Bajitianwan formula extract ameliorates bone loss induced by iron overload via activating RAGE/PI3K/AKT pathway based on network pharmacology and transcriptomic analysis.

Osteoporosis (OP) is closely related to iron overload. Bajitianwan (BJTW) is a traditional Chinese medicine formulation used for treating senile diseases such as dementia and osteoporosis. Modern pharmacological researches have found that BJTW has beneficial effect on bone loss and memory impairment in aging rats. This paper aimed to explore the role and mechanism of BJTW in ameliorating iron overload-induced bone loss. Furthermore, BJTW effectively improved the bone micro-structure of the femur in mice, and altered bone metabolism biomarkers alkaline phosphatase (ALP) and osteocalcin (OCN) in serum, as well as oxidative indexes superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) glutathione (GSH) and malondialdehyde (MDA) in liver. As for network pharmacology, 73 components collected from BJTW regulated 99 common targets merged in the BJTW and OP. The results of RNA-seq indicated that there were 418 potential targets in BJTW low dose group (BJTW-L) and 347 potential targets in BJTW high dose group (BJTW-H). Intriguingly, both PI3K-AKT signaling pathway and the AGEs-RAGE signaling pathway were contained in the KEGG pathways enrichment results of network pharmacology and transcriptomics, which were considered as the potential mechanism. Additionally, we verified that BJTW regulated the expression of related proteins in RAGE/PI3K-AKT pathways in MC3T3-E1 cells. In summary, BJTW has potent effect on protecting against iron overload-induced OP, and its mechanism may be related to the activation of the RAGE/PI3K-AKT signaling pathways.

A review on ethnopharmacology, phytochemistry, pharmacology and potential uses of Portulaca oleracea L.

ETHNOPHARMACOLOGICAL RELEVANCE: Portulaca oleracea L. (PO), popularly known as purslane, has been documented in ethnopharmacology in various countries and regions. Traditional application records indicated that PO might be used extensively to treat the common cold, dysentery, urinary tract infections, coughing, eye infections, skin problems, gynecological diseases, and pediatric illnesses. AIM OF THE REVIEW: This paper includes a systematic review of the traditional usage, phytochemicals, pharmacological activity, and potential uses of PO to provide an overview of the research for further exploitation of PO resources. MATERIALS AND METHODS: This article uses "Portulaca oleracea L." and "purslane" as the keywords and collects relevant information on PO from different databases, including PubMed, Web of Science, Springer, Science Direct, ACS, Wiley, CNKI, Baidu Scholar, Google Scholar, and ancient meteria medica. RESULTS: PO is a member of the Portulacaceae family and is grown worldwide. Traditional Chinese medicine believes that purslane has the effect of improving eyesight, eliminating evil qi, quenching thirst, purgation, diuresis, hemostasis, regulating qi, promoting hair growth, detoxifying, and avoiding epidemic qi. Recent phytochemical investigations have shown that PO is a rich source of flavonoids, homoisoflavonoids, alkaloids, organic acids, esters, lignans, terpenoids, catecholamines, sterols, and cerebrosides. The purslane extracts or compounds have exhibited numerous biological activities such as anti-inflammatory, immunomodulatory, antimicrobial, antiviral, antioxidant, anticancer, renoprotective, hepatoprotective, gastroprotective, metabolic, muscle relaxant, anti-asthmatic and anti-osteoporosis properties. The significant omega-3 fatty acids, vital amino acids, minerals, and vitamins found in purslane also provide nutritional benefits. Purslane as a food/feed additive in the food industry and animal husbandry has caused concern. Its global wide distribution and tolerance to abiotic stress characteristics make it in the future sustainable development of agriculture a certain position. CONCLUSIONS: Based on traditional usage, phytochemicals, and pharmacological activity, PO is a potential medicinal and edible plant with diverse pharmacological effects. Due to purslane's various advantages, it may have vast application potential in the food and pharmaceutical industries and animal husbandry.

Traditional Chinese Medicine in Osteoporosis Intervention and the Related Regulatory Mechanism of Gut Microbiome.

The gut microbiome (GM) has become a crucial factor that can affect the progression of osteoporosis. A number of studies have demonstrated the impact of Traditional Chinese Medicine (TCM) on GM and bone metabolism. In this review, we summarize the potential mechanisms of the relationship between osteoporosis and GM disorder and introduce several natural Chinese medicines that exert anti-osteoporosis effects by modulating the GM. It is underlined that, through the provision of the microbial associated molecular pattern (MAMP), the GM causes inflammatory reactions and alterations in the Treg-Th17 balance and ultimately leads to changes in bone mass. Serotonin and many hormones, especially estrogen, may play a crucial role in the interaction of the GM with bone metabolism. Additionally, the GM may affect the absorption of specific nutrients in the intestine, particularly minerals like calcium, magnesium, and phosphorus. Several natural Chinese herbs, such as Sambucus Williamsii, Achyranthes bidentata Blume, Pleurotus ostreatus and Ganoderma lucidum mushrooms, Pueraria Lobata, and Agaricus blazei Murill have exhibited anti-osteoporosis effects through regulating the distribution and metabolism of the GM. These herbs may increase the abundance of Firmicutes, decrease the abundance of Bacteroides, promote the GM to produce more SCFAs, modulate the immune response caused by harmful bacteria, and increase the proportion of Treg-Th17 to indirectly affect bone metabolism. Moreover, gut-derived 5-HT is an important target for TCM to prevent osteoporosis via the gut-bone axis. Puerarin could prevent osteoporosis by improving intestinal mucosal integrity and decrease systemic inflammation caused by estrogen deficiency.

Humulus lupulus L. Extract Protects against Senior Osteoporosis through Inhibiting Amyloid ß Deposition and Oxidative Stress in APP/PS1 Mutated Transgenic Mice and Osteoblasts

As aging progresses, ß-amyloid (Aß) deposition and the resulting oxidative damage are key causes of aging diseases such as senior osteoporosis (SOP). Humulus lupulus L. (hops) is an important medicinal plant widely used in the food, beverage and pharmaceutical industries due to its strong antioxidant ability. In this study, APP/PS1 mutated transgenic mice and Aß-injured osteoblasts were used to evaluate the protective effects of hops extracts (HLE) on SOP. Mice learning and memory levels were assessed by the Morris water maze. Mice femurs were prepared for bone micro-structures and immunohistochemistry experiments. The deposition of Aß in the hippocampus, cortex and femurs were determined by Congo red staining. Moreover, protein expressions related to antioxidant pathways were evaluated by Western blotting. It was found that HLE markedly improved learning abilities and ameliorated memory impairment of APP/PS1 mice, as well as regulated antioxidant enzymes and bone metabolism proteins in mice serum. Micro-CT tests indicated that HLE enhanced BMD and improved micro-architectural parameters of mice femur. More importantly, it was discovered that HLE significantly reduced Aß deposition both in the brain and femur. Further in vitro results showed HLE increased the bone mineralization nodule and reduced the ROS level of Aß-injured osteoblasts. Additionally, HLE increased the expression of antioxidant related proteins Nrf2, HO-1, NQO1, FoxO1 and SOD-2. These results indicated that Humulus lupulus L. extract could protect against senior osteoporosis through inhibiting Aß deposition and oxidative stress, which provides a reference for the clinical application of hops in the prevention and treatment of SOP.

Traditional Chinese Medicine as a Promising Strategy for the Treatment of Alzheimer's Disease Complicated With Osteoporosis.

Alzheimer's disease (AD) and osteoporosis (OP) are progressive degenerative diseases caused by multiple factors, placing a huge burden on the world. Much evidence indicates that OP is a common complication in AD patients. In addition, there is also evidence to show that patients with OP have a higher risk of AD than those without OP. This suggests that the association between the two diseases may be due to a pathophysiological link rather than one disease causing the other. Several in vitro and in vivo studies have also proved their common pathogenesis. Based on the theory of traditional Chinese medicine, some classic and specific natural Chinese medicines are widely used to effectively treat AD and OP. Current evidence also shows that these treatments can ameliorate both brain damage and bone metabolism disorder and further alleviate AD complicated with OP. These valuable therapies might provide effective and safe alternatives to major pharmacological strategies.

Hops extract and xanthohumol ameliorate bone loss induced by iron overload via activating Akt/GSK3ß/Nrf2 pathway.

INTRODUCTION: Osteoporosis is closely related to iron metabolism. This study aimed to investigate whether hops extract (HLE) and its active component xanthohumol (XAN) could ameliorate bone loss caused by iron overload, and explored its potential mechanism. MATERIALS AND METHODS: Iron overload mice induced by iron dextran (ID) were used in vivo, and were treated with HLE and XAN for 3 months. Bone micro-structure and bone morphology parameters were determined by Micro-CT and TRAP staining. Bone metabolism markers and oxidation indexes in serum and bone tissue were evaluated. For in vitro experiment, bone formation indexes were determined. Moreover, the expression of key proteins in protein kinase B (Akt)/glycogen synthetase kinase 3ß (GSK3ß)/nuclear factor E2-related (Nrf2) pathway was evaluated by Western blotting. RESULTS: HLE and XAN effectively improved the bone micro-structure of the femur in mice, altered bone metabolism biomarkers, and regulated the expression of proteins related to bone metabolism. Additionally, they significantly promoted cell proliferation, runt-related gene 2 (Runx2) expression, and increased ALP activity in ID-induced osteoblasts. Moreover, HLE and XAN markedly inhibited the increase of oxidative stress caused by iron overload in vivo and in vitro. Further studies showed that they significantly up-regulated the expression of p-Akt, p-GSK3ß, nuclear-Nrf2, NAD(P)H: quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1) in ID-induced osteoblasts. CONCLUSION: These findings indicated hops and xanthohumol could ameliorate bone loss induced by iron overload via activating Akt/GSK3ß/Nrf2 pathway, which brought up a novel sight for senile osteoporosis therapy.

Xanthohumol ameliorates memory impairment and reduces the deposition of ß-amyloid in APP/PS1 mice via regulating the mTOR/LC3II and Bax/Bcl-2 signalling pathways.

OBJECTIVES: Xanthohumol (XAN) is a unique component of Humulus lupulus L. and is known for its diverse biological activities. In this study, we investigated whether Xanthohumol could ameliorate memory impairment of APP/PS1 mice, and explored its potential mechanism of action. METHODS: APP/PS1 mice were used for in vivo test and were treated with N-acetylcysteine and Xanthohumol for 2 months. Learning and memory levels were evaluated by the Morris water maze. Inflammatory and oxidative markers in serum and hippocampus and the deposition of Aß in the hippocampus were determined. Moreover, the expression of autophagy and apoptosis proteins was also evaluated by western blot. KEY FINDINGS: Xanthohumol significantly reduced the latency and increased the residence time of mice in the target quadrant. Additionally, Xanthohumol increased superoxide dismutase level and reduced Interleukin-6 and Interleukin-1ß levels both in serum and hippocampus. Xanthohumol also significantly reduced Aß deposition in the hippocampus and activated autophagy and anti-apoptotic signals. CONCLUSIONS: Xanthohumol effectively ameliorates memory impairment of APP/PS1 mice by activating mTOR/LC3 and Bax/Bcl-2 signalling pathways, which provides new insight into the neuroprotective effects of Xanthohumol.

Humulus lupulus L. Extract Prevents Ovariectomy-Induced Osteoporosis in Mice and Regulates Activities of Osteoblasts and Osteoclasts.

OBJECTIVE: To systematically evaluate the protective effects of Humulus lupulus L. extract (HLE) on osteoporosis mice. METHODS: In vivo experiment, a total of 35 12-week-old female ICR mice were equally divided into 5 groups: the sham control group (sham); the ovariectomy with vehicle group (OVX); the OVX with estradiol valerate [EV, 0.2 mg/(kg•d)] the OVX with low- or high-dose HLE groups [HLE, 1 g/(kg•d) and 3 g/(kg•d)], 7 in each group. Treatment began 1 week after the ovariectomized surgery and lasted for 12 weeks. Bone mass and trabecular bone mircoarchitecture were evaluated by micro computed tomography, and bone turnover markers in serum were evaluated using enzyme-linked immunosorbent assay (ELISA) kits. In vitro experiment, osteoblasts and osteoclasts were treated with HLE at doses of 0, 4, 20 and 100 µg/mL. Biomarkers for bone formation in osteoblasts and bone resorption in osteoclasts were analyzed. RESULTS: Compared with the OVX group, HLE exerted bone protective effects by the increase of estradiol (P<0.05), the improvement of cancellous bone structure, bone mineral density (P<0.01) and the reduction of serum alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRAP), bone gla-protein, c-terminal telopeptides of type I collagen (CTX-I) and deoxypyridinoline levels (P<0.01 for all). In vitro experiment, compared with the control group, HLE at 20 µg/mL promoted the cell proliferation (P<0.01), and increased the expression of bone morphogenetic protein-2 and osteopontin levels in osteoblasts (both P<0.05). HLE at 100 µg/mL increased the osteoblastic ALP activities, and HLE at all dose enhanced the extracellular matrix mineralization (both P<0.01). Furthermore, compared with the control group, HLE at 20 µg/mL and 100 µg/mL inhibited osteoclastic TRAP activity (P<0.01), and reduced the expression of matrix metalloproteinase-9 and cathepsin K (both P<0.05). CONCLUSION: HLE may protect against bone loss, and have potentials in the treatment of osteoporosis.

Piper sarmentosum Roxb.: A review on its botany, traditional uses, phytochemistry, and pharmacological activities.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper sarmentosum Roxb. (Piperaceae) is a traditional medicinal plant widely distributed in India, Malaysia, Thailand, and the southeastern coastal areas of China including Fujian, Guangdong, and Guizhou. It has been used for centuries for the treatment of wind-cold cough, fever, rheumatism arthralgia, diarrhea dysentery, postpartum foot swelling, stomachache, toothache, diabetes, and traumatic injury. AIMS OF THE REVIEW: To critically anayze the literature for the botany, traditional uses, phytochemistry, pharmacology, toxicity, and clinical trials of P. sarmentosum in order to provide a scientific consensus for further research and discovery of potential candidate drugs. MATERIALS AND METHODS: The contents of this review were sourced from electronic databases including PubMed, SciFinder, Web of Science, Science Direct, Elsevier, Google Scholar, Chinese Knowledge On frastructure (CNKI), Wanfang, Chinese Scientific and Technological Periodical Database (VIP), Chinese Biomedical Database (CBM), Cochrane Controlled register of Clinical Trials, Clinical Trials. gov, and Chinese Clinical Trial Registry. Chinese medicine books published over the years were used to elucidate the traditional uses of P. sarmentosum and additional information was also collected from Yao Zhi website (https://db.yaozh.com/). RESULTS: Phytochemical analyses of the chemical constituents of P. sarmentosum include essential oil, alkaloids, flavonoids, lignans, and steroids. The literature supports the ethnomedicinal uses of P. sarmentosum for the treatment of cold, gastritis, and rheumatoid joint pain, and further confirms its relatively new pharmacological activities, including anti-inflammatory, antineoplastic, and antipyretic activities. Other biological roles such as anti-osteoporosis, antibacterial, antidepressant, anti-atherosclerotic, and hypoglycemic activities have also been reported. However, the methodologies employed in individual studies are limited. CONCLUSIONS: There is convincing evidence from both in vitro and in vivo studies supporting the traditional use of P. sarmentosum and it is imperative that natural bioactive compounds are examined further. More efforts should be focused on the pharmacodynamic constituents of P. sarmentosum to provide practical basis for quality control, and additional studies are needed to understand the mechanism of their action. Further studies on the comprehensive evaluation of medicinal quality and understandings of serum chemistry, multi-target network pharmacology, and molecular docking technology of P. sarmentosum are of great importance and should be considered.

Bajitianwan attenuates D-galactose-induced memory impairment and bone loss through suppression of oxidative stress in aging rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: Osteoporosis and Alzheimer's disease (AD) are both senile diseases, which are closely related to oxidative stress. Bajitianwan (BJTW) is a classic Chinese formulation consisting of seven herbal drugs: the root of Morinda officinalis F.C.How., root and rhizome of Acorus tatarinowii Schott, the root bark of Lycium chinense Mill., the sclerotium of Poria cocos (Schw.) Wolf, the root of Polygala tenuifolia Willd., sclerotium with host wood of Poria cocos (Schw.) Wolf and root and rhizome of Panax ginseng C. A. Mey. BJTW has been used for the treatment of osteoporosis and AD for hundreds of years. AIM OF THE STUDY: This study aimed to investigate the protective effects of BJTW in the amelioration of memory impairment and bone loss induced by D-galactose and to explore the underlying mechanism. MATERIALS AND METHODS: The aging model was established in male Wistar rats by subcutaneous injection of D-galactose (100 mg/kg), and the rats were treated with huperzine-A, alendronate sodium, or the aqueous extract of BJTW for 4 months. Cognitive performance was evaluated with the Morris water maze. Rat femurs were scanned using microcomputed tomography to obtain three-dimensional imagery of bone microstructure. The impact of D-galactose on the expression of Forkhead box O1 and superoxide dismutase 2 in femur tissue was also evaluated. RESULTS: For the model group, BJTW treatment significantly reduced the latency time for finding the target platform in the directional swimming test and increased time spent swimming in the target quadrant with the probe test. Additionally, BJTW treatment alleviated D-galactose-induced bone loss through regulation of levels of alkaline phosphatase, osteocalcin, osteoprotegerin, and receptor activator of nuclear factor kappa B ligand. Furthermore, BJTW treatment increased catalase and glutathione peroxidase levels in serum, reduced malondialdehyde content in hippocampus, and upregulated expression of Forkhead O1, which upregulated superoxide dismutase 2 in the femur. CONCLUSIONS: BJTW had positive effects on age-related memory impairments and bone loss. It may be a promising antioxidant candidate for treatment of Alzheimer's disease and osteoporosis.

Iridoid glycosides from Morinda officinalis How. exert anti-inflammatory and anti-arthritic effects through inactivating MAPK and NF-κB signaling pathways.

BACKGROUND: The root of Morinda officinalis How. (MO, the family of Rubiaceae) has long been used to treat inflammatory diseases in China and other eastern Asian countries, and iridoid glycosides extracted from MO (MOIG) are believed to contribute to this anti-inflammatory effect. However, the mechanism underlying the anti-inflammatory and anti-arthritic activities of MOIG has not been elucidated. The aim of the present study was to determine how MOIG exerted anti-inflammatory and anti-arthritic effects in vivo and in RAW 264.7 macrophages. METHODS: MOIG were enriched by XDA-1 macroporous resin. The maximum feasible dose method was adopted to evaluate its acute toxicity. The analgesic effect of MOIG was evaluated by acetic acid writhing test and the anti-inflammatory effect was evaluated by cotton-pellet granuloma test in rats and air pouch granuloma test in mice. The anti-arthritic effect was evaluated by establishing an adjuvant arthritis model induced by Complete Freund's Adjuvant (CFA). The viability of the cultured RAW 264.7 macrophages was assessed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. The anti-inflammatory activity was evaluated by measuring NO, IL-1ß, IL-6 and TNF-α levels in LPS-stimulated RAW 264.7 cells. The protein level of inflammatory responsive genes was evaluated by Western blot analysis. RESULTS: MOIG had no significant toxicity at maximum feasible dose of 22.5 g/kg. MO extracts and MOIG (50,100 and 200 mg/kg) all evoked a significantly inhibitory effects on the frequency of twisting induced by acetic acid in mice compared with the model control group. Administration of MO extracts and MOIG markedly decreased the dry and wet weight of cotton pellet granuloma in rats and air pouch granuloma in mice. MOIG significantly attenuated the paw swelling and decreased the arthritic score, weight loss, spleen index, and the serum level of inflammatory factors IL-1ß, IL-6 and IL-17a in CFA-induced arthritic rats. MOIG inhibited the production of inflammatory cytokines in LPS-stimulated RAW264.7 cells, and the expressions of iNOS, COX-2 and proteins related to MAPK and NF-κB signaling pathways in LPS-stimulated RAW 264.7 macrophages. CONCLUSION: MOIG exerted anti-inflammatory and anti-arthritic activities through inactivating MAPK and NF-κB signaling pathways, and this finding may provide a sound experimental basis for the clinical treatment of rheumatoid arthritis with MOIG.

A natural compound (LCA) isolated from Litsea cubeba inhibits RANKL-induced osteoclast differentiation by suppressing Akt and MAPK pathways in mouse bone marrow macrophages.

ETHNOPHARMACOLOGICAL RELEVANCE: Litsea cubeba (Lour.) Pers. has been traditionally used as a folk prescription for treating rheumatic diseases in China. AIM OF THE STUDY: This study aimed to investigate the effects and underlying mechanism of LCA, a new type of dibenzyl butane lignin compound extracted from L. cubeba, on macrophage colony stimulating factor (M-CSF) plus receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation in mouse-derived bone marrow macrophages (BMMs). MATERIAL AND METHODS: TRAP staining, TRAP enzyme activity assay and actin ring staining were applied to identify the effects of LCA on osteoclast differentiation. Protein expression of NFATc1, c-Fos and MMP-9, and phosphorylation of p65, Akt, JNK, ERK and p38 in RANKL-induced osteoclasts was determined using western blotting to investigate the underlying mechanism. RESULTS: LCA significantly suppressed RANKL-induced osteoclast differentiation by inhibiting TRAP activity, decreasing the number of TRAP+ multinuclear osteoclasts and reducing the formation of F-actin ring without obvious cytotoxicity in BMMs. Moreover, LCA treatment strongly reduced protein expression of NFATc1, c-Fos and MMP-9, and attenuated the phosphorylation of p65, Akt, JNK, ERK and p38 in RANKL-stimulated BMMs. CONCLUSIONS: LCA ameliorated RANKL-induced osteoclast differentiation via inhibition of Akt and MAPK signalings in BMMs, and may serve as a potential pro-drug for bone destruction prevention.

Erxian Decoction Attenuates TNF-α Induced Osteoblast Apoptosis by Modulating the Akt/Nrf2/HO-1 Signaling Pathway.

Erxian decoction (EXD), a traditional Chinese medicine formula, has been used for treatment of osteoporosis for many years. The purpose of this study was to investigate the pharmacological effect of EXD in preventing osteoblast apoptosis and the underlying mechanism of prevention. Putative targets of EXD were predicted by network pharmacology, and functional and pathway enrichment analyses were also performed. Evaluations of bone mineral density, serum estradiol level, trabecular area fraction, serum calcium levels, and tumor necrosis factor (TNF)-α levels in ovariectomized rats, as well as cell proliferation assays, apoptosis assays, and western blotting in MC3T3-E1 osteoblasts were performed for further experimental validation. Ninety-three active ingredients in the EXD formula and 259 potential targets were identified. Functional and pathway enrichment analyses indicated that EXD significantly influenced the PI3K-Akt signaling pathway. In vivo experiments indicated that EXD treatment attenuated bone loss and decreased TNF-α levels in rats with osteoporosis. In vitro experiments showed that EXD treatment increased cell viability markedly and decreased levels of caspase-3 and the rate of apoptosis. It also promoted phosphorylation of Akt, nuclear translocation of transcription factor NF-erythroid 2-related factor (Nrf2), and hemeoxygenase-1 (HO-1) expression in TNF-α-induced MC3T3-E1 cells. Our results suggest that EXD exerted profound anti-osteoporosis effects, at least partially by reducing production of TNF-α and attenuating osteoblast apoptosis via Akt/Nrf2/HO-1 signaling pathway.

6-Gingerol Attenuates Ischemia-Reperfusion-Induced Cell Apoptosis in Human AC16 Cardiomyocytes through HMGB2-JNK1/2-NF-κB Pathway.

Myocardial ischemia/reperfusion (I/R) injury is a key factor in deterioration of myocardial function. The c-Jun NH2-terminal kinase (JNK) activation and the transcription factor nuclear factor-kappaB (NF-κB) nuclear translocation have been found in I/R injury. 6-Gingerol, an important bioactive ingredient of ginger, has been reported to have cardiovascular pharmacological effects. However, the molecular mechanism through which it is beneficial is unclear. In this work, I/R induced the increase in the apoptosis and reactive oxygen species level in AC16 cardiomyocytes. 6-Gingerol administration decreased cardiomyocyte apoptosis and improved oxidative stress indexes. 6-Gingerol administration also inhibited I/R-induced HMGB2 expression upregulation and JNK activation and reduced Cleaved Poly(ADP-ribose) polymerases (PARP) and Caspase-3 expression. HMGB2 treatment mimicked the effect of I/R-induced cell damage, which was reversed by 6-gingerol administration. On the other hand, transcriptional activity of NF-κB was reduced in 6-gingerol treated cells. Thus, overall results indicated that 6-gingerol administration protected I/R-induced cardiomyocytes apoptosis via JNK/NF-κB pathway in the regulation of HMGB2. This work supported the efficacy of 6-gingerol on cardiovascular disease and partially revealed its mechanism, which was helpful for understanding the therapeutic effects of this natural drug.

Anti-allergic rhinitis effects of caffeoylquinic acids from the fruits of Xanthium strumarium in rodent animals via alleviating allergic and inflammatory reactions

Abstract The fruits of Xanthium strumarium L., Asteraceae, have been used for various diseases in Chinese folk medicine, including allergic rhinitis, tympanitis, arthritis, ozena etc. The current study was aimed to investigate the therapeutic effects of caffeoylquinic acids from fruits of X. strumarium on allergic rhinitis in animals. The toxicity test indicated that the caffeoylquinic acids have no obvious toxicity. By using HPLC assays combined with reference standards, ten caffeoylquinic acids were identified as the predominant constituents. Anti-allergic activities of the caffeoylquinic acids were evaluated using passive cutaneous anaphylaxis test and Schultz-Dale test; dimethylbenzene induced ear edema test was performed to evaluate its anti-inflammatory effect. Then, the allergic rhinitis model in rats was established to evaluate the therapeutic effects of the caffeoylquinic acids against allergic rhinitis with the following indexes: allergic rhinitis symptom scores, serum levels of pro-inflammatory cytokines, histopathological examination, and histamine release. Our study revealed that the caffeoylquinic acids showed obvious anti-allergic and anti-inflammatory properties, and its treatments were beneficial for ameliorating the nasal symptoms, decreasing pro-inflammatory cytokines, and inhibiting the releases of histamine. Collectively, the caffeoylquinic acids might be utilized as effective and safe disease therapeutic agents for allergic rhinitis.

Metabolomics Profiling Reveals Rehmanniae Radix Preparata Extract Protects against Glucocorticoid-Induced Osteoporosis Mainly via Intervening Steroid Hormone Biosynthesis.

Rehmanniae Radix Preparata (RR), the dry rhizome of Rehmannia glutinosa Libosch., is a traditional herbal medicine for improving the liver and kidney function. Ample clinical and pharmacological experiments show that RR can prevent post-menopausal osteoporosis and senile osteoporosis. In the present study, in vivo and in vitro experiments, as well as a UHPLC-Q/TOF-MS-based metabolomics study, were used to explore the preventing effect of RR on glucocorticoid-induced osteoporosis (GIOP) and its underlying mechanisms. As a result, RR significantly enhanced bone mineral density (BMD), improved the micro-architecture of trabecular bone, and intervened in biochemical markers of bone metabolism in dexamethasone (DEX)-treated rats. For the in vitro experiment, RR increased the cell proliferation and alkaline phosphatase (ALP) activity, enhanced the extracellular matrix mineralization level, and improved the expression of runt-related transcription factor 2 (RUNX2) and osteopontin (OPN) in DEX-injured osteoblasts. For the metabolomics study, a total of 27 differential metabolites were detected in the DEX group vs. the control group, of which 10 were significantly reversed after RR treatment. These metabolites were majorly involved in steroid hormone biosynthesis, sex steroids regulation, and amino acid metabolism. By metabolic pathway and Western blotting analysis, it was further ascertained that RR protected against DEX-induced bone loss, mainly via interfering steroid hormone biosynthesis, as evidenced by the up-regulation of cytochrome P450 17A1 (CYP17A1) and aromatase (CYP19A1), and the down-regulation of 11ß-hydroxysteroid dehydrogenase (HSD11B1). Collectively, these results indicated that RR had a notable preventing effect on GIOP, and the action mechanism might be related to steroid hormone biosynthesis.

Metabolomics profiling provides valuable insights into the underlying mechanisms of Morinda officinalis on protecting glucocorticoid-induced osteoporosis.

Morinda officinalis (MO) has long been used as a traditional herbal medicine for the treatment of bone fractures and joint diseases in China. Monotropein (Mon) and rubiadin-1-methyl ether (Rub) are major bioactive components in MO. Ample evidence shows that MO and its chemical constituents can prevent osteoporosis induced by estrogen-deficiency and ageing. However, there is no study reporting glucocorticoid-induced osteoporosis (GIOP). The aim of the present study was to explore the protective effect of MO on GIOP modeled rats and osteoblasts, and elucidate the underlying mechanisms via UHPLC-Q-TOF/MS based metabolomics profiling. Eight weeks after dexamethasone (DEX) injection and MO treatment in female SD rats aged 12 weeks, bone mineral density (BMD), the micro-architecture of the trabecular bone, serum level of bone metabolism markers, and urine metabolomics were assayed in vivo. Cultured osteoblasts were injured with DEX, and the effects of MO, Mon and Rub on osteoblastic proliferation, differentiation and mineralization were examined in vitro. The results showed that MO was able to increase BMD, improve the micro-architecture and intervene bone metabolism via regulating alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRAP) and c-terminal telopeptides of type I collagen (CTX-I) levels in DEX-treated rats. The in vitro experiment showed that MO, Mon and Rub all increased the cell proliferation and ALP activity, and enhanced extracellular matrix mineralization in DEX-injured osteoblasts. Metabolomics profiling identified a total of 37 differential metabolites in DEX group vs. the control group, of which 20 were reversed significantly after MO treatment. Further metabolic pathway enrichment and Western blotting analysis showed that MO prevented bone loss mainly by interfering with arachidonic acid metabolism. These results suggested MO had a notable anti-GIOP effect, and the underlying mechanisms might be related to arachidonic acid metabolism.

Pharmacokinetics and tissue distribution of monotropein and deacetyl asperulosidic acid after oral administration of extracts from Morinda officinalis root in rats.

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 AUC0-t, Cmax 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.

Morinda officinalis How. - A comprehensive review of traditional uses, phytochemistry and pharmacology.

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.

[Research progress of chemical constituents and pharmacological activities in Humulus lupulus].

Hops, the female inflorescences of the hop plant (Humulus lupulus), are widely used in the brewing industry to add bitterness and aroma to beer. Combining with the relevant literature, the chemical composition(resinae, volatile oil, polyphenol and polysaccharide) in hops and their pharmacological effects are reviewed in this paper so as to present some sights for further application research and development.