumor growth in vivoand prolonged the survival time of nude mice. Gene set enrichment analysis (GSEA) showed that transforming growth factor-β (TGF-β) signaling pathway and focal adhesion genes was correlatively with AQP1 expression. In addition, real time PCR and western blot analysis revealed that expression of TGF-β1/TGF-β2, RhoA and laminin β 2 (LAMB2) was remarkably impaired by AQP1 silencing. In conclusion, AQP1 may be a useful diagnosis and prognosis marker for osteosarcoma. AQP1 knockdown can effectively inhibit cell proliferation, adhesion, invasion and tumorigenesis by targeting TGF-β signaling pathway and focal adhesion genes, which may serve a promising therapeutic strategy for osteosarcoma.

To investigate the apoptotic mechanism of triple-negative breast cancer (TNBC) cells induced by gefitinib and PI3K inhibitor SF1126. MDA-MB-231, MDA-MB-436, and MCF-7 cells were incubated with 0.1 moll gefitinib, 1 moll gefitinib, 10 moll gefitinib, 1 moll SF1126, 0.1 moll gefitinib1 moll SF1126, 1 moll gefitinib1 moll SF1126, and 10 moll gefitinib1 moll SF1126. Then, cell viability and survival were determined using an 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst staining. The apoptosis-related factors and phosphoinositide-3-kinaseprotein kinase B, the mammalian target of rapamycin (PI3KAKT–mTOR) signaling pathway-related factors were detected by western blot. For TNBC cells, cell viability or survival was not significantly inhibited by gefitinib or SF1126 alone; however, marked cell apoptosis was noted in the gefitinib and SF1126 combination groups, and this effect was dose dependent. Also, the expressions of apoptosis markers, such as cleaved caspase-3, Bcl-2Bax, were altered by the gefitinib and SF1126 combination. Moreover, phosphorylated AKT (p-AKT) and 70 kDa ribosomal protein S6-kinase (p-p70S6K) were also inhibited by the gefitinib and SF1126 combination, which may be responsible for the apoptosis. Gefitinib combined with SF1126 could induce cell apoptosis in TNBC cells and this effect was mediated through the EGFR-PI3K-AKT-mTOR-p70S6K pathway. Our studies have set the stage for future clinical trials of TNBC therapy by the combination of gefitinib and SF1126.

Even though lymph node metastasis accounts for the vast majority of cancer death in patients with oral cancer (OC), the molecular mechanisms of lymph node metastasis remain elusive. Genome-wide microarray analyses and functional studies in vitro and in vivo, along with detailed clinical observations, have identified a number of molecules that may contribute to lymph node metastasis. These include lymphangionenic cytokines, cell adhesion molecules, basement membrane-interacting molecules, matrix enzymes and relevant downstream signaling pathways. However, defined gene signatures from different studies are highly variable, which hinders their translation to clinically relevant applications. To date, none of the identified signatures or molecular biomarkers has been successfully implemented as a diagnostic or prognostic tool applicable to routine clinical practice. In this review, we will first introduce the significance of lymph node metastasis in OC, and clinical/experimental evidences that support the underlying molecular mechanisms. We will then provide a comprehensive review and integrative analysis of the existing gene expression studies that aim to identify the metastasis-related signatures in OC. Finally, the remaining challenges will be discussed and our insights on future directions will be provided.

Abstract: pH-responsive 1O2 photosensitizing systems may serve as selective photodynamic therapy (PDT) agents by targeting the acidic interstitial fluid of many kinds of tumors. In this work, a natural and clinically used photosensitizer (Hypocrellin B, HB) and a pH indicator (Bromocresol Purple, BCP) were co-encapsulated in organically modified silica nanoparticles. BCP successfully regulated the 1O2 generation efficiency of HB through the “inner filter” effect, which shows much stronger 1O2 generation ability in an acidic than in a basic environment. In vitro experiments also demonstrated that HB-doped nanoparticles are effective in killing tumor cells by PDT.

Background: Connective tissue growth factor (CTGF)-induced angiogenesis is a crucial factor in rheumatoid arthritis (RA), but CTGF-interacting protein and related molecular mechanism of their interaction have not been fully elucidated. Methods: CTGF-interacting proteins were identified through the LC-MS/MS analysis of the Co-IP products from fibroblast-like synoviocyte (FLS) lysates, and the interaction between CTGF and annexin A2 (ANXA2) was further confirmed through Co-IP and BiFC assay. The binding domain, mutant, mechanism, and angiogenesis function were assessed by homology modeling, molecular docking, MTT, cell scratch, tube formation, and chick chorioallantoic membrane (CAM) assays. Additionally, severe combined immunodeficiency (SCID) mouse co-implantation model was constructed to confirm the effect of ANXA2/CTGF-TSP1 in the process of RA in vivo. Results: ANXA2 was identified and verified as an interaction partner of CTGF for the first time by Co-IP and LC-MS/MS analysis. Co-localization of CTGF and ANXA2 was observed in RA-FLS, and direct interaction of the TSP-1 domain of CTGF and ANXA2 was determined in HEK293T cells. The spatial conformation and stable combination of the ANXA2/CTGF-TSP1 complex were assessed by homology modeling in the biomimetic environment. The function of the ANXA2/CTGF-TSP1 complex was proved on promoting FLS proliferation, migration, and angiogenesis in vitro and deteriorating FLS invasion and joint damage in SCID mice. Conclusions: TSP-1 is the essential domain in CTGF/ANXA2 interaction and contributes to FLS migration and pannus formation, inducing the process of RA.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and joint stiffness, finally leading to tissue destruction. Connective tissue growth factor (CTGF) is a critical factor in RA progression, which promotes fibroblast-like synoviocyte (FLS) proliferation, pannus formation, and the damage of cartilage as well as bone. Resolvin D1 (RvD1) can promote inflammation resolution in acute inflammatory diseases, and recently, effects of RvD1 on chronic inflammatory diseases also attracted attention. This study aimed to examine the effect of RvD1 on pannus formation in RA and the underlying mechanism. Methods: Serum levels of RvD1 and CTGF were determined in RA patients and healthy persons by UPLC-MS/MS and ELISA respectively. The levels of CTGF and inflammatory factors were assessed by qRT-PCR and ELISA. MicroRNA expression profile was determined by miRNA microarray. The effects of CTGF, RvD1, and miR-146a-5p on angiogenesis were evaluated with tube formation and chick chorioallantoic membrane (CAM) assays. Collagen-induced arthritis (CIA) mice were constructed to detect the effects of RvD1 and miR146a-5p on RA. STAT3 activation was determined by Western blotting. Results: RvD1 levels decreased while CTGF levels increased in RA patients’ serum, and an inverse correlation of the concentrations of RvD1 and CTGF in the serum of RA patients was synchronously observed. In CIA mice, RvD1 suppressed angiopoiesis and decreased the expression of CTGF. Simultaneously, RvD1 significantly decreased CTGF and pro-inflammation cytokines levels in RA FLS. Furthermore, CTGF suppressed angiopoiesis and RvD1 inhibited the proliferation and migration of RA FLS and angiopoiesis. MiRNA microarray and qRT-PCR results showed that RvD1 upregulated miRNA-146a-5p. The transfection experiments demonstrated that miRNA-146a-5p could decrease inflammatory factors and CTGF levels. Moreover, miRNA-146a-5p decreased the proliferation of FLS and angiogenesis in vivo. MiRNA-146a-5p also suppressed angiogenesis and downregulated the expression of CTGF in CIA mice. Finally, Western blot results revealed that miRNA-146a-5p inhibited the activation of STAT3. Conclusion: RvD1 is prone to alleviate RA progression through the upregulation of miRNA-146a-5p to suppress the expression of CTGF and inflammatory mediators, thereby decreasing pannus formation and cartilage damage.

Enterocytozoon bieneusiis the most frequently diagnosed microsporidian species in humans and is also found in a wide range of animals. It is considered to be an important but neglected zoonotic pathogen. With the development of deer bred in captivity, the number of deer has been increasing in recent years in China and there are more people involved in this work. The aims of this study were to determine prevalence and genotypes of E.bieneusiin red deer (Cervuselaphus) and Siberian roe deer (Capreoluspygargus), and to assess their potential zoonotic transmission. A total of 122 fecal specimens were collected from 104 red deer and 18 roe deer from three deer farms in Heilongjiang and Jilin Provinces, China. Enterocytozoonbieneusiwas detected and genotyped by PCR and sequencing of the internal transcribed spacer (ITS) region of the rRNA gene. The average infection rate was 8.2% (10/122), with 7.7% (8/104) for red deer and 11.1% (2/18) for roe deer. Two genotypes were identified: a known genotype BEB6 (n = 9) and a novel genotype named HLJD-VI (n = 1). This is the first report of E.bieneusiinfection in Siberian roe deer. The fact that genotype BEB6 was detected previously in one human case of microsporidiosis, and that genotype HLJD-VI fell into zoonotic group 1, suggest the possibility of transmission to humans. A brief review of E.bieneusigenotypes in deer worldwide shows that 40 genotypes have been found in seven deer species, with genotype BEB6 being predominant.