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Background: Iridoid glycosides (IGs), including monotropein (MON) and deacetyl asperulosidic acid (DA) as the main ingredients, are the major chemical components in Morinda officinalis How. (MO) root, possessing various pharmacological properties including anti-osteoporosis, anti-inflammation and anti-rheumatism activities.The aim of the present study was to further elucidate the pharmacological actions of MO by investigating the pharmacokinetics and tissue distribution of IGs in MO., Methods: An ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS) method was developed and validated for simultaneous determination of MON and DA levels in plasma and various tissues of Wistar rats. MON, DA and acetaminophen (ACE) as the internal standard (IS) were extracted from rat plasma and tissue samples by direct deproteinization with methanol. The rats were administered orally at 1650 mg/kg MO and 25, 50 and 100 mg/kg MO iridoid glycosides (MOIGs) or intravenously at MOIG 25 mg/kg for pharmacokinetic study of MON and DA. In addition, 100 mg/kg MOIG was administered orally for tissue distribution study of MON and DA. Non-compartmental pharmacokinetic profiles were constructed. Tissue distributions were calculated according to the validated methods., Results: Significant differences in the pharmacokinetic parameters were observed in male and female rats. The AUC 0-t , C max and bioavailability of MON and DA in female rats were higher than those in male rats. MON and DA mainly distributed in the intestine and stomach after oral administration, and noteworthily high concentrations of MON and DA were detected in the rat hypothalamus., Conclusion: The results of the present study may shed new lights on the biological behavior of MOIGs in vivo, help explain their pharmacological actions, and provide experimental clues for rational clinical use of these IGs extracted from the MO root.

Ethnopharmacological Relevance: The medicinal plant Morinda officinalisHow. (MO) and its root have long been used in traditional medicines in China and northeast Asia as tonics for nourishing the kidney, strengthening the bone and enhancing immunofunction in the treatment of impotence, osteoporosis, depression and inflammatory diseases such as rheumatoid arthritis and dermatitis., Aim of the Review: This review aims to sum up updated and comprehensive information about traditional usage, phytochemistry, pharmacology and toxicology of MO and provide insights into potential opportunities for future research and development of this plant., Methods: A bibliographic investigation was performed by analyzing the information available on MO in the internationally accepted scientific databases including Pubmed, Scopus and Web of Science, SciFinder, Google Scholar, Yahoo, Ph.D. and M.Sc. dissertations in Chinese. Information was also obtained from some local and foreign books on ethnobotany and ethnomedicines., Results: The literature supported the ethnomedicinal uses of MO as recorded in China for various purposes. The ethnomedical uses of MO have been recorded in many regions of China. More than 100 chemical compounds have been isolated from this plant, and the major constituents have been found to be polysaccharides, oligosaccharides, anthraquinones and iridoid glycosides. Crude extracts and pure compounds of this plant are used as effective agents in the treatment of depression, osteoporosis, fatigue, rheumatoid arthritis, and infertility due to their anti-depressant, anti-osteoporosis, pro-fertility, anti-radiation, anti-Alzheimer disease, anti-rheumatoid, anti-fatigue, anti-aging, cardiovascularprotective, anti-oxidation, immune-regulatory, and anti-inflammatory activities. Pharmacokinetic studies have demonstrated that the main components of MO including monotropein and deacetyl asperulosidic acid are distributed in various organs and tissues. The investigation on acute toxicity and genotoxicity indicated that MO is nontoxic. There have no reports on significant adverse effect at a normal dose in clinical application, but MO at dose of more than 1000mg/kg may cause irritability, insomnia and unpleasant sensations in individual cases., Conclusion: MO has emerged as a good source of traditional medicines. Some uses of this plant in traditional medicines have been validated by pharmacological investigations. However, the molecular mechanism, structure-activity relationship, and potential synergistic and antagonistic effects of its multi-components such as polysaccharides, oligosaccharides, anthraquinones and iridoid glycosides need to be further elucidated, and the structural feature of polysaccharides also need to be further clarified. Sophisticated analytical technologies should be developed to comprehensively evaluate the quality of MO based on HPLC-fingerprint and content determination of the active constituents, knowing that these investigations will help further utilize this plant., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Osteoporosis is a chronic epidemic which can leads to enhanced bone fragility and consequent an increase in fracture risk. Traditional Chinese medicine (TCM) formulas have a long history of use in the prevention and treatment of osteoporosis. Antiosteoporotic TCM formulas have conspicuous advantage over single drugs. Systematic data mining of the existing antiosteoporotic TCM formulas database can certainly help the drug discovery processes and help the identification of safe candidates with synergistic formulations. In this review, the authors summarize the clinical use and animal experiments of TCM formulas and their mechanism of action, and discuss the potential antiosteoporotic activity and the active constituents of commonly used herbs in TCM formulas for the therapy of osteoporosis., Materials and Methods: The literature was searched from Medline, Pubmed, ScienceDirect, Spring Link, Web of Science, CNKI and VIP database from 1989 to 2015, and also collected from Chinese traditional books and Chinese Pharmacopoeia with key words such as osteoporosis, osteoblast, osteoclast, traditional Chinese medicine formulas to identify studies on the antiosteoporotic effects of TCM formulas, herbs and chemical constituents, and also their possible mechanisms., Results: Thirty-three TCM formulas were commonly used to treat osteoporosis, and showed significant antiosteoporotic effects in human and animal. The herb medicines and their chemical constituents in TCM formulas were summarized, the pharmacological effects and chemical constituents of commonly used herbs in TCM formulas were described in detail. The action mechanisms of TCM formulas and their chemical constituents were described. Finally, the implication for the discovery of antiosteoporotic leads and combinatory ingredients from TCM formulas were prospectively discussed., Conclusions: Clinical practice and animal experiments indicate that TCM formulas provide a definite therapeutic effect on osteoporosis. The active constituents in TCM formulas are diverse in chemical structure, and include flavonoids, lignans, saponins and iridoid glycosides. Antiosteoporotic mechanism of TCM formulas and herbs involves multi regulatory pathways, such as Wnt/β-catenin, BMP/Smad, MAPK pathway and RANKL/OPG system. Phytochemicals from TCM formulas and their compositional herb medicines offer great potential for the development of novel antiosteoporotic drugs. The active ingredients in TCM formulas can be developed in combination as potent drugs, which may exhibit better antiosteoporotic effects compared to the individual compound., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Significance: Icariin (I), ferulic acid (F) and timosaponin B II (T) derived respectively from the leaf of Epimedium brevicornu Maxim (EBM, Berberidaceae), rhizome of Anemarrhena asphodeloides Bunge (AAB, Liliaceae) and root of Angelica sinensis (Oliv.) Diels (ASD, Umbelliferae) are included in several traditional Chinese medicine (TCM) formulas for the treatment of osteoporosis. In addition, the medicinal materials and chemical constituents in many traditional Chinese formulas have been shown to have potential synergistic, additive and antagonistic effects., Aim of Study: To explore the action mechanism and interactions between I, T and F as bone anabolic ingredients on osteoblasts, and fully understand their action mechanism and rationality of the formula design., Materials and Methods: An osteoporotic model was established in bilaterally ovariectomized mice. Bone mineral density (BMD), bone mineral content (BMC) and serum biochemical parameters including alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRAP), osteoprotegerin (OPG) and deoxypyridinoline cross-links (DPD) were measured to evaluate the effects of I, T or F alone and their combinations on osteoporotic mice. UMR-106 osteoblastic cells and primary osteoblasts in neonatal rat calvarias were used to evaluate the osteogenesis effect. The immunohistochemical method and Western-blot analysis were used to detect the expression of critical proteins in the process of proliferation and differentiation of osteoblasts., Results: IFT combinations enhanced the therapeutic effect without increasing the adverse effects on osteoporotic mice, synergistically increased the osteoblast proliferation, ALP activity and mineralized nodule formation, and promoted the expression of bone matrix by regulating BMP and Wnt/β-catenin signaling pathways in osteoblasts., Conclusion: IFT combinations reinforced the therapeutic effect on osteoporosis by modulating multi-signaling pathways and action targets., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

There is an increasing interest in phytoestrogens due to their potential medical usage in hormone replacement therapy (HRT). The present study was designed to investigate the in vitro effects of estrogen-like activities of two widespread coumarins, osthole and imperatorin, using the MCF-7 cell proliferation assay and their alkaline phosphatase (ALP) activities in osteoblasts Saos-2 cells. The two compounds were found to strongly stimulate the proliferation of MCF-7 cells. The estrogen receptor-regulated ERα, progesterone receptor (PR) and PS2 mRNA levels were increased by treatment with osthole and imperatorin. All these effects were significantly inhibited by the specific estrogen receptor antagonist ICI182, 780. Cell cycle analysis revealed that their proliferation stimulatory effect was associated with a marked increase in the number of MCF-7 cells in S phase, which was similar to that observed with estradiol. It was also observed that they significantly increased ALP activity, which was reversed by ICI182,780. These results suggested that osthole and imperatorin could stimulate osteoblastic activity by displaying estrogenic properties or through the ER pathway. In conclusion, osthole and imperatorin may represent new pharmacological tools for the treatment of osteoporosis., (Copyright © 2016 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Traditional Chinese medicine (TCM) is a theoretical based system and is completely different from western medicine and states that numerous diseases, especially chronic diseases, are cured or relieved. "Zheng" (syndrome) is a summarization of the pathological changes which take place during the different stages of the development of a disease, including its location, cause and nature as well as the state of both Xie-qi (pathogenic factors) and Zheng-qi (healthy energy). Compared to a single symptom, syndrome can demonstrate the nature of a disease more extensively, completely and correctly. However, it is difficult to compare "Zheng" to the western medicine theory, which is based on scientific evidence for the diagnosis and treatment of a specific disease. Estrogen deficiency is a major pathogenetic factor in bone loss after menopause and oophorectomy with the subsequent risk of developing osteoporosis. According to TCM theory, the kidney stores essence and this can transform into bone marrow to nourish the bones, strenghthen the skeleton by promoting growth and repair. The kidney deficiency can decrease the estrogen level adjusted by the gonadal axis, causing osteoporosis. Traditional Chinese medicines tonifying the kidney can significantly enhance the level of estrogen to alleviate osteoporosis. In combination with other evidence, we further deduce that the syndrome as defined within TCM has a similar pathological mechanism to that defined by western medicine. If TCM theory is to be understood and accepted, and further fused with the western medicine theory, the micro pathological basis of TCM syndrome must be investigated extensively, which will lead to bridging the two theories together. The fusion of TCM with western medicine will pay more attention to analyzing the common nature and difference of disease and syndrome. This paper reviews the way forward for new translational advances.

The fruits of Xanthium strumarium L. (Asteraceae) have been used extensively in China for treatment of various diseases such as allergic rhinitis (AR), tympanitis, urticaria and arthritis or ozena. This study was designed to systemically investigate the effects of the caffeoylxanthiazonoside (CXT) isolated from fruits of X. strumarium on AR in rodent animals. Animals were orally administered with CXT. Anti-allergic activity of CXT was evaluated by passive cutaneous anaphylaxis test (PCA); acetic acid-induced writhing tests were used to evaluate the analgesic effects of CXT; acetic acid-induced vascular permeability tests were performed to evaluate anti-inflammatory effect of CXT. Then, the model AR in rats was established to evaluate the effects of CXT on AR with the following tests: the sneezing and nasal scratching frequencies, IgE level in serum, and histopathological examinations. Our results demonstrated that CXT had favorable anti-allergic, anti-inflammatory and analgesic effects. Additionally, we found that CXT was helpful to ameliorate the nasal symptoms and to down-regulate IgE levels in AR rats. Thus, we suggested that CXT can be treated as a candidate for treating AR., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Er-Xian Decoction (EXD) has been used for the treatment of osteoporosis disorders, menopausal syndrome, and other aging diseases in the Chinese traditional healthcare system. However, the targets and mechanism of action have not been clarified. This study was designed to investigate the effects and possible target proteins of EXD on osteoblastic UMR-106 cells and osteoclasts induced from RAW264.7 cells using the proteomic analysis technique. We found that EXD at a concentration of 50-200 microg/mL significantly enhanced osteoblastic UMR-106 cell proliferation, alkaline phosphatase (ALP) activity and formation of bone nodules, and decreased tartrate-resistant acid phosphatase (TRAP) activity and the bone resorption action of osteoclasts induced from RAW 264.7 cells. In EXD-treated osteoblasts, there were increases in the expression of heat-shock protein 1, high mobility group protein (Hmgb1), acidic ribosomal phosphoprotein P0, histone 2, carbonyl reductase 1, ATP synthase, aldolase A, and Rho GDP dissociation inhibitor (GDI)-alpha; and reduction in the expression of carbonic anhydrase 3, prohibitin, hemiferrin, far upstream element (FUSE)-binding protein. In EXD-treated osteoclasts, there were increases in the expression of vimentin, protein disulfide isomerase associated 3 and alpha-fetoprotein; and reduction in the expression of calnexin. These results indicated that EXD modulates bone metabolism through regulation of osteoblastic proliferation, apoptosis, and cell activation, and osteoclastic protein folding and aggregation.

Background: Bone formation and resorption is a balanced and continuous process. When osteoclastic bone resorption exceeds osteoblastic bone formation, bone density decreases, which can lead to osteoporosis. Er-Zhi-Wan (EZW), a famous traditional Chinese formulation, has been developed as a restorative formula for hundreds of years, which contains two herbs viz. Herba Ecliptae and Fructus Ligustri Lucidi. EZW is widely used to prevent and treat various kidney diseases for its actions of nourishing the kidney yin and strengthening tendon and bone. The objective of current study was to investigate the effects of EZW on proliferation and differentiation of osteoblasts and osteoclasts in vitro using a serum pharmacological method., Methods: The rats were orally administered EZW (0.45, 1.8 and 7.2gkg(-1)) for total seven doses and twice a day, and then the different concentrations of EZW-containing serum were prepared. The proliferation of primary cultural osteoblasts, UMR106 and RAW264.7 cells and differentiation of osteoclasts were determined after these cells were treated with different concentrations of EZW-containing serum for a period of time., Results: The serum from rats treated with EZW for 4 days did not facilitate proliferation of primary cultural osteoblasts and UMR106 cells, but evidently inhibited both proliferation of RAW264.7 cells and differentiation of osteoclasts from RAW264.7 cells induced by receptor activator of nuclear factor kappaB ligand (RANK-L) and macrophage-colony stimulating factor (M-CSF)., Conclusion: Antiosteoporotic activity of EZW is carried out mainly via restraint of osteoclastic bone resorption, which is in accordance with the traditional Chinese medicine theory on nourishing the kidney yin. Therefore EZW has favorable potency to develop a new anti-osteoporotic agent in clinic.

The antiosteoporotic effect of a herbal formula, Er-Xian Decoction (EXD), in ovariectomized (OVX) rats model of osteoporosis was investigated. The rats were divided into Sham and OVX groups. The OVX rats were further sub-divided into four groups administered orally with water, nylestriol (1 mg/kg, weekly) or EXD (300, 600 mg/kg, daily) for 12 weeks. In OVX rats, the increases of body weight, serum BGP and ALP were significantly decreased by EXD treatment. In OVX rats, atrophy of uterus and descent of BMD were suppressed by treatment with EXD and nylestriol. In addition, EXD completely corrected the decreased concentration of calcium, phosphorus, and estradiol in serum observed in OVX rats. EXD also significantly increased biomechanical strength comparable to the Sham group. This was also confirmed by histological results that showed its protective action. The findings assessed on the basis of biochemical, bone mineral density, biomechanical, and histopathological parameters strongly suggested that EXD had a definite antiosteoporotic effect, which is similar to estrogen.

Objective: To investigate the prevention effect of aqueous extract of Epimedii sagittatum (ESE) on ovariectomy-induced (OVX) bone loss in rats., Methods: Rats were divided into sham-operated and OVX groups. The OVX rats were divided into four groups treated with distilled water, 17beta-estradiol (1 mg/kg, ig) and ESE (0.5 and 1 g/kg, ig) for 11 weeks. Serum calcium, phosphorus, estradiol, bone gla protein concentrations and serum alkaline phosphatase activity were measured. Bone density was assayed by dual-energy X-ray absorptiometry. The undecalcified longitudinal proximal tibial metaphysical sections were cut and stained for the bone histomorphometric analysis., Results: In OVX rats, alkaline phosphatase activity in serum was markedly increased by ESE treatment, which had no obvious influence on the body weight. Meanwhile, atrophy of uterus and descent of bone mineral density were suppressed by ESE treatment. In addition, ESE completely corrected the decreased concentrations of calcium and E2 in serum observed in OVX rats. Histological results also showed ESE prevented the increases in trabecular separation (Tb.Sp) in OVX rats whereas it did not alter trabecular thickness (Tb.Th) and trabecular number (Tb.N) in OVX rats. Moreover, ESE had remarkable effect on bone formation rate with bone volume as referent (BFR/BV) and bone formation rate with bone surface as referent (BFR/BS)., Conclusion: The findings assessed on the basis of biochemical test, bone mineral density and histomorphometric parameters show that aqueous extract of Epimedii sagittatum has a definite antiosteoporotic effect and can prevent the OVX-induced bone loss in rats.