Autophagy aggravates multi-walled carbon nanotube-induced ferroptosis by suppressing PGC-1 dependent-mitochondrial biogenesis in lung epithelial cells.

Multi-walled carbon nanotube (MWCNT) induced respiratory toxicity has become a growing concern, with ferroptosis emerging as a novel mechanism implicated in various respiratory diseases. However, whether ferroptosis is involved in MWCNT-elicited lung injury and the underlying molecular mechanisms warrant further exploration. In this study, we found that MWCNT-induced ferroptosis is autophagy-dependent, contributing to its cellular toxicity. Inhibiting of autophagy by pharmacological inhibitors 3-MA or ATG5 gene knockdown significantly attenuated MWCNT-induced ferroptosis, concomitant with rescued mitochondrial biogenesis. Rapamycin, the autophagy agonist, exacerbated the mitochondrial damage and MWCNT-induced ferroptosis. Moreover, lentivirus-mediated overexpression of PGC-1α inhibited ferroptosis, while inhibition of PGC-1α aggravated ferroptosis. In summary, our study unveils ferroptosis as a novel mechanism underlying MWCNT-induced respiratory toxicity, with autophagy promoting MWCNT-induced ferroptosis by hindering PGC-1α-dependent mitochondrial biogenesis.

Alternative splicing of PSMD13 mediated by genetic variants is significantly associated with endometrial cancer risk.

OBJECTIVE: Accumulating evidence has shown that aberrant alternative splicing events are closely associated with the onset and development of cancer. However, whether genetic variants-associated alternative splicing is linked to risk of endometrial cancer remains largely uncertain. METHODS: We identified single nucleotide polymorphisms (SNPs) locates in the splicing number trait locus (sQTL) of endometrial cancer using the CancerSplicing QTL database. In parallel with bioinformatics analysis, we conducted a case-control study comprising 2,000 cases and 2,013 controls to assess the association between identified SNP which possesses mRNA splicing function and endometrial cancer susceptibility. Furthermore, we used the Kaplan-Meier Plotter, The Human Protein Atlas, SPNR, and Spliceman2 databases for sQTL and differential gene expression analyses to identify the genetic variant which most potentially influence the risk of endometrial cancer through alternative splicing to reveal the potential mechanism by which candidate SNPs regulate the risk of endometrial cancer. RESULTS: The results indicated that SNP rs7128029 A

Exposure characteristics of phthalate metabolites among the Zunyi cohort of pregnant women in Southwest China.

Reported evidence has increasingly indicated that exposure to phthalates can cause adverse pregnancy outcomes. However, phthalate exposure levels among pregnant women remains unclear. We aimed to evaluate the concentrations and predictors of phthalate metabolites in urine samples of the ongoing Zunyi cohort of pregnant women from Southwest China. The urine samples were collected from 1003 pregnant women during their third trimester of pregnancy. The concentrations of nine phthalate metabolites in urine samples were then determined. Data on socio-demographic profiles of the participants, lifestyle during pregnancy, parity, and sampling season were collected using questionnaires. The detectable rate of phthalate metabolites ranged from 76 to 100%. On average, mono-butyl phthalate exhibited the highest median concentration (62.45 µg/L), while mono-benzyl phthalate exhibited the lowest median concentration (0.04 µg/L). Urine concentrations of phthalate metabolites were significantly higher in older, multiparous, higher body mass index, higher income, and passive smoking during pregnancy participants. The levels of low-molecular-weight phthalate metabolites were highest during the summer. The findings indicate the health of pregnant women and fetuses in Zunyi may be generally harmed by the high exposure of phthalate metabolites, especially by mono-n-butyl phthalate. In addition, phthalate metabolites present a demographic and seasonal differential distribution among the study population. Targeted measures to reduce phthalate exposure for high-risk pregnant women and during high-exposure seasons may have potential benefits for maternal and fetal health protection.

Insight into the Protective Effect of Salidroside against H2O2-Induced Injury in H9C2 Cells.

Salidroside is the important active ingredient of Rhodiola species, which shows a wide range of pharmacological activities such as antioxidative stress, anti-inflammation, and antiliver fibrosis. In this paper, we aimed to study the protective effect and mechanism of salidroside against H2O2-induced oxidative damage in H9C2 cells by determining cell proliferation rate, intracellular reactive oxygen species (ROS) level, antioxidant enzyme activities, and the expression of apoptosis-related proteins. The results showed that salidroside significantly alleviated cell growth inhibition induced by H2O2 treatment in H9C2 cells, decreased the levels of intracellular ROS and malondialdehyde (MDA), and increased the activity of superoxide dismutase (SOD) and catalase (CAT); meanwhile, salidroside upregulated the expression of Bcl-2 while downregulated the expression of Bax, p53, and caspase-3 in H2O2-treated H9C2 cells. Furthermore, the antiapoptotic effect of salidroside was almost eliminated by the knockdown of Bcl-2. In the further exploration, the Bcl-2 expression was decreased by the p53 overexpression and increased by p53 knockdown in H2O2-treated H9C2 cells. Consequently, salidroside could protect H9C2 cells against H2O2-induced oxidative damage, and the underlying mechanism may be related to scavenging intracellular ROS, increasing the activities of intracellular antioxidant enzymes and inhibiting the expression of apoptosis-related proteins.

An Ensemble Model for Tumor Type Identification and Cancer Origins Classification.

Tissue biopsy can be wildly used in cancer diagnosis. However, manually classifying the cancerous status of biopsies and tissue origin of tumors for cancerous ones requires skilled specialists and sophisticated equipment. As a result, a data-based model is urgently needed. In this paper, we propose a data-based ensemble model for tumor type identification and cancer origins classification. Our model is an ensemble model that combines different models based on mRNA groups which serve distinct functions. The experiment on the TCGA dataset exhibits a promising result on both tasks - 98% on tumor type identification and 96.1% on cancer origin classification. We also test our model on external validation datasets, which prove the robustness of our model.

CD36 in Atherosclerosis: Pathophysiological Mechanisms and Therapeutic Implications.

PURPOSE OF REVIEW: Atherosclerosis is a chronic disease characterized by lipid retention and inflammation in the artery wall. The retention and oxidation of low-density lipoprotein (LDL) in sub-endothelial space play a critical role in atherosclerotic plaque formation and destabilization. Oxidized LDL (ox-LDL) and other modified LDL particles are avidly taken up by endothelial cells, smooth muscle cells, and macrophages mainly through several scavenger receptors, including CD36 which is a class B scavenger receptor and membrane glycoprotein. RECENT FINDINGS: Animal studies performed on CD36-deficient mice suggest that deficiency of CD36 prevents the development of atherosclerosis, though with some debate. CD36 serves as a signaling hub protein at the crossroad of inflammation, lipid metabolism, and fatty acid metabolism. In addition, the level of soluble CD36 (unattached to cells) in the circulating blood was elevated in patients with atherosclerosis and other metabolic disorders. We performed a state-of-the-art review on the structure, ligands, functions, and regulation of CD36 in the context of atherosclerosis by focusing on the pathological role of CD36 in the dysfunction of endothelial cells, smooth muscle cells, monocytes/macrophages, and platelets. Finally, we highlight therapeutic possibilities to target CD36 expression/activity in atherosclerosis.

Prevalence and Associated Factors for Depressive Symptomatology in Chinese Adults During COVID-19 Epidemic.

Background: The coronavirus disease 2019 (COVID-19) has been rapidly transmitted worldwide, which contributed to various psychological problems (such as fear, depression, and anxiety) among the general population in China. The purpose of this study is to investigate the prevalence and associated factors of depressive symptoms among Chinese adults. Methods: A cross-sectional study of Chinese adults was conducted during 17-29 February 2020. Symptoms of depression were assessed using the Center for Epidemiologic Studies Depression scale (CES-D). Results: A total of 3,399 respondents were included in the analysis. It was observed that 14.2% (481/3,399) of the participants were screened positive for depressive symptoms. In a multivariate logistic regression analysis, older age (OR = 0.98; 95% CI, 0.97-0.99), smoking (OR = 1.57; 95% CI, 1.10-2.26), self-rated health (good: OR = 0.49; 95% CI, 0.37-0.66; fairly: OR = 0.60; 95% CI, 0.45-0.80), having greater support scores (OR = 0.95; 95% CI, 0.94-0.96), knowledge about the main symptom of COVID-19 (very clearly: OR = 0.58; 95% CI, 0.42-0.79; relatively clearly: OR = 0.59; 95% CI, 0.44-0.79), and staying in Wuhan within 3 months before the outbreak of epidemic (OR = 1.78; 95% CI, 1.34-2.38) were associated with depressive symptoms. Conclusion: A considerable proportion of the general population in China had depressive symptoms during the COVID-19 epidemic. Routine screening and targeted interventions for depression are needed among high-risk depressed individuals during the COVID-19 epidemic.

Sirtuin 6 inhibits MWCNTs-induced epithelial-mesenchymal transition in human bronchial epithelial cells via inactivating TGF-ß1/Smad2 signaling pathway.

Multi-walled carbon nanotubes (MWCNTs) have been developed with numerous beneficial applications. However, rodent models demonstrate that exposure to MWCNTs via respiratory pathways results in pulmonary fibrosis. Therefore, they could elicit a potential risk of pulmonary fibrosis in humans due to occupational or consumer exposure. Sirtuin 6 (SIRT6), a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, has been proved to prevent fibrosis in the liver, renal and myocardial tissues. In this present study, we aimed to explore the role of SIRT6 in MWCNTs-induced epithelial-mesenchymal transition (EMT), one of the major contributor of lung fibrogenesis in human bronchial epithelial BEAS-2B cells. We found that the protein level of SIRT6 was elevated after exposure to MWCNTs in BEAS-2B cells. Overexpression of SIRT6 significantly inhibited MWCNTs-induced EMT and EMT-like cell behaviors in BEAS-2B cells. Moreover, wild-type SIRT6 was found to decrease MWCNTs-induced phosphorylation of Smad2, but not mutant SIRT6 (H133Y) without histone deacetylase activity. In conclusion, our study demonstrated that SIRT6 inhibited MWCNTs-induced EMT in BEAS-2B cells through TGF-ß1/Smad2 signaling pathway, which depended on its deacetylase activity, and provided evidences that targeting SIRT6 could be a potential novel therapeutic strategy for MWCNTs-induced pulmonary fibrosis.

Sirtuin 6 inhibits myofibroblast differentiation via inactivating transforming growth factor-ß1/Smad2 and nuclear factor-κB signaling pathways in human fetal lung fibroblasts.

Fibroblast-to-myofibroblast differentiation, which is characterized by increased expression of α-smooth muscle actin, is known to be involved in the pathogenesis of idiopathic pulmonary fibrosis. Sirtuin 6 (SIRT6), a member of the sirtuin family, has been proved to inhibit epithelial-to-mesenchymal transition during idiopathic pulmonary fibrosis. However, the function of SIRT6 in lung myofibroblast differentiation is still obscure. Transforming growth factor-ß1 (TGF-ß1) is one of the main factors that can powerfully promote myofibroblast differentiation. In the current study, we aimed to explore the role of SIRT6 in the cellular model of fibroblast-to-myofibroblast differentiation induced by TGF-ß1 using human fetal lung fibroblasts (HFL1). We demonstrated that the SIRT6 protein level is upregulated by TGF-ß1 in HFL1 cells. Overexpression of SIRT6 significantly suppresses TGF-ß1-induced myofibroblast differentiation in HFL1 cells. Mechanistically, SIRT6 decreases phosphorylation and nuclear translocation of Smad2 under TGF-ß1 stimulation. Nevertheless, mutant SIRT6 (H133Y) without histone deacetylase activity fails to inhibit phosphorylation and nuclear translocation of Smad2. Meanwhile, SIRT6 interacts with the nuclear factor-κB (NF-κB) subunit p65 and represses TGF-ß1-induced NF-κB-dependent transcriptional activity, which is also dependent on its deacetylase activity. Overexpression of wild-type SIRT6 but not the H133Y mutant inhibits the expression of NF-κB-dependent genes including interleukin (IL)-1ß, IL-6 and matrix metalloproteinase-9 (MMP-9) induced by TGF-ß1, all of which have been demonstrated to promote myofibroblast differentiation. Collectively, our study reveals that SIRT6 prevents TGF-ß1-induced lung myofibroblast differentiation through inhibiting TGF-ß1/Smad2 and NF-κB signaling pathways.

Sirtuin 6 inhibits epithelial to mesenchymal transition during idiopathic pulmonary fibrosis via inactivating TGF-ß1/Smad3 signaling.

Sirt6 which is implicated in the control of aging, cancer, and metabolism, has been shown to have anti-fibrosis function in heart and liver. However, whether Sirt6 inhibits idiopathic pulmonary fibrosis remains elusive. Epithelial to mesenchymal transition has been found to be involved in the pathogenesis of idiopathic pulmonary fibrosis. In the present study, forced expression of Sirt6 significantly abrogated TGF-ß1-induced epithelial to mesenchymal transition-like phenotype and cell behaviors in A549 cells. Additionally, activation of TGF-ß1/Smad3 signaling pathway and binding of Smad3-Snail1 were ameliorated by overexpression of wild-type Sirt6 but not mutant Sirt6 (H133Y) without histone deacetylase activity. Meanwhile, upregulation of epithelial to mesenchymal transition-related transcription factors by TGF-ß1 were also restored by overexpression of wild-type Sirt6 but not mutant Sirt6. Furthermore, in vivo study showed that lung targeted delivery of Sirt6 using adeno-associated virus injection blunted bleomycin-induced pulmonary epithelial to mesenchymal transition and fibrosis. Overall, our findings unravel that Sirt6 acts as a key modulator in epithelial to mesenchymal transition process, suggesting Sirt6 may be an attractive potential therapeutic target for idiopathic pulmonary fibrosis.

Sirtuin-6 inhibits cardiac fibroblasts differentiation into myofibroblasts via inactivation of nuclear factor κB signaling.

Differentiation of cardiac fibroblasts (CFs) into myofibroblasts represents a key event in cardiac fibrosis that contributes to pathologic cardiac remodeling. However, regulation of this phenotypic transformation remains elusive. Here, we show that sirtuin-6 (SIRT6), a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent histone deacetylase, plays a role in the regulation of myofibroblast differentiation. SIRT6 expression was upregulated under pathologic conditions in angiotensin II (Ang II)-stimulated CFs and in myocardium of rat subjected to abdominal aortic constriction surgery. SIRT6 depletion by RNA interference (small interfering RNA [siRNA]) in CFs resulted in increased cell proliferation and extracellular matrix deposition. Further examination of SIRT6-depleted CFs demonstrated significantly higher expression of α-smooth muscle actin (α-SMA), the classical marker of myofibroblast differentiation, and increased formation of focal adhesions. Notably, SIRT6 depletion further exacerbated Ang II-induced myofibroblast differentiation. Overexpression of SIRT6 restored α-SMA expression in SIRT6-depleted or Ang II-treated CFs. Moreover, SIRT6 depletion induced the DNA binding activity and transcriptional activity of nuclear factor κB (NF-κB). Importantly, using an NF-κB p65 siRNA or pyrrolidine dithiocarbamate, a specific inhibitor of NF-κB activity, reversed the expression of phenotypic markers of myofibroblasts. Our findings unravel a novel role of SIRT6 as a key modulator in the phenotypic conversion of CFs to myofibroblasts.

Tanshinone IIA suppresses cholesterol accumulation in human macrophages: role of heme oxygenase-1.

Accumulation of foam cells in the neointima represents a key event in atherosclerosis. We previously demonstrated that Tanshinone IIA (Tan), a lipophilic bioactive compound extracted from Salvia miltiorrhiza Bunge, inhibits experimental atherogenesis, yet the detailed mechanisms are not fully understood. In this study, we sought to explore the potential effects of Tan on lipid accumulation in macrophage foam cells and the underlying molecular mechanisms. Our data indicate that Tan treatment reduced the content of macrophages, cholesterol accumulation, and the development of atherosclerotic plaque in apolipoprotein E-deficient mice. In human macrophages, Tan ameliorated oxidized low density lipoporotein (oxLDL)-elicited foam cell formation by inhibiting oxLDL uptake and promoting cholesterol efflux. Mechanistically, Tan markedly reduced the expression of scavenger receptor class A and increased the expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 in lipid-laden macrophages via activation of the extracellular signal-regulated kinase (ERK)/nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. Tan treatment induced the phosphorylation and nuclear translocation of Nrf2 and subsequently increased the expression of HO-1, and these effects were abolished by the specific ERK inhibitors, PD98059 and U0126. Moreover, HO-1 small interfering RNA or zinc protoporphyrin (a HO-1 inhibitor) abrogated Tan-mediated suppression of lipid accumulation in macrophages. Our current findings demonstrate that a novel HO-1-dependent mechanism is involved in the regulation of cholesterol balance by Tan.