RESUMO
Exosomes are potent players in the development of metastases and they play an important role in cancer angiogenesis and exacerbation. However, it is unclear how proteins on exosomes affect development of blood vessel networks. In this study, we focused on relationships between membrane proteins on exosomes and angiogenesis using human umbilical vein endothelial cells (HUVEC). Lung tumor cell-derived exosomes induced tube formation and growth of endothelial cells in vitro in a dose-dependent manner involving MAPK activation, but this was not seen in normal lung epithelial cells. Ephrin type-A receptor 2 (EphA2) was identified by proteomic analysis and an inhibition assays showed it is a major MAPK activator on exosomes. Thus EphA2 on exosomes participates in angiogenesis as a ligand of the ephrin signaling pathway. These results support the development of novel therapeutic strategies such as blockade of remote cancer communications through exosomes.
Assuntos
Efrina-A2/metabolismo , Exossomos/metabolismo , Neoplasias Pulmonares/irrigação sanguínea , Sistema de Sinalização das MAP Quinases , Indutores da Angiogênese , Linhagem Celular Tumoral , Células Epiteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Pulmonares/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Cultura Primária de Células , Receptor EphA2 , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
The isospin character of p-n pairs at large relative momentum has been observed for the first time in the ^{16}O ground state. A strong population of the J,T=1,0 state and a very weak population of the J,T=0,1 state were observed in the neutron pickup domain of ^{16}O(p,pd) at 392 MeV. This strong isospin dependence at large momentum transfer is not reproduced by the distorted-wave impulse approximation calculations with known spectroscopic amplitudes. The results indicate the presence of high-momentum protons and neutrons induced by the tensor interactions in the ground state of ^{16}O.
RESUMO
BACKGROUND: The relationship among natural allergen exposure, induction of blocking antibody and the occurrence of atopic allergy-particularly in the presence of IgE production-is debatable. OBJECTIVE: To clarify the relationship between the dose of cutaneous exposure to dust mite allergen and susceptibility to the IgE-mediated allergic response in relation to IgG production. METHODS: NC/Nga mice were epicutaneously exposed to various doses of Dermatophagoides pteronyssinus allergen to induce atopic dermatitis-like skin lesions. We then evaluated the skin lesions, induction of mite-specific immune responses, and susceptibility to anaphylaxis. RESULTS: Dose-dependent exacerbation of atopic dermatitis-like skin lesions and increases in mite-specific IgG and IgE production were observed. However, mice exposed to relatively low doses of mite allergen showed hypersusceptibility to mite allergen-specific anaphylaxis. We also showed that adoptive transfer of total IgG from Dp-sensitized mice rescued mice from the hypersusceptibility seen in those exposed to low doses of mite allergen. CONCLUSIONS AND CLINICAL RELEVANCE: High-dose cutaneous exposure to dust mites induced effective blocking IgG production, even if accompanied by IgE production. Our data might support the concept that an increase in IgG titre, not a decrease in IgE titre, is a marker of clinical improvement in allergen-specific immunotherapy.
Assuntos
Alérgenos/administração & dosagem , Alérgenos/imunologia , Anafilaxia/prevenção & controle , Anticorpos Bloqueadores/imunologia , Antígenos de Dermatophagoides/administração & dosagem , Antígenos de Dermatophagoides/imunologia , Imunoglobulina G/imunologia , Anafilaxia/imunologia , Anafilaxia/metabolismo , Animais , Especificidade de Anticorpos/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Imunização , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , CamundongosRESUMO
Tumor necrosis factor (TNF)/TNF receptors (TNFR1/TNFR2) are considered to be potential drug targets to treat refractory diseases, including autoimmune diseases and malignant tumors. However, their specific functions, especially in the case of TNFR2, are poorly understood. In this study, we constructed a mouse TNFR2 (mTNFR2)-mediated biological assay system that shows no effects of mouse TNFR1 (mTNFR1) in order to screen mTNFR2-selective stimulating agents. Mouse TNFR1(-/-)R2(-/-) preadipocytes were transfected with the gene encoding the mTNFR2/mouse Fas (mFas) chimeric receptor in which the extracellular and transmembrane domains of mTNFR2 were fused to the intracellular domain of mFas. Our results demonstrated that this cell line exhibits highly sensitive mTNFR2-mediated cytotoxic effects. We propose that this mTNFR2-mediated biological assay system would be a useful tool to screen for mTNFR2-selective stimulating agents.
Assuntos
Adipócitos/citologia , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptor fas/genética , Animais , Bioensaio/métodos , Linhagem Celular , Camundongos , Camundongos Knockout , Receptores Tipo I de Fatores de Necrose Tumoral/efeitos dos fármacos , Receptores Tipo II do Fator de Necrose Tumoral/efeitos dos fármacos , TransfecçãoRESUMO
Detection of drug-target proteins and biomarkers that are expressed in cancer tissue has significant potential for both diagnosis and treatment of cancer. However, current immuno-histochemical and cytogenetic analyses of biopsy specimens for pre-operational diagnosis are highly invasive and often difficult to apply to lung cancer patients. The purpose of this study was to evaluate the possible utility of determining epidermal growth factor receptor (EGFR) expression on exosomal membranes using a targeted ELISA with an anti-CD81 antibody as a capture antibody for lung cancer diagnosis. While soluble EGFR (sEGFR) levels in plasma were not remarkably different between lung cancer patients and normal controls, significantly higher exosomal EGFR expression levels were observed in 5/9 cancer cases compared to normal controls. These results suggest that measurement of exosomal protein levels could be useful for in vitro diagnosis, and that exosomal EGFR is a possible biomarker for characterization of lung cancer.
Assuntos
Biomarcadores/análise , Receptores ErbB/metabolismo , Exossomos/metabolismo , Neoplasias Pulmonares/diagnóstico , Adulto , Idoso , Animais , Western Blotting , Linhagem Celular Tumoral , Meios de Cultivo Condicionados , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Masculino , Membranas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica , Pessoa de Meia-Idade , Plasmídeos , Tetraspanina 28/metabolismoRESUMO
The fullerene C60 is used in consumer products such as cosmetics owing to its antioxidative effects and is being developed for nanomedical applications. However, knowledge regarding the safety of fullerene C60, especially after oral administration, is sparse. Here, we examined the safety of fullerene C60 in mice after 7 d of exposure to orally administered polyvinylpyrrolidone (PVP)-wrapped fullerene C60 (PVP-fullerene C60). Mice treated with PVP-fullerene C60 showed few changes in the plasma levels of various markers of kidney and liver injury and experienced no significant hematologic effects. Furthermore, the histology of the colon of PVP-fullerene C60-treated mice was indistinguishable from that of control mice. These results suggest that PVP-fullerene C60 lacks toxicity after high-dose oral administration and indicate that PVP-fullerene C60 can be considered safe for oral medication. These data provide basic information that likely will facilitate the production of safe and effective forms of fullerene C60.
Assuntos
Fulerenos/farmacologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Administração Oral , Animais , Contagem de Células Sanguíneas , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colite/induzido quimicamente , Colite/patologia , Feminino , Fulerenos/administração & dosagem , Luz , Camundongos , Camundongos Endogâmicos C57BL , Povidona , Espalhamento de Radiação , Fixação de TecidosRESUMO
Since metastasis is one of the most important prognostic factors in colorectal cancer, development of new methods to diagnose and prevent metastasis is highly desirable. However, the molecular mechanisms leading to the metastatic phenotype have not been well elucidated. In this study, a proteomics-based search was carried out for metastasis-related proteins in colorectal cancer by analyzing the differential expression of proteins in primary versus metastasis focus-derived colorectal tumor cells. Protein expression profiles were determined using a tissue microarray (TMA), and the results identified Rho GDP-dissociation inhibitor alpha (Rho GDI) as a metastasis-related protein in colon and prostate cancer patients. Consequently, Rho GDI may be useful as a diagnostic biomarker and/or a therapeutic to prevent colon and prostate cancer metastasis.
Assuntos
Neoplasias do Colo/secundário , Inibidores de Dissociação do Nucleotídeo Guanina/fisiologia , Neoplasias da Próstata/secundário , Idoso , Western Blotting , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Eletroforese em Gel Bidimensional , Corantes Fluorescentes , Géis , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Humanos , Hidrólise , Imuno-Histoquímica , Masculino , Espectrometria de Massas , Análise em Microsséries , Pessoa de Meia-Idade , Tripsina/química , Inibidores da Dissociação do Nucleotídeo Guanina rho-EspecíficoRESUMO
The immune-modulating effect following intradermal injection of various-sized amorphous silica particles was analyzed in terms of induction of ovalbumin-specific CD8+ T cells in vivo. IFN-gamma ELISPOT assays revealed that only nanosilica particles with a diameter of less than 100 nm significantly enhanced CD8+ T cell responses against ovalbumin. These results indicate that the size of nanomaterials is a critical determinant in terms of their safe use.
Assuntos
Fatores Imunológicos , Nanopartículas , Dióxido de Silício/farmacologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Feminino , Interferon gama , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Tamanho da Partícula , Dióxido de Silício/química , Baço/citologia , Baço/imunologiaRESUMO
The photoluminescence spectra from a quantum-dot exciton weakly-coupled to a planar photonic-crystal cavity is experimentally investigated by temperature tuning. Significant resonance shifts of the cavity mode are observed as the cavity mode spectrally approaches that of the exciton mode, showing the appearance of cavity-to-exciton attraction or mode pulling. Cavity-mode spectral shifts are also found theoretically using a master equation model that includes incoherent pump processes for the coupled exciton and cavity, pure dephasing, and allows for photon emission via radiation modes and the leaky cavity mode. Both experiments and theory show clear cavity mode spectral shifts in the photoluminescence spectra, when certain coupling parameters are met. However, discrepancies between the experimental data and theory, including more pronounced spectral shifts in the measurements, indicate that other unknown mode-pulling effects may also be occurring.
RESUMO
The purpose of this study was to establish a long-term tooth cryopreservation method that can be used for tooth autotransplantation. Human periodontal ligament (PDL) cells were frozen in 10% dimethyl sulfoxide (Me(2)SO) using a programmed freezer with a magnetic field. Cells were cryopreserved for 7 days at -150 degrees C. Immediately after thawing, the number of surviving cells was counted and the cells were cultured; cultured cells were examined after 48 h. Results indicated that a 0.01 mT of a magnetic field, a 15-min hold-time, and a plunging temperature of -30 degrees C led to the greatest survival rate of PDL cells. Based on these findings, whole teeth were cryopreserved under the same conditions for 1 year. The organ culture revealed that the PDL cells of cryopreserved tooth with a magnetic field could proliferate as much as a fresh tooth, although the cells did not appear in the cryopreserved tooth without a magnetic field. Histological examination and the transmission electron microscopic image of cryopreserved tooth with a magnetic field did not show any destruction of cryopreserved cells. In contrast, severe cell damage was seen in cells frozen without a magnetic field. These results indicated that a magnetic field programmed freezer is available for tooth cryopreservation.
Assuntos
Criopreservação/métodos , Crioprotetores/farmacologia , Ligamento Periodontal/citologia , Bancos de Tecidos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Dimetil Sulfóxido/farmacologia , Campos Eletromagnéticos , Humanos , Magnetismo , Microscopia Eletrônica de Transmissão , Técnicas de Cultura de Órgãos , Ligamento Periodontal/efeitos dos fármacos , Ligamento Periodontal/efeitos da radiaçãoRESUMO
Adult T-cell leukemia (ATL) is a severe chemotherapy-resistant malignancy associated with prolonged infection by the human T cell-lymphotropic virus 1 (HTLV-1) retrovirus. Epidemiology studies strongly indicate that an increase in HTLV-1 virus load is an important factor during the onset of ATL. Therefore, inhibition of the growth/transmission of HTLV-1 infected cells is a promising strategy in preventing the disease. In our previous study, we revealed that arsenic trioxide (As2O3), a drug used to treat acute promyelocytic leukemia (APL), exerts an inhibitory effect on syncytium formation between HTLV-1 infected cells and HeLa cells via suppression of HTLV-1 envelope protein gp46 expression at low concentrations. In this study, we analyze the mechanism of action of As2O3 using a proteomics approach. Our results suggest that down-regulation of gp46 might be related to As2O3-induced oxidation of the 71-kDa heat shock cognate protein (HSC70) and the 78-kDa glucose-regulated protein (BiP/GRP78). We postulate that AS2O3 exerts an inhibitory effect on HTLV-1 virus transmission via down-regulation of gp46-production, which might be caused by oxidative modification of various proteins such as chaperones.
Assuntos
Arsenicais/farmacologia , Produtos do Gene env/biossíntese , Infecções por HTLV-I/metabolismo , Óxidos/farmacologia , Proteínas Oncogênicas de Retroviridae/biossíntese , Trióxido de Arsênio , Fusão Celular , Regulação para Baixo/efeitos dos fármacos , Eletroforese em Gel Bidimensional , Chaperona BiP do Retículo Endoplasmático , Géis , Produtos do Gene env/antagonistas & inibidores , Células HeLa , Humanos , Hidrólise , Imunoprecipitação , Oxirredução , Proteômica , Proteínas Oncogênicas de Retroviridae/antagonistas & inibidores , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Tripsina/químicaRESUMO
The development of a safe and effective mucosal vaccine adjuvant is a crucial step for the development of vaccines against human immunodeficiency virus type-1 (HIV). We have previously reported that a mutant tumor necrosis factor-alpha (TNF-alpha), mTNF-K90R, possessed strong mucosal vaccine adjuvant activities in mice. Here, we evaluated the potential of mTNF-K90R as a mucosal vaccine adjuvant for the induction of systemic and mucosal immune responses against HIV. Nasal immunization of BALB/c mice with 5 microg of an HIV gp120 env protein immunogen together with mTNF-K90R induced higher serum anti-HIV gp120 protein immunoglobulin G (IgG) responses than gp120 alone. Furthermore, mTNF-K90R induced anti-gp120 IgA responses in nasal as well as vaginal washes from immunized mice, although these were not administration sites. Again, responses with mTNF-K90R were higher than with gp120 alone. These results indicate that mTNF-K90R may be applicable as amucosal adjuvant for HIV vaccination to induce both systemic and mucosal immune responses.
Assuntos
Vacinas contra a AIDS/genética , Vacinas contra a AIDS/imunologia , Adjuvantes Imunológicos , Imunidade nas Mucosas/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Animais , Ensaio de Imunoadsorção Enzimática , Feminino , Proteína gp120 do Envelope de HIV/imunologia , Imunização , Imunoglobulina A/biossíntese , Imunoglobulina G/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Mucosa/imunologia , Ovalbumina/imunologiaRESUMO
Tumor necrosis factor-alpha (TNF), which binds two types of TNF receptors (TNFR1 and TNFR2), regulates the onset and exacerbation of autoimmune diseases such as rheumatoid arthritis and Crohn's disease. In particular, TNFR1-mediated signals are predominantly related to the induction of inflammatory responses. We have previously generated a TNFR1-selective antagonistic TNF-mutant (mutTNF) and shown that mutTNF efficiently inhibits TNFR1-mediated bioactivity in vitro and attenuates inflammatory conditions in vivo. In this study, we aimed to improve the TNFR1-selectivity of mutTNF This was achieved by constructing a phage library displaying mutTNF-based variants, in which the amino acid residues at the predicted receptor binding sites were substituted to other amino acids. From this mutant TNF library, 20 candidate TNFR1-selective antagonists were isolated. Like mutTNF, all 20 candidates were found to have an inhibitory effect on TNFR1-mediated bioactivity. However, one of the mutants, N7, displayed significantly more than 40-fold greater TNFR1-selectivty than mutTNF. Therefore, N7 could be a promising anti-autoimmune agent that does not interfere with TNFR2-mediated signaling pathways.
Assuntos
Receptores Tipo I de Fatores de Necrose Tumoral/antagonistas & inibidores , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Fatores de Necrose Tumoral/genética , Fatores de Necrose Tumoral/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Variação Genética , Humanos , Mutação , Biblioteca de Peptídeos , Receptores Tipo II do Fator de Necrose Tumoral/efeitos dos fármacos , Ressonância de Plasmônio de SuperfícieRESUMO
Amorphous silica nanoparticles (nSPs), are widely used in medicines, cosmetics and food. However, due to their reduced particle size they are suspected to pose new risks induced by changes in biological reactivity and kinetics, which differ from those of bulk materials. In a previous study, we showed that silica particles with a diameter of 70 nm penetrated the stratum corneum (SC) of mouse skin and were taken up by living cells such as keratinocytes and Langerhans cells. To clarify the relationship between particle size, distribution and cellular response, we have evaluated size-dependent intracellular localization and cytotoxicity of silica particles, using the mouse epidermal Langerhans cell line XS52. On treatment with silica particles of diameters 70, 300, and 1000 nm, cellular uptake and cytotoxicity increased with reduction in particle size. These results suggest that smaller sized silica particles induced greater cytotoxicity against Langerhans cells, which was correlated with the quantity of particle uptake into the cells.
Assuntos
Células de Langerhans/efeitos dos fármacos , Nanopartículas/toxicidade , Dióxido de Silício/toxicidade , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , L-Lactato Desidrogenase/metabolismo , Células de Langerhans/enzimologia , Células de Langerhans/ultraestrutura , Camundongos , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Timidina/metabolismoRESUMO
We study the origin of bright leaky-cavity mode emission and its influence on photon statistics in weakly coupled quantum dot - semiconductor cavity systems, which consist of a planar photonic-crystal and several quantum dots. We present experimental measurements that show that when the system is excited above the barrier energy, then bright cavity mode emissions with nonzero detuning are dominated by radiative recombinations of deep-level defects in the barrier layers. Under this excitation condition, the second-order photon autocorrelation measurements reveal that the cavity mode emission at nonzero detuning exhibits classical photon-statistics, while the bare exciton emission shows a clear partial anti-bunching. As we enter a Purcell factor enhancement regime, signaling a clear cavity-exciton coupling, the relative weight of the background recombination contribution to the cavity emission decreases. Consequently, the anti-bunching behavior is more significant than the bare exciton case - indicating that the photon statistics becomes more non-classical. These measurements are qualitatively explained using a medium-dependent master equation model that accounts for several excitons and a leaky cavity mode.
Assuntos
Iluminação/métodos , Modelos Teóricos , Pontos Quânticos , Simulação por Computador , Luz , Espalhamento de RadiaçãoRESUMO
Here we report the first demonstration of entanglement distribution over a record distance of 200 km which is of sufficient fidelity to realize secure communication. In contrast to previous entanglement distribution schemes, we use detection elements based on practical avalanche photodiodes (APDs) operating in a self-differencing mode. These APDs are low-cost, compact and easy to operate requiring only electrical cooling to achieve high single photon detection efficiency. The self-differencing APDs in combination with a reliable parametric down-conversion source demonstrate that entanglement distribution over ultra-long distances has become both possible and practical. Consequently the outlook is extremely promising for real world entanglement-based communication between distantly separated parties.
RESUMO
Cross sections for the 3He(e,e' pn)1H reaction were measured for the first time at energy transfers of 220 and 270 MeV for several momentum transfers ranging from 300 to 450 MeV/c. Cross sections are presented as a function of the momentum of the recoil proton and the momentum transfer. Continuum Faddeev calculations using the Argonne V18 and Bonn-B nucleon-nucleon potentials overestimate the measured cross sections by a factor 5 at low recoil proton momentum with the discrepancy becoming smaller at higher recoil proton momentum.
RESUMO
Lymphatic metastasis of tumors is one of the most important prognostic factors and provides valuable information for decisions on appropriate surgical protocols. Recent studies have demonstrated that lymphangiogenesis of lymphatic vascular endothelial cells into tumors is a key event in lymphatic metastasis. Therefore, control of lymphangiogenesis is a promising strategy for treatment or prevention of tumor metastasis and lymphatic disorders. However, mechanisms of lymphangiogenesis or its specific inhibition are not well-understood. In this study we examined effects of various types of signaling inhibitors on tube formation in human lymphatic microvascular endothelial cells (LECs) and blood microvascular endothelial cells (BECs) in vitro. We found that tube formation of LECs was specifically inhibited by 2-methoxyestradiol (2ME). This observation is of potential benefit in understanding the molecular mechanism of lymphangiogenesis. Furthermore, 2ME could therefore offer specific protection against lymphatic metastasis and lymphangiogenesis-related diseases.
Assuntos
Células Endoteliais/efeitos dos fármacos , Endotélio Linfático/citologia , Estradiol/análogos & derivados , Linfangiogênese/efeitos dos fármacos , 2-Metoxiestradiol , Vasos Sanguíneos/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Endotélio Linfático/efeitos dos fármacos , Endotélio Linfático/crescimento & desenvolvimento , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Estradiol/farmacologia , Humanos , Neovascularização Fisiológica/efeitos dos fármacos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Phage antibody library is a promising tool for rapidly creating in vitro single-chain Fv (scFv) antibodies to various antigens. The scFv can also act like a subcellularly-expressed antibody, known as intrabody, and can either be used as a novel research tool or used efficiently for targeted molecular therapy. However, there are only a few existing reports about the successful expression of scFvs as functional antibodies in the cell, mainly because poor quality scFv phage antibody libraries were used to isolate the intrabody clones. The aim of this study was to isolate intrabody-forming scFv clones from the nonimmune scFv phage antibody library we have generated. Using this library, we isolated a scFv clone against the apoptosis-related intracellular protein Bid in two weeks. To evaluate the intrabody-forming quality of this anti-Bid scFv clone, we expressed it in cultured mammalian cells after fusing it with the fluorescent protein Venus. The expression of the soluble form of anti-Bid scFv-Venus fusion protein was confirmed by fluorescence microscopy analysis. These results show that our scFv phage library is not only optimized for antibody production but can also be used to efficiently generate intrabodies.
Assuntos
Anticorpos/química , Biblioteca de Peptídeos , Sequência de Aminoácidos , Anticorpos Bloqueadores/química , Anticorpos Bloqueadores/farmacologia , Especificidade de Anticorpos , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/imunologia , Linhagem Celular Tumoral , Células Cultivadas , Clonagem Molecular , Ensaio de Imunoadsorção Enzimática , Humanos , Dados de Sequência Molecular , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/farmacologiaRESUMO
BACKGROUND: We recently reported that human protein C inhibitor (PCI), a major inhibitor of activated protein C (APC), inhibits hepatocyte growth factor activator (HGFA) by forming HGFA-PCI complexes in vitro. In this study, we evaluated whether PCI regulates HGFA-mediated liver regeneration in a human PCI gene transgenic (hPCI-Tg) mouse model. METHODS AND RESULTS: After partial hepatectomy in hPCI-Tg and wild-type (WT) mice, the degree of liver regeneration, protein and mRNA expression of HGFA, proHGF activation, plasma levels of PCI and HGFA-PCI complex, and other markers were evaluated in the remnant liver. We also evaluated the effect of anti-human PCI antibody on liver regeneration, which significantly decreased in hPCI-Tg mice compared to WT mice. HGFA mRNA levels in naive and remnant livers after hepatectomy were the same in both WT and hPCI-Tg mice; however, plasma HGFA levels and HGF activation in the liver were lower in hPCI-Tg than in WT mice. There was no difference in plasma levels of transaminases and inflammatory cytokines. However, sinusoidal congestion and bleeding were detected and the serum hyaluronic acid level was elevated in hPCI-Tg mice, indicating that human PCI aggravates sinusoidal injury by inhibiting the cytoprotective effect of APC. APC decreased thrombin-induced IL-6 production in isolated hepatic nonparenchymal cells (NPCs) in vitro. This impaired liver regeneration was reversed by anti-human PCI antibody treatment in vivo. CONCLUSION: PCI regulates liver regeneration after hepatectomy by forming an HGFA-PCI complex and aggravates hepatic NPC injury by inhibiting the cytoprotective effect of APC. Anti-PCI antibody treatment may be a novel therapy for improving liver regeneration.