Further evaluation of the potential anxiolytic activity of imidazo[1,5-a][1,4]diazepin agents selective for α2/3-containing GABAA receptors.

Positive allosteric modulators of GABAA receptors transduce a host of beneficial effects including anxiolytic actions. We have recently shown that bioavailability and anxiolytic-like activity can be improved by eliminating the ester functionality in imidazo[1,5-a][1,4]diazepines. In the present series of experiments, we further substantiate the value of heterocyle replacement of the ester for potential treatment of anxiety. None of three esters was active in a Vogel conflict test in rats that detects anxiolytic drugs like diazepam. Compounds 7 and 8, ester bioisosters, were selective for alpha 2 and 3 over alpha 1-containing GABAA receptors but also had modest efficacy at GABAA alpha 5-containing receptors. Compound 7 was efficacious and potent in this anxiolytic-detecting assay without affecting non-punished responding. The efficacies of the esters and of compound 7 were predicted from their efficacies as anticonvulsants against the GABAA antagonist pentylenetetrazole (PTZ). In contrast, the related structural analog, compound 8, did not produce anxiolytic-like effects in rats despite anticonvulsant efficacy. These data thus support the following conclusions: 1) ancillary pharmacological actions of compound 8 might be responsible for its lack of anxiolytic-like efficacy despite its efficacy as an anticonvulsant 2) esters of imidazo[1,5-a][1,4]diazepines do not demonstrate anxiolytic-like effects in rats due to their low bioavailability and 3) replacement of the ester function with suitable heterocycles markedly improves bioavailability and engenders molecules with the opportunity to have potent and efficacious effects in vivo that correspond to human anxiolytic actions.

[Recurrent syncope related to catecholaminergic polymorphic ventricular tachycardia due to de novo RyR2-R2401H mutation].

Objective: To explore the clinical and molecular genetic features of a Chinese patient with catecholaminergic polymorphic ventricular tachycardia (CPVT). Methods: Clinical data including resting electrocardiography, echocardiography and treadmill exercise testing of a patient with CPVT admitted to our department in March 2013 were analyzed, and the peripheral venous blood samples of the patient and his family members and 400 ethnicity-matched healthy controls were obtained. All exons and exon-intron boundaries of the six CPVT-related genes including RYR2, CASQ2, TRDN, CALM1, KCNJ2 and ANKB were sequenced to detect the variants related to CPVT. The relationship between the genotypes and phenotypes was analyzed to direct the target therapy. Results: Recurrent syncope induced either by exercise or extreme frightened fear was observed in this patient. There was no positive family history of syncope or sudden death. The resting electrocardiography and echocardiography of the patient were normal, while the exercise testing revealed bidirectional and polymorphic ventricular tachycardia. A cardiac ryanodine receptor gene mutation (R2401H) was identified in this patient, while this mutation was absent in his parents and sister and 400 controls. No variant was detected in the remaining five candidate genes. Treatment with high dose of metoprolol succinate (118.75 mg/d) was effective and patient was free of syncopal attack during the 2 years follow-up. Conclusion: This is the first report on RyR2-R2401H mutation in Chinese patient with CPVT, and high dose of metoptolol is the effective therapy option for CPVT related to RyR2 mutation.

Tanshinone-1 induces tumor cell killing, enhanced by inhibition of secondary activation of signaling networks.

Tumor multidrug resistance (MDR) can result from overexpression of drug transporters and deregulation of cellular signaling transduction. New agents and strategies are required for overcoming MDR. Here, we report that tanshinone-1, a bioactive ingredient in traditional Chinese medicine, directly killed MDR tumor cells and their corresponding parental cells, which was potentiated by inhibition of secondary activation of signaling networks. Tanshinone-1 was slightly more potent at inducing cytotoxicity and apoptosis in MDR cells than in corresponding parental cells. Tanshinone-1-induced MDR cell killing was independent of the function and expression of drug transporters but was partially correlated with the phosphatase-dependent reduction of phospho-705-Stat3, which secondarily activated p38-, AKT-, and ERK-involved signaling networks. Cotreatments with p38, AKT, and ERK inhibitors potentiated the anti-MDR effects of tanshinone-1. Our study presents a model for MDR cell killing using a compound of natural origin. This model could lead to new therapeutic strategies for targeting signaling network(s) in MDR cancers as well as new strategies for multitarget design.

Triterpenoids from Cimicifugae rhizoma, a novel class of inhibitors on bone resorption and ovariectomy-induced bone loss.

OBJECTIVE: Increasing research suggested that Cimicifugae rhizoma might be protective against osteoporosis. In this study, we investigated the effects of three cycloartane-type triterpenoids isolated from Cimicifugae rhizoma, cimicidol-3-O-beta-D-xyloside (1), cimicidanol-3-O-beta-D-xyloside (2) and acetylacteol-3-O-beta-d-xyloside (3) on bone resorption in vitro and bone loss in ovariectomized (OVX) mice. METHODS: The activities of the tested compounds on bone resorption were evaluated using three assays, neonatal mouse parietal bone organ culture, osteoclast-like cells (OCLs) formation and pit formation. The effects on bone mineral density (BMD) and uterine weight were examined using OVX mice. Using LC-MS/MS method, the serum concentrations of the triterpenoids were measured in mice serum collected at 0.5, 1, 3, 6 and 12h following its oral administration. RESULTS: All of the tested compounds exerted the inhibitory effects on bone resorption in bone organ culture, suppressed both of the formation and the resorbing activity of OCLs. Furthermore, a synergistic effect was observed among those compounds. In vivo studies revealed that compounds 1-3 and the mixture of compounds 1-3 prevented the bone loss in OVX mice without affecting uterine weight, and each compound was detected in the mice serum after single oral administration. CONCLUSIONS: The triterpenoids exerted the inhibitory effects on osteoclastic bone resorption through the suppression of both OCLs formation and the resorbing activity of OCLs, and also showed a significant protective effect on BMD in OVX mice. The present results might provide a new pharmacological potential for the treatment of osteoporosis.

Effects of methionine and betaine supplementation on growth performance, carcase composition and metabolism of lipids in male broilers.

1. This study was conducted to investigate the effects of methionine and betaine supplementation on growth performance, carcase composition and lipid metabolism in growing broilers. 2. A total of 450 commercial broilers, 22 d of age, were randomly allocated to three groups, each of which included three replicates (50 birds per replicate). The groups received the same methionine-deficient diet supplemented with 0 or 1 g/kg methionine, or 0.5 g/kg betaine, respectively. 3. Methionine and betaine supplementation significantly improved weight gain and feed conversion. Supplemental methionine and betaine also significantly increased breast muscle yield and decreased abdominal fat content. Meanwhile, addition of methionine and betaine significantly increased the contents of creatine and free carnitine in liver, the activity of hormone-sensitive lipase in abdominal fat and the concentration of free fatty acid in serum, whereas uric acid concentration in serum was significantly decreased. 4. The results of this study suggest that betaine can spare methionine in its function as an essential amino acid and is as effective as methionine in improving performance and carcase quality of growing broilers if the diet is moderately deficient in methionine. The decrease in abdominal fat may be due to the increased carnitine synthesis in liver and hormone-sensitive lipase activity in abdominal fat.

The duration and plantar pressure distribution during one-leg stance in Tai Chi exercise.

BACKGROUND: Tai Chi exercise improved the balance control and muscle strength of the lower extremities. The aim of this study is to quantify the one-leg stance duration and plantar pressure distribution during the one-leg stance in Tai Chi and to try to elaborate on its probable effects on the ability to balance on one leg. METHODS: Sixteen experienced Tai Chi practitioners participated in this study. The Novel Pedar-X insole system was used to record the plantar forces during the execution of a set of 42-form Tai Chi movements and during normal walking. The one-leg stance duration and plantar pressure distribution during the one-leg stance were analyzed. FINDINGS: In Tai Chi exercise, the total duration spent in the one-leg stance was less (p<0.05), the duration of each one-leg stance was longer (p<0.01) and the medial-lateral displacement of the centre of pressure was greater (p<0.05) than during normal walking. The peak pressure and pressure-time integral of the second and third metatarsal heads and the fourth and fifth metatarsal heads were significantly greater (p<0.05) than those of other plantar regions during the one-leg stance in normal walking, whereas the peak pressure and pressure-time integral of the first metatarsal head and the great toe were significantly greater (p<0.05) than those of other plantar regions during the one-leg stance in Tai Chi exercise. INTERPRETATION: The longer duration of each one-leg stance and the plantar pressure distribution characteristics during the one-leg stance in Tai Chi exercise may be associated with an improved ability to balance on one leg. The findings may provide useful information toward the development of strengthening programs, strategies for the prevention of falls, and the promotion of a physically active lifestyle.

Effects of long term Tai Chi practice and jogging exercise on muscle strength and endurance in older people.

OBJECTIVES: To investigate the influence of regular Tai Chi (TC) practice and jogging on muscle strength and endurance in the lower extremities of older people. METHODS: Twenty one long term older TC practitioners were compared with 18 regular older joggers and 22 sedentary counterparts. Maximum concentric strength of knee flexors and extensors was tested at angular velocities of 30 degrees/s and 120 degrees/s. Ankle dorsiflexors and plantar flexors were tested at 30 degrees/s and the dynamic endurance of the knee flexors and extensors was assessed at a speed of 180 degrees/s. RESULTS: The differences in the muscle strength of the knee joint amongst the three experimental groups were significant at the higher velocity. The strengths of knee extensors and flexors in the control group were significantly lower than those in the jogging group and marginally lower than those in the TC group. For the ankle joint, the subjects in both the TC and jogging groups generated more torque in their ankle dorsiflexors. In addition, the muscle endurance of knee extensors was more pronounced in TC practitioners than in controls. CONCLUSION: Regular older TC practitioners and joggers showed better scores than the sedentary controls on most muscle strength and endurance measures. However, the magnitude of the exercise effects on muscles might depend on the characteristics of different types of exercise.

Tai chi: physiological characteristics and beneficial effects on health.

OBJECTIVES: To assess the characteristic effects of Tai Chi Chuan (TCC) exercise on metabolism and cardiorespiratory response, and to measure its effect on cardiorespiratory function, mental control, immune capacity, and the prevention of falls in elderly people. DESIGN: A review of controlled experimental studies and clinical trials designed with one of two aims: either to assess physiological responses during the performance of TCC or to assess the impact of this exercise on general health and fitness. MAIN OUTCOME MEASURES: Metabolic rate, heart rate, blood pressure, ventilation, maximal oxygen uptake (VO(2)MAX), immune capacity, falls, and fall related factors. SUBJECTS: A total of 2216 men and women. RESULTS: Under review were 31 original studies, published in Chinese or English journals, that met the criteria for inclusion. Most of the papers written in Chinese had not been introduced into the Western literature. Nine of these studies showed that TCC can be classified as moderate exercise, as its does not demand more than 55% of maximal oxygen intake. When this form of exercise and others conducted at equal intensity were compared, TCC showed a significantly lower ventilatory equivalent (VE/VO(2)MAX). Evidence provided by cross sectional and longitudinal studies suggests that TCC exercise has beneficial effects on cardiorespiratory and musculoskeletal function, posture control capacity, and the reduction of falls experienced by the elderly. CONCLUSIONS: TCC is a moderate intensity exercise that is beneficial to cardiorespiratory function, immune capacity, mental control, flexibility, and balance control; it improves muscle strength and reduces the risk of falls in the elderly.

[Clinical study on analgesic mechanism of bitongxiao in treating neck pain due to cervical spondylitis].

OBJECTIVE: To study the analgesic mechanism of Bitongxiao (BTX, a Chinese herbal decoction) in treating neck pain due to cervical spondylitis (CS). METHODS: BTX and Jingfukang (JFK) granule were used to treat the treated and the control group separately in 102 CS cases. Plasma leucine enkephalin (LEK), substance P (SP) and prostaglandin E2 (PGE2) before and after treatment were assayed by radioimmunoassay (RIA). RESULTS: Twelve patients in the treated group were clinically cured, 36 markedly effectively, 3 effectively and 1 ineffectively, while in the control group they were 5, 33, 14 and 0 cases respectively. The cured and marked effective rate in the treated group was 92.3%, while that in the control group 72.0%. After treatment the pain score (VAS) of both groups were significantly reduced, but the reduction was higher in the treated group than that in the control. Before treatment, plasma LEK in all patients was abnormally low, but after treatment, it raised obviously more in the treated group than that in the control (P < 0.05). Plasma SP of both groups were obviously elevated, and PGE2 revealed unaltered after treatment. CONCLUSION: BTX has strong, fast-acting and long-lasting analgesic effect with no side-effects, it could elevate the lowered plasma LEK level in cervical spondylitis patients and increase plasma SP level. The analgesic mechanism of BTX might be associated with its effect on LEK, SP or other endorphins, directly acting on the pain modulation system.

[The analgesic and antispasmodic effects of guang tong xiao aerosol of TCM].

OBJECTIVE: To observe the analgesic and antispasmodic effects of Guang Tong Xiao Aerosol (GTXA). METHOD: Writhing test and tail-flick of physical stimulation were made to study the analgesic effect on mice and rats. RESULT AND CONCLUSION: GTXA given by gastrogavage in dose of 18.75 g.kg-1 or 12.50 g.kg-1 could markedly raise the pain threshold after chemical stimulation in mice and physical stimulation in rats, and had antispasmodic effects.

Phenylpropanoid glycosides from Smilax glabra.

Five phenylpropanoid esters of sucrose glycosides, trivially named smiglasides A-E, were isolated from the rhizomes of Smilax glabra. Their structures were elucidated on the basis of spectroscopic studies.

Balance control, flexibility, and cardiorespiratory fitness among older Tai Chi practitioners.

BACKGROUND: Tai Chi Chuan (TTC) exercise has beneficial effects on the components of physical condition and can produce a substantial reduction in the risk of multiple falls. Previous studies have shown that short term TCC exercise did not improve the scores in the single leg stance test with eyes closed and the sit and reach test. There has apparently been no research into the effects of TCC on total body rotation flexibility and heart rate responses at rest and after a three minute step test. METHODS: In this cross sectional study, 28 male TCC practitioners with an average age of 67.5 years old and 13.2 years of TCC exercise experience were recruited to form the TCC group. Another 30 sedentary men aged 66.2 were selected to serve as the control group. Measurements included resting heart rate, left and right single leg stance with eyes closed, modified sit and reach test, total body rotation test (left and right), and a three minute step test. RESULTS: Compared with the sedentary group, the TCC group had significantly better scores in resting heart rate, three minute step test heart rate, modified sit and reach, total body rotation test on both right and left side (p < 0.01), and both right and left leg standing with eyes closed (p < 0.05). According to the American Fitness Standards, the TCC group attained the 90th percentile rank for sit and reach and total body rotation test, right and left. CONCLUSION: Long term regular TCC exercise has favourable effects on the promotion of balance control, flexibility, and cardiovascular fitness in older adults.

Huperzine-A in capsules and tablets for treating patients with Alzheimer disease.

AIM: To compare the efficacy and safety between huperzine-A (Hup) in capsules and tablets for treating patients with Alzheimer disease (AD). METHODS: Using multicenter, prospective, double-blind, double-mimic, parallel, positive controlled and randomized methods, 60 patients meeting with the NINCDS-ARDRA criteria of AD were divided into 2 equal groups. Patients in the capsule group received 4 capsules of Hup (each contains 50 micrograms) and 4 tablets of placebo (lactose and starch inside); while the tablet group received 4 tablets of Hup (each contains 50 micrograms) and 4 capsules of placebo, p.o., twice a day for 60 d. All the patients were evaluated with a lot of related ranting scales, and physiological and laboratory examination. RESULTS: There were significant differences (P < 0.01) on all the psychological evaluations between 'before' and 'after' the 60-d trial of 2 groups, but there was no significant difference between 2 groups by group t test (P > 0.05). The changes of oxygen free radicals in 2 groups showed marked improvement. No severe side effect besides moderate to mild nausea was found in both groups. CONCLUSION: There is equal efficacy and safety between Hup in capsule and tablet for treating patients with AD, and Hup can reduce the pathological changes of the oxygen free radicals in the plasma and erythrocytes of patients with AD.

Tribulusamide A and B, new hepatoprotective lignanamides from the fruits of Tribulus terrestris: indications of cytoprotective activity in murine hepatocyte culture.

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).

Three phenylethanoid glycosides and an iridoid glycoside from Picrorhiza scrophulariiflora.

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.

Comparative study of seventeen Salvia plants: aldose reductase inhibitory activity of water and MeOH extracts and liquid chromatography-mass spectrometry (LC-MS) analysis of water extracts.

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.

[Clinical observation on 112 cases with non-Hodgkin's lymphoma treated by Chinese herbs combined with chemotherapy].

OBJECTIVE: To seek for the effective therapeutical method in treating non-Hodgkin's lymphoma (NHL). METHODS: One hundred and sixty seven patients with non-Hodgkin's lymphoma were randomly divided into two groups, the treatment group, which consisted of 112 cases using Chinese herbs combined with chemotherapy and 55 cases of control group were treated by chemotherapy only. RESULTS: The effective rate (CR + PR) in the combined group was 91.96% and survival rates of 1-, 3- and 5-year were 85.7%, 54.5% and 29.5% respectively, and median survival time was 554 days. In control group the effective rate was 72.73% and 1-, 3- and 5-year survival rates were 76.4%, 38.2% and 18.2% respectively, and the median survival time was 465 days. The difference of effective rates or 3-year survival rates between two groups was significant (P < 0.05). In the combined group the activity of NK cell, OKT3, OKT4 and ratio of OKT4/OKT8 were obviously raised after treatment (P < 0.01). And the level of platelet adhesion rate and the blood viscosity markedly decreased (P < 0.01), but in the control group the values of these indexes did not distinctly change. CONCLUSION: Chinese herbs could enhance the immunologic function and improve the viscosity of blood of the patients with NHL. The side effect in the combination therapy group was less and milder than that in the chemotherapy group. These showed that Chinese herbs combined with chemotherapy was a safe and effective method for treating NHL and deserve to be recommended.

Effects of Cimicifugae rhizoma on serum calcium and phosphate levels in low calcium dietary rats and on bone mineral density in ovariectomized rats.

We studied the effects of ethyl acetate-(EtOAc) soluble fractions from methanol (MeOH) extracts of Cimicifugae rhizoma derived from two species - Cimicifuga heracleifolia Komarov and C. foetida L. - and four triterpenoids (1-4) isolated from them on the serum calcium (Ca) and phosphate (P) levels in low - Ca dietary rats. The EtOAc-soluble fraction from C. heracleifolia Komarov (HE) significantly drecreased Ca levels when administered. Similarly, the EtOAc-soluble fraction from C. foetida L. (FE) significantly lowered serum Ca levels at doses of 100 and 200 mg/kg/day, while the four triterpenoids (1-4) did the same at a dose of 25mg/kg/day. Interestingly only 7,8-didehydro-24-0-acetylhydroshengmanol-3-0-ß-xyloside (4) showed a significant influence on serum P levels. The effects of HE and FE on the bone mineral density (BMD) of the lumbar spine (L 2-4) in ovariectomized rats were measured by dual energy X-ray absorptiometry (DXA). Rats treated with HE and FE showed a significant increase in BMD compared to untreated ovariectomized rats. BMD was lower in the latter than in sham-operated rats.