Relationship between dietary live microbe intake and the prevalence of COPD in adults: a cross-sectional study of NHANES 2013-2018.

OBJECTIVE: To explore the potential association between dietary live microbes and the prevalence of Chronic Obstructive Pulmonary Diseases (COPD). METHODS: In this cross-sectional study, data of 9791 participants aged 20 years or older in this study were collected from the National Health and Nutrition Examination Survey (NHANES) between 2013 and 2018. Participants in this study were classified into three groups according to the Sanders' dietary live microbe classification system: low, medium, and high dietary live microbe groups. COPD was defined by a combination of self-reported physician diagnoses and standardized medical status questionnaires. Logistic regression and subgroup analysis were used to assess whether dietary live microbes were associated with the risk of COPD. RESULTS: Through full adjustment for confounders, participants in the high dietary live microbe group had a low prevalence of COPD in contrast to those in low dietary live microbe group (OR: 0.614, 95% CI: 0.474-0.795, and p < 0.001), but no significant association with COPD was detected in the medium and the low dietary live microbe groups. This inverse relationship between dietary live microbe intake and COPD prevalence was more inclined to occur in smokers, females, participants aged from 40 to 59 years old and non-obese participants. CONCLUSION: A high dietary live microbe intake was associated with a low prevalence of COPD, and this negative correlation was detected especially in smokers, females, participants aged from 40 to 59 years old and non-obese participants.

Association between carotenoids and the prevalence of chronic obstructive pulmonary disease in the United States.

BACKGROUND: Previous studies mainly concentrated on examining the correlation between single carotenoids and Chronic obstructive pulmonary disease (COPD). However, these findings have been inconsistent. OBJECTIVES: This study aimed to evaluate both the individual and overall associations of carotenoids with the prevalence of COPD. METHODS: This study comprised 2,939 participants chosen from the National Health and Nutrition Examination Survey (NHANES) 2017-2018. The logistic regression, quantile-based G-computation regression (qgcomp), and Bayesian kernel machine regression (BKMR) models were employed to explore the association between carotenoids and the prevalence of COPD. Mediation analyses were also conducted to explore the underlying mechanism of carotenoids on COPD. RESULTS: Individuals diagnosed with COPD had significantly lower serum carotenoid concentrations than those without COPD. We found a negative relationship between combined carotenoids and the prevalence of COPD, and lutein and zeaxanthin and alpha cryptoxanthin were identified as the main contributors to this negative association. Moreover, eosinophil acted as a mediator in the relationship between lutein and zeaxanthin, alpha cryptoxanthin, and the prevalence of COPD, with mediating proportions of 2.75 % and 3.67 %. CONCLUSION: A negative association was observed between combined carotenoids and COPD prevalence, with lutein and zeaxanthin, and alpha cryptoxanthin identified as the main contributors. Eosinophils could potentially mediate the association between carotenoids and COPD.

New insights of DsbA-L in the pathogenesis of metabolic diseases.

Metabolic diseases, such as obesity, diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD), are abnormal conditions that result from disturbances of metabolism. With the improvement of living conditions, the morbidity and mortality rates of metabolic diseases are steadily rising, posing a significant threat to human health worldwide. Therefore, identifying novel effective targets for metabolic diseases is crucial. Accumulating evidence has indicated that disulfide bond A oxidoreductase-like protein (DsbA-L) delays the development of metabolic diseases. However, the underlying mechanisms of DsbA-L in metabolic diseases remain unclear. In this review, we will discuss the roles of DsbA-L in the pathogenesis of metabolic diseases, including obesity, diabetes mellitus, and NAFLD, and highlight the potential mechanisms. These findings suggest that DsbA-L might provide a novel therapeutic strategy for metabolic diseases.

Association between manganese exposure in heavy metals mixtures and the prevalence of sarcopenia in US adults from NHANES 2011-2018.

Environmental pollution is identified as an essential risk factor for sarcopenia. However, the effect of manganese (Mn) exposure on the prevalence of sarcopenia is not assessed. Our study investigated the correlation between blood Mn concentration and sarcopenia risk in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018. Three statistical methods were used to assess these correlations. Mediation analysis was performed to explore the role of inflammation in Mn exposure-induced sarcopenia. Of the 4957 individuals enrolled in this study, 398 (8 %) were diagnosed with sarcopenia. We found a positive association between the log10 Mn concentration and the prevalence of sarcopenia in the logistic regression model. Moreover, heavy metals mixtures were positively correlated with the prevalence of sarcopenia, with Mn identified as the main contributor to this association in the weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models. Furthermore, inflammation mediated the relationship between Mn exposure and the prevalence of sarcopenia, explaining 7.29 % of the effect (odds ratio: 0.03, 0.19, P = 0.002). Thus, our study results revealed that excessive Mn exposure is a contributing factor for sarcopenia. More prospective studies are required to examine the association between Mn exposure and the prevalence of sarcopenia.

Association between serum phosphate and in-hospital mortality of patients with AECOPD: A retrospective analysis on eICU database.

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is an important adverse event in the development of chronic obstructive pulmonary disease (COPD). Hyperphosphatemia is associated with higher mortality in patients with multiple diseases. In this study, we aimed to determine the relationship between serum phosphate and the risk of in-hospital mortality in patients with AECOPD. Methods: In the present study, patients with AECOPD were enrolled in the electronic Intensive Care Unit Collaborative Research Database (eICU-CRD), and divided into three groups according to the tertiles of serum phosphate level. The primary outcome measure was all-cause in-hospital mortality. The association between serum phosphate level and in-hospital mortality was investigated using multivariate logistic regression analysis. Moreover, subgroup analysis was performed to explore whether the relationship was consistent among different subgroups. Results: A total of 1199 AECOPD patients were included in this study. Non-survivors had higher serum phosphate levels than survivors. All patients were classified into lowest tertile, median tertile, and highest tertile, respectively. Multivariate logistic regression analysis indicated that serum phosphate was positively associated with in-hospital mortality after adjusting for confounders. Moreover, there was a significant trend across tertiles when serum phosphate level was diverted as a categorical variable. In addition, subgroup analysis demonstrated that serum phosphate was consistently associated with a higher risk of in-hospital mortality in different subgroups. Conclusion: Higher serum phosphate was positively associated with the increased in-hospital mortality in patients with AECOPD. Hyperphosphatemia may be an underlying high-risk factor for in-hospital mortality owing to AECOPD.

Association between ethylene oxide exposure and prevalence of COPD: Evidence from NHANES 2013-2016.

BACKGROUND: Environmental exposures are major risk factors for chronic obstructive pulmonary disease (COPD). Ethylene oxide (EO) is a ubiquitous organic compound and adversely affects human health. However, it remains unknown whether EO exposure increases the risk of COPD. This study aimed to explore the association between EO exposure and the prevalence of COPD. METHODS: In this cross-sectional study, 2243 participants were analyzed from the National Health and Nutrition Examination Survey (NHANES) between 2013 and 2016. Participants were classified into four groups according to quartiles of log10-transformed hemoglobin adducts of EO (HbEO) levels. HbEO levels were measured using the modified Edman reaction and high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). Logistic regression, restricted cubic spline regression model, and subgroup analysis were used to assess whether EO exposure was associated with the risk of COPD. A multivariate linear regression model was used to investigate the correlation between HbEO levels and inflammatory factors. A mediating analysis was conducted to estimate whether inflammatory factors were involved in the effects of HbEO on the prevalence of COPD. RESULTS: Participants with COPD had higher HbEO levels than those without COPD. Log10-transformed HbEO levels were associated with an increased risk of COPD after adjusting for all covariates. [Q4 vs. Q1 in model II: OR = 2.15, 95 % CI: 1.20-3.85, P = 0.010, P for trend = 0.009]. Moreover, a nonlinear J-shaped relationship was observed between HbEO levels and the risk of COPD. Furthermore, HbEO levels were positively correlated with inflammatory cells. In addition, white blood cells and neutrophils mediated the relationship between HbEO and the prevalence of COPD with mediated proportions of 10.37 % and 7.55 %, respectively. CONCLUSION: These findings indicate that EO exposure has a J-shaped association with the risk of COPD. Inflammation is a key mediator involved in the effects of EO exposure on COPD.

SIRT1 as a Potential Therapeutic Target for Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable disease characterized by irreversible airflow obstruction and lung function decline. It is well established that COPD represents a major cause of morbidity and mortality globally. Due to the substantial economic and social burdens associated with COPD, it is necessary to discover new targets and develop novel beneficial therapies. Although the pathogenesis of COPD is complex and remains to be robustly elucidated, numerous studies have shown that oxidative stress, inflammatory responses, cell apoptosis, autophagy, and aging are involved in the pathogenesis of COPD. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase belonging to the silent information regulator 2 (Sir2) family. Multiple studies have indicated that SIRT1 plays an important role in oxidative stress, apoptosis, inflammation, autophagy, and cellular senescence, which contributes to the pathogenesis and development of COPD. This review aimed to discuss the functions and mechanisms of SIRT1 in the progression of COPD and concluded that SIRT1 activation might be a potential therapeutic strategy for COPD.

PRKCD as a potential therapeutic target for chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common respiratory disease characterized by progressive airflow limitation and abnormal lung function due to noxious particles and gases. Although many measures are available, COPD remains one of the leading causes of morbidity and mortality worldwide. Therefore, there is an urgent need to discover novel potential therapeutic targets for COPD. Protein kinase C delta (PRKCD) is a member of thePKCfamily and possesses various biological properties. Recently, PRKCD has been reported to play an important role in the pathogenesis of COPD. However, the mechanisms of PRKCD on COPD are not fully elucidated. AIM: In this review, we will discuss the roles and mechanisms of PRKCD involved in the development of COPD. METHODS: We systematically summarized the studies on the research progress of PRKCD in COPD based on MEDLINE/PubMed databases. CONCLUSIONS: PRKCD contributes to the development of COPD by promoting inflammatory response, apoptosis, mitochondrial dysfunction and MUC5AC hypersecretion. These data provide evidence that PRKCD might be a potential therapeutic target for COPD.

Robotic-assisted thoracic surgery following neoadjuvant chemoimmunotherapy in patients with stage III non-small cell lung cancer: A real-world prospective cohort study.

Objective: Stage III non-small cell lung cancer (NSCLC) is a heterogeneous group of diseases. For this subset of patients, clinical management is still under debate and prognosis remains poor so far. In the present study, we aimed to evaluate the feasibility and safety of robotic-assisted thoracic surgery after neoadjuvant chemoimmunotherapy in stage III NSCLC. Methods: A real-world prospective cohort study was performed in a single-center setting from April 2021 to May 2022. Patients who were diagnosed with resectable or potentially resectable stage IIIA-B NSCLC and received neoadjuvant chemoimmunotherapy followed by robotic-assisted thoracic surgery were enrolled. Pathological response to neoadjuvant chemoimmunotherapy, treatment-related adverse events, and surgical outcomes of these patients were evaluated. Results: A total of 44 patients who underwent robotic-assisted thoracic surgery after three doses of neoadjuvant chemoimmunotherapy were included in this study. Of these, 36 of 44 (81.8%) patients had a major pathological response, and 26 (59.1%) had a pathological complete response based on pathological examination of surgical specimen. Eight patients (18.2%) suffered grade 3 treatment-related adverse events, including neutropenia (n = 4), increased aminotransferases (n = 3), anemia (n = 1), and cutaneous capillary endothelial proliferation (n = 1). Robotic-assisted thoracic surgery was performed subsequently, and R0 resection was achieved in all patients. Only two (4.5%) patients required conversion to thoracotomy. Surgical complications occurred in five (11.4%) patients, including air leak (n = 3), chylothorax (n = 2), and surgical site infection (n = 1). There was no re-surgery or postoperative mortality within 90 days. Conclusion: Robotic-assisted thoracic surgery following neoadjuvant chemoimmunotherapy showed good feasibility and safety in stage III NSCLC. It was not associated with unexpected perioperative morbidity or mortality and may be a promising therapeutic option in stage III NSCLC. These results need further confirmation by more large-scale clinical trials.

Effects of Glycolysis-Related Genes on Prognosis and the Tumor Microenvironment of Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is a common and deadly malignancy worldwide. Current treatment methods for hepatocellular carcinoma have many disadvantages; thus, it is urgent to improve the efficacy of these therapies. Glycolysis is critical in the occurrence and development of tumors. However, survival and prognosis biomarkers related to glycolysis in HCC patients remain to be fully identified. Methods: Glycolysis-related genes (GRGs) were downloaded from "The Molecular Signatures Database" (MSigDB), and the mRNA expression profiles and clinical information of HCC patients were obtained from TCGA. Consensus clustering was performed to classify the HCC patients into two subgroups. We used the least absolute shrinkage and selection operator (LASSO) regression analysis to construct the risk signature model. Kaplan-Meier (K-M) survival analysis was performed to evaluate the prognostic significance of the risk model, and the receiver operating characteristic (ROC) curve analysis was used to evaluate the prediction accuracy. The independent prediction ability of the risk model was validated by univariate and multivariate Cox regression analyses. The differences of immune infiltrates and relevant oncogenic signaling between different risk groups were compared. Finally, biological experiments were performed to explore the functions of screened genes. Results: HCC patients were classified into two subgroups, according to the expression of prognostic-related GRGs. Almost all GRGs categorized in cluster 2 showed upregulated expressions, whereas GRGs in cluster 1 conferred survival advantages. GSEA identified a positive correlation between cluster 2 and the glycolysis process. Ten genes were selected for risk signature construction. Patients were assigned to high-risk and low-risk groups based on the median risk score, and K-M survival analysis indicated that the high-risk group had a shorter survival time. Additionally, the risk gene signature can partially affect immune infiltrates within the HCC microenvironment, and many oncogenic pathways were enriched in the high-risk group, including glycolysis, hypoxia, and DNA repair. Finally, in vitro knockdown of ME1 suppressed proliferation, migration, and invasion of hepatocellular carcinoma cells. Conclusion: In our study, we successfully constructed and verified a novel glycolysis-related risk signature for HCC prognosis prediction, which is meaningful for classifying HCC patients and offers potential targets for the treatment of hepatocellular carcinoma.

Anlotinib plus platinum-etoposide as a first-line treatment for extensive-stage small cell lung cancer: A single-arm trial.

BACKGROUND: Anlotinib as a third-line or beyond therapy for extensive-stage small-cell lung cancer (ES-SCLC) was studied. This single-arm phase II trial was to investigate the value of anlotinib plus platinum-etoposide as first-line treatment in ES SCLC. METHODS: The primary endpoint was progression-free survival (PFS) and objective response rate (ORR). The secondary endpoints included overall survival (OS), disease control rate (DCR), time to progression (TTP), duration of remission (DoR), and safety. The subgroups of preset liver metastasis and brain metastasis were analyzed. RESULTS: In 35 ES-SCLC patients, the median PFS, ORR, DCR, and OS were 8.02 months [95% confidence interval (CI): 6.90-9.66], 85.71% (95% CI: 69.74-95.19), 94.29% (95% CI: 80.84-99.30), and 15.87 months (95% CI: 10.38-18.89), respectively. The median PFS in the liver metastasis and brain metastasis subgroups was 7.33 months (95% CI: 4.76-9.69) and 7.34 months (95% CI: 5.68-9.20), respectively. The most common AEs with grade 3-4 were hand-foot syndrome (17%), granulocytosis (17%), stomatitis (14%), hypertriglyceridemia (11%), hypercholesterolemia (11%), as well as nausea and vomiting (11%), and no grade 5 AEs were recorded. CONCLUSIONS: Anlotinib combined with platinum-etoposide provided an effective and safe therapy for patients with ES-SCLC.

Non-Coding RNA Polymorphisms (rs2910164 and rs1333049) Associated With Prognosis of Lung Cancer Under Platinum-Based Chemotherapy.

Purpose: Lung cancer is the largest cause of cancer deaths in the world. Platinum-based chemotherapy is a foundation of first-line chemotherapy. However, the prognosis of lung cancer treated with platinum-based chemotherapy is still a challenge. Single nucleotide polymorphism of non-coding RNA has the potential to be a biomarker, but its effectiveness has yet to be comprehensively assessed. In this study, we explored the association between polymorphisms of non-coding RNA and prognosis of lung cancer patients receiving platinum-based chemotherapy. Materials and Methods: For 446 lung cancer patients receiving platinum-based chemotherapy, 22 single nucleotide polymorphisms of microRNA and long noncoding RNA were genotyped by MALDI-TOF mass spectrometry. Cox regression analysis, Kaplan-Meier method, and long-rank test have been performed to assess the association of overall and progression-free survival with polymorphisms. Results: In the additive and dominant models, genetic polymorphism of ANRIL rs1333049 (G > C) was significantly associated with progression-free survival. Additive model: CC vs GC vs GG [HR = 0.84, p = 0.021, 95% CI (0.73-0.97)]; Recessive model: CC vs GG + GC [HR = 0.77, p = 0.026, 95% CI (0.61-0.97)]. In the dominant model, compared with the CC genotype patients, lower risk of death [HR = 0.81, p = 0.036, 95% CI (0.66-0.99)] and lower risk of progression [HR = 0.81, p = 0.040, 95% CI (0.67-0.99)] have been observed on the patients with CG or GG genotype in miR-146A rs2910164. Conclusion: Our research demonstrated the potential of using ANRIL rs1333049 (G > C) and miR-146A rs2910164 (C > G) as biomarkers to support the prediction of a better prognosis for lung cancer patients receiving platinum-based chemotherapy.

eIF3a R803K mutation mediates chemotherapy resistance by inducing cellular senescence in small cell lung cancer.

Drug resistance in small cell lung cancer (SCLC) significantly affects the efficacy of chemotherapy treatment. However, due to the lack of tumor tissue samples, especially serial tumor samples during chemotherapy, the mechanism of chemotherapy resistance has not been fully studied. Circulating tumor DNA, which can be obtained in a noninvasive manner, can complement tumor sampling approaches for research in this field. We identified an SCLC patient with acquired drug resistance from 52 SCLC patients for whom follow-up data were available. By comparing somatic mutations in circulating tumor DNA before and after chemotherapy, for the first time, we found that the somatic mutation eIF3A R803K may be related to acquired chemotherapy resistance. Then, the association between the eIF3A R803K mutation and chemotherapy resistance was confirmed by samples from 254 lung cancer patients receiving chemotherapy. We found that the eIF3a R803K mutation weakened the proliferation ability of tumor cells but increased their resistance to chemotherapy. Further studies revealed that the eIF3A R803K mutation promotes cellular senescence. In addition, fisetin showed a synergistic effect with chemotherapy in eIF3A R803K mutant cells. These results suggest that the eIF3A R803K somatic mutation has the potential to predict chemotherapy resistance in SCLC. Moreover, the eIF3A R803K mutation promotes chemotherapy resistance by inducing senescence. Furthermore, a senolytic drug, fisetin, can reverse chemotherapy resistance mediated by the eIF3A R803K mutation.

Exosomal long non-coding RNA SOX2 overlapping transcript enhances the resistance to EGFR-TKIs in non-small cell lung cancer cell line H1975.

Crosstalk between cancer cells and macrophages plays a crucial role in the development of cancer. In this study, our data showed that M1 macrophages attenuate, while M2 macrophages and tumor-associated macrophages enhance the EGFR-TKIs resistance in non-small cell lung cancer (NSCLC) cell line H1975. Next, long non-coding RNA SOX2 overlapping transcript (SOX2-OT) is highly expressed in NSCLC cells-derived exosomes. NSCLC cells-derived exosomes promote macrophages M2 polarization and inhibit M1 polarization through transferring SOX2-OT to macrophages. Subsequently, our results indicated that NSCLC cells-induced M2-polarized macrophages enhance the EGFR-TKIs resistance in H1975 cells. Furthermore, our data revealed that NSCLC cells-derived exosomes inhibit the expression of miR-627-3p, while promote Smads expression in THP-1 cells. SOX2-OT acts as miR-627-3p sponge to facilitate Smad2, Smad3 and Smad4 expression. Finally, our results indicated that NSCLC cells promote macrophages M2 polarization and suppress M1 polarization through targeting miR-627-3p/Smads signaling pathway by transferring exosomes to THP-1 cells. In conclusion, our data revealed that NSCLC cells promote macrophages M2 polarization through transferring exosomal SOX2-OT, thus to enhance its own EGFR-TKIs resistance. Mechanismly, NSCLC cells-derived exosomal SOX2-OT promotes macrophages M2 polarization via promoting Smads by sponging miR-627-3p. Our data provide a novel therapeutic target for EGFR-TKIs resistance in NSCLC.

Neutrophil extracellular traps induced by cigarette smoke contribute to airway inflammation in mice.

Neutrophil extracellular traps (NETs) were initially identified as an important antimicrobial barrier to capture and kill microorganisms. Emerging evidence suggests that NETs play a crucial role in chronic airway inflammation induced by cigarette smoke (CS). However, how NETs form and the mechanisms by which NETs function in CS-related airway diseases are still unclear. To explore NET formation and its potential role in CS-related airway diseases, we first established a CS-induced subacute airway inflammation model in mice and verified NET formation in the airways. Moreover, NETs degradation by aerosolized DNase I treatment significantly inhibited the airway inflammation induced by CS in mice. More importantly, by in vitro experiments, we found that cigarette smoke extract (CSE) induces NET formation in an NADPH oxidase-dependent manner, and that macrophages and human bronchial epithelial cells (HBEs) are important targets for the NETs-induced secretion of inflammatory cytokines. Therefore, NETs may represent a critical link among neutrophils, macrophages and HBEs under chronic inflammation conditions induced by CS.

The role of single strand break repair pathways in cellular responses to camptothecin induced DNA damage.

Efficient DNA repair is critical for cell survival following exposure to DNA topoisomerase I (Top1) inhibitors camptothecin, a nature product from which the common chemotherapeutic drugs irinotecan and topotecan are derived. The camptothecin-derived agents exert their antitumor activities by specifically stabilizing the Top1-DNA covalent complexes (Top1cc) and blocking the DNA religation step. When exposed to these DNA damage agents, tumor cells quickly activate DNA damage response. This allows sufficient time to remove the Top1ccs and prevent tumor cells from apoptosis. Several repair pathways have been implicated in this process. One of the most relevant repair modes is DNA single strand break repair (SSBR) pathway. The expression level or mutagenesis of specific repair factors involved in SSBR pathway may play an indispensable role in individual's capacity of repairing camptothecin induced DNA damage. Therefore, understanding of the tolerance pathways counteracted to camptothecin cytotoxicity is crucial in alleviating chemotherapy resistance. This review focus on the SSBR pathway in repair camptothecin induced DNA damage, aiming to provide insights into the potential molecular determinants of camptothecin chemosensitivity.

Circular RNA screening from EIF3a in lung cancer.

Eukaryotic initiation factor 3 (EIF3) is one of the largest and most complex translation initiation factors, which consists of 13 subunits named eukaryotic translation initiation factor 3 subunit A (EIF3a) to EIF3m. EIF3a is the largest subunit of EIF3. Previous studies suggested that EIF3a is a housekeeping gene, recent results have found that EIF3a is closely related to the tumorigenesis and drug resistance. Circular RNAs (circRNAs) derived from biologically important gene can play an important role in gene regulation. However, the mechanism underlying circRNAs' biological functions is not well understood yet. In this work, we screened 31 EIF3a-derived circRNAs, in which two circEIF3as were identified to be correlated with cisplatin drug sensitivity in lung cancer. Two circEIF3as were found involved in RNA-binding proteins-mediated biological processes and may be related to translational regulation according to bioinformatics analyses. CircEIF3as, the transcriptional initiation factor EIF3a transcribed circRNAs, are associated with both drug sensitivity and translation regulation. These findings mean that they may have a functional synergy effect with EIF3a or be valuable therapeutic targets for treatment like EIF3a. This is the first study that exploits circRNAs screening from EIF3a in lung cancer, our findings provide a novel perspective on the function of EIF3a and circEIF3as in lung cancer.

Melatonin protects against COPD by attenuating apoptosis and endoplasmic reticulum stress via upregulating SIRT1 expression in rats.

The apoptosis of bronchial and alveolar epithelial cells plays a key role in chronic obstructive pulmonary disease (COPD). The endoplasmic reticulum (ER) stress induced by cigarette smoke contributes to apoptosis. Previous studies demonstrated that melatonin prevented the development of COPD. In addition, silent information regulator 1 (SIRT1) had a protective effect against COPD. However, it remains unclear whether SIRT1 is involved in the protection of melatonin against COPD. In this study, 32 male Wistar rats were randomly assigned to 4 groups: Control, COPD, COPD + Mel, and COPD + Mel + EX527. Rats were challenged with cigarette smoke and lipopolysaccharide with or without melatonin or EX527 (a selective inhibitor of SIRT1). The lung histopathology, apoptotic index, as well as the protein expressions of cleaved caspase-3, SIRT1, C/EBP homologous protein, and caspase-12 in the lung tissues were measured. These results demonstrated that melatonin attenuated apoptosis and ER stress in the lung tissues of rats with COPD. In addition, melatonin increased SIRT1 expression in lung tissues of rats with COPD, while inhibition of SIRT1 by EX527 upregulated ER stress and abolished the protective effect of melatonin against apoptosis. In conclusion, these findings suggested that melatonin protected against COPD by attenuating apoptosis and ER stress via upregulating SIRT1 expression in rats.

Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice.

AIMS: The apoptosis and autophagy play an important role in the pathogenesis of sepsis-induced cardiac dysfunction. Previous studies have demonstrated that melatonin protects against cardiac dysfunction during sepsis. In addition, silent information regulator 1 (SIRT1) is a therapeutic target for sepsis-induced myocardial dysfunction. The aims of this study were to investigate whether SIRT1 was involved in melatonin's cardioprotection during sepsis and the mechanisms. MATERIALS AND METHODS: In this study, twenty-four male C57BL/6 mice were randomly assigned to four groups: Control group, LPS group, LPS + Melatonin group and LPS + Melatonin + EX527 group. Mice were treated with lipopolysaccharide for 8 h with or without melatonin or EX527. The cardiac function, myocardial injury biomarkers, cardiac histopathology, cardiomyocyte apoptosis, autophagosome as well as the protein expressions of SIRT1, cleaved caspase-3, LC3-II/LC3-I ratio and p62 in the myocardium were assayed. KEY FINDINGS: The results demonstrated that melatonin significantly improved cardiac function, decreased creatine kinase (CK) and creatine kinase-MB (CK-MB) levels, attenuated myocardial architecture destruction, inhibited cardiomyocyte apoptosis and increased cardiac autophagy as compared with the LPS group. In addition, melatonin significantly increased SIRT1 protein expression in the myocardium of mice with sepsis, while inhibition of SIRT1 by EX527 abolished melatonin's cardioprotection during sepsis. SIGNIFICANCE: In this study, we found that melatonin protected against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice.

Role of reciprocal interaction between autophagy and endoplasmic reticulum stress in apoptosis of human bronchial epithelial cells induced by cigarette smoke extract.

Endoplasmic reticulum stress (ERS)-induced apoptosis of airway epithelial cells plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Furthermore, autophagy is closely related to ERS under apoptosis. Here, this study aimed to investigate the role of the reciprocal interaction between autophagy and ERS in the cigarette smoke extract (CSE)-induced apoptosis of human bronchial epithelial (HBE) cells. Cell apoptosis was detected by flow cytometry analysis. Protein expression was examined by Western blot. The mRNA expression was detected using real-time quantitative reverse transcription PCR (qRT-PCR). The results showed that CSE treatment induced apoptosis, autophagy, and expression of ERS-related proteins in HBE cells. Furthermore, autophagy inhibition by 3-MA significantly decreased protein expression of GRP78, p-PERK, and p-eIF2α and increased CHOP, ATF4, and caspase-4, whereas ERS inhibition by 4-PBA led to autophagy suppression. Moreover, the CSE-induced autophagy was diminished by knockdown of GRP78, PERK, or eIF2α but enhanced by knockdown of ATF4 or CHOP; however, the CSE-induced HBE apoptosis was enhanced by knockdown of GRP78, PERK, or eIF2α but was attenuated by knockdown of ATF4 or CHOP. Additionally, both sodium hydrosulfide (NaHS) and melatonin attenuated the CSE-induced apoptosis, enhanced the CSE-induced autophagy, increased GRP78, p-PERK, and p-eIF2α, and decreased CHOP, ATF4, and caspase-4, via SIRT1/ORP150 pathway. Collectively, this study provided evidence about the role of the reciprocal interaction between autophagy and ERS in CSE-induced apoptosis of HBE cells. © 2018 IUBMB Life, 71(1):66-80, 2019.