Total lignans from Vitex negundo seeds attenuate osteoarthritis and their main component vitedoin A alleviates osteoclast differentiation by suppressing ERK/NFATc1 signaling.

The seeds of Vitex negundo have been used for inflammation-related disease treatment in traditional medicine. This study focused on the anti-osteoarthritis (OA) effects of the total lignans of V. negundo seeds (TOV) in monosodium iodoacetate-induced osteoarthritis rats and its pharmacokinetic properties, as well as the effects and potential mechanism of its main components VN1 (6-hydroxy-4-(4-hydroxy-3-methoxy-phenyl)-3-hydro-xymethyl-7-methoxy-3,4-dihydro-2-naphthaldehydeb) and VN2 (vitedoin A) on receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages (BMMs). TOV significantly attenuated osteoarthritis, leading to an increase in pain thresholds, improvement of knee articular cartilages and chondrocytes loss, and decreased total joint scores and serum levels of TNF-α, interleukin-1ß (IL-1ß), and prostaglandin E2 (PGE2) in osteoarthritis rats. The half-time (T1/2 ) was 2.82 h and 1.33 h, and the bioavailability was 15.34%-21.89% and 16.29%-22.11%, for VN1 and VN2, respectively. VN2, rather than VN1, remarkably inhibited tartrate-resistant acid phosphatase (TRAP) activity, reduced the number of TRAP-positive multinuclear cells, diminished the formation of actin ring, and decreased mRNA levels of cathepsin K (CTSK), TRAP, nuclear factor of activated T cell 1 (NFATc1), and osteoclast-associated receptor, as well as downregulated protein levels of p-ERK (phosphorylated extracellular signal-regulated kinase), TRAP, CTSK and NFATc1 in BMMs. These findings suggest TOV has promising therapeutic potential for OA treatment and VN2, in particular, attenuates osteoclast differentiation by suppressing ERK/NFATc1 signaling and actin ring, mainly accounting for the anti-OA efficacy of TOV.

Molecular Basis of Prostate Cancer and Natural Products as Potential Chemotherapeutic and Chemopreventive Agents.

Prostate cancer is the second most common malignant cancer in males. It involves a complex process driven by diverse molecular pathways that closely related to the survival, apoptosis, metabolic and metastatic characteristics of aggressive cancer. Prostate cancer can be categorized into androgen dependent prostate cancer and castration-resistant prostate cancer and cure remains elusive due to the developed resistance of the disease. Natural compounds represent an extraordinary resource of structural scaffolds with high diversity that can offer promising chemical agents for making prostate cancer less devastating and curable. Herein, those natural compounds of different origins and structures with potential cytotoxicity and/or in vivo anti-tumor activities against prostate cancer are critically reviewed and summarized according to the cellular signaling pathways they interfere. Moreover, the anti-prostate cancer efficacy of many nutrients, medicinal plant extracts and Chinese medical formulations were presented, and the future prospects for the application of these compounds and extracts were discussed. Although the failure of conventional chemotherapy as well as involved serious side effects makes natural products ideal candidates for the treatment of prostate cancer, more investigations of preclinical and even clinical studies are necessary to make use of these medical substances reasonably. Therefore, the elucidation of structure-activity relationship and precise mechanism of action, identification of novel potential molecular targets, and optimization of drug combination are essential in natural medicine research and development.

Vitex Diterpenoids: Structural Diversity and Pharmacological Activity.

Plants of the genus Vitex (Verbenaceae) are mainly distributed throughout tropical and temperate regions, and many Vitex plants have been traditionally used in folk medicine. Plants of this genus are a rich source of diterpenoids, which not only displayed versatile structural diversity with potential chemotaxonomical significance but also exhibited a wide range of biological activities, mainly including in vitro cytotoxic, antiinflammatory, antimicrobial, hormone level-regulating and antiangiogenic activities. Recently, a series of bioactive diterpenoids, with interesting carbon skeletons, have been reported and gathered considerable interest. This article systematically reviewed diterpenoids isolated from the genus Vitex that appeared in the literature up to December 2018, critically highlighting their structural diversity and pharmacological activities. Up to now, a total of 154 diterpenoids with diverse structures have been isolated and identified from Vitex plants. The authors also summarized the reported structure-activity relationships of those well explored Vitex diterpenoids. Finally, the authors discussed the challenges and potential applications of these diterpenoids in the future.

Therapeutic effects of the total lignans from Vitex negundo seeds on collagen-induced arthritis in rats.

BACKGROUND: The seeds of Vitex negundo, with rich lignans metabolites, have been widely used as a traditional Chinese medicine and Ayurvedic herbal medicine for the treatment of rheumatism and joint inflammation. The total lignans of Vitex negundo seeds (TOV) were suggested to play an important role in the treatment of arthritis. PURPOSE: The aim of the study was designed to investigate the anti-arthritic effects of TOV on collagen-induced arthritis (CIA) in rats as well as its possible mechanisms. METHODS: TOV was prepared by combined macroporous resin and polyamide column chromatography, and constituents of TOV were analyzed by HPLC. CIA model in rats was established by immunization with chicken type II collagen and then the rats were intragastrically administrated with TOV for 30 days. Rat arthritis was evaluated by measurements of hind paw edema, arthritis index score, weight growth and indices of thymus and spleen, and by histological examination. Levels of serum MMP-2, MMP-3, MMP-9, IL-1ß, IL-6, IL-8, IL-10, IL-17A and TNF-α were also examined. In addition, the expression of COX-2, iNOS and IκB, p-IκB in synovial tissues was evaluated by western blotting. The analgesic and anti-inflammatory effects of TOV were also evaluated in acetic acid-induced writhing and xylene-induced ear edema in mice, respectively. In addition, acute toxicity test was employed to preliminarily assess the safety of TOV. RESULTS: TOV significantly inhibited the paw edema and decreased the arthritis index, with no influence on the body weight and the indices of thymus and spleen of CIA rats. Meanwhile, TOV dose-dependently reduced the infiltration of inflammatory cells, synovial hyperplasia and attenuated cartilage damage. Additionally, the serum levels of IL-1ß, IL-6, IL-8, IL-17A, TNF-α, MMP-3 and MMP-9 were markedly decreased, while the level of serum IL-10 was increased in TOV-treated rats. The significant reduction of the expression of COX-2, iNOS and p-IκB and the notable increase of IκB in synovial tissues were also observed in TOV-treated animals. TOV also significantly inhibited acetic acid-induced writhing and decreased xylene-induced ear edema in mice. Finally, the maximal tolerable dose (MTD) of TOV was determined to be 16.0 g/kg. CONCLUSION: These results suggest that TOV has significant anti-arthritic effects on collagen-induced arthritis in rats, which may be attributed to the inhibition of the levels of IL-1ß, IL-6, IL-8, IL-17A, TNF-α, MMP-3 and MMP-9, and the increase of IL-10 in serum as well as down-regulation of the protein expression of COX-2 and iNOS in synovial tissues via suppressing the phosphorylation and degradation of IκB. Due to its high efficacy and safety, TOV can be regarded as a promising drug candidate for rheumatoid arthritis treatment.

Cynanchum bungei Decne and its two related species for "Baishouwu": A review on traditional uses, phytochemistry, and pharmacological activities.

ETHNOPHARMACOLOGICAL RELEVANCE: Cynanchum bungei Decne. (CB) (Asclepiadaceae) and its two related species Cynanchum auriculatum Royle ex Wight. (CA) and Cynanchum wilfordii (Maxim.) Hemsl. (CW) are well known Chinese herbal medicines known by the name Baishouwu. Among them, CB has long been used for nourishing the kidney and liver, strengthening the bones and muscles, and regulating stomachache. However, to date, no comprehensive review on Baishouwu has been published. AIM OF THE REVIEW: This review aims to provide a comprehensive summary on traditional uses, phytochemistry, pharmacology, and toxicology of the three herbal components of Baishouwu with the ultimate objective of providing a guide for future scientific and therapeutic potential use of Baishouwu. MATERIAL AND METHODS: A literature search was undertaken on CB, CA and CW by analyzing the information from scientific databases (SciFinder, Pubmed, Elsevier, Google Scholar, Web of Science, and Baidu Scholar). Information was also gathered from local classic herbal literatures and conference papers on ethnopharmacology and the information provided in this review has been obtained from peer-reviewed papers. RESULTS: Comparative analysis of literature search indicate that ethnopharmacological use of CB was recorded in China, however, CA and CW have been used in China, Korea and Japan. To date, 151 chemical compounds have been isolated from these species, and the major chemical constituents have been revealed to be acetophenones, C21-steroids, terpenoids, and alkaloids. These compounds and extracts have been proven to exhibit significant pharmacological activities, including anti-tumor, anti-inflammatory, immunomodulatory, hypolipidemic, anti-obesity, hepatoprotective, antifungal, antiviral, anti-depressant, vasodilating and estrogenic activities. CONCLUSIONS: CB, CA and CW collectively known as Baishouwu are valuable medicinal herbs with multiple pharmacological activities. The traditional use for nourishing liver is closely associated with the hepatoprotective activity. The available literature performs that various of the activity of Baishouwu can be attributed to acetophenones and C21-steroids. It is high time that more efforts should be focused on the underlying mechanisms of their beneficial bioactivities and the structure activity relationship of the constituents, as well as their potential synergistic and antagonistic effects. The proper toxicology evaluation is crucial to guarantee the safety, efficacy, and eligibility for medical use. Further research on the comprehensive evaluation of medicinal quality and the understanding of multi-target network pharmacology of Baishouwu is in great request.

Sesquiterpenoids from Vitex pierreana.

A new germacrane sesquiterpenoid with an epoxy moiety, pierreanin A (1), and a pair of unique cyclobutyl-containing sesquiterpenoid diastereoisomers, pierreanins B and C (2 and 3), were isolated from the branches and leaves of Vitex pierreana, together with 2 known analogues, identified as germacrone (4) and epiprocurcumenol (5). The structures of all isolates were evaluated by detailed analyses of NMR, IR, and MS data. The absolute configurations of 1-3 were determined by comparison of the experimental ECD spectra with reported data of analogues containing the same chromophore. The ability of three new compounds to inhibit the growth of DU145 prostate cancer cells was also evaluated, as well as their inhibitory effects against the production of NO in LPS-stimulated RAW264.7 cells.