Flavonoids such as luteolin, fisetin and apigenin are inhibitors of interleukin-4 and interleukin-13 production by activated human basophils

BACKGROUND: We have previously shown that fisetin, a flavonol, inhibits IL-4 and IL-13 synthesis by allergen- or anti-IgE-antibody-stimulated basophils. This time, we investigated the inhibition of IL-4 and IL-13 production by basophils by other flavonoids and attempted to determine the fundamental structure of flavonoids related to inhibition. We additionally investigated whether flavonoids suppress leukotriene C4 synthesis by basophils and IL-4 synthesis by T cells in response to anti-CD3 antibody. METHODS: Highly purified peripheral basophils were stimulated for 12 h with anti-IgE antibody alone or anti-IgE antibody plus IL-3 in the presence of various concentrations of 18 different kinds of flavones and flavonols. IL-4 and IL-13 concentrations in the supernatants were then measured. Leukotriene C4 synthesis was also measured after basophils were stimulated for 1 h in the presence of flavonoids. Regarding the inhibitory activity of flavonoids on IL-4 synthesis by T cells, peripheral blood mononuclear cells were cultured with flavonoids in anti-CD3-antibody-bound plates for 2 days. RESULTS: Luteolin, fisetin and apigenin were found to be the strongest inhibitors of both IL-4 and IL-13 production by basophils but did not affect leukotriene C4 synthesis. At higher concentrations, these flavonoids suppressed IL-4 production by T cells. Based on a hierarchy of inhibitory activity, the basic structure for IL-4 inhibition by basophils was determined. CONCLUSIONS: Due to the inhibitory activity of flavonoids on IL-4 and IL-13 synthesis, it can be expected that the intake of flavonoids, depending on the quantity and quality, may ameliorate allergic symptoms or prevent the onset of allergic diseases.     

Chemical and biological properties of a peptidoglycan isolated from Treponema pallidum kazan.

A peptidoglycan layer of Treponema pallidum kazan was isolated by solubilization of whole cells with 1% warm sodium dodecyl sulfate and subsequent digestion of an insoluble residue with proteases. Electron microscopy revealed that the peptidoglycan was isolated as a single-layered sacculus of less than 5 nm in thickness, freed from axial filaments and an envelope sheath. An isolated peptidoglycan fraction was mainly composed of glucosamine, muramic acid, alanine, glutamic acid, ornithine, and glycine in molar ratios of 0.65:0.68:1.63:1.00:0.75:1.03. Amino (N)- and carboxyl (C)-terminal amino acid analyses suggested the involvement of at least a part of the glycine residue in cross-linking between the amino group of ornithine residue at one strand of the stem peptide subunit and the carboxyl group of alanine of the neighboring strand. The treponemal peptidoglycan lacked the immunoadjuvant activity both to stimulate antibody production and to induce delayed-type hypersensitivity against ovalbumin, as well as the properties necessary to stimulate guinea pig and mouse splenocytes and guinea pigs peritoneal macrophages, unlike the cell walls or peptidoglycans (group A type of Schleifer and Kandler's classification, Bacteriol. Rev. 36:407-477, 1972) isolated from many bacterial species parasitic to the mammal. However, the peptidoglycan activated the human complement system through the alternative pathway, as well as the classical one, and caused a liberation of 5-hydroxytryptamine in rabbit blood platelets in a similar manner to the cell wall peptidoglycans of both group A and B types.     

Further insight into the task-dependent excitability of motor evoked potentials in first dorsal interosseous muscle in humans

We have reexamined the contradictory evidence in which task-dependent excitation of motor evoked potentials (MEPs) in the first dorsal interosseous (FDI) muscle was stronger with increasingly more complex finger tasks than with individual finger movement tasks. In the first step of the experiment, based on previous findings, we investigated remarkable functional differences between intrinsic and extrinsic hand muscles during complex finger tasks (precision and power grip). During the performance of the tasks, the optimal stimulus intensity of the transcranial magnetic stimulation (TMS) was applied to the contralateral motor cortex. MEPs of the FDI, extensor carpi radialis (ECR), and flexor carpi radialis (FCR) muscles were recorded simultaneously with increased background EMG activity step by step in both tasks. The intensity threshold of TMS was lower in the precision grip. Furthermore, the MEP amplitudes of FDI muscle dependent on the background EMG activity were different between these two tasks, i.e., MEP amplitudes and regression coefficients in a precision grip were larger than those in a power grip. Although our results for MEP amplitude and threshold in the FDI muscle were similar to previous reported evidence, the different contributions of a synergistic muscle (in particular, the ECR muscle) during performance in these tasks was new evidence. Since there were no differences in cutaneous afferent effects on both tasks, corticomotoneuronal (CM) cells connected to FDI motoneurons seemed generally to be more active during precision than power gripping, and there were different contributions from synergistic muscles during the performance of these tasks. In the second part of the experiment, the results obtained from the complex tasks were compared with those from a simple task (isolated index finger flexion). MEP amplitudes, dependent on the background EMG activity during isolated index finger flexion, varied among subjects, i.e., the relationship between the MEP amplitude and the background EMG of the FDI muscle showed individual, strategy-dependent modulation. There were several kinds of individual motor strategies for performing the isolated finger movement. The present results may explain the previous contradictory evidence related to the contribution of the CM system during coordinated finger movement.     

Retrograde labeling of mouse spinal descending tracts by a recombinant adenovirus

The present study tested whether a gene-transfer based upon the retrograde axonal transport of the lacZ adenovirus is effective in the spinal descending tracts of the adult mouse. A small volume of a replication-defective recombinant adenovirus encoding E. coli beta-galactosidase was injected into the upper lumbar cord, and, seven days later, the mice were transcardially perfused by a fixative solution. X-gal staining of coronal or sagittal sections of the spinal cord and the brain revealed that many sites of origin for rubrospinal, vestibulospinal, and reticulospinal tracts were retrogradely labeled, whereas few of the corticospinal tract neurons were retrogradely labeled. Ependymal cells surrounding the central canal of the spinal cord, which were located far from the injection site, showed a high expression of beta-galactosidase activity. Motoneurons around the injection site were strongly stained by X-gal staining, and their axons in the ventral root were anterogradely labeled. Afferent fibers in the dorsal root were labeled by the transganglionic transport of beta-galactosidase. To examine the efficacy of the uptake and retrograde transport of HRP and adenovirus, we injected a mixed solution of 10% HRP and recombinant adenovirus. The number of HRP-labeled corticospinal neurons overwhelmed the number of X-gal stained ones, while the numbers of HRP-labeled rubrospinal and subcoeruleus-spinal neurons were smaller in comparison with the numbers of beta-galactosidase-positive counterparts. The present study revealed that the origins for the spinal descending tracts except for corticospinal neurons could be efficiently gene-transferred by the retrograde infection of a recombinant adenovirus. Such a difference in efficacy of retrograde infection among the spinal descending tracts is practically important when an adenovirus-mediated gene transfer is designed to treat certain neurological diseases affecting the spinal descending tracts.     

Requirement of IL-5 for induction of autoimmune hemolytic anemia in anti-red blood cell autoantibody transgenic mice

IL-5, IL-10 and lipopolysaccharide (LPS) are known to activateB-1 cells in vivo in normal mice and anti-red blood cell autoantibodytransgenic mice (HL mice). To assess the exact role of IL-5in proliferation and activation of peritoneal B-1 cells, weanalyzed IL-5 receptor chain-deficient HL (IL-5R^–/–x HL) mice generated by the cross between IL-5R^–/–and HL mice. In IL-5R^–/– x HL mice, Ig-producingB-1 cells in the peritoneal cavity were negligible, althoughthe total number of B-1 cells in the peritoneal cavity wereas many as 30% of that in HL mice. Moreover, LPS- or IL-10-induceddifferentiation of B-1 cells into antibody-producing cells wasseverely impaired in IL-5R^–/– x HL mice. We alsoused in vivo 5-bromo-2'-deoxyuridine labeling to estimate theproliferation of B-1 cells in IL-5R^–/– mice. Theabsence of IL-5R did not affect spontaneous proliferation ofperitoneal B-1 cells. However, induced proliferation of peritorealB-1 cells by oral administration of LPS was markedly impairedin IL-5R^–/– mice. These results suggest that IL-5is required for activation-associated proliferation of B-1 cellsbut not for their spontaneous proliferation and support theidea that IL-5 plays an important role on the induction of autoantibodyproduction from B-1 cells.     

The role of γδ T cells in priming macrophages to produce tumor necrosis factor-α

The secretion of tumor necrosis factor (TNF)-α from macrophages is regulated by both priming and triggering signals. We found that macrophages from mice lacking γδ T cells [T cell receptor (TCR) δ^?/- mice], which lack the gene encoding the δ chain, produced only small amounts of TNF-α in response to lipopolysaccharide (LPS) and showed a reduced level of expression of CD14. Pre-incubation of macrophages from TCR δ-/- mice with γδ T cells from their TCR δ^+/- littermates restored their capacity to produce TNF-α in response to LPS. The priming activity of γδ T cells was in part inhibited by neutralizing anti-interferon (IFN)-γ monoclonal antibodies. Collectively, these results suggest that γδ T cells play a role in priming macrophages to a steady state of activation via IFN-γ secretion, which allows them to produce TNF-α when exposed to LPS.     

Positron CT imaging using a high resolution PCT device (Positologica-I),11CO,13NH3, and18FDG in clinical evaluation of cerebrovascular diseases

Positron computed tomography (PCT) was performed in 3 normal volunteers and 21 patients with cerebrovascular diseases using a high resolution PCT device Positologica-I and three tracers¹¹CO,¹³NH₃, and¹⁸FDG. Relatively early lesions showed various accumulation patterns, and metabolism and perfusion mismatches were clearly shown by this measurement. One type of mismatch is luxury perfusion which had a slight increase of blood volume. Another type of uncoupling is misery perfusion. Remote effects of ischemic lesions also appeared on PCT with¹⁸FDG and¹³NH₃. From our clinical results, the PCT method with a high resolution device and radiopharmaceuticals such as¹¹CO,¹³NH₃, and¹⁸FDG is very useful in the assessment of cerebrovascular diseases and in defining circulatory dysfunction in man.     

Safety and efficacy of Tolvaptan in real-world patients with autosomal dominant polycystic kidney disease- interim results of SLOW-PKD surveillance

Clinical and Experimental Nephrology - Tolvaptan is a vasopressin type 2 receptor antagonist and has been used to treat autosomal dominant polycystic kidney disease (ADPKD) since 2014. There has...     

Outcome of advanced renal cell carcinoma arising in end-stage renal disease: comparison with sporadic renal cell carcinoma

Clinical and Experimental Nephrology - The data regarding oncological outcome in advanced renal cell carcinoma (RCC) arising in end-stage renal disease (ESRD) are limited. Patients diagnosed with...