Fever and acute-phase response induced in rabbits by intravenous and intracerebroventricular injection of interleukin-6

We investigated the effect of human recombinant interleukin-6 (IL-6) on body temperature and acute-phase response, including changes in plasma levels of iron, zinc, copper, and fibrinogen and in circulating leukocyte count. The intravenous (IV) injection of IL-6 (2 micrograms/kg) produced a monophasic fever. The intracerebroventricular (ICV) injection of IL-6 produced a dose-dependent fever that developed gradually and remained elevated throughout the 5-h recording period. The IV injection of IL-6 decreased the plasma concentration of iron and zinc and increased the circulating leukocyte count. The ICV injection of IL-6 resulted in similar trace metal and leukocyte changes, and increased plasma levels of fibrinogen. These results show that IL-6 can cause fever when injected IV or ICV and induces some acute-phase responses through its action on peripheral target organs and in the central nervous system.     

Multiple Administrations of 64Cu-ATSM as a Novel Therapeutic Option for Glioblastoma: a Translational Study Using Mice with Xenografts

Glioblastoma is the most aggressive malignant brain tumor in humans and is difficult to cure using current treatment options. Hypoxic regions are frequently found in glioblastoma, and increased levels of hypoxia are associated with poor clinical outcomes of glioblastoma patients. Hypoxia plays important roles in the progression and recurrence of glioblastoma because of drug delivery deficiencies and induction of hypoxia-inducible factor-1α in tumor cells, which lead to poor prognosis. We focused on a promising hypoxia-targeted internal radiotherapy agent, ⁶⁴Cu-diacetyl-bis (N⁴-methylthiosemicarbazone) (⁶⁴Cu-ATSM), to address the need for additional treatment for glioblastoma. This compound can target the overreduced state under hypoxic conditions within tumors. Clinical positron emission tomography studies using radiolabeled Cu-ATSM have shown that Cu-ATSM accumulates in glioblastoma and its uptake is associated with high hypoxia-inducible factor-1α expression. To evaluate the therapeutic potential of this agent for glioblastoma, we examined the efficacy of ⁶⁴Cu-ATSM in mice bearing U87MG glioblastoma tumors. Administration of single dosage (18.5, 37, 74, 111, and 148 MBq) and multiple dosages (37 MBq × 4) of ⁶⁴Cu-ATSM was investigated. Single administration of ⁶⁴Cu-ATSM in high-dose groups dose-dependently inhibited tumor growth and prolonged survival, with slight and reverse signs of adverse events. Multiple dosages of ⁶⁴Cu-ATSM remarkably inhibited tumor growth and prolonged survival. By splitting the dose of ⁶⁴Cu-ATSM, no adverse effects were observed. Our findings indicate that multiple administrations of ⁶⁴Cu-ATSM have effective antitumor effects in glioblastoma without side effects, indicating its potential for treating this fatal disease.     

Long-range transport of heavy metals from the Asian continent contributes to surface sediments in Lakes Shinji and Nakaumi in western Japan

To evaluate the contribution of the long-range transport of heavy metals from the Asian continent to the enrichment of surface sediments in western Japan, heavy-metal (Cd, Cu, Pb, Sb, and Zn) concentrations were measured in sediment cores collected at three sites each in Lakes Shinji and Nakaumi. Sedimentation fluxes of these metals were calculated on the basis of their concentrations in excess of their background concentrations. Pb showed similar sedimentation fluxes in the sites, suggesting a predominant contribution of atmospheric deposition of Pb transported from the Asian continent to the input to the lakes. In contrast, the sedimentation fluxes of heavy metals other than Pb in the surface sediments were markedly high near the estuary of a principal river flowing into Lake Nakaumi. A highly positive correlation was observed between the Cd and Zn concentrations in the cores at each site (r ² = 0.84–0.97). The Cd/Zn ratios in the surface sediments (1990–2007) indicated that Lake Shinji sediments have ratios of 0.0067–0.0074, higher than those of Tokyo Bay sediments (0.0054 on average in 1990–2003), which have been polluted primarily by effluent discharges. In contrast, the ratios in Lake Nakaumi sediments (0.0053–0.0060) were close to those in Tokyo Bay sediments. Rainwater and aerosols, which were strongly affected by air pollutants from the Asian continent, have much higher Cd/Zn ratios of 0.014–0.016. This suggests that the Lake Shinji sediments with higher Cd/Zn ratios are less affected by effluent discharges. Hence, Lake Shinji sediments may be suitable for assessing the environmental impact of the long-range transport of heavy metals from the Asian continent.     

Map7/7D1 and Dvl form a feedback loop that facilitates microtubule remodeling and Wnt5a signaling

The Wnt signaling pathway can be grouped into two classes, the β‐catenin‐dependent and β‐catenin‐independent pathways. Wnt5a signaling through a β‐catenin‐independent pathway promotes microtubule (MT) remodeling during cell‐substrate adhesion, cell migration, and planar cell polarity formation. Although Wnt5a signaling and MT remodeling are known to form an interdependent regulatory loop, the underlying mechanism remains unknown. Here we show that in HeLa cells, the paralogous MT‐associated proteins Map7 and Map7D1 (Map7/7D1) form an interdependent regulatory loop with Disheveled, the critical signal transducer in Wnt signaling. Map7/7D1 bind to Disheveled, direct its cortical localization, and facilitate the cortical targeting of MT plus‐ends in response to Wnt5a signaling. Wnt5a signaling also promotes Map7/7D1 movement toward MT plus‐ends, and depletion of the Kinesin‐1 member Kif5b abolishes the Map7/7D1 dynamics and Disheveled localization. Furthermore, Disheveled stabilizes Map7/7D1. Intriguingly, Map7/7D1 and its Drosophila ortholog, Ensconsin show planar‐polarized distribution in both mouse and fly epithelia, and Ensconsin influences proper localization of Drosophila Disheveled in pupal wing cells. These results suggest that the role of Map7/7D1/Ensconsin in Disheveled localization is evolutionarily conserved.     

Ontogeny of endocrine cells in the gut of the insect Periplaneta americana

Summary The ontogeny of the endocrine cells of the gut of the cockroach Periplaneta americana was studied by immunohistochemistry. During embryogenesis, the midgut begins to be formed as an outgrowth of the foregut and hindgut invaginations. Gut endocrine cells with pancreatic polypeptide (PP)-like immunoreactivity begin to appear at the anterior and posterior ends of the forming midgut. These cells are restricted to the midgut epithelium, and no mitotic cells with PP-like immunoreactivity are observed. These results strongly suggest that the gut endocrine cells, at least those with PP-like immunoreactivity, are derived from precursor cells they have in common with other epithelial cells of the midgut.     

Effects of External KCl on Electrical Properties and K$(86Rb) Transport in the Elongating Region of Intact Phaseolus mungo Roots

Two simultaneous measurements, extracellular potential V andK^$(⁸⁶Rb) transport, and the intracellular potential of corticalcell E and potential V, were used to study the effects of externalKCl on two-day-old bean roots. High, external KCl concentrations(>10 mM) markedly enhanced K^$ loss from tissues in the elongatingregion to the external solution and induced depolarization ofthe membrane potential difference (PD=V–E). When Phaseolus roots were returned to a solution with a lowerconcentration of K^$, the K^$ loss and the potential difference,PD, were restored to their previous values. K^$ transport fromother parts of the root to the elongating region, however, didnot recover, and the potential, E, increased. These resultsclearly demonstrate that treatment of Phaseolus roots with ahigh external K^$ concentration inhibits K^$ translocation throughthe stele to the elongating cortical cells and is dependenton depolarization of the intracellular potential. (Received October 14, 1983; Accepted January 20, 1984)     

Plasminogens Tochigi II and Nagoya: two additional molecular defects with Ala-600----Thr replacement found in plasmin light chain variants

Previous studies in our laboratories (Miyata, T., et al. (1982) Proc. Natl. Acad. Sci. U.S. 79, 6132-6136) showed that the structural defect in a hereditarily abnormal plasminogen, plasminogen Tochigi, is due to replacement of Ala by Thr at position 600 from the NH2-terminal end. In the present studies, two abnormal plasminogens, plasminogens Tochigi II and Nagoya, obtained from other family members were analyzed to identify the structural impairment in these molecules. Amino acid sequence analysis of one of the tryptic peptides isolated, respectively, from plasminogens Tochigi II and Nagoya indicated that in both cases, Ala-600 (equivalent to Ala-55 of the chymotrypsin numbering system) had been replaced by Thr. No other substitutions at the active site and substrate-binding site residues, namely, His-57, Asp-102, Ser-195, and Asp-189, were found in the plasmin light chain variants, indicating that all these residues are intact. Moreover, the NH2-terminal heptapeptide sequences of the plasmin light chain variants isolated from plasminogens Tochigi II and Nagoya were identical to the sequence determined for the normal control. These results indicate that the absence of proteolytic activity of both abnormal molecules is due to the same amino acid substitution as that of previously reported plasminogen Tochigi.     

Adsorption of cellulase from Trichoderma viride on cellulose

The adsorption of cellulase from Trichoderma viride (Meicelase CEP) on the surface of pure cellulose was studied. The adsorption was found to obey apparently the Langmuir isotherm. From the data concering the effects of temperature and the crystallinity of cellulose on the Langmuir adsorption parameters, the characteristics of the adsorption of the individual cellulase components, namely CMCase (endoglucanase) and Avicelase (exoglucanase), were discussed. While beta-glucosidase also adsorbed on the surface of cellulose at 5 degrees C, it did not at 50 degrees C.     

Effect of Intralipid-infusion on erythrocyte membrane in rabbits

Through Intralipid infusion in rabbits, the phospholipids derived from Intralipid were incorporated into erythrocytes, although Intralipid is mainly composed of triglycerides. This is supported by the increase in oleic acid and the compensatory decrease in linoleic acid of the phospholipids in the erythrocyte membrane, corresponding to the content of linoleic acid in the phospholipids from Intralipid. The excess phospholipid rendered the membrane more fluid, probably by overwhelming the rigidifying effect of the increased cholesterol content. Furthermore, the shape of erythrocytes was changed from biconcave to spur, dose dependently. The morphological alterations in erythrocyte membranes could not be completely elucidated by the changes in lipid. These results suggested that the alteration in lipid metabolism in Intralipid-infused rabbits caused various effects on the erythrocyte membrane, through the elevation of triglyceride, cholesterol, and phospholipid contents in plasma.     

Termination of early pregnancy by ONO-802 (16,16-dimethyl-trans-delta2-PGE1 methyl ester)

ONO-802 was infused into the uterine cavity for the termination of early pregnancy in 45 healthy volunteers. Forty two (93%) of the 45 cases had complete abortions and two had incomplete abortions. Nine (20%) of the 45 volunteers complained of nausea, 7 (16%) vomited and 5 (11%) complained of abdominal pain. Neither diarrhea nor weakness was observed. These results suggest that ONO-802 is more acceptable for the termination of early pregnancy than is PGF2alpha.