An Adaptive Hammerstein Model for FES-Induced Torque Prediction Based on Variable Forgetting Factor Recursive Least Squares Algorithm.

Modeling the muscle response to functional electrical stimulation (FES) is an important step during model-based FES control system design. The Hammerstein structure is widely used in simulating this nonlinear biomechanical response. However, a fixed relationship cannot cope well with the time-varying property of muscles and muscle fatigue. In this paper, we proposed an adaptive Hammerstein model to predict ankle joint torque induced by electrical stimulation, which used variable forgetting factor recursive least squares (VFFRLS) method to update the model parameters. To validate the proposed model, ten healthy individuals were recruited for short-duration FES experiments, ten for long-duration FES experiments, and three stroke patients for both. The isometric ankle dorsiflexion torque induced by FES was measured, and then the test performance of the fixed-parameter Hammerstein model, the adaptive Hammerstein model based on fixed forgetting factor recursive least squares (FFFRLS) and the adaptive Hammerstein model based on VFFRLS was compared. The goodness of fit, root mean square error, peak error and success rate were applied to evaluate the accuracy and stability of the model. The results indicate a significant improvement in both the accuracy and stability of the proposed adaptive model compared to the fixed-parameter model and the adaptive model based on FFFRLS. The proposed adaptive model enhances the ability of the model to cope with muscle changes.

System pharmacology analysis to decipher the effect and mechanism of active ingredients combination from herb couple on rheumatoid arthritis in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional herb couple Angelicae pubescentis radix (APR) and Notopterygii rhizoma et radix (NRR), composition of two traditional Chinese medicinal herbs, has been used clinically in China for the treatment of rheumatoid arthritis (RA) over years. APR and NRR contain coumarins and phenolic acids, which have been reported to have analgesic and anti-inflammatory activities. AIM OF THE STUDY: The active ingredients combination (AIC) and potential therapeutic mechanism of APR and NRR (AN) herb couple remain unclear. Therefore, the present study aimed to identify the AIC and elucidate the underlying mechanism of AIC on RA. MATERIALS AND METHODS: Firstly, a novel strategy of in vitro experiments, computational analysis, UPLC-QTOF-MS and UPLC-QQQ-MS was established to confirm the optimum ratio of AN herb couple samples and identified the AIC. Then, the anti-arthritis effects of the optimal herb couple and AIC were studied with Collagen II induced rheumatoid arthritis (CIA) rats in vivo. Finally, an integrated model of network pharmacology, metabolomics, gut microbiota analysis and biological techniques were applied to clarify the underlying mechanism through a comprehensive perspective. RESULTS: AN7:3 herb couple was regarded as the optimal ratio of AN herbal samples, and AIC was screened as osthole, columbianadin, notopterol, isoimperatorin, psoralen, xanthotoxin, bergapten, nodakenin and bergaptol respectively. Additionally, AIC exerted similar therapeutic effects as AN 7:3 in CIA rats. Moreover, AIC ameliorated RA might via regulating MAPK signaling pathway, altering metabolic disorders and gut microbiome involved autoimmunity. CONCLUSIONS: our findings provided scientific evidence to support that AIC of AN herb couple could be used as a prebiotic agent for RA. Importantly, this research provided a systematic and feasible strategy to optimize the proportion of medicinal materials and screen AIC from multi-component traditional Chinese herb couples or Chinese medicine formulae. Moreover, it provided a comprehensive perspective to discover AIC, clarify the overall effects and understand the mechanisms for natural products through the perspective of database and multi-omics integration.

Homotherapy for heteropathy active components and mechanisms of Qiang-Huo-Sheng-Shi decoction for treatment of rheumatoid arthritis and osteoarthritis.

Qiang-Huo-Sheng-Shi decoction (QHSSD), a classic traditional Chinese herbal formula, which has been reported to be effective in rheumatoid arthritis (RA) and osteoarthritis (OA). However, the concurrent targeting mechanism of how the aforementioned formula is valid in the two distinct diseases OA and RA, which represents the homotherapy-for-heteropathy principle in traditional Chinese medicine (TCM), have not yet been clarified. In the present study, network pharmacology was adopted to analyze the potential molecular mechanism, and therapeutic effective components of QHSSD on both OA and RA. A total of 153 active ingredients in QHSSD were identified, 142 of which associated with 59 potential targets for the two diseases were identified. By constructing the protein-protein interaction network and the compound-target-disease network, 72 compounds and 10 proteins were obtained as the hub targets of QHSSD against OA and RA. The hub genes of ESR1, PTGS2, PPARG, IL1B, TNF, MMP2, IL6, CYP3A4, MAPK8, and ALB were mainly involved in osteoclast differentiation, the NF-κB and TNF signaling pathways. Moreover, molecular docking results showed that the screened active compounds had a high affinity for the hub genes. This study provides new insight into the molecular mechanisms behind how QHSSD presents homotherapy-for-heteropathy therapeutic efficacy in both OA and RA. For the first time, a two-disease model was linked with a TCM formula using network pharmacology to identify the key active components and understand the common mechanisms of its multi-pathway regulation. This study will inspire more innovative and important studies on the modern research of TCM formulas.

Iterative Adjustment of Stimulation Timing and Intensity During FES-Assisted Treadmill Walking for Patients After Stroke.

Functional electric stimulation (FES) is a common intervention to correct foot drop for patients after stroke. Due to the disturbances from internal time-varying muscle characteristics under electrical stimulation and external environmental uncertainties, most of the existing FES system used pre-set stimulation parameters and cannot achieve good gait performances during FES-assisted walking. Therefore, an adaptive FES control system, which used the iterative learning control to adjust the stimulation intensity based on kinematic data and a linear model to modulate the stimulation timing based on walking speed during FES-assisted treadmill walking, was designed and tested on ten patients with foot drop after stroke. In order to examine its orthotic effects, the kinematic data of the patients using the proposed control strategy were collected and compared with the data of the same patients walking using other three FES control strategies, including (1) constant pre-set stimulation intensity and timing, (2) constant pre-set stimulation intensity with speed-adaptive stimulation timing and (3) walking without FES intervention. The error between the maximum ankle dorsiflexion angle during swing phase and the target angle using the proposed control strategy was the smallest among the four conditions. Moreover, there was no significant difference in the ankle plantar flexion angle at the toe-off event and the maximum knee flexion angle during swing phase between the proposed control strategy and walking without FES. In summary, the proposed control strategy can improve FES-assisted walking performances through adaptive modulation of stimulation timing and intensity when coping with variation, and may have good potential in clinic.

Establishment of the concurrent experimental model of osteoporosis combined with Alzheimer's disease in rat and the dual-effects of echinacoside and acteoside from Cistanche tubulosa.

ETHNOPHARMACOLOGICAL RELEVANCE: Cistanche tubulosa is a precious traditional Chinese medicine that has been widely used in the treatment of osteoporosis and Alzheimer's disease. Echinacoside and acteoside are the main active constituents in Cistanche tubulosa that have the pharmacological activities with research value. It has been reported that echinacoside and acteoside could improve the learning and memory ability, promote the proliferation and differentiation of osteoblast. AIM OF STUDY: Echinacoside and acteoside from Cistanche tubulosa have shown significant activities of anti-osteoporosis and anti-Alzheimer's disease, while these effects have not been studied concurrently in a rat model. The aim of this study was to establish and verify the model of osteoporosis combined with Alzheimer's disease in rat, and to investigate the double effects of echinacoside and acteoside on this concurrent model. MATERIALS AND METHODS: Three model groups of ovariectomy (OVX), sham surgery with D-galactose and AlCl3 (D), ovariectomy with D-galactose and AlCl3 (OVX + D) were set at the same time. The rats in drug treatment groups were ovariectomized. While conducting the intraperitoneal injection of D-galactose and intragastric administration of AlCl3 in the rats of drug treatment groups, the rats were orally administered echinacoside (90 mg/kg/d), acteoside (90 mg/kg/d) and the positive control drugs of estradiol valerate (0.6 mg/kg/d), donepezil HCl (0.8 mg/kg/d), respectively. After the drug treatment of 8 weeks, Morris Water Maze (MWM) test for 6 days was firstly performed. The rats were then sacrificed to harvest the blood, uteri, femora, tibiae and brain tissues. The serum was used for biochemical tests. The uteri were used for histomorphometry. The right femora were used for Micro-CT and histomorphometry, respectively. The right tibiae were used for biomechanical test. The hippocampus collected on ice box was used for biochemical tests. The brain collected by perfusion was used for histomorphometry. RESULTS: Compared with Sham group, OVX + D group could significantly reduce the learning and memory ability by causing oxidative damage, impairing neurons in hippocampus and affecting the hydrolysis and synthesis of acetylcholine. Meanwhile, the activities of BALP and TRAP in OVX + D group increased significantly (P < 0.001) as compared to Sham group. In addition, compared with Sham group, the mean bone mineral density obviously decreased (P < 0.05), the trabecular bone mass and microarchitecture were also destroyed significantly in OVX + D group. Furthermore, the maximum load and maximum stress significantly reduced (P < 0.01) and the energy absorption also decreased greatly as compared to Sham group. After administrated with echinacoside and acteoside, the typical pathological features of osteoporosis and Alzheimer's disease were ameliorated. CONCLUSIONS: The model of osteoporosis combined with Alzheimer's disease in rat was feasible and successfully established. Echinacoside and acteoside also showed some significant effects on this concurrent model, and they could be potential candidates from Cistanche tubulosa with double effects for further study.

Integrated network pharmacology and zebrafish model to investigate dual-effects components of Cistanche tubulosa for treating both Osteoporosis and Alzheimer's Disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Osteoporosis (OP) and Alzheimer's disease (AD) are common geriatric concurrent diseases, and many studies indicate the connection of their pathogenesis. Cistanche tubulosa (Schenk) Wight (CT) is a widely used traditional Chinese medicine and has been extensively applied to treat OP and AD, respectively. However, the active ingredients for both concurrent diseases simultaneously and underlying mechanisms are limited. AIM OF STUDY: This work aimed at establishing an effective and reliable network screening method to find dual-effects compounds in CT that can protect AD and OP concurrently. And it will provide new perspectives of the link between OP and AD on molecular mechanisms. MATERIAL AND METHODS: The dual-effects of CT were systematically analyzed with integrating multiple databases and extensive analysis at a network pharmacology level. Classified drug-target interaction network was constructed to reveal differences in effects between different types of compounds. To prove the effectiveness of this network, some compounds were selected to verify in Pre-induced OP model and AlCl3-induced AD model of zebrafish according to the topological parameters. RESULTS: 22 dual-effects active ingredients in CT were initially screened out via network pharmacology with a closely connection with 81 OP and AD-related targets. Classified network analysis found the better bioactivities of phenylethanoid glycosides and flavonoids. The dual-effects of four selected compounds demonstrated that the network is reasonable and effective, suggesting the dual-effects of the remaining 18 compounds. Moreover, we identified 9 putative targets and two pathways that were significantly related to OP and AD. CONCLUSIONS: We successfully identified 22 dual-effects active components in CT. This systematic screening strategy provided a new protocol to objectively discover multi-effects compounds of traditional Chinese medicine, and even a macroscopic perspective that will improve our understanding of the link between OP and AD on molecular mechanisms.

Electrophysiological Measurement of Rat Atrial Epicardium Using a Novel Stereotaxic Apparatus.

Flexible, in vivo maneuverable electrophysiology mapping techniques are not available in rat models. A novel cardiac stereotactic electrophysiology epicardial mapping system (CREAMS) allows for various measurements, including: (1) recording unipolar electrograms at multiple sites; (2) positioning of mapped sites and precision testing (Distance between the two "centers" = 297 ± 54 µm, n = 15); (3) evaluation of electrophysiology in an in vivo Sprague-Dawley rat model with high-frequency stimulation (HFS)-induced Atrial fibrillation (AF) at high right atrium (HRA) sites. We found that of the right atrium dispersion of effective refractory period (P < 0.05) and the window of vulnerability (P < 0.01) were significantly increased (P < 0.05) after HRA HFS. CREAMS has the potential for convenient electrophysiology assessment in a rat AF model through stereo-positioning, and flexible operating manipulation.

[Reproduction-related proteins differentially expressed in the testes of the mice with kidney-yang or kidney-yin deficiency].

OBJECTIVE: To compare the differentially expressed proteins in mice with kidney-yang deficiency and those with kidney-yin deficiency induced by hydrocortisone, and explore the similar and different material bases of male infertility caused by the two types of kidney deficiency. METHODS: Thirty Kunming mice were equally randomized into a normal control, a kidney-yang deficiency and a kidney-yin deficiency group. The animals of the normal control group were injected intraperitoneally with normal saline at 0.2 ml qd for 7 days, while those of the latter two groups with hydrocortisone at 25 mg/kg/d for 10 days and 50 mg/kg/d for 7 days, respectively, for establishment of kidney-yang deficiency and kidney-yin deficiency models. Then the pathological changes in the testicular tissue of the mice were observed by HE staining and the differentially expressed proteins were compared among different groups using isobaric tags for relative and absolute quantitation (iTRAQ) and the bioinformatics method. RESULTS: Sod1 was found to be a reproduction-related node protein differentially expressed in the testis tissues of the two types of kidney-deficiency mice, more highly expressed in the kidney-yin than in the kidney-yang deficiency group (P < 0.05). Five reproduction-associated node proteins were co-expressed in the testes of the two groups of kidney-deficiency mice, with significantly up-regulated expression of Rps28 and down-regulated expressions of Rpl11, Rplp2, Svs2 and Svs3a (P < 0.01). CONCLUSIONS: Sod1 may be one of the key material bases for the differentiation of male infertility caused by kidney-yang deficiency from that induced by kidney-yin deficiency, while Rps28, Rpl11, Rplp2, Svs2 and Svs3a may be the common material bases of male infertility caused by the two types of kidney deficiency.

[Expression of G-protein coupled estrogen receptor in the testis of the male mouse with kidney yin or kidney yang deficiency and its impact on the reproductive function of the mouse].

OBJECTIVE: To investigate the expression of the G-protein coupled estrogen receptor (GPER) in the testis of the male mouse with kidney yin or kidney yang deficiency and its influence on the reproductive function of the mouse. METHODS: We randomized 30 six-week-old male Kunming mice into three groups of equal number: kidney yang deficiency, kidney yin deficiency, and normal control, and established the models of kidney yang deficiency and kidney yin deficiency by peritoneal injection of hydrocortisone at 50 mg/kg for 5 days and 25 mg/kg for 10 days, respectively. We observed the behavioral changes of the mice using the elevated plus-maze, exhaustive swimming and field experiment, examined the semen quality with the automatic sperm quality analyzer, calculated the average number of the offspring, measured the serum testosterone (T) and estradiol (E2) levels and T/E2 ratio by Roche electrochemiluminescence assay, and determined the localization and expression of GPER in the testis by immunohistochemistry and immunofluorescence staining. RESULTS: Compared with the mice with kidney yin deficiency, those with kidney yang deficiency showed remarkably fewer entries into the open arm and central area (P <0.05) and shorter time of exhaustive swimming (P <0.05), but no statistically significant difference in the time spent in the open arm or the central area (P >0.05); the latter group also exhibited significant decreases in the epididymal sperm count (ï¼»7.27 ± 1.30ï¼½ vs ï¼»3.05 ± 1.06ï¼½ ×108/g, P <0.01), sperm motility (ï¼»54.15 ± 13.52ï¼½ vs ï¼»51.57 ± 8.75ï¼½ %, P <0.01) and average number of the offspring (6.46 vs 4.33, P <0.05), a slight increase in the rate of morphologically abnormal sperm (ï¼»13.42 ± 2.32ï¼½ vs ï¼»15.39 ± 2.48ï¼½ %, P >0.05), and markedly reduced serum T (ï¼»24.96 ± 6.18ï¼½ vs ï¼»16.72 ± 5.92ï¼½ ng/dl,P <0.05), E2 (ï¼»19.81 ± 4.01ï¼½ vs ï¼»15.24 ± 1.11ï¼½ pg/ml,P <0.05) and T/E2 ratio (1.41 vs 1.25, P <0.05). The expression of GPER was found in the cytoplasm of the Leydig cells, negative in the nuclei and cell membrane, significantly higher in the kidney yang than in the kidney yin deficiency group (P <0.05). CONCLUSIONS: The numbers of sperm and offspring decreased while the percentage of morphologically abnormal sperm increased in both the kidney yang and kidney yin deficiency mice, even more significantly in the former, which might be associated with the up-regulated expression of GPER in the testis of the mouse with kidney yang deficiency and consequently the reduced serum T level and T/E2 ratio.

Baicalin modulates the Treg/Teff balance to alleviate uveitis by activating the aryl hydrocarbon receptor.

Autoimmune uveitis is a sight-threatening ocular inflammatory disorder. Immunological inflammation is regarded as the key to pathogenesis in autoimmune uveitis. Baicalin, the major bioactive component of Scutellaria baicalensis, possesses immunomodulatory properties. However, the role of baicalin in uveitis and its underlying mechanisms remain unclear. In the current study, we found that baicalin treatment obviously inhibited the intraocular inflammatory process in mice with experimental autoimmune uveitis, along with clear declines in infiltrated inflammatory cells and inflammatory cytokine transcription in the retina and draining lymph nodes. Furthermore, baicalin treatment increased the frequency and number of regulatory T cells and decreased the frequency and number of effector T cells (Th1 and Th17 cells) in the draining lymph nodes of mice with experimental autoimmune uveitis. In vitro, baicalin treatment suppressed interphotoreceptor retinoid binding protein-specific CD4+ T cell proliferation and converted CD4+ T cell differentiation. Furthermore, the expression of aryl hydrocarbon receptor was activated by baicalin treatment. Baicalin-mediated modulation of CD4+ T cell differentiation was partially abrogated by the suppression of aryl hydrocarbon receptor. These findings suggest that baicalin modulates the Treg/Teff balance and CD4+ T cell proliferation to ameliorate experimental autoimmune uveitis by activating the aryl hydrocarbon receptor.

Determination and pharmacokinetics of 6,7-dimethoxycoumarin in rat plasma after intragastric administration of different decoctions of yinchenhao tang.

A simple and sensitive reversed-phase high-performance liquid chromatography method with UV detection is developed and validated for the determination of 6,7-dimethoxycoumarin in rat plasma and comparative analysis of its pharmacokinetics after intragastric administration of 6,7-dimethoxycoumarin and three different decoctions of yinchenhao tang. The plasma samples are deproteinated with acetonitrile. The components are separated on a Kromasil C18 column (250 x 4.6 mm, 5 microm,) with methanol-1% acetic acid solution-tetrahydrofuran (30:63:7, v/v/v) as the mobile phase, and the UV detector is set at 340 nm. Coumarin is used as an internal standard. The linear calibration curve is obtained in the concentration range of 25-2500 ng/mL. The lower limit of quantitation of the method is 25 ng/mL. The intra- and inter-day precision are less than 12%, and the accuracy determined with relative error ranges from -2.9% to 1.7%. The data obtained from rat plasma are analyzed with Topfit 2.0 Pharmacokinetic Software. With pharmacokinetic analysis, the main parameters after intragastric administration of 6,7-dimethoxycoumarin, Herba Artemisiae Scopariae decoction, Artemisiae Scopariae decoction plus Radix et Rhizoma Rhei and Fructus Gardeniae decoction, yinchenhao tang are as follows: T(1/2) is 0.29, 1.30, 1.07, and 1.75 h, AUC(-->t) is 919.1, 1215.0, 2035.3, and 2537.9 ng-h/mL, AU(0-->) is 928.5, 1325.9, 2094.4, and 2612.6 ng x h/ mL, respectively.

A study of the cardioprotective effect of breviscapine during hypoxia of cardiomyocytes.

Breviscapine is a flavonoid extracted from Erigeron breviscapus. Hand.-Mazz, and it has been reported that breviscapine can activate K+ channels and block Ca2+ channels. In this paper, we studied the cardioprotective effects of breviscapine on electrocardiogram (ECG) changes (ST-segment elevation), infarction size in dog heart subjected to myocardial infarction caused by left coronary artery ligation and lactate dehydrogenase (LDH) leakage, changes of intracellular free Ca2+ levels, apoptosis and necrosis in cultured neonatal rat cardiomyocytes subjected to hypoxia. Additionally, the effect of breviscapine on myocardial oxygen consumption was detected in dog myocardium in vitro. The results showed that breviscapine treatment (1 mg/kg, 2 mg/kg and 4 mg/kg) significantly reduced ST-segment elevation and infarction size in hearts subjected to myocardial infarction, that breviscapine treatment (14.29 microg/mL, 28.57 microg/mL and 57.14 microg/mL) significantly decreased oxygen consumption in myocardium, and that breviscapine treatment (5 microg/mL, 10 microg/mL and 20 microg/mL) significantly reduced LDH leakage, intracellular free Ca2+ levels, apoptosis and necrosis in cardiomyocytes subjected to hypoxia. In conclusion, the present study indicates that breviscapine is in favor of myocardial protection.