RESUMO
We previously demonstrated that Alcaligenes-derived lipid A (ALA), which is produced from an intestinal lymphoid tissue-resident commensal bacterium, is an effective adjuvant for inducing antigen-specific immune responses. To understand the immunologic characteristics of ALA as a vaccine adjuvant, we here compared the adjuvant activity of ALA with that of a licensed adjuvant (monophosphoryl lipid A, MPLA) in mice. Although the adjuvant activity of ALA was only slightly greater than that of MPLA for subcutaneous immunization, ALA induced significantly greater IgA antibody production than did MPLA during nasal immunization. Regarding the underlying mechanism, ALA increased and activated CD11b+ CD103- CD11c+ dendritic cells in the nasal tissue by stimulating chemokine responses. These findings revealed the superiority of ALA as a mucosal adjuvant due to the unique immunologic functions of ALA in nasal tissue.
Assuntos
Alcaligenes , Lipídeo A , Animais , Camundongos , Lipídeo A/farmacologia , Adjuvantes Imunológicos/farmacologia , Células DendríticasRESUMO
Innate immune signaling via TLR4 plays critical roles in pathogenesis of metabolic disorders, but the contribution of different lipid species to metabolic disorders and inflammatory diseases is less clear. GM3 ganglioside in human serum is composed of a variety of fatty acids, including long-chain (LCFA) and very-long-chain (VLCFA). Analysis of circulating levels of human serum GM3 species from patients at different stages of insulin resistance and chronic inflammation reveals that levels of VLCFA-GM3 increase significantly in metabolic disorders, while LCFA-GM3 serum levels decrease. Specific GM3 species also correlates with disease symptoms. VLCFA-GM3 levels increase in the adipose tissue of obese mice, and this is blocked in TLR4-mutant mice. In cultured monocytes, GM3 by itself has no effect on TLR4 activation; however, VLCFA-GM3 synergistically and selectively enhances TLR4 activation by LPS/HMGB1, while LCFA-GM3 and unsaturated VLCFA-GM3 suppresses TLR4 activation. GM3 interacts with the extracellular region of TLR4/MD2 complex to modulate dimerization/oligomerization. Ligand-molecular docking analysis supports that VLCFA-GM3 and LCFA-GM3 act as agonist and antagonist of TLR4 activity, respectively, by differentially binding to the hydrophobic pocket of MD2. Our findings suggest that VLCFA-GM3 is a risk factor for TLR4-mediated disease progression.
Assuntos
Gangliosídeo G(M3)/metabolismo , Monócitos/metabolismo , Obesidade/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Animais , Gangliosídeo G(M3)/química , Gangliosídeo G(M3)/genética , Células HEK293 , Humanos , Camundongos , Camundongos Mutantes , Monócitos/química , Obesidade/genética , Multimerização Proteica , Receptor 4 Toll-Like/química , Receptor 4 Toll-Like/genéticaRESUMO
Lipopolysaccharide (LPS), a cell surface component of Gram-negative bacteria, activates innate immunity. Its active principle is the terminal glycolipid lipidâ A. Acetobacter pasteurianus is a Gram-negative bacterium used in the fermentation of traditional Japanese black rice vinegar (kurozu). In this study, we focused on A.â pasteurianus lipidâ A, which is a potential immunostimulatory component of kurozu. The active principle structure of A.â pasteurianus lipidâ A has not yet been identified. Herein, we first systematically synthesized three types of A.â pasteurianus lipidâ As containing a common and unique tetrasaccharide backbone. We developed an efficient method for constructing the 2-trehalosamine skeleton utilizing borinic acid-catalyzed glycosylation to afford 1,1'-α,α-glycoside in high yield and stereoselectivity. A common tetrasaccharide intermediate with an orthogonal protecting group pattern was constructed via [2+2] glycosylation. After introducing various fatty acids, all protecting groups were removed to achieve the first chemical synthesis of three distinct types of A.â pasteurianus lipidâ As. After evaluating their immunological function using both human and murine cell lines, we identified the active principles of A.â pasteurianus LPS. We also found the unique anomeric structure of A.â pasteurianus lipidâ A contributes to its high chemical stability.
Assuntos
Acetobacter , Lipídeo A , Lipídeo A/química , Lipídeo A/imunologia , Lipídeo A/síntese química , Humanos , Camundongos , Acetobacter/química , Animais , Oligossacarídeos/química , Oligossacarídeos/síntese química , GlicosilaçãoRESUMO
Fibroblast activation proteins (FAP) are overexpressed in the tumor stroma and have received attention as target molecules for radionuclide therapy. The FAP inhibitor (FAPI) is used as a probe to deliver nuclides to cancer tissues. In this study, we designed and synthesized four novel 211At-FAPI(s) possessing polyethylene glycol (PEG) linkers between the FAP-targeting and 211At-attaching moieties. 211At-FAPI(s) and piperazine (PIP) linker FAPI exhibited distinct FAP selectivity and uptake in FAPII-overexpressing HEK293 cells and the lung cancer cell line A549. The complexity of the PEG linker did not significantly affect selectivity. The efficiencies of both linkers were almost the same. Comparing the two nuclides, 211At was superior to 131I in tumor accumulation. In the mouse model, the antitumor effects of the PEG and PIP linkers were almost the same. Most of the currently synthesized FAPI(s) contain PIP linkers; however, in our study, we found that PEG linkers exhibit equivalent performance. If the PIP linker is inconvenient, a PEG linker is expected to be an alternative.
Assuntos
Fibroblastos , Polietilenoglicóis , Humanos , Animais , Camundongos , Células HEK293 , Piperazina/farmacologia , Polietilenoglicóis/farmacologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Radioisótopos de GálioRESUMO
α-Methyl-l-tyrosine (AMT) has a high affinity for the cancer-specific l-type amino acid transporter 1 (LAT1). Therefore, we established an anti-cancer therapy, with 211 At-labeled α-methyl-l-tyrosine (211 At-AAMT) as a carrier of 211 At into tumors. 211 At-AAMT had high affinity for LAT1, inhibited tumor cell growth, and induced DNA double-stranded breaks in vitro. We evaluated the accumulation of 211 At-AAMT in vivo and the role of LAT1. Treatment with 0.4 MBq/mouse 211 At-AAMT inhibited tumor growth in the PANC-1 tumor model and 1 MBq/mouse 211 At-AAMT inhibited metastasis in the lung of the B16F10 metastasis model. Our results suggested that 211 At would be useful for anti-cancer therapy and that LAT1 is suitable as a target for radionuclide therapy.
Assuntos
Partículas alfa/uso terapêutico , Astato/administração & dosagem , Portadores de Fármacos/farmacologia , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Neoplasias/radioterapia , alfa-Metiltirosina/farmacologia , Animais , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Modelos Animais de Doenças , Estudos de Viabilidade , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Neoplasias/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: 211At is a high-energy α-ray emitter with a relatively short half-life and a high cytotoxicity for cancer cells. Its dispersion can be imaged using clinical scanners, and it can be produced in cyclotrons without the use of nuclear fuel material. This study investigated the biodistribution and the antitumor effect of 211At-labeled gold nanoparticles (211At-AuNP) administered intratumorally. RESULTS: AuNP with a diameter of 5, 13, 30, or 120 nm that had been modified with poly (ethylene glycol) methyl ether (mPEG) thiol and labeled with 211At (211At-AuNP-S-mPEG) were incubated with tumor cells, or intratumorally administered to C6 glioma or PANC-1 pancreatic cancers subcutaneously transplanted into rodent models. Systemic and intratumoral distributions of the particles in the rodents were then evaluated using scintigraphy and autoradiography, and the changes in tumor volumes were followed for about 40 days. 211At-AuNP-S-mPEG was cytotoxic when it was internalized by the tumor cells. After intratumoral administration, 211At-AuNP-S-mPEG became localized in the tumor and did not spread to systemic organs during a time period equivalent to 6 half-lives of 211At. Tumor growth was strongly suppressed for both C6 and PANC-1 by 211At-AuNP-S-mPEG. In the C6 glioma model, the strongest antitumor effect was observed in the group treated with 211At-AuNP-S-mPEG with a diameter of 5 nm. CONCLUSIONS: The intratumoral single administration of a simple nanoparticle, 211At-AuNP-S-mPEG, was shown to suppress the growth of tumor tissue strongly in a particle size-dependent manner without radiation exposure to other organs caused by systemic spread of the radionuclide.
Assuntos
Astato/uso terapêutico , Ouro/uso terapêutico , Nanopartículas/química , Nanopartículas/uso terapêutico , Coloração e Rotulagem/métodos , Animais , Astato/química , Glioma , Ouro/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da Partícula , Polietilenoglicóis , Cintilografia/métodos , Ratos , Distribuição TecidualRESUMO
Gram-negative bacterial cell surface component lipopolysaccharide (LPS) and its active principle, lipid A, exhibit immunostimulatory effects and have the potential to act as adjuvants. However, canonical LPS acts as an endotoxin by hyperstimulating the immune response. Therefore, LPS and lipid A must be structurally modified to minimize their toxic effects while maintaining their adjuvant effect for application as vaccine adjuvants. In the field of chemical ecology research, various biological phenomena occurring among organisms are considered molecular interactions. Recently, the hypothesis has been proposed that LPS and lipid A mediate bacterial-host chemical ecology to regulate various host biological phenomena, mainly immunity. Parasitic and symbiotic bacteria inhabiting the host are predicted to possess low-toxicity immunomodulators due to the chemical structural changes of their LPS caused by co-evolution with the host. Studies on the chemical synthesis and functional evaluation of their lipid As have been developed to test this hypothesis and to apply them to low-toxicity and safe adjuvants.
Assuntos
Adjuvantes Imunológicos/farmacologia , Bactérias/imunologia , Endotoxinas/imunologia , Lipídeo A/farmacologia , Lipopolissacarídeos/imunologia , Adjuvantes Imunológicos/química , Animais , Bactérias/efeitos dos fármacos , Endotoxinas/metabolismo , Humanos , Lipídeo A/química , Lipopolissacarídeos/químicaRESUMO
Alcaligenes faecalis is the predominant Gram-negative bacterium inhabiting gut-associated lymphoid tissues, Peyer's patches. We previously reported that an A.â faecalis lipopolysaccharide (LPS) acted as a weak agonist for Toll-like receptorâ 4 (TLR4)/myeloid differentiation factor-2 (MD-2) receptor as well as a potent inducer of IgA without excessive inflammation, thus suggesting that A.â faecalis LPS might be used as a safe adjuvant. In this study, we characterized the structure of both the lipooligosaccharide (LOS) and LPS from A.â faecalis. We synthesized three lipidâ A molecules with different degrees of acylation by an efficient route involving the simultaneous introduction of 1- and 4'-phosphates. Hexaacylated A.â faecalis lipidâ A showed moderate agonistic activity towards TLR4-mediated signaling and the ability to elicit a discrete interleukin-6 release in human cell lines and mice. It was thus found to be the active principle of the LOS/LPS and a promising vaccine adjuvant candidate.
Assuntos
Alcaligenes faecalis/química , Lipídeo A/química , Lipopolissacarídeos/química , Animais , Configuração de Carboidratos , Linhagem Celular , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Lipídeo A/farmacologia , Lipopolissacarídeos/isolamento & purificação , Lipopolissacarídeos/farmacologia , Camundongos , Receptor 4 Toll-Like/agonistasRESUMO
As a mammalian toll-like receptor family member protein, TLR2 recognizes lipoproteins from bacteria and modulates the immune response by inducing the expression of various cytokines. We have developed fluorescence-labeled TLR2 ligands with either hydrophilic or hydrophobic fluorescence groups. The labeled ligands maintained the inflammatory IL-6 induction activity and enabled us to observe the internalization and colocalization of the TLR2 ligands using live-cell imaging. The time-lapse monitoring in the live-cell imaging of the fluorescence-labeled TLR2 ligand showed that TLR2/CD14 expression in the host cells enhanced the internalization of TLR2 ligand molecules.
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Seven previously undescribed preurianin-type limonoids, namely paraxylines A-G, and three known analogs were isolated from stem bark of Dysoxylum parasiticum. The structures, including absolute configurations, were established through spectroscopic analyses, quantum chemical calculations using the density functional theory method, as well as the DP4+ algorithm. Paraxylines A-G were identified as the first preurianin-type with full substitution at C, D-rings, leading to the highly oxygenated seco-limonoids skeleton. The secreted alkaline phosphate assay against an engineered human and murine TLR4 of HEK-Blue cells was performed to evaluate the immune regulating effects. Among them, paraxyline B was found to be a remarkable TLR4 agonist whereas two analogs (toonapubesins A and B) were found to antagonise lipopolysaccharide stimulation of the TLR4 pathway. Paraxylines A and C-E acted either as agonists or antagonists depending on the origin of the TLR4 receptor (human or mouse). The effect of these selected compounds on the expression of pro-inflammatory cytokines TNF-α, IL-1α, IL-1ß, and IL-6 of the NF-κB signaling pathway were examined in macrophage cell lines, revealing dose-dependent effects. Additionally, paraxylines A, C, D, and G also presented modest cytotoxic activity against MCF-7 and HeLa cell lines with IC50 values ranging from 23.1 to 43.5 µM.
Assuntos
Antineoplásicos Fitogênicos , Antineoplásicos , Limoninas , Meliaceae , Humanos , Animais , Camundongos , Limoninas/farmacologia , Limoninas/química , Receptor 4 Toll-Like , Células HeLa , Casca de Planta/química , Estrutura Molecular , Antineoplásicos Fitogênicos/química , Meliaceae/químicaRESUMO
To create a novel high-throughput lectin assay (HTPLA) method based on the emission of a luminophore by highly penetrable near-infrared excitation, sugar-attached upconversion lanthanide nanoparticles (LNPs) were synthesized as a tool to highlight the aggregates caused by the sugar-mediated specific bridging between LNP and lectin. The emissions from a mannose-coated LNP in the aggregates with a mannose-binding lectin were much stronger than those from the non-aggregated samples, being sensitive enough for HTPLA. A galactose-coated LNP was also applicable to a macrophage aggregation assay for the sugar specificity of its surface lectin.
Assuntos
Ensaios de Triagem em Larga Escala , Elementos da Série dos Lantanídeos/química , Lectinas/análise , Nanopartículas/química , Animais , Agregação Celular , Galactose/química , Medições Luminescentes , Macrófagos/química , Macrófagos/citologia , Manose/química , Camundongos , Microscopia Eletrônica de Transmissão , Nanopartículas/ultraestrutura , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
Lipopolysaccharide (LPS), a cell surface component of Gram-negative bacteria, and its active principle, lipid A, have immunostimulatory properties and thus potential to act as adjuvants. However, canonical LPS acts as an endotoxin by hyperstimulating the immune response. Therefore, it is necessary to structurally modify LPS and lipid A to minimize toxicity while maintaining adjuvant effects for use as vaccine adjuvants. Various studies have focused on the chemical synthetic method of lipid As and their structure-activity relationship, which are reviewed in this chapter.
Assuntos
Lipídeo A , Lipopolissacarídeos , Lipopolissacarídeos/farmacologia , Lipídeo A/farmacologia , Lipídeo A/química , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/química , Bactérias/metabolismo , ImunidadeRESUMO
The presence of NHAc groups in the substrates (both glycosyl donors and acceptors) significantly reduced the reactivity of glycosylation. This decrease was attributed to the NHAc groups forming intermolecular hydrogen bonds by the NHAc groups, thereby reducing molecular mobility. Hence, a diacetyl strategy involving the temporary conversion of NHAc to diacetyl imide (NAc2) was developed for the synthesis of NHAc-containing glycans. This strategy has two significant advantages for oligosaccharide synthesis. The NAc2 protection of NHAc substantially enhances the rate of glycosylation reactions, resulting in improved yields. Moreover, NAc2 can be readily reverted to NHAc by the simple removal of one acetyl group under mild basic conditions, obviating the necessity for treating the polar amino group. We have achieved the efficient synthesis of oligosaccharides containing GlcNHAc and N-glycans containing sialic acid using the diacetyl strategy.
RESUMO
An asymmetrical true-dimeric cadinane via ketonic bridge [C-15/C-3'], dysotican F (1), two symmetrical pseudo-cadinane dimers through an O-ether linkage [C-3/C-3'], dysoticans G (2) and H (3), as well as three known sesquiterpenoids 4-6 were obtained from the stem bark of Dysoxylum parasiticum (Osbeck) Kosterm. (Meliaceae). Their structures were determined by spectroscopic and quantum chemical calculations of 13C NMR shifts using a GIAO method and electronic circular dichroism (ECD) using a TDDFT method. A possible biogenetic pathway for 1-3 beginning from the known compounds (i-ii) was proposed. Cytotoxic evaluation showed that 2 as a new lead compound is the most potent against the MCF-7 and HeLa cell lines with IC50 values of 12.07 ± 0.17 µM and 9.29 ± 0.33 µM, while 1 has moderate inhibition with IC50 values of 31.59 ± 0.34 µM and 27.93 ± 0.25 µM. Furthermore, 3 is a selective inhibitor against the HeLa cell growth with an IC50 value of 39.72 ± 0.18 µM. A brief structure-activity relationship analysis of all isolated compounds 1-6 was also provided, including comparison with the coexisting molecules in the previous report.
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BACKGROUND: Clostridium perfringens and Shiga toxin (Stx)-producing Escherichia coli (STEC) are common causes of food poisoning. We previously demonstrated the efficacy of Stx2B-C-CPE, a fusion protein of the C-terminal region of C. perfringens enterotoxin (C-CPE) and Shiga toxin 2 B subunit (Stx2B), as a bivalent vaccine against C. perfringens and STEC infections. METHODS: Here, we applied an E. coli expression system and Triton X-114 phase separation to prepare tag- and endotoxin-free Stx2B-C-CPE for use in vaccine formulations. RESULTS: As we anticipated, endotoxin removal from the purified antigen reduced both Stx2B- and C-CPE-specific IgG antibody responses in subcutaneously immunized mice, suggesting that endotoxin contamination influences the immunological assessment of Stx2B-C-CPE. However, the combined use of aluminum and Alcaligenes lipid A adjuvants improved IgG antibody responses to the injected antigen, thus indicating the suitability of purified Stx2B-C-CPE for vaccine formulation. CONCLUSIONS: Our current findings provide important knowledge regarding the design of an effective commercial Stx2B-C-CPE vaccine.
Assuntos
Doenças Transmitidas por Alimentos , Vacinas , Animais , Camundongos , Clostridium perfringens , Escherichia coli , Adjuvantes Imunológicos , Doenças Transmitidas por Alimentos/prevenção & controle , Enterotoxinas , Imunoglobulina GRESUMO
Alcaligenes faecalis was previously identified as an intestinal lymphoid tissue-resident commensal bacteria, and our subsequent studies showed that lipopolysaccharide and its core active element (i.e., lipid A) have a potent adjuvant activity to promote preferentially antigen-specific Th17 response and antibody production. Here, we compared A. faecalis lipid A (ALA) with monophosphoryl lipid A, a licensed lipid A-based adjuvant, to elucidate the immunological mechanism underlying the adjuvant properties of ALA. Compared with monophosphoryl lipid A, ALA induced higher levels of MHC class II molecules and costimulatory CD40, CD80, and CD86 on dendritic cells (DCs), which in turn resulted in strong T cell activation. Moreover, ALA more effectively promoted the production of IL-6 and IL-23 from DCs than did monophosphoryl lipid A, thus leading to preferential induction of Th17 and Th1 cells. As underlying mechanisms, we found that the ALA-TLR4 axis stimulated both MyD88- and TRIF-mediated signaling pathways, whereas monophosphoryl lipid A was biased toward TRIF signaling. These findings revealed the effects of ALA on DCs and T cells and its induction pattern on signaling pathways.
Assuntos
Lipídeo A , Fator 88 de Diferenciação Mieloide , Lipídeo A/farmacologia , Lipídeo A/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor 4 Toll-Like/metabolismo , Apresentação de Antígeno , Alcaligenes/metabolismo , Transdução de Sinais , Adjuvantes Imunológicos/farmacologia , Diferenciação Celular , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Células DendríticasRESUMO
Intracellular surveillance for systemic microbial components during homeostasis and infections governs host physiology and immunity. However, a long-standing question is how circulating microbial ligands become accessible to intracellular receptors. Here we show a role for host-derived extracellular vesicles (EVs) in this process; human and murine plasma-derived and cell culture-derived EVs have an intrinsic capacity to bind bacterial lipopolysaccharide (LPS). Remarkably, circulating host EVs capture blood-borne LPS in vivo, and the LPS-laden EVs confer cytosolic access for LPS, triggering non-canonical inflammasome activation of gasdermin D and pyroptosis. Mechanistically, the interaction between the lipid bilayer of EVs and the lipid A of LPS underlies EV capture of LPS, and the intracellular transfer of LPS by EVs is mediated by CD14. Overall, this study demonstrates that EVs capture and escort systemic LPS to the cytosol licensing inflammasome responses, uncovering EVs as a previously unrecognized link between systemic microbial ligands and intracellular surveillance.
Assuntos
Vesículas Extracelulares , Inflamassomos , Humanos , Animais , Camundongos , Inflamassomos/metabolismo , Lipopolissacarídeos , Caspases/metabolismo , Piroptose , Citosol , Vesículas Extracelulares/metabolismoRESUMO
The natural limonoids distributed mainly in the Meliaceae and Rutaceae plants are known for their unique and complex structure with high degree oxidation and cyclic rearrangement. However, these compounds exhibit a broad range of biological activities such as insecticidal, antibacterial, antifungal, antimalarial, antioxidant, anticancer, antiviral, and anti-inflammatory. There is still limited report about the biological activity of the anti-inflammatory effect of limonoids isolated from plants. Therefore, this study aimed to examine the effect of intact, deformed and rearranged limonoids as anti-inflammatory agents. The majority of anti-inflammatory investigations were evaluated by in vitro and in vivo assays of the isolated pure compounds and their derivatives. For the in vitro study, intact and C-ring seco limonoids showed a potent inhibitory effect against NO production. The in vivo analysis of Intact, C-seco, and AD-seco limonoids showed a potent effect based on the inhibition of pro-inflammatory cytokines expression, indicating their potency as anti-inflammatory agents.
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Catalytic glycosylations with glycosyl fluorides using BF3·Et2O are presented. Glycosylations with both armed and disarmed donors were efficiently catalyzed by 1 mol% of BF3·Et2O in a nitrogen-filled glovebox without the use of dehydrating agents. Our finding is in sharp contrast with conventional BF3·Et2O-mediated glycosylations, where excess Lewis acid and additives are required. Mechanistic studies indicated that the chemical species formed by the reaction of in situ generated HF and glass vessels are involved in the catalytic cycle.
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Alpha-particle radiotherapy has gained considerable attention owing to its potent anti-cancer effect. 211At, with a relatively short half-life of 7.2 h, emits an alpha particle within a few cell diameters with high kinetic energy, which damages cancer cells with high biological effectiveness. In this study, we investigated the intravenous injection of 211At-labeled gold nanoparticles (AuNPs) for targeted alpha-particle therapy (TAT). Different kinds of surface-modified gold nanoparticles can be labeled with 211At in high radiochemical yield in 5 min, and no purification is necessary. The in vivo biodistribution results showed the accumulation of 5 nm 211At-AuNPs@mPEG at 2.25% injection dose per gram (% ID/g) in tumors within 3 h via the enhanced permeability and retention (EPR) effect. Additionally, we observed a long retention time in tumor tissues within 24 h. This is the first study to demonstrate the anti-tumor efficacy of 5 nm 211At-AuNPs@mPEG that can significantly suppress tumor growth in a pancreatic cancer model via intravenous administration. AuNPs are satisfactory carriers for 211At delivery, due to simple and efficient synthesis processes and high stability. The intravenous administration of 5 nm 211At-AuNPs@mPEG has a significant anti-tumor effect. This study provides a new framework for designing nanoparticles suitable for targeted alpha-particle therapy via intravenous injection.