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Ethnopharmacological relevance Pholidota articulata Lindley (PA) locally known as Hadjojen (bone jointer) belongs to family Orchidaceae is used for healing fractures in folklore tradition of Kumaon region of Uttarakhand, Himalaya, India. Bone is a dynamic organ and is constantly being remodeled in order to facilitate growth and repair. This process requires the involvement of bone forming osteoblast and bone resorbing osteoclast cells, which function in generating and mineralizing bone, giving strength and rigidity to the skeletal system. Present study was aimed to determine the therapeutic potential of ethanolic extract of PA and its isolated compound oxoflavidin, by characterizing their fracture healing properties. Materials and methods Ovariectomized (Ovx) estrogen deficient adult female Balb/c mice were used for in vivo evaluation of osteogenic or bone healing potential of ethanolic extract of PA. Further, its isolated compounds were tested for their osteogenic efficacy using alkaline phosphatase assay and mineralization assay in vitro in mice calvarial osteoblasts. Results The ethanolic extract of PA exhibited significant restoration of trabecular micro-architecture in both femoral and tibial bones. Additionally, treatment with PA extract led to better bone quality and devoid of any uterine estrogenicity in ovariectomized estrogen deficient mice. One of the isolated compound, oxoflavidin enhanced ALP activity (a marker of osteoblast differentiation), mineral nodule formation and mRNA levels of osteogenic markers like BMP-2, Type 1 Collagen, RUNX-2 and osteocalcin. Conclusion These results warrant that ethanolic extract of PA and it’s pure compound oxoflavidin have fracture healing properties. The extract and oxoflavidin exhibit a strong threapeutical potential for the treatment and management of postmenopausal osteoporosis. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Wutou (WT, Radix Aconiti ), the mother root of Aconitum carmichaelii Debx., is a famous Chinese herb against rheumatoid arthritis. In Chinese clinics, PWT is often prepared as a decoction in combination with other herbs, such as Wutou decoction (WTD). The present study aimed to compare the effects of PWT single herb and WTD on CYP3A activity ex vivo and in vivo . Materials and methods In the ex vivo study, CYP3A activity was determined by using testosterone (Tes) as a specific probe. Levels of Tes and its metabolite 6β-hydroxytestosterone (6β-OH-Tes) were measured using a validated ultra-performance liquid chromatography (UPLC) method. CYP3A protein and mRNA levels were measured by using Western blot and real-time PCR, respectively. In the in vivo study, CYP3A activity was determined by using buspirone (BP) as a specific probe. The plasma concentrations of BP and its primary metabolites, namely, 1-(2-pyrimidinyl) piperazine (1-PP) and 6′-hydroxybuspirone (6′-OH-BP), were determined using a validated UPLC-tandem mass spectrometry (UPLC/MS/MS) method. Results Compared with the control group, the formation rates of 6β-OH-Tes from Tes ex vivo significantly decreased in groups treated with PWT at the tested doses, and this decrease was accompanied by a striking decrease in CYP3A protein and mRNA levels. However, a significant increase was observed in the ratios in the WTD groups compared with PWT single herb groups. In vivo , both formation ratios of 6′-OH-BP and 1-PP from BP showed no significant change in the WTD group. Conclusions PWT can significantly inhibit CYP3A activity ex vivo at the tested doses because of the down-regulation of CYP3A protein and mRNA expression levels. WTD can significantly reverse the inhibition caused by PWT. WTD also had no significant effect on CYP3A activity in vivo . Results implied that the use of PWT as a part of the WTD prescription rather than PWT single herb is more appropriate in clinics. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Scutellariae Radix (SR), the dried root of Scutellariae baicalensis Georgi, has a lot in common with non-steroidal anti-inflammatory drugs (NSAIDs). Their similarities in therapeutic action (anti-inflammation) and metabolic pathways (phase II metabolisms) may lead to co-administration by patients with the potential of pharmacokinetic and/or pharmacodynamic interactions. The current study aims to investigate the potential interactions between SR and an NSAID, mefenamic acid (MEF), on the overall pharmacokinetic dispositions, anti-inflammatory effects and adverse effects in rats. Materials and methods The current study simultaneously monitored the pharmacokinetic and pharmacodynamic interactions in a single animal. Four groups of Sprague-Dawley rats ( n =7 each) received oral doses of a standardized SR extract (300 mg/kg, twice daily), MEF (40 mg/kg, daily), combination of SR extract and MEF, and vehicle control, respectively, for 5 days. On Day 5, blood samples were collected after first dose over 24 h for the determination of (1) plasma concentrations of SR bioactive components, MEF and its metabolites by LC-MS/MS, and (2) prostaglandin E 2 (PGE 2 ) production and cyclooxygenase-2 (COX-2) gene expression by ex vivo analyses using LPS-stimulated RAW264.7 macrophage cells, ELISA and real time-PCR. After the rats were sacrificed, stomachs were isolated to assess their gross mucosal damage. Statistical comparisons were conducted using ANOVA and t -test. Results Minimal pharmacokinetic interaction between SR extract and MEF was observed. Co-administration of SR extract and MEF did not significantly alter the plasma concentration–time profile or the pharmacokinetic parameters such as C max , AUC 0→24 , T max or clearance. Pharmacodynamic interaction via the COX-2 pathway was observed. The PGE 2 level in LPS-stimulated RAW264.7 cells treated with plasma collected from control group over the 24 h sampling (AUC 0→24[PGE2] ) was 191981±8789 pg/ml hr, which was significantly reduced to 174,780±6531 and 46,225±1915 pg/ml hr by plasma collected from rats administered with SR extract and MEF, respectively. Co-administration of SR extract and MEF further potentiated the PGE 2 inhibition, with an AUC 0→24[PGE2] of 37013±2354 pg/ml hr ( p <0.05, compared to SR or MEF group). By analyzing the COX-2 gene expression, SR extract significantly prolonged the COX-2 inhibitory effect of MEF over the 24 h ( p <0.05). Furthermore, the MEF-induced stomach ulcer after the 5-day treatment, as evidenced by the increased gross ulcer index and sum of lesion length ( p <0.05, compared to control), could be alleviated by co-administration with SR extract ( p <0.05). Conclusions Co-administration of SR extract and MEF potentiated the anti-inflammatory effects, alleviated the MEF-induced stomach adverse effect while having minimal pharmacokinetic interactions. Our findings provide insight for combination therapy of SR extract and MEF against inflammatory diseases. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Pseudolysimachion rotundum var . subintegrum (Speedwell, Plantaginaceae) is used as a traditional herbal medicine for treating bronchitis, cough and asthma in Korea, China, Russia, and Europe. Aim of the study In this study, we investigated the protective effects of the novel iridoid glycoside, piscroside C (compound 1) isolated from the methanolic extract of P. rotundum var. subintegrum against inflammatory responses using a cigarette smoke induced chronic obstructive pulmonary disease (COPD) and TNF-α-stimulated human airway epithelial NCI-H292 cells. Materials and methods The novel iridoid glycoside piscroside C was isolated from the methanolic extract of P. rotundum var. subintegrum . The chemical structure was established by NMR, HRESIMS, and optical rotation. In in vivo experiment, the mice received 1 h of cigarette smoke for 3 days. Piscroside C was administered to mice by oral gavage 1 h before cigarette smoke exposure for 3 days. In in vitro experiment, we evaluated the effect of piscroside C on proinflammatory mediators in H292 cells stimulated with TNF-α. Results Piscroside C significantly reduced the neutrophil influx, reactive oxygen species production, IL-6, TNF-α, and elastase activity in bronchoalveolar lavage fluid in COPD animals. In addition, piscroside C attenuated NF-κB and IκB phosphorylation, leading to reduced recruitment of inflammatory cells into the lung tissue. Consistent with the results of in vivo experiment, piscroside C significantly inhibited the expression of inflammatory cytokines (IL-6, IL-8 and IL-1β) by inhibiting NF-κB activation, as resulting decrease in the phosphorylation of IKKβ, IκBα and TAK1 in TNF-α-stimulated H292 cells. Conclusion These findings indicate that piscroside C effectively inhibits inflammatory responses, which is an important process in the development of COPD through suppression of IKK/NF-κB activation. Our study suggest that piscroside C might represent a useful therapeutic for the treatment of inflammatory airway disease. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance In Kenya, 22 million people are at risk of malaria, 70% of them are in rural areas and most of these people use traditional plant based medicines to treat malaria. The aim of the study was to escalate documentation, from an earlier study of medicinal plants, traditionally used to treat malaria by the Digo community of Kwale County, taking cognizance of their pharmacological information by evaluating their antiplasmodial efficacies. Materials and methods The study was carried out in Kwale County at Shimba Hills Game Reserve and adjoining part of Kinango. Traditional health practitioners (THP) were interviewed with a standard questionnaire to obtain information on medicinal plants traditionally used for management of malaria. Group interviews were also held among THPs and members of the community. The plant samples collected were tested for antiplasmodial activity against chloroquine sensitive (D6) and resistant (W2) Plasmodium falciparum using the ability of extracts, prepared from the plant species, to inhibit the incorporation of [G-3H] hypoxanthine into the malaria parasites. Results Fifty seven (57) species in forty eight (48) genera and thirty (30) families were documented and evaluated for in vitro antiplasmodial activity. Apocynaceae, Euphorbiaceae, and Rubiaceae families had each about 12% of the plant species reported as antimalarial remedy and represented the species that are most commonly used. Twelve species (21.1%) showed antiplasmodial efficacy of IC 50 <5 µg/ml and these were Boscia salicifolia , Cissampelos mucronata , Clerodendrum myricoides , Commiphora schimperi , Flueggea virosa , Maytenus undata , Maytenus senegalensis , Maytenus putterlickioides , Vernonia amygdalina , Warburgia stuhlmannii , Zanthoxylum chalybeum and Tabernaemontana pachysiphon. Conclusions These results seem to indicate that ethnopharmacological inquiry used in search for new herbal remedies as predictive and could form the basis of an ethnopharmacopoeia and search for new active principles. This is the first report on traditional use of T. pachysiphon for malaria and its antiplasmodial activity. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Eupafolin, a major bioactive compound found in Phyla nodiflora, has the anti-inflammatory property. Upregulation of cell adhesion molecules in the lung airway epithelium is associated with the epithelium–leukocyte interaction and plays a critical role in the pathogenesis of lung airway inflammatory disorders. To investigate the effects of eupafolin on tumor necrosis factor-α (TNF-α)-induced intercellular cell adhesion molecule-1 (ICAM-1) expression in A549 human lung airway epithelial cells and the underlying mechanisms. Materials and methods The effect of eupafolin on ICAM-1 expression in A549 cells were examined by Western blotting and immunofluorescent staining. The mice were injected intraperitoneally with or without eupafolin and then were left untreated or were injected intratracheally with TNF-α. To detect the effect of eupafolin on ICAM-1 expression, the lung tissues were also examined by Western blotting and immunohistochemical staining. Results Eupafolin pretreatment reduced the TNF-α-induced ICAM-1 expression and also the ERK1/2, JNK, p38, and AKT/PI3K phosphorylation. However, the increase in ICAM-1 expression with TNF-α treatment was unaffected by p38 and PI3K inhibitors. Eupafolin decreased the TNF-α-induced NF-κB p65 activation and its nuclear translocation. Furthermore, eupafolin reduced ICAM-1 expression in the lung tissues of TNF-α-treated mice. Conclusions Eupafolin exerts its anti-inflammatory activity by suppressing the TNF-α-induced ICAM-1 expression and subsequent monocyte adhesion via AKT/ERK1/2/JNK phosphorylation and nuclear translocation of NF-κB p65. These results suggest that eupafolin may represent a novel therapeutic agent targeting epithelial activation in lung inflammation. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Impatiens textori Miq. ( I. textori, Balsaminaceae) is a traditional medicinal herb used for centuries to treat several inflammatory related skin infections and allergic disorders in Asian countries. Aim of the study In this study, we elucidated the effects of whole plant extracts of I. textori on inflammasome activation using in vitro and in vivo models. Materials and methods LPS-stimulated murine bone marrow macrophages were used to study the regulatory effect of I. textori extract (IT) on inflammasome activation. ATP, nigericin and MSU were used as danger-associated molecules to activate the NLRP3 inflammasome. An LPS-induced acute lung injury (ALI) mouse model was used to study the in vivo effect of IT on inflammasome activation. Results IT treated at 25, 50, and 100 μg/mL concentrations suppressed interleukin-1β secretion through the attenuation of NLRP3 inflammasome activation ( p <0.001 at 100 μg/mL) leading to the decreased amount of ASC oligomerization and caspase-1 maturation. For the in vivo model, IT inhibited the NLRP3 expression and cell recruitment at the lung tissue in the ALI mouse model. Conclusion IT exhibited potent anti-inflammatory effects via the attenuation of NLRP3 inflammasome activation supporting the traditional claims and may provide a valuable therapeutic strategy in treating various inflammation-related disorders. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Jiegeng (Radix Platycodi), the dried root of Platycodon grandiflorum A. DC (Campanulaceae), has been used to treat cough, sore throat, bronchitis, and bronchial asthma for thousands of years. It is commonly prescribed with Gancao (Radix et Rhizoma Glycyrrhizae ) as a herbal combination in traditional Chinese medicine (TCM) to produce synergistic effects. Aim of the study To elucidate the herbaceous compatibility of Jiegeng and Gancao, we investigated the comparative pharmacokinetics, intestinal absorption, and microbial metabolism of platycodin D (PD) and deapio-platycodin D (DPD), the platycodins contained in Jiegeng. Materials and methods In the comparative pharmacokinetic study, the concentrations of PD and DPD in Jiegeng extract (JE) and the Jiegeng–Gancao herb pair (JGHP) were determined in rat plasma using liquid chromatography–tandem mass spectrometry (LC–MS/MS). In addition, the main pharmacokinetic parameters were calculated using data analysis software (DAS). Furthermore, in vitro studies using Caco-2 cells and fecal lysates were performed to contradistinguish the intestinal absorption and microbial metabolism of PD and DPD in JE from those in JGHP. Results The peak concentration ( C max ) and area under the plasma concentration curve ( AUC ) of PD in rats orally administrated JGHP significantly increased compared to that in rats treated with JE. In addition, the time to reach peak concentration ( T max ) and half-life ( t 1/2 ) of PD and DPD in combination with JGHP were all prolonged compared with those of JE. There was no significant difference in the absorption of PD between JE and JGHP in Caco-2 cells. However, the hydrolysis of both PD and DPD in JGHP were weaker than that in JE after a 2-h incubation in fecal lysate which might be responsible for the different pharmacokinetic profiles of the platycodins in JE and JGHP. Conclusion In this study, we discovered that Gancao might influence the pharmacokinetic profiles of PD and DPD in Jiegeng. Furthermore, the difference in profiles may be attributable to the inequable microbial metabolism rather than intestinal absorption of the platycodins in JE and JGHP. The results of this study elucidated the pharmacokinetic compatibility and rationale for the use of JGHP. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Pseudelephantopus spiralis (Less.) Cronquist is distributed in the Caribbean, Mesoamerica and Latin America. Preparations of the plant are traditionally used in Latin America for the treatment of various diseases including fever, malaria, and spleen or liver inflammations. Materials and methods Aerial parts of P. spiralis were extracted with either ethanol or distilled water. Seven hirsutinolide-type sesquiterpenoids were isolated: 8-acetyl-13-ethoxypiptocarphol ( 1 ), diacetylpiptocarphol ( 2 ), piptocarphins A ( 3 ), F ( 4 ) and D ( 5 ), (1S * ,4R * ,8S * ,10R * )-1,4-epoxy-13-ethoxy-1,8,10-trihydroxygermacra-5 E ,7(11)-dien-6,12-olide ( 6 ), and piptocarphol ( 7 ). Extracts and isolated compounds ( 2, 3, 5–7 ) were screened for their in vitro antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum strain FcM29-Cameroon and antileishmanial activity against three stages of Leishmania infantum. Their cytotoxicities were also evaluated against healthy VERO cell lines and J774A.1 macrophages, the host cells of the Leishmania parasites in humans. Results Aqueous extracts showed a greater inhibitory effect than alcoholic extracts, with IC 50 on P. falciparum of 3.0 µg/mL versus 21.1 µg/mL, and on L. infantum of 13.4 µg/mL versus >50 µg/mL. Both extracts were found to be cytotoxic to VERO cells (CC 50 <3 µg/mL). Sesquiterpene lactones 2 and 3 showed the best activity against both parasites but failed in selectivity. Carbon 8 hydroxylated hirsutinolides 5 – 7 presented the particularity of exhibiting two conformers observed in solution during extensive NMR analyses in CD 3 OD and UHPLC-MS. The presence of a hydroxyl function at C-8 decreased the activity of 5 – 7 on the two parasites and also on VERO cells. Conclusion The antiplasmodial activity displayed by the aqueous extract explains the traditional use of P. spiralis in the treatment of malaria. This activity seems to be attributable to the presence of sesquiterpene lactones 2 and 3 , the most active against P. falciparum . Aqueous extract and compounds 2 , 3 and 6 were also active against L. infantum but lacked in selectivity due to their cytotoxicity towards macrophages. Exploring the safety and antiplasmodial efficacy of this traditional remedy will require further toxicological and in vivo studies in the light of the cytotoxicity towards healthy cell lines displayed by the aqueous extract and compounds 2 and 3 . [ABSTRACT FROM AUTHOR]

Absrtract Ethnopharmacological relevance The compatibility of Angelicae Sinensis Radix (Danggui) and Carthami Flos (Honghua), a famous herb pair Gui-Hong, can produce synergistic and complementary hematinic effects. Our previous studies have indicated that Gui-Hong has therapeutic potential treatment in hemolytic and aplastic anemia (HAA). The present study aimed to investigate the hematinic effects of Danggui, Honghua and Gui-Hong on HAA rats induced by acetyl phenylhydrazine (APH) and cyclophosphamide (CP) and to explore the underlying hematinic regulation mechanisms. Materials and methods Rats were divided into 5 groups, and drugs were administered by oral gavage one time each day for continuous 7 days from the experiment began. Urine and plasma were analyzed by ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). Partial least-squares discriminate analysis (PLS-DA) models were built to evaluate the therapeutic effects of Danggui, Honghua and Gui-Hong. Pearson correlation matrix analysis method was used to discover the correlations between potential biomarkers and biochemical indicators of HAA rats. Results Seven potential biomarkers contribute to the separation of model group and control group were tentatively identified. The levels of l -kynurenine, phenylalanine, nicotinic acid and sphingosine increased significantly ( P <0.05) in HAA rats, while the levels of l -isoleucine, l -tyrosine and serotonin decreased significantly ( P <0.05) in comparison with control rats. Those endogenous metabolites were chiefly involved in phenylalanine, tyrosine and tryptophan biosynthesis, valine, leucine and isoleucine biosynthesis, tryptophan metabolism and tyrosine metabolism. The metabolic deviations could be regulated closer to normal level after Danggui, Honghua and Gui-Hong intervention. In term of hematinic effects, Gui-Hong was the most effective as shown by the relative distance in PLS-DA score plots and relative intensity of potential biomarkers. The result reflected the synergic action between Danggui and Honghua. The above results were found to be reasonable in explaining the hematinic effects mechanism of Gui-Hong. Conclusions The results of routine blood, urinary metabolic pattern and plasma metabolic pattern show the Danggui, Honghua and Gui-Hong groups are moving toward the control group and the HAA was being prevented and alleviated. The effect of Gui-Hong group is more remarkable than Danggui and Honghua groups. Some potential biomarkers like l -kynurenine, phenylalanine, l -isoleucine, l -tyrosine, serotonin, nicotinic acid and sphingosine have been found and identified. The work shows that the metabonomics method is a promising tool in the efficacy and mechanism research of traditional Chinese medicines. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance The fruit of Schisandra chinensis ( Turcz. ) Baill , has been traditionally used in management of liver diseases and ageing associated neurodegeneration. The bioactive compound from this medicinal plant would be valuable for its potential use in prevention and treatment of Parkinson׳s disease. Aim of the study The overall objective of the present study was to understand the neuroprotective effect of schisantherin A, a dibenzocyclooctadiene lignan from the fruit of S. chinensis ( Turcz. ) Baill , and to elucidate its underlying mechanism of action. Material and methods This study investigated the protective effect of schisantherin A against selective dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA)-induced neural damage in human neuroblastoma SH-SY5Y cells and zebrafish models. Oxidative stress and related signaling pathways underlying the neuroprotective effect were determined by multiple biochemical assays and Western blot. Results Pretreatment with schisantherin A offered neuroprotection against 6-OHDA-induced SH-SY5Y cytotoxicity. Moreover, schisantherin A could prevent 6-OHDA-stimulated dopaminergic neuron loss in zebrafish. Our mechanistic study showed that schisantherin A can regulate intracellular ROS accumulation, and inhibit NO overproduction by down-regulating the over-expression of iNOS in 6-OHDA treated SH-SY5Y cells. Schisantherin A also protects against 6-OHDA-mediated activation of MAPKs, PI3K/Akt and GSK3β. Conclusion These findings demonstrate that schisantherin A may have potential therapeutic value for neurodegenerative diseases associated with abnormal oxidative stress such as Parkinson׳s disease. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Propolis is a bee product widely used in folk medicine due to its numerous pharmacological properties. However, samples from different regions can differ in chemical composition, effectiveness, and side effects. Despite the widespread use of Brazilian red propolis, which is an isoflavone-rich variety, its toxicity has not been carefully studied. Aims of the study To assess the acute and sub-acute toxicity of the hydroethanolic extract of red propolis (HERP) administered orally to rats. Materials and methods HERP for the acute (300 mg/kg) and sub-acute (10, 100 and 200 mg/kg) toxicity studies was administered orally to rats according to OECD Guidelines 420 and 407, respectively. Clinical signs were identified, and hematological and biochemical analyses were performed. Water and food uptake as well as body and organ weights of animals were recorded. Results and conclusions The acute study revealed no lethal effects at 300 mg/kg of HERP, but toxic signs were observed, as HERP had an LD50 of more than 300 mg/kg, indicating a warning. The most toxic signals in sub-acute studies were observed in males at a dose of 200 mg/kg HERP. These results suggest estrogen-like activity, possibly from the isoflavones in HERP. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Tripterygium wilfordii Hook F (TWHF) is a traditional herbal medicine in China. Triptolide (TP), the primary bioactive compound of TWHF, is an anti-inflammatory and immunosuppressive compound that can also injure the liver and kidney. Unfortunately, the toxicity mechanism remains unknown. Aim of the study The aim of this study is to understand the regulatory role of sphingolipid (SPL) pathways in the TP-induced toxic mechanism in the liver and kidney in delayed-type hypersensitivity (DTH) Balb\c mouse. Material and methods 76 core sphingolipids and 29 species of related metabolic enzymes in liver, kidney and plasma were analyzed with previous HPLC–MS/MS and real time qPCR method, respectively. Furthermore, the data generated from these two omics underwent integrated analysis to describe TP-induced abnormal sphingolipid metabolism and identify the specific biomarkers of TP toxicity using bioinformation method. Results High-dose (LD 50 ) TP could induce severe liver and kidney injuries. Moreover, TP comprehensively influenced the enzymes involved in the sphingolipids metabolism in the liver and kidney at the mRNA expression level. Furthermore, the total levels of ceramides (Cers), sphingomyelins (SMs) and sphingosine (Sph) were all elevated, while dihydroceramides (dhCers) and hexosylceramides (HexCers) were all down-regulated. Several enzymes, including kdsr, CerS 2 , CerS 4 , CerS 5 and CerS 6 in the liver and Cerk in the kidney were probably responsible for the TP-induced toxic effect, identifying them as possible novel therapeutic targets. Besides, fractions of long chain SPL (C16–C20) exhibited significant increase, and fractions of unsaturated dhCer and Cer were significantly changed, both of which above may be due to the change of mRNA expression level of CerSs . Moreover, several biomarkers for the diagnosis of TP poisoning were discovered. Conclusion In summary, the regulation of SPL metabolism uncovered a novel mechanism underlying TP poisoning in the liver and kidney. In addition, key biomarkers and enzymes may play an important role in reducing the clinical risk associated with the use of TP. [ABSTRACT FROM AUTHOR]

Rhubarb is commonly used as laxatives in Asian countries, of which anthraquinones are the major active ingredients, but there are an increased number of concerns regarding the nephrotoxicity of anthraquinones. In this study, we compared the pharmacokinetic characteristics of rhubarb anthraquinones in rats after orally administered with rhubarb and rhubarb total free anthraquinone oral colon-specific drug delivery granules (RTFA-OCDD-GN), and then explained why these granules could reduce the nephrotoxicity of anthraquinones when they produced purgative efficacy. A sensitive and reliable high performance liquid chromatography (HPLC) method has been fully validated for simultaneous determination of the five active components of rhubarb, and successfully applied to investigate and compare the remarkable differences in pharmacokinetic study of rhubarb anthraquinones after orally administered with rhubarb and RTFA-OCDD-GN. The results showed that, compared with rhubarb group, the AUC, C max , t 1/2z and V z/F of aloe-emodin, rhein, emodin and chrysophanol in rats receiving the RTFA-OCDD-GN were significantly decreased, and the T max of the four analytes was prolonged. Moreover, the T max of rhein, the C max of chrysophanol and emodin all have significant differences (P < 0.05). Simultaneously, anthraquinone prototype excretion rates in urine and feces of aloe-emodin, rhein, emodin, chrysophanol and physcion were all increased. These findings suggested that oral colon-specific drug delivery technology made anthraquinone aglycone to colon-specific release after oral administration. This allowed anthraquinones to not only play the corresponding purgative effect but also avoid intestinal absorption and promote excretion. And thereby greatly reduced the nephrotoxicity of rhubarb. The result is a new breakthrough in rhubarb toxicity attenuated research. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Astragalus membranaceus Bunge (Leguminosae) and Salvia miltiorrhiza Bunge (Lamiaceae) are two important Chinese herbs with a long history of extensive ethnobotanical usage in the treatment of liver-related diseases over many centuries. Presently, these two herbs are being used either as a single herbal formulation or a composite formula for the treatment of liver related conditions. In response, recent studies on these two herbs have focused on elucidating their mechanisms of action, particularly with regards to their anti-hepatocarcinogenic effects. Previously, we have reported that Compound Astragalu s and Salvia miltiorrhiza extract (CASE), a synergized composite extract from Astragalus membranaceus and Salvia miltiorrhiza ameliorates liver fibrosis and hepatocellular carcinoma (HCC) by modulating the TGF-β/Smad pathway. Meanwhile, MAPK activation and MAPK-dependent linker phosphorylation of Smad2/3 and their preferential nuclear import are crucial for overall oncogenic role of TGF-β/Smad signaling in HCC. To elucidate further, we studied the effect of CASE on the MAPK pathway and how it affects MAPK-dependent regulation of TGF-β/Smad signaling using both cell and animal models of HCC. Materials and methods We used immunofluorescence and western blot techniques to monitor effect of CASE on the activation of the MAPKs (pERK, pJNK and pp38) in TGF-β 1 -stimulated hepatic stellate cells (HSCs), HepG2 cells and also diethylnitrosamine (DEN)-induced HCC in rats. Also phosphorylation and subcellular distribution of pSmad2/3, Smad4 and Imp7/8 in TGF-β 1 -stimulated HSC and HepG2 cells were monitored. The expression of pERK, pJNK, pp38 and PAI-1 gene were monitored by using western blot technique. The effect of CASE on domain-specific phosphorylation of Smad2/3 and their subcellular distribution, and the expression of Smad4 and its subcellular distribution in TGF-β 1 -stimulated HSCs and HepG2 cells were evaluated by using immunofluorescence technique. And the expression of Imp7/8 and their subcellular distribution were assessed by both immunofluorescence and western blot techniques, while PAI-1 gene expression was assessed by western blot Results In vitro , CASE in a concentration-dependent manner increased the expression of pp38 but decreased the expression of pERK and pJNK; however, in vivo , CASE in a dose dependent manner decreased the expression of pERK, pJNK as well as pp38. Also, CASE concentration dependently inhibited pSmad2C/L, pSmad3L, Smad4, Imp7/8 and their nuclear import; it had no effect on pSmad3C in HepG2 cells; significantly decreased PAI-1 gene expression in both in vitro and in vivo . Conclusions CASE blocked MAPK activation, MAPK-dependent linker phosphorylation of Smad2/3, Smad4 expression, Imp7 expression and their nuclear import leading to significant down-regulation of PAI-1 gene expression; further highlighting the multi-target anti-HCC effect of CASE and its potential drug candidature. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Traditional Chinese Medicines (TCMs) are increasingly used in combination with Western medicine. Scutellaria baicalensis Georgi (Lamiaceae) is a widely used TCM in treating various diseases. However, the in vivo metabolism of its main bioactive flavonoids, baicalin, baicalein, wogonoside and wogonin, needs further study. Materials and methods A systematic method based on ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS) technique combined with Metabolynx TM software was developed to speculate the metabolites and excretion profiles of the main flavonoids in S. baicalensis extract in rats bile, urine and feces samples after oral administration of the extract. Results Four parent components and a total of 15 metabolites were tentatively detected in vivo . All metabolites were detected including sulfate and glucuronide conjugates, hydroxylated, methylated, acetylated and deoxygenated products. Twelve metabolites were from the rat urine, five from the feces and two from the bile. Among them, several products were reported firstly. Conclusion The research provided useful information for further study of the pharmacology and mechanism of action of S. baicalensis extract in vivo and a proposed method which could develop an integrated template approach to analyze screening and identification of biological samples after oral administration of TCMs. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Petiveria alliacea L. (Phytolaccaceae) is a perennial shrub native to the Amazon region and other tropical areas such as Central America and the Caribbean. Popularly known as mucuracaá, P. alliacea is used in the folk medicine for a broad variety of therapeutic purpose and also in religious ceremonies by slaves as a sedative, which highlights its properties on the Central Nervous System (CNS). Aim of the study The present study evaluated the effects of the P. alliacea leaves hydroalcoholic extract (PaLHE) on the cognition, including learning and memory. Material and methods Three-month-old male and female Wistar rats ( n =8–10/group) were administered with 900 mg/kg of PaLHE. The behavioral assays included Step-down Inhibitory avoidance (IA) and Morris Water Maze (MWM) tests. Results Consistent with our previous reports, P. alliacea improved long-term memory. It also exerted previously unreported effects on short-term and spatial memory improvement, and increased learning in the tasks. Conclusions The P. alliacea extract elicited mnemonic effects and improved the learning process in both IA and MWM tests. Our results highlight the importance of further studies in order to identify the active substances of the PaLHE and investigate the pharmacological mechanisms that underlies the reported effects. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Wuling San, a famous prescription in Chinese medicine, is composed of Polyporus, Poria, Alismatis rhizoma, Cinnamomi cortex and Atractylodis macrocephalae rhizoma, and promotes kidney function and diuresis. The main purpose of this study was to investigate its renal protective effect in high fructose-induced hyperuricemic mice. Materials and methods ICR mice were fed with 30% fructose in drinking water for 6 weeks to induce hyperuricemia and renal dysfunction. Then mice were orally administrated for other 6 weeks with Wuling San (987, 1316, 1755 and 2340 mg/kg), allopurinol (5 mg/kg) and water daily, respectively. Serum and urine levels of uric acid, creatinine and blood urea nitrogen (BUN) were measured. Hematoxylin and eosin staining was used to assess renal histological changes. Renal interleukin (IL)-1β concentrations were measured using ELISA kit. Renal protein levels of organic ion transporters, as well as toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling and pyrin domain containing 3 (NLRP3) inflammasome were determined by Western blot assay. Results Wuling San significantly decreased serum uric acid, creatinine and BUN levels, increased fractional excretion of uric acid (FE UA ) in fructose-fed mice. It restored fructose-induced dysregulation of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), ATP-binding cassette subfamily G member 2 (ABCG2) and organic anion transporter 1 (OAT1), as well as organic cation transporter 1 (OCT1) and OCT2 in mice. Wuling San obviously alleviated infiltration of inflammation cells in kidney glomerulus of fructose-fed mice. Moreover, Wuling San suppressed the activation of TLR4/ MyD88 signaling to inhibit nuclear factor κB (NF-κB) signaling and mitogen-activated protein kinases (MAPKs) activation in fructose-fed mice. Additionally, Wuling San decreased NLRP3 inflammasome activation and IL-1β secretion in the kidney of fructose-fed mice. Conclusion Wuling San exerts renal protective effect by modulating renal organic ion transporters in fructose-induced hyperuricemic mice. The molecular mechanism of its action may be associated with the suppression of TLR4/MyD88 signaling and NLRP3 inflammasome activation to reduce IL-1β production in high fructose-induced hyperuricemic mice. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance A common plant used to treat several gastric disorders is Buddleja scordioides Kunth, commonly known as salvilla. Aim of the study To detect inflammatory markers, in order to evaluate the gastroprotective potential of salvilla infusions, as this could have beneficial impact on the population exposed to gastric ulcers and colitis. Materials and methods The present work attempted infusions were prepared with B. scordioides (1% w/w) lyophilized and stored. Total phenolic content and GC–MS analysis were performed. Wistar rats were divided into five groups ( n =8), a negative vehicle control, an indomethacin group, and three experimental groups, named preventive, curative, and suppressive. All rats were sacrificed under deep ether anesthesia (6 h) after the last oral administration of indomethacin/infusion. The rat stomachs were promptly excised, weighed, and chilled in ice-cold and 0.9% NaCl. Histological analysis, nitrites quantification and immunodetection assays were done. Results B. scordioides infusions markedly reduced the visible hemorrhagic lesions induced by indomethacin in rat stomachs, also showed down-regulation of COX2, IL-8 and TNFα and up-regulation of COX-1 with a moderate down-regulation of NFkB and lower amount of nitrites. However, this behavior was dependent on the treatment, showing most down-regulation of COX-2, TNFα and IL-8 in the curative treatment; more down-regulation of NF-kB in the preventive treatment; and more up-regulation of COX-1 for the suppressor and preventive treatments. Conclusion The anti-inflammatory potential of B. scordioides infusions could be related with the presence of polyphenols as quercetin in the infusion and how this one is consumed. [ABSTRACT FROM AUTHOR]

Objective To study the effects of Cydonia oblonga Miller (COM) total flavonoids (TF) from leaves and fruit on the blood lipid and antioxidant potentials using hyperlipidaemic rat models. Methods Hyperlipidaemic rat models were created with high-lipid emulsion. Rats were distributed into normal controls, hyperlipidaemic models, and daily high (160 mg/kg), medium (80 mg/kg) and low (40 mg/kg) TF from leaves and fruit and simvastatin (5 mg/kg) groups. After four weeks, serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), as well as hepatic superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured. Results Compared with the hyperlipidaemic model group, TF significantly reduced serum TC, TG, LDL-C ( P <0.01), ALT and AST ( P <0.01 or P <0.05) and increased HDL-C ( P <0.05 or P <0.01). TF also reduced MDA ( P <0.01 or P <0.01). Conclusion COM total flavonoids can effectively regulate the metabolism of lipids, and remove oxygen free radicals. This confirms its potential value in the prevention and treatment of hyperlipidaemia. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance In order to explore the traditional medicine practised by the ethnic communities residing in the topographically and climatically challenged Purulia, an underprivileged district of West Bengal, India, a quantitative ethnobiological approach was adopted to document the folkloric use of ethnomedicinals against different sexual, gynaecological and related ailments. Materials and methods Ethnobiological surveys were conducted during 2012–2015 by interviewing 82 informants or traditional healers with the help of a semi-structured questionnaire. The survey included questions on botanical and non-botanical ingredients and additives mixed with monoherbal and polyherbal formulations, vernacular names of the plants and animals, methods of preparation and administration and restrictions during medications. Additional quantitative indices such as use value, informant׳s consensus factor and fidelity level were used for data analysis. Results Twenty eight sexual and gynaecological disorders were found to be treated with 18 monoherbal and 31 polyherbal formulations consisting of a total number of 96 plant species from 86 genera and 47 families and four animal species. A variety of additives, either botanicals or non-botanicals were used with the formulations for higher efficacy and taste enhancement. Fabaceae (16 species) was found to be the most common family of medicinal plants whereas herbs (42.7%) and roots (32%) were the most common habit type and plant part used respectively. Use value, informant׳s consensus factor and fidelity level indicate frequency and coherence of citations. Conclusion Age old belief on traditional medicine prevails in the studied area due to its efficacy, inexpensive price and the remoteness of tribal villages from conventional medical centres. Traditional healers had detailed knowledge of preparations, doses, methods of administration, restrictions during medications, safety and efficacy of using folkloric therapeutics against sexual and gynaecological disorders. Possible synergistic interactions among phytochemicals and additives were indicated to explain enhanced therapeutic efficacy of mixed herbal formulations. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Schisandra chinensis (Turcz.) Baill. (SC) continues to be used as a traditional folk medicine in Asia, especially for the treatment of gastrointestinal (GI) disorders related to gastritis, diarrhea, enterocolitis and abnormal GI motility. Aim of the study Because GI disorders, especially abnormal GI motility, are major lifelong problems, we investigated the effects of SC on the pacemaker activity of the interstitial cells of Cajal (ICCs) in murine small intestine and GI motility. Materials and Methods Enzymatic digestions were used to dissociate ICCs from small intestines, and the whole-cell patch-clamp configuration was used to record potentials generated by cultured ICCs. In vivo effects of SC on GI motility were investigated by measuring the intestinal transit rate (ITR) of Evans blue in normal and GI motility dysfunction mice. Results SC extracts depolarized the membrane potentials of ICCs in a dose dependent manner. Pretreatment with Ca 2+ free solution or thapsigargin (a Ca 2+ -ATPase inhibitor in the endoplasmic reticulum) abolished the generation of pacemaker potentials by ICCs, and under these conditions, SC extract did not depolarize the membrane potentials of ICCs. In addition, membrane depolarizations were inhibited by intracellular GDP β S and by U-73122 (an active phospholipase C (PLC) inhibitor). In normal mice, ITRs were significantly increased by SC extract (0.1–1 g/kg, intragastrically (i.g.)) in a dose dependent manner. Also, SC extract significantly recovered the GI motility dysfunctions in acetic acid (AA)-injected and streptozotocin (STZ)-induced diabetic mice, which are the GI motility animal models. Materials and methods SC extract modulates pacemaker potentials in ICCs in a dose dependent manner via external and internal Ca 2+ regulations, and via G protein and the PLC pathway. In addition, SC extract increased ITRs in normal and abnormal GI motility mice models. This study shows that SC extract offers a basis for the development of a prokinetic agent that prevents or alleviates GI motility dysfunctions. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance This study was planned to assess pharmacological basis for the medicinal use of Flaxseed in constipation and diarrhea. Materials and methods The oil and mucilage of Flaxseeds were studied for their laxative, and antidiarrheal activities in mice. The mechanisms of laxative and antidiarrheal activities were further studied using the isolated tissue preparations (rabbit jejunum and guinea-pig ileum) immersed in Tyrode׳s solution maintained at 37 °C and aerated with carbogen gas. Isotonic responses were measured on spontaneously contracting isolated jejunum and guinea-pig ileum preparations. Results Oral administration of Flaxseed oil (30 and 70 mg/kg, orally) and mucilage (1 and 2.5 g/kg, orally) caused dose-dependent increase in wet feces in mice. The spasmogenic effect of Flaxseed oil was partially blocked by pyrilamine ( p <0.05) and atropine ( p <0.01) in isolated rabbit jejunum whereas atropine completely blocked the effect of Flaxseed mucilage on isolated guinea-pig ileum. When studied for its antidiarrheal effect, Flaxseed oil reduced the castor oil-induced diarrheal score by 49.35% and 84.41% and intestinal secretions by 19% and 33.62% at the oral doses of 100 and 300 mg/kg respectively. In isolated rabbit jejunum preparations, Flaxseed oil produced a dose-dependent inhibition of both spontaneous and low K + (25 mM) -induced contractions in rabbit jejunum. The inhibitory effect against low K + was most sensitive to tetra-ethylammonium chloride, a non-specific K + channel blocker, followed by glibenclamide, a partial ATP-dependent K + channels blocker and 4-Aminopyridine, a voltage gated K + -channel blocker. Conclusions Our results indicate that Flaxseed oil and mucilage exhibit laxative activity, mediated primarily through cholinergic pathway with weak histaminergic effect component evident in Flaxseed oil, which also showed antidiarrheal activity, mediated possibly through K + channels activation. Thus this study rationalizes the medicinal use of Flaxseed in both the constipation and diarrhea with sound mechanistic basis. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Astragali radix is one of the well-known traditional Chinese herbal medicine, and possesses various biological functions, such as hepatoprotective and anticancer. In present study, to investigate the metabolism and pharmacokinetics of the major constituents of A. radix , a sensitive ultra-performance liquid chromatography–electrospray ionization–mass spectrometry (UPLC–MS/MS) method with shorter chromatographic running time was developed and validated for simultaneous quantification of formononetin, ononin, calycosin, calycosin-7-β-glucoside, astragaloside IV and their glucuronide metabolites in rat plasma after oral administration of water extract of A. radix at two different doses. Materials and methods The chromatographic separation was achieved on a C18 column with gradient elution by using a mixture of 0.1% formic acid aqueous solution and acetonitrile as the mobile phase at a flow rate of 0.3 mL/min. A tandem mass spectrometric detection was conducted using multiple-reaction monitoring (MRM) via electrospray ionization (ESI) source in positive ionization mode. Samples were pre-treated by a single-step protein precipitation with methanol, and erlotinib was used as internal standard (IS). Results The current UPLC–MS/MS assay was validated for linearity, intra-day and inter-day precisions, accuracy, extraction recovery, matrix effects and stability. The lowest limit of quantifications (LLOQ) were 1 ng/mL for all analytes. After oral administration, the plasma concentrations of the glucuronides, especially calycosin-3′-glucuronide, were much higher than the parent compounds. The mean half-life (t 1/2 ) was between 1 and 5 h, and the metabolites were eliminated faster than the parent constituents. The median (range) time to reach maximum plasma concentration ( T max ) was between 0.5 and 1 h. Conclusions This is the first study of the pharmacokinetic study of bioactive compounds and their glucuronides in male rat plasma after oral administration of water extract of A. radix . The results demonstrated the biotransformation between the bioactive isoflavonoids and their glucuronides was extensive in rats and provided a significant basis for better understanding the absorption and metabolism mechanism of A. radix . Furthermore, this study could suggest that future studies should focus on the metabolites and biotransformation between the bioactive constituents when conducting a drug efficacy study. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance In Chinese folk medicine, the leaves of Ligustrum robustum Blume (LR) were commonly used in the treatment of obesity and hyperlipidemia. This study aimed to evaluate the anti-obesity effect and mechanisms of total phenylpropanoid glycosides from Ligustrum robustum Blume (LRTPG) in fatty diet-fed C57BL/6J mice. Materials and methods C57BL/6J mice were divided randomly into 6 groups, i.e. , control, model, positive (Orlistat 0.12 g/kg), and LRTPG at three dosages (0.3, 0.6 or 1.2 g/kg), respectively. Control mice were fed with standard diet; the others were fed with fatty diet. After 4 weeks׳ modeling, therapy mice were intragastrically administrated with positive drug or LRTPG for 5 weeks, respectively. Pharmacodynamic effects including body weight, fat weight, Lee׳s index, serum lipid levels, morphological changes and adipocyte area ratio were evaluated. The mechanisms were explored as the factors related to lipids metabolism in gene expressions by real-time PCR, and assured as the protein level of differential gene by Western blotting. Results The anti-obesity effects of LRTPG in all treated mice were shown as decreased body weight, fat mass, Lee׳s index, total cholesterol (TC) level, and adipocyte area. The mechanisms were demonstrated as elevated mRNA and protein levels of adipose leptin, and consequently decreasing mRNA of adipose acyl coenzyme A: diacylglycerol acyltransferase (DGAT) with increasing mRNA of hepatic cholesterol 7α-hydroxylase (CYP7A1), which led to inhibition of triglyceride (TG) synthesis and promotion of cholesterol catabolism. Conclusions The anti-obesity effect of LRTPG in fatty diet-fed mice was related to the up-regulation of leptin, which may provide scientific evidence supporting the traditional usage of LR on obesity in China. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance This paper provides important ethnopharmacological information on plants used in neurological and mental disorders in Navarra. Material and methods Information was collected using semi-structured ethnobotanical interviews with 667 informants in 265 locations. In order to confirm the pharmacological validation of the uses claimed by the informants, monographs from Official International Agencies (ESCOP, Commission E, WHO and EMA) were reviewed. A literature review was conducted focusing on the plants that were widely used but had no published monograph. Results A total of 172 pharmaceutical uses were reported, for 46 plants and 26 families, mainly represented by Lamiaceae (15%), Asteraceae (13%), Rosaceae and Rutaceae (7%, each one), and Clusiaceae , Malvaceae , Papaveraceae and Urticaceae (4%, each one). The most frequently used parts were inflorescence (39%), flowered aerial parts (16%), and aerial parts (13%), followed by inflorescence bract (8%) and leaves (7%). Nine out of 46 plants (20%) and 81 of 172 uses (47%), have already been pharmacologically validated. The remaining 37 plants (of total 46, 80%) have been reported for neurological and mental disorders and need to be screened through standard pharmacological and clinical procedures for their activities. The most used species are Chamaemelum nobile (L.) All., Jasonia glutinosa (L.) DC., and Santolina chamaecyparissus L. ssp. squarrosa (DC.) Nyman, in all cases the administration as infusion. Conclusions Data indicate a high degree of plants knowledge in Navarra regarding neurological and mental disorders. The present study constitutes a good basis for further phytochemical and pharmacological research of C. nobile , J. glutinosa and S. chamaecyparissus , which could be of interest in the design of new inexpensive, effective and safe drugs. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Paeonia suffruticosa Andrews (PSE) is a well-known Chinese medicine that has been widely used as an anti-tumor, anti-oxidative and anti-inflammatory agent. cis - and trans -gnetin H are two resveratrol oligomers isolated from the seeds of PSE. Although resveratrol is widely considered to be one of the most valuable natural chemopreventive agents and there are numerous studies on the antitumor activities of resveratrol, little is known about the antitumor properties of cis - and trans -gnetin H. Materials and methods The inhibitory effects of cis - and trans -gnetin H in different human cancer cell lines were assessed using fluorescent viability tests. Cytotoxicity in human lung and breast cancer cells was detected via nuclear condensation, cell permeability, and changes in the mitochondrial membrane potential (∆ψm). Apoptosis in human lung and breast cancer cells was assessed by flow cytometry, a luminescence assay and high-content screening analysis. Finally, a xenograft mice model was used to examine the efficacy of cis -gnetin H on lung tumors. Results cis - and trans -gnetin H have superior activity in inhibiting the proliferation of four human cancer cell lines, A549 (lung), BT20 (breast), MCF-7 (breast) and U2OS (osteosarcoma), and promote cell apoptosis, while having a minimal effect on two normal human epithelial cell lines, HPL1A (lung) and HMEC (breast) used as controls. cis - and trans -gnetin H promote apoptosis by releasing mitochondria cytochrome c , activating caspase 3/7 and inhibiting NF-κB activation. Flow cytometry analysis shows that cis - or trans -gnetin H arrested the cell cycle of cancer cells at the G0–G1 phase. Moreover, cis -gnetin H suppressed the growth of xenograft lung tumors in mice. Conclusion Collectively, our findings demonstrate the promise of the natural compounds cis - and trans -gnetin H as candidates for cancer chemotherapy agents. [ABSTRACT FROM AUTHOR]

Etnopharmacological relevance Infusions of Herniaria hirsuta L., Herniaria glabra L. and Herniaria fontanesii J.Gay are well known in Moroccon folk medicine for the treatment of biliary dyskinesia, (uro)lithiasis or as a diuretic. Herniariae Herba which can contain H. glabra and H. hirsuta is known in Europe as an urological drug. Aim of the study To investigate the efficacy of a standardized infusion of Herniaria hirsuta against choleltihiasis, and evaluation of its genotoxicity. Methods and materials An analytical HPLC-UV method to quantify flavonoids and saponins present in the extract of H. hirsuta was developed and validated. An in vivo experiment to evaluate the cholesterol lowering effect of a infusion of H. hirsuta in the gall bladder of dogs was carried out. Dogs were divided into 3 groups i.e. control dogs (CG), dogs treated with ursodeoxycholic acid (UDCA) (2×7.35 mg/kg body weight/day) and dogs treated with the standardized infusion (HG) (2×48.5 mg/kg body weight/day). Dogs were fed a fatty diet during 120 days after which a diet without additional fat was introduced till day 180. Treatment started 30 days after introduction of the fatty diet and lasted till the end of the experiment. A bile and blood sample of each dog was collected every 30 days, after which the concentration of cholesterol was determined. An Ames test was performed according to the OECD-guidelines. Results The validated HPLC-UV method showed a linear calibration model and an acceptable precision for the total flavonoid content (total content 4.51%) as well as the total saponin content (12.74%). The in vivo experiments already showed a minor difference for bile cholesterol between CG and HG after 30 days of treatment with the infusion, and the difference was more pronounced after 90 days of treatment. Even 30 days after discontinuation of the cholesterol-rich diet a significant difference remained between CG and HG. There was no statistically significant difference in blood cholesterol. The Ames test showed that the infusion of H. hirsuta could be considered as being free from genotoxic risks. Conclusion A method for the standardization of a infusion of Herniaria hirsuta was developed and validated. Prolonged use of this standardized H. hirsuta extract resulted in a cholesterol-lowering effect in the bile of dogs. Since this pharmacological effect prevents the formation of gallstones and can contribute to solving existing gallstones, a standardized infusion of H. hirsuta may have a positive effect in the treatment of gallstones in human patients. [ABSTRACT FROM AUTHOR]

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, 1.26 g/kg/d), and UUO/enalapril (10 mg/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-β1-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 1.26 g/kg and enalapril at 10 mg/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-β1, α-SMA, fibronectin and collagen matrix expressions were also declined with YGP treatment in both UUO kidneys and TGF-β1-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-β and its downstream regulatory signaling pathway, including Smad2/3. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance St John׳s Wort ( Hypericum perforatum , SJW) is a widely used herbal medicine in western countries but also an important Uygur drug in China. Hypericin (HY) is the main components in SJW extracts, which is used to treat fatigue, weakness, and mild depression. The aim of this study was to investigate the anti-depression effects of HY on chronic unpredictable mild stress (CUMS) model rats and identify the possible mechanisms. Materials and methods In this study, the protective effects of HY on CUMS-induced depression in rats were investigated by using a combination of behavioral assessments and urinary metabolites analysis. Urinary metabolites analyses were performed using LC–MS/MS in conjunction with principal components analysis (PCA) after oral administration of either HY or Venlafaxine (VF) for 27 days. During the procedure of experiment, food consumption, body weight, adrenal gland, thymus and spleen indices, behavior scores, sucrose consumption, and stress hormone levels were measured. Results Changes in the classic behavioral tests and pharmacological biochemical indices reflected that HY alleviated the symptoms of depression in a shorter period than VF, which was used as positive control for antidepression. Metabolites analysis of urine revealed that HY affected excitatory amino acids and monoamine neurotransmitter metabolites. Remarkably, urinary valine was increased remarkably by HY, even much higher than CUMS group. These results provide important mechanistic insights into the protective effects of HY against CUMS-induced depression and metabolic dysfunction. Conclusion As the most important active ingredient in SJW extracts, HY possesses the better protective effect against CUMS-induced depression symptoms and metabolic disturbances. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Shubat, probiotic fermented camel milk, has been used both as a drink with ethnic flavor and a medicine among Kazakh population for diabetic patients. Kazakh people have lower diabetic prevalence and impaired fasting glucose (IFG) than do other ethnic groups living in Xinjiang China, which might be related to the beneficial properties of shubat. We therefore prepared shubat in laboratory and tested anti-diabetic activity and evaluated its possible hypolipidemic and renoprotective effects in type 2 diabetic rats. Materials and methods Type 2 diabetic rats were induced by an administration of high-glucose-fat diet for 6 weeks and an intraperitoneal injection of streptozotocin (STZ, 30 mg/kg). Diabetic rats were divided randomly into four groups and treated for 28 days with sitagliptin (30 mg/kg) or shubat (6.97×10 6 lactic acid bacteria+2.20×10 4 yeasts) CFU/mL, (6.97×10 7 lactic acid bacteria+2.20×10 5 yeasts) CFU/mL and (6.97×10 8 lactic acid bacteria+2.20×10 6 yeasts) CFU/mL. In addition, a normal control group and a diabetic control group were used for comparison. All drugs were given orally once daily 10 mL/kg for 4 weeks. Fasting blood glucose (FBG) and body weight (BW) were measured before treatment and every week thereafter. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c), serum creatinine (SCr), blood urea nitrogen (BUN), C-peptide, glycated hemoglobin (HbAlc), glucagon-like peptide-1 (GLP-1) levels and pancreas tissue sections were tested after 4 weeks. Results Shubat demonstrated positive hypoglycemic activity on FBG, HbAlc, C-peptide and GLP-1 levels, high dose shubat decreased FBG ( P <0.01) and HbAlc ( P <0.05), increased C-peptide ( P <0.05) and GLP-1 ( P <0.01), decreased serum TC, TG, LDL-c ( P <0.05), increased HDL-c ( P <0.01), and improved the reduction of body weight as well as decreased SCr and BUN levels ( P <0.01) compared to diabetic controls. Histological analysis showed shubat protected the function of islets of type 2 diabetic rats. Conclusion The results of this study indicate that shubat has significant hypoglycemic potential in T2D rats and may modulate lipid metabolism and protect renal function in the type 2 diabetic condition, which might be related to various probiotics acting through promoting the release of GLP-1 and improving the function of β-cells. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Glycyrrhiza uralensis Fisch. and processed radix Aconiti kusnezoffii are the main components in many Chinese traditional patent medicines with the ratio of 1:1, which are used for treatment of rheumatoid arthritis, heart failure and so on. Glycyrrhizic acid, glycyrrhetic acid, liquiritigenin and isoliquiritigenin are the essential bioactive triterpenes and flavones in the extract of G. uralensis , which were analysis by a simple but accurate method. Materials and methods In the present study, a specific HPLC method was developed and validated for simultaneous determination of pharmacokinetic parameters of glycyrrhizic acid, glycyrrhetic acid, liquiritigenin and isoliquiritigenin in G. uralensis after oral administration of single herb extract and a combination of two herbs extracts respectively. Results The calibration curves of the four components had good linearity higher than 0.9991 in the measured range. The intra-day and inter-day precisions (RSD) at different levels were both within 9.73%, and the accuracies (RE) were in the range of −7.9–8.0%. Compared with pharmacokinetic parameters of G. uralensis administered orally, values of AUC and C max of liquiritigenin and isoliquiritigenin decreased significantly ( p <0.05), plasma concentrations of glycyrrhizic acid rose slightly and bimodal phenomenon of concentration–time of isoliquiritigenin and glycyrrhetinic acid disappeared after combined administration. Discussion and conclusions Some components in the extract of processed radix A. kusnezoffii showed different effects on the pharmacokinetics of the four ingredients in G. uralensis . [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Huangqi decoction was first described in Prescriptions of the Bureau of Taiping People׳s Welfare Pharmacy in the Song Dynasty (AD1078). It consists of Radix Astragali ( Astragalus membranceus (Fisch.) Bge. Root, Huangqi) and Radix Glycyrrhizae ( Glycyrrhiza uralensis Fisch., root and rhizome, Gancao), and it is an effective recipe that is usually used to treat consumptive disease and chronic liver diseases. Astragaloside (AS) is a main component of Radix Astragali had an effect similar to the Huangqi decoction on hepatic fibrosis. Aim of the study Cholestasis is associated with a number of chronic liver diseases and Notch signaling has been demonstrated to be involved in ductular reaction. Previous studies have shown that AS can prevent the progression of cholestatic liver fibrosis, however, whether AS affects the Notch signaling pathway is unclear. Materials and methods Cholestatic liver fibrosis was established by common bile duct ligation (BDL) in rats. At first weekend, the rats were randomly divided into a model group (BDL), an AS group, and a Sorafenib positive control group (SORA) and treated for 3 weeks. Bile duct proliferation and liver fibrosis were determined by tissue staining. Activation of the Notch signaling pathway was evaluated by analyzing expressions of Notch-1, -2, -3, -4, Jagged 1 (JAG1), Delta-like (DLL)-1, -3, -4, Hes1, Numb and RBP-Jκ. Activation of the Wnt signaling pathway was evaluated by analyzing expressions of Wnt-4, -5a, -5b, Frizzled (Fzd)-2, -3, -6 and β-catenin. Results (1) Compared with the BDL group, AS significantly reduced the deposition of collagen and the Hyp content of liver tissue and inhibited the activation of HSCs. In addition, AS significantly decreased the protein and mRNA expressions of TGF-β1 and α-SMA. In contrast, AS significantly enhanced expression of the Smad 7 protein. AS also reduced biliary epithelial cell proliferation, and reduced the mRNA and protein expressions of CK7, CK8, CK18, CK19, OV6, Sox9 and EpCAM. (2) The mRNA and protein expressions of Notch-2, -3, -4 and JAG1 were significantly reduced in the AS compared to the BDL group. In contrast, the mRNA and protein level of Numb was clearly enhanced after AS treatment. Conclusion AS may prevent biliary liver fibrosis via inhibition of the Notch signaling pathway, thereby inhibiting the abnormal proliferation of biliary epithelial cells. Results indicate that AS may be a potential therapeutic drug for cholestatic liver disease. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Eucommiae cortex (EC), the bark of Eucommia ulmoides Oliv., has been traditionally used to treat many diseases in China for more than 2000 years. The pharmacological effects are primarily attributed to the presence of lignans, iridoids and phenolics, which are main active ingredients in EC. Aim of the study First, to investigate the active ingredients that can be absorbed into the rat plasma according to which ingredients exhibit significant correlation of drug concentration–time curve. Second, to establish an efficient ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method for simultaneous determination of ingredients absorbed in rat plasma. Finally, to investigate gender effect on the pharmacokinetics of the ingredients absorbed in male and female rats plasma after oral administration with EC extract. Materials and methods 18 ingredients from EC were detected by UPLC-MS/MS, 9 out of 18 ingredients were absorbed into rat plasma. And 5 ingredients exhibit significant correlation of drug concentration–time curve. They were pinoresinol di-O- β -d-glucopyranoside (PDG), geniposide (GE), geniposidic acid (GA), aucubin (AN) and chlorogenic acid (CA). The analytes were extracted from rat plasma via a simple protein precipitation procedure and osalmid was used as the internal standard. Chromatographic separation was achieved on a Waters ACQUITY HSS T3 column (2.1 mm×100 mm, 1.8 μm) using a gradient elution program with acetonitrile and 0.1% formic acid water as the mobile phase, with a flow rate of 0.3 mL min −1 . The detection was performed on a triple-quadrupole tandem mass spectrometer by multiple reactions monitoring (MRM) mode in a positive ion mode via electrospray ionization (ESI). The transition monitored were / z 683.00[M+H] + →235.10 for PDG, / z 389.00[M+H] + →208.80 for GE, m / z 375.00[M+H] + →194.79 for GA, m / z 364.00[M+NH 4 ] + →148.81 for AN, m / z 355.10[M+H] + →162.84 for CA and m / z 230.03[M+H] + →120.77 for internal standard. Results The developed method showed good linearity over a wide concentration range, the lower limits of quantification and higher accuracy and precision for determination of the 5 analytes. Then the method was applied to study the pharmacokinetics in rats, and the results indicated that there were significant differences in pharmacokinetic parameters of the analytes between the male and female rats, and absorptions of these analytes in male group were all significantly higher than those in female group. Conclusion This study established an efficient, sensitive and selective UPLC-MS/MS method for simultaneous determination of the five ingredients in rat plasma, and it could be successfully applied to the comparative pharmacokinetic studies in male and female rats after oral administration with EC extract. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Semen Cassiae, called Juemingzi in China, is the seed of the annual Cassia obtusifolia L., of the leguminosae family. It has been used as healthy drinks to alleviate constipation and improve eyesight for many years in China. Aim of the study A simple sensitive UHPLC–MS/MS method has been developed and validated for the simultaneous determination and pharmacokinetic study of chrysophanol, emodin, aloe-emodin, rhein, physcion, obtusifolin and aurantio-obtusin in rat plasma. Materials and methods Chromatographic separation was accomplished on a C 18 column with a 5 min gradient elution. A tandem mass spectrometric detection was conducted using multiple reaction monitoring (MRM) via an electrospray ionization (ESI) source and operating in the negative ionization mode. The samples were prepared by LLE with ethyl acetate after being spiked with an internal standard (butylparaben). Results The current UHPLC–MS/MS assay was validated for linearity, intra-day and inter-day precisions, accuracy, extraction recovery and stability. The method was linear for all analytes over investigated range with all correlation coefficients greater than 0.9900. The lower limit of quantification (LLOQ) of each analyte was lower than 5 ng/mL. Intra-day and inter-day precisions were less than 14.99%. The relative errors of accuracies were in the range of −14.60% to 5.11%. The mean recoveries and matrix effects of anthraquinones were higher than 65.54% and 93.26%, respectively. After oral administration 1.25 g/kg of Semen Cassiae extract, the maximum plasma concentration ( C max) was 1189.25±333.40 ng/mL for chrysophanol, 38.48±3.15 ng/mL for emodin, 79.20±34.76 ng/mL for aloe-emodin, 152.70±23.91 ng/mL for rhein, 461.85±266.77 ng/mL for physcion, 243.59±22.71 ng/mL for obtusifolin and 1950.44±638.86 ng/mL for aurantio-obtusin, respectively. The time to reach the maximum plasma concentration ( T max ) was 0.333±0.071 h for chrysophanol, 0.333±0.059 h for emodin, 0.333±0.009 h for aloe-emodin, 0.333±0.09 h for rhein, 0.167±0.002 h for physcion, 0.5±0.074 h for obtusifolin and 0.333±0.06 h for aurantio-obtusin, respectively. Conclusion The proposed method was further applied to investigate the pharmacokinetics of seven anthraquinones after oral administration of Semen Cassia extract to rats. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Inflammatory bowel disease (IBD) is associated with chronic inflammation of the intestinal tract. Piperine (1-peperoylpiperidine), the primary lipophilic component in black pepper ( Piper nigrum ) and long pepper ( Piper longum ), has been reported to be effective for anti-inflammatory. Rencently, several ethnopharmacological purity compounds, such as baicalin and artemisinin, are reported to have potentially therapeutic role in treating IBD. In the present study, the effects of piperine on pregnane X receptor (PXR)-mediated CYP3A expression and its therapeutic role in IBD were investigated. Materials and methods LS174T cells and C57BL/6J mice were treated by the piperine. Gene expressions were analyzed by real-time PCR, Western blot analysis, transient transfections assay and histological analysis. Results Data indicated that treatment of LS174T cells with piperine markedly increased both CYP3A4 and PXR mRNA and protein. Transient transfection experiments indicated that transcriptional activation of the CYP3A4 gene via piperine was PXR-dependent. Data show that pre-administration of piperine decreased clinical hallmarks of colitis in DSS-treated PXR mice as measured by body weight loss and assessment of diarrhea, rectal bleeding, colon length, and histology. Inflammatory mediators (CCR2, ICAM-1, IL-1β, IL-6, IL-10, iNOS, MCP-1, and TNFα) after DSS treatment were significantly decreased in mice pretreated with piperine but corresponding conditions did not occur in mice with down-regulation of PXR by small interfering RNA (siRNA). Conclusion Piperine is a potential agonist of PXR and an inducer of PXR, which may induce CYP3A4 gene expression at the mRNA and protein levels. These results establish that piperine may contribute to prevention or reduction of colonic inflammation. [ABSTRACT FROM AUTHOR]

Aim Clematis terniflora DC. has been widely used as a traditional Chinese medicine for the treatment of tonsillitis, rheumatoid arthritis, and prostatitis. Despite its widespread use in China, there are currently no studies systematically examined its therapeutic effects and mechanism of action. As such, the present study was conducted to evaluate the anti-inflammatory, antinociceptive, and immunomodulatory effects of C. terniflora DC. using rodent and cellular models. Methods The anti-inflammatory properties of the 70% ethanol eluted fraction of the 70% ethanol extract of C. terniflora DC. (EECTD) were evaluated using the xylene-induced ear swelling test, the carrageenan-induced edema model, and the cotton pellet granuloma method. Its antinociceptive activities were determined using both the acetic acid-induced writhing test and the hot plate assay. In parallel, we conducted an in vitro assay in LPS-induced RAW264.7 cells to examine the anti-inflammatory effects of EECTD and its purified form, aurantiamide acetate (AA) on inhibition of nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) release. Results EECTD (300 mg/kg) significantly reduced the number of writhing, extended the pain response latency, and suppressed xylene-induced ear swelling. Each EECTD treatment group also had significant inhibition of cotton granulation formation in addition to reduced carrageenan-induced paw edema. EECTD was also shown to alleviate signs of inflammation in histopathological paw sections. However, it had a less noticeable effect on mouse ear swelling in the delayed type hypersensitivity test. A purified compound was isolated from EECTD and its structure was identified as AA. In vitro experimental results showed that both EECTD and AA were able to significantly inhibit the release of pro-inflammatory cytokines NO and PGE 2 on LPS-induced RAW264.7 cells. Conclusion These results suggest that EECTD has significant anti-inflammatory and antinociceptive activities, partially related to one of the active substances identified as AA. We hypothesize that these effects are related to its ability to inhibit the production of cytokines NO and PGE 2 . However, further work will be needed to determine its exact mechanism of action. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Radix Polygala has a long history of use as a sedative in traditional Chinese medicine and its major ingredients are saponins, which are recognized effective in memory improvement but highly toxic to gastricintestinal mucosa. Polygala saponin hydrolysates (PSH), an alkaline hydrolysis product and also the intestinal metabolites of the saponins, exhibited stronger effects in improving memory of mice and had less toxicity than its original saponins. The present study aims to develop a sensitive LC-MS/MS method for simultaneously determining PSH three major active components, 3,4,5-trimethoxycinnamylic acid (TMCA), p-methoxycinnamylic acid (PMCA) and tenuifolin (TF), in rat plasma and apply the method to a pharmacokinetic study. Materials and methods The acidic plasma (100 μl) was treated by liquid–liquid extraction with ethyl acetate and reconstituted sample was analyzed on a C 18 column eluted with acetonitrile–water (50:50) containing 0.2% formic acid at 0.4 ml/min. The mass detection in negative electrospray ionization was used. The ion pairs for multiple reaction monitoring were set at m / z 237.0/103.0, 177.0/116.6 and 679.5/425.3 for TMCA, PMCA and TF, respectively. Their pharmacokinetic profiles were studied in rats after intravenous and oral dose of PSH at 20 and 100 mg/kg, respectively. Results The calibration curves had good linearity ( r 2 >0.99) for TMCA, PMCA and TF within the tested concentration ranges. The limits of detection and quantification were 1, 10, 0.5 ng/ml and 10.0, 20.0, 1.0 ng/ml, respectively. The intra-day and inter-day precisions were less than 18.9% and accuracies between 93.2% and 113.3%, and the extraction recovery ranged from 91.2% to 112.1% for all analytes. The pharmacokinetic study showed that TMCA, PMCA and TF could be rapidly absorbed into the circulation and reached their peak concentrations at about 9.1, 9.0 and 24.0 min, respectively. TF had a lower oral bioavailability (2.0%) than TMCA (90.1%) and PMCA (96.5%), but it remained in the body much longer ( t 1/2, λz , 4.8 h, oral dose) than TMCA (0.6 h) and PMCA (0.9 h). Conclusions A sensitive LC-MS/MS method was developed and applied to a pharmacokinetic study of TMCA, PMCA and TF of PSH in rats. The three components are proved to be bio-available active components of PSH and might display their in vivo pharmacological activities at different levels and different time periods after oral administration. [ABSTRACT FROM AUTHOR]

Ethnopharmacology relevance He-Ying-Qing-Re Formula (HF) is a formula modified from “Si-Miao-Yong-An Decoction”, a traditional Chinese medical classic emerged in the Qing dynasty and has been reported for treatment of vascular diseases. HF, containing 8 herbs, has been used in local hospital for decades as a complementary method for diabetic retinopathy (DR) with retinal vascular dysfunction. Clinical reports revealed HF could ameliorate vision defects, microaneurysms, hemorrhages and macular edema. The aim of this study is to investigate the anti-DR action of HF and its underlying mechanism experimentally. Methods Chromatographic fingerprinting of HF and rodent model of DR were established; hypoglycemic effect of HF was measured by fasting, random blood glucose and glucose tolerance test; vascular degeneration was measured by retinal digestion; blood-retina-barrier (BRB) permeability was assessed with Evans Blue leakage assay. Advanced glycation end products (AGEs) were measured in vitro and in vivo level; Migration of retinal vascular endothelial cells were determined by wound healing and transwell chamber assays; permeability of endothelial monolayer was monitored with dextran transport. AGEs-related proteins and signaling were measured with immunoblotting and immunohistochemistry. Results Chlorogenic acid, ferulic acid and arctin were identified as major components in HF; HF suppresses retinal vasculature degeneration and BRB permeability damage without significant inhibition on hyperglycemia; HF reduces in vitro and in vivo formation of AGEs and AGEs-induced migration as well as permeability of retinal vascular endothelial cells. Expression of tight junction proteins Zo-1 and Claudin-1 was increased while activation of AGEs receptor and downstream signaling Akt were suppressed upon HF treatment. Conclusions HF exhibits protective effect against diabetic retinopathy, which may be associated with inhibition on AGEs and recovery on endothelial dysfunction via modulation of tight junction and AGEs downstream signaling. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance The dry ripe fruit of the Akebia quinata ( A. quinata ) plant is used as an analgesic, an antiphlogistic, and a diuretic in traditional medicine. A. quinata has also been used in Korea as a crude drug for treating obesity. The aim of the study was to determine the anti-obesity and hypolipidemic effects of A. quinata extract (AQE) in mice consuming a high-fat diet and in 3T3-L1 adipocytes. Materials and methods We measured obesity-related physiological parameters, gene expression, and protein phosphorylation in mice consuming a high-fat diet supplemented with AQE (400 mg/kg/day) for 6.5 weeks. Results AQE reduced gain in body weight, adipose tissue weight, and serum lipid levels in mice consuming a high-fat diet. AQE supplementation reduced expression of genes related to adipogenesis and increased expression of PPARα, acetyl-CoA oxidase, and adiponectin in the epididymal adipose tissue. Furthermore, AQE increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase, both of which are related to fatty acid oxidation, in vivo. HPLC analysis revealed that AQE contained chlorogenic acid, isochlorogenic acid A, and isochlorogenic acid C. AQE and all of these constituents inhibited differentiation of 3T3-L1 cells and enhanced AMPK phosphorylation. Conclusions These results suggest the AQE exerted anti-obesity and hypolipidemic effects in mice consuming a high-fat diet by regulating adipogenesis and fatty acid oxidation via AMPK activation. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Pimpinella anisum L. is considered one of the first plants used for medicinal purposes. Pharmacological actions of the plant on the central nervous system have been proven but previous analyses have focused on anticonvulsant and neuroprotective actions. In traditional medicine worldwide, the use of Pimpinella is commonly recommended as a tranquilizer, although no scientific information supporting this use is available. Therefore, it was decided to investigate the central actions of the plant to observe behavioral responses, with an emphasis on the emotional component. Aim of study To investigate the effects of the aqueous extract of Pimpinella seeds on exploratory activity and emotional behavior in rats using the open field and elevated plus maze tests. Materials and methods Seeds of Pimpinella were extracted with distilled water, concentrated and freeze-dried yielding the aqueous extract(AE). Rats were divided into four groups: control(water 5 mL/kg, p.o.) and AE 0.5, 1.0 and 2.0 g/kg, p.o. Individual observations were performed in an open field and the parameters locomotor activity, rearing, grooming and defecation were recorded. In elevated plus maze test, rats were divided into four groups: control(water 5 mL/kg, p.o.) and AE 0.5, 1.0 and 2.0 g/kg, p.o. The parameters arm entries, total time spent in open and closed arms; and total number of arrivals at the end of an open or closed arm were recorded for each rat. Results Among the parameters assessed with the open field test, only rearing was reduced in the AE 0.5 g/kg group. When AE 1.0 g/kg was administered, only the initiation of exploratory activity was delayed, without impairing the animals׳ general activity. The highest dose of AE (2.0 g/kg) induced a reduction in the animals׳ habituation during the open field test within the same session, as evidenced by the maintenance of high levels of peripheral locomotion and rearing throughout the test. On the elevated plus maze test, no alterations were observed in the responses of the animals relative to controls for all doses tested. Conclusion These results failed to support anxiety-related central action of the aqueous extract of Pimpinella seeds, invalidating popular beliefs regarding a tranquilizing effect. However, a habituation-related central action of the extract was demonstrated, suggesting action of bioactive compounds on central learning-related areas. The characterization of effects that may interfere with cognitive processes reinforces caution regarding indiscriminate consumption of the plant, especially in individuals with deficits, such as Alzheimer׳s Disease patients. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Thuja occidentalis L. (Cupressaceae) has been used in folk medicine for the treatment of rheumatism, amenorrhea, cystitis, and uterine carcinomas, and as an abortifacient and contraceptive. Aim of the study The present study aimed to determine whether T. occidentalis oil and α-thujone could be beneficial in the treatment of polycystic ovary syndrome (PCOS). Materials and methods T. occidentalis oil and α-thujone were administered to rats with letrozole-induced PCOS for 21 days. At the end of 21 days, the rats were sacrificed and blood samples were taken by cardiac puncture. The levels of serum gonadotropins, steroids, blood lipid, leptin, and glucose and the values of antioxidant parameters were measured. Results The results demonstrated that estradiol and progesterone levels significantly increased, while luteinizing hormone (LH) and testosterone levels decreased in the T. occidentalis- and α-thujone-administered groups. The plasma low-density lipoprotein-cholesterol (LDL-C), leptin, and glucose concentrations were also significantly decreased in the T. occidentalis and α-thujone groups when compared to the control group. Histopathological findings demonstrated that the T. occidentalis and α-thujone groups displayed good healing. According to the phytochemical analyses, 25 compounds were identified in the T. occidentalis oil. The main constituents of the oil were the monoterpene ketones α- and β-thujone, fenchone, and sabinene, as well as the diterpenes beyerene and rimuene. Conclusion T. occidentalis essential oil and its active component, α -thujone, can be used for the treatment of PCOS without inducing osteoporosis. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Lonicerae japonicae has shown antibacterial, anti-inflammatory, antipyretic, antioxidant, antiviral, and protective effects in animal models of chronic obstructive pulmonary disease. Aim of the study To investigate the effects of Flos L. japonicae (FLJ), a traditional Chinese medicinal herb, on acute lung inflammation induced by lipopolysaccharide (LPS), in vivo, using a murine model. Materials and methods Thirty 6-week-old female BALB/c mice were challenged with intratracheal LPS before treatment with FLJ or vehicle. FLJ was examined for its capacity to influence an LPS-induced increase in IL-10 and decrease in TNF-α, IL-1β and IL-6 as measured in murine bronchoalveolar lavage (BALF). Results FLJ increased nuclear Sp1 binding activity thereby enhancing the expression of IL-10 and decreased nuclear NF-κB binding activities thereby inhibiting the expression of TNF-α, IL-1β and IL-6 in the lung. The up-regulation of Sp1 activity by FLJ was through incremental phosphorylation of ERK. By contrast, the down-regulation of NF-κB activity by FLJ was through suppression of the phosphorylation of IκB, p38, and JNK. Conclusions We demonstrated FLJ has protective activity against LPS-induced lung inflammatory cytokine release. Anti-inflammatory cytokine, IL-10, may prove beneficial in the treatment of endotoxin-associated lung inflammation. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Gouania longipetala is commonly used in Cameroonian traditional medicine to manage women fertility and menopausal complaints. However, despite this use, the estrogenic properties of G. longipetala have not been studied until now. Aim of study The present study was aimed to assess estrogenic activities of the stem bark aqueous (GLA) and ethanolic (GLE) extracts of G. longipetala in post-menopause-like model of ovariectomized (Ovx) Wistar rats. Material and methods Animals were either sham-operated or Ovx. 84 days after ovariectomy, animals were divided into seven groups of five animals and were daily treated for 28 days with distilled water (10 mL/kg) for group 1, 2% solution of Tween 80 (10 mL/kg) for group 2, estradiol valerate (1 mg/kg) for group 3, GLA (45 or 180 mg/kg) and GLE (40 or 160 mg/kg) for groups 4 to 7 respectively. Sham-operated animals daily received distilled water (10 mL/kg). During the experimental period, the body weight was registered every week. At the day 29, blood pressure was registered by invasive method while uterine and vagina morphometry as well as body, uterine and abdominal fat weights changes were analyzed. Serum levels of total cholesterol, triglycerides, HDL-cholesterol and LDL-cholesterol were determined. Moreover, oxidative stress markers such as nitrites, reduced glutathione (GSH) and malondialdehyde (MDA) were measured in homogenized liver and aorta. Results Compared with the sham control, vagina and uterine dystrophy and elevated blood pressure were observed in Ovx rats treated with vehicles. Biochemical parameters showed a significant increase of total cholesterol, triglycerides, LDL-cholesterol and MDA as well as a significant decrease of nitrites and GSH in Ovx animals treated with vehicle as compared to sham group. GLA and GLE displayed estrogen-like effects on vagina and did not affect uterine wet weight and epithelial height compared with vehicle groups. Both extracts displayed anti-atherogenic properties by reducing AI, AIP and LDL-cholesterol level as compared to vehicles groups. GLA and GLE significantly prevented the increase of MDA induced by ovariectomy as compared to rats treated with vehicles. Conclusion This study showed that GLA and GLE exhibited estrogenic effects by providing vaginal lubrication, by modulating blood pressure and improving lipid profile, oxidative status and endothelial function and may not have an undesirable influence on the endometrium in ovariectomized rats. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Saponins of many herbs are known to possess anti-cancer effect. Aim of the study The present study aimed to investigate the growth inhibitory effect of Trillium tschonoskii steroidal saponins in a mouse model of colitis-associated colorectal cancer and a human colorectal cancer cell line HT-29, and isolate some major constituents and evaluate their anti-tumor activity. Materials and methods Forty male ICR mice were administered with 1, 2-dimethyl-hydrazine (DMH) and dextran sodium sulfate (DSS). Ten mice were given no further treatment, the rest were administered with different doses of TTS (5, 10, 20 mg/kg) orally, every three days from the 9th week to the 20th week. Results TTS effectively protected ICR mice against DMH/DSS-induced tumorigenesis. The incidence of tumor development was 90% (9/10) in the mice treated with DMH/DSS, but that was reduced to 50% (5/10), 40% (4/10), and 20% (2/10), respectively, in the mice treated with 5%, 10%, and 20% of TTS. Results of Ki-67 staining, TUNEL assay and caspase-3 activity assay revealed that TTS moderately decreased abnormal proliferation and increased apoptosis of colonic epithelial cells. It inhibited the growth and triggered the apoptosis of HT-29 cells, partly through suppressing mitogen-actived protein kinases (MAPKs) and triggering mitochondrial-mediated apoptotic pathway. Three compounds, namely, Paris saponin VII, polyphylloside III and Paris saponin VI, were important active compounds in TTS. Conclusion These data suggest that TTS has a potential role in clinical prevention and treatment for colorectal cancer. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Phyllanthus acidus (L.) Skeels (Phyllanthaceae) has traditionally been used to treat gastric trouble, rheumatism, bronchitis, asthma, respiratory disorders, and hepatitis. Despite this widespread use, the pharmacological activities of this plant and their molecular mechanisms are poorly understood. Therefore, we evaluated the immunopharmacological activities of the methanolic extract of the aerial parts of this plant (Pa-ME) and validated its pharmacological targets. Materials and methods Lipopolysaccharide (LPS)-treated macrophages, an HCl/EtOH-induced gastritis model, and an acetic acid-injected capillary permeability mouse model were employed to evaluate the anti-inflammatory activity of Pa-ME. Potentially active anti-inflammatory components of this extract were identified by HPLC. The molecular mechanisms of the anti-inflammatory activity were studied by kinase assays, reporter gene assays, immunoprecipitation analysis, and overexpression of target enzymes. Results Pa-ME suppressed the production of nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) and prevented morphological changes in LPS-treated RAW264.7 cells. Moreover, both HCl/EtOH-induced gastric damage and acetic acid-triggered vascular permeability were restored by orally administered Pa-ME. Furthermore, this extract downregulated the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 and reduced the nuclear levels of NF-κB. Signalling events upstream of NF-κB translocation, such as phosphorylation of Src and Syk and formation of Src/Syk signalling complexes, were also inhibited by Pa-ME. The enzymatic activities of Src and Syk were also suppressed by Pa-ME. Moreover, Src-induced and Syk-induced luciferase activity and p85/Akt phosphorylation were also inhibited by Pa-ME. Of the identified flavonoids, kaempferol and quercetin were revealed as partially active anti-inflammatory components in Pa-ME. Conclusion Pa-ME exerts anti-inflammatory activity in vitro and in vivo by suppressing Src, Syk, and their downstream transcription factor, NF-κB. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Salvia chinensis Benth ( S. chinensis ) is a traditional herb applied in the treatment of hepatocellular carcinoma (HCC). Polysaccharides abundantly exist in this plant. However, it remains poorly understood if polysaccharides from S. chinensis (PSSC) contribute to its anti-HCC activity. Materials and methods The in vivo anti-HCC activity of PSSC was evaluated in Kunming mice bearing H22 ascitic hepatoma cells. An array of physiological indexes was measured to evaluate toxicological effects on host animals. Subgroups of immune cells were purified by a magnetic-activated cell sorting system and analyzed by flow cytometry. Reverse transcription real-time PCR and immunoblotting were recruited to determine the effects of PSSC on the cellular signaling of different subgroup of immune cells. Results PSSC suppressed in vivo proliferation of H22 cells with undetectable toxic effects on tumor-bearing mice. PSSC alleviated tumor transplantation-induced CD4+ T cell apoptosis and dysregulation of serum cytokine profiles, which elevated cytotoxic activities of natural killer and CD8+ T cells. PSSC reduced serum levels of prostaglandin E2 (PGE2). Injection of exogenous PGE2 completely abrogated the antitumor immunostimulatory activity of PSSC. Cyclic adenosine monophosphate (cAMP) is the second messager of PGE2. In CD4+ T cells, PSSC substantially declined intracellular cAMP. This event elevated protein levels of JAK3, enhancing STAT5 phosphorylation and STAT5-depedent expression of anti-apoptotic genes. Cyclooxygenase-2 is the key enzyme mediating biosynthesis of PGE2. PSSC suppressed the transcription and translation of cyclooxygenase-2 in tumor associated macrophages. Conclusion Our data clearly showed antitumor immunostimulatory activity of PSSC against transplanted H22 HCC cells. Suppressing tumor transplantation-induced PGE2 production was implicated in the anti-tumor immunostimulatory activity of PSSC. These works provides novel insights into the traditional application of S. chinensis against HCC and supported considering PSSC as an adjuvant reagent in clinical HCC treatment. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Propolis has long been used as a popular folk medicine due to its wide spectrum of alleged biological and pharmaceutical properties. In Chile, propolis is widely used by folklore medicine as an anti-inflammatory agent; however, this property has not been demonstrated by scientific methods. Aim of the study The objective of this study was to determine the anti-inflammatory activity in vivo and in vitro and to establish the phenolic profile of propolis collected in two localities in Región Metropolitana de Santiago (RM), Chile. Materials and methods Propolis was collected in the areas of Caleu and Buin, RM Chile. Following that, the samples were unwaxed to obtain the global ethanolic extracts of propolis (EEPs) and, from these, the serial extracts of dichloromethane (EEP-DCMs) and ethanol (EEP-EtOHs). The topic anti-inflammatory effect was evaluated through mice ear edema induced by arachidonic acid (AA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) at a dose of 3 mg/ear. Nitric oxide (NO) measurements were determined spectrophotometrically (Greiss reagent) by the accumulation of nitrite in the medium of macrophages RAW 264.7 stimulated with the lipopolysaccharide (LPS, 1 μg/mL) for 20 h at different concentrations of the EEPs, EEP-DCMs and EEP-EtOHs (6.25–50.00 μg/mL). The content of total phenols and flavonoids were determined through the methods of Folin–Ciocalteau and AlCl 3 , respectively. The profile of phenolic compounds was determined by HPLC–UV–ESI-MS/MS. Results The EEP-EtOH (64%) and EEP (59%) of Buin were the most active in the inflammation induced by TPA and AA respectively, being the anti-inflammatory effect stronger than the same Caleu extracts. Regarding the release of NO, all the extracts from the Buin propolis inhibited significantly its release in a concentration-dependent manner, this inhibition was stronger than the extracts from Caleu propolis. Conclusions Our research shows for the first time a comparative study of the topical in vivo activity of two Chilean propolis. Both propolis showed in vivo topical anti-inflammatory activity against AA and TPA, the most active was Buin propolis and this difference is due in part to the variations in total phenols and flavonoids content and the phenolic profile. The phenols and flavonoids content of Buin propolis was higher than Caleu propolis. The extracts from Buin propolis result in a lower release of NO. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance The fructus Alpinia oxyphylla Miq. (AOM) has been used for treating diarrhea with spleen deficiency and gastralgia for thousands of years. A number of traditional Chinese medicine formulae provide AOM as an alternative herbal treatment for diarrhea, but the scientific basis for this usage has not been well defined. Aim of the study In this study, we tried to investigate the antidiarrheal activity and possible mechanisms of Fructus AOM, aiming to enrich our understanding to the scientific meanings and theoretical significance of Fructus AOM in clinical practice. Materials and methods The fructus of AOM collected from Hainan province in China were macerated in the 95% ethanol to obtain the crude 95% ethanol extract, followed by subjected to chromatographic separation over a Diaion HP20 column to obtain 90% and 50% ethanol eluted fractions. The activities of the crude extract and fractions on castor oil induced acute diarrhea, rhubarb induced chronic diarrhea, gastrointestinal transit (GIT) in mice, and contractions of isolated guinea-pig ileum were evaluated. Additionally, nitric oxide (NO), gastrointestinal peptides gastrin (GAS), motilin (MTL) and somatostatin (SS) levels that related to gastrointestinal motilities were detected to demonstrate the potential mechanisms. Ultimately, LC–MS/MS method was utilized to ensure the chemical consistency. Results The 95% ethanol extract and 90% ethanol eluted fraction significantly delayed the onset time and decreased the wet faeces proportion compared with control group in the castor oil induced acute diarrhea mice. In terms of further evaluation of antidiarrheal activity, the 95% ethanol extract and 90% ethanol elution displayed significant inhibition of the intestinal propulsion at the two highest oral doses of 20 g crude drug/kg and 1 g/kg. Moreover the 95% ethanol extract (10 and 20 g crude drug/kg) and 90% ethanol elution (0.5 and 1 g/kg) could significantly inhibit the GIT, which was partially attributed to the increase in NO and SS levels, and the decreased MTL. In vitro spontaneous contractions of the isolated guinea pig ileum induced by carbachol, neostigmine and histamine were attenuated by both the extract and elution. Phytochemical analysis of 95% ethanol extract and its fractions identified the presence of diphenylheptanes, sesquiterpenes, and flavones as the major components. Conclusions Our in vivo and in vitro data could partly support and justify the traditional usage of Fructus AOM on the treatment of diarrhea in traditional medicine. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Taraxacum mongolicum Hand .- Mazz is a famous medicinal plant in China, has been listed in the Pharmacopoeia of the People׳s Republic of China and used to treat infection, fever, upper respiratory tract infection, pneumonia, and other infectious diseases. This study aims to evaluate the possible mechanisms responsible for the anti-inflammation effects of water extract of T. mongolicum Hand .- Mazz (WETMHM) on lipopolysaccharide (LPS)-induced inflammatory in acute lung injury. Materials and methods Female BALB/c mice were randomly divided into five groups with 10 mice in each group: (1) control group (saline), (2) LPS group, (3) LPS+dexamethasone (LPS+Dex, 2 mg/kg, administered by gavage), (4) LPS+WETMHM (5 g/kg, administered by gavage), (5) LPS+WETMHM (10 g/kg, administered by gavage). The cell counting in the bronchoalveolar lavage fluid (BALF) was measured. The animal lung edema degree was evaluated by wet/dry weight (W/D) ratio. The superoxidase dismutase (SOD) activity and myeloperoxidase (MPO) activity were assayed by SOD and MPO kits, respectively. The levels of inflammation mediators including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 were assayed by an enzyme-linked immunosorbent assay method. Pathological changes of lung tissues were observed by hematoxylin and eosin (HE) staining. The levels of P-PI3K, PI3K, P-Akt, Akt, P-mTOR and mTOR were measured by Western blotting. Results The data showed that treatment with the WETMHM inhibited LPS-induced inflammation: (1) WETMHM attenuated inflammation cell numbers in the BALF, (2) decreased protein levels of lung PI3K/Akt/mTOR, and (3) improved SOD activity and (4) inhibited MPO activity; (5) histological studies demonstrated that WETMHM substantially inhibited LPS-induced neutrophils in lung tissue. Conclusion The results indicated that the WETMHM had a protective effect on LPS-induced ALI in mice. [ABSTRACT FROM AUTHOR]