Silicosis caused by inhalation of silica particles leads to more than ten thousand new occupational exposure-related deaths yearly. Exacerbating this issue, there are currently few drugs reported to ...effectively treat silicosis. Tetrandrine is the only drug approved for silicosis treatment in China, and despite more than decades of use, its efficacy and mechanisms of action remain largely unknown. Here, in this study, we established silicosis mouse models to investigate the effectiveness of tetrandrine of early and late therapeutic administration. To this end, we used multiple cardiopulmonary function test, as well as markers for inflammation and fibrosis. Moreover, using single cell RNA sequencing and transcriptomics of lung tissue and quantitative microarray analysis of serum from silicosis and control mice, our results provide a novel description of the target pathways for tetrandrine. Specifically, we found that tetrandrine attenuated silicosis by inhibiting both the canonical and non-canonical NLRP3 inflammasome pathways in lung macrophages. Taken together, our work showed that tetrandrine yielded promising results against silicosis-associated inflammation and fibrosis and further lied the groundwork for understanding its molecular targets. Our results also facilitated the wider adoption and development of tetrandirne, potentially accelerating a globally accepted therapeutic strategy for silicosis.
A great challenge in producing TiC reinforced metal matrix composites is encountered to directly add TiC particles into molten steel during casting owing to floating of nano-sized TiC on molten ...steels and agglomeration. As such, this work proposes a novel strategy using pre-distribution in situ nano-sized TiC/Al master alloy to fabricate 45 steel matrix composites reinforced with trace nano-sized TiC particles while without changing the original casting process; this strategy can effectively avoid the aforementioned challenge. The average grain sizes of as-cast and heat-treated 45 steel with 0.018 wt% nano-sized TiC particles remarkably decrease from 14.75 μm to 9.51 μm respectively to 8.77 μm and 5.46 μm respectively, which is attributed to that the nanoparticles provide effective nucleation sites and inhibit grain growth. Furthermore, adding trace nano-sized TiC particles significantly enhances their strength and toughness. The 45 steel matrix composites reinforced with 0.054 wt% nano-sized TiC particles exhibits the best tensile mechanical properties with yield strength of 624 MPa, ultimate strength of 920 MPa, elongation of 23.8% and impact toughness of 50.21 J/cm2, which are 19%, 13%, 10% and 38% respectively higher than the 45 steel. The strengthening and toughening mechanisms of 45 steel by nano-sized TiC are attributed to grain boundary strengthening, work hardening and dispersion strengthening. The strategy proposed in this work may provide a promising method for enhancing steel performances for industrial productions.
•Using pre-distribution TiC/Al master alloy to fabricate 45 steel matrix composites.•Microstructure of 45 steels is significantly refined by trace nano-TiC.• 45steel matrix composites exhibit significantly improved strength and toughness.•New strategy is fabricated for 45 steel matrix composites reinforced with nano-TiC.
In this study, we propose an innovative method to add trace in situ TiC nanoparticles into 40Cr steel to manipulate its microstructure and mechanical properties. The trace TiC nanoparticle/40Cr ...steels fabricated using this method exhibited better room- and high-temperature properties than those exhibited by unreinforced 40Cr steel. The yield strength, tensile strength, fracture strain, and impact toughness of the 0.054 wt% TiC nanoparticle/40Cr steel were 1293 MPa, 1460 MPa, 10.4%, and 24.2 J/cm2, respectively, which increased by 19.7%, 30.4%, 15.6%, and 33.0% than 40Cr steel. The good combination of strength, ductility, and toughness after adding trace TiC nanoparticles to 40Cr steel was attributed to fine grain strengthening, thermal mismatch strengthening, and second phase strengthening. This research provides a new method for fabricating nanosized ceramic particle-reinforced steel that can be used to develop high-performance steel with high efficiency and low cost.
•TiC nanoparticles offered nucleation sites for γFe and αFe by low lattice misfits.•In situ trace TiC nanoparticles enabled microstructure refinement of 40Cr steel.•More and fine RA were obtained by adding trace TiC nanoparticles.•Excellent strength and toughness were yielded by adding trace TiC nanoparticles.
Silicosis is a global occupational disease characterized by lung dysfunction, pulmonary inflammation, and fibrosis, for which there is a lack of effective drugs. Pirfenidone has been shown to exert ...anti-inflammatory and anti-fibrotic properties in the lung. However, whether and how pirfenidone is effective against silicosis remains unknown. Here, we evaluated the efficacy of pirfenidone in the treatment of early and advanced silicosis in an experimental mouse model and explored its potential pharmacological mechanisms. We found that pirfenidone alleviated silica-induced lung dysfunction, secretion of inflammatory cytokines (TNF-α, IL-1β, IL-6) and deposition of fibrotic proteins (collagen I and fibronectin) in both early and advanced silicosis models. Moreover, we observed that both 100 and 200 mg/kg pirfenidone can effectively treat early-stage silicosis, while 400 mg/kg was recommended for advanced silicosis. Mechanistically, antibody array and bioinformatic analysis showed that the pathways related to IL-17 secretion, including JAK-STAT pathway, Th17 differentiation, and IL-17 pathway, might be involved in the treatment of silicosis by pirfenidone. Further in vivo experiments confirmed that pirfenidone reduced the production of IL-17A induced by silica exposure via inhibiting STAT3 phosphorylation. Neutralizing IL-17A by anti-IL-17A antibody improved lung function and reduced pulmonary inflammation and fibrosis in silicosis animals. Collectively, our study has demonstrated that pirfenidone effectively ameliorated silica-induced lung dysfunction, pulmonary inflammation and fibrosis in mouse models by inhibiting the secretion of IL-17A.
Capsule endoscopy (CE) can detect lesions outside the scope of ileocolonoscopy in postoperative patients with Crohn’s disease (CD). However, the impact of such findings on patient outcomes remains ...unknown. This study is intended to evaluate the impact of CE findings on clinical management and outcomes in asymptomatic patients with CD without pharmacologic prophylaxis after ileocolonic resection.
In this retrospective cohort study, 37 patients (group 1) received ileocolonoscopy together with CE within 1 year after surgery, whereas 46 patients (group 2) only received ileocolonoscopy. Patients with endoscopic recurrence detected by either ileocolonoscopy or CE received pharmacologic therapy with azathioprine or infliximab. One year later, disease activity was re-evaluated.
In group 1, all patients with ileocolonoscopy-identified recurrence also had CE-identified recurrence. In addition, CE detected endoscopic recurrence in 11 patients missed by ileocolonoscopy. Endoscopic remission identified by ileocolonoscopy was confirmed by CE in 13 patients. One year later, endoscopic remission identified by ileocolonoscopy was maintained in all 24 patients, and none had clinical recurrence. Conversely, in group 2, of those with ileocolonoscopy-identified remission, both ileocolonoscopy-identified recurrence and clinical recurrence occurred in 9 of 31 patients 1 year later. The total clinical recurrence rate was 2.7% (1/37) in group 1 versus 21.7% (10/46) in group 2 (P = .019).
If endoscopic remission identified by ileocolonoscopy was confirmed by CE, patients could remain free of pharmacologic prophylaxis. If recurrence outside the scope of ileocolonoscopy was detected by CE, initiation of active pharmacologic therapy would be needed.
Ultrasound is valuable in tight control algorithms for Crohn's disease (CD). However, the correlation between ultrasonographic response and anti-tumor necrosis factor (TNF) drug levels remains ...unknown. Elucidating this correlation would be helpful in optimizing the use of anti-TNF drugs. Thus, the authors aimed to investigate this correlation.
Between June 2020 and June 2021, all patients with CD who completed anti-TNF induction therapy were retrospectively included. Ultrasound was performed at week 0 and week 14, and proactive therapeutic drug monitoring of anti-TNF drugs was performed at week 14. The receiver operating characteristic (ROC) curve was used in the correlation analysis.
Ninety-two patients (60 treated with infliximab and 32 with adalimumab) were included. At week 14, an ultrasonographic response was detected in 43 patients. Patients with ultrasonographic response had significantly higher median drug levels (5.9 mcg/mL for infliximab; 18.2 mcg/mL for adalimumab) than those without (0.9 mcg/mL for infliximab, P < 0.001; 4.8 mcg/mL for adalimumab, P < 0.001). The ROC curve showed a significant correlation between ultrasonographic response and anti-TNF drug levels (area under the curve = 0.79 for infliximab, P < 0.001; area under the curve = 0.86 for adalimumab, P < 0.001). The optimal cut-off values for infliximab and adalimumab correlated with ultrasonographic response were 5.0 and 10.5 mcg/mL, respectively. An incremental increase was observed in ultrasonographic response with higher anti-TNF drug levels.
Higher anti-TNF drug levels are associated with an increased likelihood of ultrasonographic response in patients with CD.
Hydroxychloroquine (HCQ), a widely used antimalarial drug, is proposed to treat coronavirus disease 2019 (COVID-19). However, no report is currently available regarding the direct effects of HCQ on ...gut microbiota, which is associated with the outcomes of elderly patients with COVID-19. Here, we first investigated the effects of HCQ on intestinal microecology in mice.
Fifteen female C57BL/6J mice were randomly divided into two groups: HCQ group (n = 10) and control group (n = 5). Mice in the HCQ group were administered with HCQ at dose of 100 mg/kg by gavage daily for 14 days. The feces of mice were collected before and on the 7th and 14th days after HCQ challenge, and then analyzed by 16S rRNA amplicon sequencing. At the end of the experiment, the hematology, serum biochemistry and cytokines were determined, respectively. The mRNA expression of tight junction proteins in colonic tissues were also studied by RT-PCR.
HCQ challenge had no effects on the counts of white blood cells, the levels of serum cytokines, and the gene expression of tight junction proteins in colon. HCQ also did not increase the content of serum d-lactate in mice. Notably, HCQ significantly decreased the diversity of gut microbiota, increased the relative abundance of phylum Bacteroidetes whereas decreased that of Firmicutes.
Short-term high dose HCQ challenge changes gut microbiota but not the intestinal integrity and immunological responses in mice. Special attention should be paid to the effects of HCQ on intestinal microecology in future clinical use.
Abstract Background Endoscopic submucosal tunneling dissection (ESTD) has been proved to be safe and effective for removal of esophageal submucosal tumors (SMTs) and can maintain the mucosal ...integrity compared with other endoscopic methods. The aim of the study was to estimate the safety and efficacy of ESTD as well as compare its efficacy with thoracoscopic enucleation for esophageal SMTs, which is used increasingly as a minimally invasive approach. Methods We retrospectively collected the clinical data of the patients with esophageal SMTs smaller than 40 mm who underwent ESTD or thoracoscopic enucleation at Nanfang hospital between January 2008 and August 2016. Epidemiological data (gender, age), tumor location, tumor size, en bloc resection rate, adverse events, pathological results, length of postoperative hospital stay and cost were compared between ESTD and thoracoscopic enucleation. Results A total of 126 patients were included, and 74 patients underwent ESTD and the other 52 received thoracoscopic enucleation. There was no significant difference between the 2 groups in gender, age, tumor size, hospitalization expense, infection, adverse events and en bloc resection rate ( p <0.05). However, patients in the ESTD groups had a shorter operating time, a less estimated blood loss, a shorter length of postoperative hospital stay and a lower chest pain level ( p <0.05). Kaplan-Meier curves for disease-free survival also shows no statistically significant difference between ESTD and thoracoscopic enucleation groups during the median follow-up of 19.5 and 42 months, respectively. Conclusions The treatment efficacy was comparable between the ESTD and thoracoscopic enucleation for esophageal SMTs smaller than 40 mm. However, there is a significant advantage in ESTD group for a shorter operating time, reduced postoperative chest pain and shorter hospitalization.
Background
Since 2011, three large-scale genome-wide association studies (GWAS) have confirmed that the CD2AP rs9349407 polymorphism is significantly connected with Alzheimer’s disease (AD) in ...individuals of European descent. Subsequently, this association has been replicated in European populations, but is unclear whether it can be replicated in Chinese. Recently, the correlation between rs9349407 and AD in the Chinese population has become a research hotspot.
Objective
To explore the association between rs9349407 polymorphism and AD in the Chinese population.
Materials and methods
Firstly, based on the exclusion and inclusion criteria, we selected 11 independent studies from 8 articles exploring the correlation between rs9349407 variation and AD in Chinese. Secondly, we conducted a meta-analysis based on fixed and random effect models and conducted a heterogeneity test. Thirdly, we used the additive model, dominant model, and recessive model for subgroup analysis.
Results
We demonstrated that the CD2AP rs9349407 polymorphism increases AD susceptibility in Chinese populations (OR = 1.33, 95% CI = 1.08–1.64,
P
= 7.45E-03), which is consistent with the effect observed in Caucasian populations. Additionally, subgroup analysis showed that rs9349407 under the additive model (GG + CC vs. GC, OR = 0.76, 95% CI = 0.61–0.97,
P
= 2.04E-02) and dominant model (GG + GC vs. CC, OR = 0.49, 95% CI = 0.32–0.74,
P
= 8.51E-04) were also significantly correlated with AD susceptibility, but not under the recessive model (GG vs. GC + CC, OR = 0.77, 95% CI = 0.58–1.03,
P
= 7.44E-02).
Conclusion
These existing data suggest that rs9349307 is significantly correlated with the susceptibility to AD in the Chinese population, but future studies with large samples are needed to confirm our findings.
Deep remission should be induced early in the disease course of Crohn's disease (CD), because it significantly prevents disease progression. Identifying predictors of deep remission before treatment ...is important to guide therapeutic strategy. Little is known about the predictors of infliximab-induced deep remission in treatment-naïve patients with isolated small bowel CD. We aimed to investigate the predictors of infliximab-induced deep remission in these patients.
From January 2015 to December 2019, all consecutive treatment-naïve patients with isolated small bowel CD who started infliximab induction therapy (5 mg/kg at week 0, 2, and 6) and underwent capsule endoscopy (CE) at week 14 were retrospectively included. Deep remission was defined as clinical remission in combination with CE-identified mucosal healing. Logistic regression was used to investigate the predictors of 14-week deep remission.
Ninety-one patients were included. At week 14 after infliximab induction therapy, deep remission was found in 42 patients. Multivariate logistic regression analysis showed that a moderate-to-severe endoscopic disease odds ratio (OR), 0.28; p = .01 and the presence of fibrofatty proliferation (OR, 0.26; p = .04) at baseline were independently associated with a decreased possibility of deep remission.
In treatment-naïve patients with isolated small bowel CD, a moderate-to-severe endoscopic disease and the presence of fibrofatty proliferation at baseline reduce the possibility of infliximab-induced deep remission. Patients with such risk factors may need more aggressive treatment at the beginning of induction therapy to promote deep remission at an early stage.
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