Network pharmacology and experimental validation methods to reveal the active compounds and hub targets of Curculigo orchioides Gaertn in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease that can lead to joint destruction and deformity. Curculigo orchioides Gaertn (CO) was previously revealed to play a significant role in RA treatment. However, the main active ingredients and molecular mechanisms of CO in regulating RA are still unclear. METHODS: The active ingredients of CO were obtained from the Traditional Chinese Medicine Systems Pharmacology database and published literature. The targets corresponding to these compounds and the targets linked to RA were collected from public databases. The "ingredient-target" and "protein-protein interaction" networks were constructed to screen the main active ingredients and hub targets of CO in the treatment of RA. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment assays were used to elucidate the potential pharmacological mechanism of CO in RA. Molecular docking was performed to detect the binding between the main active ingredients and hub targets. Collagen-induced arthritis rats were used to validate the hub targets of CO against RA. RESULTS: Network pharmacological topology analysis showed that caffeine, 2,4-dichloro-5-methoxy-3-methylphenol, curculigoside, orcinol glucoside, and orcin were the main active ingredients of CO, and matrix metalloproteinase 9 (MMP9), transcription factor AP-1 (JUN), prostaglandin-endoperoxide synthase 2 (PTGS2), brain-derived neurotrophic factor, and receptor-type tyrosine-protein phosphatase C were the hub targets of CO for RA treatment. Molecular docking revealed that curculigoside and orcinol glucoside had effective binding potential with MMP9, JUN, and PTGS2, respectively. In vivo experiments demonstrated that CO alleviated RA symptoms and inhibited the expression of MMP9, JUN, and PTGS2 proteins. CONCLUSIONS: Our study demonstrates the main active ingredients and potential targets of CO against RA, laying an experimental foundation for the development and application of CO as an anti-RA drug.

Decipher the pharmacological mechanisms of raw and wine-processed Curculigo orchioides Gaertn. on bone destruction in rheumatoid arthritis rats using metabolomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Curculigo orchioides Gaertn. (CO), a traditional Chinese herb recorded in Chinese Pharmacopoeia, can nourish kidney yang, strengthen bones, and dispell cold-dampness. Raw CO (rCO) and wine-processed CO (pCO), the main processed products of CO for clinical application, show differences in nourishing kidney yang and ameliorate osteoporosis. However, the difference in efficacy and mechanism of rCO and pCO on bone destruction in rheumatoid arthritis (RA) remain unclear. AIM OF THE STUDY: To compare the pharmacodynamics of rCO and pCO in the treatment of bone destruction in RA and to reveal the potential mechanism by which rCO and pCO exert effects by metabolomics approach. MATERIALS AND METHODS: Ultra-high performance liquid chromatography Q exactive mass spectrometry (UHPLC-Q-Exactive-MS) combined with multivariate data analysis was applied to identify the differential chemical components in rCO and pCO. Collagen-induced arthritis (CIA) rats were orally administrated with different doses of rCO and pCO for 4 weeks. The body weight, paw swelling, arthritis scores, serum inflammatory cytokines concentration, knee tumor necrosis factor (TNF)-α, interleukin (IL)-6 protein levels, and inflammatory cell infiltration were determined to investigate the effects of rCO and pCO on arthritic symptoms and inflammatory responses in CIA rats. The effects of rCO and pCO on bone destruction were assessed using safranin O-fast green and tartrate-resistant acid phosphatase (TRAP) staining, immunohistochemical analysis of osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) proteins, and micro-computed tomography (micro-CT) in rats. In addition, metabolomics was performed to explore the mechanism of rCO and pCO against bone destruction in RA. RESULTS: A total of 41 chemical constituents were identified in both rCO and pCO, 9 of which were screened out as discriminatory compounds. According to the pharmacodynamic assays, pCO exhibited a stronger effect than rCO in attenuating the severity of arthritis, reducing inflammation, and inhibiting bone destruction. The metabolomics results showed that pentose phosphate pathway was the key metabolic pathways regulated by rCO, while pCO regulated multiple metabolic pathways including phenylalanine metabolism pathways, phenylalanine, tyrosine and tryptophan biosynthesis, taurine and hypotaurine metabolism, and glycerophospholipid metabolism pathways. CONCLUSION: pCO displayed a better effect on alleviating bone destruction in RA was than rCO. This might be associated with that pCO can decrease inflammation in RA through regulating more metabolism pathways.

Machine learning-based assessment tool for imbalance and vestibular dysfunction with virtual reality rehabilitation system.

BACKGROUND AND OBJECTIVE: Dizziness is a major consequence of imbalance and vestibular dysfunction. Compared to surgery and drug treatments, balance training is non-invasive and more desired. However, training exercises are usually tedious and the assessment tool is insufficient to diagnose patient's severity rapidly. METHODS: An interactive virtual reality (VR) game-based rehabilitation program that adopted Cawthorne-Cooksey exercises, and a sensor-based measuring system were introduced. To verify the therapeutic effect, a clinical experiment with 48 patients and 36 normal subjects was conducted. Quantified balance indices were measured and analyzed by statistical tools and a Support Vector Machine (SVM) classifier. RESULTS: In terms of balance indices, patients who completed the training process are progressed and the difference between normal subjects and patients is obvious. CONCLUSIONS: Further analysis by SVM classifier show that the accuracy of recognizing the differences between patients and normal subject is feasible, and these results can be used to evaluate patients' severity and make rapid assessment.

Bioactivity-guided fractionation of physical fatigue-attenuating components from Rubus parvifolius L.

Alleviation of fatigue has been emerging as a serious issue that requires urgent attention. Health professionals and sports physiologists have been looking for active natural products and synthetic compounds to overcome fatigue in humans. This study was designed to define the anti-fatigue property of Rubus parvifolius L. (RPL) by characterization of active constituents using a mouse forced swimming test model. Four RPL fractions with different polarities containing anti-fatigue activity were sequentially isolated from the n-butanol RPL extract, followed by elution of 50% ethanol-water fraction from D101 macroporous resin chromatography to obtain nigaichigoside F1, suavissimoside R1 and coreanoside F1. Active constituents of the 50% ethanol-water eluate of RPL were total saponins. The fractions were examined based on the effect on weight-loaded swimming capacity of mice. Serum levels of urea nitrogen (SUN), triglyceride fatty acids (TG), lactate dehydrogenase (LDH), lactic acid (LA), ammonia and hepatic glycogen (HG) were also examined for potential mechanisms underlying the anti-fatigue effect of RPL extracts. During the experiment, two inflammatory markers, interleukin-6 (IL-6) and tumor necrosis factor (TNF-α) in serum, were measured. We found that total saponins from RPL possess potent capabilities to alleviate mouse fatigue induced by forced swimming and that nigaichigoside F1 was responsible for the pharmacological effect. The underlying mechanisms include delays of SUN and LA accumulation, a decrease in TG level by increasing fat consumption, increases in HG and LDH so that lactic acid accumulation and ammonia in the muscle were reduced, and suppression of increased immune activation and inflammatory cytokine production. Our findings will be helpful for functional identification of novel anti-fatigue components from natural medicinal herbs.

Characterization of the antibacterial activity and the chemical components of the volatile oil of the leaves of Rubus parvifolius L.

Rubus parvifolius L. (Rp) is a medicinal herb that possesses antibacterial activity. In this study, we extracted the volatile oil from the leaves of Rp to assess its antibacterial activity and analyze its chemical composition. A uniform distribution design was used to optimize the extraction procedure, which yielded 0.36% (w/w) of light yellowish oil from the water extract of Rp leaves. We found that the extracted oil effectively inhibited the growth of a wide range of Gram positive and negative bacteria, including Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumanii, Bacillus cloacae, and Klebsiella pneumoniae. We further analyzed the components contained in the hydro-distillated Rp volatile oil by gas chromatography-mass spectroscopy. Twenty nine compounds were identified, including 4-hydroxy-3-methoxystyrene (66%), 3,7,11,15-tetramethyl-2-hexadecen-1-ol (10%) and 4-tert-butylbenzoic acid (2%). Our results suggest that one or multiple constituents contained in Rp volatile oil may account for its antibacterial activity.