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Ding T.,Fudan University | Ding T.,SUNY Downstate Medical Center | Kabir I.,SUNY Downstate Medical Center | Li Y.,Fudan University | And 13 more authors.
Journal of Lipid Research | Year: 2015

Sphingomyelin synthase-related protein (SMSr) synthesizes the sphingomyelin analog ceramide phosphoethanolamine (CPE) in cells. Previous cell studies indicated that SMSr is involved in ceramide homeostasis and is crucial for cell function. To further examine SMSr function in vivo, we generated Smsr KO mice that were fertile and had no obvious phenotypic alterations. Quantitative MS analyses of plasma, liver, and macrophages from the KO mice revealed only marginal changes in CPE and ceramide as well as other sphingolipid levels. Because SMS2 also has CPE synthase activity, we prepared Smsr/Sms2 double KO mice. We found that CPE levels were not signifi cantly changed in macrophages, suggesting that CPE levels are not exclusively dependent on SMSr and SMS2 activities. We then measured CPE levels in Sms1 KO mice and found that Sms1 defi ciency also reduced plasma CPE levels. Importantly, we found that expression of Sms1 or Sms2 in SF9 insect cells signifi cantly increased not only SM but also CPE formation, indicating that SMS1 also has CPE synthase activity. Moreover, we measured CPE synthase Km and Vmax for SMS1, SMS2, and SMSr using different NBD ceramides. Our study reveals that all mouse SMS family members (SMSr, SMS1, and SMS2) have CPE synthase activity. However, neither CPE nor SMSr appears to be a critical regulator of ceramide levels in vivo.


PubMed | Guangzhou University of Chinese Medicine, Guangdong Medical Laboratory Animal Center, Sun Yat Sen University and Guangzhou Wanglaoji Pharmaceutical Company Ltd
Type: | Journal: Journal of ethnopharmacology | Year: 2016

Kegan Liyan oral liquid (KGLY), a Chinese prescription modified from classic formulas Yin-Qiao-San (from TCM classic Wenbing Tiaobian) and Shen-Jie-San (first mentioned in Shanghan Wenyi Tiaobian), has been reported to exert heat-clearing and detoxifying effects and used extensively for the treatment of severe pulmonary diseases in clinics including influenza, cough and pneumonia.The purpose of this study was to investigate the protective effect of KGLY on lipopolysaccharide (LPS) induced acute lung injury (ALI) in mice and to illuminate the underlying mechanisms.Mice were orally administrated with KGLY (50, 100 and 150mg/kg) before intratracheal instillation of LPS. 24h post LPS challenge, lung tissues and the bronchoalveolar lavage fluid (BALF) were collected for lung wet/dry (W/D) weight ratio, histopathological examinations and biochemical analyses. The cell counts, protein concentration, interleukin-1 (IL-1), interleukin-6 (IL-6), necrosis factor- (TNF-), macrophage inflammatory protein-2 (MIP-2) in BALF, superoxide dismutase (SOD), glutathione (GSH), myeloperoxidase (MPO) and malondialdehyde (MDA) levels were detected. Meanwhile, the activation of toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-B), as well as matrix metalloproteinases 9 (MMP-9) were determined by western blot assay.KGLY significantly prolonged mice survival time and ameliorated LPS-induced edema, thickening of alveolar septa and inflammatory cell infiltration in a dose-dependent manner. Additionally, KGLY markedly attenuated LPS-induced acute pulmonary inflammation via decreasing the expressions of cytokines and chemokines (IL-1, IL-6, TNF-, and MIP-2), enhanced the activities of anti-oxidative indicators (SOD and GSH), suppressed the levels of MPO and MDA, and down-regulated the expressions of TLR4, NF-B and MMP9.The results suggested that the relieving effect of KGLY against LPS-induced ALI might be partially due to suppression of oxidative stress and inflammatory response, inhibition of TLR4-mediated NF-B activation, and down-regulation of MMP9 expression, indicating it may be a potential therapeutic agent for ALI.


Liao C.,Guangzhou Medical College | Fu F.,Guangzhou Medical College | Li R.,Guangzhou Medical College | Li R.,Sun Yat Sen University | And 9 more authors.
European Journal of Medical Genetics | Year: 2013

The molecular basis of autosomal dominant microcephaly, a disorder associated with small head circumferences that results in variable mental retardation, is largely unknown. In the present study, we conducted a variation analysis of the DPP6 gene in patients with autosomal dominant microcephaly and variable mental retardation. The copy number variation analysis of DPP6 was performed on DNA samples from 22 patients with microcephaly using high-resolution, array-based genomic hybridization, and sequence analysis was performed to screen mutations in another 50 microcephalic patients. Two de novo deletions and one missense mutation in familial microcephalic patients were identified. The transfection of plasmids encoding green fluorescent protein-pLLU2G-shDPP6 fusion proteins in mouse brains revealed that the decreased expression of the DPP6 gene slightly reduced the weight of the mouse brains and resulted in mouse learning disabilities compared with their wild-type littermates. Our data indicate that the loss-of-function variations in DPP6 are associated with autosomal dominant microcephaly and mental retardation. DPP6 appears to play a major role in the regulation of proliferation and migration of neurons in neurogenesis, most likely by participating in neuronal electrical excitability, synaptic integration, and plasticity. © 2013 Elsevier Masson SAS.


Tang X.,Guangdong Medical Laboratory Animal Center | Wu X.,Guangdong Medical Laboratory Animal Center | Dubois A.M.,State University of New York at Buffalo | Sui G.,Guangdong Medical Laboratory Animal Center | And 10 more authors.
Bulletin of Environmental Contamination and Toxicology | Year: 2013

Extensive uses of methyltin compounds in polyvinyl chloride (PVC) production have led to a dramatic increase of occupational-related methyltin poisoning accidents and the widespread contamination of methyltins in various environmental media. Here, we conducted studies to compare the acute toxicity induced by trimethyltin (TMT) and dimethyltin (DMT), and investigated the cumulative toxic effects of TMT in rats and mice. Neurobehavioral changes were observed in rats and mice treated with either DMT or TMT, but we also observed that both TMT and DMT exposure in rats significantly lowered the blood potassium level. Moreover, the cumulative toxic coefficient factor of TMT was 1.7 in rats versus 3.8 in mice, suggesting a high cumulative risk for rats and a moderate risk for mice. In summary, we demonstrated that acute and chronic exposure to methyltin compounds induced neurotoxicity and hypokalemia. Moreover, our study suggests that TMT can accumulate in the body and pose a risk for workers chronically exposed to a low dose of TMT. © 2013 Springer Science+Business Media New York.


Zhang H.,Lingnan Normal University | Li Z.,Sun Yat Sen University | Zhou Z.,Lingnan Normal University | Yang H.,Lingnan Normal University | And 2 more authors.
Pharmacology Biochemistry and Behavior | Year: 2016

Ginsenoside Rb3 has been proved to have antidepressant-like effects, which possesses 1 xylose and 3 glucose moieties with 20(S)-protopanaxadiol (PPD) as the aglycone. However, it is commonly accepted that orally ingested ginsenosides can be deglycosylated or partially deglycosylated into active derivatives by the intestinal bacteria. To identify potential antidepressant drug candidates, we compared the antidepressant-like activities between ginsenoside Rb3 and its four deglycosylated derivatives, Rg3, Rh2, compound K (C-K), and PPD. Effects of acute (1-day), short chronic (7-days), and longer chronic treatments (14-days) with these ginsenosides (50 and 100 mg/kg, p.o.) on the behavioral changes in the forced swim test (FST), tail suspension test (TST) and open field test were investigated. Serum corticosterone and adrenocorticotropic hormone (ACTH) levels and mouse brain monoamine neurotransmitters 5-HT, NA and DA levels were measured using commercially available competitive enzyme-linked immunosorbent assay (ELISA) kits. Interestingly, C-K showed antidepressant-like activities similar to that of Rb3, and Rg3 displayed antidepressant-like effects at lower dosage and faster time, indicating it has better effects than Rb3, whereas Rh2 and PPD failed to show any effect. Our results also showed, unlike the positive control fluoxetine, Rb3, Rg3 and C-K significantly increased the NA levels in the brain regions of mice exposed to FST but did not affect the 5-HT and DA levels. Moreover, treatment with Rg3 could reverse swim stress-induced increased levels of serum ACTH and corticosterone. These results suggest that C-K and Rg3 are the active deglycosylated derivatives, especially the latter compound, which is more potent than Rb3 and exerts antidepressant-like effects by regulating NA, ACTH and corticosterone levels. © 2015 Elsevier Inc. All rights reserved.


PubMed | Guangdong Medical Laboratory Animal Center, Sun Yat Sen University and Lingnan Normal University
Type: | Journal: Pharmacology, biochemistry, and behavior | Year: 2015

Ginsenoside Rb3 has been proved to have antidepressant-like effects, which possesses 1 xylose and 3 glucose moieties with 20(S)-protopanaxadiol (PPD) as the aglycone. However, it is commonly accepted that orally ingested ginsenosides can be deglycosylated or partially deglycosylated into active derivatives by the intestinal bacteria. To identify potential antidepressant drug candidates, we compared the antidepressant-like activities between ginsenoside Rb3 and its four deglycosylated derivatives, Rg3, Rh2, compound K (C-K), and PPD. Effects of acute (1-day), short chronic (7-days), and longer chronic treatments (14-days) with these ginsenosides (50 and 100mg/kg, p.o.) on the behavioral changes in the forced swim test (FST), tail suspension test (TST) and open field test were investigated. Serum corticosterone and adrenocorticotropic hormone (ACTH) levels and mouse brain monoamine neurotransmitters 5-HT, NA and DA levels were measured using commercially available competitive enzyme-linked immunosorbent assay (ELISA) kits. Interestingly, C-K showed antidepressant-like activities similar to that of Rb3, and Rg3 displayed antidepressant-like effects at lower dosage and faster time, indicating it has better effects than Rb3, whereas Rh2 and PPD failed to show any effect. Our results also showed, unlike the positive control fluoxetine, Rb3, Rg3 and C-K significantly increased the NA levels in the brain regions of mice exposed to FST but did not affect the 5-HT and DA levels. Moreover, treatment with Rg3 could reverse swim stress-induced increased levels of serum ACTH and corticosterone. These results suggest that C-K and Rg3 are the active deglycosylated derivatives, especially the latter compound, which is more potent than Rb3 and exerts antidepressant-like effects by regulating NA, ACTH and corticosterone levels.


PubMed | Guangdong Medical Laboratory Animal Center, Sun Yat Sen University, Golden Health Foshan Technology Co., State University of New York at Buffalo and Guangdong Poison Control Center
Type: | Journal: Toxicology and applied pharmacology | Year: 2016

Chronic exposure to cadmium compounds (Cd(2+)) is one of the major public health problems facing humans in the 21st century. Cd(2+) in the human body accumulates primarily in the kidneys which leads to renal dysfunction and other adverse health effects. Efforts to find a safe and effective drug for removing Cd(2+) from the kidneys have largely failed. We developed and synthesized a new chemical, sodium (S)-2-(dithiocarboxylato((2S,3R,4R,5R)-2,3,4,5,6 pentahydroxyhexyl)amino)-4-(methylthio) butanoate (GMDTC). Here we report that GMDTC has a very low toxicity with an acute lethal dose (LD50) of more than 10,000mg/kg or 5000mg/kg body weight, respectively, via oral or intraperitoneal injection in mice and rats. In in vivo settings, up to 94% of Cd(2+) deposited in the kidneys of Cd(2+)-laden rabbits was removed and excreted via urine following a safe dose of GMDTC treatment for four weeks, and renal Cd(2+) level was reduced from 12.9g/g to 1.3g/g kidney weight. We observed similar results in the mouse and rat studies. Further, we demonstrated both in in vitro and in animal studies that the mechanism of transporting GMDTC and GMDTC-Cd complex into and out of renal tubular cells is likely assisted by two glucose transporters, sodium glucose cotransporter 2 (SGLT2) and glucose transporter 2 (GLUT2). Collectively, our study reports that GMDTC is safe and highly efficient in removing deposited Cd(2+) from kidneys assisted by renal glucose reabsorption system, suggesting that GMDTC may be the long-pursued agent used for preventive and therapeutic purposes for both acute and chronic Cd(2+) exposure.


Yan W.,Guangdong Institute of Microbiology | Li T.,Guangdong Institute of Microbiology | Zhong Z.,Guangdong Medical Laboratory Animal Center
Food and Function | Year: 2014

Cordyceps guangdongensis T. H. Li, Q. Y. Lin & B. Song (Cordycipitaceae) is a novel food approved by the Ministry of Public Health of China in 2013. Preliminary studies revealed that this novel food has multiple pharmacological activities such as anti-fatigue effect, antioxidant ability, prolonging life, anti-avian influenza virus activity, and therapeutic effect on chronic renal failure. However, the anti-inflammatory effect on chronic bronchitis and the effective constituent are still unknown. The purpose of this study was to investigate both the anti-inflammatory effect of the edible fungus on experimental rats with chronic bronchitis induced by tobacco smoking, and the pilot effective constituent. Test rats were intragastrically administered with 3 doses of hot-water extract from C. guangdongensis (0.325, 0.65 and 1.30 g kg-1 bw daily for low, middle and high dose, respectively) for 26 days. Biochemical indices and histological examinations in rats with chronic bronchitis induced by tobacco smoking were determined. The content and molecular weights of the polysaccharide from the hot-water extract were detected by the phenol-sulfuric acid method and gel permeation chromatography, respectively. Biochemical indices in the low, middle and high-dose groups with the hot-water extract of C. guangdongensis were only 53.4%, 46.0% and 40.4% of those in the model control group (total leukocytes), respectively; 70.7%, 60.3% and 58.1% (macrophages); 33.0%, 26.8% and 16.1% (neutrophils); and 22.2%, 23.5% and 13.6% (lymphocytes) of those in the model control group. The bronchial lesions and inflammatory cell infiltration were significantly alleviated in all groups with hot-water extract of C. guangdongensis. This study indicates that the hot-water extract from C. guangdongensis has a significant anti-inflammatory effect on chronic bronchitis. The content of the polysaccharide was 6.92%; the molecular weights of the 3 polysaccharide components were respectively 1.28 × 106, 2.36 × 104 and 5.21 × 103 Da. © 2014 the Partner Organisations.


Li Z.,New York University | Li Z.,VA New York Harbor Healthcare System | Jiang H.,New York University | Ding T.,New York University | And 8 more authors.
Gastroenterology | Year: 2015

Background and Aims Phosphatidylcholines (PCs) are structural and functional constituents of cell membranes. The activity of acyltransferase (lysophosphatidylcholine acyltransferase [LPCAT]) is required for addition of polyunsaturated fatty acids to the sn-2 position of PCs and is therefore required to maintain cell membrane structure and function. LPCAT3 is the most abundant isoform of LPCAT in the small intestine and liver, which are important sites of plasma lipoprotein metabolism. We investigated the effects of Lpcat3 disruption on lipid metabolism in mice. Methods We disrupted the gene Lpcat3 in C57BL/6J mice to create LPCAT3 knockout (KO) mice. Livers and small intestinal tissues were collected from LPCAT3 KO and C57BL/6J parental strain (controls), and levels of LPCAT messenger RNAs and protein were measured. Levels of lipids and lipoproteins were measured in plasma samples. We isolated enterocytes from mice and measured levels of RNAs and proteins involved in lipid uptake by real-time polymerase chain reaction and immunoblot assays, respectively. We assessed lipid absorption and PC subspecies in the enterocyte plasma membrane using liquid chromatography with tandem mass spectometry. Results LPCAT3 KO mice survived only 3 weeks after birth. Oil Red O staining showed that the control but not LPCAT3 KO mice accumulated lipids in the small intestine; levels of Niemann-Pick C1-like 1 (NPC1L1) and fatty acid transporter protein 4 (FATP4), which regulate lipid uptake, were greatly reduced in the small intestines of LPCAT3 KO mice. Oral administration of PC and olive oil allowed the LPCAT3 KO mice to survive with the same body weights as controls, but the KO mice had shorter and wider small-intestinal villi and longer and bigger small intestines. Plasma membranes of enterocytes from LPCAT3 KO mice also had significant reductions in the composition of polyunsaturated PCs and reduced levels of NPC1L1, CD36, and FATP4 proteins. These reductions were associated with reduced intestinal uptake of lipid by the small intestine and reduced plasma levels of cholesterol, phospholipid, and triglyceride. Conclusions LPCAT3 KO mice have longer and larger small intestines than control mice, with shorter wide villi, reduced lipid absorption, and lower levels NPC1L1, CD36, and FATP4 proteins. Inhibition of LPCAT3 in the small intestine could be developed as an approach to treat hyperlipidemia. © 2015 AGA Institute.


Piao X.-L.,Minzu University of China | Xing S.-F.,Minzu University of China | Lou C.-X.,Guangdong Medical Laboratory Animal Center | Chen D.-J.,Minzu University of China
Bioorganic and Medicinal Chemistry Letters | Year: 2014

Two new dammarane saponins, 2α,3β,12β-trihydroxydammar-20(22),24-diene-3-O-[β-d-glucopyranoxyl(1→2)-β-d-6″-O-acetylglucopyranoside (1, namely damulin C) and 2α,3β,12β-trihydroxydammar-20(21),24-diene-3-O-[β-d-glucopyranoxyl(1→2)-β-d-6″-O-acetylglucopyranoside (2, namely damulin D), were isolated from the ethanol extract of Gynostemma pentaphyllum, which had been heat processed by steaming at 125 °C. The NMR spectroscopic data of the novel saponins were completely assigned by using a combination of 2D NMR experiments including 1H-1H COSY, HSQC, and HMBC. Their cytotoxic activities of human liver adenocarcinoma HepG2 cells were evaluated in vitro. They showed cytotoxicities against HepG2 cell line with IC50 of 40 ± 0.7 and 38 ± 0.5 μg/ml, respectively. © 2014 Elsevier Ltd. All rights reserved.

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