Roflumilast reduces the number of lung adenocarcinomas, inflammation, and emphysema in a smoking-induced mouse model.

Background: The prognosis of lung cancer complicated by chronic obstructive pulmonary disease is poor, and effective prophylactic agents have not been established. Given that inflammation is a shared pathogenic mechanism of both diseases, we aimed to evaluate the efficacy of roflumilast, a novel anti-inflammatory drug, in preventing emphysema and lung cancer using a smoking-induced lung cancer mouse model.

Methods: Male A/J mice were exposed to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a potent carcinogen, and intermittent mainstream cigarette smoke for 20 weeks.

Celecoxib prevents malignant progression of smoking-induced lung tumors via suppression of the COX-2/PGE signaling pathway in mice.

Introduction: Lung cancer is characterized by a poor prognosis and is a significant comorbidity of chronic obstructive pulmonary disease (COPD). Therefore, effective chemopreventive agents are warranted. We evaluated the effects of the cyclooxygenase-2 (COX-2) inhibitor celecoxib on the prevention of lung-carcinoma development using an intermittent smoking-induced lung-carcinoma mouse model.

Exploring the pathophysiology of anemia in COPD: Insights from chest CT and longitudinal clinical data.

Background: Although anemia has been associated with chronic obstructive pulmonary disease (COPD) severity, the underlying risk factors, such as chest imaging indicators, remain poorly understood. In this study, we aimed to investigate the relationship between anemia and clinical features, including pulmonary and extrapulmonary indicators on chest computed tomography (CT), and to clarify the pathophysiology of anemia in COPD.

Methods: A total of 400 patients with COPD were prospectively followed for 3 years.

Impact of smoking on gut microbiota and short-chain fatty acids in human and mice: Implications for COPD.

We aimed to elucidate the dynamic changes in short-chain fatty acids (SCFA) produced by the gut microbiota following smoking exposure and their role in chronic obstructive pulmonary disease (COPD) pathogenesis. SCFA concentrations were measured in human plasma, comparing non-smokers (n = 6) and smokers (n = 12). Using a mouse COPD model induced by cigarette smoke exposure or elastase-induced emphysema, we modulated SCFA levels through dietary interventions and antibiotics to evaluate their effects on inflammation and alveolar destruction.

Dysregulation of PI4P in the trans Golgi regions activates the mammalian Golgi stress response.

The Golgi stress response is an important cytoprotective system that enhances Golgi function in response to cellular demand, while cells damaged by prolonged Golgi stress undergo cell death. OSW-1, a natural compound with anticancer activity, potently inhibits OSBP that transports cholesterol and phosphatidylinositol-4-phosphate (PI4P) at contact sites between the endoplasmic reticulum and the Golgi apparatus. Previously, we reported that OSW-1 induces the Golgi stress response, resulting in Golgi stress-induced transcription and cell death.

Effect of Linker Length on the Function of Biotinylated OSW-1 Probes.

The biotinylated probes based on anticancer saponin OSW-1 with varied linker lengths were synthesized and their cell growth inhibitory activity and affinity pulldown efficiency were evaluated. All probes demonstrated comparable cytotoxicity to the parent natural product, highlighting that the linker moiety had a minimal impact on cell uptake or target engagement. In contrast, when evaluated against the known target proteins, OSBP and ORP4, the biotinylated probe 3 with PEG5 linker enabled most effective enrichment of target proteins in the affinity pulldown assay, suggesting that the cytotoxicity and pulldown efficiency did not correlate among the probes studied.

Effects of passive smoking on cortical spreading depolarization in male and female mice.

Background: Patients with migraine are typically advised to avoid passive smoking because it may aggravate headaches and other health conditions. However, there is insufficient high-quality evidence on the association between passive smoking and migraine, which warrants further investigation using animal models. Therefore, using a mouse model, we examined the effect of passive smoking on susceptibility to cortical spreading depolarization (CSD), the biological basis of migraine with aura.

Dichlorotriazine-based multivalent probe for selective affinity labeling of carbohydrate-binding proteins.

A new series of multivalent gold nanoparticle probes bearing different electrophilic groups were synthesized and their affinity labeling reactivities were evaluated. The dichlorotriazine group was identified as a useful protein-reactive label, allowing selective capture of a target protein at nanomolar probe concentrations.

Anthocyanin glucosylation mediated by a glycoside hydrolase family 3 protein in purple carrot.

Purple carrot accumulates anthocyanins modified with galactose, xylose, glucose, and sinapic acid. Most of the genes associated with anthocyanin biosynthesis have been identified, except for the glucosyltransferase genes involved in the step before the acylation in purple carrot. Anthocyanins are commonly glycosylated in reactions catalyzed by UDP-sugar-dependent glycosyltransferases (UGTs).

Prognostic significance of chronic kidney disease and impaired renal function in Japanese patients with COVID-19.

Background: Renal impairment is a predictor of coronavirus disease (COVID-19) severity. No studies have compared COVID-19 outcomes in patients with chronic kidney disease (CKD) and patients with impaired renal function without a prior diagnosis of CKD. This study aimed to identify the impact of pre-existing impaired renal function without CKD on COVID-19 outcomes.

Differential impacts between fat mass index and fat-free mass index on patients with COPD.

Background: Differences in the clinical impacts of fat mass index (FMI) and fat-free mass index (FFMI) remain unclear in patients with chronic obstructive pulmonary disease (COPD). We hypothesized that FMI and FFMI have different impacts on 1) emphysema and 2) pulmonary function and health-related quality of life of COPD patients.

Methods: Patients with COPD (n = 228), enrolled in a multicenter prospective 3-year cohort were classified into four groups based on baseline median FMI and FFMI values.

Characteristics and clinical effectiveness of COVID-19 vaccination in hospitalized patients in Omicron-dominated epidemic wave - a nationwide study in Japan.

Objectives: COVID-19 was severe in the Delta variant-dominated epidemic wave (fifth wave) in Japan. The clinical characteristics and effectiveness of COVID-19 vaccination are not fully understood in the Omicron variant-dominated wave (sixth and seventh waves), especially in hospitalized patients. We investigated the relationship between vaccination and disease severity in the Omicron-dominated wave and compared these variant-dominated waves.

Golgi-Targeting Anticancer Natural Products.

The Golgi apparatus plays an important role in maintaining cell homeostasis by serving as a biosynthetic center for glycans, lipids and post-translationally modified proteins and as a sorting center for vesicular transport of proteins to specific destinations. Moreover, it provides a signaling hub that facilitates not only membrane trafficking processes but also cellular response pathways to various types of stresses. Altered signaling at the Golgi apparatus has emerged as a key regulator of tumor growth and survival.

Elucidation of OSW-1-Induced Stress Responses in Neuro2a Cells.

OSW-1, a steroidal saponin isolated from the bulbs of Ornithogalum saundersiae, is a promising compound for an anticancer drug; however, its cytotoxic mechanisms have not been fully elucidated. Therefore, we analyzed the stress responses triggered by OSW-1 in the mouse neuroblastoma cell line Neuro2a by comparing it with brefeldin A (BFA), a Golgi apparatus-disrupting reagent. Among the Golgi stress sensors TFE3/TFEB and CREB3, OSW-1 induced dephosphorylation of TFE3/TFEB but not cleavage of CREB3, and induction of the ER stress-inducible genes GADD153 and GADD34 was slight.

Deciphering the Biological Activities of Antifungal Agents with Chemical Probes.

The growing number of fungal infections caused by pathogens resistant to one or more classes of antifungal drugs emphasizes the threat that these microorganisms pose to animal and human health and global food security. Open questions remain regarding the mechanisms of action of the limited repertoire of antifungal agents, making it challenging to rationally develop more efficacious therapeutics. In recent years, the use of chemical biology approaches has resolved some of these questions and has provided new promising concepts to guide the design of antifungal agents.

Impact of upper and lower respiratory symptoms on COVID-19 outcomes: a multicenter retrospective cohort study.

Background: Respiratory symptoms are associated with coronavirus disease 2019 (COVID-19) outcomes. However, the impacts of upper and lower respiratory symptoms on COVID-19 outcomes in the same population have not been compared. The objective of this study was to characterize upper and lower respiratory symptoms and compare their impacts on outcomes of hospitalized COVID-19 patients.

Clinical Utility of the Electrocardiographic P-Wave Axis in Patients with Chronic Obstructive Pulmonary Disease.

Background: The vertical P-wave axis on electrocardiography (ECG) is a useful criterion for screening patients with chronic obstructive pulmonary disease (COPD). This study aimed to investigate the clinical characteristics of patients with COPD with a vertical P-wave axis as they have not yet been elucidated.

Methods: Keio University and its affiliated hospitals conducted an observational COPD cohort study over 3 years.

Reactivity Analysis of New Multivalent Electrophilic Probes for Affinity Labeling of Carbohydrate Binding Proteins.

We have designed and synthesized six different multivalent electrophiles as carbohydrate affinity labeling probes. Evaluation of the reactivity of the electrophiles against peanut agglutinin (PNA) and Ricinus communis agglutinin (RCA) showed that p- and m-aryl sulfonyl fluoride are effective protein reactive groups that label carbohydrate binding lectins in a ligand-dependent fashion at a nanomolar probe concentration. Analysis of the selectivity of affinity labeling in the presence of excess BSA as a nonspecific protein indicated that m-arylsulfonyl fluoride is a more selective protein-reactive group, albeit with attenuated reactivity.