Downregulation of astroglial glutamate transporter GLT-1 in the lateral habenula is associated with depressive-like behaviors in a rat model of Parkinson's disease.

Recent studies show that neuron-glial communication plays an important role in neurological diseases. Particularly, dysfunction of astroglial glutamate transporter GLT-1 has been involved in various neuropsychiatric disorders, including Parkinson's disease (PD) and depression. Our previous studies indicated hyperactivity of neurons in the lateral habenula (LHb) of hemiparkinsonian rats with depressive-like behaviors. Thus, we hypothesized that impaired expression or function of GLT-1 in the LHb might be a potential contributor to LHb hyperactivity, which consequently induces PD-related depression. In the study, unilateral lesions of the substantia nigra pars compacta (SNc) by 6-hydroxydopamine in rats induced depressive-like behaviors and resulted in neuronal hyperactivity as well as increased glutamate levels in the LHb compared to sham-lesioned rats. Intra-LHb injection of GLT-1 inhibitor WAY-213613 induced the depressive-like behaviors in both groups, but the dose producing behavioral effects in the lesioned rats was lower than that of sham-lesioned rats. In the two groups of rats, WAY-213613 increased the firing rate of LHb neurons and extracellular levels of glutamate, and these excitatory effects in the lesioned rats lasted longer than those in sham-lesioned rats. The functional changes of the GLT-1 which primarily expresses in astrocytes in the LHb may attribute to its downregulation after degeneration of the nigrostriatal pathway. Bioinformatics analysis showed that GLT-1 is correlated with various biomarkers of PD and depression risks. Collectively, our study suggests that astroglial GLT-1 in the LHb regulates the firing activity of the neurons, whereupon its downregulation and dysfunction are closely associated with PD-related depression.

Effects of the stem extracts of Schisandra glaucescens Diels on collagen-induced arthritis in Balb/c mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra glaucescens Diels (SGD) is used in a subclass of traditional Chinese medicine known as "Tujia drugs". It has been long used for the treatment of rheumatoid arthritis (RA), cough with dyspnea, spontaneous sweating, night sweating, chronic diarrhea, and neurasthenia. As a woody liana growing in mountain jungles at the altitudes of 750-1800m, it is mainly distributed in Sichuan and Hubei Provinces of China. AIM OF THE STUDY: To evaluate the antiarthritic activity of acetate (EA) and n-butanol (Bu) fractions of SGD extract on a collagen-induced arthritis mice model. MATERIALS AND METHODS: Acute toxicity of EA and Bu fractions of SGD extract was evaluated by gavage on normal mice. Pharmacological investigations were conducted on arthritis male Balb/c mice. The animal model was induced by immunization with type II bovine collagen (CII) on the 1st and the 14th day of the experimental schedule. EA fraction (104, 312, 936mg/kg), Bu fraction (156, 469, 1407mg/kg) of SGD extract was orally administered every two days since the 15th day for 3 weeks. Progression of edema in the paws was measured using a vernier caliper every 3 days since the 10th day. At the end of the experiment, the spleen index and histological changes of the hind knee joints were investigated. Additionally, to explore the possible antirheumatic mechanisms of the EA and Bu fractions, ELISA was carried out to analyze TNF-α, IL-10, IL-6 and IL-1ß in the serum. RESULTS: The half lethal doses of both EA and Bu fractions were much higher than the dose administered in the pharmacological investigations. Oral administration of EA fraction and Bu fraction of SGD extract significantly and does-dependently inhibited type ІІ collagen induced arthritis (CIA) in mice, as indicated by the effects on paws swelling and spleen index. Histopathological examinations demonstrated that SGD effectively protected the bones and cartilages of knee joints from erosion, lesion and deformation. Besides, the serum concentrations of cytokines TNF-α, IL-1ß and IL-6 were significantly lower than the ones from the vehicle control group. Respectively, while cytokine IL-10 was remarkably higher compare with the vehicle control group. CONCLUSIONS: SGD might be a safe and effective candidate for the treatment of RA, and deserves further investigation on the chemical components in both EA and Bu fractions of SGD extract.

[Chemical constituents from stems of Hedyotis hedyotidea and their immunosuppressive activity].

Hedyotis hedyotidea has been traditionally used for the treatment of arthritis, cold, cough, gastro-enteritis, headstroke, etc. But few studies have screened the active compounds from extracts of H. hedyotidea. In this study, the structure of the chemical constituents from stems of H. hedyotidea were determined and the immunosuppressive activity of the compounds was evaluated. The compounds were separated and purified with silica gel, gel column chromatographies and preparative HPLC, and their structures were identified by spectral methods such as MS and NMR. Eleven compounds were obtained and identified as(6S,9S) -vomifoliol (1), betulonic acid (2), betulinic acid (3), betulin(4), 3-epi-betulinic acid (5), ursolic acid (6), ß-sitosterol (7), stigmast-4-en-3-one (8), 7ß-hydroxysitosterol (9), (3ß,7ß) -7-methoxystigmast-5-en-3-ol (10) and morindacin (11). This is the first report of compounds 1, 2, 4, 8, 9, 10 and 11 from H. hedyotidea. Compounds 1, 2 and 8-11 were firstly isolated from the genus Hedyotis, and compounds 9 and 10 were isolated from the family Rubiaceae for the first time. The immunosuppressive activity of these compounds was tested using the lymphocyte transsormationtest. Compounds 4, 6 and 9 showed significant immunosuppressive activity.

Two new compounds from Schisandra glaucescens.

One new lignan (7S,8R,7'R,8'R)-7-(3,4-methylenedioxyphenyl)-8,8'-dimethyl-8'-hydroxyl-7'-methoxyl-7'-(3',4'-methylenedioxyphenyl)-tetrahydrofuran (1), one new sesquiterpene 2-hydroxy-11,12-dehydrocalamenene (2), one new natural product erythro-1-(3,4-dimethoxyphenyl)-4-(3,4-methylenedioxyphenyl)-2,3-dimethyl-butane (3), and two known lignans (+)-anwulignan(erythro-1-(4-hydroxy-3-methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-2,3-dimethyl-butane) (4) and ( - )-zuonin-A (5) were isolated from the stems of Schisandra glaucescens Diels. Their structures were elucidated by spectroscopic methods. The cytotoxicity of compounds 1 and 2 was assayed.

Lutein and zeaxanthin supplementation reduces photooxidative damage and modulates the expression of inflammation-related genes in retinal pigment epithelial cells.

Oxidative damage and inflammation are related to the pathogenesis of age-related macular degeneration (AMD). Epidemiologic studies suggest that insufficient dietary lutein and zeaxanthin intake or lower serum zeaxanthin levels are associated with increased risk for AMD. The objective of this work is to test the protective effects of lutein and zeaxanthin against photooxidative damage to retinal pigment epithelial cells (RPE) and oxidation-induced changes in expression of inflammation-related genes. To mimic lipofuscin-mediated photooxidation in vivo, we used ARPE-19 cells that accumulated A2E, a lipofuscin fluorophore and photosensitizer, as a model system to investigate the effects of lutein and zeaxanthin supplementation. The data show that supplementation with lutein or zeaxanthin in the medium resulted in accumulation of lutein or zeaxanthin in the RPE cells. The concentrations of lutein and zeaxanthin in the cells were 2- to 14-fold of that detected in the medium, indicating that ARPE-19 cells actively take up lutein or zeaxanthin. As compared with untreated cells, exposure of A2E-containing RPE to blue light resulted in a 40-60% decrease in proteasome activity, a 50-80% decrease in expression of CFH and MCP-1, and an~20-fold increase in expression of IL-8. The photooxidation-induced changes in expression of MCP-1, IL-8, and CFH were similar to those caused by chemical inhibition of the proteasome, suggesting that inactivation of the proteasome is involved in the photooxidation-induced alteration in expression of these inflammation-related genes. Incubation of the A2E-containing RPE with lutein or zeaxanthin prior to blue light exposure significantly attenuated the photooxidation-induced inactivation of the proteasome and photooxidation-induced changes in expression of MCP-1, IL-8, and CFH. Together, these data indicate that lutein or zeaxanthin modulates inflammatory responses in cultured RPE in response to photooxidation. Protecting the proteasome from oxidative inactivation appears to be one of the mechanisms by which lutein and zeaxanthin modulate the inflammatory response. Similar mechanisms may explain salutary effects of lutein and zeaxanthin in reducing the risk for AMD.

[Sesquiterpenes from stem of Schisandra glaucescens].

OBJECTIVE: To study the chemical constituents from Schisandra glaucescens. METHOD: The chemical constituents were separated and purifed with silica gel, gel column chromatography preparative HPLC, and their structures were identified by such spectral methods as MS and NMR. RESULT: Twelve compounds were separated from petroleum ether fractions, and identified as t-cadinol (1), alpha-cadinol (2), torreyol (3), (+)-ent-epicubenol (4), ent-T-muurolol (5), (-)-15-hydroxycalamenene (6), (-)-cubebol (7), 4-epi-cubebol (8), caryophyllenol-I (9), caryophyllenol-II (10), oxyphyllenodiols A (11), caryolane-1,9/3-diol (12). CONCLUSION: Compounds 4, 6-12 were separated from the genus for the first time, while compounds 1-12 were separated from this plant for the first time.

Lutein and zeaxanthin supplementation reduces H2O2-induced oxidative damage in human lens epithelial cells.

PURPOSE: Epidemiological studies suggest that dietary intake of lutein and zeaxanthin is inversely related to the risk for senile cataract. The objectives of this work were to investigate the mechanisms by which these nutrients provide anti-cataract effects. We evaluated their modulation of oxidative damage in human lens epithelial cells (HLEC) and their interaction with intracellular glutathione (GSH). METHODS: Subconfluent HLEC were pre-incubated with or without 5 µM lutein, zeaxanthin, or α-tocopherol for 48 h and then exposed to 100 µM H(2)O(2) for 1 h. Levels of protein carbonyls in the cells were measured by western-blotting analysis following reaction with 2,4-dinitrophenylhydrazine (DNPH). Levels of malondialdehyde (MDA), reduced glutathione (GSH) and oxidized glutathione (GSSG) were measured by an HPLC system. DNA damage was assessed using comet assays. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. RESULTS: In the absence of H(2)O(2), HLEC had very low levels of protein carbonyl and MDA. Supplementation with lutein, zeaxanthin, or α-tocopherol to the unstressed HLEC had no detectable effects on levels of oxidized proteins and lipid in the cells. Exposure of HLEC to H(2)O(2) significantly increased levels of oxidized proteins, lipid peroxidation, and DNA damage. Pre-incubation with lutein, zeaxanthin, or α-tocopherol dramatically reduced the levels of H(2)O(2) -induced protein carbonyl, MDA, and DNA damage in HLEC. The protective effects of lutein, zeaxanthin, and α-tocopherol against protein oxidation, lipid peroxidation, and DNA damage were comparable. Supplementation with lutein, zeaxanthin, or α-tocopherol increased GSH levels and GSH:GSSG ratio, particularly in response to oxidative stress. Depletion of GSH resulted in significant increase in susceptibility to H(2)O(2)-induced cell death. Supplementation with α-tocopherol, but not lutein or zeaxanthin, can partially restore the resistance of GSH-depleted cells to H(2)O(2). CONCLUSIONS: These data indicate that lutein or zeaxanthin supplementation protects lens protein, lipid, and DNA from oxidative damage and improves intracellular redox status upon oxidative stress. The protective effects are comparable to that of α-tocopherol, except that lutein and zeaxanthin cannot compensate for GSH depletion. The data imply that sufficient intake of lutein and zeaxanthin may reduce the risk for senile cataract via protecting the lens from oxidative damage.