Mechanisms of fatigue in normal young and old mice.
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Publications and source records attributed to T Namba.
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Four unprecedented diarylheptanoids-calyxin H (1) and epicalyxin H (2), possessing a diarylheptanoid unit and a chalcone moiety, and blepharocalyxins A (3) and B (4), possessing two diarylheptanoid units and a chalcone moiety-were isolated from the seeds of Alpiniablepharocalyx. The structures of 1-4, including absolute stereochemistry, were elucidated by spectroscopic means and after a consideration of their biogenesis.
In order to evaluate the role played by muscular and extramuscular factors in the development of fatigue in old age, the time course of fatigue in isolated skeletal muscles and spontaneous motor activity and endurance of whole animals were monitored using young (3-6 months) and old (34-36 months) CF57BL/6J mice. The isolated extensor digitorum longus (EDL) and soleus muscles from old mice had smaller (P < 0.05) mass and developed lower (P < 0.02) maximal tetanic tension at 100-Hz stimulation than the muscles of young mice. During stimulation at 30 Hz every 2.5 s, a 50% decline in original tetanic tension occurred by 109 s in young EDL and 129 s in old EDL, but by 482 s in young soleus and 1134 s (projected) in old soleus, indicating more (P < 0.05) resistance to fatigue in old than young soleus. However, the old mice showed significantly fewer (P < 0.002) spontaneous ambulatory movements than the young mice. On a treadmill with a belt speed of 10 m/min at an inclination of 0 degrees, the old mice could only run for 22 min compared to 39 min ran by young mice (P < 0.02). They took more rest periods (P< 0.02) than the young mice. In a quantitative swimming monitor, the old mice swam for a shorter (P < 0.05) time than young mice (20.4 min compared to 28.6 min). Integrated swimming activity at 20 min was smaller (P < 0.05) in old mice than in young mice (413 g/s compared to 628 g/s). Hence increased fatigue in old age is not caused by impairment of processes within the muscles, but by impairment of central or extramuscular processes.
We report herein the case of a patient with an aortoesophageal fistula (AEF) who was managed successfully by surgery. A 5-mm oval, well circumscribed aortic perforation just above the orifice of the celiac axis and a 4-mm defect in the esophagus were primarily closed, and an omental flap was placed between the aorta and the esophagus. No definite etiology could be determined. Our experience of this case suggests that primary closure for defects in both the aorta and the esophagus is the best option when the defects are small, and that the possibility of an AEF must be considered in patients with midthoracic pain or hematemesis, even if there is no history of thoracic aortic aneurysm, foreign body ingestion, trauma, or esophageal disease.
We describe herein the case of a patient who presented with total occlusion of all the major arteries in the unilateral iliofemoral region, including the distal deep femoral artery, on whom an aortolateral circumflex femoral-popliteal artery sequential bypass was successfully performed. This case report serves to demonstrate that the lateral circumflex femoral artery can provide a suitable midway outflow for aortopopliteal bypass in patients with extensive thrombosis of the iliofemoral arteries.
Three new phenylethanoid glycoside, named scrosides A-C and a new iridoid glycosides, named picroside IV, have been isolated from the underground parts of Picrorhiza scrophulariiflora, together with 11 known compounds. Their structures were elucidated by the means of 2D NMR spectroscopy and chemical methods.
Rhus javanica has been shown to exhibit anti-herpes simplex virus (HSV) activity and potentiate the anti-HSV activity of acyclovir in vitro and in vivo. This extract was examined for its suppressive efficacy on recurrent genital infection in guinea pigs. Guinea pigs were primarily infected intravaginally with HSV type 2 (HSV-2). Prophylactic oral administration, at the dose corresponding to human use, of R. javanica significantly reduced the incidence, severity and/or frequency of spontaneous and severe skin lesions as compared with latently infected guinea pigs administered with water. This prophylactic efficacy was confirmed by the crossover administration, for more than 2 months, of R. javanica and water to the infected guinea pigs. Toxicity, such as weight loss, from R. javanica administration was not observed in the guinea pigs. When recurrent HSV-2 disease was induced by ultraviolet irradiation 3 months after primary infection, the prophylaxis with R. javanica was also significantly effective in reducing the severity of ultraviolet-induced skin lesions. Thus, prophylaxis of recurrent genital HSV-2 infection with R. javanica may preserve the efficacy of acyclovir by reducing both the use of acyclovir and the appearance of acyclovir-resistant viruses.
PURPOSE: To evaluate the clinical characteristics of anastomotic aneurysms that develop in surgically treated patients with Takayasu's arteritis. METHODS: Among 103 patients with Takayasu's arteritis treated surgically over 40 years, 91 patients with 259 anastomoses (allowing for exclusion of 12 operative deaths) participated in follow-up study from 1 month to 37.3 years with a mean value +/- SEM of 17.3 +/- 1.1 years with a follow-up completion rate of 93% at 30 years. The clinical characteristics of anastomotic aneurysms were clarified, and the influences of several factors (sites of anastomoses, occlusive or aneurysmal disease, suture material, preoperative systemic inflammation, and administration of corticosteroids) on formation of anastomotic aneurysms were analyzed by means of life-table method and Cox regression analysis. RESULTS: Twenty-two uninfected anastomotic aneurysms were found among 14 patients (22 of 259 anastomoses, 8.5%). The interval between the previous operation and diagnosis varied from 1.6 to 30 years with a mean value +/- SEM of 9.8 +/- 1.8 years. The cumulative incidence of anastomotic aneurysm at 20 years was 12.0%. Systemic inflammation or steroid administration had little influence on formation of anastomotic aneurysm. Instead, anastomotic aneurysm tended to occur after operations for aneurysmal lesions. CONCLUSIONS: Anastomotic aneurysm can occur anytime after operations for Takayasu's arteritis. The development of anastomotic aneurysm is not influenced by any factor specific to this disease except the presence of an aneurysmal lesion.
A new diarylheptanoid, 1,7-bis(4-hydroxyphenyl)-3-hydroxy-1,3-heptadien-5-one (1), along with seven other known compounds, were isolated from the seeds of Alpinia blepharocalyx. Of these, compounds 1 and 3 showed strong inhibition of collagen-induced, arachidonic acid-induced, and adenosine diphosphate-induced platelet aggregation of human whole blood. Compound 3 also strongly inhibited ristocetin-induced platelet aggregation. Structures of these compounds were elucidated by spectroscopic and chemical means.
The effect of spikelets of Miscanthus sinensis Andersson (M. sinensis) on IgE-mediated biphasic cutaneous reactions was investigated in BALB/c mice. Mice were passively sensitized by an intravenous (i.v.) injection of monoclonal antidinitrophenol IgE antibody (anti-DNP IgE mAb), or actively by an intraperitoneal (i.p.) injection of DNP-derivatized ovalbumin (DNP-OVA) plus aluminium hydroxide gel (Alum) as an adjuvant. Skin reactions were elicited by an epicutaneous challenge of dinitrofluorobenzene (DNFB) and occurred biphasically with peak responses at 1 and 24 h in both animal models. The administrations of a nondialysable water extract of M. sinensis within 2 h before or after DNFB challenge via oral or i.p. route significantly inhibited the biphasic cutaneous reactions in passively and actively sensitized mice. The inhibitory effect was much stronger than those of a glucocorticoid, prednisolone, and histamine release inhibitor, amlexanox, as positive controls. The active component(s) was predominantly located in the glycoprotein fraction by gel chromatography. In the ears of DNFB-challenged mice, this fraction suppressed the accumulation of inflammatory cells, including mast cells and neutrophils/macrophages. In addition, the biphasic ear swelling was also improved by an administration of the glycoprotein fraction 24 h before active sensitization. These findings indicate that the glycoprotein fraction of M. sinensis was able to inhibit not only the IgE-mediated allergic inflammatory reaction but also the IgE formation. Thus, this fraction may be a useful antiallergic therapy.
Four phenylethanoids isolated from the stems of Cistanche deserticola, acteoside (1), 2'-acetylacteoside (2), isoacteoside (3) and tubuloside B (4), significantly suppressed NADPH/CCl4-induced lipid peroxidation in rat liver microsomes. Addition of them to primary cultured rat hepatocytes efficiently prevented cell damage induced by exposure to CCl4 or D-galactosamine (D-GalN). Acteoside (1) further showed pronounced anti-hepatotoxic activity against CCl4 in vivo.
Tribulusamides A (1) and B (2), new lignanamides embracing two cinnamic amide parts joined in a cis configuration, were isolated from the fruits of Tribulus terrestris, together with four known compounds, N-trans-feruloyltyramine (3), terrestriamide (4), N-trans-coumaroyltyramine (5), and beta-sitosterol. The structures were elucidated by 2D-NMR spectroscopy. Addition of compounds 1-5, especially 1 and 2, to primary cultured mouse hepatocytes significantly prevented cell death induced by D-galactosamine (D-GalN)/tumor necrosis factor alpha (TNF-alpha).
We have investigated the anti-metastatic effect of Celosia argentea seed extracts (CAE), which have traditionally been used as a therapeutic drug for eye and hepatic diseases in China and Japan. Intraperitoneal (i.p.) administration of CAE for 7 d before tumor inoculation significantly inhibited liver metastasis caused by intraportal injection of colon 26-L5 carcinoma cells in a dose-dependent manner. CAE also showed concentration dependent mitogenic activity on BALB/c whole splenocytes, whereas incubation of the non-adherent fraction of splenocytes with CAE did not induce this activity. CAE has the ability to induce interleukin (IL)-12 production from macrophages in vitro. Following i.p. administration of CAE the maximal levels of IL-12 and interferon (IFN)-gamma production in serum were achieved at 2-3 and 6 h, respectively. Experiments using macrophage- or NK cell-deficient mice revealed that CAE-induced IL-12 in serum was not mediated by macrophages and that IFN-gamma production was mainly dependent on natural killer (NK) cells. Since CAE was inactive when the contributions of macrophages were removed in our system, its inhibitory mechanism is likely to be mainly associated with the activation of macrophages to an anti-metastatic state rather than NK cells. CAE administration resulted in increased production of IL-2, IFN-gamma and decreased production of a Th2 cytokine (IL-4) from splenocytes stimulated by PMA and A23187. Thus, the anti-metastatic effect by CAE is based on its immunomodulating properties including induction of cytokines such as IL-12, IL-2 and IFN-gamma leading to a Th1 dominant immune state and activating macrophages to the tumoricidal state. This may provide a basis for the inhibition of cancer metastasis.
Four water extracts of Kampo formulae (Yi-kkan-sen, Dai-ho-in-gan, Ni-chi-gan, Tsu-kan-gan) were screened for their inhibitory activities on bone resorption induced by parathyroid hormone (PTH) in organ culture using neonatal mouse parietal bones. Among the Kampo formulae, Tsu-kan-gan (TKG) showed the most potent inhibitory activity. We further fractionated the TKG water extract by monitoring the inhibitory activity on bone resorption stimulated by PTH in vitro. The MeOH fraction of the water extract inhibited PTH-stimulated bone resorption, and its inhibitory activity was more potent than those of other fractions. The MeOH fraction was then subjected to Sephadex LH-20 column chromatography to give fractions I, II and III, which were examined for bone resorption activity. Fraction I inhibited PTH-stimulated bone resorption, and its inhibitory activity was more potent than those of the other fractions. Upon oral administration of the three fractions (100 mg/kg/d) to ovariectomized (OVX) mice, fractions I and III prevented the decrease of bone mineral density (BMD) of the lumbar vertebra. Eleven compounds isolated from the MeOH fraction were examined for their inhibitory effect on PTH-stimulated bone resorption. Among them, berberine (1), syringin (3), limonin (4) and mangiferin (10) showed a significant inhibitory effect on bone resorption. In the formation assay of osteoclast-like cells, these compounds decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs). The inhibitory effect of TKG on bone resorption may be at least partly due to the inhibitory action of these compounds.
Thirteen novel diarylheptanoids bearing a chalcone or a flavanone moiety (1-13), a new curcumin derivative, 1,2-dihydrobis(de-O-methyl)curcumin (14), and two known flavonoids (15 and 16) isolated from the seeds of Alpinia blepharocalyx K. Schum. were tested for their inhibitory effects on nitric oxide (NO) production in lipopolysaccaride (LPS)-activated murine macrophages J774.1 in vitro. All the tested compounds inhibited NO production in a concentration-dependent manner (IC50=36-568 microM). Among the compounds examined, blepharocalyxin B (13) was the most potent inhibitor of NO production (IC50=36 microM). Analysis of the structure activity relationship among these novel diarylheptanoids led to the conclusion that the position of attachment of a chalcone or a flavanone to a diarylheptanoid does not affect their inhibitory potency although their presence in association causes a substantial enhancement of the inhibitory activity. Moreover, a conjugated double bond in a chalcone moiety potentiated the inhibitory activity. On the other hand, hexamethoxydeoxycalyxin A (17) and pentamethoxycalyxin B (18), a methylated product of calyxin A (1) and an epimeric mixture of calyxin B, showed greatly reduced activity suggesting that phenolic hydroxyl groups are involved in the inhibitory activity.
We previously found that a methanolic extract of the stems of Sambucus sieboldiana inhibited bone resorption in organ culture. In this study, we further fractionated the methanol extract guided by the activity towards bone resorption stimulated by parathyroid hormone (PTH) in vitro. The ethyl acetate fraction (EtOAc Fr.) of the methanolic extract inhibited PTH-stimulated bone resorption of neonatal mouse bones, and the inhibitory activity was more potent than those of other fractions. Oral administration of the EtOAc Fr. (50 and 100 mg/kg/d) to ovariectomized (OVX) rat prevented the decrease in bone mineral density (BMD) of the lumbar (L2-4) vertebra, indicating that the EtOAc Fr. is effective in vivo. Furthermore, the EtOAc Fr. (50, 100 and 150 mg/kg/d) decreased the serum calcium level elevated in low calcium dietary rats. The phenolic constituents of the EtOAc fraction were examined for their inhibitory effect on bone resorption stimulated by PTH in neonatal mouse bone. Among them, vanillic acid, vanillin and coniferyl alcohol showed significant inhibitory effects on bone resorption. Of the compounds examined, vanillic acid was found to have a significant inhibitory effect on the decrease of BMD in OVX mice. Therefore, the EtOAc Fr. of S. sieboldiana showed a suppressive effect on bone resorption in vitro and in vivo. In addition, the inhibitory effects of the EtOAc Fr. on bone resorption may be at least partly due to the inhibitory action of vanillic acid.
The dry root and rhizome of Salvia miltiorhiza (Lamiaceae) are used as a crude drug Danshen, while those of S. deserta (Xinjiang-Danshen) are mixed in Danshen at Xinjiang province when the former is in short supply. The water and MeOH extracts of S. deserta showed strong aldose reductase (AR) inhibitory activity, and their active constituents were determined to be polar compounds different from "tanshinones" of S. miltiorhiza, i.e., lithospermic acid B (1), salvianolic acid K (2), salviaflaside (3), and rosmarinic acid (4) (IC50, 2.63-3.91 microM). We also examined the AR inhibitory activity of water and MeOH extracts of seventeen Salvia plants, including ten species of Danshen resources (S. bowleyana, S. deserta, S. miltiorhiza, S. miltiorhiza var. miltiorhiza f. alba, S. paramiltiorhiza, S. paramiltiorhiza f. purpureo-rubra, S. przewalskii, S. przewalskii var. mandarinorum, S. sinica f. purpurea, S. trijuga), and their water extracts were also analyzed by liquid chromatography-mass spectrometry (LC-MS). The results indicated that there were four types with regard to the AR inhibitory activity and three types with regard to the amount of 1. Ten species used as Danshen resources showed good correlation between the AR inhibitory activity and the morphological classification. However, the intensities of their AR inhibitory activity varied, and they contained 1 in varying amounts. These facts suggested that the ten species were not the same, and thus their use as a Danshen resource should be based on their activity and/or active constituents.
Traditional medicines contain various metabolites derived from nucleic acid, protein, and lipid metabolism. Some of these specific metabolites may recognize the differences between viral and host metabolism resulting in anti-viral activity; hence traditional medicines may be useful sources for new antiviral agents. Traditional medicines can be cheaply obtained and have been orally administered as hot-water extracts. Therefore, they may be used for the prophylactic and therapeutic treatment of viral infection by drinking them, such as coffee or tea. Here we describe how the antiviral activity of traditional medicines was screened in vitro and how their therapeutic antiviral activities were verified in vivo, to obtain traditional antiviral medicines that can be clinically used. Therefore, we have selected 12 herbal extracts, from more than 250 herbal medicines, that exhibit therapeutic activities against cutaneous herpes simplex virus (HSV) type 1 (HSV-1) infection in mice. Four of the 12 augmented the therapeutic efficacy of acyclovir (ACV) in mice and showed potent anti-HSV activity against infection with ACV-resistant HSV-1 mutants in mice. These herbal extracts selectively inhibited viral DNA synthesis and showed a different mode of anti-HSV-1 action from that of ACV. They were also effective against both recurrent HSV and cytomegalovirus infections, without toxicity. Such prophylactic and therapeutic antiviral activities of the traditional medicines were verified by the purification of major active compounds. We could show new indications of traditional medicines as antiviral agents. Thus, the drinking of the extracts, in a daily tea or coffee, may be used for prophylaxis and therapy of diseases caused by herpes virus infection and improve the quality of life.