Neoadjuvant chemotherapy and radiation for inoperable carcinoma of the maxillary antrum: a matched-control study

A matched-control study comparing standard radiotherapy versus neoadjuvant chemotherapy and radiation was undertaken to clarify the effects of neoadjuvant systemic chemotherapy for locally advanced squamous cell carcinoma of the maxillary antrum. Thirty-four patients with inoperable maxillary cancer were treated with neoadjuvant chemotherapy and radiotherapy (Group II). Before starting radiotherapy, all patients in Group II received two or three cycles of neoadjuvant chemotherapy consisting of cisplatin and a 5-day continuous infusion of 5-fluorouracil with or without intravenous injection of vinblastine. Radiation doses ranged from 66 Gy to 75 Gy (median, 70 Gy). The response rate, patterns of failure, toxicity, and survival for Group II were compared with those for 34 stage-matched patients treated with radiation alone (Group I). Despite a higher response rate to neoadjuvant chemotherapy, the recurrence rate and patterns of treatment failure were not influenced by the addition of neoadjuvant chemotherapy. In most cases, neoadjuvant chemotherapy did not interfere with subsequent radiotherapy, and radiation-induced late complications occurred equally in both treatment groups. After a median follow-up of 48 months, there was no significant difference in 5-year actuarial survival or disease-free survival between the two treatment groups. Radiation alone for inoperable maxillary cancer was clearly suboptimal for improving local control and survival rate, but neoadjuvant chemotherapy in addition to standard radiotherapy failed to demonstrate any therapeutic advantage over radiation alone.     

Methylisogermabullone isolated from radish roots stimulates small bowel motility via activation of acetylcholinergic receptors

We have previously reported that extract of radish roots exhibits an increase in gastrointestinal motility through the activation of muscarinic acetylcholine (ACh) receptors. Based on the stimulatory activity-guided fractionation on rat ileal segments, this study isolated methylisogermabullone (MIGB, C23H31O5NS, MW 433) from methanol extracts of radish roots. MIGB caused a significant increase of the isolated rat ileal contraction in a concentration-dependent manner (23-693 microM), and the pattern of MIGB-induced ileal contraction was different in the time course to that produced by ACh. The EC50 value of MIGB, to produce 50% maximum ileal contraction, was estimated to be 45.5 microM. MIGB (230 microM)-induced ileal contractions were enhanced by pretreatment of segments with ACh (0.1 microM). Ileal contractions produced by MIGB (230 microM) or ACh (0.1 microM) at submaximal concentration were partially inhibited by pretreatment of hexamethonium (0.1 mM), a ganglionic blocker, whereas they were almost completely abolished by atropine (10 microM). Oral administration of MIGB to mice stimulated the small intestinal transit of charcoal in a dose-dependent manner (10-100 mg kg(-1)), and MIGB (100 mg kg(-1))-induced stimulation of small intestinal transit was significantly attenuated by co-administration of atropine (50 mg kg(-1)). Taken together, these results demonstrate that MIGB isolated from radish roots stimulates the small bowel motility through the activation of ACh receptors. These findings suggest that MIGB may become a potential regulatory agent for therapeutic intervention in dysfunction of gastrointestinal motility.     

Ionic currents in single smooth muscle cells of the human vas deferens

PURPOSE: Smooth muscle cells of the vas deferens have an important role in carrying sperms to the exterior but little is known of their electrophysiological properties. We characterized the voltage-gated ion channel currents in single smooth muscle cells of the human vas deferens (HVSMCs). MATERIALS AND METHODS: We observed contractile responses of 8 circular smooth muscle strips of the human vas deferens to a high concentration (10 mM) of tetraethylammonium. HVSMCs were isolated using proteolytic enzymes (collagenase and papain), and were used for an electro-physiological study using whole cell and inside-out patch clamp configurations. RESULTS: The application of 10 mM tetraethylammonium induced rhythmic contractions of the strips. When HVSMCs were dialyzed with a KCl solution, step depolarizations of membrane potential evoked oscillatory outward K currents that were not inactivated. The large conductance Ca activated K (BKCa) and delayed rectifier components of the outward current were identified. The BKCa channel showed a large single channel conductance (162.7 +/- 13.2 pS with 5 mM K in the patch pipette). Two types of Ca currents were identified in the whole cell configuration. With a cell held at -50 mV an L-type Ca current was present during a depolarizing step pulse. From a holding potential of -90mV L-type and T-type Ca currents were elicited by depolarizing step pulses. CONCLUSIONS: HVSMCs have 2 (L and T) types of Ca channels and 2 types of K (BKCa and delayed rectifier) channels. Voltage dependent changes of these ion channels and their interactions may be important in regulating vas contractility.     

Inhibitory effect of pyridyloxy- or phenoxylphenoxyalkanate derivatives on rat lens aldose reductase and rat platelet aggregation

The therapeutic potential of aldose reductase inhibitors for the prevention of the secondary complications of diabetes has been extensively reported. On the other hand, the hyperaggregability of platelets in diabetic patients has also been reported as a cause of chronic diabetic complications. The purpose of this study was to develop new compounds with these dual effects from pyridyloxy- or phenoxylphenoxyalkanate synthesized derivatives and examine the effect of their structure-activity relationships on the inhibition of rat lens aldose reductase (RLAR) as well as on platelet aggregation. 2-[4-(2,6-dichloro-3-methyl-phenoxy)-3-nitro-phenoxy]-propionic acid (3) exhibited the most potent inhibitory effect (IC(50) = 3.0 +/- 0.21 microM), comparable to tetramethylene glutaric acid (IC(50) = 6.1 +/- 0.2 microM), which is used as a positive control on RLAR, and showed potent inhibitory activities on rat platelet aggregation induced by ADP and collagen (IC(50) = 0.093 +/- 0.01 and 0.032 +/- 0.01 microM, respectively) comparable with aspirin (IC(50) = 0.15 +/- 0.05 and 0.047 +/- 0.01 microM, respectively), used as a positive control.     

Involvement of Nrf2 and JNK1 in the Activation of Antioxidant Responsive Element (ARE) by Chemopreventive Agent Phenethyl Isothiocyanate (PEITC)

Purpose. Phenethyl isothiocyanate (PEITC) has been of great interest as a promising cancer chemopreventive agent. To better understand its chemopreventive activity, we examined the effect of PEITC on the antioxidant responsive element (ARE), which is an important gene regulatory element of many phase II drug-metabolizing/detoxification enzymes as well as cellular defensive enzymes. Methods. HeLa cells were transiently transfected with different cDNA plasmids using calcium phosphate precipitation. Subsequently, the cells were maintained in fresh media, and various concentrations of PEITC were added to the transfected cells. After harvesting and lysing of the cells, ARE-luciferase reporter gene activity was measured and normalized against -galactosidase activity. Results. Treatments of HeLa cells with PEITC transiently stimulated ARE-reporter gene expressions in a dose-dependent manner. Overexpression of wild-type NF-E2 related factor-2 (Nrf2) dramatically increased ARE-reporter gene expression in a dose-dependent manner. Similar effects were seen when wild-type c-Jun N-terminal kinase 1 (JNK1) was transfected, although the transactivating potential of JNK1 was much less than that of Nrf2. Cotransfection of Nrf2 and JNK1 showed additional enhancement of ARE reporter gene expression, implying that JNK1 might be an upstream activator of Nrf2. To support this, overexpression of dominant-negative JNK1 suppressed Nrf2-induced ARE reporter gene expression in a dose-dependent manner. When PEITC was added, slight enhancement of ARE reporter gene expression was observed in either Nrf2- or JNK1-transfected cells. Finally, ARE reporter activity induced by PEITC was substantially attenuated by transfection of either dominant-negative mutant of Nrf2 or dominant-negative mutant of JNK1. Conclusion. Taken together, these data suggest that JNK1 acts as an upstream activator of Nrf2 and that PEITC activates ARE-mediated phase II drug metabolism gene expressions via the JNK1- and Nrf2-dependent pathways.     

Seungnoidan increases cerebrocortical ATP and acetylcholine contents in ovariectomized rats

This study investigated the effects of Seungnoidan (SND), which has been widely used as a remedy for cerebroneuronal diseases in Korean folk medicine, on the cerebrocortical adenosine triphosphate (ATP) and acetylcholine (ACh) contents in ovariectomized (OVX) rats. Female Sprague-Dawley rats were ovariectomized and maintained for 12 weeks to deplete ovarian steroid hormones, followed by oral administration of SND at 500 mg/kg/day for 14 weeks. SND markedly attenuated the high rate of body weight increase in OVX rats, and also reduced the decline of cerebral weight caused by ovariectomy (p < 0.05). Superfusion of SND at 50 mg/kg significantly increased the rate of cerebral blood fl ow, but did not change the mean arterial blood pressure. Deprivation of ovarian steroid hormones significantly decreased the cerebral ATP, choline and ACh contents, and these reductions were reduced by treatment of OVX rats with SND (p < 0.01). Additionally, SND also significantly elevated the cerebral choline acetyltransferase activities reduced by OVX (p < 0.01). Taken together, these results suggest that the pharmacological properties of SND may be implicated in the improvement of metabolic pathways of cerebral energy and cholinergic neurotransmitter function induced by deprivation of ovarian steroid hormones, and SND may be a promising herbal remedy for treatment of cerebral dysfunctions including dementia.     

Fucoxanthin Protects Cultured Human Keratinocytes against Oxidative Stress by Blocking Free Radicals and Inhibiting Apoptosis

Fucoxanthin is an important carotenoid derived from edible brown seaweeds and is used in indigenous herbal medicines. The aim of the present study was to examine the cytoprotective effects of fucoxanthin against hydrogen peroxide-induced cell damage. Fucoxanthin decreased the level of intracellular reactive oxygen species, as assessed by fluorescence spectrometry performed after staining cultured human HaCaT keratinocytes with 2'',7''-dichlorodihydrofl uorescein diacetate. In addition, electron spin resonance spectrometry showed that fucoxanthin scavenged hydroxyl radical generated by the Fenton reaction in a cell-free system. Fucoxanthin also inhibited comet tail formation and phospho-histone H2A.X expression, suggesting that it prevents hydrogen peroxideinduced cellular DNA damage. Furthermore, the compound reduced the number of apoptotic bodies stained with Hoechst 33342, indicating that it protected keratinocytes against hydrogen peroxide-induced apoptotic cell death. Finally, fucoxanthin prevented the loss of mitochondrial membrane potential. These protective actions were accompanied by the down-regulation of apoptosispromoting mediators (i.e., B-cell lymphoma-2-associated x protein, caspase-9, and caspase-3) and the up-regulation of an apoptosis inhibitor (B-cell lymphoma-2). Taken together, the results of this study suggest that fucoxanthin defends keratinocytes against oxidative damage by scavenging ROS and inhibiting apoptosis.