Possible Application of the Medicinal Plant Hyoscyamus albus in Phytoremediation: Excess Copper Compensates for Iron Deficiency, Depending on the Light Conditions

Seedlings of the medicinal plant Hyoscyamus albus were supplied with an excess of Cu to examine the possible application in phytoremediation. The seedlings were cultured in B5 medium supplied with basal 0.1 μM Cu and 200 μM Cu under various light conditions: short day (SD); long day (LD); and continuous light (CL). In addition, the effect of supplying 200 μM Cu under Fe deficiency was determined, in order to elucidate the interaction between Cu and Fe. Interestingly, Fe-deficiency symptoms that developed in plants grown with basic levels of Cu under LD almost disappeared when excess Cu was supplied. Plant growth mainly depended on the photo irradiation period (SD < LD~CL); and 200 μM Cu did not inhibit growth at all when Fe was available, whereas in the absence of Fe, CL caused damage to growth. Analysis of the Cu and Fe contents of the plants revealed that Cu was distributed equally in both the aerial parts and roots, whereas most of the Fe was found in the roots; under Fe deficiency, Cu accumulation in the roots apparently increased. Cu was mainly distributed in the soluble fraction, which included vacuoles and the cell-wall fraction. These results provide evidence indicating that H. albus seedlings are tolerant of Cu present in excess. Furthermore, excess Cu was able to compensate for Fe deficiency, depending on the light conditions. Continuous light inhibited this effect, probably as a result of the induction of Mn deficiency. The possible applications of this newly discovered cuprophyte are discussed

Lactobacillus bulgaricus OLL1181 activates the aryl hydrocarbon receptor pathway and inhibits colitis

Increasing evidence suggests that the aryl hydrocarbon receptor (AhR) pathway has an important role in the regulation of inflammatory responses. Most recently, we have shown that the activation of the AhR pathway by a potent AhR agonist inhibits the development of dextran sodium sulfate (DSS)-induced colitis, a model of human ulcerative colitis, by the induction of prostaglandin E2 (PGE2) in the large intestine. Because several strains of probiotic lactic acid bacteria have been reported to inhibit DSS-induced colitis by unidentified mechanisms, we hypothesized that particular strains of lactic acid bacterium might have the potential to activate the AhR pathway, thereby inhibiting DSS-induced colitis. This study investigated whether there are specific lactic acid bacterial strains that can activate the AhR pathway, and if so, whether this AhR-activating potential is associated with suppression of DSS-induced colitis. By using AhR signaling reporter cells, we found that Lactobacillus bulgaricus OLL1181 had the potential to activate the AhR pathway. OLL1181 also induced the mRNA expression of cytochrome P450 family 1A1 (CYP1A1), a target gene of the AhR pathway, in human colon cells, which was inhibited by the addition of an AhR antagonist, α-naphthoflavon (αNF). In addition, mice treated orally with OLL1181 showed an increase in CYP1A1 mRNA expression in the large intestine and amelioration of DSS-induced colitis. Thus, OLL1181 can induce activation of the intestinal AhR pathway and inhibit DSS-induced colitis in mice. This strain of lactic acid bacterium has therefore the potential to activate the AhR pathway, which may be able to suppress colitis

日本語の破裂音/g/と/k/の調音的と音声的差異 ―MRIによるケーススタディー―

標準語話者の有声，無声の破裂音/g/，/k/の調音と音声の特徴を/agise/，/akise/の検査語を用いて検討した．音声では閉鎖区間，formant onset time (FOT)，子音区間は/k/が/g/より長く，先行母音と後続母音は/g/に隣接する場合に/k/に隣接する場合より長かった．先に報告した同じ話者の調音上の特徴に，閉鎖区間が/k/が/g/より長いこと，閉鎖のタイミングが/k/が/g/より早いことがあった．これらはそれぞれ音声上の閉鎖区間が/k/が/g/より長かったこと，/g/に先行する母音が/k/に先行する場合より長かったことに対応する．MRIの/g/，/k/の最大閉鎖フレームのトレース画を用いた計測では，/k/は/g/に比べ正中面上の閉鎖の範囲が長い傾向が見られたが，咽頭面積は個人差が大きく/g/と/k/で一定の傾向が確認できなかった

The Development of the Bengamides as New Antibiotics against Drug-Resistant Bacteria

The bengamides comprise an interesting family of natural products isolated from sponges belonging to the prolific Jaspidae family. Their outstanding antitumor properties, coupled with their unique mechanism of action and unprecedented molecular structures, have prompted an intense research activity directed towards their total syntheses, analogue design, and biological evaluations for their development as new anticancer agents. Together with these biological studies in cancer research, in recent years, the bengamides have been identified as potential antibiotics by their impressive biological activities against various drug-resistant bacteria such as Mycobacterium tuberculosis and Staphylococcus aureus. This review reports on the new advances in the chemistry and biology of the bengamides during the last years, paying special attention to their development as promising new antibiotics. Thus, the evolution of the bengamides from their initial exploration as antitumor agents up to their current status as antibiotics is described in detail, highlighting the manifold value of these marine natural products as valid hits in medicinal chemistry.Supported by grants RTI2018-098296-BI00 (Ministerio de Ciencia e Innovación), PI19/01478 from Instituto de Salud Carlos III (ISCIII) (FEDER), P20_00540 (Andalusian Government and FEDER), K99GM138758 and R35GM136286 (National Institute of General Medical Sciences of the National Institutes of Health), A-CTS-666-UGR20 (University of Granada) (FEDER), CTS-107 (Andalusian Government) and 2021-GRIN-30998 (University of Castilla-La Mancha). Partial funding for open access charge: Universidad de Málag

Diversity oriented clicking delivers β-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors

Diversity Oriented Clicking (DOC) is a discovery method geared toward the rapid synthesis of functional libraries. It combines the best attributes of both classical and modern click chemistries. DOC strategies center upon the chemical diversification of core "SuFExable" hubs-exemplified by 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs)-enabling the modular assembly of compounds through multiple reaction pathways. We report here a range of stereoselective Michael-type addition pathways from SASF hubs including reactions with secondary amines, carboxylates, 1H-1,2,3-triazole, and halides. These high yielding conjugate addition pathways deliver unprecedented β-substituted alkenyl sulfonyl fluorides as single isomers with minimal purification, greatly enriching the repertoire of DOC and holding true to the fundamentals of modular click chemistry. Further, we demonstrate the potential for biological function - a key objective of click chemistry - of this family of SASF-derived molecules as covalent inhibitors of human neutrophil elastase

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Structural requirement and stereospecificity of tetrahydroquinolines as potent ecdysone agonists.

Tetrahydroquinoline (THQ)-type compounds are a class of potential larvicides against mosquitoes. The structure-activity relationships (SAR) of these compounds were previously investigated (Smith et al., Bioorg. Med. Chem. Lett. 2003, 13, 1943-1946), and one of cis-forms (with respect to the configurations of 2-methyl and 4-anilino substitutions on the THQ basic structure) was stereoselectively synthesized. However, the absolute configurations of C2 and C4 were not determined. In this study, four THQ-type compounds with cis configurations were synthesized, and two were submitted for X-ray crystal structure analysis. This analysis demonstrated that two enantiomers are packed into the crystal form. We synthesized the cis-form of the fluorinated THQ compound, according to the published method, and the enantiomers were separated via chiral HPLC. The absolute configurations of the enantiomers were determined by X-ray crystallography. Each of the enantiomers was tested for activity against mosquito larvae in vivo and competitive binding to the ecdysone receptor in vitro. Compared to the (2S, 4R) enantiomer, the (2R, 4S) enantiomer showed 55 times higher activity in the mosquito larvicidal assay, and 36 times higher activity in the competitive receptor binding assay

Occurrence of urea-based soluble epoxide hydrolase inhibitors from the plants in the order Brassicales.

Recently, dibenzylurea-based potent soluble epoxide hydrolase (sEH) inhibitors were identified in Pentadiplandra brazzeana, a plant in the order Brassicales. In an effort to generalize the concept, we hypothesized that plants that produce benzyl glucosinolates and corresponding isothiocyanates also produce these dibenzylurea derivatives. Our overall aim here was to examine the occurrence of urea derivatives in Brassicales, hoping to find biologically active urea derivatives from plants. First, plants in the order Brassicales were analyzed for the presence of 1, 3-dibenzylurea (compound 1), showing that three additional plants in the order Brassicales produce the urea derivatives. Based on the hypothesis, three dibenzylurea derivatives with sEH inhibitory activity were isolated from maca (Lepidium meyenii) roots. Topical application of one of the identified compounds (compound 3, human sEH IC50 = 222 nM) effectively reduced pain in rat inflammatory pain model, and this compound was bioavailable after oral administration in mice. The biosynthetic pathway of these urea derivatives was investigated using papaya (Carica papaya) seed as a model system. Finally, a small collection of plants from the Brassicales order was grown, collected, extracted and screened for sEH inhibitory activity. Results show that several plants of the Brassicales order could be potential sources of urea-based sEH inhibitors