Trierixin, a novel Inhibitor of ER stress-induced XBP1 activation from Streptomyces sp. 1. Taxonomy, fermentation, isolation and biological activities

In the course of screening for an inhibitor of ER stress-induced XBP1 activation, we isolated a new member of the triene-ansamycin group compound, trierixin, from a culture broth of Streptomyces sp. AC 654. Trierixin was purified by column chromatography on silica gel and by HPLC. The molecular formula of trierixin is C(37)H(52)N(2)O(8)S. Trierixin inhibited thapsigargin-induced XBP1-luciferase activation in HeLa/XBP1-luc cells and endogenous XBP1 splicing in HeLa cells with an IC(50) of 14 ng/ml and 19 ng/ml, respectively. Moreover, in the process of isolating trierixin, we isolated structurally related mycotrienin II and trienomycin A as inhibitors of ER stress-induced XBP1 activation from a culture broth of a trierixin-producing strain. This study provides the first observation that triene-ansamycins have a novel inhibitory effect against XBP1 activation.     

Effect of triterpenoids isolated from the floral spikes of Betula platyphylla var. japonica on P-glycoprotein function

One of the major causes of multidrug resistance (MDR) in cancer cells is over-expression of P-glycoprotein (P-gp). We studied the effects of 20 triterpenes isolated from the floral spikes of Betula platyphylla var. japonica ( B. platyphylla) on P-gp function based on our previous finding that some of them showed MDR reversing effects. We evaluated accumulations and effluxes of rhodamine 123 as a P-gp substrate with P-gp over-expressing KB-C2 cells. Among the 20 triterpenes, compounds 3, 4, 8, 9, 13, 15, and 20 increased rhodamine 123 accumulations in KB-C2 cells, and three ( 8, 13, and 20) of them also inhibited efflux of rhodamine 123 out of cells. In addition, compounds 13 and 20 showed a weak inhibitory activity of P-gp ATPase. These results suggested that MDR reversing effects of compounds 13 and 20 are partly involved in inhibition of P-gp ATPase.     

Effects of a novel histone deacetylase inhibitor, N-(2-aminophenyl) benzamide, on a reversible hypertrophy induced by isoproterenol in in situ rat hearts

The aim of the present study was performed to determine whether a novel histone deacetylase (HDAC) inhibitor, N-(2-aminophenyl)-4-{[benzyl(2-hydroxyethyl)amino]methyl} benzamide (K-183), prevents a reversible cardiac hypertrophy induced by isoproterenol and improves left ventricular (LV) dysfunction in rats. Either isoproterenol or vehicle was infused for 3 days by osmotic minipump. One hour prior to the implantation of isoproterenol, K-183 or trichostatin A (TSA) was injected twice a day for 3 days. We recorded continuous LV pressure-volume (P-V) loops of in situ hearts one hour after removal of the osmotic minipump. LV work capability (systolic P-V area at midrange LV volume: PVA(mLVV)) and hemodynamics were evaluated. K-183 per se induced neither cardiac hypertrophy nor collagen production. Although K-183 did not prevent the hypertrophy, where PVA(mLVV) remained decreased, K-183, differently from TSA, significantly attenuated the decrease of cardiac output and the increase of effective arterial elastance in the hypertrophied heart. These results indicate that the novel HDAC inhibitor K-183 has some beneficial effects on hemodynamics, although K-183 has no effects of anti-hypertrophic modalities.     

Triterpenoids from the floral spikes of Betula platyphylla var. japonica and their reversing activity against multidrug-resistant cancer cells

Four new triterpenes, together with 16 known triterpenes, were isolated from the floral spikes of Betula platyphylla var. japonica in a search for compounds capable of reversing multidrug resistance in cancer cells. The structures of the new triterpenes were elucidated as 3,4-seco-olean-4(23),13(18)-dien-3-oic acid (1), 3,4-seco-urs-4(23),20(30)-dien-3-oic acid (2), 3-O-methylmalonylepiocotillol II (6), and 3-O-methylmalonylcabraleahydroxylactone (16) by spectroscopic examination. The cytotoxicity of the isolated triterpenes against human cancer cell lines as well as multidrug-resistant cancer cell lines was evaluated. Most of the isolated triterpenes showed very weak cellular toxicities. Although no discernible differences were found in the cytotoxicities for the tested compounds against sensitive and resistant cell lines, the cytotoxicities for several triterpenes against multidrug-resistant cancer cell lines (KB-C2 or K562/Adr) were enhanced in the presence of nontoxic concentrations of colchicine or doxorubicin. Compound 10 reversed the cytotoxicity of colchicine against KB-C2 cells at 8.1 microM and showed comparable potency to 5 microM verapamil.     

A case report: Primary extragonadal yolk sac tumor of penile shaft in a 2-year-old child

Abstract:   A 2-year-old boy, who had the chief complaints of penile swelling and pain, was brought to the hospital by his mother. Penile contusion/trauma was suspected and he was admitted the same day to undergo emergency surgery to eliminate hematoma. The surgery revealed that the origin of the bleeding was not trauma but a tumor lesion of the penile shaft. It was histopathologically identified as a yolk sac tumor and no tumorous lesions were found except that in the penis. Therefore the patient was diagnosed as definitely having a yolk sac tumor originating in the penis. The patient received four cycles of cisplatin, etoposide and bleomycin treatment as adjuvant chemotherapy. Although it was impossible to completely resect the tumor, cisplatin, etoposide and bleomycin chemotherapy was effective and a complete response was achieved. We plan to carefully monitor the patient in the future.     

Implanted Port Catheter System Infection Caused by Methicillin-resistant Staphylococcus pseudintermedius ST71-SCCmec type III

Staphylococcus pseudintermedius is commonly associated with skin and soft tissue infections in dogs. However, infections caused by S. pseudintermedius are only rarely reported in humans, and this pathogen is frequently misidentified as S. aureus. We herein report a case of an implanted port catheter system infection caused by methicillin-resistant S. pseudintermedius (MRSP) in a patient with hepatocellular carcinoma. The patient was also a dog owner. S. pseudintermedius was first identified using the Vitek2 system (BioMérieux). Whole-genome sequencing revealed that this MRSP was a sequence type 71-carrying staphylococcal cassette chromosome mec type III (ST71-SCCmec III) isolate.     

Decline of T cell-related immune functions in cancer patients and an attempt to restore them through infusion of activated autologous T cells

We developed a scoring system that can combine several immunological parameters and express the immune status of individuals as a simple numeral. T cell immune score was obtained by using 5T cell-related parameters: number of T cells, ratio of CD4(+)T cells to CD8(+)T cells, number of na?ve T cells, ratio of na?ve T cells to memory T cells, and T cell proliferative index (TCPI). TCPI was calculated by using number of T cells and their proliferative activity. We assessed T cell immune score in 103 patients with colorectal cancer and 51 healthy age-matched controls. The results were as follows: (1) T cell-immune score of patients in stages I-IV before surgery was significantly decreased as compared with controls. (2) The number of regulatory T cells in patients in stages I-IV gradually increased with disease progression. (3) T cell immune score was strongly suppressed after surgery, but were recovered to the initial level within a month. (4) Furthermore, restoration of immunological function was attempted in cancer patients by infusion of activated autologous T cells. The effectiveness was confirmed by an increase of TCPI in many cancer patients.     

Reliability of linear distance measurement for dental implant length with standardized periapical radiographs

The purpose of this study was to investigate the accuracy of distance measurements of implant length based on periapical radiographs compared with that of other modalities. We carried out an experimental trial to compare precision in distance measurement. Dental implant fixtures were buried in the canine and first molar regions. These were then subjected to periapical (PE) radiography, panoramic (PA) radiography, conventional (CV) and medical computed (CT) tomography. The length of the implant fixture on each film was measured by nine observers and degree of precision was statistically analyzed. The precision of both PE radiographs and CT tomograms was closest at the highest level. Standardized PE radiography, in particular, was superior to CT tomography in the first molar region. This suggests that standardized PE radiographs should be utilized as a reliable modality for longitudinal and linear distance measurement, depending on implant length at local implantation site.     

Occult fractures of articular eminence and glenoid fossa presenting as temporomandibular disorder: a case report

We report an unusual case of occult fractures of the articular eminence and glenoid fossa due to a previous traffic accident presenting as a temporomandibular disorder. A 24-year-old Japanese man was referred for trismus and pain in the right temporomandibular joint, and was suspected of having temporomandibular disorder. Although the magnetic resonance image did not show displacement of the articular disk, T2-weighted images revealed disruption of the cortical low-intensity line of the right articular eminence. On a computerized tomography (CT) scan, an isolated bone fragment of the right articular eminence was clearly seen, and fractures of the right glenoid fossa and articular eminence were noted. The patient was treated by instructing him not to open his mouth widely and to remain on a soft diet for 4 weeks. A CT examination performed 1 year after the treatment showed complete healing of the fracture in the right articular eminence and glenoid fossa.