Design, synthesis and activity evaluation of arctigenin derivatives with HDAC inhibition activity.

Arctigenin, a natural product with diverse pharmacological activities, can inhibit cell proliferation and survival and has shown promising potential in cancer research. In this study, we designed a series of arctigenin derivatives with HDAC inhibitory activity based on the synergistic effects between HDAC inhibitors and arctigenin. Among them, compound B7 exhibited significantly higher antiproliferative activity in the MV411 cell line compared to the positive control, tucidinostat. Additionally, enzymatic activity testing was performed with compound B7. Further mechanistic studies indicated that compound B7 induced apoptosis through the Caspase-3 pathway in MV411 cells and enhanced histone acetylation levels in the MV411 cell line. These findings highlight the broad potential application of these arctigenin derivatives in cancer therapy.

Anti-prostate cancer mechanism of black ginseng during the "nine steaming and nine sun-drying" process based on HPLC analysis combined with vector space network pharmacology.

HPLC analysis determined six small-molecule organic acids, maltol, 5-hydroxymethylfurfural (5-HMF), 17 ginsenosides, four oligosaccharides, and 20 amino acids in black ginseng samples with different processing times. Based on the content determination results, the differential ingredients in the processing of black ginseng were screened by multivariate statistical analysis. Network pharmacological methods obtained the core targets and pathways of the above ingredients against prostate cancer. Finally, the entropy weight method was used to assign values to the above ingredients, targets, and pathways, and the vector space network pharmacology method was established to study the anti-prostate cancer mechanism of black ginseng in the process of "nine steaming and nine sun-drying". Based on principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA), fructose, glucose, dencichin, glutamate, ginsenoside 20 (S)-Rg3, 20 (R)-Rg3, 20 (S)-Rh2, Rg1, Re, and Rc were the main differential ingredients in various steaming and sun-drying cycle periods of black ginseng. The results of vector space network pharmacology showed that the main reason for the change in the anti-prostate cancer pathway of black ginseng with the number of steaming and sun-drying was the different regulatory ability of black ginseng on the PI3K-Akt signaling pathway and chemical carcinogenesis-receptor activation pathway. It gave researchers a fresh perspective for exploring the anti-prostate cancer active components of black ginseng and the change in the mechanism of the effect of traditional Chinese medicine in processing.

Effective substances and mechanism of red ginseng on rats with spleen-deficiency syndrome based on the substance and energy metabolism as well as the "brain-gut" axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Red ginseng (RG), a processed product of ginseng (GS), is a generally used qi-tonifying medicine in Traditional Chinese Medicine (TCM). According to the TCM principle, RG is also generally applied to spleen-deficiency syndrome (SDS) clinically for its warmer property. However, the effective substances and mechanism of RG on SDS have not been well investigated. AIM OF THE STUDY: The aim of this study was to explore the effective substances and their mechanism of RG on SDS. MATERIALS AND METHODS: The SDS model was established with a compound factor method involving an irregular diet, excessive fatigue and sennae folium with a bitter-cold property. The medicine of RG was split by multi-mode separation methods and analyzed by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS). The appearance indexes such as body weight, body temperature, swimming endurance, urine output, and water content of fecal were determined. The biochemical indexes such as D-xylose, SP, VIP and AChE in the digestive system, CRH, ACTH, CORT, E, T3, T4, T, E2 and 5-HT in the endocrine system, CS, NCR, IDH1, COX and Na+-K+-ATPase in the metabolism of substance and energy, cAMP and cGMP in the cyclic nucleotide system were analyzed by Enzyme-linked immunosorbent assay (ELISA) kits and biochemical kits. The serum metabolites were analyzed by UPLC-QTOF/MS. Furthermore, the gut microbiota and short-chain fatty acids (SCFAs) in feces were analyzed by 16S rRNA sequencing and headspace gas chromatography-mass method. RESULTS: The pharmacological experiments showed that total saponin fraction (RGTSF), less polar fraction (RGLPF), and polysaccharides faction (RGPSF) significantly modulated the "brain-gut" axis-related indexes (the levels of VIP, AChE, and 5-HT). Besides, RGTSF also significantly modulated the hypothalamic-pituitary-adrenal (HPA) axis-related indexes as well as the substance and energy metabolism-related indexes (the levels of ACTH, CORT, A, Na+-K+-ATPase, COX, NCR and CS). RGPSF also significantly modulated the hypothalamus-pituitary-thyroid (HPT) axis-related indexes (the levels of T3 and T4). Secondly, metabolomics indicated that RGTSF could significantly regulate the abnormal metabolic pathways associated with the development of SDS, which involved steroid hormone biosynthesis, taurine and hypotaurine metabolism, primary bile acid biosynthesis, and amino acid metabolism. Subsequently, the study of gut microbiota indicated that RGLPF could increase the diversities of the gut microbiota and the relative abundance of Firmicutes in rats with SDS, while RGWEF significantly increased the relative abundance of Bacteroidetes. At the genus level, RGLPF could increase the relative abundance of Lactobacillus in rats with SDS and decrease that of Akkermansia. Meanwhile, the water-eluted fraction (RGWEF) showed a stronger regulation in SCFAs. CONCLUSION: It is for the first time that the effective substances of red ginseng on spleen-deficiency syndrome were studied systematically, and the different mechanisms of the RG fractions involved in substance and energy metabolism as well as the "brain-gut" axis were revealed. The present study demonstrated that RGTSF, RGPSF, and RGLPF were the effective substances of red ginseng for ameliorating spleen-deficiency syndrome, indicating that ginsenosides composed of primary and secondary saponins as well as polysaccharides were the main effective substances for red ginseng in ameliorating spleen-deficiency syndrome.

Semen raphani weakened the action of ginseng under chronic fatigue condition.

ETHNOPHARMACOLOGICAL RELEVANCE: Fatigue is a kind of subhealth status and people paid much more attention on it. Ginseng is used to treating fatigue as a kind of qi -tonifying drug in Chinese medicine. In the traditional applications, there is a viewpoint that ginseng could not be used with semen raphani and supposed that semen raphani is a kind of qi regulating drug, which will reduce the qi invigorating effect of ginseng. However, the underlying combination mechanism of the two drugs remained unclear. AIM OF THE STUDY: The aim of this study is to explore whether ginseng can be used with semen raphani or not to remedy acute and chronic fatigue conditions. METHODS: We used normal and weight-bearing swimming method combined with appetite control animals. The biochemical indexes in energy metabolism, antioxidant, regulating endocrine system and immunity capacities were performed to explore the antagonism effect of semen raphani on ginseng under acute and chronic fatigue conditions. The serum and urine metabolomics were investigated using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF/MS). Fecal flora was analyzed via 16S rRNA amplicon sequencing. RESULTS: The combination of ginseng with semen raphani have no influence on acute fatigue effect compared with ginseng alone. Both can improve the exhausted swimming time, the activity of GSH-Px, LDH and Na+-K+-ATPase. Furthermore, the combination of ginseng with semen raphani can increase the urine volume of rats and down-regulate the content of AQP-3, which can alleviate the "fireness" side-effect of ginseng. But the abundance and diversity of bacterial are decreased under acute fatigue experiment. Both the combination of ginseng with semen raphani and ginseng alone can remedy chronic-fatigue. They can also regulate the endocrine system, immune system, citric acid cycle metabolism, tryptophan metabolism, fatty acid metabolism, glycolysis/gluconeogenesis, etc. Furthermore, they can promote substance metabolism and energy metabolism in qi deficiency rats, and increase the abundance and diversities of the flora. While with the increased content of semen raphani, the combination of ginseng and semen raphani weaken the capacity of antioxidant, lactic acid metabolism, energy metabolism, flora diversity and regulation of endocrine system. CONCLUSION: Compared with ginseng alone, the combination of ginseng with semen raphani can weaken the qi invigorating ability under chronic fatigue condition. The more ratios of semen raphani is in the combination of the two drugs, the less the power of treating chronic fatigue is. Compared with ginseng alone, the combination of ginseng with semen raphani have no influence on the qi invigorating ability under actue fatigue experiment. But the combination of ginseng with semen raphani will benefit for the "fireness" side-effect of ginseng.

Traditional ancient Egyptian medicine: A review.

The ancient Egyptians practiced medicine with highly professional methods. They had advanced knowledge of anatomy and surgery. Also, they treated a lot of diseases including dental, gynecological, gastrointestinal, and urinary disorders. They could diagnose diabetes and cancer. The used therapeutics extended from different plants to include several animal products and minerals. Some of these plants are still used in the present day. Fortunately, they documented their life details by carving on stone, clay, or papyri. Although a lot of these records have been lost or destroyed, the surviving documents represent a huge source of knowledge in different scientific aspects including medicine. This review article is an attempt to understand some information about traditional medicine in ancient Egypt, we will look closely at some basics, sources of information of Egyptian medicine in addition to common treated diseases and therapeutics in this great civilization.

The Ameliorative Effects of Arctiin and Arctigenin on the Oxidative Injury of Lung Induced by Silica via TLR-4/NLRP3/TGF-ß Signaling Pathway.

Silicosis remains one of the most serious diseases worldwide, with no effective drug for its treatment. Our research results have indicated that arctiin and arctigenin could increase the mitochondrial membrane potential, which in turn reduces the production of reactive oxygen species (ROS), blocks the polarization of macrophages, and inhibits the differentiation of myofibroblasts to reduce oxidative stress, inflammation, and fibrosis. Further, our study revealed that arctiin and arctigenin suppressed the activation of NLRP3 inflammasome through the TLR-4/Myd88/NF-κB pathway and the silica-induced secretion of TNF-α, IL-1ß, TGF-ß, and α-SMA. Besides, the silica-induced increase in the levels of serum ceruloplasmin and HYP was also inhibited. Results of metabolomics indicated that arctiin and arctigenin could regulate the abnormal metabolic pathways associated with the development of silicosis, which involve pantothenate and CoA biosynthesis, cysteine and methionine metabolism, linoleic acid metabolism, and arginine and proline metabolism successively. Furthermore, the analysis of metabolomics, together with network topological analysis in different phases of silicosis, revealed that urine myristic acid, serum 4-hydroxyproline, and L-arginine could be regarded as diagnosis biomarkers in the early phase and formation of pulmonary fibrosis in the latter phases of silicosis. Arctiin and arctigenin could downregulate the increased levels of myristic acid in the early phase and serum 4-hydroxyproline in the latter phase of silicosis. Interestingly, the integration of TLR-4/NLRP3/TGF-ß signaling and metabolomics verified the importance of macrophage polarization in the silicosis fibrosis process. To the best of our knowledge, this is the first study reporting that arctiin and arctigenin both can ameliorate silicosis effectively, and the former is a little stronger than its aglycone arctigenin because of its high oral bioavailability, low toxicity, and multimolecular active metabolites as determined by AdmetSAR and molecular docking analysis.

Poria ameliorates the side effects of rhubarb in pair treatment.

To investigate the effect of Poria and effective constituents on gastrointestinal injury animals in the area of the side effects which caused by Rhubarb. Mice were administered i.g. with Rhubarb until the induction of diarrhea followed by gastrointestinal injury. The gastrointestinal injured mice were treated with high, medium and low doses of poria water extract and it's subfractions for 5 days. All indexes were determined to evaluate the action of poria in the pair treatment. The results showed that the higher dose of poria water decoction was discovered to be the most effective dose to treat gastrointestinal injury induced by rhubarb. Body weight, thymus and spleen indexes, the small intestinal propulsion rate and D-xylose absorption in mice with diarrhea and intestinal injury were analyzed to reveal the significant difference with the model group (P<0.01). EAF (Ethyl Acetate Fraction), PEF (Petroleum Ether Fraction) and CPF (Crude Polysaccharide Fraction) not only increase the levels of AMS, GAS and VIP significantly but also ameliorate diarrhea and intestinal injury situation compared with the model group (P<0.01). EAF, PEF and CPF were the most effective components to alleviate diarrhea and gastrointestinal injury induced by rhubarb.

Chemical Constituents of Stems and Leaves of Tagetespatula L. and Its Fingerprint.

Tagetespatula L. is a widely cultivated herbal medicinal plant in China and other countries. In this study, two new 2, 3-dihydrobenzofuran glucosides (1, 2) and fourteen known metabolites (3-16) were isolated from the stems and leaves of T. patula (SLT). The chemical structures of the isolated compounds were characterized comprehensively based on one- and two-dimensional NMR spectroscopy and high resolution mass spectrometry. Absolute configurations of compounds 1 and 2 were determined by ECD calculations. Compounds 1 and 2 exhibited moderate in vitro inhibitory activities against human gastric cancer cell lines (AGS) with IC50 values of 41.20 µmol/L and 30.43 µmol/L, respectively. The fingerprint profiles of stems and leaves of T. patula with three color types of flowers (Janie Yellow Bright, Jinmen Orange, Shouyao Red and Yellow color) were established by high-performance liquid chromatography (HPLC). Ten different batches of stems and leaves were examined as follow: Shouyao Red and Yellow color (1, 2, 3), Janie Yellow Bright (4, 5, 6, 7) and Jinmen Orange (8, 9, 10). Twenty-two common peaks were identified with similarity values ranging from 0.910 to 0.977. Meanwhile, the average peak area of SLT in the three types of flowers was different and it was the highest in Janie Yellow Bright.

Mechanism Investigation of Tagetes patula L. against Chronic Nonbacterial Prostatitis by Metabolomics and Network Pharmacology.

The major objective of this study was to investigate the anti-chronic nonbacterial prostatitis (CNP) mechanism of T. patula by metabolomics and network pharmacology. The study demonstrated that the flavonoids and polysaccharides of T. patula could alleviate prostatitis by improving the level of DHT, reducing the secretion of PSA and TNF-α. Besides, both could enhance Na+/K+-ATPase activity, decrease the O2 consumption, CO2 production, heat production, energy expenditure of rats and promote respiratory exchange ratio of rats. Up to 28 potential biomarkers and 8 key metabolic pathways related to the treatment of CNP were elucidated by the metabolomics analysis, including phenylalanine metabolism, taurine and hypotaurine metabolism, tryptophan metabolism etc. Network pharmacology prediction also reflected the potential mechanism was associated with tryptophan metabolism and energy pathway. Generally, the potential anti-CNP mechanism of flavonoids and polysaccharides of T. patula might be through reducing the expression of inflammation factors, adjusting the level of hormone and regulating the amino acid metabolism, energy metabolism and glucose and lipid metabolism.

The Chinese herbal formulae (Yitangkang) exerts an antidiabetic effect through the regulation of substance metabolism and energy metabolism in type 2 diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Type 2 diabetes mellitus (T2DM) regarded as a "hot" disease in traditional Chinese medicine (TCM). Accordingly, TCM uses a cold drug or formula such as the Chinese herbal formulae "Yitangkang" (YTK) as a treatment. YTK exhibited a good clinical antidiabetic effect in several experiments. The correlation between the properties of a TCM drug or formula and its ability to regulate the substance metabolism, the energy metabolism and the endocrine system has been proven. AIM OF THE STUDY: The present study aiming to evaluate the mechanism of antidiabetic action of YTK from the above perspective. MATERIALS AND METHODS: Three groups of streptozotocin (STZ)-diabetic rats have been treated with YTK at oral doses of 56 g/kg/d, 28 g/kg/d and 14 g/kg/d for 28 days using metformin as a reference drug. After treatment, several indices correlated with energy metabolism (superoxide dismutase, glutathione peroxidase, lactic dehydrogenase, adenotriphos, creatine phosphate kinase, AMPK, Na+-K+-ATPase and Respiratory Chain Complex I, II, III, IV), substance metabolism (hepatic glycogen, acetyl-coenzyme A, pyruvic acid, adipose triglyceride lipase, triglycerides, high-density lipoproteins, low-density lipoproteins, malonyldialdehyde), endocrine system (triiodothyronine, thyroxine, 17-hydroxycorticosteroid) and cyclic nucleotide system (cyclic adenosine monophosphate, cyclic guanosine monophosphate) have been determined. The specialty and tendency of YTK's effects were analyzed to elucidate its property and mechanism of action according to the theory of TCM. RESULTS: Our findings showed that the formulae YTK could effectively regulate the levels of blood glucose, HbA1c, glucagon-like peptide-1, and significantly down-regulate the substance metabolism, energy metabolism and endocrine system indices of the diabetic rats. CONCLUSION: These results were consistent with the TCM description of YTK as a "cold" treatment. It could provide an effective way to interpret the scientific connotation and comprehensive system of the Chinese herbal formulae.

Two new sesquiterpene lactones from leaves of yacon, Smallanthus sonchifolius.

The chemical constituents of 95% EtOH extract of yacon leaves were separated to yield two new sesquiterpene lactones, together with three known compounds. The two new compounds were characterized to be 8ß-angeloyloxy-13-methoxyl-11, 13-dihydromelampolid-14-oic acid methyl ester (1) and 8ß-(3-methylbut-2-enoyl) oxy-13-methoxyl-11, 13-dihydromelampolid-14-oic acid methyl ester (2) on the basis of NMR spectra, HR-MS and other spectroscopic methods. The cytotoxicity of compounds 1-5 were evaluated on human hepatoma cell Bel-7402 and all the compounds showed moderate cytotoxicity.

Evaluation of anti-sepsis activity by compounds with high affinity to lipid a from HuanglianJiedu decoction.

CONTEXT: HuanglianJiedu decoction (HJD) is a classic prescription for heat-clearing away and detoxifying, which is used for the clinical treatment of sepsis, due to sepsis refers to the systemic inflammatory response induced by infection in western medicine, and infection belongs to the category of poison-heat syndrome in traditional Chinese medicine. OBJECTIVES: Previous study had elucidated the effective components from HJD with high affinity to lipid A, which can generate the release of pro-inflammatory-cytokines, resulting in sepsis. Now the anti-sepsis activities of these compounds were evaluated. MATERIALS AND METHODS: Immunofluorescence, immunohistochemical staining, ELISA and MTT methods were used to evaluated these compounds. RESULTS: Immunofluorescence analysis evaluated the effects of compounds on the binding of FITC-LPS to RAW264.7 cells, and showed the fluorescence intensity was significant attenuated in geniposides, palmatine, baicalin and berberine groups (64 and 128 µg/mL) compared with model group (p < 0.05), which showed these compounds inhibit the combination of LPS with receptor of cells; immunohistochemical staining and ELISA method showed the TLR4 receptor expression, IL-6 and TNF-α levels were significant decreased in the groups treated with compounds, indicating that geniposides, baicalin, palmatine and berberine can play the role of anti-sepsis by inhibiting the expression of TLR4, the releasing of IL-6 and TNF-α; MTT assay showed that palmatine and berberine had a weak effect on cell viability, while others not, indicating that the compounds have protective activity. DISCUSSION AND CONCLUSIONS: It could be concluded the high affinity binding between these compounds and lipid A may be an important basis for its anti-LPS activity in vitro.

The effect of red ginseng and ginseng leaves on the substance and energy metabolism in hypothyroidism rats.

BACKGROUND: Recent studies have revealed that the properties Traditional Chinese Medicine is mostly associated with are substance and energy metabolism. Our study aimed to compare the effect of red ginseng (RG) (warm property) and ginseng leaves (GL; cold property) on the substance and energy metabolism of rats with hypothyroidism. MATERIALS AND METHODS: Rats were administered propylthiouracil intraperitoneally for 20 d to cause hypothyroidism. The reference group was orally administered Aconiti Lateralis Radix Praeparaia [FZ (Fuzi in Chinese)], while both the RG and GL groups were orally administrated crude drugs. The rectal, tail, toe, and axilla temperature of the rats were assayed every 3 d. Oxygen consumption, carbon dioxide production, heat production, and energy expenditure were measured via TSE phenoMaster/LabMaster animal monitoring system. Adenosine monophosphate-activated protein kinase, Na+-K+-ATPase, fumarase, pyruvic acid and cyclic adenosine monophosphate/cyclic guanosine monophosphate were determined. RESULTS: The lower levels of triiodothyronine, tetraiodothyronine, and thyrotropin-releasing hormone and the higher level of thyroid stimulating hormone revealed the successful establishment of a hypothyroidism model. Oxygen consumption, carbon dioxide production, heat production, and energy expenditure in the FZ and RG groups were obviously increased. The activity of Na+-K+-ATPase and fumarase in the FZ and RG groups was significantly increased. The cyclic adenosine monophosphate/cyclic guanosine monophosphate level in the FZ and RG groups was increased, while the GL group showed the opposite. CONCLUSION: Our research provides a new way to explore the efficiency of Chinese medicine on the basis of the relationship between drug property and effects on substance and energy metabolism.

Metabolomics analysis of anaphylactoid reaction reveals its mechanism in a rat model.

BACKGROUND: Anaphylactoid reactions, accounting for more than 77% of all immune-mediated immediate hypersensitivity reactions, have become a serious threat to public health, but their effect mechanism is not clear and diagnostic tests are limited. Comprehensive metabolite analysis may reveal the anaphylactoid effect mechanism systematically and provide reference for future diagnostic purposes. METHODS: Plasma from Brown Norway rats given intravenous injection of saline, compound 48/80 (2.5 mL/kg) or ovalbumin (20 mL/kg) in 20 s for the first time was used to study the effect mechanism of anaphylactoid reactions through metabolomics (UPLC-qTOF-MS/MS). Metabolomics integrated with proteomics data were used to analyze the anaphylactoid pathways by MetaboAnalyst followed by integrated pathway analysis. RESULTS: Thirty metabolites were identified through the METLIN database by MS/MS and 18 of them were confirmed by authentic standards. The results showed that adenosine, histamine, N-acetylhistamine, N(α)-γ-glutamylhistamine, malate and xanthine are important indices for anaphylactoid reactions. It could be concluded that the effect mechanism is mainly composed of histidine metabolism, arachidonic acid metabolism, energy metabolism, purine metabolism and other small molecules through 30 metabolites. Multiple linear regression analysis indicated that not only histamine but also N(α)-γ-glutamylhistamine and arachidonic acid could be used to evaluate anaphylactoid symptoms of animals. Furthermore, the citrate cycle, histidine metabolism and arachidonic acid metabolism could be the main pathways of anaphylactoid reactions as determined by MetaboAnalyst. CONCLUSION: The results may provide a reference to improve diagnostic accuracy and predict and monitor treatment efficacy in anaphylactoid reactions in the clinical setting.

A new sesquiterpene lactone from yacon leaves.

The chemical constituents of 60% EtOH extract of yacon leaves were separated to yield a new compound, together with four known compounds, which were isolated for the first time from yacon. The new compound was characterised and named as chlorodalin (1) on the basis of NMR (1D and 2D), HR-MS and other spectral methods. The cytotoxic activities of 1-5 were evaluated on two human tumour cell lines and the new compound showed significant cytotoxic activity.

Arctigenin Attenuates Learning and Memory Deficits through PI3k/Akt/GSK-3ß Pathway Reducing Tau Hyperphosphorylation in Aß-Induced AD Mice.

Arctigenin is a phenylpropanoid dibenzylbutyrolactone lignan compound possessing antitumor, anti-inflammatory, anti-influenza, antioxidant, antibacterial, and hypoglycaemic activities. Our previous study demonstrated that arctigenin exerts neuroprotective effects both in vitro and in vivo in a Parkinson's disease model. However, the exact mechanism through which arctigenin improves amyloid beta-induced memory impairment by inhibiting the production of the hyperphosphorylated tau protein is unknown. Amyloid ß1-42 was slowly administered via the intracerebroventricular route in a volume of 3 µL (≈ 410 pmmol/mouse) to mice. The mice were administered arctigenin (10, 40, or 150 mg/kg) or vehicle starting from the second day after amyloid ß1-42 injection to the end of the experiment. Behavioural tests were performed from days 9 to 15. On day 16 after the intracerebroventricular administration of amyloid ß1-42, the mice were sacrificed for biochemical analysis. Arctigenin (10-150 mg/kg) significantly attenuated the impairment of spontaneous alternation behaviours in the Y-maze task, decreased the escape latency in the Morris water maze test, and increased the swimming times and swimming distances to the platform located in the probe test. Arctigenin attenuated the level of phosphorylated tau at the Thr-181, Thr-231, and Ser-404 sites in the hippocampus, and increased the phosphorylation levels of phosphatidylinositol-3-kinase, threonine/serine protein kinase B, and glycogen synthase kinase-3ß. Arctigenin effectively provides protection against learning and memory deficits and in inhibits hyperphosphorylated tau protein expression in the hippocampus. The possible mechanism may occur via the phosphatidylinositol-3-kinase/protein kinase B-dependent glycogen synthase kinase-3ß signalling pathway.

The ginseng's fireness is associated with the lowering activity of liver Na(+)-K(+)-ATPase.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng is an herbal medicine used worldwide that possesses a wide range of pharmacological activities. However, its side effects are rarely discussed. The experience of Chinese medicine has revealed that taking ginseng at a high dose chronically can cause fireness, i.e., the ginseng-abuse syndrome. Here, we explored the mechanism of ginseng's fireness by comparing the energy metabolism of mice affected by red ginseng (RG), ginseng (GS), ginseng leaves (GL) and American ginseng (AG), which exhibit different drug properties according to the theory of TCM. MATERIALS AND METHODS: KM mice were randomly divided into five groups (n≥30 per group) and administered distilled water or drugs, respectively. Mice receiving RG, GS, or GL received 4.5g/(kgday), while the mice receiving AG received 3g/(kgday). Control mice received distilled water. The duration of exposure for all groups was 31 days. The mice's physical characteristics, such as eye condition, rectal temperature, saliva secretion, urine, stool weight, blood coagulation time and swimming time, were measured at different times after administration. Energy metabolism indexes were measured via TSE phenoMaster/LabMaster animal monitoring system, including the mice' 24h oxygen consumption (VO2), carbon dioxide production (VCO2), heat production (H) and energy expenditure (EE). Biochemical indices were measured by ultraviolet spectrophotometer and microplate reader, including pyruvic acid content in serum and succinate dehydrogenase (SDH) activity, lactate dehydrogenase (LDH) activity, the Na(+)-K(+)-ATPase activity and the content of glycogen in the liver tissue. RESULTS: After 31 days of drug administration, mice in the RG and GS groups exhibited obviously more eye secretions, less saliva secretion and less urine. Compared with the control group, the swimming times of mice in the GS, AG and GL groups were significantly prolonged; the clotting time of mice in the GL was extended significantly; VCO2, H and EE of mice in the GS group were obviously increased; Pyruvate content of mice in the RG group showed an initial decrease followed by an increase; SDH activity of mice in the AG and GL groups was significantly inhibited; LDH activity of the mice showed no significant difference among different groups; Na(+)-K(+)-ATP enzyme activity of the RG and GS groups showed up-regulation initially and then down-regulation; the content of hepatic glycogen of mice in the GS and GL groups increased significantly. CONCLUSION: The results demonstrated that RG and GS with their warm drug nature could enhance the body's energy metabolism to produce their dryness to the body. The liver Na(+)-K(+)-ATP enzyme activity may be the primary index for indicating the fireness of ginseng. In addition, our results demonstrated that ginseng, especially red ginseng, is not suitable for long time application with a higher dose.

The effective components of Huanglian Jiedu Decoction against sepsis evaluated by a lipid A-based affinity biosensor.

ETHNOPHARMACOLOGICAL RELEVANCE: Huanglian Jiedu Decoction (HJD), the classical recipe for relieving fever and toxicity, has been used for treating sepsis in China for sixteen years. However, the effective components of HJD have not been elucidated until now. Therefore, there is a need to elucidate the effective components of HJD against sepsis on animal models induced by endotoxin (LPS). The affinity force of the effective components of HJD with lipid A was evaluated by a biosensor. MATERIALS AND METHODS: Lipid A is regarded as the bioactive center of LPS and is always used as a drug target. In order to obtain the effective components of HJD against sepsis, seven fractions from HJD were tested by a biosensor method for assessing the affinity for lipid A. After further separation, the components were isolated from high lipid A-binding fractions and their affinities to lipid A were assessed with the aid of a biosensor. Their activities were then assayed by an in vivo experiment administered through a tail vein injection. The levels of LPS, TNF-α, and IL-6 from the blood were found and pathology experiments were performed. RESULTS: Three out of the seven fractions exhibited high lipid A-binding affinities. Berberine, baicalin and geniposide were obtained from the three high lipid A-binding fractions. The animal experiments indicated that the levels of LPS, TNF-α and IL-6 in the medicated treatment groups were much lower than that of the model group ((**)P<0.01). The medicated treatment groups exhibited stronger protective activities on varying organs in the animal model. CONCLUSIONS: Berberine, baicalin and geniposide could neutralize LPS by binding with lipid A and then reduce the release of IL-6 and TNF-α induced by LPS. Furthermore, berberine, baicalin and geniposide exhibited protective activities on varying organs compared to the animal model established by the LPS-induced. These results validate that the components from HJD neutralized LPS and then depressed the release of IL-6 and TNF-α induced by LPS. This gives further evidence that HJD would be a suitable treatment for sepsis and protecting vital organs.

Proteomics Study on Nonallergic Hypersensitivity Induced by Compound 4880 and Ovalbumin.

Nonallergic hypersensitivity reaction (NHR) accounts for more than 77% of all immune-mediated immediate hypersensitivity reactions and has become a serious threat to public health. Here, proteomics was used to study the NHR mechanism of two typical substances, the compound 4880 and ovalbumin. Twelve different proteins were suggested as potential biomarkers for examining the NHR mechanism, and our results revealed that the mechanism mainly encompassed 2 processes, i.e., generation and effect processes. The generation process could be classified as direct stimulation, complement (classical and alternative), coagulation, kallikrein-kinin, and integrated pathways. Thus glutathione peroxidase 1, terminal complement complex (complement factor 4d and Bb), coagulation 13, kininogen-1, and IgE could be used as candidate biomarkers for the indication of the corresponding pathways respectively, the proteins were further confirmed by ELISA. And the effect process was mainly composed of histamine as well as proteins such as DCD and MYLPF, which could be used as important indices for the symptoms of NHR. Our study differs from previous studies in that C4880 was found to not only be involved in the direct stimulation pathway, but also in the activated complement and kallikrein-kinin pathways through the coagulation pathway. We also report for the first time that ovalbumin-induced NHR could be a combination of the coagulation, classical complement, and integrated pathways.

Antitumor effects of dammarane-type saponins from steamed Notoginseng.

Six dammarane-type saponins were extracted from steamed Panax notoginseng. Their chemical structures were identified spectroscopically as ginsenosides Rh1 (1), Rg1 (2), 20 (S)-Rg3 (3), 20 (R)-Rg3 (4), Rb3 (5), and Rb1 (6). Compounds (0.1-10 µM) were tested for inhibition of tumor necrosis factor-α (TNF)-induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) luciferase reporter activity using a human kidney 293T cell-based assay. Ginsenoside Rb3 (5) showed the most significant activity with an IC50 of 8.2 µM. This compound also inhibited the induction of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) messenger Ribonucleic acid (mRNA) in a dose-dependent manner after HepG2 cells had been treated with TNF-α (10 ng/mL).