Ferroptosis is a necrotic form of regulated cell death (RCD) mediated by phospholipid peroxidation in association with free iron-mediated Fenton reactions. Disrupted iron homeostasis resulting in ...excessive oxidative stress has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we demonstrate the involvement of ferroptosis in COPD pathogenesis. Our in vivo and in vitro models show labile iron accumulation and enhanced lipid peroxidation with concomitant non-apoptotic cell death during cigarette smoke (CS) exposure, which are negatively regulated by GPx4 activity. Treatment with deferoxamine and ferrostatin-1, in addition to GPx4 knockdown, illuminate the role of ferroptosis in CS-treated lung epithelial cells. NCOA4-mediated ferritin selective autophagy (ferritinophagy) is initiated during ferritin degradation in response to CS treatment. CS exposure models, using both GPx4-deficient and overexpressing mice, clarify the pivotal role of GPx4-regulated cell death during COPD. These findings support a role for cigarette smoke-induced ferroptosis in the pathogenesis of COPD.
nCycloparaphenylenes (nCPPs, where n is the number of phenylene groups), consisting of 1,4-linked phenylene unit, have attracted much attention due to their cyclic π-conjugated structures and ...physical properties. However, functionalizing of the benzene rings of smaller nCPPs (n < 7) has been a challenge due to ring strain and steric hindrance of the substituents that hampers their synthesis. Here we show successful synthesis of a new 6CPP derivative with twelve methoxy groups at the 2,5-positions of all benzene rings by utilizing our developed CPP synthesis method via a macrocyclic gold complex. This molecule exhibited a significantly higher oxidation potential caused by the electron-donating ability of the methoxy groups and the tubular molecular conformation, allowing facile oxidation to give dicationic species with in-plane aromaticity. Furthermore, this molecule successfully included with the guest molecules with a flexible alkyl chain in the cavity, enabling the creation of a CPP-based rotaxane, which exploited its mechanically interlocked molecular structure to the first experimental observation that the in-plane aromaticity in the center of the macrocycle.
The diagnosis of pancreatic cystic lesions remains challenging. This study aimed to investigate the diagnostic ability of carcinoembryonic antigen (CEA), cytology, and artificial intelligence (AI) by ...deep learning using cyst fluid in differentiating malignant from benign cystic lesions. We retrospectively reviewed 85 patients who underwent pancreatic cyst fluid analysis of surgical specimens or endoscopic ultrasound-guided fine-needle aspiration specimens. AI using deep learning was used to construct a diagnostic algorithm. CEA, carbohydrate antigen 19-9, carbohydrate antigen 125, amylase in the cyst fluid, sex, cyst location, connection of the pancreatic duct and cyst, type of cyst, and cytology were keyed into the AI algorithm, and the malignant predictive value of the output was calculated. Area under receiver-operating characteristics curves for the diagnostic ability of malignant cystic lesions were 0.719 (CEA), 0.739 (cytology), and 0.966 (AI). In the diagnostic ability of malignant cystic lesions, sensitivity, specificity, and accuracy of AI were 95.7%, 91.9%, and 92.9%, respectively. AI sensitivity was higher than that of CEA (60.9%, p = 0.021) and cytology (47.8%, p = 0.001). AI accuracy was also higher than CEA (71.8%, p < 0.001) and cytology (85.9%, p = 0.210). AI may improve the diagnostic ability in differentiating malignant from benign pancreatic cystic lesions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The barrier function of the small intestinal mucosa prevents the introduction of undesired pathogens into the body. Breakdown of this barrier function increases intestinal permeability. This has been ...proposed to induce not only gastrointestinal diseases, including inflammatory bowel disease and irritable bowel syndrome, but also various other diseases, including allergies, diabetes mellitus, liver diseases, and collagen diseases, which are associated with this so called "leaky gut syndrome." As such, a method to prevent leaky gut syndrome would have substantial clinical value. However, no drugs have been demonstrated to improve disturbed intestinal permeability in humans to date. Therefore, we investigated whether a drug used to treat chronic constipation, lubiprostone, was effective for this purpose.
Healthy male volunteers were treated with lubiprostone (24 μg/day) for 28 days. Intestinal permeability was evaluated by measuring the lactulose-mannitol ratio (LMR) after administration of diclofenac and compared with an untreated group. The examination was conducted three times in total, i.e., at baseline before diclofenac administration and after 14 and 28 days of lubiprostone treatment. Blood endotoxin activity was also evaluated at the same time points.
The final analysis was conducted on 28 subjects (14 in the lubiprostone group and 14 in the untreated group). The LMR after 28 days of treatment was significantly lower in the lubiprostone group than that in the untreated group (0.017 vs. 0.028, respectively; 95% confidence interval, -0.022--0.0001; p = 0.049). Blood endotoxin activity exhibited almost no change over time in the lubiprostone and untreated groups and displayed no significant differences at any time point of examination.
This study is the first to report an improvement in leaky gut using an available drug in humans. The result suggests that lubiprostone may prevent and ameliorate "leaky gut syndrome". However, a pivotal trial is needed to confirm our finding.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The imbalanced redox status in lung has been widely implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. To regulate redox status, hydrogen peroxide must be adequately reduced to water by ...glutathione peroxidases (GPx). Among GPx isoforms, GPx4 is a unique antioxidant enzyme that can directly reduce phospholipid hydroperoxide. Increased lipid peroxidation products have been demonstrated in IPF lungs, suggesting the participation of imbalanced lipid peroxidation in IPF pathogenesis, which can be modulated by GPx4. In this study, we sought to examine the involvement of GPx4-modulated lipid peroxidation in regulating TGF-β-induced myofibroblast differentiation. Bleomycin-induced lung fibrosis development in mouse models with genetic manipulation of GPx4 were examined. Immunohistochemical evaluations for GPx4 and lipid peroxidation were performed in IPF lung tissues. Immunohistochemical evaluations showed reduced GPx4 expression levels accompanied by increased 4-hydroxy-2-nonenal in fibroblastic focus in IPF lungs. TGF-β-induced myofibroblast differentiation was enhanced by GPx4 knockdown with concomitantly enhanced lipid peroxidation and SMAD2/SMAD3 signaling. Heterozygous GPx4-deficient mice showed enhancement of bleomycin-induced lung fibrosis, which was attenuated in GPx4-transgenic mice in association with lipid peroxidation and SMAD signaling. Regulating lipid peroxidation by Trolox showed efficient attenuation of bleomycin-induced lung fibrosis development. These findings suggest that increased lipid peroxidation resulting from reduced GPx4 expression levels may be causally associated with lung fibrosis development through enhanced TGF-β signaling linked to myofibroblast accumulation of fibroblastic focus formation during IPF pathogenesis. It is likely that regulating lipid peroxidation caused by reduced GPx4 can be a promising target for an antifibrotic modality of treatment for IPF.
Background
The treatment of small (≤ 2 cm), sporadic localized non-functional pancreatic neuroendocrine neoplasms (PNENs) is often controversial. This study aimed to investigate the clinical outcomes ...with observation and surgical resection in small PNENs.
Methods
Seventy-five patients with small localized sporadic non-functional PNENs ≤ 2 cm, who underwent observation or surgical resection, were retrospectively reviewed. Changes in tumor size during follow-up in the observation group were also investigated.
Results
The median age of the cohort was 61 (range 35–81) years. The tumor grades were G1, G2, and unknown, in 61 (81.3%), 8 (10.7%), and 6 (8.0%) patients, respectively. The mean follow-up periods in the observation (
n
= 23) and surgical resection groups (
n
= 52) were 52.3 (range 6.8–133.3) months and 73.0 (range 9.1–179.9) months, respectively. The median overall survival was not reached. During follow-up, no patient died of PNENs, two died of other diseases, three had lymph node metastases, and one experienced recurrence after surgical resection. There was no significant difference in overall survival between the observation and surgical resection groups (hazard ratio: 0.031,
P
= 0.417). The mean change in tumor size in the observation group was + 0.30 mm (range − 1.6 to + 3.0 mm). No deaths, tumor progression, lymph node metastases, distant metastases, or recurrence were noted in patients with PNENs ≤ 1 cm (
n
= 36).
Conclusions
The prognosis of small localized PNENs is good. Observation may be an alternative to surgery in high-risk patients and those with small G1 tumors, particularly those measuring ≤ 1 cm.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background/Purpose
Placement of uncovered self‐expandable metallic stents (U‐SEMSs) of patients with unresectable perihilar cholangiocarcinoma (UPHC) is recommended as the treatment of first choice ...to address bile stasis. The aim of this study was to determine which of the following two endoscopic stents might be the stent of first choice for the treatment of biliary stasis in patients with UPHC: plastic stents (PSs) or U‐SEMSs.
Methods
U‐SEMSs, deployed as a stent‐in‐stent, were selected as the stents of first choice from 2013 and 2014, while PSs began to be selected as the stents of first choice from 2015 onward.
Results
The median time to recurrent biliary obstruction were 66 days in the PS group (N = 38) and 105 days in the U‐SEMS group (N = 37; P = .04). Emergency endoscopy was necessitated in 76.3% (29/38) of patients of the PS group and 54.1% (20/37) of patients of the U‐SEMS group (P = .0434). The success rate of the first reintervention was 96.5% (27/29) in the PS group and 55% (11/20) in the U‐SEMS group (P = .0002). Sustainable chemotherapy could be carried out in 55.2% of patients in the PS group and 32.4% of patients in the U‐SEMS group (P = .0472). Multivariate analysis identified selection of U‐SEMS as the stent of first choice as the only independent factor predictive of successful reintervention (P = .0016, odds ratio = 0.058). However, the stent selection was not an independent factor for feasible chemotherapy.
Conclusions
Plastic stent placement could enhance the success rate of reintervention in patients with UPHC and might be facilitated by sustainable chemotherapy. However, stent selection might not have an influence on the prognosis.
Highlight
Placement of uncovered self‐expandable metallic stents is recommended as the treatment of choice in patients with unresectable perihilar cholangiocarcinoma. Iwasaki and colleagues conclude that plastic stent placement could enhance the success rate of reintervention in these patients and might facilitate sustainable chemotherapy. Stent selection, however, may not affect the prognosis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cigarette smoke (CS)-induced mitochondrial damage with increased reactive oxygen species (ROS) production has been implicated in COPD pathogenesis by accelerating senescence. Mitophagy may play a ...pivotal role for removal of CS-induced damaged mitochondria, and the PINK1 (PTEN-induced putative kinase 1)-PARK2 pathway has been proposed as a crucial mechanism for mitophagic degradation. Therefore, we sought to investigate to determine if PINK1-PARK2-mediated mitophagy is involved in the regulation of CS extract (CSE)-induced cell senescence and in COPD pathogenesis. Mitochondrial damage, ROS production, and cell senescence were evaluated in primary human bronchial epithelial cells (HBEC). Mitophagy was assessed in BEAS-2B cells stably expressing EGFP-LC3B, using confocal microscopy to measure colocalization between TOMM20-stained mitochondria and EGFP-LC3B dots as a representation of autophagosome formation. To elucidate the involvement of PINK1 and PARK2 in mitophagy, knockdown and overexpression experiments were performed. PINK1 and PARK2 protein levels in lungs from patients were evaluated by means of lung homogenate and immunohistochemistry. We demonstrated that CSE-induced mitochondrial damage was accompanied by increased ROS production and HBEC senescence. CSE-induced mitophagy was inhibited by PINK1 and PARK2 knockdown, resulting in enhanced mitochondrial ROS production and cellular senescence in HBEC. Evaluation of protein levels demonstrated decreased PARK2 in COPD lungs compared with non-COPD lungs. These results suggest that PINK1-PARK2 pathway-mediated mitophagy plays a key regulatory role in CSE-induced mitochondrial ROS production and cellular senescence in HBEC. Reduced PARK2 expression levels in COPD lung suggest that insufficient mitophagy is a part of the pathogenic sequence of COPD.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Immune checkpoint inhibitors are widely used in clinical practice, and immune-related adverse events (irAE) have been reported. An irAE liver injury, cholangitis, has been reported to occur ...frequently in patients who respond to treatment with immune checkpoint inhibitors. Sclerosing cholangitis is rare, occurring in only 4.5% of patients with liver injury who respond to immune checkpoint inhibitor therapy, and often difficult to diagnose. Ultrasonography shows thickness of the bile duct wall, cholangiography shows no obvious obstruction or stenosis, and cholangioscopy shows erosions and ulcerative changes on the surface of the bile duct. In patients who use immune checkpoint-inhibitors, damage of the biliary system should always be considered as irAE sclerosing cholangitis, and a definitive diagnosis should be made using various imaging studies. Although irAE sclerosing cholangitis is treated using steroids, it is often refractory to treatment and intractable.
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