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Introduction: Cancer remains one of the leading causes of mortality and financial distress worldwide. In South Korea, the government introduced a benefit extension system in 2013 aimed at mitigating the financial strain associated with cancer treatment. However, cancer patients continue to bear significant out-of-pocket (OOP) expenses. This study aims to quantify the incremental healthcare utilization and OOP expenditures incurred by cancer patients in South Korea., Methods: Utilizing data from the 2019 Korean Health Panel (KHP), we assessed cancer-related healthcare utilization and OOP expenditures. A generalized linear regression model, adjusted for demographic and socioeconomic variables, was employed. Healthcare utilization was measured by hospital admissions, outpatient visits, and emergency room (ER) visits, while OOP expenditures encompassed services including both covered and not covered by the National Health Insurance (NHI) system., Results: Cancer patients experienced 0.39 more hospitalizations, 4.91 additional outpatient visits, and 0.11 more ER visits annually compared to non-cancer patients. Their incremental OOP expenses amounted to $482.8 per year, with $340.2 attributable to inpatient services. Notable variations in healthcare utilization and expenditures were observed across different cancer types., Discussion: Despite the implementation of the benefit extension system, cancer patients continue to face considerable OOP expenses, particularly for inpatient care. With cancer incidence expected to rise, there is a pressing need for more comprehensive healthcare policies that alleviate the financial burden and prioritize cost-effective treatments for cancer patients., Conclusion: This study underscores the substantial economic impact of cancer on South Korean patients. Expanding the benefit extension system and promoting cost-effective care strategies are critical to easing the growing financial pressures on cancer patients., (© 2025 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Tumor microenvironment (TME) is composed of diverse cell types whose interactions, both direct and indirect, significantly influence tumorigenesis and therapeutic outcomes. Within TME, reactive oxygen species (ROS) are produced by various cells and exhibit a dual role: moderate ROS levels promote tumor initiation and progression, whereas excessive levels induce cancer cell death, influencing the efficacy of anticancer therapies. Inflammasomes, cytosolic multiprotein complexes, are pivotal in multiple stages of tumorigenesis and play a crucial role in establishing the inflammatory TME. By releasing cytokines such as IL-1β and IL-18, inflammasomes contribute to immune cell recruitment and sustain a chronic inflammatory state that supports tumor growth. ROS are critical regulators of inflammasome activation, with the impact of ROS-mediated activation differing across cell types, leading to distinct influences on tumor progression and therapeutic responses. This review explores how ROS drive inflammasome activation in various TME-associated cells and the reciprocal ROS generation induced by inflammasomes, examining their multifaceted impact on tumorigenesis and therapeutic efficacy. By elucidating the complex interplay between ROS and inflammasomes in TME, we provide insights into potential therapeutic approaches that could modulate cancer progression and enhance treatment outcomes., Competing Interests: Declarations. Conflict of interest: The authors claim no conflicts of interest., (© 2025. The Pharmaceutical Society of Korea.)

Streptococcus pneumonia is a Gram-positive and facultative anaerobic bacterium that causes a number of diseases, including otitis media, community-acquired pneumonia, sepsis, and meningitis. With the emergence of antibiotic-resistant strains, there is an urgent need to develop antibiotics with a novel mechanism. The toxin-antitoxin (TA) system, which is primarily found in prokaryotes, consists of a toxin and its equivalent antitoxin genes. The YefM-YoeB module is a Type II TA system, where the YoeB toxin functions as a putative mRNA interferase upon activation, while the YefM antitoxin acts as a transcription repressor by binding to its promoter region along with YoeB. In this study, we determined the crystal structure of the YefM-YoeB complex from S. pneumoniae TIGR4 to comprehend the binding mechanism of the TA system. Furthermore, an in vitro ribonuclease activity assay was conducted to identify the ribonuclease activity of the YoeB toxin. Additionally, furthermore, the oligomeric state of the YefM-YoeB complex in solution was investigated, and a DNA-binding mode was proposed. These structural and functional insights into the YefM-YoeB complex could provide valuable information for the development of novel antibiotics targeting S. pneumonia-associated diseases., (© 2025 Wiley Periodicals LLC.)

Objective: To describe the oral health of older people by region and family status using data from the National Health and Nutrition Survey., Background: As the ageing of Korean society intensifies, health inequalities based on region and family status are also deepening., Methods: Data from the 8th National Health and Nutrition Survey (2020-2021) conducted by the Korea Centers for Disease Control and Prevention were used, and a total of 3437 older people aged 65 or older were selected as study participants. Chewing discomfort and oral health behaviours were assessed by region and family status using multivariable logistic regression analysis with the complex sample survey design., Results: We found an association between living alone and greater chewing discomfort. Residing in rural areas was also associated with a higher prevalence of this. In urban areas, chewing discomfort was 1.27 times higher among older people living alone than in those not living alone, while in rural areas, the discomfort was 1.52 times higher among the older people who lived alone., Conclusions: Region and family status were associated with greater chewing discomfort in older people. In Korean society, where the number of single-person older people households is increasing, along with the ageing population, attention to resolving the disparities in oral health in older people is needed., (© 2023 Gerodontology Association and John Wiley & Sons Ltd.)

HEPN-MNT, a type VII TA module, comprises the HEPN toxin and the MNT antitoxin, which acts as a nucleotidyltransferase that transfers the NMP moiety to the corresponding HEPN toxin, thereby interfering with its toxicity. Here, we report crystal structures of the Legionella pneumophila HEPN-MNT module, including HEPN, AMPylated HEPN, MNT, and the HEPN-MNT complex. Our structural analysis and biochemical assays, suggest that HEPN is a metal-dependent RNase and identify its active site residues. We also elucidate the oligomeric state of HEPN in solution. Interestingly, L. pneumophila MNT, which lacks a long C-terminal α4 helix, controls the toxicity of HEPN toxin via a distinct binding mode with HEPN. Finally, we propose a comprehensive regulatory mechanism of the L. pneumophila HEPN-MNT module based on structural and functional studies. These results provide insight into the type VII HEPN-MNT TA system., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Prostaglandin E 2 (PGE 2 ) interacts with four specific G protein-coupled receptors, namely EP1, EP2, EP3, and EP4, playing a pivotal role in determining the fate of cells. Our previous findings highlighted that stimulating the EP4 receptor with its agonist, CAY10598, triggers apoptosis in colon cancer HCT116 cells via the production of reactive oxygen species (ROS). This process also reduces the phosphorylation of the oncogenic protein JAK2 and leads to its degradation in these cells. In this study, our goal was to explore the pathways through which CAY10598 leads to JAK2 degradation. We focused on Hsp90, a heat shock protein family member known for its role as a molecular chaperone maintaining the stability of several key proteins including EGFR, MET, Akt, and JAK2. Our results show that CAY10598 decreases the levels of client proteins of Hsp90 in HCT116 cells, an effect reversible by pretreatment with the ROS scavenger N -acetyl cysteine (NAC) or the proteasome inhibitor MG132, indicating that the degradation is likely driven by ROS. Furthermore, we observed that CAY10598 cleaves both α and β isoforms of Hsp90, the process inhibited by NAC. Inhibition of EP4 with the antagonist GW627368x not only prevented the degradation of Hsp90 client proteins but also the cleavage of Hsp90 itself in CAY10598-treated HCT116 cells. Additionally, CAY10598 suppressed the growth of HCT116 cells implanted in mice. Our findings reveal that CAY10598 induces apoptosis in cancer cells by a novel mechanism involving the ROS-dependent cleavage of Hsp90, thereby inhibiting the function of crucial Hsp90 client proteins.

Mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. Cyclooxygenase-2 (COX-2) is a key enzyme involved in inflammatory signaling. While being transiently upregulated upon inflammatory stimuli, COX-2 has been found to be consistently overexpressed in human colorectal cancer and several other malignancies. The association between chronic inflammation and cancer has been revisited: cancer can arise when inflammation fails to resolve. Besides its proinflammatory functions, COX-2 also catalyzes the production of pro-resolving as well as anti-inflammatory metabolites from polyunsaturated fatty acids. This may account for the side effects caused by long term use of some COX-2 inhibitory drugs during the cancer chemopreventive trials. This review summarizes the latest findings highlighting the dual functions of COX-2 in the context of its implications in the development, maintenance, and progression of cancer., Competing Interests: Declaration of competing interest 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 Elsevier Inc. All rights reserved.)

Peptide-based therapeutics have traditionally faced challenges, including instability in the bloodstream and limited cell membrane permeability. However, recent advancements in α-helix stapled peptide modification techniques have rekindled interest in their efficacy. Notably, these developments ensure a highly effective method for improving peptide stability and enhancing cell membrane penetration. Particularly in the realm of antimicrobial peptides (AMPs), the application of stapled peptide techniques has significantly increased peptide stability and has been successfully applied to many peptides. Furthermore, constraining the secondary structure of peptides has also been proven to enhance their biological activity. In this review, the entire process through which hydrocarbon-stapled antimicrobial peptides attain improved drug-like properties is examined. First, the essential secondary structural elements required for their activity as drugs are validated, specific residues are identified using alanine scanning, and stapling techniques are strategically incorporated at precise locations. Additionally, the mechanisms by which these structure-based stapled peptides function as AMPs are explored, providing a comprehensive and engaging discussion.

Iron is crucial for the metabolism and growth of most prokaryotic cells. The ferric uptake regulator (Fur) protein plays a central role in regulating iron homeostasis and metabolic processes in bacteria. It ensures the proper utilization of iron and the maintenance of cellular functions in response to environmental cues. Fur proteins are composed of an N-terminal DNA-binding domain (DBD) and a C-terminal dimerization domain (DD), typically existing as dimers in solution. Fur proteins have conserved metal-binding sites named S1, S2, and S3. Among them, site S2 serves as a regulatory site, and metal binding at S2 results in conformational changes. Additionally, as a transcriptional regulator, Fur specifically binds to a consensus DNA sequence called the Fur box. To elucidate the structural and functional properties of Fur proteins, various structures of metal- or DNA-bound Fur proteins or apo-Fur proteins have been determined. In this review, we focus on the structural properties of Fur proteins according to their ligand-bound state and the drug development strategies targeting Fur proteins. This information provides valuable insights for drug discovery.

β-lactam antibiotics are the most successful and commonly used antibacterial agents, but the emergence of resistance to these drugs has become a global health threat. The expression of β-lactamase enzymes produced by pathogens, which hydrolyze the amide bond of the β-lactam ring, is the major mechanism for bacterial resistance to β-lactams. In particular, among class A, B, C and D β-lactamases, metallo-β-lactamases (MBLs, class B β-lactamases) are considered crucial contributors to resistance in gram-negative bacteria. To combat β-lactamase-mediated resistance, great efforts have been made to develop β-lactamase inhibitors that restore the activity of β-lactams. Some β-lactamase inhibitors, such as diazabicyclooctanes (DBOs) and boronic acid derivatives, have also been approved by the FDA. Inhibitors used in the clinic can inactivate mostly serine-β-lactamases (SBLs, class A, C, and D β-lactamases) but have not been effective against MBLs until now. In order to develop new inhibitors particularly for MBLs, various attempts have been suggested. Based on structural and mechanical studies of MBL enzymes, several MBL inhibitor candidates, including taniborbactam in phase 3 and xeruborbactam in phase 1, have been introduced in recent years. However, designing potent inhibitors that are effective against all subclasses of MBLs is still extremely challenging. This review summarizes not only the types of β-lactamase and mechanisms by which β-lactam antibiotics are inactivated, but also the research finding on β-lactamase inhibitors targeting these enzymes. These detailed information on β-lactamases and their inhibitors could give valuable information for novel β-lactamase inhibitors design., Competing Interests: Declaration of competing interest 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 © 2023. Published by Elsevier B.V.)

Lipids, as multifunctional molecules, play a crucial role in a variety of cellular processes. These include regulating membrane glycoprotein functions, controlling membrane trafficking, influencing apoptotic pathways, and affecting drug transport. In addition, lipid metabolites can alter the surrounding microenvironment in ways that might encourage tumor progression. The reprogramming of lipid metabolism is pivotal in promoting tumorigenesis and cancer progression, with tumors often displaying significant changes in lipid profiles. This review concentrates on the essential factors that drive lipid metabolic reprogramming, which contributes to the advancement and drug resistance in melanoma. Moreover, we discuss recent advances and current therapeutic strategies that employ small-molecule inhibitors to target lipid metabolism in skin cancers, particularly those associated with inflammation and melanoma.

Numerous natural antimicrobial peptides (AMPs) exhibit a cationic amphipathic helical conformation, wherein cationic amino acids, such as lysine and arginine, play pivotal roles in antimicrobial activity by aiding initial attraction to negatively charged bacterial membranes. Expanding on our previous work, which introduced a de novo design of amphipathic helices within cationic heptapeptides using an 'all-hydrocarbon peptide stapling' approach, we investigated the impact of lysine-homologue substitution on helix formation, antimicrobial activity, hemolytic activity, and proteolytic stability of these novel AMPs. Our results demonstrate that substituting lysine with ornithine enhances both the antimicrobial activity and proteolytic stability of the stapled heptapeptide AMP series, while maintaining low hemolytic activity. This finding underscores lysine-homologue substitution as a valuable strategy for optimizing the therapeutic potential of diverse cationic AMPs., Competing Interests: Declaration of competing interest 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 Elsevier Ltd. All rights reserved.)

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) such as gefitinib and osimertinib have primarily been used as first-line treatments for patients with EGFR-activating mutations in non-small cell lung cancer (NSCLC). Novel biomarkers are required to distinguish patients with lung cancer who are resistant to EGFR-TKIs. The aim of the study is to investigate the expression and functional role of YES1, one of the Src-family kinases, in EGFR-TKI-resistant NSCLC. YES1 expression was elevated in gefitinib-resistant HCC827 (HCC827/GR) cells, harboring EGFR mutations. Moreover, HCC827/GR cells exhibited increased reactive oxygen species (ROS) levels compared to those of the parent cells, resulting in the phosphorylation/activation of YES1 due to oxidation of the cysteine residue. HCC827/GR cells showed elevated expression levels of YES1-associated protein 1 (YAP1), NF-E2-related factor 2 (Nrf2), cancer stemness-related markers, and antioxidant proteins compared to those of the parent cells. Knockdown of YES1 in HCC827/GR cells suppressed YAP1 phosphorylation, leading to the inhibition of Bcl-2, Bcl-xL, and Cyclin D1 expression. Silencing YES1 markedly attenuated the proliferation, migration, and tumorigenicity of HCC827/GR cells. Dasatinib inhibited the proliferation of HCC827/GR cells by targeting YES1-mediated signaling pathways. Furthermore, the combination of gefitinib and dasatinib demonstrated a synergistic effect in suppressing the proliferation of HCC827/GR cells. Notably, YES1- and Nrf2-regulated genes showed a positive regulatory relationship in patients with lung cancer and in TKI-resistant NSCLC cell lines. Taken together, these findings suggest that modulation of YES1 expression and activity may be an attractive therapeutic strategy for the treatment of drug-resistant NSCLC., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Klebsiella pneumoniae causes severe human diseases, but its resistance to current antibiotics is increasing. Therefore, new antibiotics to eradicate K. pneumoniae are urgently needed. Bacterial toxin-antitoxin (TA) systems are strongly correlated with physiological processes in pathogenic bacteria, such as growth arrest, survival, and apoptosis. By using structural information, we could design the peptides and small-molecule compounds that can disrupt the binding between K. pneumoniae MazE and MazF, which release free MazF toxin. Because the MazEF system is closely implicated in programmed cell death, artificial activation of MazF can promote cell death of K. pneumoniae . The effectiveness of a discovered small-molecule compound in bacterial cell killing was confirmed through flow cytometry analysis. Our findings can contribute to understanding the bacterial MazEF TA system and developing antimicrobial agents for treating drug-resistant K. pneumoniae .

Src family kinases (SFKs) are non-receptor tyrosine kinases that are recognized as proto-oncogenic products. Among SFKs, YES1 is frequently amplified and overexpressed in a variety of human tumors, including lung, breast, ovarian, and skin cancers. YES1 plays a pivotal role in promoting cell proliferation, survival, and invasiveness during tumor development. Recent findings indicate that YES1 expression and activation are associated with resistance to chemotherapeutic drugs and tyrosine kinase inhibitors in human malignancies. YES1 undergoes post-translational modifications, such as lipidation and nitrosylation, which can modulate its catalytic activity, subcellular localization, and binding affinity for substrate proteins. Therefore, we investigated the diverse mechanisms governing YES1 activation and its impact on critical intracellular signal transduction pathways. We emphasized the function of YES1 as a potential mechanism contributing to the anticancer drug resistance emergence.

Mycobacterium tuberculosis , a major cause of mortality from a single infectious agent, possesses a remarkable mycobacterial cell envelope. Penicillin-Binding Proteins (PBPs) are a family of bacterial enzymes involved in the biosynthesis of peptidoglycan. PBP4 (DacB) from M. tuberculosis (MtbPBP4) has been known to function as a carboxypeptidase, and the role and significance of carboxypeptidases as targets for anti-tuberculosis drugs or antibiotics have been extensively investigated over the past decade. However, their precise involvement remains incompletely understood. In this study, we employed predictive modeling and analyzed the three-dimensional structure of MtbPBP4. Interestingly, MtbPBP4 displayed a distinct domain structure compared to its homologs. Docking studies with meropenem verified the presence of active site residues conserved in PBPs. These findings establish a structural foundation for comprehending the molecular function of MtbPBP4 and offer a platform for the exploration of novel antibiotics., Competing Interests: The authors declare no conflicts of interest.

The reprogramming of lipid metabolism and its association with oncogenic signaling pathways within the tumor microenvironment (TME) have emerged as significant hallmarks of cancer. Lipid metabolism is defined as a complex set of molecular processes including lipid uptake, synthesis, transport, and degradation. The dysregulation of lipid metabolism is affected by enzymes and signaling molecules directly or indirectly involved in the lipid metabolic process. Regulation of lipid metabolizing enzymes has been shown to modulate cancer development and to avoid resistance to anticancer drugs in tumors and the TME. Because of this, understanding the metabolic reprogramming associated with oncogenic progression is important to develop strategies for cancer treatment. Recent advances provide insight into fundamental mechanisms and the connections between altered lipid metabolism and tumorigenesis. In this review, we explore alterations to lipid metabolism and the pivotal factors driving lipid metabolic reprogramming, which exacerbate cancer progression. We also shed light on the latest insights and current therapeutic approaches based on small molecular inhibitors and phytochemicals targeting lipid metabolism for cancer treatment. Further investigations are worthwhile to fully understand the underlying mechanisms and the correlation between altered lipid metabolism and carcinogenesis., (© 2023. The Author(s).)

Objective: A growing number of Korean adolescents consume energy drinks, which may increase the risk of obesity, anxiety and insomnia. We examined whether poor sleep was associated with energy drink consumption among study participants., Design: We used a cross-sectional design., Setting: The Korea Youth Risk Behavior Web-Based Survey data from 2019., Participants: To determine the association between sleep and energy drink consumption, we compared the independent variables for 50,455 adolescents in Korea (aged 14-19 years) using multivariate logistic regression and sensitivity analyses., Results: In Korea, 69·5 % adolescents consumed energy drinks, 17·1 % slept for less than 5 h, 22·4 % slept for 5-6 h, 23·8 % slept for 6-7 h, 19·9 % slept for 7-8 h and 16·7 % slept for 8 h or more. Regarding sleep satisfaction, 21·0 % reported sufficient, 32·6 % reported just enough and 46·5 % reported insufficient. Regarding sleep duration, it was found that less than 5 h (OR, 2·36; 95 % CI (2·14, 2·60)) and lower sleep satisfaction (OR, 1·12; 95 % CI (1·03, 1·21)) were highly associated with energy drink consumption, with statistical significance at P < 0·05. Adolescents with lower sleep duration (adjusted OR (aOR), 6·37; 95 % CI (4·72, 8·61)) and a lack of sleep satisfaction (aOR, 1·44; 95 % CI (1·16, 1·78)) reported drinking a high amount of energy drinks, that is, at least once a day., Conclusion: In addition to efforts to decrease the amount of energy drinks consumed, sleep hygiene education needs to be strengthened.

Health providers are striving to create a more positive, patient-centred experience. However, existing scholarly research about the association between determinants of patient choice of provider and patient-reported experience remains insufficient to effectively promote patient-centredness in healthcare systems. This study used a sample from the nationally representative 2020 Healthcare Experience Survey. Among the respondents (n = 12 133), 6809 who used outpatient services were selected for analysis. The variable of interest was the determinant of the patient choice of provider, and the dependent variables were patient-reported experiences (e.g. general satisfaction, experience with doctors, and experience with health providers and nurses). Data were analyzed using a multivariable logistic regression model by correcting for covariates. General satisfaction was positively associated with providers' expertise factors and public image factors [providers' expertise factors: odds ratio (OR), 2.96; 95% confidence interval (CI), 2.44-3.59; public image factors: OR, 1.26; 95% CI, 1.02-1.55] satisfied more general satisfaction. Similar results were found for experience with doctors (providers' expertise factors: OR, 4.50; 95% CI, 2.77-7.32; other factors: OR, 0.37; 95% CI, 0.16-0.81) and experience with health providers and nurses (providers' expertise factors: OR, 2.66; 95% CI, 1.99-3.57; image factors: OR, 1.53; 95% CI, 1.09-2.14). Our study's findings suggest that to improve patient-reported experience, health providers must better manage providers' expertise factors and public image factors. Health providers can improve patient-reported experience by increasing communication skills and proper information about the nature is important. Moreover, health providers must manage public image factors comprehensively and continuously by maintaining good quality of care and to brand patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The objective was to determine the association between health-related behaviour with overweight and obesity in South Korean adults by using the Korean National Health and Nutritional Examination Survey (KNHANES) 2018-2020. The study participants were 16,784 aged ≥ 20years. The variables were socio-demographic, lifestyle, food habits and metabolic conditions. The logistic regression analysis performed to find the association by the odds ratio (OR, 95% CI). MCA performed to identify risk factors were computed for overweight and obesity. Overweight and obesity were significantly associated with health behaviour, high income (OR = 1.26; 95% CI: 1.15-1.39), smoking(OR = 1.29; 95% CI: 1.08-1.53), low physical activity(OR = 3.23; 95% CI: 1.79-4.69), diabetes(OR = 2.70; 95% CI: 1.62-4.50), high cholesterol and low HDL(OR = 3.98; 95%CI:2.65-5.97). The high discriminant variables of MCA were aged over 60years, lower education, high income, diabetes, lack of physical activity, and high cholesterol. The findings confirm that the OR of obesity and overweight was likely associated with health behaviour patterns. Besides, it indicates the MCA would be very effective to identify the population-based data context than individual data and it may suggest that more research on association between health behaviours and obesity prevention interventions should be developed for each age group for better health outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kim 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.)

Background: Frequent Emergency Department (ED) visitors are identified by the policymakers to reduce avoidable ED visits and lessen the financial and operational burden. This study aimed to identify the factors related to the frequent use of ED services., Methods: This nationwide, cross-sectional observational study was conducted using information obtained from the 2019 National Emergency Department Information System (NEDIS) database. Frequent ED users were defined as patients with four or more ED visits a year. We performed multiple logistic regression analyses to verify the relationship among sociodemographic characteristics, residential characteristics, clinical characteristics, and frequency of ED visits., Results: Among 4,063,640 selected patients, 137,608 patients visited the ED four or more times a year (total number of visits = 735,502 times), which accounted for 3.4% and 12.8% of the total number of ED users and ED visits, respectively. A high ED visit frequency was associated with male sex, age < 9 or ≥ 70 years, Medical Aid (based on the insurance type), lower number of medical institutions and beds compared with that of the national average, and conditions, such as cancer, diabetes, renal failure, and mental illness. A low ED-visit frequency was associated with residence in regions vulnerable to emergency medical care and regions with high income. The possibility of frequent ED visits was high for patients with level 5 severity (non-emergent) and those with an increased need for medical treatment, including older patients and patients with cancer or mental illness. The possibility of frequent ED visits was low for patients aged > 19 years with level 1 severity (resuscitation)., Conclusions: Health service accessibility factors, including low income and medical resource imbalance, were associated with frequent ED visits. Future large-scale prospective cohort studies are warranted to establish an efficient emergency medical system., (© 2023. The Author(s).)

Polyketide metabolism-associated proteins in Mycobacterium tuberculosis play an essential role in the survival of the bacterium, which makes them potential drug targets for the treatment of tuberculosis (TB). The novel ribonuclease protein Rv1546 is predicted to be a member of the steroidogenic acute regulatory protein-related lipid-transfer (START) domain superfamily, which comprises bacterial polyketide aromatase/cyclases (ARO/CYCs). Here, we determined the crystal structure of Rv1546 in a V-shaped dimer. The Rv1546 monomer consists of four α-helices and seven antiparallel β-strands. Interestingly, in the dimeric state, Rv1546 forms a helix-grip fold, which is present in START domain proteins, via three-dimensional domain swapping. Structural analysis revealed that the conformational change of the C-terminal α-helix of Rv1546 might contribute to the unique dimer structure. Site-directed mutagenesis followed by in vitro ribonuclease activity assays was performed to identify catalytic sites of the protein. This experiment suggested that surface residues R63, K84, K88, and R113 are important in the ribonuclease function of Rv1546. In summary, this study presents the structural and functional characterization of Rv1546 and supplies new perspectives for exploiting Rv1546 as a novel drug target for TB treatment., (© 2023 The Protein Society.)

The dysregulation of lipid metabolism and alterations in the ratio of monounsaturated fatty acids (MUFAs) to saturated fatty acids (SFAs) have been implicated in cancer progression and stemness. Stearoyl-CoA desaturase 1 (SCD1), an enzyme involved in lipid desaturation, is crucial in regulating this ratio and has been identified as an important regulator of cancer cell survival and progression. SCD1 converts SFAs into MUFAs and is important for maintaining membrane fluidity, cellular signaling, and gene expression. Many malignancies, including cancer stem cells, have been reported to exhibit high expression of SCD1. Therefore, targeting SCD1 may provide a novel therapeutic strategy for cancer treatment. In addition, the involvement of SCD1 in cancer stem cells has been observed in various types of cancer. Some natural products have the potential to inhibit SCD1 expression/activity, thereby suppressing cancer cell survival and self-renewal activity.

It remains uncertain whether albuminuria can identify elderly patients with diabetes at a high risk of incident end-stage kidney disease (ESKD) or mortality. 3065 patients (aged ≥ 65 years) with type 2 diabetes were included. We examined the association between albuminuria stages (normoalbuminuria, A1; microalbuminuria, A2; and macroalbuminuria, A3) and the risk of incident ESKD and all-cause mortality for each age group (65-69, 70-74, and ≥ 75 years). A2 and A3 were observed in 25.5% and 9.4% of the subjects, respectively. For A1, A2, and A3, the probabilities of ESKD at 8 years were 1.0%, 6.3%, and 29.7% (P < 0.001 for all), and the all-cause mortality was 13.1%, 27.4%, and 31.7% (P < 0.001 for A1 vs A2, P < 0.001 for A1 vs A3), respectively. Albuminuria stages were independently associated with an increased risk of ESKD [fully adjusted hazard ratios (HR): 3.650 (1.987-6.702) for A2, 10.404 (5.706-18.972) for A3 vs. A1]. The HRs of all-cause mortality were 1.742 (1.411-2.153) for A2 and 1.810 (1.344-2.441) for A3. The associations between albuminuria stages and the risk of ESKD and all-cause mortality were consistent across all age groups. Even microalbuminuria is also a risk factor for incident ESKD and mortality in elderly patients with diabetes., (© 2023. The Author(s).)

Rationale: The production of bottled water requires a forensic discriminant technique that enables the identification of the brands or accidents caused by intended contaminants. The bottled water poisoning crimes have drawn much attention, and such crimes may recur in the future. The water is colorless and odorless, and thus it is difficult to detect contaminated water through visual observation. Thus, bottled water can be easily exploited for poisoning, and a method for tracing their origin is currently required., Methods: In this study, a total of 27 brands of bottled water samples were analyzed to determine stable oxygen isotopes, strontium isotopes, major and trace elements. The geographical origin of the water was traced based on the climatic and geographical characteristics of the location from where water was sourced, which was assumed to be reflected in the bottled water. Furthermore, we investigated whether this method can be applied to identify bottled water products., Results: The results demonstrated that the characteristics of the bottled water, including the oxygen stable isotope ratios, reflect the latitude and altitude of bottled water source in South Korea, from the high-latitude region to the coastal regions. In addition, the results indicated that excellent discrimination was achieved using strontium isotopes to identify source areas with different types of bedrock, complex underlying lithologies, and ocean areas in South Korea. A statistical method based on discriminant analysis was applied to measure trace elements, and the results effectively reflected the characteristics of water-rock interactions (cross-validated classification probability: ≥92%)., Conclusions: These data suggest that the geographical characteristics of the source area are well reflected in commercial bottled water in South Korea. The proposed analytical methods can be utilized to trace the geographical origin of different bottled water samples and identify bottled water products used in poisoning crimes., (© 2022 John Wiley & Sons Ltd.)

This study aimed to investigate the association between socioeconomic status (SES) and healthcare utilization by children with allergic diseases. We determined SES based on parental occupation and household income. A cross-sectional study was conducted using the Korean National Health and Nutritional Examination Survey (KNHANES) between 2015 and 2019 with participants who were under 18 years of age. The presence of allergic conditions was determined by a self-reported survey of parental response and healthcare utilization data (such as inpatient and outpatient visits). Moreover, we categorized SES into four quantiles (Q1-Q4) based on household income per annum. Then, the data were analyzed using chi-square tests and multivariate logistic regression analysis with confidence intervals (CIs) of 95%, and p < 0.05 was considered significant. A total of 3250 participants were involved in this study. The percentage of allergic diseases was 67.9% for allergic asthma and 32.1% for atopic dermatitis. It was found that the participants who were over 13 years old had atopic dermatitis and were more likely to visit the hospital than younger children. Additionally, the highest SES group in Q4 demonstrated higher healthcare utilization (OR = 1.58; 95% CI, 1.14-1.76) than other SES groups. Our study reveals that parental socioeconomic characteristics are related to the use of healthcare services for children with allergic disorders in Korea. These results highlight the need for public health actions and research to overcome the SES gap among children with allergic diseases.

Owing to its unique nucleophilicity, cysteine is an attractive sulfhydryl-containing proteinogenic amino acid. It is also utilized in various metabolic pathways and redox homeostasis, as it is used for the component of major endogenous antioxidant glutathione and the generation of sulfur-containing biomolecules. In addition, cysteine is the most nucleophilic amino acid of proteins and can react with endogenous or exogenous electrophiles which can result in the formation of covalent bonds, which can alter the cellular states and functions. Moreover, post-translational modifications of cysteines trigger redox signaling and affect the three-dimensional protein structure. Protein phosphorylation mediated by kinases and phosphatases play a key role in cellular signaling that regulates many physiological and pathological processes, and consequently, the modification of cysteine regulates its activities. The modification of cysteine residues in proteins is critically important for the design of novel types of pharmacological agents. Therefore, in cancer metabolism and cancer cell survival, cysteine plays an essential role in redox regulation of cellular status and protein function. This review summarizes the diverse regulatory mechanisms of cysteine bound to or free from proteins in cancer. Furthermore, it can enhance the comprehension of the role of cysteine in tumor biology which can help in the development of novel effective cancer therapies., 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 © 2023 Min, Chun and Kim.)

Aims: Aberrant overactivation/overexpression of NRF2 is implicated as a driving event in tumor progression, which has been attributed to its mutation or inactivation of the inhibitory protein, KEAP1. However, alternative mechanisms responsible for sustained activation of NRF2 are less understood., Main Methods: Human colon cancer cell lines and tissues obtained from colorectal cancer (CRC) patients were used. To examine the expression levels of ARD1 and NRF2, Western blot and immunofluorescence analyses were performed. To investigate the potential relevance of NRF2 and ARD1 to human CRC, NRF2 and ARD1 were individually silenced in human colon cancer cells (HCT-116) by transfection with their specific small interfering RNA (siRNA). To determine the functional role of ARD1 in NRF2 regulation, in situ proximate ligation, co-immunoprecipitation, nano-LC-ESI MS/MS, and in vitro acetylation assays were performed., Key Findings: ARD1 knockdown in human colon cancer cell lines significantly reduced the protein levels of NRF2 without affecting its mRNA expression; however, silencing of NRF2 did not alter ARD1 protein expression. In addition, these two proteins were co-localized and physically interacted with each other both in human colon cancer cells (HCT-116) and human colon tumor tissues. Mechanistically, ARD1 overexpression increased the acetylation levels of NRF2. Moreover, an in vitro acetylation assay and mass spectrometric analysis demonstrated that ARD1 could directly acetylate NRF2. Ectopic expression of mutant forms of ARD1 with defective acetyltransferase activity reduced the stability of NRF2., Significance: In conclusion, ARD1 may potentiate the oncogenic function of NRF2 in human colon cancer by stabilizing this transcription factor., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Hypoxia-inducible factor-1α (HIF-1α) is highly expressed/activated in most hypoxic tumors including hepatocellular carcinoma (HCC). Another key transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2), is also constitutively overactivated in HCC. In an attempt to determine whether HIF-1α and NRF2 could play complementary roles in HCC growth and progression, we investigated the crosstalk between these two transcription factors and underlying molecular mechanisms in cultured HCC cells and experimentally induced hepatocarcinogenesis as well as clinical settings. While silencing of HIF-1α in HepG2 human hepatoma cells did not alter the protein expression of NRF2, NRF2 knockdown markedly reduced the nuclear accumulation of HIF-1α without influencing its mRNA expression. In diethylnitrosamine-induced hepatocarcinogenesis in wild type mice, there was elevated NRF2 expression with concomitant upregulation of HIF-1α. However, this was abolished in Nrf2 knockout mice. NRF2 and HIF-1α co-localized and physically interacted with each other as assessed by in situ proximity ligation and immunoprecipitation assays. In addition, the interaction between NRF2 and HIF-1α as well as their overexpression was found in tumor specimens obtained from HCC patients. In normoxia, HIF-1α undergoes hydroxylation by a specific HIF-prolyl hydroxylase domain protein (PHD), which facilitates ubiquitination and proteasomal degradation of HIF-1α. NRF2 contributes to pseudohypoxia, by directly binding to the oxygen-dependent degradation (ODD) domain of HIF-1α, which hampers the PHD2-mediated hydroxylation, concomitant recruitment of von-Hippel-Lindau and ubiquitination of HIF-1α., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Normal cells express surface proteins that bind to immune checkpoint proteins on immune cells to turn them off, whereby the immune system does not attack normal healthy cells. Cancer cells can also utilize this same protective mechanism by expressing surface proteins that can interact with checkpoint proteins on immune cells to overcome the immune surveillance. Immunotherapy is making the best use of the body's own immune system to reinforce anti-tumor responses. The most generally used immunotherapy is the control of immune checkpoints including the cytotoxic T lymphocyte-associated molecule 4 (CTLA-4), programmed cell deathreceptor 1 (PD-1), or programmed cell death ligand-1 (PD-L1). In spite of the clinical effectiveness of immune checkpoint inhibitors, the overall response rate still remains low. Therefore, there have been considerable efforts in searching for alternative immune checkpoint proteins that may work as new therapeutic targets for treatment of cancer. Recent studies have identified several additional novel immune checkpoint targets, including lymphocyte activation gene-3, T cell immunoglobulin and mucin-domain containing-3, T cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain, V-domain Ig suppressor of T cell activation, B7 homolog 3 protein, B and T cell lymphocyte attenuator, and inducible T cell COStimulator. Natural compounds, especially those present in medicinal or dietary plants, have been investigated for their anti-tumor effects in various in vitro and in vivo models. Some phytochemicals exert anti-tumor activities based on immunoregulatioby blocking interaction between proteins involved in immune checkpoint signal transduction or regulating their expression/activity. Recently, synergistic anti-cancer effects of diverse phytochemicals with anti-PD-1/PD-L1 or anti-CTLA-4 monoclonal antibody drugs have been continuously reported. Considering an increasing attention to noteworthy therapeutic effects of immune checkpoint inhibitors in the cancer therapy, this review focuses on regulatory effects of selected phytochemicals on immune checkpoint protein network and their combinational effectiveness with immune checkpoint inhibitors targeting tumor cells., Competing Interests: Declaration of Competing Interest The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: This study examined whether pandemic related family economic hardships influenced adolescents' mental health during the COVID-19 pandemic in Korea., Methods: Data were collected from 54,948 adolescents who participated in the 2020 Korea Youth Risk Behavior Web-Based Survey. We performed a multiple logistic regression analysis to examine the association between family economic hardship and mental health (anxiety, depressive symptoms, and suicidal ideation)., Results: Among the adolescents, 39.7, 24.7, and 5.9% reported slight, moderate, and severe economic hardship, respectively. COVID-19 related family economic hardship was significantly associated with higher odds of adolescents reporting anxiety, depressive symptoms, and suicidal ideation. This association was stronger among adolescents with low to middle family economic status., Conclusions: This study suggests that adolescents from more economically vulnerable families are likely to be at a higher risk for long-term mental health effects due to the financial consequences of the COVID-19 pandemic., 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 Kim, Kim, Jang, Shin, Lee and Kim.)

This study aimed to identify the characteristics of walk-in patients who visited a dental university hospital more than once (returning patient). The factors affecting walk-in visits were analyzed in relation to demographic, appointment, and treatment characteristics among 146,567 cases treated between 1 March 2019 and 29 February 2020. Multiple logistic regression was used to assess factors influencing walk-in visits. The walk-in rate was 14.1%. The likelihood of walk-in visits was higher in men, patients aged 20-39 years, patients residing in Seoul, and hospital employees or their family members. Walk-in visits were more likely to take place from 8:00 to 9:59 and on Saturdays and Mondays. The walk-in odds ratios differed depending on the treatment department and diagnosis. Return patients had higher odds of walk-in visits for treatments not covered by insurance. The probability of being a walk-in patient was lower among patients who also received treatment in other departments on the same day than among those who did not. These results indicate that each examined factor has a predictable pattern. The findings also suggest a relatively high percentage of walk-in cases in dental university hospitals and that walk-in patients differ in their characteristics from patients with appointments.

Objective: This study aimed to investigate the association of sleep with mental health among Korean adolescents during the coronavirus disease (COVID-19) pandemic., Methods: Using data from the 16th Korea Youth Risk Behavior Web-Based Survey (2020) of 46,475 adolescents, we examined sleep duration and satisfaction and examined mental health for depressive symptoms, anxiety, and suicidal ideation. The data were analyzed using complex sample descriptive statistics and a multiple logistic regression model., Results: In 2020, the average sleep duration was 6.3 hours, and the sleep satisfaction rate was 30.8%. Depressive symptom and suicidal ideation rates were 24.2 and 10.3, respectively. These values are slightly better than those previously reported, before COVID-19. However, poor sleep was still associated with mental health. The likelihood of mental health problems was higher among those who slept for six hours or less than for those who slept for eight hours or more (p<0.05). Additionally, the results showed that the lower the sleep satisfaction, the higher the likelihood of mental health problems (p<0.05)., Conclusion: Even after the COVID-19 outbreak, poor sleep associated with mental health problems remained as high as before the outbreak of COVID-19.

Type II toxin-antitoxin (TA) systems encode two proteins: a toxin that inhibits cell growth and an antitoxin that neutralizes the toxin by direct inter-molecular protein-protein inter-actions. The bacterial HipBA TA system is implicated in persister formation. The Haemophilus influenzae HipBA TA system consists of a HipB antitoxin and a HipA toxin, the latter of which is split into two fragments, and here we investigate this novel three-com-ponent regulatory HipBA system. Structural and functional analysis revealed that HipA N corresponds to the N-ter-minal part of HipA from other bacteria and toxic HipA C is inactivated by HipA N , not HipB. This study will be helpful in understanding the detailed regulatory mechanism of the HipBA N+C system, as well as why it is constructed as a three-com-ponent system., (© Ji Sung Koo et al. 2022.)

Purpose: This study aimed to evaluate the association between hypertension management education and the adoption of multiple healthy behaviors., Design: Cross-sectional study., Setting: Data from the 2019 Community Health Survey in Korea., Subjects: Of the 213,900 participants in the 2019 database, 89,773 (42.0%) were hypertensive and 124,127 (58.0%) were normotensive., Measures: Secondary data analysis included a 1:1 computer-assisted personal interview. "Multiple healthy behaviors" included not smoking, not drinking excessively, and walking briskly. "Hypertension management education" referred to information on hypertension management that participants received from clinics, hospitals, and public health centers, outside consultation with a doctor., Analysis: The association between hypertension management education and the adoption of multiple healthy behaviors was evaluated using multiple logistic regression., Results: In total, 89,773 (42.0%) participants were hypertensive. Among 61,589 patients with diagnosed hypertension, only 7,719 (12.5%) received hypertension management education. Participants who received such education were more likely to adopt multiple healthy behaviors (odds ratio [OR] = 1.27, 95% confidence interval [CI]: 1.21-1.34) than their counterparts (OR = 0.91, 95% CI: 0.89-0.93). Participants with undiagnosed hypertension were least likely to adopt multiple healthy behaviors (OR = 0.89, 95% CI: 0.86-0.92). No causal relationships were ascertained because of the cross-sectional study design., Conclusions: Education can improve the adoption of multiple healthy lifestyles among hypertensive patients. Patients should be encouraged to participate in hypertension management education.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor involved in protection against initiation of carcinogenesis in normal cells. Notably, recent studies have demonstrated that aberrant activation of NRF2 accelerates the proliferation and progression of cancer cells. The differential effects of NRF2 on multi-stage carcinogenesis have raised a concern about the validity of NRF2 activators for chemoprevention. This prompted us to assess the effects of sulforaphane (SFN), a prototypic NRF2 activating chemopreventive phytochemical, on experimentally induced carcinogenesis. In the present study, SFN was daily injected intraperitoneally (25 mg/kg) for 3 months to male C57BL/6 mice at 6 months after single intraperitoneal administration of a hepatocarcinogen, diethylnitrosamine (DEN). The liver to body weight ratio, tumor growth, and the number and the size of hepatomas measured at 9 months after DEN administration were significantly higher in SFN-treated mice than those in vehicle-treated mice. Moreover, the expression of NRF2, its target protein NAD(P)H:quinone oxidoreductase 1, and the cell proliferation marker, proliferating cell nuclear antigen was further elevated in DEN plus SFN-treated mice. These results suggest that once hepatocarcinogenesis is initiated, SFN may stimulate tumor progression.

Sirtuin 1 (SIRT1), an NAD + -dependent histone/protein deacetylase, has multifaceted functions in various biological events such as inflammation, aging, and energy metabolism. The role of SIRT1 in carcinogenesis, however, is still under debate. Recent studies have indicated that aberrant overexpression of SIRT1 is correlated with metastasis and poor prognosis in several types of malignancy, including colorectal cancer. In the present study, we found that both SIRT1 and SIRT1 phosphorylated on serine 27 were coordinately upregulated in colon cancer patients' tissues and human colon cancer cell lines. This prompted us to investigate a role of phospho-SIRT1 in the context of colon cancer progression. A phosphorylation-defective mutant form of SIRT1, in which serine 27 was substituted by alanine (SIRT1-S27A), exhibited lower protein stability compared to that of wild-type SIRT1. Notably, human colon cancer (HCT-116) cells harboring the SIRT1-S27A mutation showed decreased cell proliferation and reduced capability to form xenograft tumor in athymic nude mice, which was accompanied by diminished transcriptional activity of Snail. HCT-116 cells carrying SIRT1-S27A were less capable of deacetylating the Snail protein, with a concomitant decrease in the levels of interleukin (IL)-6 and IL-8 mRNA transcripts. Taken together, these observations suggest that SIRT1 stabilized through phosphorylation on serine 27 exerts oncogenic effects at least partly through deacetylation-dependent activation of Snail and subsequent transcription of IL-6 and IL-8 in human colon cancer cells., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Cancer-associated fibroblasts (CAFs) represent a major component of the tumor microenvironment and interplay with cancer cells by secreting cytokines, growth factors and extracellular matrix proteins. When estrogen receptor-negative breast cancer MDA-MB-231 cells were treated with the CAF-conditioned medium (CAF-CM), Akt and STAT3 involved in cell proliferation and survival were activated through phosphorylation. CAFs secrete fibroblast growth factor 2 (FGF2), thereby stimulating breast cancer cell progression. Akt activation induced by CAF-CM in MDA-MB-231 cells was abolished when FGF2-neutralizing antibody was added. Treatment of MDA-MB-231 cells directly with FGF2 enhanced the phosphorylation of Akt and the FGF receptor (FGFR) substrate, FRS2α. These events were abrogated by siRNA-mediated silencing of FGFR1. In a xenograft mouse model, co-injection of MDA-MB-231 cells with activated fibroblasts expressing FGF2 dramatically enhanced activation of Akt. Stable knockdown of FGFR1 blunted Akt phosphorylation in xenograft tumors. MDA-MB-231 cells co-cultured with CAFs or directly stimulated with FGF2 exhibited enhanced nuclear localization of FGFR1. Notably, FGF2 stimulation produced reactive oxygen species (ROS) accumulation in MDA-MB-231 cells, and FGF2-induced nuclear accumulation of FGFR1 was abrogated by the ROS scavenging agent, N -acetylcysteine., Competing Interests: CONFLICTS OF INTEREST No potential conflicts of interest were disclosed., (Copyright © 2022 Korean Society of Cancer Prevention.)

Staphylococcus aureus is a notorious and globally distributed pathogenic bacterium. New strategies to develop novel antibiotics based on intrinsic bacterial toxin-antitoxin (TA) systems have been recently reported. Because TA systems are present only in bacteria and not in humans, these distinctive systems are attractive targets for developing antibiotics with new modes of action. S. aureus PemIK is a type II TA system, comprising the toxin protein PemK and the labile antitoxin protein PemI. Here, we determined the crystal structures of both PemK and the PemIK complex, in which PemK is neutralized by PemI. Our biochemical approaches, including fluorescence quenching and polarization assays, identified Glu20, Arg25, Thr48, Thr49, and Arg84 of PemK as being important for RNase function. Our study indicates that the active site and RNA-binding residues of PemK are covered by PemI, leading to unique conformational changes in PemK accompanied by repositioning of the loop between β1 and β2. These changes can interfere with RNA binding by PemK. Overall, PemK adopts particular open and closed forms for precise neutralization by PemI. This structural and functional information on PemIK will contribute to the discovery and development of novel antibiotics in the form of peptides or small molecules inhibiting direct binding between PemI and PemK., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The polo-box domain (PBD) of Plk1 is a promising target for cancer therapeutics. We designed and synthesized novel phosphorylated macrocyclic peptidomimetics targeting PBD based on acyclic phosphopeptide PMQSpTPL. The inhibitory activities of 16e on Plk1-PBD is >30-fold higher than those of PMQSpTPL. Both 16a and 16e possess excellent selectivity for Plk1-PBD over Plk2/3-PBD. Analysis of the cocrystal structure of Plk1-PBD in complex with 16a reveals that the 3-(trifluoromethyl)benzoyl group in 16a interacts with Arg516 through a π-stacking interaction. This π-stacking interaction, which has not been reported previously, provides insight into the design of novel and potent Plk1-PBD inhibitors. Furthermore, 16h , a PEGlyated macrocyclic phosphopeptide derivative, induces Plk1 delocalization and mitotic failure in HeLa cells. Also, the number of phospho-H3-positive cells in a zebrafish embryo increases in proportion to the amount of 16a . Collectively, the novel macrocyclic peptidomimetics should serve as valuable templates for the design of potent and novel Plk1-PBD inhibitors.

This study aimed to investigate the current situation of firefighting burn injuries and personal protective equipment (PPE) in Korea using a questionnaire. A questionnaire was constructed and then distributed to fire stations via the Fire & Disaster Headquarters of Korea. Responses from a total of 536 firefighters who were currently responsible for suppressing fire or doing rescue work were analysed (39.2 ± 8.58 y in age, 173.8 ± 5.0 cm in height, 73.4 ± 8.9 kg in body weight). The results showed that 22% of firefighters had experienced burns but of these 93% of were burns of less than 1% of total body surface area. The most common body site of burn injury was the hands (37%) and the head (face and neck) (34%). There were significant relationships between PPE non-compliance and career years, especially for the hood and boots. According to firefighters their gloves were the most vulnerable part of their PPE. We also elucidated relationships between the body sites most vulnerable to burn injuries and PPE wear compliance by item. The present results suggest that officially-undisclosed minor burn injuries but prevailing among firefighters can be reduced through improving firefighters' protective helmet, hoods and gloves.

Objectives: AXL-mediated activation of aberrant tyrosine kinase drives various oncogenic processes and facilitates an immunosuppressive microenvironment. We evaluated the anti-tumor and anti-metastatic activities of SKI-G-801, a small-molecule inhibitor of AXL, alone and in combination with anti-PD-1 therapy., Methods: In vitro pAXL inhibition by SKI-G-801 was performed in both human and mouse cancer cell lines. Immunocompetent mouse models of tumor were established to measure anti-metastatic potential of SKI-G-801. Furthermore, SKI-G-801, anti-PD-1 or their combination was administered as an adjuvant or neoadjuvant in the 4T1 tumor model to assess their potential for clinical application., Results: SKI-G-801 robustly inhibited pAXL expression in various cell lines. SKI-G-801 alone or in combination with anti-PD-1 potently inhibited metastasis in B16F10 melanoma, CT26 colon and 4T1 breast models. SKI-G-801 inhibited the growth of B16F10 and 4T1 tumor-bearing mice but not immune-deficient mice. An antibody depletion assay revealed that CD8 + T cells significantly contributed to SKI-G-801-mediated survival. Anti-PD-1 and combination group were observed the increased CD8 + Ki67 + and effector T cells and M1 macrophage and decreased M2 macrophage, and granulocytic myeloid-derived suppressor cell (G-MDSC) compared to the control group. The neoadjuvant combination of SKI-G-801 and anti-PD-1 therapy achieved superior survival benefits by inducing more profound T-cell responses in the 4T1 syngeneic mouse model., Conclusion: SKI-G-801 significantly suppressed tumor metastasis and growth by enhancing anti-tumor immune responses. Our results suggest that SKI-G-801 has the potential to overcome anti-PD-1 therapy resistance and allow more patients to benefit from anti-PD-1 therapy., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

While functioning as a second messenger in the intracellular signaling, ROS can cause oxidative stress when produced in excess or not neutralized/eliminated properly. Excessive ROS production is implicated in multi-stage carcinogenesis. Our body is equipped with a defense system to cope with constant oxidative stress caused by the external insults, including redox-cycling chemicals, radiation, and microbial infection as well as endogenously generated ROS. The transcription factor, nuclear transcription factor erythroid 2-related factor 2 (NRF2) is a master switch in the cellular antioxidant signaling and plays a vital role in adaptive survival response to ROS-induced oxidative stress. Although NRF2 is transiently activated when cellular redox balance is challenged, this can be overwhelmed by massive oxidative stress. Therefore, it is necessary to maintain the NRF2-mediated antioxidant defense capacity at an optimal level. This review summarizes the natural NRF2 inducers/activators, especially those present in the plant-based diet, in relation to their cancer chemopreventive potential in humans. The molecular mechanisms underlying their stabilization or activation of NRF2 are also discussed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Autophagy is a lysosome-dependent intracellular degradation machinery that plays an essential role in the regulation of cellular homeostasis. As many studies have revealed that autophagy is related to cancer, neurodegenerative diseases, metabolic diseases, and so on, and it is considered as a promising drug target. Recent advances in structural determination and computational technologies provide important structural information on essential autophagy-related proteins. Combined with high-throughput screening methods, structure-activity relationship studies have led to the discovery of molecules that modulate autophagy. In this review, we summarize the recent structural studies on autophagy-related proteins and the discovery of modulators, indicating that targeting autophagy can be utilized as an effective strategy for novel drug development.

SIRT1 is a mammalian NAD + -dependent deacetylase, which is known to be involved in various physiological events, such as adaptive response to environmental stresses including caloric restriction, as well as in aging and cellular senescence. However, recent studies have revealed overexpression of SIRT1 in many different types of human malignancies, particularly colon cancer. Interleukin-1β (IL-1β) is a proinflammatory cytokine that plays a major role in invasiveness, stemness and progression of colon cancer. However, the interaction between IL-1β and SIRT1 in the tumor development and progression remains elusive. In this study, we found that IL-1β induces SIRT1 protein expression in human colon cancer HCT-116 cells. IL-1β-induced SIRT1 upregulation led to enhanced expression of mRNA transcripts of pro-inflammatory cytokines, IL-6 and IL-8 as well as that of IL-1β. Knockdown of SIRT1 prevented IL-1β-induced phosphorylation and nuclear accumulation of c-Jun. Furthermore, pharmacologic inhibition of SIRT1 abrogated clonogenicity and migrative capability of human colon cancer cells stimulated with IL-1β. In summary, IL-1β-induced SIRT1 upregulation stimulates production of proinflammatory cytokines via a nuclear accumulation of c-Jun, leadng to colon cancer growth and progression., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Heregulin-β1, a ligand of ErbB-2 and ErbB-3/4 receptors, has been reported to potentiate oncogenicity and metastatic potential of breast cancer cells. In the present work, treatment of human mammary cancer (MCF-7) cells with heregulin-β1 resulted in enhanced cell migration and expression of manganese superoxide dismutase (MnSOD) and its mRNA transcript. Silencing of MnSOD abrogated clonogenicity and migrative ability of MCF-7 cells. Heregulin-β1 treatment also increased nuclear translocation, antioxidant response element binding and transcriptional activity of NF-E2-related factor 2 (Nrf2). A dominant-negative mutant of Nrf2 abrogated heregulin-β1-induced MnSOD expression. Treatment with heregulin-β1 caused activation of protein kinase B (Akt) and extracellular signal-regulated protein kinase (ERK). The pharmacological inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase 1/2, which are upstream of Akt and ERK, respectively, attenuated heregulin-β1-induced MnSOD expression and nuclear localization of Nrf2. In conclusion, heregulin-1 induces upregulation of MnSOD and activation of Nrf2 via the Akt and ERK signaling in MCF-7 cells, which may confer metastatic potential and invasiveness of these cells., Competing Interests: CONFLICTS OF INTEREST No potential conflicts of interest were disclosed., (Copyright © 2021 Korean Society of Cancer Prevention.)

Redox homeostasis is not only essential for the maintenance of normal physiological functions, but also plays an important role in the growth, survival, and therapy resistance of cancer cells. Altered redox balance and consequent disruption of redox signaling are implicated in the proliferation and progression of cancer cells and their resistance to chemo- and radiotherapy. The nuclear factor erythroid 2 p45-related factor (Nrf2) is the principal stress-responsive transcription factor that plays a pivotal role in maintaining cellular redox homeostasis. Aberrant Nrf2 overactivation has been observed in many cancerous and transformed cells. Uncontrolled amplification of Nrf2-mediated antioxidant signaling results in reductive stress. Some metabolic pathways altered due to reductive stress have been identified as major contributors to tumorigenesis. This review highlights the multifaceted role of reductive stress in cancer development and progression.

The structure-function relationships of toxin-antitoxin (TA) systems from Mycobacterium tuberculosis have prompted the development of novel and effective antimicrobial agents that selectively target this organism. The artificial activation of toxins by peptide inhibitors can lead to the growth arrest and eventual death of bacterial cells. Optimizing candidate peptides by hydrocarbon α-helix stapling based on structural information from the VapBC TA system and in vitro systematic validation led to V26-SP-8 , a VapC26 activator of M. tuberculosis . This compound exhibited highly enhanced activity and cell permeability owing to the stabilizing helical propensity of the peptide. These characteristics will increase its efficacy against multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. Similar approaches utilizing structural and biochemical information for new antibiotic targets opens a new era for developing TB therapies.

The inflammatory tumor microenvironment has been known to be closely connected to all stages of cancer development, including initiation, promotion, and progression. Systemic inflammation in the tumor microenvironment is increasingly being recognized as an important prognostic marker in cancer patients. Inflammasomes are master regulators in the first line of host defense for the initiation of innate immune responses. Inflammasomes sense pathogen-associated molecular patterns and damage-associated molecular patterns, following recruitment of immune cells into infection sites. Therefore, dysregulated expression/activation of inflammasomes is implicated in pathogenesis of diverse inflammatory disorders. Recent studies have demonstrated that inflammasomes play a vital role in regulating the development and progression of cancer. This review focuses on fate-determining roles of the inflammasomes and the principal downstream effector cytokine, IL-1β, in the tumor microenvironment.

Bacterial toxin-antitoxin (TA) systems correlate strongly with physiological processes in bacteria, such as growth arrest, survival and apoptosis. Here, the first crystal structure of a type II TA complex structure of Klebsiella pneumoniae at 2.3 Å resolution is presented. The K. pneumoniae MazEF complex consists of two MazEs and four MazFs in a heterohexameric assembly. It was estimated that MazEF forms a dodecamer with two heterohexameric MazEF complexes in solution, and a truncated complex exists in heterohexameric form. The MazE antitoxin interacts with the MazF toxin via two binding modes, namely, hydro-phobic and hydro-philic interactions. Compared with structural homologs, K. pneumoniae MazF shows distinct features in loops β1-β2, β3-β4 and β4-β5. It can be inferred that these three loops have the potential to represent the unique characteristics of MazF, especially various substrate recognition sites. In addition, K. pneumoniae MazF shows ribonuclease activity and the catalytic core of MazF lies in an RNA-binding pocket. Mutation experiments and cell-growth assays confirm Arg28 and Thr51 as critical residues for MazF ribonuclease activity. The findings shown here may contribute to the understanding of the bacterial MazEF TA system and the exploration of antimicrobial candidates to treat drug-resistant K. pneumoniae ., (© Jin et al. 2021.)