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Engineered Biomimetic Platelet Membrane-Coated Nanoparticles Block Staphylococcus aureus Cytotoxicity and Protect Against Lethal Systemic Infection

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Engineering 2021年第8期7卷 1149-1156页

作者： Jwa-Kyung Kim satoshi Uchiyama Hua Gong Alexandra Stream Liangfang Zhang Victor Nizet Division of Nephrology Department of Internal Medicine&Kidney Research InstituteHallym University Sacred Heart HospitalAnyang 14068Republic of Korea Department of Clinical Immunology Hallym University Sacred Heart HospitalAnyang 14068Republic of Korea Division of Host-Microbe Systems and Therapeutics Department of PediatricsUniversity of California San DiegoLa JollaCA 92093USA Department of NanoEngineering University of California San DiegoLa JollaCA 92093USA Moores Cancer Center University of California San Diego HealthLa JollaCA 92037USA Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San DiegoLa JollaCA 92093USA

Staphylococcus aureus(S.aureus)is a leading human pathogen capable of producing severe invasive infections such as bacteremia,sepsis,and endocarditis with high morbidity and mortality,exacerbated by the increasingly widespread antibiotic resistance exemplified by methicillin-resistant strains(MRSA).S.aureus pathogenesis is fueled by the secretion of toxins—such as the membrane-damaging pore-forming atoxin,which have diverse cellular targets including the epithelium,endothelium,leukocytes,and platelets.Here,we examine the use of human platelet membrane-coated nanoparticles(PNPs)as a biomimetic decoy strategy to neutralize S.aureus toxins and preserve host cell defense functions.The PNPs blocked platelet damage induced by S.aureus secreted toxins,thereby supporting platelet activation and bactericidal activity.Likewise,the PNPs blocked macrophage damage induced by S.aureus secreted toxins,thus supporting macrophage oxidative burst,nitric oxide production,and bactericidal activity,and diminishing MRSA-induced neutrophil extracellular trap release.In a mouse model of MRSA systemic infection,PNP administration reduced bacterial counts in the blood and protected against mortality.Taken together,the results from the present work provide a proof of principle of the therapeutic benefit of PNPs in toxin neutralization,cytoprotection,and increased host resistance to invasive S.aureus infection.

关键词： Nanoparticle Nanosponge Platelet Staphylococcus aureus Bacterial toxins Sepsis

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基于中空微型水轮机的污水发电可行性研究

Engineering 2016年第4期2卷 131-139页

作者： Tomomi uchiyama satoshi Honda Tomoko Okayama Tomohiro Degawa Institute of Materials and Systems for Sustainability Nagoya UniversityNagoya 464-8603Japan Graduate School of Information Science Nagoya UniversityNagoya 464-8601Japan Faculty of Human Studies Taisho UniversityTokyo 170-8470Japan

本文利用微型水轮机技术,着重对污水管道水力发电的可行性进行了研究。首先,对日本丰川河流域排水系统两连接点处的污水流量进行了一年以上的观测,借此分析污水的水力势能;其次,假定微型水轮机被安装在污水管道的连接点位置,通过实验室... 详细信息

本文利用微型水轮机技术,着重对污水管道水力发电的可行性进行了研究。首先,对日本丰川河流域排水系统两连接点处的污水流量进行了一年以上的观测,借此分析污水的水力势能;其次,假定微型水轮机被安装在污水管道的连接点位置,通过实验室试验研究微型水轮机的性能。研究表明:污水管道的连接点处蕴藏有可用于全年发电的水力势能,同时,微型水轮机在该位置可以有效地进行污水水力发电。

关键词：微型水轮机污水发电连接点水力势能

Protection Against Lethal Multidrug-Resistant Bacterial Infections Using Macrophage Cell Therapy

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Infectious Microbes & Diseases 2019年第2期1卷 61-69页

作者： Robert Tacke Josh Sun satoshi Uchiyama Anya Polovina Deborah G.Nguyen Victor Nizet Cellular Approaches San Diego CA92037USA Collaborative to Halt Antibiotic-Resistant Microbes(CHARM) UC San DiegoLa JollaCA 92093USA Department of Pediatrics UC San DiegoLa JollaCA 92093USA Skaggs School of Pharmacy and Pharmaceutical Sciences UC San DiegoLa JollaCA 92093USA

Multidrug-resistant(MDR)bacterial infections exert a tremendous burden on the public health system throughout the developing and developedworld.Slowing development of novel antibiotic scaffolds,over-prescription of antibiotics,extensive agricultural antibiotic use,and the increasingly complex hospitalized patient populations undergoing treatment,all fuel the rise of highly MDR“superbugs.”Unfortunately,host-directed therapies to boost immune resistance to infection are not currently available for treatment of MDR pathogens.Hematopoietic cells are endowed with a variety ofmechanismsto control microbial invasion.Macrophages in particular have long been appreciated as potent antimicrobial immune cells equipped with several receptors that allow for rapid recognition,phagocytosis,and killing of pathogenic microbes,coupled to secretion of immunostimulatory cytokines to further orchestrate a robust multifaceted antibacterial immune response.To investigate the utility of macrophages as a cell therapy for MDR bacterial infections,we developed a therapeutically translatable process to generate,harvest,and cryopreserve monocyte-derived macrophages(ICONIMACTM).These cells effectively killed both Gram-positive and Gram-negative MDR pathogens in vitro,and conferred protection in vivo against experimental lethal peritonitis and lung infection.Our discoveries provide a proof-of-concept for a novel immunotherapeutic approach against MDR bacterial infections,urgently needed to supplement the diminishing antibiotic pipeline.

关键词： antibiotic resistance innate immunity bacterial infection macrophage cell therapy ICONIMACTM Staphylococcus aureus Pseudomonas aeruginosa Klebsiella pneumoniae

The Group A Streptococcus Interleukin-8 Protease SpyCEP Promotes Bacterial Intracellular Survival by Evasion of Autophagy

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Infectious Microbes & Diseases 2022年第3期4卷 116-123页

作者： RenéBergmann Giuseppe Gulotta Federica Andreoni Tomoko Sumitomo Shigetada Kawabata Annelies S.Zinkernagel Gursharan S.Chhatwal Victor Nizet Manfred Rohde satoshi Uchiyama Central Unit for Microscopy(ZEIM) Helmholtz Centre for Infection ResearchBraunschweigGermany Division of Infectious Diseases and Hospital Epidemiology University Hospital ZurichZurichSwitzerland Department of Oral and Molecular Microbiology Osaka University Graduate School of DentistrySuita-OsakaJapan Division of Host-Microbe Systems and Therapeutics Department of PediatricsUniversity of CaliforniaSan DiegoLa JollaCalifornia

Autophagy serves an innate immune function in defending the host against invading bacteria,including group A Streptococcus(GAS).Autophagy is regulated by numerous host proteins,including the endogenous negative regulator calpain,a cytosolic protease.Globally disseminated serotypeM1T1 GAS strains associated with high invasive disease potential express numerous virulence factors and resist autophagic clearance.Upon in vitro infection of human epithelial cell lines with representative wild-type GAS M1T1 strain 5448(M1.5448),we observed increased calpain activation linked to a specific GAS virulence factor,the interleukin-8 protease SpyCEP.Calpain activation inhibited autophagy and decreased capture of cytosolic GAS in autophagosomes.In contrast,the serotype M6 GAS strain JRS4(M6.JRS4),which is highly susceptible to host autophagy-mediated killing,expresses low levels of SpyCEP and does not activate calpain.Overexpression of SpyCEP in M6.JRS4 stimulated calpain activation,inhibited autophagy,and significantly decreased bacterial capture in autophagosomes.These paired loss-and gain-of-function studies reveal a novel role for the bacterial protease SpyCEP in enabling GAS M1 evasion of autophagy and host innate immune clearance.

关键词： group A Streptococcus SpyCEP virulence factor epithelial cells intracellular survival autophagy xenophagy calpain

Site-Specific Conjugation of Cell Wall Polyrhamnose to Protein SpyAD Envisioning a Safe Universal Group A Streptococcal Vaccine

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Infectious Microbes & Diseases 2021年第2期3卷 87-100页

作者： Nina J.Gao satoshi Uchiyama Lucy Pill Samira Dahesh Joshua Olson Leslie Bautista Shilpa Maroju Aym Berges Janet ZLiu Raymond HZurich Nina Mvan Sorge Jeff Fairman Neeraj Kapoor Victor Nizet Division of Host-Microbe Systems and Therapeutics Department of PediatricsUC San DiegoLa JollaCaliforniaUSA Vaxcyte Inc.Foster CityCaliforniaUSA Department of Medical Microbiology and Infection Prevention Amsterdam University Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands Netherlands Reference Laboratory for Bacterial Meningitis Amsterdam University Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands Skaggs School of Pharmacy and Pharmaceutical Sciences UC San DiegoLa JollaCaliforniaUSA

Development of an effective vaccine against the leading human bacterial pathogen group A Streptococcus(GAS)is a public health priority.The species defining group A cell wall carbohydrate(GAC,Lancefield antigen)can be engineered to remove its immunodominant N-acetylglucosamine(GlcNAc)side chain,implicated in provoking autoimmune cross-reactivity in rheumatic heart disease,leaving its polyrhamnose core(GACPR).Here we generate a novel protein conjugate of the GACPR and test the utility of this conjugate antigen in active immunization.Instead of conjugation to a standard carrier protein,we selected SpyAD,a highly conserved GAS surface protein containing both B-cell and T-cell epitopes relevant to the bacterium that itself shows promise as a vaccine antigen.SpyAD was synthesized using the XpressTM cell-free protein expression system,incorporating a non-natural amino acid to which GACpr was conjugated by site-specific click chemistry to yield high molecular mass SpyAD-GACPR conjugates and avoid disruption of important T-cell and B-cell immunological epitopes.The conjugated SpyAD-GACPR elicited antibodies that bound the surface of multiple GAS strains of diverse M types and promoted opsonophagocytic killing by human neutrophils.Active immunization of mice with a multivalent vaccine consisting of SpyAD-GACPR,together with candidate vaccine antigens streptolysin O and C5a peptidase,protected against GAS challenge in a systemic infection model and localized skin infection model,without evidence of cross reactivity to human heart or brain tissue epitopes.This general approach may allow GAC to be safely and effectively included in future GAS subunit vaccine formulations with the goal of broad protection without autoreactivity.

关键词： group A Streptococcus Streptococcus pyogenes group A carbohydrate Lancefield antigen conjugate vaccine XpressCFTM non-natural amino acids SpyAD Introduction

Rebamipide promotes healing of colonic ulceration through enhanced epithelial restitution

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World Journal of Gastroenterology 2011年第33期17卷 3802-3809页

作者： Tomohisa Takagi Yuji Naito Kazuhiko uchiyama Toshimitsu Okuda Katsura Mizushima Takahiro Suzuki Osamu Handa Takeshi Ishikawa Nobuaki Yagi satoshi Kokura Hiroshi Ichikawa Toshikazu Yoshikawa Department of Molecular Gastroenterology and Hepatology Graduate School of Medical ScienceKyoto Prefectural University of Medicine6028566 KyotoJapan

AIM:To investigate the efficacy of rebamipide in a rat model of colitis and restitution of intestinal epithelial cells in vitro.METHODS:Acute colitis was induced with trinitrobenzene sulfonic acid(TNBS)in male Wistar rats.Rats received intrarectal rebamipide treatment daily starting on day 7 and were sacrificed on day 14 after TNBS administration.The distal colon was removed to evaluate the various parameters of inflammation.Moreover,wound healing assays were used to determine the enhanced restitution of rat intestinal epithelial(RIE)cells treated with rebamipide.RESULTS:Intracolonic administration of rebamipide accelerated TNBSinduced ulcer healing.Increases in the wet weight of the colon after TNBS administration were significantly inhibited by rebamipide.The wound assay revealed that rebamipide enhanced the migration of RIE cells through phosphorylation of extracellular signalregulated kinase(ERK)and activation of Rho kinase.CONCLUSION:Rebamipide enema healed intestinal injury by enhancing restitution of RIE cells,via ERK activation.Rebamipide might be a novel therapeutic approach for inflammatory bowel disease.

关键词：肠上皮细胞伤口愈合结肠炎复原溃疡 Wistar大鼠灌肠治疗大鼠模型

Bi-predual spaces of generalized Campanato spaces with variable growth condition

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Acta Mathematica Sinica,English Series 2024年

作者： satoshi YAMAGUCHI Eiichi NAKAI Katsunori SHIMOMURA Department of Mathematics Ibaraki University

In this paper we extend the duality(■)*= H1(Rd) to generalized Campanato spaces with variable growth condition Lp,φ(Rd) instead of BMO(Rd). We also extend the characterization of Cc∞omp(Rd)BMO(Rd)by uchiyama(1978) to ■. Moreover, using this characterization, we prove the boundedness of singular and fractional integral operators on ■.The function space Lp,φ(Rd) treated in this paper covers the case that it is coincide with Lipαon one area, with BMO on another area and with the Morrey space on the other area, for example.

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Historical Cohort Study of the Efficacy and Safety of Piperacillin/Tazobactam Versus Fourth-Generation Cephalosporins for Empirical Treatment of Febrile Neutropenia in Patients with Hematological Malignancies

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International Journal of Clinical Medicine 2011年第1期2卷 18-22页

作者： Takashi Saito Tatsuo Ichinohe Junya Kanda Miki Nagao Shunji Takakura Yutaka Ito Yoshitsugu Iinuma Kouhei Yamashita Tadakazu Kondo Takayuki Ishikawa Takashi uchiyama satoshi Ichiyama Department of Infection Control and Prevention Kyoto University Hospital Department of Hematology and Oncology Kyoto University Hospital Department of Infection Control and Prevention Shiga Medical Center for Adults

We retrospectively evaluated the efficacy and safety of the combination drug piperacillin/tazobactam (PIPC/TAZ) in comparison with those of fourth-generation cephalosporins (4th Cephs) as initial empirical treatment in hematological malignancies patients with febrile neutropenia (FN). Among 200 patients assessed in this study, 49 had received PIPC/TAZ and 151 4th Cephs. Patient background characteristics were comparable between the two treatment groups. The overall efficacy rate in those receiving 4th Cephs and PIPC/TAZ was 57.0% (86/151 patients) and 59.2% (29/49 patients), respectively, with no significant difference detected between the two treatment regimens (P = 0.78). Treat-ment did not need to be discontinued or interrupted due to development of adverse drug reactions in any of the patients. Therefore in this study the efficacy and safety of PIPC/TAZ as initial antimicrobial treatment for FN in patients with hematological malignancies were not inferior to those of 4th Cephs. Based on the preliminary data obtained in this study, we propose to conduct a multicenter, prospective, controlled study to compare PIPC/TAZ versus CFPM given as empirical antimicrobial treatment against FN in patients with hematological malignancies.

关键词： Febrile Neutropenia Piperacillin/Tazobactam Fourth-Generation Cephalosporins Safety Efficacy