IL-17A mediates pyroptosis via the ERK pathway and contributes to steroid resistance in CRSwNP.

BACKGROUND: Pyroptosis is closely related to inflammation. However, the molecular mechanisms and pathologic contributions of pyroptotic epithelial cell are not yet fully understood. OBJECTIVE: This study aimed to explore the function and molecular mechanisms of IL-17A on human nasal epithelial cell (hNEC) pyroptosis. METHODS: The expression of pyroptosis-related biomarkers and IL-17A was assessed in sinonasal mucosa from control individuals, patients with chronic rhinosinusitis without nasal polyps, and patients with chronic rhinosinusitis with nasal polyps (CRSwNP) by using quantitative RT-PCR. Their localization was analyzed via immunohistochemistry and immunofluorescence. The ultrastructural characteristics of IL-17A-induced pyroptosis in hNECs were visualized by using electron microscopy. IL-17A functional assays were performed on hNECs and airway epithelial cell lines. Cytokine levels were quantified via ELISA. The signaling pathways involved in IL-17A-induced pyroptosis were studied via unbiased RNA sequencing and Western blotting. RESULTS: The expression of IL-17A and the pyroptotic biomarkers NOD-like receptor family, pyrin domain containing 3 (NLRP3), caspase-1, gasdermin D, and IL-1ß was increased in nasal mucosa from patients with CRSwNP compared with in those with chronic rhinosinusitis without nasal polyps and the control subjects. IL-17A was positively correlated and colocalized with the pyroptotic biomarkers. IL-17A treatment induced pyroptosis in the hNECs and cell lines analyzed, primarily through the extracellular signal-regulated kinase (ERK)-NLRP3/caspase-1 signaling pathway, and increased IL-1ß and IL-18 secretion in hNECs. Moreover, IL-17A-induced pyroptosis contributed to steroid resistance by affecting glucocorticoid receptor-α and glucocorticoid receptor-ß expression, and the inhibition of pyroptotic proteins partially abolished IL-17A-induced steroid resistance in hNECs. CONCLUSION: Elevated IL-17A level promotes pyroptosis in hNECs through the ERK-NLRP3/caspase-1 signaling pathway and contributes to glucocorticoid resistance by affecting glucocorticoid receptor homeostasis in patients with CRSwNP.

Cnidium lactone prevents bone loss in an ovariectomized rat model through the estrogen-α/BMP-2/Smad signaling pathway.

BACKGROUND: The present study aimed to investigate the effect of cnidium lactone on ovariectomy (OVX)-induced bone loss and determine whether it exerts its effects by mediating the estrogen receptor-α (ERα)/bone morphogenetic protein-2 (BMP-2)/Smad signaling pathways. METHODS: Fifty-five female rats were randomly assigned to the following treatment groups: the OVX group, the sham-operated (sham) group, and groups treated with cnidium lactone at different doses (10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day). Treatments were administered for 60 days. Search Tool for Interacting Chemicals (STITCH; http://stitch.embl.de) was used to identify the interaction between cnidium lactone and target proteins. Bone mineral density (BMD), mechanical strength, serum osteoblastic and osteoclastic markers, and hematoxylin and eosin (HE) staining of the distal femur were evaluated. Moreover, western blot analyses were also performed to evaluate the effect of cnidium lactone on the ERα/BMP-2/Smad signaling pathway. RESULTS: Cnidium lactone treatment was associated with an increase in the BMD of the distal femur compared to that of the OVX group. Moreover, cnidium lactone significantly increased biomechanical properties in a dose-dependent manner compared to those of the OVX group (p < 0.05). Treatment with cnidium lactone significantly enhanced the BMP-2/Smad signaling pathway by up-regulating the expression of ERα, BMP-2, p-Smad1 and p-Smad4. Cnidium lactone treatment improved the microstructure of trabecular bone in the distal femurs of OVX rats, as shown by HE staining. CONCLUSIONS: Cnidium lactone exerts potent antiosteoporotic activity in ovariectomized mice, and the underlying molecular mechanism may be related to the ERα/BMP-2/Smad signaling pathways.

Solvation controlled excited-state dynamics in a donor-acceptor phenazine-imidazole derivative.

In the past few decades, significant efforts have been devoted to developing phenazine derivatives in various fields such as medicine, pesticides, dyes, and conductive materials owing to their highly Stokes-shifted fluorescence and distinctive photophysical properties. The modulation of the surrounding environment can effectively influence the luminescent behavior of phenazine derivatives, prompting us to investigate the solvent effect on the excited state dynamics. Herein, we present the solvent controlled excited state dynamics of a novel triphenylamine-based phenazine-imidazole molecule (TPAIP) through steady-state spectra and femtosecond transient absorption spectra. The fluorescence emission spectrum exhibited a redshift with increasing solvent polarity, indicating the existence of a charge transfer state. Furthermore, by tracking the femtosecond transient absorption spectra of TPAIP, we found that the nature of the relaxed S1 state was strongly influenced by the solvent polarity: intersystem crossing character appears in apolar solvent, whereas intramolecular charge transfer character occurs in polar solvent because of solvation. These findings provide significant theoretical insights into the impact of solvents on the excited state dynamics within phenazine derivatives. This understanding supports diverse applications ranging from advanced biological probe design to photocatalysis and pharmaceutical research.

Accuracy of 3.0T magnetic resonance angiography for the detection of arteriovenous fistula dysfunction in hemodialysis patients requiring interventional therapy: a prospective study.

Background: Color Doppler ultrasonography (CDUS) is feasible to detect arteriovenous fistula (AVF) dysfunction in hemodialysis patients but is not sufficient to map the structure of fistula required for interventions. This study is designed to evaluate the diagnostic accuracy of three-dimensional time-of-flight magnetic resonance angiography (TOF-MRA) at 3.0T versus CDUS for AVF dysfunction, by using digital subtraction angiography (DSA) as reference. Methods: This prospective study enrolled 68 consecutive patients with dysfunctional AVF who underwent both CDUS and TOF-MRA at Shanghai Sixth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine. The analysis of the dysfunctional AVFs was divided into three regions: the feeding artery, fistula and draining veins. In the whole- and per-regional-based analyses, two observers who were blinded to the clinical and DSA results independently analyzed all CDUS and TOF-MRA datasets. The image quality and stenosis severity of the lesions on TOF-MRA were evaluated. A receiver operating characteristic curve was applied to analyze the detection of AVF dysfunction with TOF-MRA. Results: A total of 204 vessel regions were evaluated. The whole-region-based image quality of TOF-MRA was poorer in patients with a total occlusion (1.8±0.8) than in those with stenosis (2.7±0.6, P<0.001). In the whole-region analyses, TOF-MRA had higher sensitivity [99.1% (94.6-100.0%) vs. 82.9% (74.6-89.0%), P<0.001] and similar specificity [93.1% (85.0-97.1%) vs. 94.3% (86.5-97.9%), P=0.755] than CDUS. The per-region-based analyses showed that TOF-MRA yielded higher sensitivity [fistula region, 98.1% (88.4-99.9%) vs. 80.8% (67.0-89.9%); P=0.004; draining vein region, 100.0% (92.5-100.0%) vs. 85.0% (72.9-2.5%); P=0.003] and similar specificity [fistula region, 88.2% (62.3-97.8%) vs. 88.2% (62.3-97.9%); P>0.99; draining vein region, 100.0% (59.8-100.0%) vs. 87.5% (46.7-99.3%); P>0.99] than CDUS. Sensitivity and specificity of TOF-MRA were comparable to those of CDUS in feeding artery region. Conclusions: TOF-MRA is a feasible and accurate method to display AVF dysfunction in hemodialysis patients, and this method might fulfill the endovascular treatment planning requirements.

The Direct Anterior Approach versus the Posterolateral Approach on the Outcome of Total Hip Arthroplasty: A Retrospective Clinical Study.

OBJECTIVE: To compare the clinical results of the direct anterior approach (DAA) and posterolateral approach (PLA) in total hip arthroplasty (THA) patients. METHODS: From January 2017 to September 2019, 80 patients who received primary THA in our hospital were retrospectively selected based on the propensity score matching (PSM) method. Baseline characteristics of patients who underwent the DAA and PLA were collected. Moreover, the incision length, intraoperative blood loss, operative time, length of stay, and Harris hip score were compared between patients in the two groups. The CK level was used to assess muscle damage between patients in the DAA and PLA groups. The complications of these two approaches were also evaluated at patients' 12-month follow-up evaluation. RESULTS: There was no significant difference in baseline characteristics between patients in the two groups (p > 0.05). The patients in the DAA group had a shorter incision length (9.2 ± 0.2 vs 14.7 ± 0.5, respectively; p < 0.05) and shorter length of hospital stay (9.5 ± 0.7 vs 12.9 ± 0.8, respectively, p < 0.05) than patients in the PLA group. Moreover, the DAA was associated with a decrease in intraoperative blood loss compared with the PLA (109.1 ± 12.6 vs 305.1 ± 14.1 ml, respectively, p < 0.05). However, the operation time was longer in patients in the DAA group (130.7 ± 1.7) than in patients in the PLA group (112.6 ± 1.3 min, p < 0.05). The CK level of patients in the DAA group was lower than that of patients in the PLA group (p < 0.05). The CK level at 48 h post-surgery was negatively correlated with the Harris hip scores at 6 months after THA (r = -0.538, p = 0.000). Compared with patients in the PLA group, the muscle strength of patients in the DAA group was significantly higher than that of patients in the DAA group at 4 days (p < 0.05) and 7 days (p < 0.05) after THA. The Harris hip scores of patients in the DAA group and PLA group were 81.0 ± 0.8 vs 70.8 ± 0.7 at 6 weeks, 93.4 ± 0.9 vs 86.4 ± 0.6 at 3 months, and 96.8 ± 1.1 vs 93.4 ± 0.8 at 6 months, respectively, both p < 0.05. There was no significant difference in the incidence of complications between patients in the DAA and PLA groups (p > 0.05). CONCLUSION: DAA was superior to the PLA in improving hip function after THA. Compared with the PLA, the DAA could reduce muscle damage, which is negatively correlated with hip function. Further multi-institution studies are required with longer follow-up durations, and larger patient populations are needed to provide more definitive conclusions.

[Application value of liquid crystal digital display goniometer in total hip arthroplasty].

OBJECTIVE: To investigate the application value of liquid crystal digital display goniometer in total hip arthroplasty. METHODS: From January 2018 to December 2019, 83 patients underwent primary total hip arthroplasty, including 28 males and 55 females, aged 42 to 81 (70.4±7.9) years. There were 63 cases of femoral neck fracture and 20 cases of avascular necrosis of femoral head. All patients used liquid crystal digital goniometer to control the anteversion of acetabular cup prosthesis during operation, and CT scanning was used to measure the anteversion of acetabular cup after operation. The two methods were compared to understand the accuracy of using liquid crystal digital goniometer. RESULTS: Postoperative CT measurement showed that the acetabular anteversion of all patients was in the safe area advocated by Lewinnek. The anteversion angle of acetabular cup measured by liquid crystal digital goniometer was 14.20(12.80 to 15.40)°, and the anteversion angle of acetabular cup measured by postoperative CT scan was 14.20 (13.40 to 15.50)°. There was no significant difference between the two (Z=-1.725, P=0.085). CONCLUSION: It is an accurate and reliable method to control the anteversion of acetabular cup with liquid crystal digital display angle instrument, which has a good auxiliary reference value.

[Anatomical research on proximal humeral fracture treated with humeral head replacement].

OBJECTIVE: To explore the efficacy of shoulder arthroplasty for comminuted proximal humeral fracture and measure anatomical specimens to determine the proximal humeral data for placing a shoulder prosthesis and designing a new prothesis. METHODS: A total of 68 Chinese adult cadaveric humeri were selected. The parameters of humeral breadth of proximal epiphysis, across diameter of humeral head, vertical diameter of humeral head, retroverion angle, maximal interval of humeral head-tuberosity and humeral head-shaft angle were measured and analyzed with SPSS 10 program. RESULTS: The data were as follows: Across diameter of humeral head: left (40.7 ± 1.9) mm, right (40.5 ± 1.4) mm; Vertical diameter of humeral head: left (44.5 ± 1.3) mm, right (43.4 ± 1.5) mm; Retroversion angle: left (26.6 ± 1.4)°, right (26.8 ± 1.6)°; Max interval of humeral head-tuberosity: left (6.6 ± 1.1) mm, right (6.8 ± 1.0) mm; Head-shaft angle: left (134.3 ± 3.5)°, right (135.6 ± 1.5)°; Superior breadth: left (47.2 ± 1.3) mm, right (46.9 ± 1.5) mm. CONCLUSION: Ideally the fitting prosthesis' diameter is 40 - 45 mm with a retroversion angle of approximately 30°. And the prosthesis should be higher than the greater tubercle by 6-8 mm.

Bioinformatics analysis of differentially expressed genes in subchondral bone in early experimental osteoarthritis using microarray data.

BACKGROUND: Osteoarthritis (OA) is the most common arthritic disease in humans, affecting the majority of individuals over 65 years of age. The aim of this study is to identify the gene expression profile specific to subchondral bone in OA by comparing the different expression profiles in experimental and sham-operation groups. METHODS: Gene expression profile GSE30322 was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were obtained by limma package. And Database for Annotation, Visualization and Integrated Discovery (DAVID) databases were further used to identify the potential gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Furthermore, a protein-protein interaction (PPI) network was constructed and significant modules were extracted. RESULTS: Totally, 588 DEGs were identified including 199 upregulated DEGs and 389 downregulated DEGs screened in OA and sham-operation. GO showed that DEGs were significantly enhanced for ribosomal subunit export from nucleus and molting cycle. KEGG pathway analysis revealed that target genes were enriched in thiamine metabolism. CONCLUSION: These key candidate DEGs that affect the progression of OA, and these genes might serve as potential therapeutic targets for OA.

A systematic review and meta-analysis of rituximab combined with methotrexate versus methotrexate alone in the treatment of rheumatoid arthritis.

BACKGROUND: This meta-analysis aimed to explore the efficacy and safety of rituximab combined with methotrexate (MTX) versus MTX alone in the treatment of rheumatoid arthritis (RA). METHODS: We performed an electronic search of PubMed (1950-January 2018), EMBASE (1974-January 2018), the Cochrane Library (January 2018 Issue 3), the Google database (1950-January 2018), and the Chinese Wanfang database (1950-January 2018). Only randomized controlled trials (RCTs) were included. The American College of Rheumatology 20% improvement criteria (ACR20), ACR50, ACR70, total complication rate, and infection rate were the outcomes. A fixed/random effects model was used according to the heterogeneity assessed by the I statistic. Data analysis was performed using Stata 12.0 software. RESULTS: A total of five RCTs with 3299 patients (rituximab combined with MTX group = 1787, MTX only group = 1512) were included in the meta-analysis. The pooled risk ratio showed that the administration of rituximab combined with MTX was associated with more ACR20, ACR50, and ACR70 than the administration of MTX only (P < .05). There were no significant differences between the two groups in terms of the total complication rate and the infection rate (P > .05). CONCLUSION: The administration of rituximab combined with MTX was effective and safe for RA patients. Additional high-quality RCTs with long-term follow-ups should be conducted in the future to identify the potential complications in the long term.

Proprioceptive training on the recovery of total knee arthroplasty patients: A meta-analysis protocol of randomized controlled trial.

BACKGROUND: Total knee arthroplasty is a common surgery for end-stage of knee osteoarthritis. Proprioceptive training has become an important part in athletes training programmes in different sports. However, the effects of proprioceptive training on the recovery of total knee arthroplasty were unknown. This meta-analysis, with its comprehensive and rigorous methodology, will provide better insight into this problem. METHODS AND ANALYSIS: Electronic databases including PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI) database, Wanfang Database and Chinese Biomedical Literature Database (CBM) were searched from its inception to October 21, 2020. We only included proprioceptive training vs placebo in patients after total knee arthroplasty and pooled results were summarized by STATA 12.0 software. Two researchers independently selected the study and assessed the quality of the included studies. The heterogeneity was measured by I2 tests (I2 < 50 indicates little heterogeneity, I2 ≥ 50 indicates high heterogeneity). Publication bias was ruled out by funnel plot and statistically assessed by Beggs test (P > .05 as no publication bias). RESULTS: Results will be published in relevant peer-reviewed journals. CONCLUSION: Our study aims to systematically present the clinical effects of proprioceptive training after total knee arthroplasty patients, which will be provide clinical guidance for total knee arthroplasty patients.

Cnidium lactone stimulates osteogenic differentiation of bone marrow mesenchymal stem cells via BMP-2/smad-signaling cascades mediated by estrogen receptor.

Our aim was to study the osteogenic effect of cnidium lactone for bone marrow mesenchymal stem cells (BMSCs) and its potential mechanism. BMSCs were isolated and identified by flow cytometry and multidirectional differentiation capacity. Cell Counting Kit-8 (CCK-8) was used to identify the optimal concentration of cnidium lactone. Alkaline Phosphatase (ALP) and Alizarin Red S (ARS) was performed to identify whether cnidium lactone has effect on osteogenesis at early and late phase respectively. Moreover, we used estrogen receptor antagonist, ICI182780, to identify the receptor of cnidium lactone. The expression of Runt-related transcription factor 2 (RUNX2), Osterix (OSX), osteopontin (OPN), estrogen receptor (ER), Smad4, p-Smad1, Smad1 and bone morphogenetic protein 2 (BMP-2) protein were measured by PCR and western blot. Cnidium lactone (2 µM) demonstrated increased osteogenesis after osteogenic inducible medium (OIM) induction, as evidenced by more ALP activity and mineralization. When blocked with ICI182780, osteogenesis capacity was decreased. Moreover, the polymerase chain reaction (PCR) and western blotting results indicated that cnidium lactone enhanced ER, BMP2, Smad1, Smad4, RUNX2, OSX, and OPN expression and Smad1 phosphorylation. Cnidium lactone can effectively stimulates osteogenic differentiation of BMSCs via BMP-2/Smad-Signaling cascades mediated by ER.

Direct anterior versus lateral approaches for clinical outcomes after total hip arthroplasty: a meta-analysis.

OBJECTIVE: To compare the outcomes of the direct anterior approach (DAA) with the lateral approach (LA) for total hip arthroplasty (THA) patients. METHODS: Three English databases, PubMed, Embase, and the Cochrane Library, were searched for randomized controlled trials (RCTs) comparing the DAA with LA for THA. Information on the country, sample size, intervention, outcomes, and follow-up were extracted. Meta-analysis was performed using Stata 12.0. RESULTS: Five RCTs totaling 475 patients (DAA = 236, LA = 239) were included in this meta-analysis. Compared with the LA, the DAA was associated with a reduction in the VAS at 6 weeks (weighted mean difference (WMD) = - 0.41, 95% confidence interval (CI) - 0.63 to - 0.19, P = 0.000) and total blood loss for THA patients (WMD = - 45.73, 95% CI - 84.72 to - 6.02, P = 0.024). Moreover, the DAA was associated with an increase in walking velocity (WMD = 5.01, 95% CI 2.32 to 7.70, P = 0.000), stride length (WMD = 3.12, 95% CI 2.42 to 3.82, P = 0.000), and step length (WMD = 4.09, 95% CI 1.03 to 7.14, P = 0.009) compared with the LA group. There was no significant difference between groups in the Harris hip score, operation time, transfusion rate, length of hospital stay, and the occurrence of complications. CONCLUSION: Current evidence demonstrated a trend showing that the DAA had a better effect on pain relief and blood-saving effects for THA patients. However, considering the number and sample size of the included trials, more large-scale RCTs with high quality are needed to confirm our conclusion.

A systematic review and meta-analysis of direct anterior approach versus posterior approach in total hip arthroplasty.

BACKGROUND: This meta-analysis aimed to evaluate the postoperative clinical outcomes and safety of the direct anterior approach (DAA) versus posterior approach (PA) in total hip arthroplasty (THA). METHODS: We searched PubMed, Embase, Web of Science, the Cochrane Library, and Google databases from inception to June 2018 to select studies that compared the DAA and PA for THA. Only randomized controlled trials (RCTs) were included. Outcomes included Harris hip score at 2 weeks, 6 weeks, 12 weeks, and 1 year; VAS at 24 h, 48 h, and 72 h; incision length, operation time, postoperative blood loss, length of hospital stay, and complications (intraoperative fracture, postoperative dislocation, heterotopic ossification (HO), and groin pain). RESULTS: Nine RCTs totaling 754 THAs (DAA group = 377, PA group = 377) met the criteria to be included in this meta-analysis. The present meta-analysis indicated that, compared with PA group, DAA group was associated with an increase of the Harris hip score at the 2-week and 4-week time points. No significant difference was found between DAA and PA groups of the Harris hip scores at 12 weeks, 1 year length of hospital stay (p > 0.05). DAA group was associated with a reduction of the VAS at 24 h, 48 h, and 72 h with statistical significance (p < 0.05). What is more, DAA was associated with a reduction of the incision length and postoperative blood loss (p < 0.05). There was no significant difference between the operation time and complications (intraoperative fracture, postoperative dislocation, HO, and groin pain). CONCLUSION: In THA patients, compared with PA, DAA was associated with an early functional recovery and less pain scores. What is more, DAA was associated with shorter incision length and blood loss.