Thioredoxin interacting protein, a key molecular switch between oxidative stress and sterile inflammation in cellular response.

Tissue and systemic inflammation have been the main culprit behind the cellular response to multiple insults and maintaining homeostasis. Obesity is an independent disease state that has been reported as a common risk factor for multiple metabolic and microvascular diseases including nonalcoholic fatty liver disease (NAFLD), retinopathy, critical limb ischemia, and impaired angiogenesis. Sterile inflammation driven by high-fat diet, increased formation of reactive oxygen species, alteration of intracellular calcium level and associated release of inflammatory mediators, are the main common underlying forces in the pathophysiology of NAFLD, ischemic retinopathy, stroke, and aging brain. This work aims to examine the contribution of the pro-oxidative and pro-inflammatory thioredoxin interacting protein (TXNIP) to the expression and activation of NLRP3-inflammasome resulting in initiation or exacerbation of sterile inflammation in these disease states. Finally, the potential for TXNIP as a therapeutic target and whether TXNIP expression can be modulated using natural antioxidants or repurposing other drugs will be discussed.

A retrospective study on the predictive implications of clinical characteristics and therapeutic management in patients with rheumatoid arthritis-associated interstitial lung disease.

BACKGROUND: Rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) is associated with significant morbidity and is a critical cause of mortality in patients with RA. OBJECTIVE: Our aim was to evaluate predictive and prognostic factors for RA-ILD and to describe the therapeutic management of the condition from a large China cohort. METHODS: This was a retrospective cohort study. We collected data of 1121 RA patients who underwent chest HRCT from 2008 to 2017. Patients without ILD at RA diagnosis were included in the analysis. The development and evolution of ILD in RA patients were followed up. Determinants of ILD development and progression were identified through multivariable logistic analysis. Cox hazards analysis was used to determine significant variables associated with survival. RESULTS: A total of 923 patients without ILD at RA diagnosis were identified and enrolled. Among them, 278 cases (30.12%) were diagnosed as ILD during follow-up. Logistic regression analysis showed that advanced age (> 60 years old) at RA onset (OR: 1.485), male (OR: 1.882), short duration of RA (0~5 years) (OR: 2.099), RF positive (OR: 1.728), elevated lactate dehydrogenase (LDH) (OR: 3.032), and no medication (OR: 1.833) were closely correlated to the development of RA-ILD. No correlation was found between ILD development and traditional DMARDs such as methotrexate and leflunomide. According to the follow-up data, 83 RA-ILD patients were identified as interstitial lung disease (ILD) progression, and 102 participants were stable. Logistic regression modeling demonstrated that DLCO% < 45% (OR: 3.025) and UIP possible pattern on HRCT (OR: 3.476) were independent risk factors for the ILD progression. No correlation was found between ILD progression and traditional DMARDs such as methotrexate and leflunomide. A total of 53 RA-ILD deaths occurred during follow-up. Cox hazards analysis revealed that advanced age (> 60 years old) at RA-ILD diagnosis (HR: 3.181) and extensive lung involvement on HRCT (HR: 2.401) were associated with worse survival. Treatment with cyclophosphamide (HR: 0.210) was associated with better survival. CONCLUSIONS: Advanced age, male, short duration of RA, RF positive, elevated LDH, and no medication are closely correlated with RA-ILD. No correlation was found between traditional DMARDs and ILD development. DLCO% < 45% and UIP possible pattern are predictive factors for ILD progression. No correlation was found between traditional DMARDs and ILD progression. Advanced age and extensive lung involvement on HRCT independently predict mortality; cyclophosphamide treatment helps to improve the prognosis of RA-ILD.Key Points• We designed this study to investigate the predictive and prognostic factors for RA-ILD and to explore the potential role of DMARDs in the evolution of RA-ILD from the development to progression and death.• Patients without ILD at RA diagnosis were enrolled and followed up retrospectively.• Our results showed that no correlation was found between traditional DMARDs and the development and progression of ILD, and regular treatment may improve the development of RA-ILD.• Our results revealed that clinical variables appeared predictive implications for the diagnosis of ILD and physiological and radiological variables appeared predictive implications for the prognosis of ILD, which can provide reference to rheumatologists and help to improve poor prognosis of RA-ILD.

A preliminary study of lung abnormalities on HRCT in patients of rheumatoid arthritis-associated interstitial lung disease with progressive fibrosis.

OBJECTIVE: This retrospective study evaluates lung abnormalities on high-resolution CT (HRCT) and clarifies which abnormality can predict the progressive fibrosis of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD). OBJECTS AND METHODS: We identified 1096 RA patients, and enrolled 213 patients with a diagnosis of RA-ILD who underwent serial chest HRCT. Clinical data of the patients were obtained. The presence, extent, and distribution of lung abnormalities were assessed on CT scans. Logistic regression analysis was used to determine positive indicators with predictive value for progressive fibrosis, and 2 × 2 contingency tables were constructed to assess their diagnostic efficiency. RESULT: Of 213 RA-ILD patients, 106 (49.8%) were diagnosed as progressive fibrosis. The rates of advanced age, male, smoking history, shortness of breath, and anti-CCP antibody high titer positive were higher, and RA duration was shorter in progressive fibrosis patients. Reticular pattern (RP), peribronchovascular interstitium (PBVI) thickening, interlobular septal thickening, and traction bronchiolectasis were more common in the progressive fibrosis group (84.9% vs 42.1%, P < 0.001; 79.3% vs 45.8%, P < 0.001; 74.5% vs 43.9%, P < 0.001; 67.0% vs 40.2%, P < 0.001; respectively). Lung abnormalities demonstrated subpleural predominance, and the subpleural RP and/or interlobular septal thickening had a wide distribution in the progressive fibrosis group (71.7% vs 14.0%, P < 0.001). The overall extent of lung abnormalities was more extensive in the progressive fibrosis group (18.4% vs 14.2%, P < 0.05). Logistic regression analysis showed that a wide distribution of subpleural RP and/or interlobular septal thickening (OR, 18.15) and PBVI thickening (OR, 4.98) were independent risk factors predictive of progressive fibrosis. For the combination of these two CT abnormalities, sensitivity was 63.2%, specificity was 92.5%, positive likelihood ratio was 8.5, and negative likelihood ratio was 0.4 in predicting progressive fibrosis. CONCLUSIONS: A wide distribution of subpleural RP and/or interlobular septal thickening and PBVI thickening on HRCT appear predictive of progressive fibrosis in RA-ILD. The combined evaluation of these two CT abnormalities has a good judgment value. Key Points • We designed this study to investigate the risk factors for progressive fibrosis in patients with RA-ILD. Factors including clinical, physiological, radiological and therapeutic variables were all included in the data analysis. • Our results showed HRCT abnormalities, rather than other parameters, appeared predictive of progressive fibrosis in RA-ILD. • The methods and results of image evaluation in this article would provide reference to rheumatologists in identifying early stage of progressive fibrosis which helps to improve poor prognosis of RA-ILD.

Risk factors for progression and prognosis of rheumatoid arthritis-associated interstitial lung disease: single center study with a large sample of Chinese population.

BACKGROUND: Factors associated with progression and survivals in rheumatoid arthritis-associated interstitial lung disease (RA-ILD) have not been described in a large center China cohort. METHODS: Seven-hundred and ninety-one consecutive RA patients who completed lung HRCT were considered as potential participants in this retrospective cohort study. Determinants of ILD progression were identified through multivariable logistic analysis. Cox hazards analysis was used to determine significant variables associated with survival. RESULTS: Of 307 patients diagnosed with RA-ILD, 266 were finally included. The 3-year survival rate of RA-ILD patients was 81.24%, and the 5-year survival rate was 69.71%. A total of 82 deaths occurred during follow-up, of which 56 died of respiratory failure due to ILD progression and/or pneumonia while 14 with malignancies (8 with lung cancer). Logistic regression analysis showed that anti-CCP antibody high titer positive (OR: 4.03, 95% CI: 1.04-15.69) and DLCO% < 45% (OR: 8.31, 95% CI: 2.17-31.75) were independent risk factors for the ILD progression. Cox hazards analysis revealed that advanced age (> 60 years old) of RA-ILD diagnosis (HR: 2.32, 95% CI: 1.27-4.25) and extensive lung involvement on HRCT (HR: 2.19, 95% CI: 1.24-3.87) were associated with worse survival. Treatment with cyclophosphamide (HR: 0.43, 95% CI: 0.26-0.69) was associated with better survival. CONCLUSIONS: In RA-ILD patients, anti-CCP antibody high titer positive and DLCO% < 45% are risk factors for ILD progression. Advanced age and extensive lung involvement on HRCT, rather than the baseline UIP pattern, independently predict mortality after controlling for potentially influential variables. Furthermore, cyclophosphamide treatment helps to improve the prognosis in real-world experience.

Thermodynamic performance of SNG and power coproduction from MSW with recovery of chemical unreacted gas.

A cogeneration system for simultaneously producing synthetic natural gas (SNG) and electric power from municipal solid waste (MSW) is developed. This process provides a disposal method for MSW that is environmentally sustainable and uses as an alternative energy sources. Rather than converting all of the synthesis gas into end products, in the proposed system the unconverted gas is recovered for power generation in a combined-cycle unit. The overall efficiency of the proposed system is 36.33%. The energy efficiency of this system is approximately 8.7% higher than that of a standalone SNG production system, and 15.02% higher than that of an MSW incineration system. A sensitivity analysis shows that by increasing the H2/CO ratio (α), SNG production and SNG conversion efficiency can be increased, but the overall efficiency does not increase. Increasing the recycling ratio of the unconverted gas (Ru) benefits for the SNG yield up to a value before Ru/(Ru+1)=0.7, and the overall system efficiency reaches its maximum value at Ru/(Ru+1)=0.9. Therefore, partial recycling of the unreacted gas is more efficient up to a point, and higher recycling ratios are less efficient.

MSW to synthetic natural gas: System modeling and thermodynamics assessment.

To achieve environmental-friendly and energy-efficiency synthetic natural gas (SNG) production routing from municipal solid waste (MSW), a MSW-to-SNG process is unprecedentedly presented in this work, of which the designed configuration is developed and simulated with the aid of Aspen Plus. In addition, sensitivity analyses on major operation parameters, such as equivalence volume ratio (ER), steam-to-MSW mass ratio (S/M) and methanation pressure, are performed with the discussion of process efficiencies and SNG quality. In parallel, the comparison analysis is considered by adopting various MSW material. In this work, the composition of SNG mainly consists of 87.7% CH4, 2.9% CO2, 2.3% H2 and 7.1% N2. And lower heating value (LHV) together with Wobbe index of SNG are separately 31.66MJ/Nm(3) and 45.90MJ/Nm(3). Moreover, the wood-to-SNG, MSW-to-SNG and coal-to-SNG processes are carried out to demonstrate the superiority of the MSW-to-SNG process. The results reveal that the MSW-to-SNG process is a promising option to dispose MSW environmentally, meanwhile converting MSW to the valuable SNG.

The effects and mechanisms of mycophenolate mofetil on pulmonary arterial hypertension in rats.

Pulmonary arterial hypertension (PAH) is a severe clinical and pathophysiologic syndrome with no effective treatment at present. Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), has been applied widely to the treatment of connective tissue diseases with the effect of immunosuppressant. Its anti-proliferation has been found recently. Thereby, we tried to examine the effects of MMF on rats with PAH which was induced by monocrotaline injection, so as to investigate the mechanisms of treatment on PAH by MMF. The results substantiated that MMF therapy can alleviate thickening of pulmonary arterial walls and inhibit abnormal vascular remodeling, and the MPA concentrations which demonstrated efficacy in this study are within clinical applicable range, suggesting huge potentiality of MMF in the treatment of human PAH.