Postural instability via a loss of intermittent control in elderly and patients with Parkinson's disease: A model-based and data-driven approach.

Postural instability is one of the major symptoms of Parkinson's disease. Here, we assimilated a model of intermittent delay feedback control during quiet standing into postural sway data from healthy young and elderly individuals as well as patients with Parkinson's disease to elucidate the possible mechanisms of instability. Specifically, we estimated the joint probability distribution of a set of parameters in the model using the Bayesian parameter inference such that the model with the inferred parameters can best-fit sway data for each individual. It was expected that the parameter values for three populations would distribute differently in the parameter space depending on their balance capability. Because the intermittent control model is parameterized by a parameter associated with the degree of intermittency in the control, it can represent not only the intermittent model but also the traditional continuous control model with no intermittency. We showed that the inferred parameter values for the three groups of individuals are classified into two major groups in the parameter space: one represents the intermittent control mostly for healthy people and patients with mild postural symptoms and the other the continuous control mostly for some elderly and patients with severe postural symptoms. The results of this study may be interpreted by postulating that increased postural instability in most Parkinson's patients and some elderly persons might be characterized as a dynamical disease.

Two new sesquiterpenes from Artemisia annua L.

Investigation of the dried whole plants of Artemisia annua led to the isolation of two new sesquiterpenes, artemanins A (1) and B (2), along with twenty-nine known compounds. The structures of the new compounds were elucidated by spectroscopic and chemical means.

[Diversity of Secondary Metabolites from Some Medicinal Plants and Cultivated Lichen Mycobionts].

Studies on the structural determination, biosynthesis, and biological activities of secondary metabolites from natural sources are significant in the field of natural products chemistry. This review focuses on diverse secondary metabolites isolated from medicinal plants and cultivated mycobionts of lichens in our laboratory. Monoterpene-tetrahydroisoquinoline glycosides and alkaloids isolated from Cephaelis acuminata and Alangium lamarckii gave important information on the biosynthesis of ipecac alkaloids. A variety of glycosides linked with a secologanin unit and indole alkaloids were obtained from medicinal plants belonging to the families of Rubiaceae, Apocynaceae, and Loganiaceae. Plant species of the four genera Fraxinus, Syringa, Jasminum, and Ligustrum of the family Oleaceae were chemically investigated to provide several types of secoiridoid and iridoid glucosides. The biosynthetic pathway leading from protopine to benzophenanthridine alkaloids in suspension cell cultures of Eschscholtzia californica was elucidated. The structures and biological activities of the bisbenzylisoquinoline alkaloids of Stephania cepharantha and Nelumbo nucifera were also investigated. In addition, the mycobionts of lichens were cultivated to afford various types of metabolites that differ from the lichen substances of intact lichens but are structurally similar to fungal metabolites. The biosynthetic origins of some metabolites were also studied. These findings suggest that cultures of lichen mycobionts could be sources of new bioactive compounds and good systems for investigating secondary metabolism in lichens.

Polyprenylated Benzoylphloroglucinols with DNA Polymerase Inhibitory Activity from the Fruits of Garcinia schomburgkiana.

Chemical investigation of the fruits of Garcinia schomburgkiana collected in Vietnam led to the isolation of eight new schomburgkianones, A-H (1-8), four known (9-12) polyprenylated benzoylphloroglucinols, and four known biflavonoids. The structures of these compounds were elucidated by spectroscopic and chemical means. The absolute configuration at C-40 of 1 and 2 was determined by (1)H NMR analyses of their MPA esters. The configuration of the bicyclo[3.3.1]nonane core of the polyprenylated benzoylphloroglucinols was assigned by comparison of their experimental ECD spectra with those of related compounds. The polyprenylated benzoylphloroglucinols exhibited inhibitory activities against mammalian DNA polymerases α and λ, with IC50 values ranging from 5.0 to 8.8 µM. Compounds 1, 2, 4, 5, and 9-11 showed cytotoxic effects against HeLa human cervical cancer cells with median lethal dose values lower than 10 µM.

Screening of mammalian DNA polymerase and topoisomerase inhibitors from Garcinia mangostana L. and analysis of human cancer cell proliferation and apoptosis.

We purified and identified eight xanthones from mangosteen (Garcinia mangostana L.) and investigated whether these compounds inhibited the activities of mammalian DNA polymerases (Pols) and human DNA topoisomerases (Topos). ß-Mangostin was the strongest inhibitor of both mammalian Pols and human Topos among the isolated xanthones, with 50% inhibitory concentration (IC50) values of 6.4-39.6 and 8.5-10 µM, respectively. Thermal transition analysis indicated that ß-mangostin did not directly bind to double-stranded DNA, suggesting that this compound directly bound the enzyme protein rather than the DNA substrate. ß-Mangostin showed the strongest suppression of human cervical cancer HeLa cell proliferation among the eight compounds tested, with a 50% lethal dose (LD50) of 27.2 µM. This compound halted cell cycle in S phase at 12-h treatment and induced apoptosis. These results suggest that decreased proliferation by ß-mangostin may be a result of the inhibition of cellular Pols rather than Topos, and ß-mangostin might be an anticancer chemotherapeutic agent.

Alkaloids from the Tuber of Stephania cf. rotunda.

Chemical investigation of the tuber of Stephania cf. rotunda collected in Vietnam led to the isolation of a new stephaoxocane-type alkaloid, stepharotudine (1), twenty -eight known alkaloids, and two known amides. The chemical structures of the isolated compounds were determined by spectroscopic and chemical methods. The absolute configuration of the new compound was determined from its CD spectrum and by 1H NMR analyses of its MPA esters. For the known alkaloids ()crebanme-ß-N-oxide (2), uthongine (3), and palmatrubine (4), fully assigned NMR data are also reported for the first time.

Postural flexibility during quiet standing in healthy elderly and patients with Parkinson's disease.

Postural instability is one of the predominant symptoms of Parkinson's disease (PD). Despite its significant impact on the deterioration in quality of life in PD patients, mechanistic causes of the instability have not been clarified. Joint inflexibility at ankle and hip joints might be such a major cause, leading to small variability in the center of pressure (CoP) during quiet stance. However, this conjecture is still controversial. Thus, quantitative characterization of CoP patterns during quiet stance in PD patients remains a matter of research. Here we performed a linear discriminant analysis for CoP data in PD patients and age-matched healthy elderly during quiet stance, and showed that CoP variations in PD patients and those in healthy elderly could be well distinguished with an accuracy of about 90%, to which appropriately selected sway indices characterizing aspects of power spectrum for the CoP variations contributed. Specifically, major factors responsible for the discrimination were all associated with increase in the power at a high-frequency band (near and over 1 Hz) along with reduction at the low-frequency regime (lower than about 0.7 Hz). Then, the power-ratio, defined as the relative spectral power in a band around 1 Hz, was examined, since the power in this band reflects postural sway with anti-phase coordinated motions of the ankle and hip joints. We showed that the power-ratio values were significantly smaller in the PD patients than those in the healthy subjects. This difference as well as the results of the linear discriminant analysis suggest joint inflexibility in PD patients, particularly at hip joint, which diminished anti-phase coordination between trunk and lower extremity, leading to postural instability in PD patients.

Cinnamtannin B-1 Promotes Migration of Mesenchymal Stem Cells and Accelerates Wound Healing in Mice.

Substances that enhance the migration of mesenchymal stem cells to damaged sites have the potential to improve the effectiveness of tissue repair. We previously found that ethanol extracts of Mallotus philippinensis bark promoted migration of mesenchymal stem cells and improved wound healing in a mouse model. We also demonstrated that bark extracts contain cinnamtannin B-1, a flavonoid with in vitro migratory activity against mesenchymal stem cells. However, the in vivo effects of cinnamtannin B-1 on the migration of mesenchymal stem cells and underlying mechanism of this action remain unknown. Therefore, we examined the effects of cinnamtannin B-1 on in vivo migration of mesenchymal stem cells and wound healing in mice. In addition, we characterized cinnamtannin B-1-induced migration of mesenchymal stem cells pharmacologically and structurally. The mobilization of endogenous mesenchymal stem cells into the blood circulation was enhanced in cinnamtannin B-1-treated mice as shown by flow cytometric analysis of peripheral blood cells. Whole animal imaging analysis using luciferase-expressing mesenchymal stem cells as a tracer revealed that cinnamtannin B-1 increased the homing of mesenchymal stem cells to wounds and accelerated healing in a diabetic mouse model. Additionally, the cinnamtannin B-1-induced migration of mesenchymal stem cells was pharmacologically susceptible to inhibitors of phosphatidylinositol 3-kinase, phospholipase C, lipoxygenase, and purines. Furthermore, biflavonoids with similar structural features to cinnamtannin B-1 also augmented the migration of mesenchymal stem cells by similar pharmacological mechanisms. These results demonstrate that cinnamtannin B-1 promoted mesenchymal stem cell migration in vivo and improved wound healing in mice. Furthermore, the results reveal that cinnamtannin B-1-induced migration of mesenchymal stem cells may be mediated by specific signaling pathways, and the flavonoid skeleton may be relevant to its effects on mesenchymal stem cell migration.

Serotonergic mechanisms are involved in antidepressant-like effects of bisbenzylisoquinolines liensinine and its analogs isolated from the embryo of Nelumbo nucifera†Gaertner seeds in mice.

OBJECTIVES: We attempted to ascertain if bisbenzylisoquinoline alkaloids, liensinine and isoliensinine from Nelumbo nucifera Gaertner have antidepressant-like effects and compare the effects with those previously obtained by their analogue neferine. METHODS: Using mice, the forced swimming test (FST) was carried out after treatment with liensinine, isoliensinine and neferine. KEY FINDINGS: Liensinine and isoliensinine elicited antidepressant-like effects in mice after the FST. Anti-immobility effects of liensinine and isoliensinine were antagonized by the 5-hydroxytryptamine1 A (5-HT1 A ) receptor antagonist WAY 100635, but not by the α1 -adrenoceptor antagonist prazosin. The anti-immobility effects of liensinine, isoliensinine and neferine were blocked by pretreatment with p-chlorophenylalanine (PCPA), which depletes serotonin (5-HT). CONCLUSIONS: These data suggest that liensinine and isoliensinine from Nelumbo nucifera Gaertner have antidepressant-like effects and that antidepressant-like effects of liensinine and its analogues are closely related to serotonergic mechanisms.

Universal and individual characteristics of postural sway during quiet standing in healthy young adults.

The time course of the center of pressure (CoP) during human quiet standing, corresponding to body sway, is a stochastic process, influenced by a variety of features of the underlying neuro-musculo-skeletal system, such as postural stability and flexibility. Due to complexity of the process, sway patterns have been characterized in an empirical way by a number of indices, such as sway size and mean sway velocity. Here, we describe a statistical approach with the aim of estimating "universal" indices, namely parameters that are independent of individual body characteristics and thus are not "hidden" by the presence of individual, daily, and circadian variations of sway; in this manner it is possible to characterize the common aspects of sway dynamics across healthy young adults, in the assumption that they might reflect underlying neural control during quiet standing. Such universal indices are identified by analyzing intra and inter-subject variability of various indices, after sorting out individual-specific indices that contribute to individual discriminations. It is shown that the universal indices characterize mainly slow components of sway, such as scaling exponents of power-law behavior at a low-frequency regime. On the other hand, most of the individual-specific indices contributing to the individual discriminations exhibit significant correlation with body parameters, and they can be associated with fast oscillatory components of sway. These results are consistent with a mechanistic hypothesis claiming that the slow and the fast components of sway are associated, respectively, with neural control and biomechanics, supporting our assumption that the universal characteristics of postural sway might represent neural control strategies during quiet standing.

Polyketides from the cultured lichen mycobiont of a Vietnamese Pyrenula sp.

A spore-derived mycobiont of a crustose Pyrenula sp. lichen collected in Vietnam was cultivated on a malt-yeast extract medium supplemented with 10% sucrose. Chemical investigation of the cultivated colonies led to the isolation of eight new alkylated decalin-type polyketides (1-8) along with three known compounds. The structures of these compounds were elucidated by spectroscopic and chemical means. This is the first instance of this type of polyketide being isolated from a cultured lichen mycobiont. The isolated polyketides 1 and 7 exhibited inhibitory activities against mammalian DNA polymerases α and ß with IC50 values ranging from 8.1 to 19.5 µM. Compound 1 showed cytotoxic effects against the HCT116 human colon carcinoma cultured cell line with an IC50 value of 6.4 ± 0.7 µM.

Three acetophenones from Acronychia pedunculata.

Phytochemical investigation of the leaves and twigs of Acronychia pedunculata has led to the isolation of three new acetophenone monomers 1-3 as well as 1-[2',4'-dihydroxy-3',5'-di-(3″-methyl-2″-butenyl)-6'-methoxy]phenylethanone (4), acronyculatin E (5), a mixture of ß-sitosterol and stigmasterol, and sesamin. The structures of these new compounds were elucidated spectroscopically. The inhibitory activities of the isolated acetophenone derivatives against mammalian DNA polymerases and human cancer cell growth were also assessed.

Eremophilane-type sesquiterpenes from cultured lichen mycobionts of Sarcographa tricosa.

Spore-derived mycobionts of the crustose lichen Sarcographa tricosa were cultivated on a malt-yeast extract medium supplemented with 10% sucrose. Chemical investigation of the cultivated colonies led to isolation of three eremophilane-type sesquiterpenes, 3-epi-petasol (1), dihydropetasol (2) and sarcographol (3), together with six known eremophilanes and ergosterol peroxide. These structures were elucidated by spectroscopic and chemical methods. This is the first report of eremophilane-type sesquiterpenes from the cultured mycobionts of lichen.

Synthesis and pharmacological activity of alkaloids from embryo of lotus, Nelumbo nucifera.

Bisbenzylisoquinoline alkaloid, nelumboferine which was recently isolated from the embryo of Nelumbo nucifera, and stereoisomers of neferine, which is a major alkaloid of the embryo of N. nucifera, were stereoselectively synthesized. Pharmacological activity of nelumboferine, stereoisomers of neferine, liensinine, isoliensinine, and O-methylneferine were evaluated.

A 14-membered macrolide and isocoumarin derivatives from the cultured lichen mycobionts of Graphis vestitoides.

Spore-derived mycobionts of the crustose lichen Graphis vestitoides collected in Vietnam were cultivated on a malt-yeast extract medium supplemented with 10% sucrose. The investigation of their metabolites resulted in isolation of a novel 14-membered macrolide and a new isocoumarin, together with five known isocoumarin derivatives. Their structures were determined by spectroscopic and chemical means. This is the first instance of isolation of a 14-membered macrolide from a lichen mycobiont.

Noisy interlimb coordination can be a main cause of freezing of gait in patients with little to no parkinsonism.

Freezing of gait in patients with Parkinson's disease is associated with several factors, including interlimb incoordination and impaired gait cycle regulation. Gait analysis in patients with Parkinson's disease is confounded by parkinsonian symptoms such as rigidity. To understand the mechanisms underlying freezing of gait, we compared gait patterns during straight walking between 9 patients with freezing of gait but little to no parkinsonism (freezing patients) and 11 patients with Parkinson's disease (non-freezing patients). Wireless sensors were used to detect foot contact and toe-off events, and the step phase of each foot contact was calculated by defining one stride cycle of the other leg as 360°. Phase-resetting analysis was performed, whereby the relation between the step phase of one leg and the subsequent phase change in the following step of the other leg was quantified using regression analysis. A small slope of the regression line indicates a forceful correction (phase reset) at every step of the deviation of step phase from the equilibrium phase, usually at around 180°. The slope of this relation was smaller in freezing patients than in non-freezing patients, but the slope exhibited larger step-to-step variability. This indicates that freezing patients executed a forceful but noisy correction of the deviation of step phase, whereas non-freezing patients made a gradual correction of the deviation. Moreover, freezing patients tended to show more variable step phase and stride time than non-freezing patients. Dynamics of a model of two coupled oscillators interacting through a phase resetting mechanism were examined, and indicated that the deterioration of phase reset by noise provoked variability in step phase and stride time. That is, interlimb coordination can affect regulation of the gait cycle. These results suggest that noisy interlimb coordination, which probably caused forceful corrections of step phase deviation, can be a cause of freezing of gait.

Bisbenzylisoquinoline Alkaloids from Nelumbo nucifera.

From the embryos of the seeds of Nelumbo nucifera, three bisbenzylisoquinoline alkaloids, nelumboferine and nelumborines A and B, were isolated along with four known compounds, neferine, liensinine, isoliensinine and anisic acid. The structures of the new alkaloids were determined mainly by spectroscopic methods.

Phenolic compounds from the cultured mycobionts of Graphis proserpens.

Spore-derived mycobionts of the lichen Graphis proserpens were cultivated on a malt-yeast extract medium supplemented with 10% sucrose and their metabolites were investigated. Isocoumarin derivatives 1-3 and 7-oxo-5,7-dihydrooxepino[4,3,2-de]isochromene derivatives, proserins A-C (4-6), were isolated along with three known isocoumarin derivatives and three benzoic acid derivatives. Their structures were determined by spectroscopic methods.

Inhibitory effects of docosyl p-coumarate on DNA topoisomerase activity and human cancer cell growth.

We previously found six compounds of alkyl p-coumarates from a composite plant Artemisia annua L., and chemically synthesized these compounds (cis-isomer of C20, C22 and C24, and trans-isomer of C20, C22 and C24 of p-coumarates are compounds 1-6, respectively). This report describes the inhibitory activities of these alkyl p-coumarates against DNA polymerase (pol), DNA topoisomerase (topo), and human cancer cell growth. Among the compounds tested, compounds 1 and 4 weakly inhibited repair-related pol beta activity, but no compound influenced the activity of replicative pol alpha. Compounds 4-6 and compounds 2 and 5 were potent inhibitors of human topos I and II, respectively. Compounds 2, 4, 5 and 6 also suppressed the growth of human colon carcinoma cell line, HCT116, with or without p53, suggesting that cell growth inhibition had the same tendency as the inhibition of topos rather than pols. Compound 5 (docosyl p-coumarate), which was the strongest inhibitor of topo II and cancer cell growth in the compounds tested, halted HCT116 p53(+/+) cells in G2/M phases, and induced apoptosis, although this compound did not affect the cell cycle of HCT116 p53(-/-) cells. These results suggest that the effect of p53-dependent cell cycle arrest may be effective for topo inhibition by com-pound 5. From these findings, the action mode of alkyl p-coumarates as an anti-cancer agent is discussed.