Polymyositis associated with infliximab treatment for rheumatoid arthritis.
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Antibodies, Monoclonal↗
Biomedical subjects
Yutaka Mizushima
Publications and source records attributed to Yutaka Mizushima.
Drusen, choroidal neovascularization, and retinal pigment epithelium dysfunction in SOD1-deficient mice: a model of age-related macular degeneration.
Oxidative stress has long been linked to the pathogenesis of neurodegenerative diseases; however, whether it is a cause or merely a consequence of the degenerative process is still unknown. We show that mice deficient in Cu, Zn-superoxide dismutase (SOD1) have features typical of age-related macular degeneration in humans. Investigations of senescent Sod1(-/-) mice of different ages showed that the older animals had drusen, thickened Bruch's membrane, and choroidal neovascularization. The number of drusen increased with age, and exposure of young Sod1(-/-) mice to excess light induced drusen. The retinal pigment epithelial cells of Sod1(-/-) mice showed oxidative damage, and their beta-catenin-mediated cellular integrity was disrupted, suggesting that oxidative stress may affect the junctional proteins necessary for the barrier integrity of the retinal pigment epithelium. These observations strongly suggest that oxidative stress may play a causative role in age-related retinal degeneration, and our findings provide evidence for the free radical theory of aging. In addition, these results demonstrate that the Sod1(-/-) mouse is a valuable animal model to study human age-related macular degeneration.
Animals↗
Dioxin immunosensor using anti-2,3,7,8-TCDD antibody which was produced with mono 6-(2,3,6,7-tetrachloroxanthene-9-ylidene) hexyl succinate as a hapten.
To detect dioxin using a quartz crystal microbalance (QCM) immunosensor, anti-2,3,7,8-tetrachloro-p-dibenzodioxin (TCDD) monoclonal antibodies (MAbs) were produced as types of IgG1 and IgM, with mono 6-(2,3,6,7-tetrachloroxanthene-9-ylidene) hexyl succinate (as a hapten) conjugated with bovine serum albumin (dioxin-BSA). Furthermore, ScFv was generated from hybridoma-producing IgG1 MAb. Among these antibodies, ScFv showed excellent capability for dioxin detection using QCM immunosensors.
Animals↗
Transdermal delivery of CaCO3-nanoparticles containing insulin.
BACKGROUND: This study evaluates the pharmacokinetic and pharmacodynamic effects of a transdermally delivered insulin using novel CaCO(3)-nanoparticles in normal mice and those with diabetes. METHODS: CaCO3-nanoparticles encapsulating insulin (nanoinsulin) were transdermally applied to the back skin of normal ddY mice and dB/dB and kkAy mice with diabetes after fasting for 1 h. Serum insulin levels of ddY mice were analyzed by enzyme immunoassay, and blood glucose of normal mice and those with diabetes was monitored. RESULTS: Maximum serum insulin was 67.1 +/- 25.9 microIU/mL at 4 h with 200 microg of transdermal nanoinsulin in ddY mice, whereas that after subcutaneous injection of 3 microg of monomer insulin was 462 +/- 20.9 microIU/mL at 20 min. Transdermal nanoinsulin decreased glucose levels in a dose-dependent manner. A maximum decrease in blood glucose of 48.3 +/- 3.9% (ddY), 32.5 +/- 9.8% (dB/dB), and 26.2 +/- 7.6% (kkAy) after 6 h was observed with 200 microg of transdermal nanoinsulin, compared with 64.1+/-1.0% (ddY), 57.9 +/-3.4% (dB/dB), and 24.1 +/- 6.7% (kkAy) after 1 h with 3 microg of subcutaneous monomer insulin. Insulin bioavailability until 6 h with transdermal nanoinsulin in ddY mice was 0.9% based on serum insulin level and 2.0% on pharmacodynamic blood glucose-lowering effects. CONCLUSIONS: This CaCO(3)-nanoparticle system successfully delivered insulin transdermally, as evidenced by a significant sustained decrease in blood glucose in normal mice and those with diabetes. These results support the feasibility of developing transdermal nanoinsulin for human applications.
Administration, Cutaneous↗
[Corticosteroid-loading PLA/PLGA-nanospheres].
We developed nanospheres for the intravenous injection that have had sustained release and targeting to the efficiently anti-inflammation effect. These nanospheres formed by poly(D,L-lactic/glycolic acid) (PLGA) or poly(D,L-lactic acid) (PLA), biodegradability and biocompatibility polymer, that were encapsulated betamethasone phosphate and zinc. Result of experimental inflammation models shown that there nanospheres increased effect by targeting to inflammatory sites and also promoted sustained release of betamethasone phosphate from the nanospheres. Moreover, the effect of nanospheres were stronger than clinical pharmaceutical preparation. We propose that these nanospheres are the pharmaceutical preparation to have efficient powerful inflammation action.
Adrenal Cortex Hormones↗
Treatment of experimental autoimmune uveoretinitis with poly(lactic acid) nanoparticles encapsulating betamethasone phosphate.
We have developed nanoparticles (NPs), which are capable of targeting a specific lesion and gradually releasing the agent at the site over a prolonged time period after a single intravenous administration. In this study, we evaluated the effects of intravenously administered poly(lactic acid) nanoparticles encapsulating betamethasone phosphate (BP-PLA NPs) on experimental autoimmune uveoretinitis (EAU) in Lewis rats. To determine the localization of NPs within the retina and choroid of rats with EAU, rhodamine (Rh)-encapsulated PLA NPs were injected intravenously and visualized by confocal microscopy. After the disease onset of EAU induced by S-antigen peptide in Lewis rats, either BP-PLA NPs, BP, or saline was injected intravenously, and the eyes were obtained 7 days following treatment and the histological score was determined. The clinical course of EAU was examined using pathological findings and the expression of the glial fibrillary acidic protein, rod opsin, and the surface markers of inflammatory cells (ED1 and pan T-cell) were immunohistochemically determined. Furthermore, T-cell proliferation and delayed-type hypersensitivity (DTH) to S-antigen were assessed. Intravenously injected Rh-PLA NPs accumulated in the retina and choroid of rats with EAU within 3 hr and remained over the succeeding 7-day-period. Furthermore, systemically administered BP-PLA NPs reduced the clinical scores of rats with EAU in 1 day, which were maintained for 2 weeks and decreased the histological scores. In addition, the ocular infiltration of activated T-cells and macrophages in addition to the hypertrophy of Müller cells were markedly reduced with this treatment. Meanwhile, T-cell proliferation and DTH of BP-PLA NPs-treated rats against S-antigen peptide were not significantly different from those of saline-treated rats. Systemically administered BP-PLA NPs inhibit the development of EAU due to the targeting and the sustained release of steroids in situ. The results of these studies suggest that the systemic administration of BP-PLA NPs may lead to a new therapeutic strategy in controlling intraocular inflammation.
Animals↗
Injectable porous hydroxyapatite microparticles as a new carrier for protein and lipophilic drugs.
Hydroxyapatite (Ca10 (PO4)6(OH)2) is a biodegradable material that forms a major component of bones and teeth. We prepared injectable spherical porous hydroxyapatite microparticles (SP-HAp) as a drug carrier by the spray-drying method. We then examined the usefulness of SP-HAp as a carrier for drugs such as interferon alpha (IFNalpha), testosterone enanthate (TE), and cyclosporin A (CyA). SP-HAp had an average diameter of 5 mum and a porosity of approximately 58%. It could be injected subcutaneously through a 27-gauge needle. SP-HAp was observed to be biodegradable. The speed of degradation of SP-HAp could be regulated by altering the calcination temperature. IFNalpha was adsorbed well to SP-HAp particles, but INFalpha was released faster from the particles, than the particles could degrade in both in vitro and in vivo experiments. Addition of human serum albumin and zinc (reinforcement) to IFNalpha-adsorbed SP-HAp caused marked prolongation of release in vivo. The in vivo release of testosterone enanthate and CyA from SP-HAp preparation, which was easily injectable, was similarly prolonged to that from the oil preparation. In conclusion, the SP-HAp seems to be useful as a biodegradable and subcutaneously injectable drug carrier. It is suggested that the reinforcement of the SP-HAp is very effective on the sustained release of drugs.
Animals↗
Role of zinc in formulation of PLGA/PLA nanoparticles encapsulating betamethasone phosphate and its release profile.
The purpose of this study was to develop poly(D,L-lactic/glycolic acid) (PLGA) or poly(D,L-lactic acid) (PLA) nanoparticles of less than 200 nm in diameter that encapsulated water-soluble corticosteroid derivatives for sustained release and targeting to inflammatory sites. Nanoparticles were prepared with PLGA (or PLA), zinc, betamethasone phosphate and surfactant by an oil-in-water solvent diffusion method. With this method, the efficiency of encapsulating betamethasone phosphate in the nanoparticles and the particle size were significantly affected by various factors, such as the concentration of PLGA (or PLA) and the amount of zinc added. Nanoparticles ranging from 80 to 250 nm in diameter could be prepared, with a maximum betamethasone phosphate content of 8% (w/w). Betamethasone phosphate was gradually released from the nanoparticles in diluted serum, and the release rate depended on the glycolic/lactic acid ratio and on the molecular weight of PLGA or PLA. Betamethasone was gradually released over at least 8 days from murine macrophages that had internalized betamethasone phosphate-encapsulated nanoparticles in vitro, and the rate of release was slower than from nanoparticles prepared without zinc. These results suggest that zinc increases the efficiency of encapsulating betamethasone phosphate in nanoparticles and also promotes sustained release of betamethasone phosphate from the nanoparticles.
Animals↗
Successful treatment of photo-damaged skin of nano-scale atRA particles using a novel transdermal delivery.
We show a novel drug delivery system (DDS) for improved all-trans retinoic acid (atRA) therapy for external treatments of photo-damaged skin. We prepared inorganic-coated atRA nanoparticles, in turn an egg-like structure in nano-scale (Nano-atRA), using boundary-organized reaction droplets. The interfacial properties of organic architectures, in atRA micelles, were used to template the nucleation of inorganic minerals. As a result, irritation and inflammation associated with atRA therapy were substantially reduced due to the complete encapsulation of the carboxylic function. Both irritative symptoms and physicochemical instability of the atRA micelle were improved. Since Nano-atRA which is prepared following to this new DDS system developmentally improved the permeability to the stratum corneum, the remarkable pharmacological effects were resulted in comparison with atRA as such as follows: (1) thicker epidermis than classical atRA treatment and (2) the overexpression of mRNA for heparin-binding epidermal growth factor (HB-EGF) as the provocation epidermal hyperplasia. Furthermore, we found a surprising boost in production of hyaluronan (HA) among the intercellular spaces of the basal and spinous cell layers in epidermis. Nano-atRA technology for atRA therapy could not only efficiently regulate keratinocyte cell proliferation and differentiation, but also markedly produce the additional benefit. Severely injured human skin by chronic ultraviolet irradiation will completely repair due to the accelerated turnover of skin tissue, which is induced by Nano-atRA.
Administration, Cutaneous↗
Brain-derived neurotrophic factor bound with lecithin derivative showed a markedly enhanced pharmacological potency due to its potent cell membrane affinity followed by prolonged MAPK activation.
We synthesized lecithinized brain-derived neurotrophic factor (lecithinized-BDNF), in which an average of three molecules of a lecithin derivative were bound to recombinant human BDNF. We evaluated its pharmacological activity in C57BL/KsJ-db/db mice, and assessed its targetability and affinity for the nervous system. Subcutaneously administered lecithinized-BDNF markedly reduced the plasma glucose level, food intake, and body weight in C57BL/KsJ-db/db diabetic mice. Its potency was more than 20 times greater than that of unmodified BDNF. We then studied the mechanism for the markedly enhanced pharmacological activity. In vitro cell growth activity of lecithinized-BDNF using the MTT assay was lower than unmodified BDNF, probably due to steric hindrance of the lecithin moieties. While the plasma BDNF level after subcutaneous administration of lecithinized-BDNF was not higher compared with unmodified BDNF. However, higher amount of lecithinized-BDNF accumulated in the spinal cord was observed. Lastly, we found that in vitro binding capacity of lecithinized-BDNF for PC-pAB1 neural cells was much higher than unmodified BDNF. Moreover, lecithinized-BDNF bound to PC-pAB1 cells did not exchange with an excessive amount of unmodified BDNF or an excess of lecithinized-BDNF. PC-pAB1 cells treated with lecithinized-BDNF showed sustained mitogen-activated protein kinase (MAPK, ERK1/2) activation. These data would indicate that the high affinity of lecithinized-BDNF for the target cells, followed by prolonged MAPK activation, would play an important role in its potent pharmacological activity.
Animals↗
Ear involvement in patients with rheumatoid arthritis.
OBJECTIVE: This study evaluates the degree of hearing impairment in patients with rheumatoid arthritis (RA) and examines the correlation between hearing impairment and the clinical data or chemical mediators. BACKGROUND: Both sensorineural hearing loss (SNHL) and conductive hearing loss (CHL) have been reported in patients with RA, but the results of most studies are not in agreement, and the pathophysiology of hearing impairment in RA is not well known. METHODS: Hearing in patients with RA and controls was examined using pure-tone audiometry and tympanometry. Also, the amounts of pro-inflammatory cytokines and matrix metalloproteinases in addition to antibodies against type II collagen in plasma of the patients with RA were determined using enzyme-linked immunosorbent assay. RESULTS: The frequency of SNHL in the patients with RA was higher than in normal controls (36.1% versus 13.9%), and bone conduction at 2,000 Hz differed significantly between the patients with RA and the controls (p < 0.01). Moreover, the presence of SNHL was related to ESR (p < 0.05), plasma interleukin-6 (p < 0.05), and plasma matrix metalloproteinase-3 (p < 0.001). On the other hand, CHL was not observed, whereas As-type tympanograms increased in the patients with RA (p < 0.01). Abnormal tympanograms were not related to any clinical findings or any chemical mediators tested. CONCLUSION: We demonstrated that there is increased SNHL in patients with RA, which may result from systemic inflammation and tissue injury, and increased latent-type CHL caused by stiffness of the middle ear system whose mechanisms are not yet clear.
Acoustic Impedance Tests↗
Drug delivery to the cochlea using PLGA nanoparticles.
OBJECTIVES: This study aimed to investigate the efficacy of encapsulating therapeutic molecules in poly lactic/glycolic acid (PLGA) nanoparticles for drug delivery to the cochlea. STUDY DESIGN: An experimental study. METHODS: We examined the distribution of rhodamine, a fluorescent dye, in the cochlea, liver, and kidney of guinea pigs. Intravenous injection of rhodamine or rhodamine-encapsulated PLGA nanoparticles was used to target the fluorescent dye systemically to the liver, kidney, and cochlea, and these molecules were applied locally to the round window membrane (RWM) of the cochlea. The localization of rhodamine fluorescence in each region was quantitatively analyzed. RESULTS: After systemic application of rhodamine nanoparticles, fluorescence was identified in the liver, kidney, and cochlea. The systemic application of nanoparticles had a significant effect on targeted and sustained delivery of rhodamine to the liver but not the kidney or cochlea. Rhodamine nanoparticles placed on the RWM were identified in the scala tympani as nanoparticles, indicating that the PLGA nanoparticles can permeate through the RWM. Furthermore, the local application of rhodamine nanoparticles to the RWM was more effective in targeted delivery to the cochlea than systemic application. CONCLUSIONS: These findings indicate that PLGA nanoparticles can be an useful drug carrier to the cochlea via local application.
Animals↗
Novel heparin/alginate gel combined with basic fibroblast growth factor promotes nerve regeneration in rat sciatic nerve.
We have developed an alginate gel crosslinked with covalent bonds for regeneration of dermis, nerve, and bone. Recently, a novel matrix (H/A gel) which consists of heparin and alginate covalently crosslinked with ethylenediamine, was designed. It can stabilize and release biologically active basic fibroblast growth factor (bFGF) for 1 month, which is one of the heparin-binding growth factors. In the present report, we examined the effect of this novel H/A gel on nerve regeneration in the rat sciatic nerve. In this study, regenerated axons in H/A gel with bFGF grew faster than in ordinary alginate gel with bFGF in the early stage. Myelinated fibers showed a tendency to increase in diameter toward the normal size in the later stage. Nerve bundles in the implantation exhibited minimal fibrosis and good vascularization. H/A gel with bFGF exhibited better-developed vascularization than ordinary alginate gel with bFGF. These findings suggested that H/A gel with bFGF could serve not only as an efficient cellular scaffold, but also as a stabilizing matrix for bFGF for peripheral nerve regeneration.
Alginates↗
Optimum formulation for sustained-release insulin.
Our aim was to prepare an optimum formulation for a sustained-release preparation of insulin using biodegradable polymer composed of co-poly(D,L-lactic/glycolic) acids (PLGA)(L/G ratio: 50/50). Various kinds of PLGA microcapsules containing 3% insulin were administered subcutaneously (250 U/kg) as a single dose to rats with streptozotocin-induced diabetes, and plasma insulin levels were monitored. The following results were obtained. (1) Glycerin and water were suitable additives to prepare a reproducible injectable formulation. (2) Addition of zinc compounds was essential to diminish rapid insulin release and six-fold molar excess of ZnO to insulin was desirable. (3) The size of insulin particles showed the following order: human insulin > lyophilized human insulin > Zn-free human insulin. Zn-free insulin was similar to lyophilized insulin with respect to control of rapid release, so a smaller particle size was essential. (4) The size of the microcapsules also affected the release of insulin. With larger microcapsules (approximately 30 microm), there was gradual release and a significant second phase of insulin release, while smaller microcapsules did not allow sustained release. Some variation in microcapsule size contributed to more constant and sustained release. (5) Based on the insulin release profile in vivo, a suitable molecular weight for PLGA was around 6000. The biological activity of insulin extracted from the formulation was similar to that of normal insulin. These experiments allowed us to prepare a desirable sustained-release insulin formulation.
Animals↗
Effects of prolonged delivery of brain-derived neurotrophic factor on the fate of neural stem cells transplanted into the developing rat retina.
One of the major roles of brain-derived neurotrophic factor (BDNF) is to promote the differentiation and support the survival of neurons in the central nervous system. The objective of the present study was to evaluate the effect of BDNF on the fate of adult rat hippocampus-derived neural stem cells (AHPCs) transplanted into the developing rat retina. Immunohistochemical analysis showed a significant increase in the ratio of grafted AHPCs stained for MAP2ab (P<0.05) and a marked decrease in the ratio of nestin-positive grafted cells in the slow-releasing BDNF group compared with the control group. The respective changes in the ratios of MAP5 and GFAP-positive grafted cells were comparable for the two groups. The results reported here suggest a potentially beneficial role for extended delivery of BDNF in the differentiation of grafted neural stem cells, which may lead to a novel modification of stem cell transplantation.
Animals↗
Action of microparticles of heparin and alginate crosslinked gel when used as injectable artificial matrices to stabilize basic fibroblast growth factor and induce angiogenesis by controlling its release.
Alginate is an acidic polysaccharide like the glycosaminoglycans and is a candidate for use as an artificial matrix. We developed a novel alginate gel sheet that is crosslinked with heparin (H/A gel sheet) and discovered its properties of releasing biologically active basic fibroblast growth factor (bFGF), a representative member of the heparin-binding growth factors (HBGFs), for about 1 month in vitro and of inducing angiogenesis in vivo. In the present study, the H/A gel sheet was mechanically broken up to produce easily injectable 50- to 200 microm microparticles of the gel (H/A gel particles), the properties of which were analyzed. The H/A gel particles cumulatively released 2.8 times as much bFGF as the H/A gel sheet, despite both having the same amount of bFGF adsorbed onto their gels. In addition, the bFGF-adsorbed H/A gel particles released a significant amount of bFGF, which stimulated cellular growth in a culture of human umbilical venous endothelial cells for up to 5 weeks. The subcutaneous injection of the bFGF-adsorbed H/A gel particles induced the formation of numerous microvessels in the tissue surrounding the gel. These results indicate that the H/A gel particles not only stabilize bFGF by preventing the occurrence of proteolysis or denaturation but also modulate its release from the gel. Because the H/A gel particles can be easily injected into the target tissues, this artificial matrix may be useful for the local delivery of HBGFs in the treatment of ischemic arterial diseases, as well as for regenerating or constructing tissues.
Alginates↗
Expression of metallothionein-III induced by hypoxia attenuates hypoxia-induced cell death in vitro.
Metallothioneins (MTs) are metal-binding proteins that are expressed in many tissues including brain. MTs protect cells and organs against metal toxicity and oxidants. Among MTs, a brain-predominant subtype MT-III has prominent neuroprotective activity against various types of damage. Here we show that the expression of MT-III is induced in cultured normal human astrocytes by hypoxia, and that overexpressed MT-III protects human embryonic kidney cells from hypoxia, suggesting that MT-III can protect the brain from hypoxic damage.
Astrocytes↗