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Background : Exposure to particulate matter <2.5 μm (PM 2.5 ) is linked to chronic obstructive pulmonary disease (COPD), but most studies lack individual PM 2.5 measurements. Seasonal variation and their impact on clinical outcomes remain understudied. Objective : This study investigated the impact of PM 2.5 concentrations on COPD-related clinical outcomes and their seasonal changes. Methods : A multicentre panel study enrolled 105 COPD patients (age range: 46-82) from July 2019 to August 2020. Their mean forced expiratory volume in 1 second after bronchodilation was 53.9%. Individual PM 2.5 levels were monitored continuously with indoor measurements at residences and outdoor data from the National Ambient Air Quality Monitoring Information System. Clinical parameters, including pulmonary function tests, symptom questionnaires (CAT and SGRQ-C), and impulse oscillometry (IOS), were assessed every three months over the course of one year. Statistical analysis was conducted using a linear mixed-effect model to account for repeated measurements and control for confounding variables, including age, sex, smoking status and socioeconomic status. Results : The mean indoor and outdoor PM 2.5 concentrations were 16.2 ± 8.4 μg m -3 and 17.2 ± 5.0 μg m -3 , respectively. Winter had the highest PM 2.5 concentrations (indoor, 18.8 ± 11.7 μg m 3 ; outdoor, 22.5 ± 5.0 μg m -3 ). Higher PM 2.5 concentrations significantly correlated with poorer St. George's Respiratory Questionnaire for COPD (SGRQ-C) scores and increased acute exacerbations, particularly in winter. Patients of lower socioeconomic status were more vulnerable. Increased PM 2.5 concentrations were also associated with amplified small airway resistance ( R 5- R 20). Conclusions : PM 2.5 concentration changes are positively correlated with poorer SGRQ-C scores and increased acute exacerbations in COPD patients with significant seasonal variations, especially in winter.

Introduction: Ca2+ signaling in fibroblasts would be one of the important mediators of lung fibrosis. This study investigated the relationship between calcium channel blocker usage and the risk of developing interstitial lung disease and idiopathic pulmonary fibrosis., Material and Methods: This cohort study used data from the Korean National Health Screening Cohort spanned from January 1, 2004, to December 31, 2015. The study included 394,142 participants. CCB usage, as a time-dependent variable assessed every two years, was categorized by medication status (ever-users and never-users) and further divided into five groups based on cumulative defined daily dose: <182.5, 182.5-365.0, 365.0-547.5, and ≥547.5. Incidence rates of ILD and IPF among CCB users compared to never-users, analyzed using time-dependent Cox regression models., Results: The incidence rates were 27.7 per 100,000 person-years for ILD and 15.0 per 100,000 person-years for IPF among never-users, compared to 19.5 per 100,000 person-years for ILD and 13.9 per 100,000 person-years for IPF among ever-users. The adjusted hazard ratios (aHRs) were 0.68 [95 % confidence interval (CI), 0.55-0.83] for ILD and 0.69 (95 % CI, 0.54-0.88) for IPF. Increasing categories of CCB usage were significantly associated with a lower risk of ILD [aHRs: 1.23 (95 % CI, 0.97-1.56), 1.20 (0.85-1.71), 0.49 (0.30-0.81), and 0.27(0.19-0.39)] and IPF [aHRs: 1.21 (95 % confidence interval, 0.89-1.64), 1.45 (0.96-2.20), 0.83 (0.52-1.33), and 0.25 (0.16-0.38)], compared to never-users., Conclusions: This study found that individuals using CCBs had a significantly lower risk of interstitial lung disease and idiopathic pulmonary fibrosis compared to never-users in a dose-response manner., Competing Interests: Declaration of competing interest The authors state that they have no conflict of interest., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Autophagy is a crucial intracellular degradation process that provides energy and supports nutrient deprivation adaptation. However, the mechanisms by which these cells detect lipid scarcity and regulate autophagy are poorly understood. In this study, we demonstrate that protein kinase A (PKA)-dependent lipolysis delays autophagy initiation during short-term nutrient deprivation by inhibiting AMP-activated protein kinase (AMPK). Using coherent anti-Stokes Raman spectroscopy, we visualized free fatty acids (FFAs) in vivo and observed that lipolysis-derived FFAs were used before the onset of autophagy. Our data suggest that autophagy is triggered when the supply of FFAs is insufficient to meet energy demands. Furthermore, PKA activation promotes lipolysis and suppresses AMPK-driven autophagy during early fasting. Disruption of this regulatory axis impairs motility and reduces the lifespan of Caenorhabditis elegans during fasting. These findings establish PKA as a critical regulator of catabolic pathways, prioritizing lipolysis over autophagy by modulating AMPK activity to prevent premature autophagic degradation during transient nutrient deprivation., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Despite significant strides in big data technology, extracting information from unstructured clinical data remains a formidable challenge. This study investigated the utility of large language models (LLMs) for extracting clinical data from unstructured radiological reports without additional training. In this retrospective study, 1800 radiologic reports, 600 from each of the three university hospitals, were collected, with seven pulmonary outcomes defined. Three pulmonology-trained specialists discerned the presence or absence of diseases. Data extraction from the reports was executed using Google Gemini Pro 1.0, OpenAI's GPT-3.5, and GPT-4. The gold standard was predicated on agreement between at least two pulmonologists. This study evaluated the performance of the three LLMs in diagnosing seven pulmonary diseases (active tuberculosis, emphysema, interstitial lung disease, lung cancer, pleural effusion, pneumonia, and pulmonary edema) utilizing chest radiography and computed tomography scans. All models exhibited high accuracy (0.85-1.00) for most conditions. GPT-4 consistently outperformed its counterparts, demonstrating a sensitivity of 0.71-1.00; specificity of 0.89-1.00; and accuracy of 0.89 and 0.99 across both modalities, thus underscoring its superior capability in interpreting radiological reports. Notably, the accuracy of pleural effusion and emphysema on chest radiographs and pulmonary edema on chest computed tomography scans reached 0.99. The proficiency of LLMs, particularly GPT-4, in accurately classifying unstructured radiological data hints at their potential as alternatives to the traditional manual chart reviews conducted by clinicians., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Park et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study investigated the correlation between the individual chemical constituents of particulate matter 2.5 μm (PM 2.5 ) and respiratory parameters as well as the living environment and daily behaviors in patients with chronic obstructive pulmonary disease (COPD). Data were obtained from prospective COPD panel conducted in South Korea. Following collection via a microPEM, 18 metallic elements were determined using energy-dispersive X-ray fluorescence spectroscopy. All participants completed detailed questionnaires on living environments and lifestyle practices. Eighty-nine stable COPD patients (mean age 68.1 years; 94.4% male) were analyzed. Several constituents (titanium, aluminum, bromine, and silicone) were significantly associated with respiratory outcomes. Copper and manganese concentrations were significantly associated with the living environment. Increased ventilation time and air purifier operation were associated with lower concentrations of copper, silicone, barium, and titanium. These findings suggest varying relationships between PM 2.5 constituents and clinical parameters in COPD patients, providing a basis for personalized interventions and future research.

Background: Exposure to noxious particles, including cigarette smoke and fine particulate matter (PM 2.5 ), is a risk factor for chronic obstructive pulmonary disease (COPD) and promotes inflammation and cell death in the lungs. We investigated the combined effects of cigarette smoking and PM 2.5 exposure in patients with COPD, mice, and human bronchial epithelial cells., Methods: The relationship between PM 2.5 exposure and clinical parameters was investigated in patients with COPD based on smoking status. Alveolar destruction, inflammatory cell infiltration, and pro-inflammatory cytokines were monitored in the smoking-exposed emphysema mouse model. To investigate the mechanisms, cell viability and death and pyroptosis-related changes in BEAS-2B cells were assessed following the exposure to cigarette smoke extract (CSE) and PM 2.5 ., Results: High levels of ambient PM 2.5 were more strongly associated with high Saint George's respiratory questionnaire specific for COPD (SGRQ-C) scores in currently smoking patients with COPD. Combined exposure to cigarette smoke and PM 2.5 increased mean linear intercept and TUNEL-positive cells in lung tissue, which was associated with increased inflammatory cell infiltration and inflammatory cytokine release in mice. Exposure to a combination of CSE and PM 2.5 reduced cell viability and upregulated NLRP3, caspase-1, IL-1β, and IL-18 transcription in BEAS-2B cells. NLRP3 silencing with siRNA reduced pyroptosis and restored cell viability., Conclusions: PM 2.5 aggravates smoking-induced airway inflammation and cell death via pyroptosis. Clinically, PM 2.5 deteriorates quality of life and may worsen prognosis in currently smoking patients with COPD., (© 2024. The Author(s).)

Background: Endobronchial valve (EBV) therapy, a validated method for bronchoscopic lung volume reduction (BLVR) in severe emphysema, has been explored for persistent air-leak (PAL) management. However, its effectiveness and safety in the Asian population require further real-world evaluation. In this study, we assessed the outcomes of treatment with EBV within this demographic., Methods: We conducted a retrospective analysis of medical records from 11 Korean centers. For the emphysema cohort, inclusion criteria were patients diagnosed with emphysema who underwent bronchoscopy intended for BLVR. We assessed these patients for clinical outcomes of chronic obstructive pulmonary disease. All patients with PAL who underwent treatment with EBV were included. We identified the underlying causes of PAL and evaluated clinical outcomes after the procedure., Results: The severe emphysema cohort comprised 192 patients with an average age of 70.3 years, and 95.8% of them were men. Ultimately, 137 underwent treatment with EBV. Three months after the procedure, the BLVR group demonstrated a significant improvement in forced expiratory volume in 1 s (+160 mL vs. +30 mL; P = 0.009). Radiographic evidence of lung volume reduction 6 months after BLVR was significantly associated with improved survival (adjusted hazard ratio 0.020; 95% confidence interval 0.038-0.650; P = 0.010). Although pneumothorax was more common in the BLVR group (18.9% vs. 3.8%; P = 0.018), death was higher in the no-BLVR group (38.5% vs. 54.5%, P = 0.001), whereas other adverse events were comparable between the groups. Within the subset of 18 patients with PAL, the predominant causes of air-leak included spontaneous secondary pneumothorax (44.0%), parapneumonic effusion/empyema (22.2%), and post-lung resection surgery (16.7%). Following the treatment, the majority (77.8%) successfully had their chest tubes removed. Post-procedural complications were minimal, with two incidences of hemoptysis and one of empyema, all of which were effectively managed., Conclusions: Treatment with EBV provides substantial clinical benefits in the management of emphysema and PAL in the Asian population, suggesting a favorable outcome for this therapeutic approach., (© 2024. The Author(s).)

Stellera chamaejasme L. (SCL) is a perennial herb with demonstrated bioactivities against inflammation and metabolic dysfunction. Adipocyte differentiation is a critical regulator of metabolic homeostasis and a promising target for the treatment of metabolic diseases, so we examined the effects of SCL on adipogenesis. A methanol extract of SCL dose-dependently suppressed intracellular lipid accumulation in adipocyte precursors cultured under differentiation induction conditions and reduced expression of the adipogenic transcription factors PPARγ and C/EBPα as well as the downstream lipogenic genes fatty acid binding protein 4, adiponectin, fatty acid synthase, and stearoyl-CoA desaturase. The extract also promoted precursor cell proliferation and altered expression of the cell cycle regulators cyclin-dependent kinase 4, cyclin E, and cyclin D1. In addition, SCL extract stimulated extracellular signal-regulated kinase (ERK) phosphorylation, while pharmacological inhibition of ERK effectively blocked the inhibitory effects of SCL extract on preadipocyte differentiation. These results suggest that SCL extract contains bioactive compounds that can suppress adipogenesis through modulation of the ERK pathway., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yeon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In mammals, brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) execute sequential thermogenesis to maintain body temperature during cold stimuli. BAT rapidly generates heat through brown adipocyte activation, and further iWAT gradually stimulates beige fat cell differentiation upon prolonged cold challenges. However, fat depot-specific regulatory mechanisms for thermogenic activation of two fat depots are poorly understood. Here, we demonstrate that E3 ubiquitin ligase RNF20 orchestrates adipose thermogenesis with BAT- and iWAT-specific substrates. Upon cold stimuli, BAT RNF20 is rapidly downregulated, resulting in GABPα protein elevation by controlling protein stability, which stimulates thermogenic gene expression. Accordingly, BAT-specific Rnf20 suppression potentiates BAT thermogenic activity via GABPα upregulation. Moreover, upon prolonged cold stimuli, iWAT RNF20 is gradually upregulated to promote de novo beige adipogenesis. Mechanistically, iWAT RNF20 mediates NCoR1 protein degradation, rather than GABPα, to activate PPARγ. Together, current findings propose fat depot-specific regulatory mechanisms for temporal activation of adipose thermogenesis., (© 2024. The Author(s).)

Adipose tissue invariant natural killer T (iNKT) cells are a crucial cell type for adipose tissue homeostasis in obese animals. However, heterogeneity of adipose iNKT cells and their function in adipocyte turnover are not thoroughly understood. Here, we investigate transcriptional heterogeneity in adipose iNKT cells and their hierarchy using single-cell RNA sequencing in lean and obese mice. We report that distinct subpopulations of adipose iNKT cells modulate adipose tissue homeostasis through adipocyte death and birth. We identify KLRG1 + iNKT cells as a unique iNKT cell subpopulation in adipose tissue. Adoptive transfer experiments showed that KLRG1 + iNKT cells are selectively generated within adipose tissue microenvironment and differentiate into a CX3CR1 + cytotoxic subpopulation in obese mice. In addition, CX3CR1 + iNKT cells specifically kill enlarged and inflamed adipocytes and recruit macrophages through CCL5. Furthermore, adipose iNKT17 cells have the potential to secrete AREG, and AREG is involved in stimulating adipose stem cell proliferation. Collectively, our data suggest that each adipose iNKT cell subpopulation plays key roles in the control of adipocyte turnover via interaction with adipocytes, adipose stem cells, and macrophages in adipose tissue., (© 2023. The Author(s).)

Background: Recent studies have suggested that combination therapy with pirfenidone and nintedanib is safe and tolerable in patients with idiopathic pulmonary fibrosis (IPF). However, data from real-world practice are limited. Thus, we aimed to investigate the safety and efficacy of this combination therapy in patients with IPF in a real-world setting. Methods: A multicenter retrospective cohort study was conducted to investigate the safety and efficacy of combination therapy with pirfenidone and nintedanib in 45 patients with IPF. Incidences of adverse events and rates of lung function decline were compared before and after the combination therapy. Propensity score matching was performed to compare the outcomes between the combination and monotherapy groups. Results: The mean age of the patients was 68.8 years, and 82.2% of them were male. The median follow-up duration after combination therapy was 12.1 months. The majority of the patients (97.8%) received nintedanib as an add-on to pirfenidone. The most common adverse events after the combination therapy were diarrhea and anorexia. Pirfenidone or nintedanib was stopped in 12 patients owing to gastrointestinal AEs, lung transplantation, or financial problems. In patients with serial lung function data, the rate of decline in the forced vital capacity was significantly reduced after the combination therapy. In the matched analysis, the combination group had a higher incidence of diarrhea than the monotherapy group without an increase in serious adverse events; however, the two groups had similar changes in forced vital capacity (FVC). Conclusion: The combination of pirfenidone and nintedanib in patients with IPF has the potential to reduce the rate of FVC decline. However, in the matched analysis, FVC decline was comparable between the patients on combination therapy and those on monotherapy. The incidence of certain adverse events, particularly diarrhea, was higher with combination therapy, but serious adverse events were similar between the groups., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Huh, Lee and Song.)

Background: Nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity is common; however, many patients do not receive an accurate diagnosis and are using unnecessary alternative drugs or have medication restrictions., Objective: To establish a protocol for provocation tests that can be performed safely and effectively at home to give patients an accurate diagnosis, whereas also delabeling NSAID hypersensitivity., Methods: We retrospectively analyzed the medical records of 147 patients with NSAID hypersensitivity. All patients had NSAID-induced urticaria/angioedema with less than 10% body surface area skin involvement. One specialist developed the protocol through history taking and chart review. If NSAID hypersensitivity was confirmed, an oral provocation test was performed to confirm the safe alternative medications (group A). If it was undetermined, an oral provocation test was performed to confirm the diagnosis and alternative medications (group B). All oral provocation tests were performed by patients in their homes according to the protocol., Results: Approximately 26% of group A patients had urticaria or angioedema symptoms with alternative drugs, whereas the remaining 74% was safe. In group B, 34% of the patients were diagnosed with having NSAID hypersensitivity. However, 61% did not respond to the culprit drug; therefore, NSAID hypersensitivity had been misdiagnosed. During this at-home self-provocation test, no severe hypersensitivity reactions occurred., Conclusion: Many patients originally suspected of having NSAID hypersensitivity were confirmed to have been misdiagnosed. We successfully conducted an effective and safe at-home self-provocation test., (Copyright © 2023. Published by Elsevier Inc.)

Particulate matter (PM) is a major air pollutant that has led to global health concerns and can cause and exacerbate chronic obstructive pulmonary disease (COPD). We asked patients with COPD to complete a detailed questionnaire about their lifestyle practices to reduce PM 2.5 exposure and analyzed the relationship between ambient PM 2.5 concentrations and lifestyle practices. We prospectively enrolled 104 COPD patients from four hospitals in different areas of Korea. They completed detailed questionnaires twice (at enrollment and the end of the study) and Internet of Things-based sensors were installed in their homes to continuously measure PM 2.5 for 1 year. The relationship between PM 2.5 concentrations, lifestyle practices, and COPD exacerbations were analyzed in each season. The PM 2.5 concentration was higher outdoors than indoors in all seasons except summer, and the difference was largest in winter. The six lifestyle practices that significantly lowered the annual indoor PM 2.5 concentration compared with the outdoors. The higher the economic status and educational level of patients, the lower the indoor PM 2.5 concentration. Some lifestyle practices were associated with reduced small airway resistance, presented as R5-R20 determined by impulse oscillometry, and scores of the St. George's Respiratory Questionnaire. Some lifestyle practices are associated with reduced indoor PM 2.5 concentrations and can even affect clinical outcomes, including small airway resistance and quality of life of COPD patients., (© 2023. The Author(s).)

Cough is one of the most common symptoms of acute coronavirus disease 2019, but cough may persist for weeks or months. This study aimed to examine the clinical characteristics of patients with post-coronavirus disease (COVID) persistent cough in the Omicron era. We conducted a pooled analysis comparing 3 different groups: 1) a prospective cohort of post-COVID cough (> 3 weeks; n = 55), 2) a retrospective cohort of post-COVID cough (> 3 weeks; n = 66), and 3) a prospective cohort of non-COVID chronic cough (CC) (> 8 weeks; n = 100). Cough and health status was assessed using patient-reported outcomes (PROs). Outcomes, including PROs and systemic symptoms, were longitudinally evaluated in the prospective post-COVID cough registry participants receiving usual care. A total of 121 patients with post-COVID cough and 100 with non-COVID CC were studied. Baseline cough-specific PRO scores did not significantly differ between post-COVID cough and non-COVID CC groups. There were no significant differences in chest imaging abnormality or lung function between groups. However, the proportions of patients with fractional exhaled nitric oxide (FeNO) ≥ 25 ppb were 44.7% in those with post-COVID cough and 22.7% in those with non-COVID CC, which were significantly different. In longitudinal assessment of the post-COVID registry (n = 43), cough-specific PROs, such as cough severity or Leicester Cough Questionnaire (LCQ) scores, significantly improved between visits 1 and 2 (visit interval: median 35 [interquartile range, IQR: 23-58] days). In the LCQ score, 83.3% of the patients showed improvement (change ≥ +1.3), but 7.1% had worsened (≤ -1.3). The number of systemic symptoms was median 4 (IQR: 2-7) at visit 1 but decreased to median 2 (IQR: 0-4) at visit 2. In summary, post-COVID persistent cough was similar in overall clinical characteristics to CC. Current cough guideline-based approaches may be effective in most patients with post-COVID cough. Measurement of FeNO levels may also be useful for cough management., Competing Interests: W.-J.S. declares grants from Merck Sharp & Dohme Corp. and AstraZeneca, consulting fees from Merck, AstraZeneca, Shionogi and GSK, and lecture fees from Merck, AstraZeneca, GSK and Novartis. Other authors declare that they have no competing interests., (Copyright © 2023 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

In mammals, brown adipose tissue (BAT) is specialized to conduct non-shivering thermogenesis for survival under cold acclimation. Although emerging evidence suggests that lipid metabolites are essential for heat generation in cold-activated BAT, the underlying mechanisms of lipid uptake in BAT have not been thoroughly understood. Here, we show that very-low-density lipoprotein (VLDL) uptaken by VLDL receptor (VLDLR) plays important roles in thermogenic execution in BAT. Compared with wild-type mice, VLDLR knockout mice exhibit impaired thermogenic features. Mechanistically, VLDLR-mediated VLDL uptake provides energy sources for mitochondrial oxidation via lysosomal processing, subsequently enhancing thermogenic activity in brown adipocytes. Moreover, the VLDL-VLDLR axis potentiates peroxisome proliferator activated receptor (PPAR)β/δ activity with thermogenic gene expression in BAT. Accordingly, VLDL-induced thermogenic capacity is attenuated in brown-adipocyte-specific PPARβ/δ knockout mice. Collectively, these data suggest that the VLDL-VLDLR axis in brown adipocytes is a key factor for thermogenic execution during cold exposure., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Legionella species are important causative organisms of severe pneumonia. However, data are limited on predictors of progression to severe Legionella pneumonia (LP). Therefore, the risk factors for LP progression from non-severe to the severe form were investigated in the present study., Methods: This was a retrospective cohort study that included adult LP patients admitted to a 2,700-bed referral center between January 2005 and December 2019., Results: A total of 155 patients were identified during the study period; 58 patients (37.4%) initially presented with severe pneumonia and 97 (62.6%) patients with non-severe pneumonia. Among the 97 patients, 28 (28.9%) developed severe pneumonia during hospitalization and 69 patients (71.1%) recovered without progression to severe pneumonia. Multivariate logistic regression analysis showed platelet count ≤150,000/mm3 (odds ratio [OR], 2.923; 95% confidence interval [CI], 1.100-8.105; P=0.034) and delayed antibiotic treatment >1 day (OR, 3.092; 95% CI, 1.167-8.727; P=0.026) were significant independent factors associated with progression to severe pneumonia., Conclusions: A low platelet count and delayed antibiotic treatment were significantly associated with the progression of non-severe LP to severe LP.

Background: The development of non-caseating epithelioid cell granulomas in cancer patients who do not fulfill the systemic sarcoidosis criteria is termed sarcoid-like reaction (SLR). Little is known about this condition's natural course and impact on the prognosis of malignancy. We aimed to investigate the natural course and prognostic value of cancer-associated SLR., Methods: Clinical data were retrospectively analyzed in 32 patients with biopsy-proven cancer-associated SLR. Among patients with non-small cell lung cancer (NSCLC), SLR cases ( n = 8) were matched with non-SLR cases ( n = 78) for survival analysis., Results: Among the included patients, the mean age was 59.7 years, and 68.8% were female. The median follow-up period was 35.6 months [interquartile range (IQR): 14.0-61.4 months]. Of all the included malignancies ( n = 32), breast cancer (25.0%) and NSCLC (25.0%) were the most common, with stage I being the most frequent tumor stage (59.4%). During follow-up, SLR progression to overt sarcoidosis was not observed. In the 28 patients with available follow-up computed tomography images (median interval: 24.9 months; IQR: 14.4-41.7), 4 patients received corticosteroids ( n = 4), resulting to a decrease of SLR lesions. Meanwhile, among those who did not receive treatment ( n = 24), the extent of SLR decreased or did not change in 85.7% of them, whereas 3.6% had increased SLR extent. Furthermore, among patients with NSCLC, SLR was not associated with overall survival [hazard ratio (HR) = 1.28, 95% confidence interval (CI): 0.02-67.71, P = 0.882] and recurrence of malignancy (HR = 1.27, 95% CI 0.21-7.51, P = 0.793) in the Cox proportional hazard regression model., Conclusions: During the follow-up of cancer-related SLR, we found no further evidence for systemic sarcoidosis, and most of the lesions decreased or did not change. Development of SLR was also not associated with overall survival or disease-free survival in patients with NSCLC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huh, Moon and Song.)

Excessive hepatic glucose production (HGP) is a key factor promoting hyperglycemia in diabetes. Hepatic cryptochrome 1 (CRY1) plays an important role in maintaining glucose homeostasis by suppressing forkhead box O1 (FOXO1)-mediated HGP. Although downregulation of hepatic CRY1 appears to be associated with increased HGP, the mechanism(s) by which hepatic CRY1 dysregulation confers hyperglycemia in subjects with diabetes is largely unknown. In this study, we demonstrate that a reduction in hepatic CRY1 protein is stimulated by elevated E3 ligase F-box and leucine-rich repeat protein 3 (FBXL3)-dependent proteasomal degradation in diabetic mice. In addition, we found that GSK3β-induced CRY1 phosphorylation potentiates FBXL3-dependent CRY1 degradation in the liver. Accordingly, in diabetic mice, GSK3β inhibitors effectively decreased HGP by facilitating the effect of CRY1-mediated FOXO1 degradation on glucose metabolism. Collectively, these data suggest that tight regulation of hepatic CRY1 protein stability is crucial for maintaining systemic glucose homeostasis., (© 2022 by the American Diabetes Association.)

Foreign body aspiration can produce a medical emergency. Obstruction of the airways can be life-threatening, and complications may develop in less-severe cases if it is left untreated. Although it is more prevalent in children by approximately three times, adults can still experience it, and it is more frequently related to healthcare in adults. Objects used in dental treatment are usually placed in the oral cavity and can be ingested or inhaled by accident. Dental treatment has been identified as an important cause of the misplacement of foreign bodies in the airway. However, few reports have been published on dentistry-related foreign body aspiration. This paper discusses the disease course, management, and clinical outcomes of foreign body aspiration, especially those associated with dentistry. The patient must be examined for respiratory distress. If the patient is unstable, urgent airway management and the maneuvers for removal should be performed. Radiographs and computed tomography can help identify and locate the object. The treatment of choice is often bronchoscopy, and both flexible and rigid endoscopes can be used depending on the situation. Preventive measures need to be implemented to avoid inhalation accidents given the potential consequences. Though the incidence is rare, healthcare levels need to be enhanced to avert morbidity and mortality. Radiological evaluation and bronchoscopy are vital for management., Competing Interests: CONFLICT OF INTEREST: The author has no conflicts of interest., (Copyright © 2022 Journal of Dental Anesthesia and Pain Medicine.)

Skin antiseptics have important implications for public health and medicine. Although conventional antiseptics have considerable antimicrobial activity, skin toxicity and the development of resistance are common problems. Plasma-treated water has sterilization and tissue-regenerative effects. Therefore, the aim of this study was to identify whether plasma-activated water (PAW) manufactured by our microwave plasma system can be used as a novel antiseptic solution for skin protection. PAW was produced by dissolving reactive nitrogen oxide gas using microwave plasma in deionized water. The antibacterial effects of PAW against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Bacillus cereus, and Salmonella typhimurium and effective concentrations were investigated by a solid agar plate assay. The factors mediating the effects of PAW were evaluated by the addition of reactive species scavengers. Cytotoxicity and cell viability assays were performed to examine the protective effect of PAW on normal skin cells. PAW exhibited excellent sterilization and no toxicity in normal skin cells. Experiments also confirmed the potential of PAW as a sanitizer for SARS-CoV-2. Our findings support the use of PAW as an effective skin disinfectant with good safety in the current situation of a global pandemic., (© 2022. The Author(s).)

The comparative effectiveness of different inhaler therapies in mild-to-moderate asthma remains unclear. To assess this, we performed a systematic review and network meta-analysis of randomized controlled trials on the use of inhalers for mild-to-moderate asthma by searching PubMed, Cochrane, and Embase. A total of 29 trials including 43,515 patients and 12 types of inhaler therapies were included. For the prevention of severe and moderate-to-severe exacerbations, inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) as maintenance and reliever (SMART) showed the highest rank for effectiveness. As-needed ICS/LABA or short-acting β2-agonist (SABA) was similar to low-dose ICS and superior to as-needed SABA or LABA for the prevention of severe and moderate-severe exacerbations. As for lung function (FEV 1 ), low-dose ICS/LABA had the highest rank; as-needed ICS/LABA was inferior to regular low-dose ICS but superior to placebo. Higher-dose ICS had a superior effect on the Asthma Control Questionnaire (ACQ) scores, and as-needed ICS/LABA and as-needed SABA or LABA had lower ranks in p-rankogram than did the regular use of low-dose ICS. As-needed ICS with LABA or SABA was more effective than a similar dose of regular ICS for preventing exacerbation in mild-to-moderate asthma. As-needed ICS showed some weakness in improving lung function and controlling asthma symptoms., (© 2022. The Author(s).)

In mammals, white adipose tissues are largely divided into visceral epididymal adipose tissue (EAT) and subcutaneous inguinal adipose tissue (IAT) with distinct metabolic properties. Although emerging evidence suggests that subpopulations of adipose stem cells (ASCs) would be important to explain fat depot differences, ASCs of two fat depots have not been comparatively investigated. Here, we characterized heterogeneous ASCs and examined the effects of intrinsic and tissue micro-environmental factors on distinct ASC features. We demonstrated that ASC subpopulations in EAT and IAT exhibited different molecular features with three adipogenic stages. ASC transplantation experiments revealed that intrinsic ASC features primarily determined their adipogenic potential. Upon obesogenic stimuli, EAT-specific SDC1 + ASCs promoted fibrotic remodeling, whereas IAT-specific CXCL14 + ASCs suppressed macrophage infiltration. Moreover, IAT-specific BST2 high ASCs exhibited a high potential to become beige adipocytes. Collectively, our data broaden the understanding of ASCs with new insights into the origin of white fat depot differences., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Rationale: Chronic obstructive lung disease (COPD) is a chronic progressive disease. Although smoking is the most important risk factor, 30% of patients with COPD are never-smokers, and environmental agents are also influential. The effects of air pollutants and meteorological factors on COPD exacerbations have not been studied extensively. Objectives: We aimed to investigate the air pollutants and meteorological factors that impact the incidence of COPD exacerbations. Methods: We obtained clinical data of COPD exacerbation cases from The National Health Insurance Service and merged it with 24-hour average values of air pollutants and meteorological factors from national databases. Patients who reside in eight metropolitan cities, where observatory stations are densely located, were selected for analysis. Results: In 1,404,505 patients with COPD between 2013 and 2018, 15,282 COPD exacerbations leading to hospitalization or emergency room visits were identified. Among the various air pollutants and meteorological factors, particulate matter ⩽2.5 μm in aerodynamic diameter (PM 2.5 ), particulate matter ⩽10 μm in aerodynamic diameter (PM 10 ), NO 2 , SO 2 , CO, O 3 , average temperature, and diurnal temperature range (DTR) were associated with COPD exacerbations. Generalized additive mode model analysis with cubic splines showed an inverted U-shaped relationship with PM 2.5 , PM 10 , CO, NO 2 , SO 2 , O 3 , DTR, and humidity, whereas it displayed a U-shaped pattern with the average temperature. Distinct patterns were found from 2015-2016 to 2017-2018. Conclusions: PM 2.5 , PM 10 , CO, NO 2 , O 3 , SO 2 , average temperature, humidity, and DTR affected the incidence of COPD exacerbations in various patterns, up to 10 lag days.

Introduction: Chronic obstructive pulmonary disease (COPD) is commonly affected by particulate matter (PM) exposure. In this study, we aimed to evaluate whether behavioral interventions to reduce PM exposure improve clinical outcomes in patients with COPD., Methods: A multicenter randomized controlled trial will be conducted involving 120 participants recruited from 3 hospitals in the capital region of the Republic of Korea. Patients aged 40 to 80 years with a diagnosis of COPD and a forced expiratory volume at 1 s <80% of the predicted value are eligible for inclusion. The participants will be randomized to either the intervention group or the usual care group (2:1). The behavioral interventions will comprise the following activities: checking air quality forecast; operating indoor air cleaners and regular check-ups of filters; ventilating the home regularly by opening windows; adhering to inhaler treatment; and refraining from going out on high air pollution days. "Internet-of-things"-based, gravimetric, and light-scattering methods will be used to measure indoor and outdoor PM concentrations. To estimate the degree of individual PM exposure, a time-activity diary and land use regression modeling will be used. The efficacy of the behavioral interventions on the following outcomes will be analyzed: amount of PM exposure, changes in forced expiratory volume at 1 s from the baseline, changes in respiratory symptoms and quality of life, risks of exacerbation, hospitalization, and death., Discussion: Given the harmful effect of air pollutants, individual-level interventions to reduce exposure may be significant. However, there is a lack of evidence on how effective such interventions are to date. This study will be able to provide physicians and patients with evidence-based strategies to reduce PM exposure in daily life., Trial Registration Number: NCT04878367., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Adipose tissue dysfunction is a hallmark of obesity and contributes to obesity-related sequelae such as metabolic complications and insulin resistance. Compelling evidence indicates that adipose-tissue-specific gene expression is influenced by gene interactions with proximal and distal cis-regulatory elements; the latter exert regulatory effects via three-dimensional (3D) chromosome conformation. Recent advances in determining the regulatory mechanisms reveal that compromised epigenomes are molecularly interlinked to altered cis-regulatory element activity and chromosome architecture in the adipose tissue. This review summarizes the roles of epigenomic components, particularly DNA methylation, in transcriptional rewiring in adipose tissue. In addition, we discuss the emerging roles of DNA methylation in the maintenance of 3D chromosome conformation and its pathophysiological significance concerning adipose tissue function., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is strongly associated with obesity-related ectopic fat accumulation in the liver. Hepatic lipid accumulation encompasses a histological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma. Given that dysregulated hepatic lipid metabolism may be an onset factor in NAFLD, understanding how hepatic lipid metabolism is modulated in healthy subjects and which steps are dysregulated in NAFLD subjects is crucial to identify effective therapeutic targets. Additionally, hepatic inflammation is involved in chronic hepatocyte damage during NAFLD progression. As a key immune signaling hub that mediates NF-κB activation, the IκB kinase (IKK) complex, including IKKα, IKKβ, and IKKγ (NEMO), has been studied as a crucial regulator of the hepatic inflammatory response and hepatocyte survival. Notably, TANK-binding kinase 1 (TBK1), an IKK-related kinase, has recently been revealed as a potential link between hepatic inflammation and energy metabolism. Here, we review (1) the biochemical steps of hepatic lipid metabolism; (2) dysregulated lipid metabolism in obesity and NAFLD; and (3) the roles of IKKs and TBK1 in obesity and NAFLD., (© 2021. The Author(s).)

Macrophage proinflammatory activation is an important etiologic component of the development of insulin resistance and metabolic dysfunction in obesity. However, the underlying mechanisms are not clearly understood. Here, we demonstrate that a mitochondrial inner membrane protein, adenine nucleotide translocase 2 (ANT2), mediates proinflammatory activation of adipose tissue macrophages (ATMs) in obesity. Ant2 expression was increased in ATMs of obese mice compared with lean mice. Myeloid-specific ANT2-knockout (ANT2-MKO) mice showed decreased adipose tissue inflammation and improved insulin sensitivity and glucose tolerance in HFD/obesity. At the molecular level, we found that ANT2 mediates free fatty acid-induced mitochondrial permeability transition, leading to increased mitochondrial reactive oxygen species production and damage. In turn, this increased HIF-1α expression and NF-κB activation, leading to proinflammatory macrophage activation. Our results provide a previously unknown mechanism for how obesity induces proinflammatory activation of macrophages with propagation of low-grade chronic inflammation (metaflammation).

White adipose tissue (WAT) is a key regulator of systemic energy metabolism, and impaired WAT plasticity characterized by enlargement of preexisting adipocytes associates with WAT dysfunction, obesity, and metabolic complications. However, the mechanisms that retain proper adipose tissue plasticity required for metabolic fitness are unclear. Here, we comprehensively showed that adipocyte-specific DNA methylation, manifested in enhancers and CTCF sites, directs distal enhancer-mediated transcriptomic features required to conserve metabolic functions of white adipocytes. Particularly, genetic ablation of adipocyte Dnmt1, the major methylation writer, led to increased adiposity characterized by increased adipocyte hypertrophy along with reduced expansion of adipocyte precursors (APs). These effects of Dnmt1 deficiency provoked systemic hyperlipidemia and impaired energy metabolism both in lean and obese mice. Mechanistically, Dnmt1 deficiency abrogated mitochondrial bioenergetics by inhibiting mitochondrial fission and promoted aberrant lipid metabolism in adipocytes, rendering adipocyte hypertrophy and WAT dysfunction. Dnmt1-dependent DNA methylation prevented aberrant CTCF binding and, in turn, sustained the proper chromosome architecture to permit interactions between enhancer and dynamin-1-like protein gene Dnm1l (Drp1) in adipocytes. Also, adipose DNMT1 expression inversely correlated with adiposity and markers of metabolic health but positively correlated with AP-specific markers in obese human subjects. Thus, these findings support strategies utilizing Dnmt1 action on mitochondrial bioenergetics in adipocytes to combat obesity and related metabolic pathology., Competing Interests: The authors declare no competing interest.

Accumulating evidence reveals that adipose tissue is an immunologically active organ that exerts multiple impacts on the regulation of systemic energy metabolism. Adipose tissue immunity is modulated by the interactions between adipocytes and various immune cells. Nevertheless, the underlying mechanisms that control inter-cellular interactions between adipocytes and immune cells in adipose tissue have not been thoroughly elucidated. Recently, it has been demonstrated that adipocytes utilize lipid metabolites as a key mediator to initiate and mediate diverse adipose tissue immune responses. Adipocytes present lipid antigens and secrete lipid metabolites to determine adipose immune tones. In addition, the interactions between adipocytes and adipose immune cells are engaged in the control of adipocyte fate and functions upon metabolic stimuli. In this review, we discuss an integrated view of how adipocytes communicate with adipose immune cells using lipid metabolites. Also, we briefly discuss the newly discovered roles of adipose stem cells in the regulation of adipose tissue immunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Park, Sohn, Han, Park, Huh, Choe and Kim.)

Hepatic TANK (TRAF family member associated NFκB activator)-binding kinase 1 (TBK1) activity is increased during obesity, and administration of a TBK1 inhibitor reduces fatty liver. Surprisingly, liver-specific TBK1 knockout in mice produces fatty liver by reducing fatty acid oxidation. TBK1 functions as a scaffolding protein to localize acyl-CoA synthetase long-chain family member 1 (ACSL1) to mitochondria, which generates acyl-CoAs that are channeled for β-oxidation. TBK1 is induced during fasting and maintained in the unphosphorylated, inactive state, enabling its high affinity binding to ACSL1 in mitochondria. In TBK1-deficient liver, ACSL1 is shifted to the endoplasmic reticulum to promote fatty acid re-esterification in lieu of oxidation in response to fasting, which accelerates hepatic lipid accumulation. The impaired fatty acid oxidation in TBK1-deficient hepatocytes is rescued by the expression of kinase-dead TBK1. Thus, TBK1 operates as a rheostat to direct the fate of fatty acids in hepatocytes, supporting oxidation when inactive during fasting and promoting re-esterification when activated during obesity., Competing Interests: Declaration of Interests A.R.S. is a founder of Elgia Therapeutics and named inventor on several patent applications that include amlexanox. The other authors declare that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Numerous reports have elucidated that TiO 2 nanoparticles (TiO 2 -NPs) exhibit respectable photocatalytic degradation capacities due to their high specific surface areas. However, the current recovery process leads to a loss of TiO 2 -NPs; therefore, there is a need to immobilize TiO 2 -NPs on the substrate used. Herein, TiO 2 -coated yttria-stabilized zirconia/silica nanofiber (TiO 2 -coated YSZ/silica NF) was prepared by coating TiO 2 on the surface of YSZ/silica NF using a sol-gel process. The TiO 2 coating layer on the nanofiber surface improved the separation ability of the membrane as well as the photocatalytic degradation ability. The pore size of the TiO 2 -coated YSZ/silica NF membrane was less than that of the pristine YSZ/silica NF membrane, and it rejected over 99.6% of the 0.5 μm polymeric particles. In addition, the TiO 2 -coated YSZ/silica NF membrane showed excellent adsorption/degradation of humic acid (HA, 88.2%), methylene blue (MB, 92.4%), and tetracycline (TC, 99.5%). Six recycling tests were performed to evaluate the reusability of the TiO 2 -coated YSZ/silica NF membrane. The adsorption/degradation efficiency for HA, MB, and TC decreased by 3.7%, 2.8%, and 2.2%, respectively. We thus verified the high separation ability, excellent photocatalytic degradation ability, and excellent reusability of the TiO 2 -coated YSZ/silica NF membranes.

Background and Purpose: Chopsticks are a primary eating utensil in East Asia, but systematic assessments of chopsticks skills in parkinsonian disorders is lacking. We aimed to identify any differences in chopsticks skills in the early stages of Parkinson's disease (PD) and atypical parkinsonism (AP), including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal syndrome (CBS)., Methods: We consecutively recruited 111 patients with PD and 74 with AP (40 with PSP, 30 with MSA, and 4 with CBS) who were in a drug-naïve state. The motor and cognitive functions of the patients were evaluated using a standardized protocol. Everyday chopsticks skills were evaluated using a chopsticks questionnaire developed in-house. The chopsticks skills test (CST) involved counting the number of pills that the subject was able to carry using chopsticks between two dishes separated by 20 cm within 20 seconds., Results: Patient responses to the questionnaire indicating poor chopsticks skills ("I cannot pick up some of the food items" or "I cannot use chopsticks anymore") were present in 23.0% of AP patients and 30% of PSP patients, compared to only 5.6% of PD patients [odd ratio (OR)=5.07 and OR=7.29, p ≤0.001 in both]. The performance in the CST was worse in PSP than in PD ( p <0.001). The CST results were correlated with hand motor skills including in the coinrotation test, timed figure-tapping test, and motor Unified Parkinson's Disease Rating Scale scores in all of the patient groups ( p <0.001). In PSP, a decline in visuospatial function and frontal executive function was associated with a poor performance in the CST in addition to poor motor performance ( p <0.05)., Conclusions: Impairments in chopsticks skills were more common in PSP than in PD during the early stages of parkinsonism. This suggests that early functional impairment of chopsticks skills can be used as a warning sign for PSP., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2020 Korean Neurological Association.)

In obesity, adipose tissue undergoes dynamic remodeling processes such as adipocyte hypertrophy, hypoxia, immune responses, and adipocyte death. However, whether and how invariant natural killer T (iNKT) cells contribute to adipose tissue remodeling are elusive. In this study, we demonstrate that iNKT cells remove unhealthy adipocytes and stimulate the differentiation of healthy adipocytes. In obese adipose tissue, iNKT cells were abundantly found nearby dead adipocytes. FasL-positive adipose iNKT cells exerted cytotoxic effects to eliminate hypertrophic and pro-inflammatory Fas-positive adipocytes. Furthermore, in vivo adipocyte-lineage tracing mice model showed that activation of iNKT cells by alpha-galactosylceramide promoted adipocyte turnover, eventually leading to potentiation of the insulin-dependent glucose uptake ability in adipose tissue. Collectively, our data propose a novel role of adipose iNKT cells in the regulation of adipocyte turnover in obesity., (© 2019 Park et al.; Published by Cold Spring Harbor Laboratory Press.)

Decreased adipose tissue oxygen tension and increased HIF-1α expression can trigger adipose tissue inflammation and dysfunction in obesity. Our current understanding of obesity-associated decreased adipose tissue oxygen tension is mainly focused on changes in oxygen supply and angiogenesis. Here, we demonstrate that increased adipocyte O 2 demand, mediated by ANT2 activity, is the dominant cause of adipocyte hypoxia. Deletion of adipocyte Ant2 improves obesity-induced intracellular adipocyte hypoxia by decreasing obesity-induced adipocyte oxygen demand, without effects on mitochondrial number or mass, or oligomycin-sensitive respiration. This led to decreased adipose tissue HIF-1α expression and inflammation with improved glucose tolerance and insulin resistance in both a preventative or therapeutic setting. Our results suggest that ANT2 may be a target for the development of insulin sensitizing drugs and that ANT2 inhibition might have clinical utility., Competing Interests: Authors have no competing interest to declare.

In this paper, it is first reported that gray hydrogenated TiO 2 sphere photocatalysts (H-TiO 2 ) with high reactivity to solar light are mass produced within a few minutes using an underwater discharge plasma modified sol-gel method at room temperature and atmospheric pressure. This plasma modified system is an easy one-step in-situ synthetic process and the crystallinity, hydrogenation, and spherical structure of H-TiO 2 are achieved by the synergy effect between the continuous reaction of highly energetic atomic and molecular species generated from the underwater plasma and surface tension of water. The resultant H-TiO 2 demonstrated high anatase/rutile bicrystallinity and extended optical absorption spectrum from the ultraviolet (UV) to visible range. Furthermore, various defects including oxygen vacancies and hydroxyl species on the TiO 2 surface permitted the enhancement of the photocatalytic performance. It was demonstrated that H-TiO 2 photocatalysts showed significant degradation efficiencies for reactive black 5 (RB 5), rhodamine B (Rho B), and phenol (Ph) under solar light irradiation, up to approximately 5 times higher than that of commercial anatase TiO 2 (C-TiO 2 ), which resulted in good water purification. Notably, it was also possible to cultivate HepG2 cells using such well-purified water (to degrees up to 76%), with minimal cytotoxicity. Considering all these results, we believe that this novel plasma technology is promising for important environmental applications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Adipose tissue is a metabolic organ that plays a central role in controlling systemic energy homeostasis. Compelling evidence indicates that immune system is closely linked to healthy physiologic functions and pathologic dysfunction of adipose tissue. In obesity, the accumulation of pro-inflammatory responses in adipose tissue subsequently leads to dysfunction of adipose tissue as well as whole body energy homeostasis. Simultaneously, adipose tissue also activates anti-inflammatory responses in an effort to reduce the unfavorable effects of pro-inflammation. Notably, the interplay between adipocytes and resident invariant natural killer T (iNKT) cells is a major component of defensive mechanisms of adipose tissue. iNKT cells are leukocytes that recognize lipids loaded on CD1d as antigens, whereas most other immune cells are activated by peptide antigens. In adipose tissue, adipocytes directly interact with iNKT cells by presenting lipid antigens and stimulate iNKT cell activation to alleviate pro-inflammation. In this review, we provide an overview of the molecular and cellular determinants of obesity-induced adipose tissue inflammation. Specifically, we focus on the roles of iNKT cell-adipocyte interaction in maintaining adipose tissue homeostasis as well as the consequent modulation in systemic energy metabolism. We also briefly discuss future research directions regarding the interplay between adipocytes and adipose iNKT cells in adipose tissue inflammation.

Obesity-induced adipose tissue inflammation is regulated by various immune cells for innate and adaptive immunity. Among adipose tissue immune cells, it has been proposed that invariant Natural Killer T (iNKT) cells play crucial roles in anti-inflammatory responses in obesity. iNKT cells recognize 'lipid' antigens loaded on CD1d of antigen presenting cells and modulate immune responses by secreting Th1 or Th2 type cytokines depending on species of lipid antigens, antigen presenting cell types, and environmental cytokine milieu. However, the regulatory mechanisms of antigen presenting cells for adipose iNKT cell stimulation have not been clearly elucidated. Recently, we have reported that CD1d expressing adipocytes could act as an antigen presenting cell for adipose iNKT cells by characterization of adipocyte-specific CD1d knockout (CD1d ADKO ) mice. Upon high-fat diet (HFD) feeding, CD1d ADKO mice aggravated adipose tissue inflammation and insulin resistance compared with CD1d f/f mice. In this commentary, we provide the additional data of adipocyte CD1d-dependent regulation of adipose iNKT cell responses as well as systemic insulin sensitivity. In addition, we discuss how the interaction between adipocytes and iNKT cells would be regulated with the progression of obesity.

Competing Interests: Authors' Disclosures of Potential Conflicts of Interest: No potential conflicts of interest relevant to this article were reported.

Background: The steep rise in thyroid cancer observed in recent decades has caused an increase in the population of long-term thyroid cancer survivors. Other than recurrences of cancer, the long-term health consequences of surviving thyroid cancer, particularly metabolic syndrome, have not yet been determined. The aim of this study was to estimate the risk of metabolic syndrome in thyroid cancer survivors., Materials and Methods: Population-based data from the Korean National Health and Nutrition Examination Survey (KNHANES) were used for the analysis. The data of KNHANES IV-VI from 2007-2014 were obtained. After excluding subjects who were under 19 years old, whose fasting interval was less than 8 hours, and whose data for predefined variables including metabolic syndrome components were incomplete, 34,347 subjects were analyzed. The incidence of metabolic syndrome and its components were evaluated in three groups: subjects with no history of thyroid cancer, subjects diagnosed with thyroid cancer within 3 years of the survey date, and subjects diagnosed more than 3 years before the survey date., Results: Thyroid cancer diagnoses were made within 3 years of the survey date for 95 subjects (group 1, short-term survivors) and more than 3 years earlier than the survey date for 60 subjects (group 2, long-term survivors). Metabolic syndrome was frequently observed with clinical significance (odds ratio [OR] 1.986 [95% confidence interval [CI] 1.0-3.70], p = 0.030) in short-term survivors compared with subjects with no thyroid cancer history. Risks for having high blood pressure and high fasting glucose were estimated to be higher in the short-term survivor group (OR 2.115 [CI 1.23-3.64], p = 0.006 and OR 1.792 [CI 1.03-3.11], p = 0.038, respectively). No significant associations were noticed in the long-term survivor group when compared with the group with no thyroid cancer history., Conclusion: Risks for metabolic syndrome, especially high blood pressure and high fasting glucose, were increased in short-term survivors of thyroid cancer but not in long-term survivors when compared with subjects with no history of thyroid cancer.

Adipose tissue inflammation is an important factor in obesity that promotes insulin resistance. Among various cell types in adipose tissue, immune cells actively regulate inflammatory responses and affect whole-body energy metabolism. In particular, invariant natural killer T (iNKT) cells contribute to mitigating dysregulation of systemic energy homeostasis by counteracting obesity-induced inflammation in adipose tissue. However, the molecular mechanisms by which adipose iNKT cells become activated and mediate anti-inflammatory roles in obese adipose tissue have not been thoroughly understood yet. In the current study, we demonstrate that adipocyte CD1d plays a key role in the stimulation of adipose iNKT cells, leading to anti-inflammatory responses in high-fat diet (HFD)-fed mice. Accordingly, adipocyte-specific CD1d-knockout (CD1d ADKO ) mice showed reduced numbers of iNKT cells in adipose tissues and decreased responses to α-galactosylceramide-induced iNKT cell activation. Additionally, HFD-fed CD1d ADKO mice revealed reduced interleukin-4 expression in adipose iNKT cells and aggravated adipose tissue inflammation and insulin resistance. Collectively, these data suggest that adipocytes could selectively stimulate adipose iNKT cells to mediate anti-inflammatory responses and attenuate excess proinflammatory responses in obese adipose tissue., (© 2017 by the American Diabetes Association.)

The adipose tissue is a central metabolic organ in the regulation of whole-body energy homeostasis. The white adipose tissue functions as a key energy reservoir for other organs, whereas the brown adipose tissue accumulates lipids for cold-induced adaptive thermogenesis. Adipose tissues secrete various hormones, cytokines, and metabolites (termed as adipokines) that control systemic energy balance by regulating appetitive signals from the central nerve system as well as metabolic activity in peripheral tissues. In response to changes in the nutritional status, the adipose tissue undergoes dynamic remodeling, including quantitative and qualitative alterations in adipose tissue-resident cells. A growing body of evidence indicates that adipose tissue remodeling in obesity is closely associated with adipose tissue function. Changes in the number and size of the adipocytes affect the microenvironment of expanded fat tissues, accompanied by alterations in adipokine secretion, adipocyte death, local hypoxia, and fatty acid fluxes. Concurrently, stromal vascular cells in the adipose tissue, including immune cells, are involved in numerous adaptive processes, such as dead adipocyte clearance, adipogenesis, and angiogenesis, all of which are dysregulated in obese adipose tissue remodeling. Chronic overnutrition triggers uncontrolled inflammatory responses, leading to systemic low-grade inflammation and metabolic disorders, such as insulin resistance. This review will discuss current mechanistic understandings of adipose tissue remodeling processes in adaptive energy homeostasis and pathological remodeling of adipose tissue in connection with immune response.

In obesity, adipocyte hypertrophy and proinflammatory responses are closely associated with the development of insulin resistance in adipose tissue. However, it is largely unknown whether adipocyte hypertrophy per se might be sufficient to provoke insulin resistance in obese adipose tissue. Here, we demonstrate that lipid-overloaded hypertrophic adipocytes are insulin resistant independent of adipocyte inflammation. Treatment with saturated or monounsaturated fatty acids resulted in adipocyte hypertrophy, but proinflammatory responses were observed only in adipocytes treated with saturated fatty acids. Regardless of adipocyte inflammation, hypertrophic adipocytes with large and unilocular lipid droplets exhibited impaired insulin-dependent glucose uptake, associated with defects in GLUT4 trafficking to the plasma membrane. Moreover, Toll-like receptor 4 mutant mice (C3H/HeJ) with high-fat-diet-induced obesity were not protected against insulin resistance, although they were resistant to adipose tissue inflammation. Together, our in vitro and in vivo data suggest that adipocyte hypertrophy alone may be crucial in causing insulin resistance in obesity., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Recent findings, notably on adipokines and adipose tissue inflammation, have revised the concept of adipose tissues being a mere storage depot for body energy. Instead, adipose tissues are emerging as endocrine and immunologically active organs with multiple effects on the regulation of systemic energy homeostasis. Notably, compared with other metabolic organs such as liver and muscle, various inflammatory responses are dynamically regulated in adipose tissues and most of the immune cells in adipose tissues are involved in obesity-mediated metabolic complications, including insulin resistance. Here, we summarize recent findings on the key roles of innate (neutrophils, macrophages, mast cells, eosinophils) and adaptive (regulatory T cells, type 1 helper T cells, CD8 T cells, B cells) immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. In particular, the roles of natural killer T cells, one type of innate lymphocyte, in adipose tissue inflammation will be discussed. Finally, a new role of adipocytes as antigen presenting cells to modulate T cell activity and subsequent adipose tissue inflammation will be proposed.

SREBP1c is a key transcription factor that regulates de novo lipogenesis during anabolic periods. However, the molecular mechanisms involved in the suppression of SREBP1c under nutritional deprivation are largely unknown. In this study, we demonstrate that the small ubiquitin-related modifier (SUMO) E3 ligase, a protein inhibitor of activated STAT Y (PIASy), sumoylates SREBP1c at Lys98, leading to suppression of the hepatic lipogenic program upon fasting-induced signals. In primary hepatocytes, ablation of PIASy stimulated intracellular lipid accumulation through the induction of SREBP1c and its target genes. Given that protein kinase A (PKA) plays important roles in catabolic responses, activated PKA enhances the sumoylation of SREBP1c and potentiates the interaction between SREBP1c and PIASy. Notably, overexpression of PIASy in obese db/db mice ameliorated hepatic steatosis, while suppression of PIASy in lean (wild-type) mice stimulated hepatic lipogenesis with increased expression of SREBP1c target genes. Furthermore, PKA-mediated SREBP1c phosphorylation augmented SREBP1c sumoylation, subsequently leading to degradation of SREBP1c via ubiquitination. Together, these data suggest that PKA-induced SREBP1c sumoylation by PIASy is a key regulatory mechanism to turn off hepatic lipogenesis during nutritional deprivation.