Antitumor activity of dextran derivatives immobilizing platinum complex (II)

The in vivo antitumor activity and toxicity of a newly synthesized polymeric prodrug of cisplatin was investigated and also compared with plain cisplatin. The prodrug included a dicarboxymethyl-dextran conjugate of cisplatin (DCM-Dex/CDDP). DCM-Dex/CDDP was i.v. injected in mice bearing s.c. Colon 26 mouse colon cancer cells. The tissue distribution of platinum was thereafter determined by flameless atomic absorption spectrophotometry. The platinic concentration of the organs showed a high rate of retention at 24 h after injection in the DCM-Dex/CDDP-treated mice. No biochemical or hematologically adverse effects were observed. In addition, DCM-Dex/CDDP showed a significantly higher antitumor activity than cisplatin alone. These results indicate that DCM-Dex/CDDP may therefore be a potentially effective cancer chemotherapy.     

Myocardial infarction in Kawasaki disease: clinical analyses in 195 cases

We analyzed clinical data from 195 patients (141 boys) with myocardial infarction complicating Kawasaki disease, collected from 74 major hospitals in Japan. The myocardial infarction usually occurred within the first year of illness, but 27.2% of the patients had myocardial infarction more than 1 year later. In 63% of the patients it occurred during sleep or at rest. The main symptoms of acute myocardial infarction were shock, unrest, vomiting, abdominal pain, and chest pain; chest pain was much more frequently recognized in the survivors and in older patients. The myocardial infarctions were asymptomatic in 37% of the patients. Twenty-two percent of the patients died during the first attack. Sixteen percent of the survivors of a first attack had a second attack. Forty-three percent of all survivors of the first or subsequent attack are doing well; however, others have some type of cardiac dysfunction, such as mitral regurgitation, decreased ejection fraction of the left ventricle, or left ventricular aneurysm. Coronary angiographic studies indicate that in most of the fatal cases there was obstruction either in the main left coronary artery or in both the main right coronary artery and the anterior descending artery. In survivors, one-vessel obstruction was frequently recognized, particularly in the right coronary artery.     

Effect of <Emphasis Type="Italic">Kaempferia parviflora</Emphasis> extract on knee osteoarthritis

Knee osteoarthritis (OA) is becoming more prevalent worldwide due to increases in the numbers of elderly and obese patients. Currently, pharmaceutical medicines used for the treatment of OA are for symptomatic therapy and therefore new therapeutic agents are needed. Kaempferia parviflora (KP) is a plant growing naturally in Southeast Asia and has various pharmacological effects including an anti-inflammatory effect, but no effect on OA has yet been reported. We therefore conducted a search for the effects KP and the active components of KP extract (KPE) exert on OA as well as its mechanism of action. Results from a study of KPE using the monoiodoacetic acid rat OA model revealed that KPE reduced the pain threshold and severity of osteoarthritic cartilage lesions. The mechanism of action and active components were then investigated using IL-1β-treated human knee-derived chondrocytes. KPE, as well as 5,7-dimethoxyflavone and 5,7,4′-trimethoxyflavone, which are key constituents of KPE and highly absorbable into the body, reduced the expression of matrix metalloproteinases (MMPs), which are the main extracellular matrix enzymes that degrade collagen within cartilage. As mentioned above, KPE acted to suppress OA and 5,7-dimethoxyflavone and 5,7,4′-trimethoxyflavone were shown to be involved as part of KPE’s mechanism that inhibits MMPs.     

Investigation of inflammation inducing substances in PM2.5 particles by an elimination method using thermal decomposition

The substances associated with PM2.5‐induced inflammatory response were investigated using an elimination method. PM2.5 were heated at temperatures of 120, 250, and 360°C. The results demonstrated microbial substances such as LPS and b‐glucan, and chemicals including BaP, 1,2‐NQ, and 9,10‐PQ were reduced drastically in PM2.5 heated at 120°C. On the other hand, DBA, 7,12‐BAQ, and BaP‐1,6‐Q were not noticeably reduced. Most of these substances had disappeared in PM2.5 heated at 250°C and 360°C. Metals (eg, Fe, Cu, Cr, Ni) in PM2.5 exhibited a slight thermo‐dependent increase. RAW264.7 macrophages with or without NAC were exposed to unheated PM2.5, oxidative stress‐related and unrelated inflammatory responses were induced. PM2.5‐induced lung inflammation in mice is caused mainly by thermo‐sensitive substances (LPS, b‐glucan, BaP, 1,2‐NQ, 9,10‐PQ, etc.). Also, a slight involvement of thermo‐resistant substances (DBA, 7,12‐BAQ, BaP‐1,6‐Q, etc.) and transition metals was observed. The thermal decomposition method could assist to evaluate the PM2.5‐induded lung inflammation.     

Effects of Asian sand dust particles on the respiratory and immune system

Epidemiologic studies have reported that Asian sand dust (ASD) particles can affect respiratory health; however, the mechanisms remain unclear. We investigated the effects of ASD on airway epithelial cells and immune cells, and their contributing factors to the effects. Human airway epithelial cells were exposed to ASD collected on 1–3 May (ASD1) and on 12–14 May (ASD2) 2011 in Japan and heat‐treated ASD1 for excluding heat‐sensitive substances (H‐ASD) at a concentration of 0, 3, 30 or 90 µg ml^–1 for 4 or 24 h. Furthermore, bone marrow‐derived dendritic cells (BMDC) from atopic prone mice were differentiated by culture with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) then these BMDC were exposed to the ASD for 24 h. Also splenocytes as mixture of immune cells were exposed to the ASD for 72 h. All ASD dose dependently reduced viability of airway epithelial cells. Non‐heated ASD showed a dose‐dependent increase in the protein release of interleukin (IL)‐6 and IL‐8. The raises induced by ASD1 were higher than those by ASD2. ASD1 and ASD2 also elevated ICAM‐1 at the levels of mRNA, cell surface protein and soluble protein in culture medium. In contrast, H‐ASD did not change most of these biomarkers. Non‐heated ASD showed enhancement in the protein expression of DEC205 on BMDC and in the proliferation of splenocytes, whereas H‐ASD did not. These results suggest that ASD affect airway epithelial cells and immune cells such as BMDC and splenocytes. Moreover, the difference in ASD events and components adhered to ASD can contribute to the health effects. Copyright © 2013 John Wiley & Sons, Ltd.     

Immunohistochemically demonstrated variation in expression of cathepsin E between uracil-induced papillomatosis and N-butyl-N-(4-hydroxybutyl)nitrosamine-induced preneoplastic and neoplastic changes in rat urinary bladder

Expression of rat urinary bladder cathepsin E in benign papillomatosis induced by uracil and various stages of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced carcinogenesis was investigated immunohistochemically. Seven-week-old, male F344/DuCrj rats were used. In the normal urothelium of control rats, cathepsin E stained in all layers of cells, although in umbrella cells and some basal cells the reaction was relatively weak. In rats given a diet containing 3% uracil for 5 weeks immunoreactivity of cathepsin E in uracil-induced papillomatosis was consistently homogeneous in all layers, but weaker than in normal urothelium. In rats given 0.05% BBN in drinking water for 12 weeks and subsequently maintained without treatment for 48 weeks cells with little cathepsin E, never observed in normal urothelium, appeared at 5 weeks above the basement membrane in the earliest stage of BBN-induced urinary bladder cancer (simple hyperplasia). Throughout the neoplastic process, groups of cells with a little cathepsin E were randomly distributed, with expression in the urothelium being markedly unstable. Almost all areas of squamous cell proliferation in TCC were negative for cathepsin E. Instability of cathepsin E expression in rat urothelium therefore appears characteristic for carcinogenesis and offers the possibility of using this feature as an early biomarker for urinary bladder carcinogenesis.     

The role of IL-17 in systemic lupus erythematosus and its potential as a therapeutic target

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies production and immune complex deposition with systemic clinical manifestations. Interleukin (IL)-17-producing cells play a crucial role in disease pathogenesis and represent an attractive therapeutic target.

Areas covered: This review provides an update on the possibility of targeting IL-17 in SLE. The rational for this approach as well as currently available and future targets are discussed.

Expert opinion: Although human expression studies and animal models indicate that IL-17 blocking may be a promising therapeutic strategy for SLE, direct evidence for IL-17 inhibition in SLE patients is unavailable. Biologic therapies and small-molecule drugs that target IL-17 production are required for the achievement of a favorable clinical effect in SLE patients.     

Ultrastructure of lentigo maligna in the oral cavity

A rare case of lentigo maligna in the oral cavity was investigated by light and electron microscopy. Cutaneous lentigo malignas often develop to malignant melanomas. However, the electron microscopic examination revealed that even though there were a large number of melanosomes, most of them were late stage and had membrane structure, and positive staining with HMB-45 was not recognized. From our findings, it is difficult to conclude that oral lentigo malignas develop malignant melanomas, and thus further studies are needed.     

Novel mutations in the guanosine triphosphate cyclohydrolase 1 gene associated with DYT5 dystonia

OBJECTIVES: To better understand the relationship between mutation of the guanosine triphosphate cyclohydrolase I (GCH1) gene and the etiology of DYT5 dystonia and to accumulate data on the mutation in the Japanese population for genetic diagnosis of the disease. SETTING: Japanese population. Patients Eight Japanese patients with suspected DYT5 dystonia were analyzed. Intervention Direct genomic sequencing of 6 exons of GCH1 was performed. MAIN OUTCOME MEASURES: For patients who did not exhibit any abnormality in the sequence analysis, the possibility of exon deletions was examined. In cases for which cerebrospinal fluid was available, the concentrations of neopterin and biopterin were measured as an index of GCH1 enzyme activity. RESULTS: In 2 patients, we found a new T106I mutation in exon 1 of GCH1, a position involved in the helix-turn-helix structure of the enzyme. In the third patient, we found a new mutation (a 15-base pair nucleotide deletion) in exon 5 that may cause a frameshift involving the active site. In the fourth patient, we detected a known nucleotide G>A substitution in the splice site of intron 5, which has been reported to produce exon 5-skipped messenger RNA. The concentrations of both neopterin and biopterin in the cerebrospinal fluid of the third and fourth patients were markedly lower than the normal range, indicating that the GCH1 enzyme was functionally abnormal in these mutations. Gene dosage analysis showed that the fifth patient had a deletion of both exon 3 and exon 4, whereas the sixth patient had a deletion of exon 3. CONCLUSIONS: We found several novel, as well as known, GCH1 mutations in Japanese patients with DYT5 dystonia. In some of them, the GCH1 enzyme activity was proved to be impaired.