Catechol-O-methyltransferase and monoamine oxidase B inhibitory activities of Australian bee pollen.

Bee pollen is an apicultural product collected by honeybees from flower stamens and used as a functional food worldwide. In the present study, we aim to elucidate the functions of Australian bee pollen. Australian bee pollen extracts and their main components were tested for catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAOB) inhibitory activities. These enzymes are key neurotransmitters involved in Parkinson's disease and depression. Myricetin (5), tricetin (6), and luteolin (7) exhibited high COMT inhibitory activities (half maximal inhibitory concentration [IC50] = 23.3, 13.8, and 47.4 µM, respectively). In contrast, 5, 7, and annulatin (8) exhibited MAOB inhibitory activities (IC50 = 89.7, 32.8, and 153 µM, respectively). Quantitative analysis via high-performance liquid chromatography revealed that 5 was abundant in Australian bee pollen extracts. Our findings suggest that 5 contributes to the COMT and MAOB inhibitory activities of Australian bee pollen.

Prenylated acetophenones from the roots of Calendula officinalis and their anti-inflammatory activity.

Calendula officinalis is a medicinal plant in the Asteraceae family, and it has a broad range of biological activities. In this study, we focused on the roots of C. officinalis, which have remarkable anti-inflammatory properties. By using a bioassay-guided fractionation approach, prenylated acetophenones 1 and 2-of which 1 was previously unknown-were isolated, and their structures were determined by spectroscopic analysis. Both compounds decreased lipopolysaccharide-stimulated NO production in J774.1 cells. This study could lead to the use of the Calendula roots as a natural source of inflammatory mediators.

Postoperative tegafur-uracil for stage I lung adenocarcinoma: first real-world data with an exploratory subgroup analysis.

PURPOSE: The effect of postoperative tegafur-uracil on overall survival (OS) after resection of stage I adenocarcinoma has been shown in clinical trials. The purpose of this study was to investigate whether findings from randomized trials of adjuvant tegafur-uracil are reproducible in a real-world setting. METHODS: A retrospective cohort study was performed using a multi-institutional database that included all patients who underwent complete resection of pathological stage I adenocarcinoma between 2014 and 2016. Survival outcomes for patients managed with and without tegafur-uracil were analyzed using the Kaplan-Meier method and a Cox proportional hazards model for the whole patient cohort and in a selected cohort based on eligibility criteria of a previous randomized trial. Propensity score matching was used to adjust for confounding effects. RESULTS: After propensity score matching, the hazard ratios for OS were 0.57 (95% confidence interval (CI) 0.29-1.14, P = 0.11) in the whole cohort and 0.69 (95% CI 0.32-1.50, P = 0.35) in the selected cohort. CONCLUSIONS: The effects of tegafur-uracil in this retrospective study appear to be consistent with those found in randomized clinical trials. These effects may be maximized in patients aged from 45 to 75 years.

Catechol-O-methyltransferase Inhibitors from Calendula officinalis Leaf.

Calendula officinalis is commonly known as marigold and its flowers are used in herbal medicines, cosmetics, perfumes, dyes, pharmaceutical preparations, and food products. However, the utility of its leaves has not been studied in depth. The purpose of the present study was to identify the major compounds in C. officinalis leaves and to determine the inhibitory properties of the isolated compounds toward human catechol-O-methyltransferase (COMT), a key neurotransmitter involved in Parkinson's disease and depression. We isolated and identified ten compounds, including two phenylpropanoids and seven flavonoids, from C. officinalis leaf extracts, of which four flavonoids were identified from C. officinalis leaves for the first time. Eight compounds exhibited COMT inhibitory activities with IC50 values of less than 100 µM. Our results indicate that compounds in C. officinalis leaves are potentially effective for preventing Parkinson's disease and depression. Thus, C. officinalis leaves may hold promise as dietary supplements.

Thermostability and catechol-O-methyltransferase inhibitory activity of acylated anthocyanins from purple yam.

The thermostability of purple yam was investigated to be used as natural colorants. In addition, the inhibitory properties of purple yam and its isolated anthocyanins toward human catechol-O-methyltransferase (COMT), a key neurotransmitter involved in Parkinson's disease and depression, were also investigated. The thermostability of purple yam was higher than that of the reference samples (purple sweet potato and purple potato). Quantitative HPLC analysis revealed that alatanin A (2) contributed to the thermostability of purple yam. Methanol extracts of purple yam exhibited the highest COMT inhibitory activity of the tested samples. Alatanin D (1) showed the highest inhibitory activity of the anthocyanins in purple yam (IC50 19 µM). This study revealed the thermostability and COMT inhibitory activity of purple yam and may lead to its use not only as a thermostable natural source of colorants, but also for the prevention and treatment of Parkinson's disease and depression.

Are volume-dependent parameters in positron emission tomography predictive of postoperative recurrence after resection in patients with thymic carcinoma?

This study aimed to investigate the association between the volume-dependent parameters in 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG PET/CT) and a recurrence of thymic carcinoma. A retrospective chart review was performed based on our multi-institutional database to identify patients undergoing PET prior to resection of thymic carcinoma or neuroendocrine carcinoma between 1991 and 2018. The PET parameters (metabolic tumor volume and total lesion glycolysis) were evaluated retrospectively. The relevant factors were extracted and a survival analysis was performed using the Kaplan-Meier method. Sixteen patients were thus deemed to be eligible for analysis. The median follow-up period following resection was 2.65 years (range: 0.96-0.68 years). The recurrence-free survival was significantly longer in patients with a metabolic tumor volume < = 22.755 cm3 and with total lesion glycolysis < = 105.4006 g/mL (p = 0.001 and 0.001, respectively, by a log-rank test). The metabolic tumor volume and total lesion glycolysis may, therefore, be predictive of the postoperative recurrence of thymic carcinoma.

The treatment and survival of patients with postoperative recurrent thymic carcinoma and neuroendocrine carcinoma: a multicenter retrospective study.

PURPOSE: There are few data available on the outcomes of postoperative recurrent thymic carcinoma (TC) and thymic neuroendocrine carcinoma (TNEC). The aim of this study is to evaluate the treatment and survival in patients with recurrent TC and TNEC after undergoing surgical resection. METHODS: A retrospective chart review was performed using our multicenter database to identify patients with a postoperative recurrence of TC and TNEC from 1995 to 2018. The clinicopathological factors were reviewed and the survival outcomes were analyzed. RESULTS: Sixty patients were identified among 152 patients who underwent resection of TC and TNEC. The median follow-up period from the first recurrence was 14.8 months (range 0-144). The 5-year post-recurrence survival was 23% for the whole cohort. According to a univariable analysis, advanced stage [hazard ratio (HR) 2.81, 95% confidence interval (CI) 1.09-9.54], interval between primary surgery and recurrence (HR 0.97, 95% CI 0.95-0.99), any treatment for recurrence (HR: 0.27, 95% CI 0.13-0.58) and chemotherapy for recurrence (HR: 0.46, 95% CI 0.22-0.95) were significant factors related to post-recurrence survival. CONCLUSIONS: Chemotherapy rather than surgery appears to be the mainstay treatment for managing patients with postoperative recurrent TC and TNEC and it may also be considered in multidisciplinary management. Further studies with a larger sample size are required to confirm our findings.

Effects of HMGB1 on Tricellular Tight Junctions via TGF-ß Signaling in Human Nasal Epithelial Cells.

The airway epithelium of the human nasal mucosa acts as a physical barrier that protects against inhaled substances and pathogens via bicellular and tricellular tight junctions (bTJs and tTJs) including claudins, angulin-1/LSR and tricellulin. High mobility group box-1 (HMGB1) increased by TGF-ß1 is involved in the induction of nasal inflammation and injury in patients with allergic rhinitis, chronic rhinosinusitis, and eosinophilic chronic rhinosinusitis. However, the detailed mechanisms by which this occurs remain unknown. In the present study, to investigate how HMGB1 affects the barrier of normal human nasal epithelial cells, 2D and 2.5D Matrigel culture of primary cultured human nasal epithelial cells were pretreated with TGF-ß type I receptor kinase inhibitor EW-7197 before treatment with HMGB1. Knockdown of angulin-1/LSR downregulated the epithelial barrier. Treatment with EW-7197 decreased angulin-1/LSR and concentrated the expression at tTJs from bTJs and increased the epithelial barrier. Treatment with a binder to angulin-1/LSR angubindin-1 decreased angulin-1/LSR and the epithelial barrier. Treatment with HMGB1 decreased angulin-1/LSR and the epithelial barrier. In 2.5D Matrigel culture, treatment with HMGB1 induced permeability of FITC-dextran (FD-4) into the lumen. Pretreatment with EW-7197 prevented the effects of HMGB1. HMGB1 disrupted the angulin-1/LSR-dependent epithelial permeability barriers of HNECs via TGF-ß signaling in HNECs.

Propolis Components from Stingless Bees Collected on South Sulawesi, Indonesia, and Their Xanthine Oxidase Inhibitory Activity.

Three new compounds, namely, 4-(4'-hydroxy-3'-methoxyphenyl)-3,5,7-trihydroxycoumarin (1) and sulawesins A (2) and B (3), were isolated from the propolis of stingless bees ( Tetragonula aff. biroi) collected on South Sulawesi, Indonesia. In addition, five known compounds, glyasperin A, broussoflavonol F, (2 S)-5,7-dihydroxy-4'-methoxy-8-prenylflavanone, (1' S)-2- trans,4- trans-abscisic acid, and (1' S)-2- cis,4- trans-abscisic acid, were identified. The structures of the new compounds were determined by a combination of methods that included mass spectrometry and NMR spectroscopy. The absolute configuration of sulawesin A (2), a new podophyllotoxin derivative, was determined by X-ray crystallography. The absolute configuration of sulawesin B (3) was also determined by the ECD calculation. 4-(4'-Hydroxy-3'-methoxyphenyl)-3,5,7-trihydroxycoumarin (1) and sulawesin A (2) were examined for xanthine oxidase (XO) inhibitory activity; 1 exhibited XO inhibitory activity, with an IC50 value of 3.9 µM.

Survival outcomes after minimally invasive thymectomy for early-stage thymic carcinoma.

Minimally invasive surgery (MIS) has occasionally been used for selected patients with thymoma, but there is little information on the MIS approach for thymic carcinoma. The aim of this study was to evaluate survival outcomes after MIS for early-stage (Masaoka stage I-II) thymic carcinoma and thymic neuroendocrine carcinoma. A retrospective chart review of the cases recorded in our multi-institutional database was performed to identify patients who underwent resection for thymic carcinoma between 1995 and 2017. MIS thymectomy was performed in 17 cases (VATS, n = 14; RATS, n = 3. male, 41%; median age, 72 years). The median follow-up period was 32.7 (range 7.4-106) months. The five-year overall survival and relapse-free survival rates were 84.4% and 77.8%, respectively. The present study demonstrated encouraging preliminary results regarding MIS for the treatment of early-stage thymic carcinoma and thymic neuroendocrine carcinoma. Further studies with a larger sample size are required to evaluate the indications for this surgery.

Clarithromycin prevents human respiratory syncytial virus-induced airway epithelial responses by modulating activation of interferon regulatory factor-3.

Macrolide antibiotics exert immunomodulatory activity by reducing pro-inflammatory cytokine production by airway epithelial cells, fibroblasts, vascular endothelial cells, and immune cells. However, the underlying mechanism of action remains unclear. Here, we examined the effect of clarithromycin (CAM) on pro-inflammatory cytokine production, including interferons (IFNs), by primary human nasal epithelial cells and lung epithelial cell lines (A549 and BEAS-2B cells) after stimulation by Toll-like receptor (TLR) and RIG-I-like receptor (RLR) agonists and after infection by human respiratory syncytial virus (RSV). CAM treatment led to a significant reduction in poly I:C- and RSV-mediated IL-8, CCL5, IFN-ß and -λ production. Furthermore, IFN-ß promoter activity (activated by poly I:C and RSV infection) was significantly reduced after treatment with CAM. CAM also inhibited IRF-3 dimerization and subsequent translocation to the nucleus. We conclude that CAM acts a crucial modulator of the innate immune response, particularly IFN production, by modulating IRF-3 dimerization and subsequent translocation to the nucleus of airway epithelial cells. This newly identified immunomodulatory action of CAM will facilitate the discovery of new macrolides with an anti-inflammatory role.

Irsogladine maleate regulates gap junctional intercellular communication-dependent epithelial barrier in human nasal epithelial cells.

The airway epithelium of the human nasal mucosa acts as the first physical barrier that protects against inhaled substances and pathogens. Irsogladine maleate (IM) is an enhancer of gastric mucosal protective factors via upregulation of gap junctional intercellular communication (GJIC). GJIC is thought to participate in the formation of functional tight junctions. However, the effects of IM on GJIC and the epithelial barrier in human nasal epithelial cells (HNECs) remain unknown. To investigate the effects of IM on GJIC and the tight junctional barrier in HNECs, primary cultures of HNECs transfected with human telomerase reverse transcriptase (hTERT-HNECs) were treated with IM and the GJIC inhibitors oleamide and 18ß-GA. Some cells were pretreated with IM before treatment with TLR3 ligand poly(I:C) to examine whether IM prevented the changes via TLR3-mediated signal pathways. In hTERT-HNECs, GJIC blockers reduced the expression of tight junction molecules claudin-1, -4, -7, occludin, tricellulin, and JAM-A. IM induced GJIC activity and enhanced the expression of claudin-1, -4, and JAM-A at the protein and mRNA levels with an increase of barrier function. GJIC blockers prevented the increase of the tight junction proteins induced by IM. Furthermore, IM prevented the reduction of JAM-A but not induction of IL-8 and TNF-α induced by poly(I:C). In conclusion, IM can maintain the GJIC-dependent tight junctional barrier via regulation of GJIC in upper airway nasal epithelium. Therefore, it is possible that IM may be useful as a nasal spray to prevent the disruption of the epithelial barrier by viral infections and exposure to allergens in human nasal mucosa.

Pseudomonas aeruginosa elastase causes transient disruption of tight junctions and downregulation of PAR-2 in human nasal epithelial cells.

BACKGROUND: Pseudomonas aeruginosa causes chronic respiratory disease, and the elastase enzyme that it produces increases the permeability of airway epithelial cells owing to the disruption of tight junctions. P. aeruginosa is also implicated in prolonged chronic rhinosinusitis. However, the effects of P. aeruginosa elastase (PE) against the barrier formed by human nasal epithelial cells (HNECs) remain unknown. METHODS: To investigate the mechanisms involved in the disruption of tight junctions by PE in HNECs, primary cultures of HNECs transfected with human telomerase reverse transcriptase (hTERT-HNECs) were used. The hTERT-HNECs were pretreated with inhibitors of various signal transduction pathways, PKC, MAPK, p38MAPK, PI3K, JNK, NF-κB, EGF receptor, proteasome, COX1 and COX2 before treatment with PE. Some cells were pretreated with siRNA and agonist of protease activated receptor-2 (PAR-2) before treatment with PE. Expression and structures of tight junctions were determined by Western blotting, real-time PCR, immunostaining and freeze-fracture. Transepithelial electrical resistance (TER) was examined as the epithelial barrier function. RESULTS: PE treatment transiently disrupted the epithelial barrier and downregulated the transmembrane proteins claudin-1 and -4, occludin, and tricellulin, but not the scaffold PDZ-expression proteins ZO-1 and -2 and adherens junction proteins E-cadherin and ß-catenin. The transient downregulation of tight junction proteins was controlled via distinct signal transduction pathways such as the PKC, MAPK, PI3K, p38 MAPK, JNK, COX-1 and -2, and NF-κB pathways. Furthermore, treatment with PE transiently decreased PAR-2 expression, which also regulated the expression of the tight junction proteins. Treatment with a PAR-2 agonist prevented the downregulation of the tight junction proteins after PE treatment in HNECs. CONCLUSIONS: PE transiently disrupts tight junctions in HNECs and downregulates PAR-2. The transient disruption of tight junctions by PE might occur repeatedly during chronic rhinosinusitis.

Clustered Circulating Tumor Cells as a Predictor of Adjuvant-chemotherapy Efficacy in Lung Cancer.

BACKGROUND: Surrogate markers of minimal residual disease primarily include cell-free tumor DNA and circulating tumor cells. Cell-free tumor DNA might aid precise decision-making regarding who should receive adjuvant chemotherapy. However, there are no relevant reports on circulating tumor cells. Therefore, we aimed to verify whether perioperative clustered circulating tumour cells identification is a predictor of therapeutic efficacy in non-small cell lung cancer adjuvant chemotherapy. METHODS: Circulating tumor cells were diagnosed under light microscopy using a size selection method in 128 patients with clinical stage I/II non-small cell lung cancer around surgery. The main endpoint was recurrence-free survival, and the effect of adjuvant chemotherapy was verified in both groups based on perioperative clustered circulating tumor cell identification. RESULTS: In total, 49 and 79 patients were included in the clustered circulating tumor cell-positive and clustered circulating tumor cell-negative patient groups, respectively. In the clustered circulating tumor cell-positive patient group, adjuvant chemotherapy was performed in 18 patients (2-year recurrence-free survival rate, 71.8%). However, the 2-year recurrence-free survival rate was 36.3% in 31 patients who did not receive adjuvant chemotherapy (P < .01). In the clustered circulating tumor cell-negative patient group, adjuvant chemotherapy was provided in 11 patients (2-year recurrence-free survival rate, 90.9%). However, 68 patients did not receive adjuvant chemotherapy (2-year recurrence-free survival rate, 94.9%) (not significant). CONCLUSIONS: In surgical cases of clinical stage I/II non-small cell lung cancer, patients with perioperative clustered circulating tumor cells had a poor prognosis, but adjuvant chemotherapy improved their prognosis.

A case of attempted transbronchial spigot insertion for fistulous pyothorax in the residual pleural airspace after pleurectomy/decortication for malignant pleural mesothelioma.

Pleurectomy/decortication for malignant pleural mesothelioma is a relatively recent surgical approach for which there is a dearth of information on complications, especially in the late postoperative period. A 70-year-old man was diagnosed with right epithelioid malignant pleural mesothelioma and underwent pleurectomy/decortication. Computed tomography at 6 months after surgery revealed nodules on the surface of the right lung. These nodules gradually increased in size and were diagnosed as recurrent disease. Immunotherapy was started, but treatment was discontinued a few days after the first course due to pneumonitis. Subsequent oral prednisolone therapy for about 2 months ameliorated pneumonitis, but fistulous pyothorax developed. During attempted transbronchial occlusion of the responsible bronchus, some spigots penetrated the empyema cavity. Open window thoracotomy was performed on the following day. This case suggests that if there is no change in diameter between the proximal and distal parts of the responsible bronchus, transbronchial occlusion should not be chosen.

Effect of Tegafur-Uracil in Resected Stage IB Lung Adenocarcinoma According to Presence or Absence of Epidermal Growth Factor Receptor Gene Mutation: A Retrospective Cohort Study.

PURPOSE: Tegafur-uracil (UFT) is the standard postoperative adjuvant therapy for stage IB lung adenocarcinoma (LUAD) in Japan. This study aimed to determine whether UFT is effective in stage IB LUAD with and without epidermal growth factor receptor (EGFR) mutations. METHODS: This retrospective study included 169 patients with stage IB LUAD who underwent complete resection at our department between 2010 and 2021. We investigated the clinicopathological and prognostic impact of EGFR mutations as well as the postoperative use of UFT. RESULTS: EGFR mutation-positive cases tended to show a higher cumulative recurrence rate than EGFR mutation-negative cases (p = 0.081), while overall survival was comparable between the groups (p = 0.238). In the entire cohort, UFT administration was not an independent prognostic factor in the multivariate regression analysis (p = 0.112). According to a stratification analysis, UFT administration was independently associated with favorable overall survival (p = 0.031) in EGFR mutation-negative cases, while it was not associated with recurrence-free survival (p = 0.991) or overall survival (p = 0.398) in EGFR mutation-positive cases. CONCLUSION: UFT administration can improve the prognosis of EGFR mutation-negative LUAD but not EGFR mutation-positive LUAD. Thus, clinical trials of adjuvant-targeted therapy for EGFR mutation-positive stage IB LUAD should also be conducted in Japan.

Control of Polar/Antipolar Layered Organic Semiconductors by the Odd-Even Effect of Alkyl Chain.

Some rodlike organic molecules exhibit exceptionally high layered crystallinity when composed of a link between π-conjugated backbone (head) and alkyl chain (tail). These molecules are aligned side-by-side unidirectionally to form self-organized polar monomolecular layers, providing promising 2D materials and devices. However, their interlayer stacking arrangements have never been tunable, preventing the unidirectional arrangements of molecules in whole crystals. Here, it is demonstrated that polar/antipolar interlayer stacking can be systematically controlled by the alkyl carbon number n, when the molecules are designed to involve effectively weakened head-to-head affinity. They exhibit remarkable odd-even effect in the interlayer stacking: alternating head-to-head and tail-to-tail (antipolar) arrangement in odd-n crystals, and uniform head-to-tail (polar) arrangement in even-n crystals. The films show excellent field-effect transistor characteristics presenting unique polar/antipolar dependence and considerably improved subthreshold swing in the polar films. Additionally, the polar films present enhanced second-order nonlinear optical response along normal to the film plane. These findings are key for creating polarity-controlled optoelectronic materials and devices.

Protocol for cell-type-specific tissue reconstruction in the murine lung fibrogenic microenvironment.

Pulmonary fibrosis is a process characterized by epithelial injury and fibroblast activation. It is also well recognized as a predisposition to lung cancer. Here, we present a protocol to establish an in vivo model to evaluate the dynamics of alveolar epithelial type 2 cells and lung cancer cells in the context of the lung fibrogenic microenvironment. Utilizing the cell transfer technique, we detail a basis for therapeutic approaches in pulmonary fibrosis and tools for precision medicine against lung cancer. For complete details on the use and execution of this protocol, please refer to Miyata et al. (2022).1.