Inhibition of Amyloid Beta Aggregation and Deposition of Cistanche tubulosa Aqueous Extract.

Cistanche tubulosa aqueous extract (CTE) is already used as a botanical prescription drug for treating dementia in China. Our previous studies reported that phenylethanoid glycosides of CTE have anti-Alzheimer's disease (AD) activity by inhibiting amyloid ß peptide (Aß) aggregation and deposition. However, recent studies considered that the phenylethanoid glycosides may be metabolized by intestinal bacteria, because all analysis results showed that the bioavailability of phenylethanoid glycosides is extremely low. In this study we demonstrate how iron chelation plays a crucial role in the Aß aggregation and deposition inhibition mechanism of phenylethanoid glycosides of CTE. In addition, we further proved phenylethanoid glycosides (1⁻3) could reach brain. Active CTE component and action mechanism confirmation will be a great help for product quality control and bioavailability studies in the future. At the same time, we provide a new analysis method useful in determining phenylethanoid glycosides (1⁻3) in plants, foods, blood, and tissues for chemical fingerprint and pharmacokinetic research.

Acteoside and Isoacteoside Protect Amyloid ß Peptide Induced Cytotoxicity, Cognitive Deficit and Neurochemical Disturbances In Vitro and In Vivo.

Acteoside and isoacteoside, two phenylethanoid glycosides, coexist in some plants. This study investigates the memory-improving and cytoprotective effects of acteoside and isoacteoside in amyloid ß peptide 1-42 (Aß 1-42)-infused rats and Aß 1-42-treated SH-SY5Y cells. It further elucidates the role of amyloid cascade and central neuronal function in these effects. Acteoside and isoacteoside ameliorated cognitive deficits, decreased amyloid deposition, and reversed central cholinergic dysfunction that were caused by Aß 1-42 in rats. Acteoside and isoacteoside further decreased extracellular Aß 1-40 production and restored the cell viability that was decreased by Aß 1-42 in SH-SY5Y cells. Acteoside and isoacteoside also promoted Aß 1-40 degradation and inhibited Aß 1-42 oligomerization in vitro. However, the memory-improving and cytoprotective effects of isoacteoside exceeded those of acteoside. Isoacteoside promoted exploratory behavior and restored cortical and hippocampal dopamine levels, but acteoside did not. We suggest that acteoside and isoacteoside ameliorated the cognitive dysfunction that was caused by Aß 1-42 by blocking amyloid deposition via preventing amyloid oligomerization, and reversing central neuronal function via counteracting amyloid cytotoxicity.

Reversal by aqueous extracts of Cistanche tubulosa from behavioral deficits in Alzheimer's disease-like rat model: relevance for amyloid deposition and central neurotransmitter function.

BACKGROUND: Cistanche tubulosa (Schenk) R. Wight (CT) is commonly used to treat forgetfulness by traditional Chinese physicians. This study presents the ameliorating effects of CT extract which was quantified with three phenylpropanoid glycosides in Alzheimer's disease (AD)-like rat model. METHODS: Amyloid ß peptide 1-42 (Aß 1-42) intracisternally infused to rats by osmotic pump (Alzet 2002) was used as an AD-like rat model. The major pathological makers were measured including Aß 1-42 immunohistochemical stain, behavioral tests (inhibitory avoidance task and Morris water maze) and central neurotransmitter functions. RESULTS: Aß 1-42 caused the cognitive deficits, the increase in the amyloid deposition and acetylcholinesterase activities, and the decrease in the levels of brain's acetylcholine and dopamine. Daily administration of CT extract throughout Aß 1-42 infusion periods ameliorated the cognitive deficits, decreased amyloid deposition and reversed cholinergic and hippocampal dopaminergic dysfunction caused by Aß 1-42. Donepezil also ameliorated the cognitive dysfunction, but only blocked the amyloid deposition and cholinergic dysfunction caused by Aß 1-42. CONCLUSIONS: We suggest that CT extract, containing enough echinacoside and acteoside, ameliorated the cognitive dysfunction caused by Aß 1-42 via blocking amyloid deposition, reversing cholinergic and hippocampal dopaminergic neuronal function.

Poria cocos Lanostane Triterpenoids Extract Promotes Collagen and Hyaluronic Acid Production in D-Galactose-Induced Aging Rats.

The global aging population is expanding at an increasingly rapid pace, with approximately one-fourth of the world's population expected to be composed of elderly individuals by 2050. Aging skin is one of the major characteristics expressed in the elderly. The study comprehensively utilizes both cell and animal experiments to confirm the skin anti-aging effects of Poria cocos (P. cocos), which is one of the most important traditional Chinese medicines classified as tonic Chinese medicine, commonly used to treat physical weakness and aging-associated diseases. We demonstrate in this study that P. cocos lanostane triterpenoids extract (Lipucan®) ameliorates aging skin and promotes collagen accumulation and hyaluronic acid production in galactose-induced aging rats. Purified lanostane triterpenoids were initially identified as active components in P. cocos, which significantly increased collagen and hyaluronic acid levels in cultured human skin cells.

The Lanostane Triterpenoids in Poria cocos Play Beneficial Roles in Immunoregulatory Activity.

Poria cocos (Schwein) F.A. Wolf (syn. Wolfiporia cocos) dried sclerotium, called fuling, is an edible, saprophytic fungus commonly used as a tonic and anti-aging traditional Chinese medicine. It is traditionally used in combination with other traditional Chinese medicines to enhance immunity. This study showed that P. cocos extract (Lipucan®) containing lanostane triterpenoids has no immunotoxicity and enhances non-specific (innate) immunity though activating natural killer cells and promotes interferon γ (IFN-γ) secretion by Type 1 T-helper (Th1) cells immune response. In addition, P. cocos extract significantly decreased interleukin (IL-4 and IL-5) secretion by Type 2 T-helper (Th2) cells immune response, which are related to the allergy response. The purified lanostane triterpenoids were first identified as active ingredients of P. cocos with enhanced non-specific immunity by promoting interferon γ (IFN-γ) secretion in a preliminary study. Our findings support that the P. cocos extract plays beneficial roles in immunoregulatory activity.

Poria cocos Modulates Th1/Th2 Response and Attenuates Airway Inflammation in an Ovalbumin-Sensitized Mouse Allergic Asthma Model.

Poria cocos, called fuling, is a famous tonic in traditional Chinese medicine that reportedly possesses various pharmacological properties, including anti-inflammation and immunomodulation. However, few studies have investigated the effects of P. cocos on allergic diseases, such as allergic asthma. Allergic asthma is caused primarily by Th2 immune response and characterized by airway inflammation. This study first demonstrated the anti-allergic and anti-asthmatic effects of P. cocos extract (Lipucan®). P. cocos extract distinctly exhibited reduced inflammatory cell infiltration in the peribronchial and peribronchiolar regions compared to the asthma group in the histological analysis of pulmonary tissue sections. Prolonged P. cocos extract administration significantly reduced eosinophil infiltration, PGE2 levels, total IgE, and OVA-specific IgE. Moreover, P. cocos extract markedly suppressed Th2 cytokines, IL-4, IL-5, and IL-10. On the other hand, P. cocos extract significantly elevated IL-2 secretion by Th1 immune response. In addition, P. cocos extract elevated the IFN-γ level at a lower dose. We also observed that P. cocos extract increased the activity of NK cells. Our results suggest that P. cocos extract remodels the intrinsic Th1/Th2 response to prevent or alleviate allergy-induced asthma or symptoms.

A new macrocyclic diterpenoid from Anisomeles indica.

A new macrocyclic diterpenoid, 4ß,5ß-dihydroxyovatodiolide (1), together with twenty-two known compounds (2-23) were isolated from the MeOH extract of the dried aerial parts of Anisomeles indica (L.) O. Kuntze (Labiatae). The structure of 1 was established on the basis of spectral evidence. Phenylethanoids, acteoside (5) and isoacteoside (6) showed significant inhibitory to IL-2 secretion of with respect to phorbol myristate acetate and anti-CD28 monoclonal antibody co-stimulated activation of human peripheral blood T cells.

Tyrosinase inhibitors isolated from the roots of Paeonia suffruticosa.

The inhibition of mushroom tyrosinase by Paeonia suffruticosa root-derived materials was evaluated. Six tyrosinase inhibitors were isolated by ethanol extraction, n-hexane, ethyl acetate, n-BuOH, and water partition, silica gel column chromatography, Sephadex LH-20, Lobar PR-8, and high-performance liquid chromatography methods, and they were identified as kaempferol (I), quercetin (II), mudanpioside B (III), benzoyloxypaeoniflorin (IV), mudanpioside H (V), and pentagalloyl-beta-(D)-glucose (VI) on the basis of spectroscopic evidence. The inhibitory activities of compounds I to VI against mushroom tyrosinase were determined with IC(50) values of 0.120, 0.108, 0.368, 0.453, 0.324, and 0.063 mM, respectively. The kinetic study indicated that all purified inhibitors acted competitively for the L-dopa binding site of the enzyme, with an exception of compound VI, which acted non-competitively.

Effect of ginsenosides on glucose uptake in human Caco-2 cells is mediated through altered Na+/glucose cotransporter 1 expression.

In this study, we measured the effect of ginsenosides on glucose uptake using the Caco-2 cell system. At submicromolar concentrations, these compounds exhibited marked effects on the rate of glucose transport across the differentiated Caco-2 cell monolayer. Compound K (CK), the main intestinal bacterial metabolite of the protopanaxadiol ginsenosides, significantly enhanced the steady-state glucose transport rate to about 50% of the control sample rate (from 1.54 +/- 0.09 to 2.25 +/- 0.15 nmol/min). Conversely, the protopanaxatriol ginsenoside Rg1 inhibited glucose transport to about 70% of the original rate (from 1.54 +/- 0.09 to 1.02 +/- 0.05 nmol/min). Consistent with the effect on glucose uptake rate, CK and Rg1 conferred a significant and paralleled alteration on both the protein and mRNA expression levels of the Na+/glucose cotransporter 1 (SGLT1) gene. Unlike SGLT1, there is no significant alteration on the protein or mRNA levels of GLUTs in CK- or Rg1-treated cells. Taken together, our results demonstrate that ginsenosides CK and Rg1 elicited potent enhancing and suppressing effects, respectively, on glucose uptake across human intestinal Caco-2 monolayer through modulation of SGLT1 expression.

Echinacoside ameliorates the memory impairment and cholinergic deficit induced by amyloid beta peptides via the inhibition of amyloid deposition and toxicology.

Echinacoside is a phenylethanoid glycoside and possesses neuroprotective activity in vitro and in vivo. This study investigates the role of the amyloid cascade and central neuronal function on the protective effects of echinacoside in amyloid ß peptide 1-42 (Aß 1-42)-treated SH-SY5Y cells and an Aß 1-42-infused rat. Echinacoside inhibited Aß 1-42 oligomerization in vitro and restored the cell viability that was reduced by Aß 1-42 in SH-SY5Y cells. Intracisternal infusion with Aß 1-42 by an osmotic pump caused cognitive deficits, an increase in amyloid deposition and acetylcholinesterase activities, and a decrease in the brain's levels of acetylcholine and dopamine. Echinacoside reduced the cognitive deficits and amyloid deposition, and it reversed the cortical cholinergic dysfunction that was caused by Aß 1-42 in rats. Echinacoside further reversed the memory impairment in the Morris water maze task caused by scopolamine in mice. Therefore, we suggest that echinacoside ameliorated cognitive dysfunction that was caused by Aß 1-42 by blocking amyloid deposition via inhibiting amyloid oligomerization and reversing the cortical cholinergic neuronal function via decreasing amyloid neurotoxicity.

Sesquiterpenes from Baizhu Stimulate Glucose Uptake by Activating AMPK and PI3K.

Baizhu, the dried rhizome of Atractylodes Macrocephala Koidz (Compositae), is one of the most important traditional Chinese herbal medicines. Baizhu is generally used to treat digestive disorders and diabetes in Asian countries. This study investigates the activity of two sesquiterpenes isolated from Baizhu, atractylenolide I (AT-I) and atractylenolide II (AT-II), for their effects on glucose uptake in mouse skeletal muscle C2C12 cells, and the corresponding mechanism. These compounds show a significant stimulatory effect on glucose uptake in C2C12 myotubes. Both AT-I and AT-II significantly increased GLUT4 but not GLUT1 protein levels, and promoted GLUT4 translocation to the plasma membrane. The increased glucose uptake induced by these compounds is associated with activation of AMP-activated protein kinase (AMPK) and PI3K/Akt pathways in these cells. Further studies have indicated that AT-I and AT-II ameliorate TNF-[Formula: see text]-induced insulin resistance in C2C12 myotubes. In summary, our findings highlight the insulin mimetic activity of Baizhu in myotubes, and provide insights into the action mechanism underlying these effects. Our findings may also prove highly relevant to the development of novel therapeutic applications for these compounds.

Immunosuppressive flavones and lignans from Bupleurum scorzonerifolium.

Two lignans, isochaihulactone and chaihunaphthone, together with eleven known compounds were isolated from the root of Bupleurum scorzonerifolium. Their structures were established on the basis of spectral evidence. In biological testing, eugenin and saikochromone potently inhibited CD28-costimulated activation of human peripheral blood T cells.

Cytotoxic effect of triterpenoids from the root bark of Hibiscus syriacus.

In this study, 4 new triterpenoids-3ß- acetoxy-olean-11-en,28,13ß-olide (1), 3ß- acetoxy-11α,12α-epoxy-olean-28,13ß-olide (2), 19α-epi-betulin (3), and 20, 28-epoxy-17ß,19ß-lupan-3ß-ol (4)-and 12 known compounds, were isolated from the root bark of Hibiscus syriacus L. by using acetone extraction. Their structures were characterized by extensive spectroscopic analysis. To investigate cytotoxicity, A549 human lung cancer cells were exposed to the extract and the compounds identified from it. Significantly reduced cell viability was observed with betulin-3-caffeate (12) (IC50, 4.3 µM). The results of this study indicate that betulin-3-caffeate (12) identified from H. syriacus L. may warrant further investigation for potential as anticancer therapies.

Alkaloids from Coptis chinensis root promote glucose uptake in C2C12 myotubes.

The root of Coptis chinensis Franch. (COCH) is regularly used for medicinal purposes, and has been prescribed alone or in combination with other traditional herbs for the treatment of diabetes. To investigate the effects of COCH on glucose utilization by skeletal muscles, we prepared an ethanol extract of COCH root (COCH-Et) partitioned with dichloromethane, n-butanol, and water and tested its effects on glucose uptake in differentiated C2C12 myotubes. We found that dichloromethane and n-butanol sub-fractions of COCH-Et promoted glucose uptake in differentiated C2C12 cells at 50 µg/mL. Further fractionation of these preparations by using column chromatography, analysis of their effects on glucose uptake and characterization using nuclear magnetic resonance, mass spectrometry, and thin layer chromatography helped identify two new alkaloids, 8,13-dioxocoptisine hydroxide (1) and coptisonine (2), together with eleven known compounds. These were isolated from the dichloromethane layer of COCH-Et. In particular, exposure of C2C12 cells to berberine (6) at 12.5 and 6.25 µg/mL for 24h resulted in significant promotion of glucose uptake. Coptisonine (2) and octadecyl caffeate (9) also stimulated glucose uptake at 25 and 50 µg/mL. These findings indicate that active constituents of COCH root may help alleviate hyperglycemia in diabetes by promoting glucose uptake by skeletal muscles.

Pachymic acid stimulates glucose uptake through enhanced GLUT4 expression and translocation.

In an effort to investigate the effect and mechanism of Poria cocos on glucose uptake, six lanostane-type triterpenoids were isolated and analyzed. Among them, pachymic acid displayed the most significant stimulating activity on glucose uptake in 3T3-L1 adipocytes. The effect of pachymic acid on the expression profile of glucose transporters in differentiated 3T3-L1 adipocytes was also analyzed. Our results demonstrated that pachymic acid induced an increase in GLUT4, but not GLUT1, expression at both the mRNA and protein levels. The role of GLUT4 was further confirmed using the lentiviral vector-derived GLUT4 short hairpin RNA (shRNA). The stimulating activity of pachymic acid on glucose uptake was abolished when the endogenous GLUT4 expression was suppressed in 3T3-L1 adipocytes. In addition to increased GLUT4 expression, pachymic acid stimulated GLUT4 redistribution from intracellular vesicles to the plasma membrane in adipocytes. Exposure of the differentiated adipocytes to pachymic acid increased the phosphorylation of insulin receptor substrate (IRS)-1, AKT and AMP-activated kinase (AMPK). The involvement of PI3K and AMPK in the action of pachymic acid was further confirmed as PI3K and AMPK inhibitors completely blocked the pachymic acid-mediated activities in adipocytes. In addition, pachymic acid was shown to induce triglyceride accumulation and inhibit lipolysis in differentiated adipocytes. Taken together, we demonstrated the insulin-like activities of this compound in stimulating glucose uptake, GLUT4 gene expression and translocation, and promoting triglyceride accumulation in adipocytes. Our study provides important insights into the underlying mechanism of hypoglycemic activity of P. cocos.

Müllerianosis of ureter: a rare cause of hydronephrosis.

Müllerianosis of the urinary tract is a very rare and morphologically complex tumor-like lesion. It is composed of several types of müllerian-type lesions, including endometriosis, endocervicosis, and endosalpingiosis. We present a case of ureteral müllerianosis in woman with a history of a cesarean section about 20 years previously but with silent clinical symptoms. She was treated with segmental ureteral resection, followed by ureteroureteral anastomosis. The pathogenesis and treatment of this lesion are discussed.

Identifying 6,7,4'-trihydroxyisoflavone as a potent tyrosinase inhibitor.

A known biotransformed compound, 6,7,4'-trihydroxyisoflavone, was identified as a potent tyrosinase inhibitor. It inhibited mushroom tyrosinase with an IC50 value of 9.2 microM, which is six times the anti-tyrosinase activity of kojic acid (IC50 = 54.4 microM). The inhibition kinetics, analyzed by Lineweaver-Burk plots, indicated 6,7,4'-trihydroxyisoflavone to be a competitive inhibitor of tyrosinase when L-tyrosine was used as a substrate. Its biosynthesis precursors and analogs, including glycitein, daidzein, and genistein, showed little anti-tyrosinase activity. The results suggest that hydroxyl groups at the C-6 and C-7 positions of the isoflavone skeleton might play an important role in the expression of tyrosinase inhibitory activity.

Immunosuppressive iridoids from the fruits of Gardenia jasminoides.

A new iridoid, gardaloside (1), and a new safranal-type monoterpene, jasminoside G (2), together with 10 known compounds including nine iridoids and a second safranal-type monoterpene, were isolated from the fruits of Gardenia jasminoides. The structures of 1 and 2 were established on the basis of spectroscopic evidence. Of these compounds, geniposide (3), 6alpha-hydroxygeniposide (5), ixoroside (7), and shanzhiside (8) showed significant inhibition of IL-2 secretion by phorbol myristate acetate and anti-CD28 monoclonal antibody co-stimulated activation of human peripheral blood T cells.