Brain-Derived Neurotrophic Factor (BDNF)-Induced Tropomyosin-Related Kinase B (Trk B) Signaling Is a Potential Therapeutic Target for Peritoneal Carcinomatosis Arising from Colorectal Cancer

Tropomyosin-related receptor kinase B (TrkB) signaling, stimulated by brain-derived neurotrophic factor (BDNF) ligand, promotes tumor progression, and is related to the poor prognosis of various malignancies. We sought to examine the clinical relevance of BDNF/TrkB expression in colorectal cancer (CRC) tissues, its prognostic value for CRC patients, and its therapeutic potential in vitro and in vivo. Two hundred and twenty-three CRC patient specimens were used to determine both BDNF and TrkB mRNA levels. The expression of these proteins in their primary and metastatic tumors was investigated by immunohistochemistry. CRC cell lines and recombinant BDNF and K252a (a selective pharmacological pan-Trk inhibitor) were used for in vitro cell viability, migration, invasion, anoikis resistance and in vivo peritoneal metastasis assays. Tissue BDNF mRNA was associated with liver and peritoneal metastasis. Tissue TrkB mRNA was also associated with lymph node metastasis. The co-expression of BDNF and TrkB was associated with liver and peritoneal metastasis. Patients with higher BDNF, TrkB, and co-expression of BDNF and TrkB had a significantly poor prognosis. BDNF increased tumor cell viability, migration, invasion and inhibited anoikis in the TrkB-expressing CRC cell lines. These effects were suppressed by K252a. In mice injected with DLD1 co-expressing BDNF and TrkB, and subsequently treated with K252a, peritoneal metastatic nodules was found to be reduced, as compared with control mice. BDNF/TrkB signaling may thus be a potential target for treating peritoneal carcinomatosis arising from colorectal cancer.     

Comparison of TRH and its analog (NS-3) in thermoregulatory and cardiovascular effects.

The effects of TRH and its metabolically stable analog NS-3 [(3R,6R)-6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-pro linamide tetrahydrate] on thermoregulation and circulatory control have been investigated. Both NS-3 (1-100 ng/kg ICV) and TRH (0.1-10 micrograms/kg ICV) increased rectal temperature and metabolic rate with a transient cutaneous vasoconstriction in conscious rabbits. They also increased arterial blood pressure, heart rate, respiratory rate, and renal sympathetic nerve activity (RSNA) in urethane-anesthetized rabbits. Ten ng/kg of NS-3 and 10 micrograms/kg of TRH had comparable hyperthermic, pressor, and tachycardic activities, while the relative potency of NS-3 to increase RSNA was greater and that to increase metabolic rate was smaller than the other effects. In conclusion, NS-3 was more potent than TRH in all of the effects measured, but there was a dissociation in the relative potency of NS-3 in the different autonomic effects.     

Semilunar rhythm in the zoea-release activity of the land crabs Sesarma

Summary The number of the land crabs Sesarma which released zoeae in a river was counted and recorded for 2 years. The number of crabs releasing zoeae reached a maximum at around every syzygy and decreased to a minimum at around every half moon, showing a semilunar rhythm (Fig. 2). This semilunar rhythm, when examined temporally, showed a peculiar pattern accurately synchronized with the lunar cycle. On the day of and during 4–5 days prior to the syzygy, the peak of zoea-release activity came just after sunset. A few days later, the peak gradually shifted to later in the evening and became flattened until temporal concentration was no longer observed. About 2 days after the half moon, the peak appeared again just after sunset (Figs. 3, 4 and 5). It is not likely that the tide itself affects the semilunar rhythm of Sesarma, but it is supposed that the lunadian factor is involved in it. The adaptive significance of this semilunar rhythm may be interpreted to mean that zoeae released in the river just after the time of spring high tides will successfully arrive at the sea and that the lunadian modification of the peak in the temporal structure will also ensure that the zoeae will be released at the time of high tides and will have a better chance of arriving at the sea than they would otherwise do.Contributions from Shimoda Marine Research Center, The University of Tsukuba, No 331     

5,5-dimethyl-1-pyrroline-N-oxide alone enhances the spontaneous superoxide generation by primaquine.

Primaquine (PQ), a well-known antimalarial drug, has been reported to generate superoxide (O2-) in the presence of reducing agents such as NADPH. In the present study, chemiluminescence was detected by adding only PQ to aqueous 2-methyl-6-[p-methoxyphenyl]-3,7-dihydroimidazo-[1,2-alpha] pyrazin-3-one (MCLA), which is a specific chemiluminescent probe for O2-, and was quenched by superoxide dismutase (SOD), indicating that PQ alone can generate O2- in aerobic conditions. Furthermore, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) enhanced the O2- generation by PQ. Superoxide spin adduct, DMPO-OOH, was also detected by ESR both in aqueous solutions and in dimethyl sulfoxide with DMPO. The level of O2- generation showed a linear correlation with the DMPO concentration, and SOD competitively inhibited the DMPO-OOH formation. The results suggested that in aerobic conditions PQ is autoxidized to 5-hydroxy-PQ, which generates O2-, and DMPO accelerates the autoxidation process by trapping O2-. DMPO or M4PO alone enhances the spontaneous O2- generation by PQ, therefore cautious evaluation is necessary in all studies using the ESR/spin trapping technique to elucidate the mechanism of PQ-related radical generation.     

Threshold dissociation of thermoregulatory effector responses in febrile rabbits

When the core temperature stabilizes at a hyperthermic level after iv injection of lipopolysaccharide (LPS), the threshold core temperature for cutaneous vasoconstriction (Thcv) is significantly increased in hot and neutral environments, while the threshold core temperature for shivering (Thsh) is not significantly altered in hot or cold environments but is significantly reduced at thermoneutrality. This type of dissociated threshold alterations of thermoregulatory effector responses seems to be typical for the febrile response of rabbits to LPS. Because the same threshold dissociation can be demonstrated after icv injection of LPS, the systemic and the central effects of LPS in the generation of fever seem to be mediated by identical mechanisms. Prostaglandins of the E series (PGE), one of the mediators considered as important in fever generation, cause parallel increases in Thcv and Thsh when injected icv. This indicates that the mode of action of PGE on the central targets producing hyperthermia differs from that of the ensemble of mediators involved in the generation of LPS fever in rabbits. In rabbits pretreated with aspirin, the threshold dissociation after iv LPS injection still occurs. This indicates that factors other than PGE play an important role in the generation of the threshold dissociation of thermoregulatory effector responses, which is typical for LPS fever. These data indicate also that the states of activity of the thermoregulatory effectors involved in the febrile responses can be altered individually and that the activities of these effectors during LPS fever are quite different from their activities in the control state.     

Filopodium-derived vesicles produced by MIM enhance the migration of recipient cells

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