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Discovery of (R)-(3-fluoropyrrolidin-1-yl)(6-((5-(trifluoromethyl) pyridin-2-yl)oxy)quinolin-2-yl)methanone (ABBV-318) and analogs as small molecule Nav1.7/Nav1.8 blockers for the treatment of pain

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BIOORGANIC & MEDICINAL CHEMISTRY 2022年 63卷 116743页

作者： Patel, Meena, V Peltier, Hillary M. Matulenko, Mark A. Koenig, John R. Scanio, Marc J. C. Gum, Rebecca J. El-Kouhen, Odile f. fricano, Meagan M. Lundgaard, Greta L. Neelands, Torben Zhang, Xu-feng Zhan, Cenchen Pai, Madhavi Ghoreishi-Haack, Nayereh Hudzik, Thomas Gintant, Gary Martin, Ruth McGaraughty, Steve Xu, Jun Bow, Daniel Kalvass, John C. Kym, Philip R. DeGoey, David A. Kort, Michael E. AbbVie Res & Dev Dept R467AP10-1081 North Waukegan Rd N Chicago IL 60064 USA

The voltage-gated sodium channel Na(v)1.7 is an attractive target for the treatment of pain based on the high level of target validation with genetic evidence linking Na(v)1.7 to pain in humans. Our effort to identify selective, CNS-penetrant Na(v)1.7 blockers with oral activity, improved selectivity, good drug-like properties, and safety led to the discovery of 2-substituted quinolines and quinolones as potent small molecule Na(v)1.7 blockers. The design of these molecules focused on maintaining potency at Na(v)1.7, improving selectivity over the hERG channel, and overcoming phospholipidosis observed with the initial leads. The structure-activity relationship (SAR) studies leading to the discovery of (R)-(3-fluoropyrrolidin-1-yl)(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-2-yl)methanone (ABBV-318) are described herein. ABBV-318 displayed robust in vivo efficacy in both inflammatory and neuropathic rodent models of pain. ABBV-318 also inhibited Na(v)1.8, another sodium channel isoform that is an active target for the development of new pain treatments.

关键词： Na v 1.7 voltage-gated sodium channel type 7 CIP congenital insensitivity to pain SCN9A sodium channel, voltage-gated, type IX, R subunit VGSC voltage-gated sodium channel SAR structure activity relationship hERG human Ether-à-go-go-Related Gene fRET fluorescence Resonance Energy Transfer MIA-OA mono-iodoacetate-induced osteoarthritis HEK human embryonic kidney CNS central nervous system PK pharmacokinetic Clint,u in- vitro intrinsic clearance, unbound f oral bioavailability TfA trifluoroacetic acid HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5– b ]pyridinium 3-oxid hexafluorophosphate) TBTU O-(benzotriazol-1-yl)- N,N,N′,N′- tetramethyluronium tetrafluoroborate DMSO dimethyl sulfoxide DRG Dorsal root ganglion LMA Locomotor assay SNL Spinal nerve ligation

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Phyllanthus muellerianus and ficus exasperata exhibit anti-proliferative and pro-apoptotic activities in human prostate cancer PC-3 cells by modulating calcium influx and activating caspases

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BIOLOGIA 2022年第7期77卷 1981-1994页

作者： Deeh, Patrick Brice Defo Arumugam, Madankumar Alagarsamy, Karthik Karanam, Gayathri Natesh, Nagabhishek Sirpu Watcho, Pierre Vishwakarma, Vinita Univ Dschang Anim Physiol & Phytopharmacol Lab POB 67 Dschang Cameroon Sathyabama Inst Sci & Technol Ctr Nanosci & Nanotechnol Chennai Tamil Nadu India Sathyabama Inst Sci & Technol Mol & Nanomed Res Unit Chennai 600119 Tamil Nadu India

Phyllanthus muellerianus (PM) and ficus exasperata (fE) are plants used against cancers. We evaluated the phytochemical profiles and in vitro antioxidant potentials of PM and fE, and investigate their effects on cell proliferation, intracellular calcium ([Ca2+](i)), caspases 3/9, apoptosis, oxidative stress markers, and Bax/cytochrome C expression in PC-3 cells. The phytochemical profiles were evaluated by liquid chromatography-mass spectrometry (LC-MS), and the antioxidant by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals scavenging method. The cells were incubated for 24 h with 3% tween 80, paclitaxel (5 nM), PM (800 and 1200 mu g/ml), and fE (800 and 1200 mu g/ml). After treatments, [Ca2+](i), caspases 3/9, apoptosis and oxidative stress parameters were measured using colorimetric kits, while the mRNA levels of Bax and cytochrome C were quantified by RT-qPCR. Nitidine, phloridzin and linoleic acid were identified in PM, while docosane, cardanol and chlorogenic acid were revealed in fE. The in vitro antioxidant potential of PM was greater than that of fE. Both plants inhibited the growth of PC-3 cells in a dose-dependent manner, but significantly (p < 0.5-0.001) increased [Ca2+](i), apoptosis level, caspase 3/9 activities, reactive oxygen species production and lipid peroxidation, compared with control. Moreover, the activities of superoxide dismutase, catalase and glutathione peroxidase were significantly decreased in the cells incubated with the plant extracts, PM being the most effective. Paclitaxel, PM and fE upregulated Bax and cytochrome C genes in PC-3 cells. PM and fE inhibited the growth of PC-3 cells by modulating the [Ca2+](i) and inducing apoptosis through Bax/Cytochrome C/Caspase 3-9 signaling pathway.

关键词： P muellerianus f exasperata Prostate cancer Apoptosis PC-3 cells

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Lonicera rupicola *** Thoms flavonoids ameliorated dysregulated inflammatory responses, intestinal barrier, and gut microbiome in ulcerative colitis via PI3K/AKT pathway

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PHYTOMEDICINE 2022年 104卷 154284页

作者： Li, Congcong Zhao, Juebo Wei, Yucai Zhai, Shuo Tan, Min Guan, Kuikui Huang, Zhihong Chen, Chaoxi Southwest Minzu Univ Coll Anim & Vet Sci Chengdu 610041 Peoples R China Southwest Minzu Univ Key Lab Qinghai Tibetan Plateau Anim Genet Resourc Chengdu 610041 Peoples R China Southwest Minzu Univ Coll Anim & Vet Sci Key Lab Qinghai Tibetan Plateau Anim Genet Resourc Chengdu 610041 Peoples R China

Background: Lonicera rupicola *** Thoms (LRH) is used as a customary medicinal herb in Tibetans. And LRH flavonoids have excellent anti-inflammatory and antioxidant pharmacological activities. However, the specific effects of LRH and its mechanism remain unknown, and there is a deficiency of systematic research, leading to the waste of LRH as a medicinal ***: In this study, in an attempt to rationalize the development and utilization of Tibetan herbal resources, the therapeutic efficacy and the underlying molecular mechanisms of LRH flavonoids on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) were investigated, establishing the favorable basis for the pharmacodynamic material basis of LRH and providing a scientific basis for the discovery of new drugs for the treatment of UC. Methods: firstly, ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was used for identification and detection of the flavonoid components of LRH. Meanwhile, their potential targets, biological functions and signaling pathways were predicted with the assistance of network pharmacology analysis. Subsequently, pharmacological efficacy of LRH were evaluated by body weight loss, colon length, disease activity index (DAI), histology observation and the expression levels of inflammatory mediators, messenger RNA (mRNA) and tight junction proteins. Moreover, in the present investigation, we also profiled the gut microbiome via high-throughput sequencing of the V3 -V4 region of 16S ribosomal DNA (rDNA) for bacterial community composition and diversity by Illumina MiSeq platforms. finally, the key regulatory proteins in the PI3K/AKT pathways were measured to investigate their underlying molecular ***: A total of 37 LRH flavonoid components were identified and detected by UPLC-MS/MS, and 12 potential active components were obtained after screening. 137 of their common targets with UC were further predicted. GO and KEGG pathway enri

关键词： inflammation intestinal barrier gut microbiome ulcerative colitis PI3K AKT pathway Lonicera rupicola Hook f et Thoms

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Quercetin and Luteolin may be the New Effective Drugs for Radiation Pneumonitis: Based on a Systems Pharmacology

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NATURAL PRODUCT COMMUNICATIONS 2022年第10期17卷

作者： Zhang, Mengmei Li, Guangcai Hu, Huaqing Yi, Mu Li, Yang Luo, Jihang Tang, Yan Xu, Guangmin Yang, Ze Liu, Xiao Zunyi Med & Pharmaceut Coll Zunyi Guizhou Peoples R China Gushi Cty Peoples Hosp Gu Shi Peoples R China Zunyi Med Univ Zunyi Guizhou Peoples R China Zunyi Med Univ Affiliated Hosp 2 Zunyi Guizhou Peoples R China Zunyi Med Univ Affiliated Hosp Zunyi Guizhou Peoples R China Jinan Univ Zhuhai Hosp Zhuhai Peoples R China

Background: The occurrence of radiation pneumonia not only affects the efficacy of radiotherapy, but also seriously threatens the health of patients undergoing radiotherapy for lung cancer. Studies have suggested that a feining granule is a potentially effective drug for the treatment of radiation pneumonitis, but its mechanism and main components are still unclear. Our study used bioinformatics methods to analyze the main drug Aster tataricus L. f. in feining granules and aims to gain the main mechanism in the treatment of radiation pneumonitis. Methods: Analyzed the effective drug components and targets of A tataricus through the Traditional Chinese Medicine Systems Pharmacology website. And obtained gene targets related to radiation pneumonia through the website of OMIM, Genecard, and Disgenet. Protein-protein interaction (PPI), gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of the obtained drugs and gene-related targets were conducted. Verify the effects of small molecule drugs on corresponding targets by conducting molecular docking experiments. Results: In total, 193 targets were identified for 13 molecules of A tataricus, and 897 genes were identified to be related to radiation pneumonia. finally, we obtained 111 genes by crossing drug and disease-related target genes. Using PPI, GO, and KEGG analysis, we found TP53, HSP90AA1, RELA, JUN, AKT1, mitogen-activated protein kinase 1 (MAPK1), tumor necrosis factor (TNf), and interleukin-6 (IL-6) are the most critical genes, which were mainly focused on the GOs of DNA-binding transcription factor, RNA polymerase II-specific DNA-binding transcription factor and protein serine/threonine kinase activity, and the pathways of lipids and atherosclerosis, advanced glycation end products and their receptors, and IL-17. Conclusion: Through molecular docking experiments, it was found that the small molecules of quercetin and luteolin bind tightly to RELA and JUN proteins. We reveal the mechani

关键词： lung cancer radiation pneumonitis Aster tataricus L f network pharmacology traditional Chinese medicine

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Ripening mechanism of astringent persimmon by ethylene under cold storage

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JOURNAL Of HORTICULTURAL SCIENCE & BIOTECHNOLOGY 2022年第3期97卷 376-384页

作者： Park, Dosu Tilahun, Shimeles Jeong, Cheon Soon Cornell Univ Coll Agr & Life Sci Sch Integrat Plant Sci Hort Sect Ithaca NY 14850 USA Kangwon Natl Univ Dept Hort Chunchon South Korea

The mechanism of ripening and the expression of ethylene response genes of astringent persimmon (Diospyros kaki L.f.) treated with ethylene at different times during cold storage has been investigated. freshly harvested fruit was stored at 0 degrees C and 85% relative humidity for up to 2 months, and treated with 100 mu L L (-1) ethylene at 0, 1, and 2 months. The ethylene treatment was proceeding at 25 degrees C until 4 d. Ethylene production patterns were similar in fruit from the ethylene treatment regardless of the treatment time point, but maximum ethylene production occurred earlier with longer storage periods. Softening of ethylene treated fruit was more rapid after storage than at harvest. Although the reduction of soluble tannin was similar in fruit from all ethylene treatments, it was faster with longer storage periods. Expression of DKEIL, DKERf3, DKERf5, and DKERf8 transcript levels was higher in stored fruit than at harvest. The results of this study suggest that the astringency removal and ripening of cold stored persimmon fruit could be accelerated by 1-2 d compared with ripening at harvest.

关键词： Astringency removal diospyros kaki L f cold storage softening post harvest gene expression

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Genetic Identification and Relationship Analysis of Captive Breeding falcons

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RUSSIAN JOURNAL Of GENETICS 2022年第6期58卷 705-717页

作者： Belokon, M. M. Belokon, Y. S. Nechaeva, A. V. Sylvestrov, N. A. Sarychev, E. I. Beme, I. R. Russian Acad Sci Vavilov Inst Gen Genet Moscow 119991 Russia Moscow MV Lomonosov State Univ Moscow 119991 Russia Vitasphera Co Ltd Breeding Ctr Slobodino 140170 Moscow Oblast Russia

for three species of captive breeding falcons-gyrfalcon (falco rusticolus), saker falcon (f. cherrug), and peregrine falcon (f. peregrinus)-a universal system of genetic identification based on multilocus microsatellite genotypes has been tested. The estimates of relatedness in the species groups of birds from breeding centers are analyzed. A set of 13 nuclear microsatellite loci makes it possible to reliably identify individuals and clarify whether individuals belong to related groups, and in some cases, it makes it possible to recognize interspecific hybrids. The results of this study can be used in breeding and introduced into the practice of forensic molecular genetic examination.

关键词： gyrfalcon falco rusticolus saker falcon f cherrug peregrine falcon f peregrinus microsatellites identification certification relationship

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Optimization of pig models for translation of subcutaneous pharmacokinetics of therapeutic proteins: Liraglutide, insulin aspart and insulin detemir

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TRANSLATIONAL RESEARCH 2022年 239卷 71-84页

作者： Pedersen, Karen-Margrethe Gradel, Anna Katrina Jogvansdottir Ludvigsen, Trine Pagh Christoffersen, Berit Ostergaard fuglsang-Damgaard, Caroline Amalie Bendtsen, Kristian Moss Madsen, Suzi Hogh Manfe, Valentina Refsgaard, Hanne Hoffmann frolund Novo Nordisk AS Global Drug Discovery Novo Nordisk Pk 1 DK-2760 Malov Denmark Univ Copenhagen Dept Vet & Anim Sci Sect Expt Anim Models Copenhagen Denmark Novo Nordisk AS Translat Med Novo Nordisk Pk 1 DK-2760 Malov Denmark Novo Nordisk AS Global Res Technol Novo Nordisk Pk 1 DK-2760 Malov Denmark

Prediction of human pharmacokinetics (PK) from data obtained in animal studies is essential in drug development. Here, we present a thorough examination of how to achieve good pharmacokinetic data from the pig model for translational purposes by using single-species allometric scaling for selected therapeutic proteins: liraglutide, insulin aspart and insulin detemir. The predictions were based on non-compartmental analysis of intravenous and subcutaneous PK data obtained from two injection regions (neck, thigh) in two pig breeds, domestic pig and Gottingen Minipig, that were compared with PK parameters reported in humans. The effects of pig breed, injection site and injection depth (insulin aspart only) on the PK of these proteins were also assessed. Results show that the prediction error for human PK was within two-fold for most PK parameters in both pig breeds. furthermore, pig breed significantly influenced the plasma half-life and mean absorption time (MAT), both being longer in G6ttingen Minipigs compared to domestic pigs (P <0.01). In both breeds, thigh vs neck dosing was associated with a higher dose-normalized maximum plasma concentration and area under the curve as well as shorter MAT and plasma half-life (P <0.01). finally, more superficial injections resulted in faster absorption, higher C-max/dose and bioavailability of insulin aspart (P <0.05, 3.0 vs 5.0 mm injection depth). In conclusion, pig breed and injection region affected the PK of liraglutide, insulin aspart and insulin detemir and reliable predictions of human PK were demonstrated when applying single-species allometric scaling with the pig as a pre-clinical animal model.

关键词： ANOVA Analysis of Variance AUC Area under the plasma concentration vs time curve from time zero to infinity AUC/dose Dose-normalized area under the plasma concentration vs time curve from time zero to infinity AUMC Area under the first moment curve AUC% Extrapolated Percentage of AUC inf due to extrapolation from time of last measurable concentration to infinity BW Body weight C max Maximum plasma concentration C max /dose Dose-normalized maximum plasma concentration CV Coefficient of variation GLP-1 Glucagon-like peptide 1 f Bioavailability fraction i.v. Intravenous(ly) LLOQ Lower limit of quantification LOCI Luminescence oxygen channeling immunoassay MAT Mean Absorption Time MRT Mean Residence Time NCA Non-Compartmental Analysis PK Pharmacokinetic(s) s.c. Subcutaneous(ly) T ½ Half-life in plasma T max Time to maximum plasma concentration

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1,2,4-triazolyldithiocarbamate silver nano conjugate: potent seed priming agent against bakanae disease of rice (Oryzae sativa)

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EUROPEAN JOURNAL Of PLANT PATHOLOGY 2022年第4期162卷 825-841页

作者： Sharma, Anju Bala Sidhu, Anjali Manchanda, Pooja Ahuja, Radha Punjab Agr Univ Dept Plant Breeding & Genet Ludhiana Punjab India Punjab Agr Univ Dept Soil Sci Ludhiana Punjab India Punjab Agr Univ Sch Agr Biotechnol Ludhiana Punjab India

Bakanae disease of rice caused by fusarium fujikuroi is a significant disease of rice worldwide. The use of inoculum free seeds works well to act against this seed borne disease. Increased restrictions by the environmental protection agency (EPA) on the use of chemical seed-dressing products have made this disease a major concern among seed producers. In the present studies, 1,2,4-triazole derivatized with dithiocarbamate was further conjugated on silver nanoparticles to get 1,2,4-triazolyldithiocarbamate conjugated silver nanoparticles (TDTC-AgNPs) and its in vitro antifungal evaluation against f. fujikuroi (carbendazim as a standard fungicide) revealed its significant potential at a low dose. Double staining of hyphae with calcofluor white and propidium iodide (PI) revealed the disruption of cell membrane on treatment with TDTC-AgNPs which was further confirmed by ultramicroscopic details. Abrupt soluble protein leakage (250 mu g/g) was observed within 50 min of in vitro treatment on test fungus which was further supported by the hyphal distortion as their mode of action. Priming of rice seeds revealed TDTC-AgNPs as promising materials for the development of novel antifungal agents against f. fujikuroi. field evaluation studies of novel synthesized TDTC-AgNPs revealed that percent disease incidence was minimum (1.89 and 5.90) in the plots where seed priming with TDTC-AgNPs was given during cropping seasons 2018 and 2019 in both the varieties (PUSA 1509 and PUSA 1121) used in the experiments. Percent disease incidence (3.5 and 12.82;6.78 and 11.46 on PUSA 1509 and PUSA 1121 during 2018 and 2019, respectively) was even less than that obtained with seed treatment with standard fungicide (carbendazim) treated seeds. Seed yield was also maximum (11.25 and 10.45;13.30 and 12.20 q/acre for PUSA 1509 and PUSA 1121 during 2018 and 2019, respectively) in plots where seedlings obtained from TDTC-AgNPs primed seeds were transplanted.

关键词： AgNPs Bakanae Dithiocarbamate f fujikuroi 1 2 4-triazole

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The effect of riboflavin supplementation on the systemic redox status in healthy volunteers: A post-hoc analysis of the RIBOGUT trial

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fREE RADICAL BIOLOGY AND MEDICINE 2022年 190卷 169-178页

作者： Bourgonje, Arno R. Otten, Antonius T. Sadabad, Mehdi Sadaghian von Martels, Julius Z. H. Bulthuis, Marian L. C. faber, Klaas Nico van Goor, Harry Dijkstra, Gerard Harmsen, Hermie J. M. Univ Groningen Univ Med Ctr Groningen Dept Gastroenterol & Hepatol Groningen Netherlands Univ Groningen Univ Med Ctr Groningen Dept Med Microbiol Groningen Netherlands Univ Groningen Univ Med Ctr Groningen Dept Pathol & Med Biol Groningen Netherlands Univ Groningen Univ Med Ctr Groningen Dept Med Microbiol POB 30-001 NL-9700 RB Groningen Netherlands

Background: Riboflavin is a redox-active vitamin that plays a pivotal role in human energy metabolism. Riboflavin may have beneficial health effects by increasing extracellular antioxidant capacity, thereby alleviating oxidative stress. Reduced levels of free thiols in blood reflect systemic oxidative stress, since they are readily oxidized by reactive species. In this study, we aimed to study the potential of riboflavin supplementation to improve the systemic redox status in healthy ***: This study was a post-hoc analysis of the RIBOGUT study, a randomized, double-blind, placebocontrolled human intervention trial that investigated the effect of riboflavin supplements on the gut microbiota composition of healthy individuals. Serum free thiols were quantified before and after intervention and adjusted to serum albumin levels. Changes in albumin-adjusted free thiols were analyzed, as well as potential associations with routine laboratory parameters and faecal bacterial quantification by fluorescence in-situ hybridization (fISH).Results: Participants were randomized to either placebo (n = 34), riboflavin 50 mg daily (n = 32), or riboflavin 100 mg daily (n = 33). At baseline, no significant differences in albumin-adjusted serum free thiols were observed. After intervention with either placebo or riboflavin, albumin-adjusted serum free thiols did not significantly change (P > 0.05), however, observed changes were inversely associated with changes in C-reactive protein (CRP) levels (r = -0.22, P < 0.05). At baseline, albumin-adjusted serum free thiols were positively associated with faecal relative abundances of faecalibacterium prausnitzii (P < 0.01).Conclusion: Riboflavin did not change the systemic redox status in healthy individuals as reflected by serum free thiols, but observed changes in albumin-adjusted free thiol levels were negatively associated with changes in CRP levels. Strikingly, albumin-adjusted free thiols were independently associated with

关键词： Riboflavin Oxidative stress Redox Thiols Gut microbiota f prausnitzii

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Parvimonas micra is associated with tumour immune profiles in molecular subtypes of colorectal cancer

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CANCER IMMUNOLOGY IMMUNOTHERAPY 2022年第10期71卷 2565-2575页

作者： Lowenmark, Thyra Li, Xingru Lofgren-Burstrom, Anna Zingmark, Carl Ling, Agnes Kellgren, Therese G. Larsson, Par Ljuslinder, Ingrid Wai, Sun Nyunt Edin, Sofia Palmqvist, Richard Umea Univ Dept Med Biosci Pathol Bldg 6M S-90185 Umea Sweden Umea Univ Northern Register Ctr Dept Publ Hlth & Clin Med Umea Sweden Umea Univ Dept Radiat Sci Oncol Umea Sweden Umea Univ Dept Mol Biol Umea Sweden

The importance of the tumour microbiome in different aspects of colorectal cancer (CRC) has been increasingly recognised, but many questions remain. The aim of this study was to explore the effect of specific CRC associated microbes on the tumour immune response, which has a considerable prognostic value in CRC. We applied specific qPCR to detect Parvimonas micra and fusobacterium nucleatum in tumour tissues from an immunologically well-characterised cohort of 69 CRC patients. This cohort included detailed analyses of immune profiles based on flow cytometry and transcriptomics in tumour tissue and blood, along with comprehensive analyses of molecular subtypes. P. micra and f. nucleatum were detected in 24% and 64% of tumour tissues, respectively. We found a significant association of P. micra with high-grade tumours and tumours of CMS1 subtype. f. nucleatum was significantly associated with right-sided tumours, microsatellite instability, and CMS1 tumours. The immunological analyses revealed significant associations of P. micra with activated CD69(+) T lymphocytes and increased antigen-presenting HLA-DR+ B lymphocytes. P. micra was also positively associated with M1 and M2 macrophage traits. The impact of P. micra tumour colonisation on the immune response was further assessed using transcriptomics in validation of our findings. No associations were found between f. nucleatum and immune profiles in this study. Our findings support novel associations between P. micra and the immune response in CRC. A better understanding of these interactions might help to identify important predictive and prognostic tools as well as new targets for therapy.

关键词： Mucosal microbiota P micra f nucleatum Immunity Colorectal cancer

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