Fibrotic responses involve multiple cellular processes, including epigenetic changes. Epigenetic changes are sensitive to alterations in the tissue microenvironment such as the flux of tricarboxylic acid (TCA) cycle metabolites. TCA metabolites directly regulate epigenetic states, in part, by regulating histone modification related enzymes. Glutaminolysis is a critical metabolic process by which glutamine is converted to glutamate by glutaminase then to α-ketoglutarate (α-KG), a TCA cycle metabolite. Idiopathic pulmonary fibrosis (IPF) is a disease characterized by aberrant metabolism, including enhanced glutaminolysis. IPF fibroblasts are apoptosis-resistant. In this study, we explored the relationship between glutaminolysis and resistance to apoptosis of IPF fibroblasts. Inhibition of glutaminolysis decreased expression of XIAP and survivin, members of inhibitor of apoptosis protein (IAP) family. α-KG is a co-factor for JMJD3 histone demethylases, which targets H3K27me3. In the absence of glutamine, JMJD3 activity in fibroblasts is significantly decreased while H3K27me3 levels are increased. ChIP assays confirmed that JMJD3 directly interacts with XIAP and survivin promoter regions in a glutamine-dependent manner. Exogenous α-KG partially restores JMJD3 function and its interaction with the XIAP and survivin promoter regions under glutamine-deficient conditions. Interestingly, α-KG up-regulates XIAP, but not survivin, suggesting differential α-KG dependent and independent mechanisms by which glutamine regulates these IAPs. Our data demonstrate a novel mechanism of metabolic regulation in which glutaminolysis promotes apoptosis resistance of IPF fibroblasts through epigenetic regulation of XIAP and survivin.

(−)-Epigallocatechin-3-gallate (EGCG) is the main bioactive catechin in green tea. The antitumor activity of EGCG has been confirmed in various types of cancer, including lung cancer. However, the precise underlying mechanisms are still largely unclear. In the present study, we investigated the metabolite changes in A549 cells induced by EGCG in vitro utilizing liquid chromatography-mass spectrometry (LC-MS)-based metabolomics. The result revealed 33 differentially expressed metabolites between untreated and 80 μM EGCG-treated A549 cells. The altered metabolites were involved in the metabolism of glucose, amino acid, nucleotide, glutathione, and vitamin. Two markedly altered pathways, including glycine, serine and threonine metabolism and alanine, aspartate and glutamate metabolism, were identified by MetaboAnalyst 5.0 metabolic pathway analysis. These results may provide potential clues for the intramolecular mechanisms of EGCG’s effect on A549 cells. Our study may contribute to future molecular mechanistic studies of EGCG and the therapeutic application of EGCG in cancer management.

Background Idiopathic pulmonary fibrosis (IPF) is a chronic diffuse interstitial lung disease, of which the etiology has been poorly understood. Several studies have focused on the relationship between IPF and diabetes mellitus (DM) in the past years but have failed to reach a consensus. This meta-analysis aimed to examine the association between diabetes to IPF. Methods We accumulated studies investigating the association between DM and IPF from databases including Medline, Cochrane Library, Embase, Web of Science, and China National Knowledge Infrastructure. RevMan 5.3 and the Newcastle–Ottawa Scale (NOS) were utilized to analyze the data and assess the quality of the included studies. The value of odds ratio (OR) with 95% confidence interval (CI) was used as the measure to estimate the risk of DM in IPF. Heterogeneity was assessed by I2 statistics. We also performed subgroup analysis, meta-regression, and Egger’s test for bias analysis. Results Nine case–control studies with 5096 IPF patients and 19,095 control subjects were included in the present meta-analysis, which indicated a positive correlation between DM and IPF (OR 1.65, 95% CI 1.30–2.10; P < 0.0001). Meta-regression and subgroup analysis negated the influence of covariates like cigarette smoking, age and gender, but the heterogeneity existed and could not be fully explained. Conclusion IPF and DM may be associated, but the causal relationship remains indeterminate till now. Further rigorously designed studies are required to confirm the present findings and investigate the possible mechanisms behind the effect of DM on IPF.

Background: Tripterygium wilfordii Hook. F (TwHF), a Chinese herbal medicine used to treat CTD-ILD patients in China, has been previously found to have immunoinhibitory, antifibrotic and anti inflammatory effects. It has also shown good results in treating autoimmune and inflammatory diseases.Objectives: This systematic review and meta-analysis aims to evaluate the efficacy and safety of TwHF for CTD-ILD.Methods: A systematic search was performed on PubMed, Embase, Cochrane Library, Web of Science, PsycINFO, Scopus, CNKI, Wanfang, VIP, and CBM databases up to May 2021. Randomized controlled trials (RCTs) comparing TwHF plus conventional therapy versus conventional therapy alone were included. We followed the PRISMA checklist, and applied Cochrane handbook 5.1.0 and RevMan 5.3 for data analysis and quality evaluation of the included studies.Results: Based on Cochrane handbook 5.1.0, nine RCTs consisting 650 patients met the inclusion/exclusion criteria and were selected for further analysis. The obtained data showed significant improvement in lung function with TwHF plus conventional treatment compared with conventional treatment (post-treatment FVC% (MD= 8.68, 95%Cl (5.10, 12.26), p &lt; 0.00001), FEV1% (MD = 11.24, 95%Cl (6.87, 15.61), p &lt; 0.00001), TLC% (MD = 5.28, 95%Cl (0.69, 9.87), p = 0.02)], but no significant difference in the post-treatment DLCO% [(MD = 4.40, 95%Cl (−2.29, 11.09), p = 0.20)]. Moreover, the data showed that TwHF combined with conventional treatment significantly reduced the HRCT integral of patients [MD = -0.65, 95% (-1.01, -0.30), p = 0.0003], the level of erythrocyte sedimentation rate (MD = −9.52, 95%Cl (−11.55, −7.49), p &lt; 0.00001), c-reactive protein (CRP) (MD = −8.42, 95%Cl (−12.47, −4.38), p &lt; 0.0001), and rheumatoid factor (MD = −25.48, 95%Cl (−29.36, −21.60), p &lt; 0.00001). Compared to conventional therapy, TwHF combined with conventional therapy significantly improved clinical effects (RR = 1.33, 95%Cl (1.17, 1.51), p &lt; 0.0001), in five trials with 354 patients. In terms of improvement of symptoms and signs, the TwHF group showed a more significant improvement than the conventional treatment group (Cough (MD = −0.96, 95%Cl (−1.43, −0.50), p &lt; 0.0001), velcro rales (MD = −0.32, 95%Cl (−0.44, −0.20), p &lt; 0.00001), shortness of breath (MD = −1.11, 95%Cl (−1.67, −0.56), p &lt; 0.0001)], but no statistical difference in dyspnea (MD = −0.66, 95%Cl (−1.35, 0.03), p = 0.06). There was no statistical significance in the incidence of adverse reactions.Conclusion: The performed meta-analysis indicated that TwHF combined with conventional treatment was more beneficial to patients for improving symptoms, lung function and laboratory indicators. As it included studies with relatively small sample size, the findings require confirmation by further rigorously well-designed RCTs.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic diffuse interstitial lung disease, of which the etiology has been poorly understood. Several studies have focused on the relationship between IPF and diabetes mellitus (DM) in the past years but have failed to reach a consensus. This meta-analysis aimed to examine the association between diabetes to IPF.Methods: We accumulated studies investigating the association between DM and IPF from databases including Medline, Cochrane Library, Embase, Web of Science, and China National Knowledge Infrastructure. RevMan 5.3 and the Newcastle-Ottawa Scale (NOS) were utilized to analyze the data and assess the quality of the included studies. The value of odds ratio (OR) with 95% confidence interval (CI) was used as the measure to estimate the risk of DM in IPF. Heterogeneity was assessed by I2 statistics. We also performed subgroup analysis, meta-regression, and Egger’s test for bias analysis. Results: Nine case-control studies with 5,096 IPF patients and 19,095 control subjects were included in the present meta-analysis, which indicated that DM could increase the risk of IPF (OR: 1.65, 95% CI: 1.30-2.10; P < 0.0001). Meta-regression and subgroup analysis negated the influence of covariates like cigarette smoking, age and gender, but the heterogeneity existed and could not be fully explained. Conclusion: The meta-analysis indicated that DM is highly probably related to IPF. Further rigorously designed studies are required to confirm the present findings and investigate the possible mechanisms behind the effect of DM on IPF.

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Background The effects of body mass index (BMI) on mortality of sepsis remain unknown, since previous meta-analyses have reported conflicting results. Several observational studies published recently have provided new evidence. Thus, we performed this updated meta-analysis. Methods PubMed, Embase, Web of Science, and Cochran Library were searched for articles published before February 10, 2023. Observational studies that assessed the association of BMIs with mortality of sepsis patients aged > 18 years were selected. We excluded studies of which data were unavailable for quantitative synthesis. Odds ratios (OR) with 95% confidence interval (CI) were the effect measure, which were combined using fixed-effect or random-effect models. The Newcastle–Ottawa Scale was applied for quality assessment. Subgroups analyses were conducted according to potential confounders. Results Fifteen studies (105,159 patients) were included in the overall analysis, which indicated that overweight and obese BMIs were associated with lower mortality (OR: 0.79, 95% CI 0.70–0.88 and OR: 0.74, 95% CI 0.67–0.82, respectively). The association was not significant in patients aged ≤ 50 years (OR: 0.89, 95% CI 0.68–1.14 and OR: 0.77, 95% CI 0.50–1.18, respectively). In addition, the relationship between morbidly obesity and mortality was not significant (OR: 0.91, 95% CI 0.62–1.32). Conclusions Overweight and obese BMIs (25.0–39.9 kg/m2) are associated with reduced mortality of patients with sepsis or septic shock, although such survival advantage was not found in all crowds. Trial registration The protocol of this study was registered in PROSPERO (registration number CRD42023399559).