Design, concise synthesis and evaluation of novel amide-based combretastatin A-4 analogues as potent tubulin inhibitors.

As our ongoing work, a novel series of the amide-based CA-4 analogues were successfully designed, synthesized, and explored for their biological evaluation. Among these compounds, 7d and 8a illustrated most potent antiproliferative activity toward A549, HeLa, HCT116, and HT-29 cell lines. Most importantly, these two compounds didn't display noticeable cytotoxic activity on the non-tumoural cell line HEK-293. Further mechanism studies revealed that analogue 8a was identified as a novel tubulin polymerization inhibitor with an IC50 value of 6.90 µM, which is comparable with CA-4. The subsequent investigations unveiled that analogue 8a not only effectively caused cell cycle arrest at the G2/M phase but also induced apoptosis in A549 cells via a concentration-dependent manner. The molecular docking revealed that 8a could occupy well the colchicine-binding site of tubulin. Collectively, these findings indicate that amide-based CA-4 scaffold could be worthy of further evaluation for development of novel tubulin inhibitors with improved safety profile.

Design, synthesis, and biological evaluation of N-(pyridin-3-yl)pyrimidin-4-amine analogues as novel cyclin-dependent kinase 2 inhibitors for cancer therapy.

The discovery and development of CDK2 inhibitors has currently been validated as a hot topic in cancer therapy. Herein, a series of novel N-(pyridin-3-yl)pyrimidin-4-amine derivatives were designed and synthesized as potent CDK2 inhibitors. Among them, the most promising compound 7l presented a broad antiproliferative efficacy toward diverse cancer cells MV4-11, HT-29, MCF-7, and HeLa with IC50 values of 0.83, 2.12, 3.12, and 8.61 µM, respectively, which were comparable to that of Palbociclib and AZD5438. Interestingly, these compounds were less toxic on normal embryonic kidney cells HEK293 with high selectivity index. Further mechanistic studies indicated 7l caused cell cycle arrest and apoptosis on HeLa cells in a concentration-dependent manner. Moreover, 7l manifested potent and similar CDK2/cyclin A2 nhibitory activity to AZD5438 with an IC50 of 64.42 nM. These findings revealed that 7l could serve as ahighly promisingscaffoldfor CDK2 inhibitors as potential anticancer agents and functional probes.

Paeoniflorin, the Main Monomer Component of Paeonia lactiflora, Exhibits Anti-inflammatory Properties in Osteoarthritis Synovial Inflammation.

OBJECTIVE: To explore the mechanism of paeoniflorin (PF) on osteoarthritis (OA) synovial inflammation from network pharmacology to experimental pharmacology. METHODS: Targets of OA were constructed by detecting the database of network database platforms (Therapeutic Target database, DrugBank and GeneCards), and the targets of PF were constructed by PubChem and Herbal Ingredients' Targets database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of these co-targeted genes were conducted via Database for Annotation, Visualization, and Integrated Discovery (DAVID) database, and protein-protein interaction (PPI) networks were conducted via the search tool for the retrieval of interacting genes (STRING) database. Cell counting kit-8 (CCK-8) assay was performed to assess the potential toxicity of PF on human OA fibroblast-like synoviocytes (FLS), quantitative real-time polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA) and Western blot were used to verify the potential mechanism of PF in synovial inflammation. RESULTS: Twenty-six co-targeted genes were identified. GO enrichment results showed that these co-targeted genes were most likely localized in the cytoplasm, and the biological processes mainly involved 'cellular response to hypoxia' 'lipopolysaccharide (LPS)-mediated signaling pathway' and 'positive regulation of gene expression'. KEGG pathway analysis indicated that these co-targeted genes may function through pathways associated with 'hypoxia-inducible factor-1 (HIF-1) signaling pathway' and 'tumor-necrosis factor (TNF) signaling pathway'. The PPI network showed that the top 3 hub genes were TP53, TNF, and CASP3. Molecular docking results showed that PF was well docking with TNF. CCK-8 showed no potential toxicity of 10, 20 and 50 µmol/L PF on human OA FLS. And PF significantly decreased the expression levels of interleukin-1 ß, interleukin-6, TNF-α matrix metalloproteinase 13 (MMP13), and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and TNF-α in LPS-induced OA FLS. CONCLUSION: PF exhibited potent anti-inflammatory effect in OA synovial inflammation.

MicroRNA-191 regulates oral squamous cell carcinoma cells growth by targeting PLCD1 via the Wnt/ß-catenin signaling pathway.

BACKGROUND: Studies have shown that microRNA-191 (miR-191) is involved in the development and progression of a variety of tumors. However, the function and mechanism of miR-191 in oral squamous cell carcinoma (OSCC) have not been clarified. METHODS: The expression level of miR-191 in tumor tissues of patients with primary OSCC and OSCC cell lines were detected using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. OSCC cells were treated with miR-191 enhancers and inhibitors to investigate the effects of elevated or decreased miR-191 expression on OSCC cells proliferation, migration, cell cycle, and tumorigenesis. The target gene of miR-191 in OSCC cells were analyzed by dual-Luciferase assay, and the downstream signaling pathway of the target genes was detected using western blot assay. RESULTS: The expression of miR-191 was significantly upregulated in OSCC tissues and cell lines. Upregulation of miR-191 promoted proliferation, migration, invasion, and cell cycle progression of OSCC cells, as well as tumor growth in nude mice. Meanwhile, reduced expression of miR-191 inhibited these processes. Phospholipase C delta1 (PLCD1) expression was significantly downregulated, and negatively correlated with the expression of miR-191 in OSCC tissues. Dual-Luciferase assays showed that miR-191-5p could bind to PLCD1 mRNA and regulate PLCD1 protein expression. Western blot assay showed that the miR-191 regulated the expression of ß-catenin and its downstream gene through targeting PLCD1. CONCLUSION: MicroRNA-191 regulates oral squamous cell carcinoma cells growth by targeting PLCD1 via the Wnt/ß-catenin signaling pathway. Thus, miR-191 may serve as a potential target for the treatment of OSCC.

Value Analysis of Neoadjuvant Radiotherapy for Breast Cancer after Modified Radical Mastectomy Based on Data Mining.

Over the last two generations, there has been a surge of interest in nonmutilating treatment for women with early breast cancer. Neoadjuvant radiation therapy, which is progressively being provided to breast cancer patients, could be used to decrease tumor burden while also providing an ability to examine treatment response. This paper aims to explore the effects of the initiation time of radiotherapy after modified adjuvant radical mastectomy on the prognosis of breast cancer. The EMR data can be used to mine hidden rules, which are of great significance for treatment and prognosis analysis. In collaboration with breast cancer, the appropriate prediction model and visualization method are selected and a visual analysis system for breast cancer group and treatment plan based on electronic medical record is constructed. Patients with multiple dimensions are reduced and clustered to form patient groups. The differences of characteristics among patient groups are intuitively displayed by using Nightingale diagram, word cloud, and time axis visualization methods. The support vector machine (SVM) model is used to predict the treatment scheme. The radiotherapy time after modified radical surgery in the two groups was within 15 weeks (observation group) and 15 weeks (routine group), respectively. The incidence of complications, local recurrence rate, progression-free survival, and quality of life scores of patients in the routine group and observation group were compared. The total incidence of complications differed significantly between the observation and routine groups. The physical function, material function, psychological function, and social function of the observation group were significantly higher than the routine group (P < 0.05). Radiotherapy within 15 weeks after modified radical mastectomy for breast cancer can not only reduce the local recurrence rate but also prolong the progression-free survival of patients, and the incidence of complications will not increase, which will greatly help improve the quality of life of patients.

The relationship between post-traumatic stress and negative emotions in patients with breast cancer: the mediating role of emotion regulation.

Purpose:Negative emotions can adversely affect the treatment and recovery of breast cancer patients. Post-traumatic stress caused by cancer can increase the negative emotions of patients. This study assessed the relationship between post-traumatic stress and emotional regulation strategies, and the role of emotional regulation in the relationship between post-traumatic stress and negative emotions in breast cancer patients.Design:Cross-sectional questionnaire with sample of 214 Chinese women with breast cancerMethods:Participants completed the Impact of Event Scale-Revised, Hospital Anxiety and Depression Scale, and Emotion Regulation Questionnaire. Correlation and mediation analyses were conducted to assess associations among the scores of these scales.Findings:Patients with low post-traumatic stress chose cognitive reappraisal strategies, while those with high post-traumatic stress chose expressive suppression strategies. Cognitive reappraisal had a significant negative predictive effect on negative emotions, while expressive suppression had a significant positive predictive effect on patient's negative emotions.Conclusions:Cognitive reappraisal may reduce the impact of post-traumatic stress on negative emotions experienced by breast cancer patients. Implications for psychosocial providers or policy: Psychosocial workers in China should conduct cognitive reappraisal training for breast cancer patients with high negative emotions and severe post-traumatic stress. For Chinese breast cancer patients living in other regions, the local oncology social workers should take into account their cultural background and lack of expression, and encourage them to choose cognitive reappraisal strategies.

Toll-Like Receptor 9 Signaling Pathway Contributes to Intestinal Mucosal Barrier Injury in Mice With Severe Acute Pancreatitis.

OBJECTIVES: The purpose of this study was to investigate the role and mechanism of toll-like receptor 9 (TLR9) in intestinal mucosal barrier injury in mice with severe acute pancreatitis (SAP). METHODS: The mice were randomly divided into 3 groups: control group, SAP group, and TLR9 antagonist-treated group. The expression of tumor necrosis factor-α, interleukin-1ß, interleukin-6, diamine oxidase, and endotoxin core antibodies were detected by enzyme-linked immunosorbent assay. The protein expression of zonula occluden-1 (ZO)-1, occludin, TLR9, myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF6), p-nuclear factor (NF)-κB p65, and NF-κB p65 were detected by Western blot. TdT-mediated dUTP nick-end labeling staining was used for detecting intestinal epithelial cell apoptosis. RESULTS: The expression of TLR9 and its related pathway proteins MyD88, TRAF6, and p-NF-κB p65 in the intestinal tract of SAP mice were significantly increased compared with that of control mice. Inhibition of the TLR9 expression could reduce the level of serum proinflammatory cytokines, reduce the apoptosis of intestinal epithelial cells, improve intestinal permeability, and ultimately reduce the damage of intestinal mucosal barrier function in SAP. CONCLUSIONS: Toll-like receptor 9/MyD88/TRAF6/NF-κB signaling pathway plays an important role in intestinal mucosal barrier injury of SAP.

Mobile Bearing versus Fixed Bearing for Total Knee Arthroplasty: Meta-analysis of Randomized Controlled Trials at Minimum 10-Year Follow-up.

This meta-analysis aimed to compare the clinical and radiographic outcomes between mobile-bearing total knee arthroplasty (MB-TKA) and fixed-bearing total knee arthroplasty (FB-TKA) at a minimum 10-year follow-up. PubMed, EMBASE, and Cochrane databases were searched. All included articles were evaluated by two trained reviewers according to the guidelines of the Cochrane Collaboration Handbook for potential risk, and the Consolidated Standards on Reporting Trials (CONSORT) checklist and scoring system was also used to assess the methodological quality of each study. The extracted data included function scores, range of motion (ROM) of the knee, incidence of adverse events or revision, survivorship analysis, and radiographic outcomes. Seven randomized controlled trials (RCTs) were included in this meta-analysis, and all RCTs had a follow-up period longer than 10 years. This meta-analysis shows no significant difference between the two groups with respect to the Keen Society Score (KSS; p = 0.38), KSS function score (p = 0.30), the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC; p = 0.59), ROM (p = 0.71), radiolucent line (p = 0.45), femoral and tibial component positions in the coronal plane (p = 0.55 and 0.35, respectively), revision incidence (p = 0.77), and survivorship rates (p = 0.39). Meanwhile, it showed a slight difference between the two groups in the tibial component position in the sagittal plane (p = 0.003). According to this meta-analysis, the current best available evidence suggests no significant difference between the MB-TKA and FB-TKA groups with respect to the clinical outcomes, radiographic outcomes, revision, and survivorship at a minimum 10-year follow-up. This is a Level II, meta-analysis study.

Development of pteridin-7(8H)-one analogues as highly potent cyclin-dependent kinase 4/6 inhibitors: Synthesis, structure-activity relationship, and biological activity.

CDK4/6 have been validated as the cancer therapeutic targets. Here, we describe a series of pteridin-7(8H)-one analogues as potent CDK4/6 inhibitors. Among them, the most promising compound 7s demonstrated remarkable and broad-spectrum antiproliferative activities toward HCT116, HeLa, MDA-MB-231, and HT-29 cells with IC50 values of 0.65, 0.70, 0.39, and 2.53 µM, respectively, which were more potent than that of the anticancer drug Palbociclib. Interestingly, 7s also manifested the greatest inhibitory activities toward both CDK4/cyclin D3 and CDK6/cyclin D3 (IC50 = 34.0 and 65.1 nM, respectively), which was comparable with Palbociclib. Additionally, molecular simulation indicated that 7s bound efficiently at the ATPbindingsitesofCDK4 and CDK6. Further mechanistic studies revealed that compound 7s could concentration-dependently induce cell cycle arrest and apoptosis in HeLa cells. Takentogether, 7s represents a promising novel CDK4/6 inhibitor for the potential treatment of cancer.

Efficacy and Mechanism of Electroacupuncture Treatment of Rabbits With Different Degrees of Knee Osteoarthritis: A Study Based on Synovial Innate Immune Response.

Knee osteoarthritis (KOA) is a chronic degenerative bone and joint disease, which is often clinically manifested as pain, joint swelling, and deformity. Its pathological manifestations are mainly synovial inflammation and cartilage degeneration. This study aims to investigate the efficacy of electro-acupuncture (EA) on model rabbits with varying degrees of KOA and to study the mechanism of EA on KOA based on the innate immune response. Mild and moderate rabbit KOA models were established using a modified Hluth method, and EA was given to both the mild and moderate model groups. The Lequesne-MG index was used to evaluate the behavioral changes in the rabbits before and after EA treatment. Morphological changes in the synovial membrane and cartilage of each group were observed by H&E staining. The Mankin scoring standard and the Krenn scoring standard were used to score the pathology of the cartilage tissue and synovial tissue, respectively. The inflammatory factors and metalloproteinases were detected in the serum of each group by ELISA. The protein and messenger RNA (mRNA) expressions of important elements related to Toll-like receptors (TLRs)-mediated innate immune response in the synovial tissue were detected by Western blot and quantitative PCR (qPCR). The Lequesne-MG index score of the rabbits gradually increased with the modeling prolonged but decreased significantly after EA treatment, indicating that EA has a better effect on alleviating the pain and improving the dysfunction. The morphological analysis showed that the inflammation of and the damage to the synovial membrane and the cartilage tissue gradually deteriorated with the modeling prolonged. However, the synovial membrane inflammation was significantly relieved after EA treatment, and the cartilage injury showed signs of repair. The ELISA analysis showed that, with the modeling prolonged, the serum-related inflammatory factors and mechanism of metalloproteinases gradually increased but decreased after EA treatment. The tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and matrix metalloproteinase3 (MMP3) of EA1 group were significantly lower than those of EA2 group. Both Western blot and qPCR results showed that the protein and mRNA expressions of the elements related to the innate immune response in the synovial membrane increased gradually with the modeling prolonged, but decreased significantly after EA treatment. Additionally, the expression of some components in EA1 group was significantly lower than that in EA2 group. These results confirm that synovial inflammation gradually aggravated with time from the early to mid-stage of KOA. EA alleviated the inflammation and histological changes in KOA rabbits by inhibiting the TLRs-mediated innate synovial immune response. This suggests that using EA in the early stage of KOA may achieve a desirable efficacy.

PCDD/Fs characteristics in flue gas and surrounding environment of iron and steel smelting industry.

Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) concentrations and distributions, emission factors and amounts, and ambient air and soil potential sources were investigated by collecting flue gas, ambient air, and soil samples from ten sintering furnaces and two electric arc furnaces of eight iron and steel smelting industries (ISSI) in China. In flue gas, the concentrations of PCDD/Fs ranged from 0.05 to 2.93 ng I-TEQ Nm-3 (mass, from 0.38 to 30.67 ng Nm-3), with an average of 0.42 ng I-TEQ Nm-3 (mass, 4.99 ng Nm-3), respectively. In ambient air, the concentrations ranged from 0.05 to 0.35 pg I-TEQ m-3 (mass, from 0.66 to 5.66 pg m-3), with an average of 0.20 pg I-TEQ m-3 (mass, 2.96 pg m-3), respectively. In surface soil, the concentrations ranged from 1.80 to 21.02 ng I-TEQ kg-1 (mass, from 34.29 to 836.00 ng kg-1), with an average of 5.82 ng I-TEQ kg-1 (mass, 252.10 ng kg-1), respectively. In deep soil, the concentrations ranged from 1.17 to 12.00 ng I-TEQ kg-1 (mass, from 56.83 to 1488.00 ng kg-1), with an average of 7.76 ng I-TEQ kg-1 (mass, 433.20 ng kg-1), respectively. Compared with emission limits for PCDD/Fs, the compliance was 78.9% in flue gas, 100% in ambient air, and 77.3% in soil. In congener profiles, the contributions of PCDFs were much higher than those of PCDDs in flue gas and ambient air, but the opposite was observed in soil. In ten sintering furnaces, the emission factors ranged from 22.11 to 901.22 ng I-TEQ t-1, with an average of 373.80 ng I-TEQ t-1, respectively. In two electric arc furnaces, the emission factors were 1667.52 and 894.96 ng I-TEQ t-1, with an average of 1281.24 ng I-TEQ t-1. According to both principal component analysis and hierarchical cluster analysis, all ambient air samples were affected by the emissions of PCDD/Fs from ISSIs, but to different degrees. However, the concentrations of PCDD/Fs in most soil samples were not influenced by the ISSI emissions.

Synthesis and antiproliferative evaluation of novel 8-cyclopentyl-7,8-dihydropteridin-6(5H)-one derivatives as potential anticancer agents.

Based on our previous work, a novel class of 8-cyclopentyl-7,8-dihydropteridin-6(5H)-one derivatives were synthesized and evaluated as antiproliferative agents. Structure-activity relationship analysis revealed that the greatest activities were achieved with a 4-(4-methylpiperazin-1-yl)aniline group at C-2 position of dihydropteridin-6(5H)-one core, and the most promising compound 6k demonstrated comparable antiproliferative activity with Palbociclib and more potent than our parent derivative 4 toward four cell lines including HCT-116, HeLa, HT-29, and MDA-MB-231 with IC50 values of 3.29, 6.75, 7.56, and 10.30 µM, respectively. Moreover, the mechanism studies revealed that compound 6k could induce cell cycle arrest at G2/M phase via a concentration-dependent manner. In general, these preliminary observations suggested that these compounds could serve as promising scaffolds for further modification to develop novel and highly potent cancer therapy agents.

Needle knife therapy plus sodium hyaluronate injection for knee osteoarthritis: A protocol for a systematic review and meta-analysis.

BACKGROUND: Knee osteoarthritis (KOA) is a worldwide disease and more and more people are suffered from it. With the increasing number of patients, it brings a huge burden on social economy and security system. There are varieties of methods to cure KOA, such as Traditional Chinese Medicine and surgery. Needle knife therapy plus Sodium hyaluronate Injection is one of the prevalent treatments for KOA. Therefore, we perform a systematic review and meta-analysis to evaluate the evidence for the treatment of needle knife therapy plus sodium hyaluronate Injection. METHODS: Randomized controlled trials will be used to compare the effect of needle knife therapy plus sodium hyaluronate injection with needle knife alone for KOA patients. Six studies will be included in this meta-analysis, and the relative risk and weight mean difference with 95% CI for the Lysholm knee score, visual analogue scale, and effective rate will be evaluated by using RevMan 5.3 software. Besides, the bias assessment of the included studies will be evaluated using the Cochrane risk of bias tool, and the Grading of Recommendations, Assessment Development, and Evaluation system will be applied to assess the overall quality of the evidence. RESULTS: From the study we will assess the effectiveness, safety of needle knife therapy plus sodium hyaluronate injection on joint pain relief and functional improvement in patients with KOA. CONCLUSION: The study will provide a new evidence to confirm the effect of needle knife therapy plus sodium hyaluronate injection on KOA, which can further guide the selection of therapy. PROSPERO REGISTRATION NUMBER: CRD42020169602.

Development of triazolothiadiazine derivatives as highly potent tubulin polymerization inhibitors: Structure-activity relationship, in vitro and in vivo study.

Based on our prior work, we reported the design, synthesis, and biological evaluation of fifty-two new triazolothiadiazine-based analogues of CA-4 and their preliminary structure-activity relationship. Among synthesized compounds, Iab was found to be the most potent derivative possessing IC50 values ranging from single-to double-digit nanomolar in vitro, and also exhibited excellent selectivity over the normal human embryonic kidney HEK-293 cells (IC50 > 100 µM). Further mechanistic studies revealed that Iab significantly blocked tubulin polymerization and disrupted the intracellular microtubule network of A549 cells. Moreover, Iab induced G2/M cell cycle arrest by regulation of p-cdc2 and cyclin B1 expressions, and caused cell apoptosis through up-regulating cleaved PARP and cleaved caspase-3 expressions, and down-regulating of Bcl-2. Importantly, in vivo, Iab effectively suppressed tumor growth of A549 lung cancers in a xenograft mouse model without obvious signs of toxicity, confirming its potential as a promising candidate for cancer treatment.

Cinnamic Aldehyde Inhibits Lipopolysaccharide-Induced Chondrocyte Inflammation and Reduces Cartilage Degeneration by Blocking the Nuclear Factor-Kappa B Signaling Pathway.

Osteoarthritis (OA), as one of the top 10 causes of physical disability, is characterized by inflammation of the synovial membrane and progressive destruction of the articular cartilage. Cinnamic aldehyde (CA), an α,ß-unsaturated aldehyde extracted from the traditional Chinese herbal medicine cinnamon (Cinnamomum verum J.Presl), has been reported to have anti-inflammatory, antioxidant, and anticancer properties. However, the anti-inflammatory effect of CA on OA remains unclear. The purpose of the present study was to investigate the effects of CA on inflammation, and cartilage degeneration in OA. A CCK-8 assay was performed to assess the potential toxicity of CA on cultured human OA chondrocytes. Following treatment with lipopolysaccharide (LPS) and CA, the expression of proinflammatory cytokines, including interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alfa (TNF-α), was evaluated using quantitative real-time polymerase chain reaction (RT-qPCR) analysis, enzyme-linked immunosorbent assay, and Western blotting (WB). The production of matrix metalloproteinase-13 (MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) was also examined using RT-qPCR and WB. Furthermore, to investigate the potential anti-inflammatory mechanism of CA, biomarkers of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway (p65, IKB-α) were detected using WB. The results demonstrated that CA significantly inhibited the expressions of IL-1ß, IL-6, TNF-α, MMP-13, and ADAMTS-5 in LPS-induced OA chondrocytes. CA dramatically suppressed LPS-stimulated NF-κB activation. Collectively, these results suggest that CA treatment may effectively prevent OA.

[Effect of Tongluo Zhitong (, TLZT) gel preparation on p53 /miR-502-5p /NF-κBp65 in synovial tissue of knee osteoarthritis].

OBJECTIVE: To observe effects of Tongluo Zhitong (, TLZT) gel preparation on p53, miR-502-5p, NF-κBp65 in synovial tissue of knee osteoarthritis (KOA), and to explore mechanism of TLZT gel preparation in treating KOA. METHODS: Thirthy-six Wistar rats aged 8 weeks and weighed 200 to 220 g (meaned 208 g) were randomly divided into normal group, model group and traditional Chinese medicine (TCM) group, 12 rats in each group. KOA model was established by modified Hulth method. After 4 weeks of modeling, TCM group treated with TLZT gel preparation for external use, 3 times daily for 2 weeks;normal group and model group were fed normally without intervention. After treatment, morphological changes of specimens in each group were observed, changes of miR-502-5p in synovial tissue were detected by qPCR, and contents of p53, NF-κBp65, IL-1ß, TNF-α, MMP-13 in synovial tissue were detected by qPCR and Western Blot respectively. RESULTS: (1)Morphological observation of specimens showed that the articular cartilage in model group was hyaline and uneven, the synovial membranes were hypertrophic and proliferative with a large number of inflammatory cells infiltrating, the joint fluid was thicker in texture;the articular cartilage in TCM group was more transparent and smooth, synovial hyperplasia was mild with a small amount of inflammatory cell infiltration, the texture of articular fluid was clear and sparse. (2) Compared with normal group, content of miR-502-5p of synovial tissue in model and TCM group were increased, mRNA and expression of p53 decreased, expression of NF-κBp65, IL-1ß, TNF-α, MMP-13 increased. (3)Compared with model group, content of miR-502-5p in synovial tissue of TCM group decreased (P<0.05), mRNA and protein expression of p53 increased (P<0.05), mRNA and protein expression of NF-κBp65, IL-1ß, TNF-α, MMP-13 decreased (P<0.05). CONCLUSION: Expression of p53, miR-502 -5p, NF -κBp65 in synovial tissue is closely related to synovial hyperplasia and inflammatory reaction, TLZT gel preparation may reduce proliferation and inflammatory reaction of KOA synovium by regulating the expression of p53, miR- 502-5p, NF-κBp65 in synovial tissues.

Extraction and identification of synovial tissue-derived exosomes by different separation techniques.

OBJECTIVE: The aim of this study is to compare the efficiency of different separation techniques for extracting synovial tissue-derived exosomes. METHODS: The synovial tissue discarded during knee arthroscopy or total knee arthroplasty surgery was collected from the Third Affiliated Hospital of Beijing University of Chinese Medicine. Ultracentrifugation (UC), filtration combined with size exclusion chromatography (SECF), and 8% polyethylene glycol (PEG) were used to extract synovial tissue-derived exosomes. Transmission electron microscopy (TEM), nanoparticle tracer analysis (NTA), and Western Blot (WB) were used to detect the morphology, particle size, and biomarker proteins (CD9, CD63, Flotillin-1, and calnexin) of exosomes. RESULTS: The extracts of enriched round and discoid vesicles were successfully extracted with UC, SECF, and PEG. The results of TEM have shown that all three extraction methods can extract circular or elliptical vesicles with disc- and cup-shaped structures from the synovial tissue, with the diameter is about 30-150 nm. NTA suggested the main peaks of three groups of exosomes are around 100-120 nm, and the concentration of the three groups of exosomes was greater than 1 × 1010/ml. The results of WB showed that three positive protein markers (CD9, CD63, and Flotillin-1) were highly expressed in the suspension extracted by the three methods and low in the synovial tissue. However, the negative protein (calnexin) was highly expressed in synovial tissues and PEG group, while low in UC and SECF group. CONCLUSION: Morphology, particle size, and labeled protein marker detection confirmed that UC, SECF, and PEG can extract exosomes derived from synovial tissue; UC and SECF are more recommended for the extraction of synovial tissue-derived exosomes, which provides a methodological basis for studying the function and mechanism of synovial tissue exosomes in the future.

The benefits of expressive writing among newly diagnosed mainland Chinese breast cancer patients.

The study aimed to evaluate the effects of an expressive writing intervention on quality of life (QoL) among mainland Chinese breast cancer patients. A total of 118 Chinese breast cancer patients were randomly assigned to one of four groups: a cancer-facts writing condition (CTL group), an emotional disclosure writing condition (EMO group), a self-regulation writing condition (SR group), or a neutral control condition with no writing tasks (CON group). QoL was assessed by FACT-B at baseline, 3-, and 6-month follow-ups. A repeated measure analysis of variance revealed significant effects of time (F = 13.9, P < 0.001, η2 = 0.20) and the time × group interaction (F = 3.5, P < 0.01, η2 = 0.08) on QoL. Residualized change models showed that the CTL, EMO and SR groups reported higher levels of QoL than the CON group at the 6-month follow-up. The EMO group had a higher level of QoL than the SR group. The CTL group had higher level of physical well-being compared to the SR group. Mainland Chinese breast cancer patients shortly after diagnosis benefit from expressive writing. They benefited more from cancer-facts and emotional disclosure compared to self-regulation. The study indicated that the impact of expressive writing may differ due to stage of cancer survivorship, social, and cultural context.

Intra-articular platelet-rich plasma injection for knee osteoarthritis: a summary of meta-analyses.

OBJECTIVE: The purpose of this study was (1) to perform a summary of meta-analyses comparing platelet-rich plasma (PRP) injection with hyaluronic acid (HA) and placebo injection for KOA patients, (2) to determine which meta-analysis provides the best available evidence to making proposals for the use of PRP in the treatment of KOA patients, and (3) to highlight gaps in the literature that require future investigation. MATERIAL AND METHODS: PubMed, EMBASE, and Cochrane databases search were performed for meta-analyses which compared PRP injection with HA or placebo. Clinical outcomes and adverse events were extracted from these meta-analyses. Meta-analysis quality was assessed using the Quality of Reporting of Meta-analyses (QUOROM) systems and the Oxman-Guyatt quality appraisal tool. The Jadad decision algorithm was also used to determine which meta-analysis provided the best available evidence. RESULTS: Four meta-analyses were included in our study, and all of these articles were Level I evidence. The QUOROM score of each included meta-analysis range from 14 to 17 points (mean score 15, maximum score 18), and the Oxman-Guyatt score range from 4 to 6 points (mean score 5, maximum score 7). Three meta-analyses indicated PRP showed more benefit in pain relief and functional improvement than the control group, and the other one suggested no difference between these groups. All included meta-analyses found no statistical difference in adverse events between these groups. In addition, a meta-analysis conducted by Shen et al. got the highest methodological quality score and suggested that PRP provided better pain relief and function improvement in the treatment of KOA. CONCLUSIONS: For short-term follow-up (≤1 year), intra-articular PRP injection is more effective in terms of pain relief and function improvement in the treatment of KOA patients than HA and placebo, and there is no difference in the risk of an adverse event between PRP and HA or placebo. LEVEL OF EVIDENCE: Level I evidence, a summary of meta-analyses TRIAL REGISTRATION: PROSPERO ID CRD42018116168.

Flexible PVC materials grafted with castor oil derivative containing synergistic flame retardant groups of nitrogen and phosphorus.

Internally plasticized PVC by replacement of chlorine with castor oil derivative containing synergistic flame retardant groups of nitrogen and phosphorus, that is, castor oil derivative grafted onto PVC matrix, is reported. Low glass transition temperature (Tg) of modified PVC was produced although thermal stability was reduced. However, the migration was completely suppressed. The combination of castor oil derivative containing synergistic flame retardant groups of nitrogen and phosphorus with PVC matrix through modifying PVC materials with click reaction prepared flexible PVC materials with zero migration and enhanced flame retardant property.