Ophiopogonin D alleviates acute lung injury by regulating inflammation via the STAT3/A20/ASK1 axis.

BACKGROUND: Acute lung injury (ALI) is characterized by acute pulmonary inflammatory infiltration. Alveolar epithelial cells (AECs) release numerous pro-inflammatory cytokines, which result in the pathological changes seen in ALI. Ophiopogonin D (OD), extracted from the roots of Ophiopogon japonicus (Thunb.) Ker Gawl. (Liliaceae), reduces inflammation; however, the efficacy of OD in ALI has not been reported and the underlying molecular mechanisms remain unclear. PURPOSE: This study investigated the anti-inflammatory effects of OD, as well as the underlying mechanisms, in AECs and a mouse ALI model. METHODS: Lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α) were used to stimulate macrophages and A549 cells, and a mouse ALI model was established by intratracheal LPS administration. The anti-inflammatory effects and mechanisms of OD in the TNF-α-induced in vitro inflammation model was evaluated using real-time quantitative polymerase chain reaction qPCR), enzyme-linked immunosorbent assay (ELISA), western blotting, nuclear and cytoplasmic protein extraction, and immunofluorescence. The in vivo anti-inflammatory activity of OD was evaluated using hematoxylin and eosin staining, qPCR, ELISA, and western blotting. RESULTS: The bronchoalveolar lavage fluid and lung tissue of LPS-induced ALI mice exhibited increased TNF-α expression. TNF-α induced a significantly greater pro-inflammatory effect in AECs than LPS. OD reduced inflammation and mitogen-activated protein kinase (MAPK) and transcription factor p65 phosphorylation in vivo and in vitro and promoted signal transducer and activator of transcription 3 (STAT3) phosphorylation and A20 expression, thereby inducing apoptosis signal-regulating kinase 1 (ASK1) proteasomal degradation. CONCLUSION: OD exerts an anti-inflammatory effect by promoting STAT3-dependent A20 expression and ASK1 degradation. OD may therefore have therapeutic value in treating ALI and other TNF-α-related inflammatory diseases.

Risk factors and prognosis of interstitial lung disease for primary Sjögren syndrome patients: A retrospective case‒control study.

OBJECTIVE: To determine the prevalence, clinical features, risk factors, and prognosis of interstitial lung disease (ILD) in patients with primary Sjogren's syndrome (pSS). METHODS: Data from 274 pSS patients from August 2013 to August 2022 were reviewed. The clinical features of pSS with ILD were revealed. Logistic regression was used to determine risk factors for ILD in pSS patients. Survival analysis and Cox regression were used to analyse the prognosis and prognostic factors of pSS patients. RESULTS: In pSS patients, the prevalence of ILD was 22.3% (61/274). The pSS patients with ILD were characterized by a late onset and long disease course, with a nonspecific interstitial pneumonia (NSIP) pattern as the predominant high-resolution computed tomography (HRCT) finding. Logistic regression results indicated that an age over 50 years old (OR 4.786, 95% CI 1.602-14.299; P = 0.005), purpuric rash (OR 4.695, 95% CI 1.537-14.339; P = 0.007), AMA-M2 antibody positivity (OR 2.582, 95% CI 1.166-5.722; P = 0.019), and diabetes (OR 2.514, 95% CI 1.025-6.167; P = 0.044) were risk factors for ILD in pSS patients. Cox regression results showed that advanced age (HR 1.240, 95% CI 1.088-1.413; P = 0.001) and cancer history (HR 8.411, 95% CI 1.771-39.934; P = 0.007) were risk factors for pSS patient survival. CONCLUSION: This study showed that pSS patients with ILD tended to have a late onset and long course of pSS. An age over 50 years, purpuric rash, AMA-M2 antibody positivity, and diabetes were risk factors for ILD in pSS patients. Advanced age and cancer history were prognostic factors in pSS patients. Key Points • This study showed that pSS patients with ILD tended to have a late-onset and lengthy course of pSS, with the NSIP pattern as the predominant lung image. • The risk factors for ILD in pSS patients determined in this study were an age over 50 years, purpuric rash, AMA-M2 antibody positivity, and diabetes. • The prognostic risk factors for pSS patients were advanced age and cancer history.

Reversal of EGFR inhibitors' resistance by co-delivering EGFR and integrin αvß3 inhibitors with nanoparticles in non-small cell lung cancer.

Purpose: Tumor cells, with drug resistance, are associated with failed treatment and poor prognosis. Our aim was to explore potential strategy to overcome the epidermal growth factor receptor (EGFR) inhibitors resistance in non-small cell lung cancer (NSCLC).Materials and methods: Flow cytometry was used to examine and sort cells. Using MTT assay, we detected the cell viability under different conditions. Using RT-qPCR and Western blot, we determined the targeted gene expression in mRNA and protein levels. The morphology of the prepared nanoparticles was pictured by transmission electron microscopy. We also performed immunohistochemistry (IHC) and immunofluorescence (IF) to detect the proteins expression. Subcutaneous cancer models in nude mice were constructed to evaluate the anti-cancer effects in vivoResults: Here, we observed enhanced expression of integrin αvß3 in tumor tissues from EGFR inhibitors resistant patients. Also, integrin αvß3-positive NSCLC cells revealed significant EGFR inhibitors resistance, resulting from the activation of Galectin-3/KRAS/RalB/TBK1/NF-κB signaling pathway. Co-encapsulating integrin αvß3 inhibitor and EGFR inhibitor further improved the drug delivery system, leading to superior anti-cancer effects and reduced systemic toxicity.Conclusion: Our results demonstrated that co-encapsulation of erlotinib and cilengitide by MPEG-PLA (Erlo+Cilen/PP) nanoparticles revealed enhanced tumor suppression along with reduced organ damages, providing an innovative approach for NSCLC treatment.

Qi-Dong-Huo-Xue-Yin Inhibits Inflammation in Acute Lung Injury in Mice via Toll-Like Receptor 4/Caveolin-1 Signaling.

Acute lung injury (ALI) is a critical illness with no current effective treatment. Caveolin-1 indirectly activates inflammation-associated signaling pathways by inhibiting endothelial nitric oxide synthase (eNOS). This induces an imbalance between pro- and anti-inflammatory cytokine levels, which are involved in the pathogenesis of ALI. The compound Chinese prescription Qi-Dong-Huo-Xue-Yin (QDHXY) is efficacious for ALI treatment via an anti-inflammatory effect; however, the exact underlying mechanism is unknown. Therefore, we explored the protective effect of QDHXY against lipopolysaccharide- (LPS-) induced ALI in mice. Histopathological changes in mouse lung tissues were studied. Furthermore, alterations in the serum levels of pro- and anti-inflammatory cytokines were investigated. The levels of tumor necrosis factor- (TNF-)α, interleukin- (IL-) 6, IL-1ß, and interferon-γ-induced protein 10 in bronchoalveolar lavage fluid were measured. Additionally, the expression levels of myeloid differentiation factor 88 (MyD88), caveolin-1, and eNOS were assessed. QDHXY significantly reduced lung infiltration with inflammatory cells and the production of serum pro- and anti-inflammatory cytokines and inhibited the expression of TNF-α, IL-1ß, caveolin-1, and MyD88 but not eNOS. These indicate that QDHXY significantly improved the balance between pro- and anti-inflammatory cytokine levels, possibly by inhibiting the caveolin-1 signaling pathway. Therefore, QDHXY may be a potential treatment for ALI.

Resveratrol upregulates SOCS1 production by lipopolysaccharide-stimulated RAW264.7 macrophages by inhibiting miR-155.

Resveratrol is a polyphenolic compound extracted from grapes and the Chinese herb, Polygonum cuspidatum. In the present study, in order to elucidate the molecular mechanisms of action of resveratrol in host immune cells, we examined the effects of resveratrol on the inflammatory response in lipopolysaccharide (LPS)­stimulated RAW264.7 murine macrophages. The cells were treated with resveratrol prior to stimulation with LPS (1 µg/ml). Resveratrol downregulated the expression of inflammatory markers, such as tumor necrosis factor (TNF)-α and interleukin (IL)­6, induced by LPS, and inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) and signal transducer and activator of transcription (STAT)1/STAT3. Resveratrol also upregulated the production of suppressor of cytokine signaling 1 (SOCS1; a STAT inhibitor) and suppressed the expression of miR­155, which plays an essential role in the innate and adaptive immune response. Given the elevated levels of SOCS1 in LPS-induced inflammation, our results suggest that resveratrol exerts anti-inflammatory effects due to the upregulation of SOCS1, which is a potential target of miR­155, as well as of miR­155 mimics and inhibitors. These findings suggest the benefits of resveratrol, which are derived from its regulation of SOCS1 expression via the inhibition of miR­155, and indicate that resveratrol may be developed as a useful agent for the treatment of inflammatory diseases.

Anti-inflammatory effect of resveratrol through the suppression of NF-κB and JAK/STAT signaling pathways.

Resveratrol, the most important ingredient extracted from Polygonum cuspidatum, exerts cytoprotective effects via anti-inflammatory actions in vitro. In this study, we investigated this effect of resveratrol on the lipopolysaccharide (LPS)-induced inflammatory response and its underlying molecular mechanism of action in RAW264.7 murine macrophages. Results showed that resveratrol down-regulated the expression of inducible nitric oxide synthase (iNOS) and interleukin-6 (IL-6), therefore, suppressed the production of nitric oxide and the secretion of IL-6 in LPS-stimulated RAW264.7 cells in a dose-dependent manner. Resveratrol also inhibited the translocation of high-mobility group box 1 (HMGB1) from the nucleus to the cytoplasm and of nuclear transcription factor kappa-B (NF-κB) p65 from the cytoplasm to the nucleus; it suppressed the phosphorylation of IκBα. Furthermore, these actions were mediated by suppressing the phosphorylation of signal transducer and activator of transcription (STAT)-1 and -3. In conclusion, these data indicate that resveratrol exerts anti-inflammatory effects, at least in part by reducing the release of HMGB1 and modulating the NF-κB and Janus kinase/STAT signaling pathways. Resveratrol could potentially be developed as a useful agent for the chemoprevention of inflammatory diseases.

Effect of high/low dose N-acetylcysteine on chronic obstructive pulmonary disease: a systematic review and meta-analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and morbidity worldwide, characterised by persistent airflow limitation, mucus hypersecretion, oxidative stress and airway inflammation. N-acetylcysteine (NAC) have anti-oxidant and anti-inflammatory properties, which have been shown an uncertain benefit in COPD patients. METHOD: Systematic searches were conducted in Cochrane, Medline and Embase electronic databases. A meta-analysis was performed to evaluate the different effect between high and low-dose NAC treatment on COPD exacerbation. RESULTS: This review yielded 11 studies. The methodological quality of included studies were scored using the Jadad score, with a scale of 1 to 5 (score of 5 being the highest). Data showed high-dose NAC can reduce both the total number of exacerbations (RR = 0.59, 0.47 to 0.74, 95%CI, p < 0.001) and the proportion of patients with at least one exacerbation (RR = 0.76, 0.59 to 0.98, 95%CI, p = 0.03). In the low-dose group, subgroup with jadad ≤ 3 showed a significant decrease (RR = 0.69, 0.61 to 0.77, 95%CI, p < 0.001) in the proportion of patients with exacerbation, the other subgroup with Jadad score > 3 showed no significant decrease (RR = 0.98, 0.90 to 1.06, 95%CI, p = 0.59). And low-dose NAC showed no benefit in the total number of exacerbations (RR = 0.97, 0.68 to 1.37, 95%CI, p = 0.85). Neither high nor low-dose NAC treatment showed benefit in forced expiratory volume in one second(FEV1)(WMD = 1.08, -9.97 to 12.13, 95%CI, p = 0.85). CONCLUSION: Long-term high-dose NAC treatment may lead to a lower rate of exacerbations. But the effect of low-dose NAC treatment remains uncertain. Further researches are needed to confirm this outcome and to clarify its mechanisms.