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Biomedical subjects

H Maeda

Publications and source records attributed to H Maeda.

At least 73 records · Page 4Linked to original sources
PubMed2001

Tumor growth inhibition by arsenic trioxide (As2O3) in the orthotopic metastasis model of androgen-independent prostate cancer.

Arsenic trioxide (As2O3) induces clinical remission of patients with acute promyelocytic leukemia. As a novel anticancer agent for treatment of solid cancers, As2O3 is promising, but no in vivo experimental investigations of its efficacy on solid cancers have been done at clinically obtained concentrations. In addition, the cell death mechanism of As2O3 has yet to be clarified, especially in solid cancers. In this study, human androgen-independent prostate cancer cell lines, PC-3, DU-145, and TSU-PR1 were examined as cellular models for As2O3 treatment, and As2O3-induced cell death and inhibition of cell growth and colony formation were evaluated. The involvement of p38, c-Jun NH2-terminal kinase (JNK), caspase-3, and reactive oxygen species (ROS) were investigated in As2O3-induced cell death. Finally, As2O3 was administered to severe combined immunodeficient mice inoculated orthotopically with PC-3 cells to estimate in vivo efficacy. In all three of the cell lines, at high concentrations, As2O3 induced apoptosis and, at low concentrations, growth inhibition. As2O3 activated p38, JNK, and caspase-3 dose dependently. Treatment with the p38 inhibitor and over-expression of dominant-negative JNK did not guard against As2O3-induced cell death. In contrast with partial protection by the caspase-3 inhibitor, the antioxidant N-acetyl-L-cysteine gave marked protection from As2O3-induced apoptosis and eliminated the activation of p38, JNK, and caspase-3, and the generation of ROS. The orthotopic murine metastasis model showed in vivo tumor growth inhibition in orthotopic and metastatic lesions with no signs of toxicity. This study establishes that As2O3 provides a novel, safe approach for treatment of androgen-independent prostate cancer. Generation of ROS as a therapeutic target for the potentiation of As2O3-induced apoptosis also was shown.

Androgens↗
PubMed2001

Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS.

This review article describes three aspects of polymeric drugs. The general mechanism of the EPR (enhanced permeability and retention) effect and factors involved in the effect are discussed, in view of the advantages of macromolecular therapeutics for cancer treatment, which are based on the highly selective EPR-related delivery of drug to tumor. Also described are advantages of more general water-soluble polymeric drugs as primary anticancer agents, using SMANCS as an example. Last, SMANCS/Lipiodol is discussed with reference to the type of formulation for arterial injection with most pronounced tumor selective delivery, as well as its advantages, precautions, and side effects from the clinical standpoint.

Amino Acid Sequence↗
PubMed2001

Development of a new drug delivery system for protein drugs using silicone (II).

In order to achieve a zero-order release of protein drugs, we have developed a new drug delivery system using silicone, which is named the covered-rod-type formulation. Preparation of the covered-rod-type formulation was conducted under mild conditions without heat treatment or the use of organic solvents. The covered-rod-type formulation released human serum albumin (HSA) or interferon (IFN) at a constant rate for 30-100 days in vitro without significant initial burst. When the IFN covered-rod-type formulation was implanted in nude mice, the serum IFN concentration was maintained at a constant level during the period of observation, i.e., 28 days. The covered-rod-type formulation enabled precise control of the release of the protein drugs and would be expected to increase the duration of the drug effect and to reduce the frequency of administration and side effects.

Animals↗
PubMed2001

Low-degree oxidized scleroglucan and its hydrogel.

A controlled oxidation of scleroglucan was performed with sodium periodate to prepare aldehyde derivatives (scleraldehyde) with a low degree of oxidation (10 and 20%), which were utilized for crosslinking reactions with hexamethylenediamine. The structural characterization of scleraldehydes and their corresponding hydrogels was attempted by small-angle X-ray scattering (SAXS). While scleraldehyde with a higher degree of oxidation (> or = 50%), according to an earlier research, was found to disentangle into single chains as the degree of oxidation increases; scleroglucan bearing a low percentage of aldehydic groups (up to 20%) retains mainly the conformation of the natural polysaccharide, thus the system can be represented as composed of triple helices with only minor disentanglements at the sites where the aldehyde groups are present. The hydrogel prepared from scleraldehyde with a low degree of oxidation is brittle and fragmented, in contrast to the elastic/homogeneous hydrogel earlier prepared from scleraldehyde with a high degree of oxidation. The hydrogel from scleraldehyde with a low degree of oxidation was found to possess a network structure that consisted mostly of the triple helices crosslinked in specific points where the triple helices are disentangled into single chains because of the presence of the aldehyde groups.

Aldehydes↗
PubMed2001

Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutathiolation via disulfide S-oxide formation.

Oxidative stress may cause tissue injury through activation of the precursors of matrix metalloproteinase (proMMPs). In this study, we observed glutathione (GSH)-dependent proMMP activation induced by peroxynitrite, a potent oxidizing agent formed during inflammatory processes. Peroxynitrite strongly activated all three types of purified human proMMPs (proMMP-1, -8, and -9) in the presence of similar concentrations of GSH. Of the potential reaction products between peroxynitrite and GSH, only S-nitroglutathione (GSNO(2)) caused proMMP activation. Extensive S-glutathiolation of the proMMP protein occurred during activation of proMMP by peroxynitrite and GSH, as shown by radiolabeling studies with [(35)S]GSH or [(3)H]GSH. Evidence of appreciable S-glutathiolation persisted even after dithiothreitol and protein-denaturing treatment, however, suggesting that some S-glutathiolation did not occur through formation of simple mixed disulfide. Matrix-assisted laser-desorption ionization-time-of-flight mass spectrometry indicated that not only peroxynitrite plus GSH but also synthetic GSNO(2) produced dithiothreitol-resistant S-glutathiolation of the synthetic peptide PRCGVPD, which is a well conserved Cys-containing sequence of the propeptide autoinhibitory domain of proMMPs. PRCGVPD S-glutathiolation is presumed to be formed through glutathione disulfide S-oxide (GS(O)SR), based on the m/z 1064. Our results illustrate a unique mechanism of oxidative proMMP activation and oxidative tissue injury during inflammation.

Amino Acid Sequence↗
PubMed2001

Photoallylation and photoreduction of cyclohexylidenepropanedinitrile by use of allyltrimethylsilane via photoinduced electron transfer: control of the product ratio depending on pK(a) values of additives.

Irradiation of an acetonitrile solution containing cyclohexylidenepropanedinitrile (1) and allyltrimethylsilane (2) in the presence of phenanthrene afforded two kinds of allylated products (3, 4) and a reduction product (5). The product ratio of 3, 4, and 5 dramatically changed depending on the pK(a) values of additives.

Journal Article↗
PubMed2001

Acid-base and spectroelectrochemical properties of doubly N-confused porphyrins.

The cis-doubly N-confused porphyrin, H2N2CP, containing two adjacent confused pyrrole rings has been investigated from the point of view of its acid-base and electrochemical behavior in dichloromethane. This novel porphyrin isomer can form two metal-carbon bonds in the central core, stabilizing metal ions in unusually high oxidation states. Furthermore, the two outside N-pyrrole atoms remain available for acid-base and specific solvent interactions. Protonation of the pyrrole N atoms proceeds according to two successive steps, while only a single deprotonation step has been observed in the presence of bases. Similarly, in the case of the silver and copper complexes the protonation and deprotonation of the outer pyrrole rings have been detected, confirming the structure of the metalated species as M(III)-HN2CP. The electrochemical reduction of the metal ions (III/II redox process) and oxidation of the macrocycle ring have been detected respectively at -0.9 and 1.4 V based on spectroelectrochemical measurements in conjunction with the acid/base equilibrium studies. Additional waves observed around -0.5 and 1.3 V have been assigned to redox processes involving water molecules associated with the doubly N-confused porphyrins.

Journal Article↗
PubMed2001

Immunohistochemical investigation of pulmonary surfactant-associated protein A in fatal poisoning.

To evaluate the immunohistochemical distribution of pulmonary surfactant-associated protein A (SP-A) in fatal poisoning in relation to the effects of drugs and poisons on respiratory function, 42 forensic autopsy cases were examined by scoring the staining intensity. The highest scores of SP-A staining, with dense granular deposits (aggregates) in the intra-alveolar space, were observed in fatalities from pancuronium bromide (muscle relaxant) injection and petroleum (butane) gas inhalation. Poisoning with organophosphate pesticides and arsenic (ingestion) showed a second grade SP-A score. However, The SP-A scores were relatively low in ethanol and sedative-hypnotic intoxication. Carbon monoxide intoxication showed a varied degree of SP-A score, and the aggregated SP-A score tended to be higher in cases of lower blood carboxyhemoglobin concentration. A varied SP-A score was also observed in methamphetamine fatalities, in which the score was relatively low in cases with a higher serum drug level. Increase of SP-A was not always associated with the intra-alveolar effusion or hemorrhages. The above-described observations suggested that the immunohistochemical score of SP-A may be a possible indication for intensity and duration of drug/poison-dependent respiratory distress.

Adolescent↗
PubMed2001

SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy.

This review discusses the development and therapeutic potential of prototype macromolecular drugs for use in cancer chemotherapy, in particular the development and use of SMANCS, a conjugate of neocarzinostatin and poly(styrene-comaleic acid). The various topics covered include a brief description of the chemistry and polymer conjugation, the binding of the conjugate to albumin and the biological behaviour in vitro and in vivo after arterial injection in animals, including plasma half-life, and the lipid solubility of SMANCS in medium chain triglycerides and Lipiodol, a lipid contrast medium suitable for use in X-ray-computed tomography. The biological response-modifying effects and the tumor-targeting mechanism of SMANCS and other macromolecular drugs are also discussed. The latter mechanism is accounted for in terms of a tumor 'enhanced permeability and retention' (or EPR) effect. A principal advantage in the use of SMANCS or other macromolecular drugs is the potential for a reduction or elimination of toxicity. Macromolecular drugs such as a pyran copolymer-NCS conjugate show a marked reduction in bone marrow toxicity normally associated with the use of NCS. This is believed to be due to a hypothetical blood-bone marrow 'barrier' which, relative to NCS, restricts or limits access of the macromolecular drug to the bone marrow. In addition, the clinical possibilities for SMANCS are discussed, including the suggestion that angiotensin II-induced hypertension has clinical potential in improving the selective delivery of macromolecular drugs (i.e. SMANCS) to tumors. Aqueous SMANCS formulations have been tested in pilot studies in patients with solid tumors of the ovary, esophagus, lung, stomach, adrenal gland and in the brain. Formulations based on SMANCS/Lipiodol have been shown to be effective both as a diagnostic tool and for therapeutic use in solid tumors where the formulations are given arterially via a catheter. In a pilot study in primary unresectable hepatoma, an objective reduction in tumor size was observed for about 90% of cases when an adequate amount of the macromolecular drug was administered. A patient receiving such treatment with no active liver cirrhosis and tumor nodules/lesion confined within one liver segment might expect to have a 90% chance of survival after treatment for at least 5 years.

Animals↗
PubMed2001

Photorearrangement of vinylidenecyclopropanes to 1,2,3-butatriene derivatives.

[reaction: see text] Photoirradiation of benzene solutions containing 1-diarylvinylidene-2,2,3,3-tetramethylcyclopropanes (2a--d) afforded rearranged products 1,2,3-butatrienes (3a-d) in good to high yields. Photorearrangement from 2,2,3-trimethyl and 2,2- and 2,3-dimethyl derivatives 2e--g also proceeded, but the rates of the rearrangement were lower than those of 2a--d. A singlet mechanism is proposed for this photorearrangement, where alkyl migration occurs from 1,3-biradical intermediates generated via the homolysis of the C1-C2 bond. Generation of diarylvinylidene carbenes from 1,3-biradicals might be competitive with the formation of 3.

Journal Article↗
PubMed2001

Fatal traumatic rupture of an aortic aneurysm of the sinus of Valsalva: an autopsy case.

This report describes an autopsy case of a rare type of aortic sinus of Valsalva aneurysm, which caused fatal rupture from a blunt chest impact. A 51-year-old male was hit in the chest with a fist, lost consciousness after about 15min and died after approximately 7h. The postmortem examination revealed a large saccular aneurysm of the right coronary sinus bulging on the right atrium, which had a full laceration causing pericardial hematoma (cardiac tamponade). A related chest wall injury was observed in the right outer mammary region. A rare type of bulging onto the right atrium and subsequent sclerosis of the right coronary artery appeared to have greatly contributed to the fatal rupture.

Aortic Rupture↗
PubMed2001

Post-mortem urinary myoglobin levels with reference to the causes of death.

To evaluate pathophysiological significance of post-mortem urinary myoglobin levels in determining the cause of death, we investigated 210 forensic autopsy cases, partially in comparison with serum levels. Post-mortem serum myoglobin levels were extraordinary high in most cases possibly due to post-mortem change. Urinary myoglobin levels did not correlate with the serum levels, showing possible post-mortem elevation in cases of a prolonged post-mortem period over 48h. A high (>1000 ng/ml), moderate (100-1000 ng/ml), slight (50-100 ng/ml) and not significant (<50 ng/ml) elevation of urinary myoglobin were observed in 26, 43, 31 and 110 cases, respectively. Half the highly elevated cases were those with a survival time over 24h. In cases of minor muscle injury such as head trauma, elevation of urinary myoglobin level was closely related to longer survival. In acute/subacute deaths with a post-mortem interval within 48h, a significant difference was observed in relation to the blood carboxyhemoglobin (COHb) levels of fire victims: myoglobinuria over 100 ng/ml was more frequently and markedly observed in cases with COHb below 60% than over 60%, suggesting muscle damage in fatal burns. Similar elevation was observed in heat stroke victims, and also in some cases of acute and subacute death from polytrauma, asphyxiation, drowning, electricity and spontaneous cerebral bleeding, but not in myocardial infarction. Thus, it was suggested that high post-mortem urinary myoglobin levels in acute and subacute death cases may be a possible indicator of antemortem massive skeletal muscle damage as well as exertional muscle hyperactivity or convulsive disorders associated with hypoxia.

Adolescent↗
PubMed2001

Matrix metalloproteinases induction by pseudomonal virulence factors and inflammatory cytokines in vitro.

The pathogenesis of pseudomonal keratitis was investigated by focusing on induction and activation of matrix metalloproteinases (MMPs) by pseudomonal virulence factors and proinflammatory cytokines. Corneal lesions and MMP induction in vivo were evaluated in rabbit corneas infected with a clinical isolate of Pseudomonas aeruginosa. Effects of pseudomonal virulence factors [elastase, alkaline protease, exotoxin A and lipopolysaccharide (LPS)], tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta on MMP induction and activation were further examined in vitro in rabbit corneal fibroblasts (RCF) and human fibrosarcoma (HT1080) cells using reverse transcriptase-polymerase chain reaction (RT-PCR), zymography and immunoblotting. Corneal ulcers with typical ring abscesses were observed 12-24 h after infection, and MMPs, particularly MMP-9, were upregulated in infected corneas. Pseudomonal elastase caused the most extensive damage to both cell types. RCF treated with pseudomonal exoproteases or LPS expressed and secreted MMP-9. Exotoxin A had no effect on MMP expression. Both IL-1beta and TNF-alpha augmented MMP-9 expression in HT1080 cells. Pseudomonal elastase proteolytically activated MMP-2 and MMP-9 released from the cells. In conclusion, corneal destruction seen with P. aeruginosa infections may result from enhanced expression of MMPs by corneal stromal cells stimulated with pseudomonal exoproteases and proinflammatory cytokines and the proteolytic activation of MMPs by pseudomonal elastase.

ADP Ribose Transferases↗
PubMed2001

Binding rate constant of Tc-99m DTPA galactosyl human serum albumin measured by quantitative dynamic SPECT--clinical evaluation as a total and regional liver function test.

To evaluate the clinical utility of a new method with dynamic single photon emission computed tomography (SPECT) and scatter and attenuation compensation to estimate both total and regional liver function quantitatively. Five controls, 20 patients with chronic liver disease, and 2 patients with Budd-Chiari syndrome were studied. Dynamic liver SPECT data were acquired during 20 minutes after injection of Technetium (Tc)-99m diethylenetriaminepentaacetic acid (DTPA) galactosyl human serum albumin (GSA) with scatter and attenuation compensation. The binding rate constant of Tc-99m GSA (Ku) was derived quantitatively from the Patlak plot based on kinetic models for GSA receptor binding. The mean Ku was obtained by dividing the Ku value (total Ku) by the liver volume. Both total and mean Ku were significantly lower in patients with chronic liver disease than in controls (302 +/- 112 vs. 523 +/- 78 ml/min; p < 0.001, 0.26 +/- 0.11 vs. 0.43 +/- 0.03 ml/min/cm3; p < 0.001). In the patient group, both total and mean Ku were significantly correlated with the results of conventional liver function tests and the histological severity of chronic liver disease. In 2 patients with Budd-Chiari syndrome, the mean Ku was lower in the right lobe, where the hepatic veins were occluded, than in the left lobe, where draining veins were patent. In conclusion, this method is a reliable diagnostic technique for estimating total and regional liver function.

Adult↗
PubMed2001

Intranuclear ubiquitin immunoreactivity in the pigmented neurons of the substantia nigra in fire fatalities.

To evaluate the significance of immunohistochemical staining of ubiquitin (heat shock protein) in the midbrain for medico-legal investigation of death in fires, we examined forensic autopsy cases of fire fatalities (n = 35) in comparison with controls (n = 27; brain stem injury, acute myocardial infarction and carbon monoxide poisoning other than fire fatality). There were two intranuclear staining patterns in the nuclei of pigmented substantia nigra neurons: a type of inclusion (possible Marinesco bodies) and a diffuse staining. Percentage of nuclear ubiquitin positivity (Ub-positive %) in fire fatalities (2.7-44.7%; mean, 18.5%) was significantly higher than in brain stem injury (n = 9; 0-10.4%; mean, 4.5%) and myocardial infarction (n = 14; 1.5-14.6%; mean, 6.9%), independently of blood carboxyhemoglobin (COHb) levels. Age-dependent increase in Ub-positive % was observed in lower COHb (< 60%) cases. The intranuclear diffuse ubiquitin staining was not observed in cases of high blood cyanide level (> 1.0 microg/ml). These observations showed that intranuclear ubiquitin immunoreactivity of the pigmented substantia nigra neurons in the midbrain was induced by severe stress in fires.

Aged↗
PubMed2001

Intranuclear ubiquitin immunoreactivity of the pigmented neurons of the substantia nigra in fatal acute mechanical asphyxiation and drowning.

To evaluate the significance of immunohistochemical staining of ubiquitin (heat shock protein) in the midbrain for the medico-legal diagnosis of fatal asphyxiation and drowning, we investigated forensic autopsy cases of fatal mechanical asphyxia (n = 18), manual/ligature strangulation (n = 9), hanging (n = 4), aspiration/choking (n = 5) and drowning (n = 16). These were compared to control groups (n = 30) consisting of fatalities from brainstem injury (n = 12) and acute myocardial infarction (n = 18). Ubiquitin was clearly demonstrated in the nuclei of pigmented substantia nigra neurons, showing two intranuclear staining patterns: a type of inclusion (possibly Marinesco bodies) and a diffuse staining. The diffuse staining was significantly more frequently observed in cases of drowning. The percentage of total ubiquitin positive neurons was frequently higher in strangulation (5.1-28.4%, mean 17.0%), aspiration/choking (5.3-32.0%, mean 17.6%) and drowning (7.0-34.1%, mean 19.8%), but relatively low in hanging (5.1-12.7%, mean 8.6%), brainstem injury (0-10.4%, mean 5.0%) and acute myocardial infarction (1.5-16.9%, mean 8.3%). These observations suggest that intranuclear ubiquitin immunoreactivity of the pigmented substantia nigra neurons in the midbrain was induced by a fatal severe stress on the central nervous system in asphyxiation and drowning.

Adult↗