Isolation of C-29 oxygenated oleanane triterpenoids and a (+)-muurolene type sesquiterpenoid from the fruiting bodies of Fuscoporia torulosa and their bioactivities.

Basidiomycetes with a wide variety of skeletons of secondary metabolites can be expected to be the source of new interesting biological compounds. During our research on basidiomycetes, two new C-29 oxygenated oleanane-type triterpenes (1 and 2) and torulosacid (3), a muurolene type sesquiterpenoid with a five-membered ether ring along with nine known compounds (4-12), were isolated from the MeOH extract of the fruiting bodies of Fuscoporia torulosa. The structures of 1-3 were determined by NMR and HREIMS analysis. Further studies on the stereochemistry of 3 were conducted using X-ray crystallographic analysis and comparison of experimental and calculated ECD spectra. In the antimicrobial assay of isolates, 1, 7, and 9 showed growth inhibitory activity against methicillin-resistant Staphylococcus aureus and other gram-positive strains. Isolation of oleanane type triterpenes from fungi including basidiomycetes, is a unique report that could lead to further isolation of new compounds and the discovery of unique biosynthetic enzymes.

Ternifolipyrons A-J: new cytotoxic α-pyrones from Isodon ternifolius (D. Don) Kudô.

Isodon ternifolius (D.Don) Kudô is an important Asian herb used in traditional medicine against several diseases. Nineteen compounds were isolated from the dichloromethane-methanol (1 : 1) extract of I. ternifolius roots, including ten new α-pyrone derivatives, named ternifolipyrons A-J. The chemical structures of the isolates were determined by a combination of 1D and 2D NMR, along with LR- and HRMS spectroscopy. The absolute configurations of the α-pyrone derivatives were constructed based upon the X-ray signal crystal of the bromobenzoyl derivative of 1 as well as the electronic circular dichroism (ECD). All isolates (1-19) were investigated for their growth-inhibitory potential towards CCRF-CEM-leukemia cells at a fixed concentration of 30 µM. The compounds which exerted more than 50% inhibition at this concentration, compounds (7, 10, 12, 15-17), were tested at a different concentration range to determine their IC50 values in CCRF-CEM leukemia, MDA-MB-231 triple-negative breast cancer, and MCF7 breast cancer cell lines. Ursolic acid (16) showed the most potent activity against the three cancer cell lines with IC50 values of 8.37, 18.04, and 18.93 µM, respectively.

Bifusicoumarins A-D: Cytotoxic 3S-dihydroisocoumarins from the entomopathogenic fungus Cordyceps bifusispora (NBRC 108997).

Cordyceps is a genus of ascomycete fungi with some of them being edible and/or having a long tradition in Chinese medicine. The chemical characterization of a solvent extract of the entomopathogenic fungus Cordyceps bifusispora afforded four undescribed coumarins, bifusicoumarin A-D (1-4), along with previously reported metabolites (5-8). Structural elucidation was performed via NMR, UV and HRMS analyses, X-ray single crystal diffraction and experimental ECD. A high throughput resazurin reduction assay, that measures cell viability, indicated that 5 has a IC50 between 1 and 15 µM for several assayed tumor lines. Moreover, a protein-interaction network indicated that C. bifusispora is a promising source of additional antitumor metabolites based on SwissTargetPrediction software predictions.

Report on the 1st and 2nd Japan Young Psychiatrists Organization Online International Networking Meetings (JOIN meetings) in 2021 and 2022.

Since 2002, the Japan Young Psychiatrists Organization (JYPO) has conducted an annual face-to-face Course for Academic Development of Psychiatrists (CADP). Since 2021, we held two international online meetings and studied whether it was possible to acquire professional and leadership skills. We found that participants were able to acquire knowledge and become acquainted with professional and leadership skills in online meetings. However, they didn't enough enable participants to get to know each other, develop friendships, or acquire professional and leadership skills. The advantages of online meetings included lower cost, avoiding infection during the pandemic, and the easy use of course materials.

Antimicrobial metabolite of Cordyceps tenuipes targeting MurE ligase and histidine kinase via in silico study.

Cordyceps spp. are widely healthy foods around the world with several traditional uses and bio-functionalities. The chemical characterization of ethyl acetate-soluble extract of the entomopathogenic fungus Cordyceps tenuipes NBRC 111,630 afforded two new metabolites with 1,6-dioxaspiro[4.4]nonane motif, tenuipesone A (1) and tenuipesone B (2), along with four well-known metabolites (3-6). The elucidation of the chemical structures was carried out via extensive spectroscopic experiments including FTIR, HRMS, 1D-NMR, and 2D-NMR. The probable biosynthetic pathway of 1 and 2 was hypothesized. From the six isolates, beauvericin (6) exhibited antimicrobial activity against Bacillus subtilis and Staphylococcus aureus with respective MIC of 6.25 and 12.5 µM. Docking results exhibited that beauvericin (6) has significant binding affinities against MurE and HK proteins with ΔG = - 8.021 and - 8.585 kcal/mol, respectively. KEY POINTS: • Six compounds, including two new, were isolated from the entomopathogenic fungus Cordyceps tenuipes. • Plausible biosynthetic pathway of compounds 1, 2, 4, and 5 was hypothesized. • Beauvericin (6) exhibited significant antimicrobial activity against Bacillus subtilis and Staphylococcus aureus alongside binding affinities against MurE and HK proteins in MOE study.

Sex and Age Stratified Voice Data in Japanese Vocally Healthy Individuals: Vocal Capacity.

OBJECTIVE: There is no normative voice dataset regarding the vocal capacity of Japanese speakers in the English literature. We collected age- and sex-stratified data on the vocal capacity of vocally healthy Japanese speakers. METHODS: In total, 111 vocally healthy Japanese speakers (42 men and 69 women) were divided into the young (13 men and 30 women), middle-aged (18 men and 27 women), and elderly (11 men and 12 women) groups. Participants underwent duration-, intensity-, and pitch-related vocal capacity tests using either a conventional method or an aerodynamic method or both. The data obtained were statistically analyzed in terms of age and sex. RESULTS: Overall, the duration- and pitch-related parameters measured by the conventional method were generally comparable to the previous results in the literature, while duration-, pitch-, and intensity-related parameters measured by the aerodynamic method differed significantly from them. Significant sex differences were noted in all parameters in the duration-, intensity-, and pitch-related vocal capacity tests. Furthermore, significant age-related changes were observed in all parameters, except for the mean flow rate and highest pitch measured by the aerodynamic method. CONCLUSION: This study is the first to provide a sex- and age-stratified database of the normative vocal capacity data of Japanese speakers. However, further improvements will be needed in the assessment protocols, conditions, or devices used for the duration-, intensity-, and pitch-related vocal capacity tests in the aerodynamic method.

Total Syntheses of Proposed Structures of 4,10-Dihydroxy-8,12-guaianolides.

The first total syntheses of two 4,10-dihydroxy-8,12-guaianolides that were reported to be natural products were achieved. Toward the syntheses of a collection of related guaianolides, the typical 5,7-fused system of 8,12-guaianolides was constructed by a ring expansion reaction of a hydroxylated coronafacic acid analogue that can be practically synthesized and optically resolved. The total syntheses of these compounds revealed that the previously reported structures of both natural products were incorrect.

Gender- and Age- Stratified Normative Voice Data in Japanese-Speaking Subjects: Analysis of Sustained Habitual Phonations.

INTRODUCTION: There is no normative voice dataset for Japanese speakers in the English literature. We constructed age- and gender-stratified normative voice data with the assistance of vocally healthy Japanese speakers. METHODS: A total of 111 vocally healthy Japanese speakers (42 men, 69 women) were divided into young (13 men, 30 women), middle-aged (18 men, 27 women), and elderly (11 men, 12 women) groups. Participants underwent aerodynamic, acoustic, and audio-perceptual studies of sustained habitual vowel phonations, and the obtained data were statistically analyzed in terms of age and gender. RESULTS: Both gender- and age-related differences were noted in fundamental frequencies, sound pressure level, shimmer, and amplitude perturbation quotient, while only gender-related differences were noted in mean flow rate and only age-related changes were observed in subglottal pressure; laryngeal resistance; and G, R, B, and S scores of the GRBAS scale. The gender- and age-related difference data were comparable with the reported data in other languages, ethnicities, or countries. CONCLUSIONS: The present study is the first to provide a database of normative voice data of Japanese speakers. The idiosyncrasy of Japanese is considered minor in sustained habitual vowel phonations.

Multivariate Analysis of Vocal Fold Vibrations in Normal Speakers Using High-Speed Digital Imaging.

INTRODUCTION: Little is known about the normal variations in vocal fold vibrations. We conducted a prospective study on normal subjects using high-speed digital imaging (HSDI) to elucidate key parameters regarding age/gender-related normal variations. METHODS: Forty-six healthy adult volunteers were divided into young (aged ≤35 years) male, young female, elderly (aged ≥65 years) male, and elderly female subgroups. HSDI data of sustained phonation of /i/ at a comfortable pitch and loudness were obtained, and vibratory parameters were calculated using the visual-perceptual rating, laryngotopography, digital kymography, and glottal area waveform. Multivariate analysis was then performed on these parameters to clarify the subgroup-specific key parameters. RESULTS: Four key parameters were identified from a total of 83: one from visual perceptual rating and three from laryngotopography. Subgroup analyses showed that posterior-to-anterior longitudinal phase difference (PD) and high fundamental frequency (F0) were specific to young female participants. A low F0 was specific to young male participants. Large anterior-to-posterior longitudinal PD and its left-right difference were specific to elderly male participants. There were no key parameters for elderly female participants. CONCLUSIONS: Methods that can assess F0 and longitudinal PD, such as visual-perceptual rating and laryngotopography, were effective in the evaluation of normal vocal fold vibrations and their variations.

A Concise Total Synthesis of Dehydroantofine and Its Antimalarial Activity against Chloroquine-Resistant Plasmodium falciparum.

The total synthesis of dehydroantofine was achieved by employing a novel, regioselective, azahetero Diels-Alder reaction of easily accessible 3,5-dichloro-2H-1,4-oxazin-2-one with 14 a as a key step. Furthermore, it is demonstrated that dehydroantofine is a promising candidate as a new antimalarial agent in a biological assay with chloroquine-resistant Plasmodium falciparum.

Design and synthesis of dual active neovibsanin derivatives based on a chemical structure merging method.

A hybrid compound consisting of neovibsanin and trans-banglene was designed according to a structure merging method and synthesized via a sequence of key steps including a Diels-Alder cycloaddition, stereoselective alkynylation, and intramolecular oxa-Michael addition reaction. The biological activity of the synthetized acetal compound and its hemiacetal analogue was investigated in PC12 cells. These studies revealed that the designed hybrid compounds displayed neuritogenic activity. Furthermore, a relatively strong neurite outgrowth promoting activity was observed in the presence of NGF. These results suggest that the designed hybrid compound exhibited a dual activity.

New alkaloidal metabolites from cultures of entomopathogenic fungus Cordyceps takaomontana NBRC 101754.

Two new alkaloidal metabolites, cordytakaoamides A (1) and B (2), as well as, 2-[(2-hydroxyethyl) amino] benzoic acid (3) and 2E-decenamide (4), and three known compounds (5-7) were isolated from ethyl acetate and n-butanol soluble portions of the entomopathogenic fungus, Cordyceps takaomontana NBRC 101754. Compounds 3 and 4 were isolated here for first time from natural resources. The chemical structures were established depending upon spectroscopic techniques such as 1D, 2D NMR, and HRMS. The absolute configuration of 1 and 2 was elucidated via the total synthesis of 1 as well as the experimental circular dichroism. Compound 3 was confirmed by a signal crystal X-ray analysis.

Asymmetric Total Syntheses and Structure Elucidations of (+)-Eurotiumide F and (+)-Eurotiumide G.

Asymmetric total syntheses of dihydropyran containing natural products, (+)-eurotiumide F and (+)-eurotiumide G have been described. These total syntheses revealed the absolute configuration of eurotiumide F and G, and confirmed the reported structure of eurotiumide F and revised the reported structure of eurotiumide G. Highlight of these syntheses is thermal rearrangement with 4-methoxyisochroman-1-one derivative having propargyl ether on phenolic ether under thermal condition to construct dihydropyran ring. X-Ray crystallographic analysis of (+)-eurotiumide G clarified the stereochemistry at the C1-position.

Marylosides A-G, Norcycloartane Glycosides from Leaves of Cymbidium Great Flower 'Marylaurencin'.

Seven novel norcycloartane glycosides, maryloside A-G (1-7), were isolated from the leaves of Cymbidium Great Flower 'Marylaurencin', along with a known norcycloartane glycoside, cymbidoside (8). These structures were determined on the basis of mainly NMR experiments as well as chemical degradation and X-ray crystallographic analysis. The isolated compounds (1-6 and 8) were evaluated for the inhibitory activity on lipopolysaccharide (LPS) and interferon-γ (IFN-γ)-stimulated nitric oxide (NO) production in RAW 264.7 cells. Consequently, 1 and 3 exhibited moderate activity.

Kaemgalangol A: Unusual seco-isopimarane diterpenoid from aromatic ginger Kaempferia galanga.

A new unusual seco-isopimarane, kaemgalangol A (1) and 12 usual analogs (2-13) were isolated from the rhizomes of Kaempferia galanga (Family: Zingiberaceae). KaemgalangolA (1) represented a rarely isolated 9,10-seco-isopimarane skeleton. The chemical structures of the isolated compounds were mainlyinvestigated by spectroscopic techniques such as 1D, 2D NMR, and HRMS. The absolute configuration of 1-3 was studied by X-ray diffraction analysis as well as experimental and TDDFT-calculated electronic circular dichroism. Among the isolated diterpenoids, 5, 6 and 9 exhibited cytotoxic activity against HeLa (IC50 75.1, 74.2 and 76.5 µM, respectively) and HSC-2 (IC50 69.9, 53.3 and 58.2 µM, respectively) cancer cells.

Tetrahydrofuran lignans: Melanogenesis inhibitors from Premna integrifolia wood collected in Myanmar.

Two new tetrahydrofuran lignans, taungtangyiols A (1) and B (2), and eight known furofuran lignans (3-10), were isolated from the chloroform extract of Premna integrifolia wood collected in Myanmar. Their structures were elucidated by extensive spectroscopic techniques. The X-ray crystal structure of 1 clearly indicated its relative configuration. Taungtangyiols A (1) and B (2) inhibited the deposition of melanin in B16F10 mouse melanoma cells, with IC50 values of 50.7 and 40.9 µM, respectively, without notable cytotoxicity. An SAR study demonstrated that the furofuran and dioxymethylene moieties of the lignans play a vital role in inhibiting melanogenesis.

Characterization of Vocal Fold Vibration in Sulcus Vocalis Using High-Speed Digital Imaging.

Purpose: The aim of the present study was to qualitatively and quantitatively characterize vocal fold vibrations in sulcus vocalis by high-speed digital imaging (HSDI) and to clarify the correlations between HSDI-derived parameters and traditional vocal parameters. Method: HSDI was performed in 20 vocally healthy subjects (8 men and 12 women) and 41 patients with sulcus vocalis (33 men and 8 women). Then HSDI data were evaluated by assessing the visual-perceptual rating, digital kymography, and glottal area waveform. Results: Patients with sulcus vocalis frequently had spindle-shaped glottal gaps and a decreased mucosal wave. Compared with the control group, the sulcus vocalis group showed higher open quotient as well as a shorter duration of the visible mucosal wave, a smaller speed index, and a smaller glottal area difference index ([maximal glottal area - minimal glottal area]/maximal glottal area). These parameters deteriorated in order of the control group and Type I, II, and III sulcus vocalis. There were no gender-related differences. Strong correlations were noted between the open quotient and the type of sulcus vocalis. Conclusions: HSDI was an effective method for documenting the characteristics of vocal fold vibrations in patients with sulcus vocalis and estimating the severity of dysphonia.

High-speed Videolaryngoscopy: Quantitative Parameters of Glottal Area Waveforms and High-speed Kymography in Healthy Individuals.

OBJECTIVES: We conducted a study to obtain quantitative parameters of the vocal dynamic using high-speed videolaryngoscopy and to characterize the vocal fold vibration pattern of healthy individuals by analyzing glottal area waveforms and high-speed kymography. METHODS: Laryngeal images of 45 healthy individuals were captured using high-speed videolaryngoscopy. The open and speed quotients of the glottal area waveforms and high-speed kymography were obtained and statistically analyzed according to the gender of each individual. RESULTS: Glottal area waveforms revealed average values of 0.85 and 1.16 for open and speed quotients, respectively, for women, and 0.70 and 1.19 for men. Using high-speed kymography, quantitative parameters of open and speed quotients for women were 0.62 and 1.02, respectively, and for men were 0.57 and 1.12. By gender, a significant statistical difference emerged for open quotients obtained from both glottal area waveforms (P = 0.004) and high-speed kymography (P = 0.013). CONCLUSION: Obtained by using computational tools specifically for analyzing laryngeal images from high-speed videolaryngoscopy, quantitative parameters of glottal area waveforms and high-speed kymography in healthy individuals provide reference data and normality for future studies.

Aryl-Allene Cyclization via a Hg(OTf)2-Catalytic Pathway.

Hg(OTf)2-catalyzed aryl-allene cyclization accompanied by formation of a quaternary carbon center has been realized. Deuterium-labeling experiments and computational modeling were used to propose a novel catalytic pathway involving direct H-transfer from the aromatic ring to the vinyl mercury moiety followed by mercury 1,2-migration.

Chemical Hybridization of Vizantin and Lipid A to Generate a Novel LPS Antagonist.

Lipopolysaccharide (LPS) antagonists have attracted considerable interest as promising candidates for the treatment of severe sepsis triggered by Gram-negative bacteria. In this article, we describe the development of a novel LPS antagonist based on chemical hybridization of vizantin and the hydrophobic molecular unit of LPS (lipid A). Vizantin, 6,6'-bis-O-(3-nonyldodecanoyl)-α,α'-trehalose, was designed as an immunostimulator from a structure-activity relationship (SAR) study with trehalose 6,6'-dicorynomycolate (TDCM). Our recent study indicated that vizantin displays adjuvant activity by specifically binding to the Toll-like receptor 4 (TLR4)/MD2 protein complex. Because lipid A unit (or LPS) is also known to trigger an inflammatory response via the same TLR4/MD2 complex as vizantin, we designed a hybrid compound of vizantin and lipid A with the aim of developing a novel biofunctional glycolipid. Focusing on the antagonism to Escherichia coli LPS in an in vitro model with human macrophages (THP-1 cells), we identified a potent LPS antagonist among the synthesized hybrid compounds. The novel LPS antagonist effectively inhibited LPS-induced release of tumor necrosis factor-alpha (TNF-α) in a dose-dependent manner with an IC50 value of 3.8 nM, making it a candidate for the treatment drug of Gram-negative sepsis and/or septic shock.