Dynamic phase evolution of MoS3 accompanied by organodiselenide mediation enables enhanced performance rechargeable lithium battery.

Considerable efforts have been devoted to Li-S batteries, typically the soluble polysulfides shuttling effect. As a typical transition metal sulfide, MoS2 is a magic bullet for addressing the issues of Li-S batteries, drawing increasing attention. In this study, we introduce amorphous MoS3 as analogous sulfur cathode material and elucidate the dynamic phase evolution in the electrochemical reaction. The metallic 1T phase incorporated 2H phase MoS2 with sulfur vacancies (SVs-1T/2H-MoS2) decomposed from amorphous MoS3 achieves refined mixing with the "newborn" sulfur at the molecular level and supplies continuous conduction pathways and controllable physical confinement. Meanwhile, the in situ-generated SVs-1T/2H-MoS2 allows lithium intercalation in advance at high discharge voltage (≥1.8 V) and enables fast electron transfer. Moreover, aiming at the unbonded sulfur, diphenyl diselenide (PDSe), as a model redox mediator is applied, which can covalently bond sulfur atoms to form conversion-type organoselenosulfides, changing the original redox pathway of "newborn" sulfur in MoS3, and suppressing the polysulfides shuttling effect. It also significantly lowers the activation energy and thus accelerates the sulfur reduction kinetics. Thus, the in situ-formed intercalation-conversion hybrid electrode of SVs-1T/2H-MoS2 and organoselenosulfides realizes enhanced rate capability and superior cycling stability. This work provides a novel concept for designing high-energy-density electrode materials.

Association between postoperative nadir platelet count and postoperative cardiovascular complications following septal myectomy in patients with hypertrophic cardiomyopathy: a retrospective cohort study.

BACKGROUND: Platelet count is associated with cardiovascular risk and mortality in several cardiovascular diseases, but the association of the nadir platelet counts post-septal myectomy with the cardiovascular complication risk in hypertrophic obstructive cardiomyopathy patients remains unclear. METHODS: This retrospective cohort study reviewed all adult patients who underwent septal myectomy at a single tertiary referral center over a 5-year period. Postoperative nadir platelet count was defined as the lowest platelet count in the first 4 postoperative days or until hospital discharge. The composite outcome included cardiovascular death, myocardial infarction, heart failure, malignant arrhythmia, cardiac tamponade, and major bleeding events within 30 days postoperatively. Univariable and multivariable logistic regression and restricted cubic spline models were used to assess the association between postoperative nadir platelet count and the 30-day postoperative cardiovascular complication risk. RESULTS: Among the 113 enrolled patients, 23 (20.4%) developed cardiovascular events within 30 days postoperatively. The incidence of postoperative cardiovascular complications was significantly higher in patients with a nadir platelet count ≤ 99 × 109/L than in those with a nadir platelet count > 99 × 109/L (33.3% vs. 7.1%, crude risk ratio: 4.67, 95% confidence interval: 1.69-12.85, P < 0.001). Multivariable logistic regression revealed that postoperative nadir platelet count was negatively associated with 30-day postoperative cardiovascular complications (adjusted odds ratio: 0.97; 95% confidence interval: 0.95-0.99; P = 0.005) and the association was linear (Pnonlinearity = 0.058) after full adjustment. The association between nadir platelet count and cardiovascular complications within 30 days post-surgery was consistent in all predefined subgroups (Pinteraction > 0.05). CONCLUSION: The postoperative nadir platelet count was significantly associated with the 30-day post-myectomy risk of cardiovascular complications in hypertrophic obstructive cardiomyopathy patients. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov (NCT04275544).

A Fluorous Peptide Amphiphile with Potent Antimicrobial Activity for the Treatment of MRSA-induced Sepsis and Chronic Wound Infection.

The rising prevalence of global antibiotic resistance evokes the urgent need for novel antimicrobial candidates. Cationic lipopeptides have attracted much attention due to their strong antimicrobial activity, broad-spectrum and low resistance tendency. Herein, a library of fluoro-lipopeptide amphiphiles was synthesized by tagging a series of cationic oligopeptides with a fluoroalkyl tail via a disulfide spacer. Among the lipopeptide candidates, R6F bearing six arginine moieties and a fluorous tag shows the highest antibacterial activity, and it exhibits an interesting fluorine effect as compared to the non-fluorinated lipopeptides. The high antibacterial activity of R6F is attributed to its excellent bacterial membrane permeability, which further disrupts the respiratory chain redox stress and cell wall biosynthesis of the bacteria. By co-assembling with lipid nanoparticles, R6F showed high therapeutic efficacy and minimal adverse effects in the treatment of MRSA-induced sepsis and chronic wound infection. This work provides a novel strategy to design highly potent antibacterial peptide amphiphiles for the treatment of drug-resistant bacterial infections.

Differentiation of malignant from benign pleural effusions based on artificial intelligence.

INTRODUCTION: This study aimed to construct artificial intelligence models based on thoracic CT images to perform segmentation and classification of benign pleural effusion (BPE) and malignant pleural effusion (MPE). METHODS: A total of 918 patients with pleural effusion were initially included, with 607 randomly selected cases used as the training cohort and the other 311 as the internal testing cohort; another independent external testing cohort with 362 cases was used. We developed a pleural effusion segmentation model (M1) by combining 3D spatially weighted U-Net with 2D classical U-Net. Then, a classification model (M2) was built to identify BPE and MPE using a CT volume and its 3D pleural effusion mask as inputs. RESULTS: The average Dice similarity coefficient, Jaccard coefficient, precision, sensitivity, Hausdorff distance 95% (HD95) and average surface distance indicators in M1 were 87.6±5.0%, 82.2±6.2%, 99.0±1.0%, 83.0±6.6%, 6.9±3.8 and 1.6±1.1, respectively, which were better than those of the 3D U-Net and 3D spatially weighted U-Net. Regarding M2, the area under the receiver operating characteristic curve, sensitivity and specificity obtained with volume concat masks as input were 0.842 (95% CI 0.801 to 0.878), 89.4% (95% CI 84.4% to 93.2%) and 65.1% (95% CI 57.3% to 72.3%) in the external testing cohort. These performance metrics were significantly improved compared with those for the other input patterns. CONCLUSIONS: We applied a deep learning model to the segmentation of pleural effusions, and the model showed encouraging performance in the differential diagnosis of BPE and MPE.

IL-20 promotes cutaneous inflammation and peripheral itch sensation in atopic dermatitis.

Atopic dermatitis (AD) is a chronic skin disease, which is associated with intense itch, skin barrier dysfunction and eczematous lesions. Aberrant IL-20 expression has been implicated in numerous inflammatory diseases, including psoriasis. However, the role of IL-20 in AD remains unknown. Here, RNA-seq, Q-PCR, and immunocytochemistry were utilized to examine disease-driven changes of IL-20 and its cognate receptor subunits in skin from healthy human subjects, AD patients and murine AD-models. Calcium imaging, knockdown and cytokine array were used to investigate IL-20-evoked responses in keratinocytes and sensory neurons. The murine cheek model and behavioral scoring were employed to evaluate IL-20-elicited sensations in vivo. We found that transcripts and protein of IL-20 were upregulated in skin from human AD and murine AD-like models. Topical MC903 treatment in mice ear enhanced IL-20R1 expression in the trigeminal sensory ganglia, suggesting a lesion-associated and epidermal-driven mechanism for sensitization of sensory IL-20 signaling. IL-20 triggered calcium influx in both keratinocytes and sensory neurons, and promoted their AD-related molecule release and transcription of itch-related genes. In sensory neurons, IL-20 application increased TLR2 transcripts, implicating a link between innate immune response and IL-20. In a murine cheek model of acute itch, intradermal injection IL-20 and IL-13 elicited significant itch-like behavior, though only when co-injected. Our findings provide novel insights into IL-20 function in peripheral (skin-derived) itch and clinically relevant intercellular neuron-epidermal communication, highlighting a role of IL-20 signaling in the pathophysiology of AD, thus forming a new basis for the development of a novel antipruritic strategy via interrupting IL-20 epidermal pathways.

Association of intraoperative cerebral and somatic tissue oxygen saturation with postoperative acute kidney injury in adult patients undergoing multiple valve surgery.

BACKGROUND: The association between tissue oxygenation with postoperative acute kidney injury (AKI) in adult patients undergoing multiple valve surgery has not been specifically studied. METHODS: In this prospective exploratory cohort study, 99 patients were enrolled. The left forehead, the left forearm, the left upper thigh, and the left renal region tissue oxygen saturation using near-infrared spectroscopy were monitored. The association between each threshold and AKI was assessed. The relative and absolute thresholds were < 70%, < 75%, < 80%, < 85%, < 90%, < 95%, and < 100% baseline, and baseline-standard deviation (SD), -1.5 SD, -2 SD, -2.5 SD, and -3 SD. Multivariate logistic regression analysis was adopted to explore the association. RESULTS: AKI occurred in 53 (54%) patients. The absolute value-based SrrO2 thresholds associated with AKI were baseline-3 SD (odds ratio [OR], 4.629; 95% confidence interval [CI], 1.238-17.314; P = 0.023) and baseline-2.5 SD (OR, 2.842; 95% CI, 1.025-7.881; P = 0.045) after adjusting for the potential confounders, those are renal region tissue oxygen saturation of 55% and 60%, but not statistically significant after correcting for multiple testing (corrected P = 0.114 and 0.179, respectively). CONCLUSION: The SrrO2 desaturation, defined as < baseline - 2.5 SD or < baseline - 3 SD, may be associated with AKI. The thresholds need to be verified in future large-scale studies. TRIAL REGISTRATIONS: The study was registered at ClinicalTrials.gov, first trial registration: 26/10/2017, identifier: NCT03323203.

Evaluation of uveitis events in real-world patients receiving immune checkpoint inhibitors based on the FAERS database.

PURPOSE: Immune checkpoint inhibitors (ICIs) have emerged as a novel class of drugs carrying a potential risk of uveitis. Due to the rarity, current knowledge on this safety issue is still incomplete. This study employed the post-marketing surveillance data to comprehensively describe and assess the uveitis events after the use of ICIs. METHODS: Data between 2004 and 2021 were downloaded from the Food and Drug Administration Adverse Event Reporting System (FAERS), and the uveitis events reported for ICIs were identified and included in this study. Clinical details of these reports were collected and analysed. Four data mining methods were utilised to investigate the potential associations between uveitis and different ICI regimens. RESULTS: Overall, 461 uveitis cases after exposure to ICI therapies were reported. Melanoma (58.79%) was revealed as the most common indication for receiving ICIs. The median onset time of uveitis was 41 (interquartile range 18-91) days after ICI initiation. 9.54% of these cases resulted in disability. Data mining results showed 5 ICIs generated positive uveitis signals when used alone. Ipilimumab yielded the most noticeable uveitis signal with the highest reporting odds ratio (ROR = 6.73, 95% two-sided CI = 5.26, 8.60), proportional reporting ratio (PRR = 6.69, χ2=308.52), information component (IC = 2.74, IC025 = 2.14) and empirical Bayes geometric mean (EBGM = 6.66, EBGM05 = 5.42), followed by pembrolizumab, cemiplimab, nivolumab and atezolizumab. When nivolumab, pembrolizumab or atezolizumab was administrated together with ipilimumab, obviously stronger uveitis signal was detected than that for either of them. CONCLUSIONS: This study provided an overview of the clinical features of ICI-related uveitis cases in the FAERS. Data mining results revealed that positive uveitis signals commonly existed within this drug class, but signal strength varied among ICIs. When ICIs were used in a combined way, uveitis signals became obviously stronger. Therefore, early ophthalmic monitoring is important when applying ICIs to patients, especially those with a tendency for uveitis, such as melanoma patients.

Activation of Bulk Li2 S as Cathode Material for Lithium-Sulfur Batteries through Organochalcogenide-Based Redox Mediation Chemistry.

Lithium sulfide (Li2 S) is considered as a promising cathode material for sulfur-based batteries. However, its activation remains to be one of the key challenges against its commercialization. The extraction of Li+ from bulk Li2 S has a high activation energy (Ea ) barrier, which is fundamentally responsible for the initial large overpotential. Herein, a systematic investigation of accelerated bulk Li2 S oxidation reaction kinetics was studied by using organochalcogenide-based redox mediators, in which phenyl ditelluride (PDTe) can significantly reduce the Ea of Li2 S and lower the initial charge potential. Simultaneously, it can alleviate the polysulfides shuttling effect by covalently anchoring the soluble polysulfides and converting them into insoluble lithium phenyl tellusulfides (PhTe-Sx Li, x>1). This alters the redox pathway and accelerates the reaction kinetics of Li2 S cathode. Consequently, the Li||Li2 S-PDTe cell shows excellent rate capability and enhanced cycling stability. The Si||Li2 S-PDTe full cell delivers a considerable capacity of 953.5 mAh g-1 at 0.2 C.

Modulating Coordination of Iron Atom Clusters on N,P,S Triply-Doped Hollow Carbon Support towards Enhanced Electrocatalytic Oxygen Reduction.

Constructing atom-clusters (ACs) with in situ modulation of coordination environment and simultaneously hollowing carbon support are critical yet challenging for improving electrocatalytic efficiency of atomically dispersed catalysts (ADCs). Herein, a general diffusion-controlled strategy based on spatial confining and Kirkendall effect is proposed to construct metallic ACs in N,P,S triply-doped hollow carbon matrix (MACs /NPS-HC, M=Mn, Fe, Co, Ni, Cu). Thereinto, FeACs /NPS-HC with the best catalytic activity for oxygen reduction reaction (ORR) is thoroughly investigated. Unlike the benchmark sample of symmetrical N-surrounded iron single-atoms in N-doped carbon (FeSAs /N-C), FeACs /NPS-HC comprises bi-/tri-atomic Fe centers with engineered S/N coordination. Theoretical calculation reveals that proper Fe gathering and coordination modulation could mildly delocalize the electron distribution and optimize the free energy pathways of ORR. In addition, the triple doping and hollow structure of carbon matrix could further regulate the local environment and allow sufficient exposure of active sites, resulting in more enhanced ORR kinetics on FeACs /NPS-HC. The zinc-air battery assembled with FeACs /NPS-HC as cathodic catalyst exhibits all-round superiority to Pt/C and most Fe-based ADCs. This work provides an exemplary method for establishing atomic-cluster catalysts with engineered S-dominated coordination and hollowed carbon matrix, which paves a new avenue for the fabrication and optimization of advanced ADCs.

Electro-assisted Molecular Assembly Giving Atomic-Scale Catalytic Active-Site Detection.

The artificially accurate design of nonmetal electrocatalysts' active site has been a huge challenge because no pure active species with the specific structure could be strictly controlled by traditional synthetic methods. Species with a multiconfiguration in the catalyst hinder identification of the active site and the subsequent comprehension of the reaction mechanism. We have developed a novel electro-assisted molecular assembly strategy to obtain a pure pentagon ring on perfect graphene avoiding other reconstructed structures. More importantly, the active atom was confirmed by the subtle passivation process as the topmost carbon atom. Recognition of the carbon-defect electrocatalysis reaction mechanism was first downsized to the single-atom scale from the experimental perspective. It is expected that this innovative electro-assisted molecular assembly strategy could be extensively applied in the active structure-controlled synthesis of nonmetal electrocatalysts and verification of the exact active atom.

Intracardiac masses in a giant right atrium: Tumors or thrombus?

The coexist of primary angiosarcoma and thrombosis is a rare clinical entity. A 46-year-old male was presented with multiple right atrial (RA) masses. Two different vascular patterns in these masses were identified by contrast echocardiography. The possibility of coexistence of malignant tumors and thrombus in RA was implicated, which was further confirmed by computed tomography, magnetic resonance imaging, positron emission tomography/computer tomography, and pathologic examination. This case highlights the advantages of contrast echocardiography in the differential diagnosis of cardiac masses.

Therapeutic Nanoparticles from Grape Seed for Modulating Oxidative Stress.

The therapeutic potential of nanomaterials toward oxidative damage relevant diseases has attracted great attentions by offering promising advantages compared with conventional antioxidants. Although different kinds of nanoantioxidants have been well developed, the facile fabrication of robust and efficient nanoscavengers is still met with challenges like the use of toxic and high-cost subunits, the involvement of multistep synthetic process, and redundant purification work. Herein, a direct fabrication strategy toward polyphenol nanoparticles with tunable size, excellent biocompatibility, and reactive oxygen species (ROS) scavenging capacities from grape seed via an enzymatic polymerization method is reported. The resulting nanoparticles can efficiently prevent cell damage from ROS and exert promising in vivo antioxidant therapeutic effects on several oxidative stress-related diseases, including accelerating wound healing, inhibiting ulcerative colitis, and regulating the oxidative stress in dry eye disease. This study can stimulate the development of more kinds of low-cost, safe, and efficient biomass-based antioxidative nanomaterials via similar fabrication methodologies.

Maternal tobacco exposure and health-related quality of life during pregnancy: a national-based study of pregnant women in China.

BACKGROUND: With the increase of the number of smokers, tobacco exposure among pregnant women is becoming more and more common. Pregnant women exposed to first-hand smoke and second-hand smoke are susceptible to physiological and psychological health issues has been proved in previous studies. Nevertheless, there are no enough studies focus on the impact of third-hand smoke during pregnancy. This study aimed to assess and compare health-related quality of life for pregnant women with exposure to first-hand smoke, second-hand smoke, third-hand smoke and non-exposure to tobacco in mainland China. METHODS: National-based cross-sectional study is based on a questionnaire survey which collects information including demographics, smoking behaviors and self-evaluation. All questionnaires were delivered and collected from August to September 2019. EuroQol group's visual analog scale and EuroQoL Five-dimension Questionnaire were used to collect data in mainland China. RESULTS: Totally, 15,682 pregnant women were included in this study, among which non-exposure to smoke were 7564 (48.2%), exposed to first-hand smoke, second-hand smoke and third-hand smoke were 89 (0.6%), 2349 (15.0%), and 5680 (36.2%) respectively. Pregnant women without tobacco exposure had the highest EuroQol group's visual analog scale score (mean value = 85.4[SD = 14.0]), while those with first-hand smoke had the lowest score (mean value = 77.4[SD = 22.2]). Among all five dimensions of EuroQoL Five-dimension Questionnaire, there were significant differences of EQ-index among groups with different tobacco exposure in usual activity and anxiety or depression dimensions (p < 0.001). CONCLUSIONS: Third-hand smoke exposure had close relationship with low health-related quality of life in pregnant women. Moreover, second-hand smoke exposure significantly led more problems on mental dimension of pregnant women.

Bifunctional and Bioreducible Dendrimer Bearing a Fluoroalkyl Tail for Efficient Protein Delivery Both In Vitro and In Vivo.

Rational design of stimuli-responsive polymers for cytosolic protein delivery with robust efficiency is of great importance but remains a challenging task. Here, we reported a bioreducible and amphiphilic dendrimer bearing a fluoroalkyl tail for this purpose. The fluorolipid was conjugated to the focal point of a cysteamine-cored polyamidoamine dendrimer via disulfide bond, while phenylboronic acid moieties were decorated on dendrimer surface for efficient protein binding. The yielding polymer showed high protein binding capability and complex stability and could efficiently release the cargo proteins in a glutathione-responsive manner. The designed polymer was effective in the delivery of various membrane-impermeable proteins into living cells with reserved bioactivities. In addition, the polymer efficiently delivered a toxin protein saporin into 4T1 breast cancer cells and inhibited the tumor growth in vivo after intravenous injection. The developed polymer in this study is a promising vector for the delivery of membrane-impermeable proteins to treat various diseases.

Natural polyphenol assisted delivery of single-strand oligonucleotides by cationic polymers.

Single-strand oligonucleotides provide promising potential as new therapeutics towards various diseases. However, the efficient delivery of oligonucleotide therapeutics is still challenging due to their susceptibility to nuclease degradation and the lack of effective carriers for condensation. In this study, we reported the use of natural polyphenol to facilitate the condensation of single-strand oligonucleotides by cationic polymers. Green tea catechin complexed with single-strand oligonucleotides to form anionic nanoparticles, which were further coated by low molecular weight cationic polymers to increase their cell internalization. The resulting core-shell structured nanoparticles, so-called green nanoparticles (GNPs), showed improved cargo stability, and achieved high efficiency in the delivery of several types of single-strand oligonucleotides including antisense oligonucleotides, anti-miRNA, and DNAzyme. This study provides a facile strategy for the efficient delivery of single-strand oligonucleotides.

Enhanced Antistatic and Self-Heatable Wearable Coating with Self-Tiered Structure Caused by Amphiphilic MXene in Waterborne Polymer.

The antistatic and self-heatable flexible coating is highly desired for next-generation multifunctional clothing. MXene is a promising filler that possesses an excellent conductivity, an efficient photothermal conversion, and an outstanding compatibility with the waterborne polymer. In this study, MXene was integrated with waterborne polyacrylate by a solution-blending method. The polyacrylate/MXene composites display a self-tiered structure, and the composite coated leather possesses a surface resistivity of 7.85 × 109 Ω with 2 wt % loading, satisfying the B-level of the antistatic standard. The polyacrylate/MXene-0.5 wt % shows a higher temperature increase of 46.9 °C than that of pure polyacrylate after being irradiated by a 275 W IR light for 5 min, and the surface temperature of polyacrylate/MXene-0.5 wt % composite coated leather is 5.4 °C higher than that of polyacrylate coated leather after being irradiated by sunlight for 30 min. The tensile strength of the polyacrylate/MXene-1 wt % composite is increased by 28.3% compared with that of pure polyacrylate. All of the results prove its promising application in the multifunctional coating. Moreover, amphiphilic MXene was produced by changing the etching degree, which resulted in a self-tiered structure of the polyacrylate/MXene composite owing to the improved interfacial activity of MXene. The amphiphilic MXene possesses a decreased surface tension and can serve as a stabilizer for a Pickering emulsion, which suggests novel routes for constructing a multifunctional polymer/MXene composite.

Modifiable Factors Associated with Non-Adherence to Secondary Ischaemic Stroke Prevention Strategies.

BACKGROUND: Secondary stroke-prevention strategies proven to reduce stroke recurrence include pharmaceutical agents and lifestyle modifications. AIMS: We aimed to study factors associated with adherence to medications and lifestyle modifications amongst ischaemic stroke and transient ischaemic attack (TIA) patients. METHODS: In a prospective cohort study, we surveyed 200 outpatients attending stroke clinic at a Singaporean tertiary hospital. We determined medication knowledge and lifestyle modification adherence through direct questioning. We also administered the Beliefs About Medicines Questionnaire, Trust in Physician Scale, Patient Health Questionnaire and Hospital Anxiety and Depression Scale. Multivariable logistic regression models were used to identify factors associated with adherence. RESULTS: The rates of adherence to medications, smoking cessation, dietary modification, and exercise were 52.3%, 71.0%, 80.0% and 78.5% respectively. Subjects who lacked medication knowledge (OR=3.47; 95% CI=1.55-7.74) or possessed negative medication beliefs (OR=1.20; 95% CI=0.72-0.96) were less likely to be adherent to medications. TIA as an index event (OR=5.04; 95% CI=1.39-18.32), younger age (OR=1.04; 95% CI=1.01-1.08) and higher income (OR=2.40; 95% CI=1.09-5.25) were also associated with medication non-adherence. There were no associations between adherence to medications and lifestyle modifications. Dietary adherence was independently associated with exercise adherence (OR=17.2; 95% CI=3.21-92.22). CONCLUSIONS: Our findings of suboptimal adherence to medications and lifestyle modifications show that many stroke patients are not benefitting from proven secondary stroke prevention strategies. We identified medication knowledge and medication beliefs as potential target areas for studies to improve medication adherence.

Lead-Free Halide Perovskite Nanocrystals: Crystal Structures, Synthesis, Stabilities, and Optical Properties.

In recent years, there have been rapid advances in the synthesis of lead halide perovskite nanocrystals (NCs) for use in solar cells, light emitting diodes, lasers, and photodetectors. These compounds have a set of intriguing optical, excitonic, and charge transport properties, including outstanding photoluminescence quantum yield (PLQY) and tunable optical band gap. However, the necessary inclusion of lead, a toxic element, raises a critical concern for future commercial development. To address the toxicity issue, intense recent research effort has been devoted to developing lead-free halide perovskite (LFHP) NCs. In this Review, we present a comprehensive overview of currently explored LFHP NCs with an emphasis on their crystal structures, synthesis, optical properties, and environmental stabilities (e.g., UV, heat, and moisture resistance). In addition, strategies for enhancing optical properties and stabilities of LFHP NCs as well as the state-of-the-art applications are discussed. With the perspective of their properties and current challenges, we provide an outlook for future directions in this rapidly evolving field to achieve high-quality LFHP NCs for a broader range of fundamental research and practical applications.

Reactive oxygen and nitrogen species induce cell apoptosis via a mitochondria-dependent pathway in hyperoxia lung injury.

Hyperoxia-induced lung injury limits the application of mechanical ventilation on rescuing the lives of premature infants and seriously ill and respiratory failure patients, and its mechanisms are not completely understood. In this article, we focused on the relationship between hyperoxia-induced lung injury and reactive oxygen species (ROS), reactive nitrogen species (RNS), mitochondria damage, as well as apoptosis in the pulmonary epithelial II cell line RLE-6TN. After exposure to hyperoxia, the cell viability was significantly decreased, accompanied by the increase in ROS, nitric oxide (NO), inflammatory cytokines, and cell death. Furthermore, hyperoxia triggered the loss of mitochondrial membrane potential (▵Ψm), thereby promoting cytochrome c to release from mitochondria to cytoplasm. Further studies conclusively showed that the Bax/Bcl-2 ratio was enlarged to activate the mitochondria-dependent apoptotic pathway after hyperoxia treatment. Intriguingly, the effects of hyperoxia on the level of ROS, NO and inflammation, mitochondrial damage, as well as cell death were reversed by free radical scavengers N-acetylcysteine and hemoglobin. In addition, a hyperoxia model of neonatal Sprague-Dawley (SD) rats presented the obvious characteristics of lung injury, such as a decrease in alveolar numbers, alveolar mass edema, and disorganized pulmonary structure. The effects of hyperoxia on ROS, RNS, inflammatory cytokines, and apoptosis-related proteins in lung injury tissues of neonatal SD rats were similar to that in RLE-6TN cells. In conclusion, mitochondria are a primary target of hyperoxia-induced free radical, whereas ROS and RNS are the key mediators of hyperoxia-induced cell apoptosis via the mitochondria-dependent pathway in RLE-6TN cells.

The three branches of the unfolded protein response exhibit differential significance in breast cancer growth and stemness.

The unfolded protein response (UPR) is widely activated in cancers. The mammalian UPR encompasses three signaling branches, namely inositol-requiring enzyme-1α (IRE1α), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6α (ATF6α). The functional significance of each branch in tumorigenesis is incompletely understood, especially in cancer stem cells (CSCs). Here, we report that inhibition and silencing of the three UPR sensors has differential effects on breast cancer growth and the CSC population. The levels of PERK and ATF6α strongly correlate with the expression of sex determining region Y (SRY)-box 2 (SOX2), a pluripotency regulator, in human breast cancer tissues. UPR activation is also elevated in the CSC-enriched mammospheres. Inhibition of the UPR sensors or excess ER stress markedly reduces the formation and maintenance of mammospheres, suggesting that an appropriate level of UPR activation is critical for the CSC survival. Mechanistically, transcription factors from UPR and pluripotency pathways interact and reciprocally influence each other. A transcription modulator, CCAAT-enhancer-binding protein delta (C/EBPδ), interacts with pluripotency regulator, SOX2, and UPR transcription factors, thus likely serving as a link to coordinate UPR and pluripotency maintenance in CSCs. Our findings demonstrate that UPR is critical for both cancer growth and pluripotency, and highlight the differential role and complexity of the three UPR branches in tumorigenesis.