Ethnopharmacological uses, phytochemistry, biological activities, and therapeutic applications of Alpinia oxyphylla Miquel: A review.

ETHNOPHARMACOLOGICAL USAGES: Fructus Alpiniae oxyphyllae (A. oxyphylla) is an important medicinal plant that is used not only as an edible fruit, but also as an important traditional medicine for benefiting cognitive performance and alleviating a wide spectrum of diseases. Such as; warming kidney, securing essence and arresting polyuria, as well as warming the spleen and stopping diarrhea and saliva. AIMS: The purpose of this review is to provide updated, comprehensive and categorized information on the traditional uses, phytochemistry and pharmacological research of A. oxyphylla in order to explore their therapeutic potential and establish a solid foundation for directing future research. MATERIALS AND METHODS: All the available information on A. oxyphylla was collected via electronic search (using Pubmed, SciFinder, Scirus, Google Scholar and Web of Science) and additionally a number of unpublished resources, (e.g. books, Ph.D. and M.Sc. dissertations, government reports). RESULTS: Phytochemical research on A. oxyphylla has led to the isolation of components such as essential oils, terpenes, diarylheptanoids, flavones, nucleobases and nucleosides, steroids and others. Crude extracts, fractions and phytochemical constituents isolated from A. oxyphylla showed a wide spectrum of in vitro and in vivo pharmacological activities like neuroprotective, anti-diarrheal, anti-diuretic, anti-neoplastic, anti-oxidant, anti-inflammatory, anti-allergic, viscera protective and anti-diabetic activities. Neuroprotective, anti-cancer, anti-diarrheal and anti-diuretic effects are major areas of research conducted on A. oxyphylla. CONCLUSIONS: Modern pharmacological studies have supported many traditional uses of A. oxyphylla, including nervous system, urinary system and gastrointestinal system disease. There was convincing evidence in experimental animal models in support of its neuroprotection, secure essence, reduce urination, and anti-carcinogenic effects. However, all the reported pharmacological activities were carried out at pre-clinical level and the authors urge further investigation in clinical trials about these therapeutic fields of A. oxyphylla.

Methylated flavonoids as anti-seizure agents: Naringenin 4',7-dimethyl ether attenuates epileptic seizures in zebrafish and mouse models.

Epilepsy is a neurological disease that affects more than 70 million people worldwide and is characterized by the presence of spontaneous unprovoked recurrent seizures. Existing anti-seizure drugs (ASDs) have side effects and fail to control seizures in 30% of patients due to drug resistance. Hence, safer and more efficacious drugs are sorely needed. Flavonoids are polyphenolic structures naturally present in most plants and consumed daily with no adverse effects reported. These structures have shown activity in several seizure and epilepsy animal models through allosteric modulation of GABAA receptors, but also via potent anti-inflammatory action in the brain. As such, dietary flavonoids offer an interesting source for ASD and anti-epileptogenic drug (AED) discovery, but their pharmaceutical potential is often hampered by metabolic instability and low oral bioavailability. It has been argued that their drug-likeness can be improved via methylation of the free hydroxyl groups, thereby dramatically enhancing metabolic stability and membrane transport, facilitating absorption and highly increasing bioavailability. Since no scientific data is available regarding the use of methylated flavonoids in the fight against epilepsy, we studied naringenin (NRG), kaempferol (KFL), and three methylated derivatives, i.e., naringenin 7-O-methyl ether (NRG-M), naringenin 4',7-dimethyl ether (NRG-DM), and kaempferide (4'-O-methyl kaempferol) (KFD) in the zebrafish pentylenetetrazole (PTZ) seizure model. We demonstrate that the methylated flavanones NRG-DM and NRG-M are highly effective against PTZ-induced seizures in larval zebrafish, whereas NRG and the flavonols KFL and KFD possess only a limited activity. Moreover, we show that NRG-DM is active in two standard acute mouse seizure models, i.e., the timed i.v. PTZ seizure model and the 6-Hz psychomotor seizure model. Based on these results, NRG-DM is proposed as a lead compound that is worth further investigation for the treatment of generalized seizures and drug-resistant focal seizures. Our data therefore highlights the potential of methylated flavonoids in the search for new and improved ASDs.

Targeting activator protein 1 signaling pathway by bioactive natural agents: Possible therapeutic strategy for cancer prevention and intervention.

Activator protein 1 (AP-1) is a key transcription factor in the control of several cellular processes responsible for cell survival proliferation and differentiation. Dysfunctional AP-1 expression and activity are involved in several severe diseases, especially inflammatory disorders and cancer. Therefore, targeting AP-1 has recently emerged as an attractive therapeutic strategy for cancer prevention and therapy. This review summarizes our current understanding of AP-1 biology and function as well as explores and discusses several natural bioactive compounds modulating AP-1-associated signaling pathways for cancer prevention and intervention. Current limitations, challenges, and future directions of research are also critically discussed.

Ethanol extract and its dichloromethane fraction of Alpinia oxyphylla Miquel exhibited hepatoprotective effects against CCl4-induced oxidative damage in vitro and in vivo with the involvement of Nrf2.

Alpinia oxyphylla Miq. (A. oxyphylla), as a kind of medicine which also be used as food, is widely used in East Asian for the treatment of dyspepsia, diarrhea, abdominal pain and deficiency cold of spleen and stomach. This study aimed to investigate the protective effects of ethanol extract (EE) and its dichloromethane fraction (DM) of A. oxyphylla, which are rich in phenolic compounds, against CCl4-induced hepatic injury in vitro and in vivo. EE, DM and silymarin ameliorated CCl4-induced decrease of cell viability and increase of reactive oxygen species (ROS) in HepG2 cells. The CCl4-induced changes of glutathione (GSH) and methane dicarboxylic aldehyde (MDA) levels, and the decrease of superoxide dismutase (SOD) and catalase (CAT) activities were all restored with the pretreatment of EE, DM and silymarin. The results in liver injury model in rats showed that EE, DM and silymarin could significant decrease the levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin than the model group. Liver histopathology revealed that EE and DM attenuated the incidence of liver lesions triggered by CCl4 intoxication. They also effectively relieved CCl4-induced oxidative damage. Western blot analysis indicated NF-E2-related factor (Nrf2) pathway played an critical role in the protection of EE and DM against CCl4-induced oxidative stress. In conclusion, the extracts from A. oxyphylla might be used as hepatoprotective agents.

You-gui Pill ameliorates renal tubulointerstitial fibrosis via inhibition of TGF-ß/Smad signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: You-gui Pill (YGP), a traditional Chinese medicinal prescription, was widely used to warm and recuperate "kidney-yang" clinically for hundreds of years in China. Recent studies found that YGP had a potential benefit for renoprotection. AIM OF THE STUDY: The present study aimed to elucidate the in vivo and in vitro efficacy of YGP on renal tubulointerstitial fibrosis, and the molecular mechanism is also investigated. MATERIALS AND METHODS: Rat renal tubulointerstitial fibrosis model was elicited by unilateral ureteral obstruction (UUO). Sprague-Dawley rats underwent UUO and were studied after 14 days. Animals were randomly subjected to six groups: sham, UUO, UUO/YGP (0.14, 0.42, 1.26g/kg/d), and UUO/enalapril (10mg/kg/d). HE, Masson and ELISA were used for evaluate renal injury and function. Immunohistochemical analysis and western blot were used to detect the expressions of α-SMA, fibronectin, collagen matrix and Smads. In vitro studies were investigated in TGF-ß1-stiumlated NRK-49F cell line. RESULTS: Oral administration of YGP significantly decreased UUO-induced inflammatory cell infiltration, tubular atrophy and interstitial fibrosis, and there was no significant difference between YGP at 1.26g/kg and enalapril at 10mg/kg treatment (P>0.05). Meanwhile, serum creatinine and blood urea nitrogen levels were reduced dramatically (P<0.01). In coincide with the decreased of TGF-ß1, α-SMA, fibronectin and collagen matrix expressions were also declined with YGP treatment in both UUO kidneys and TGF-ß1-stimulated NRK-49F cell line. Additionally, nuclear translocation of p-Smad2/3 was markedly down-regulated by YGP (P<0.001), with a relative mild up-regulated expression of Smad7 (P<0.05). CONCLUSIONS: Our findings demonstrate that YGP had a renoprotective effect in ameliorating renal tubulointerstitial fibrosis, and this activity possibly via suppression of the TGF-ß and its downstream regulatory signaling pathway, including Smad2/3.

Structure-activity relationship of flavonoids as potent inhibitors of carbonyl reductase 1 (CBR1).

Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, reduces a variety of carbonyl compounds including therapeutic drugs. CBR1 is involved in the reduction of the anthracycline anticancer drugs to their less anticancer C-13 hydroxy metabolites, which are cardiotoxic. CBR1 inhibitors are thought to be promising agents for adjuvant therapy with twofold beneficial effect in prolonging the anticancer efficacy of the anthracyclines while decreasing cardiotoxicity, a side effect of the drugs. In this study, we evaluated 27 flavonoids for their inhibitory activities of CBR1 in order to explore the structure-activity relationship (SAR). Among them, luteolin (2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one) showed the most potent inhibition (IC5095nM), which is also more potent compared to all known classes of CBR1 inhibitors. The inhibition of luteolin was noncompetitive with respect to the substrate in the NADPH-dependent reduction direction, but CBR1 exhibited moderate NADP(+)-dependent dehydrogenase activity for some alicyclic alcohols, in which the luteolin inhibition was competitive with respect to the alcohol substrate (Ki59nM). The SAR of the flavonoids indicated that the 7-hydroxy group of luteolin was responsible for the potent inhibition of CBR1. The molecular docking of luteolin in CBR1-NADPH complex showed that theflavonoid binds to the substrate-binding cleft, in which its 7-hydroxy group formed a H-bond with main-chain oxygen of Met234, in addition to H-bond interactions (of its 5-hydroxy and 4-carbonyl groups with catalytically important residues Tyr193 and/or Ser139) and a π-stacking interaction (between its phenyl ring and Trp229).