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1.  The lin-4 Gene Controls Fat Accumulation and Longevity in Caenorhabditis elegans 
Previous studies have determined that lin-4, which was the first miRNA to be discovered, controls the timing of cell fate determination and life span in Caenorhabditis elegans. However, the mechanism of lin-4 involvement in these processes remains poorly understood. Fat storage is an essential aspect of the life cycle of organisms, and the function of lin-4 in fat accumulation is not clear. In this study, we showed that the fat content is reduced remarkably in C. elegans lin-4 mutants. Quantitative RT-PCR analysis revealed a considerable decrease in the levels of SBP-1 and OGA-1 mRNA in lin-4 mutants. We also showed that lin-4 mutants have a significantly shorter life span than wild-type worms. DCF assay experiments showed that the reactive oxygen species (ROS) levels increased and mitochondrial DNA (mtDNA) copy number decreased in loss-of-function lin-4 mutants. These mutants also showed attenuation of locomotion. Taken together, our findings suggest that lin-4 may play an important role in regulating fat accumulation and locomotion and that lin-4 may control the life span of C. elegans by mediating ROS production.
PMCID: PMC3100830  PMID: 21614175
lin-4; Caenorhabditis elegans; fat accumulation; life span; locomotion
2.  Gastric nNOS reduction accompanied by natriuretic peptides signaling pathway upregulation in diabetic mice 
AIM: To investigate the relationship between neuronal nitric oxide synthase (nNOS) expression and the natriuretic peptide signaling pathway in the gastric fundus of streptozotocin (STZ)-induced diabetic mice.
METHODS: Diabetic mice were induced by injection of STZ solution. Immunofluorescence labeling of HuC/D, nNOS and natriuretic peptide receptor-A, B, C (NPRs) in the gastric fundus (GF) was used to observe nNOS expression and whether NPRs exist on enteric neurons. The expression levels of nNOS and NPRs in the diabetic GF were examined by western blotting. An isometric force transducer recorded the electric field stimulation (EFS)-induced relaxation and contraction in the diabetic GF. An intracellular recording method assessed EFS-induced inhibitory junction potentials (IJP) on the GF. GF smooth muscles acquired from normal mice were incubated with different concentrations of the NPRs agonist C-type natriuretic peptide (CNP) for 24 h, after which their nNOS expressions were detected by western blotting.
RESULTS: Eight weeks after injection, 43 diabetic mice were obtained from mouse models injected with STZ. Immunofluorescence indicated that the number of NOS neurons was significantly decreased and that nNOS expression was significantly downregulated in the diabetic GF. The results of physiological and electrophysiological assays showed that the EFS-induced relaxation that mainly caused by NO was significantly reduced, while the contraction was enhanced in the diabetic GF. EFS-induced IJP showed that L-NAME sensitive IJP in the diabetic GF was significantly reduced compared with control mice. However, both NPR-A and NPR-B were detected on enteric neurons, and their expression levels were upregulated in the diabetic GF. The nNOS expression level was downregulated dose-dependently in GF smooth muscle tissues exposed to CNP.
CONCLUSION: These findings suggested that upregulation of the NPs signaling pathway may be involved in GF neuropathy caused by diabetes by decreasing nNOS expression.
PMCID: PMC4000499  PMID: 24782615
Diabetic gastroparesis; Natriuretic peptides; Nitric oxide synthase; Enteric neuron
3.  A paradox: Insulin inhibits expression and secretion of resistin which induces insulin resistance 
AIM: To confirm whether insulin regulates resistin expression and secretion during differentiation of 3T3-L1 preadipocytes and the relationship of resistin with insulin resistance both in vivo and in vitro.
METHODS: Supernatant resistin was measured during differentiation of 3T3-L1 preadipocytes. L6 rat myoblasts and hepatoma cell line H4IIE were used to confirm the cellular function of resistin. Diet-induced obese rats were used as an insulin resistance model to study the relationship of resistin with insulin resistance.
RESULTS: Resistin expression and secretion were enhanced during differentiation 3T3-L1 preadipocytes. This cellular differentiation stimulated resistin expression and secretion, but was suppressed by insulin. Resistin also induced insulin resistance in H4IIE hepatocytes and L6 myoblasts. In diet-induced obese rats, serum resistin levels were negatively correlated with insulin sensitivity, but not with serum insulin.
CONCLUSION: Insulin can inhibit resistin expression and secretion in vitro, but insulin is not a major regulator of resistin in vivo. Fat tissue mass affects insulin sensitivity by altering the expression and secretion of resistin.
PMCID: PMC2673399  PMID: 18176969
Resistin; Insulin; Insulin resistance
4.  Voltage Dependent Potassium Channel Remodeling in Murine Intestinal Smooth Muscle Hypertrophy Induced by Partial Obstruction 
PLoS ONE  2014;9(2):e86109.
Partial obstruction of the small intestine causes obvious hypertrophy of smooth muscle cells and motility disorder in the bowel proximate to the obstruction. To identify electric remodeling of hypertrophic smooth muscles in partially obstructed murine small intestine, the patch-clamp and intracellular microelectrode recording methods were used to identify the possible electric remodeling and Western blot, immunofluorescence and immunoprecipitation were utilized to examine the channel protein expression and phosphorylation level changes in this research. After 14 days of obstruction, partial obstruction caused obvious smooth muscle hypertrophy in the proximally located intestine. The slow waves of intestinal smooth muscles in the dilated region were significantly suppressed, their amplitude and frequency were reduced, whilst the resting membrane potentials were depolarized compared with normal and sham animals. The current density of voltage dependent potassium channel (KV) was significantly decreased in the hypertrophic smooth muscle cells and the voltage sensitivity of KV activation was altered. The sensitivity of KV currents (IKV) to TEA, a nonselective potassium channel blocker, increased significantly, but the sensitivity of IKv to 4-AP, a KV blocker, stays the same. The protein levels of KV4.3 and KV2.2 were up-regulated in the hypertrophic smooth muscle cell membrane. The serine and threonine phosphorylation levels of KV4.3 and KV2.2 were significantly increased in the hypertrophic smooth muscle cells. Thus this study represents the first identification of KV channel remodeling in murine small intestinal smooth muscle hypertrophy induced by partial obstruction. The enhanced phosphorylations of KV4.3 and KV2.2 may be involved in this process.
PMCID: PMC3916336  PMID: 24516526
5.  Metabolic heterogeneity of follicular amino acids in polycystic ovary syndrome is affected by obesity and related to pregnancy outcome 
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder frequently accompanied by obesity and by insulin resistance, and patients with this syndrome suffer from infertility and poor pregnancy outcome. Disturbances in plasma amino acid (AA) metabolism have been implicated in women with PCOS. However, direct evidence on follicular AA metabolic profiles in PCOS patients and their relationship with pregnancy outcome is sparse.
We conducted a prospective study in 63 PCOS patients and 48 controls in the Division of Reproductive Center, Peking University Third Hospital. Follicular AA levels were measured by the liquid chromatography-tandem mass spectrometric method, and the results were analyzed based on different grouping criteria.
The levels of aromatic amino acid (AAA) increased in PCOS patients independent of obesity (P < 0.05), whereas the levels of branched-chain amino acid (BCAA), glutamic acid, phenylalanine, alanine, and arginine increased with body mass index irrespective of the PCOS status (all P < 0.05). In addition, compared with non insulin resistant-PCOS patients and controls, insulin resistant-PCOS group had higher levels of leucine, valine and glutamic acid (all P < 0.05). In PCOS group, aspartic acid and serine levels were elevated in pregnant patients compared with the non-pregnant subjects (both P < 0.05). Moreover, the levels of BCAA and valine were higher in the non-pregnant group than in the pregnant group (both P < 0.05). The pregnancy rate (45.00%) of subjects with elevated BCAA level was significantly lower than that (66.67%) in control subjects (P = 0.036) at a BCAA cutoff value of 239.10 μM, while the abortion rate was much higher (33.33% versus 2.78%, P = 0.004).
Both PCOS and obesity were accompanied by follicular AA metabolic disturbances, with obesity exerting a more pronounced effect on AA metabolic profiles. The disruptions in specific AAs in the follicular fluid might account for the inferior pregnancy outcome in obese patients and increased risk of abortion in PCOS patients.
PMCID: PMC3897995  PMID: 24410809
PCOS; Amino acid; Obesity; Follicular fluid
6.  MiR-155 promotes proliferation of human breast cancer MCF-7 cells through targeting tumor protein 53-induced nuclear protein 1 
MiR-155 has emerged as an “oncomiR”, which is the most significantly up-regulated miRNA in breast cancer. However, the mechanisms of miR-155 functions as an oncomiR are mainly unknown. In this study, the aims were to investigate the effects of miR-155 on cell proliferation, cell cycle, and cell apoptosis of ERalpha (+) breast cancer cells and to verify whether TP53INP1 (tumor protein 53-induced nuclear protein 1) is a target of miR-155, and tried to explore the mechanisms of miR-155 in this process.
The expression of miR-155 is significantly higher in MCF-7 cells compared with MDA-MB-231 cells. Ectopic expression of TP53INP1 inhibits growth of MCF-7 cells by inducing cell apoptosis and inhibiting cell cycle progression. Overexpression of miR-155 increases cell proliferation and suppress cell apoptosis, whereas abrogating expression of miR-155 suppress cell proliferation and promotes cell apoptosis of MCF-7 cells. In addition, miR-155 negatively regulates TP53INP1 mRNA expression and the protein expression of TP53INP1, cleaved-caspase-3, -8, -9, and p21, and luciferase reporter reveals that TP53INP1 is targeted by miR-155.
TP53INP1 is the direct target of miR-155. MiR-155, which is overexpressed in MCF-7 cells, contributes to proliferation of MCF-7 cells possibly through down-regulating target TP53INP1.
PMCID: PMC4015120  PMID: 24152184
MiR-155; TP53INP1 (tumor protein 53-induced nuclear protein 1); Proliferation; MCF-7 breast cancer cells
7.  Metabolic profiles characterizing different phenotypes of polycystic ovary syndrome: plasma metabolomics analysis 
BMC Medicine  2012;10:153.
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder accompanied with an increased risk of developing type 2 diabetes mellitus and cardiovascular disease; despite being a common condition, the pathogenesis of PCOS remains unclear. Our aim was to investigate the potential metabolic profiles for different phenotypes of PCOS, as well as for the early prognosis of complications.
A total of 217 women with PCOS and 48 healthy women as normal controls were studied. Plasma samples of subjects were tested using two different analytical platforms of metabolomics: 1H nuclear magnetic resonance (NMR) and gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS).
Our results showed that carbohydrate, lipid and amino acid metabolisms were influenced in PCOS. The levels of lactate, long-chain fatty acids, triglyceride and very low-density lipoprotein were elevated, while glucose, phosphatidylcholine and high-density lipoprotein (HDL) concentrations were reduced in PCOS patients as compared with controls. Additionally, the levels of alanine, valine, serine, threonine, ornithine, phenylalanine, tyrosine and tryptophan were generally increased, whereas the levels of glycine and proline were significantly reduced in PCOS samples compared to controls. Furthermore, the ratio of branched-chain amino acid to aromatic amino acid concentrations (BCAA/AAA) in PCOS plasma was significantly reduced in PCOS patients and was insusceptible to obesity and insulin sensitivity.
Our results suggested that the enhanced glycolysis and inhibited tricarboxylic acid cycle (TAC) in women with PCOS. Decrease of BCAA/AAA ratio was directly correlated with the development of PCOS. Ovulatory dysfunction of PCOS patients was associated with raised production of serine, threonine, phenylalanine, tyrosine and ornithine. Elevated levels of valine and leucine, and decreased concentrations of glycine in PCOS plasma could contribute to insulin sensitivity and could be considered as the potential biomarkers for long-term risk assessment of diabetes mellitus.
PMCID: PMC3599233  PMID: 23198915
polycystic ovary syndrome; amino acid metabolism; carbohydrate and lipid metabolism; insulin resistance; inflammation
8.  μ-Oxalato-κ4 O 1,O 2:O 1′,O 2′-bis­[aqua­(2,2′-bipyridine-κN)(nitrato-κ2 O,O′)lead(II)] 
The title compound, [Pb2(C2O4)(NO3)2(C10H8N2)2(H2O)2], was synthesized hydro­thermally. The binuclear complex mol­ecule is centrosymmetric, the inversion centre being located at the mid-point of the oxalate C—C bond. The PbII ion is hepta­coordinated by the O atom of one water mol­ecule, two oxalate O atoms, two nitrate O atoms and two 2,2′-bipyridine N atoms, forming an irregular coordination environemnt. Inter­molecular O—H⋯O hydrogen bonds between water mol­ecules and oxalate and nitrate ions result in the formation of layers parallel to (010). π–π inter­actions between pyridine rings in adjacent layers, with centroid–centroid distances of 3.584 (2) Å, stabilize the structural set-up.
PMCID: PMC3470178  PMID: 23125622
9.  Genomic DNA Methylation Changes in NYGGF4-Overexpression 3T3-L1 Adipocytes 
NYGGF4, an obesity-related gene, is proposed to be involved in the development of insulin resistance; however, the underlying molecular mechanisms remain unclear. In the present analysis, NimbleGen tiling arrays were used to determine the patterns of genomic DNA methylation at CpG islands and promoters in NYGGF4-overexpression adipocytes. A total of 2352 CpG dinucleotides in 2018 genes and 3490 CpG dinucleotides in 3064 genes were found to be hypermethylated or hypomethylated, respectively, in NYGGF4-overexpression adipocytes. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis revealed enrichment of biological processes associated with energy metabolism and signal transduction events, including the peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway, and mitogen-activated protein kinases(MAPK) and Ras homolog gene family, member A (RhoA) signaling. These data demonstrate that differentially methylated genes are significantly overrepresented in NYGGF4-overexpression adipocytes, providing valuable clues for further exploration of the role of NYGGF4 in insulin sensitivity regulation.
PMCID: PMC3546650  PMID: 23443082
NYGGF4; DNA methylation; insulin resistance; adipocytes
10.  Regulation of LYRM1 Gene Expression by Free Fatty Acids, Adipokines, and Rosiglitazone in 3T3-L1 Adipocytes 
Experimental Diabetes Research  2011;2012:820989.
LYR motif containing 1 (LYRM1) is a novel gene that is abundantly expressed in the adipose tissue of obese subjects and is involved in insulin resistance. In this study, free fatty acids (FFAs) and tumor necrosis factor-α (TNF-α) are shown to upregulate LYRM1 mRNA expression in 3T3-L1 adipocytes. Conversely, resistin and rosiglitazone exert an inhibitory effect on LYRM1 mRNA expression. These results suggest that the expression of LYRM1 mRNA is affected by a variety of factors that are related to insulin sensitivity. LYRM1 may be an important mediator in the development of obesity-related insulin resistance.
PMCID: PMC3205718  PMID: 22110480
11.  (6aS,11aR,11cS)-8-Sulfanylidene-2,3,5,6,6a,7,11,11a,11b,11c-decahydro-3a,7a-diaza-1H,4H-benzo[de]anthracen-3a-ium chloride hemihydrate 
The title compound, C15H23N2S+·Cl−·0.5H2O, was prepared from (6aS,11aR,11cS)-2,3,5,6,6a,7,11,11a,11b,11c-deca­hydro-3a,7a-diaza-1H,4H-benzo[de]anthracene-8-one (sophocarpine) and Lawesson’s reagent. The thione-substituted ring is in an envelope conformation and the three other six-membered rings are in chair conformations. In the crystal, anions and cations are linked by N—H⋯Cl and weak C—H⋯Cl hydrogen bonds. One 0.5-occupancy solvent water mol­ecule lies on a twofold rotation axis and another 0.25-occupancy solvent water mol­ecule is in a general position. The H atoms of these water mol­ecules were not located or included in the refinement.
PMCID: PMC3151885  PMID: 21837131
12.  Effect of Same-dose Single or Dual Field Irradiation on Damage to Miniature Pig Parotid Glands 
To evaluate the effect of single or dual field irradiation (IR) with the same dose on damage to miniature pig parotid glands.
Sixteen miniature pigs were divided into two IR groups (n=6) and a control group (n=4). The irradiation groups were subjected to 20 Gy X-radiation to one parotid gland using single-field or dual-field modality by linear accelerator. The dose-volume distributions between two IR groups were compared. Saliva from parotid glands and blood were collected at 0, 4, 8 and 16 weeks after irradiation. Parotid glands were removed at 16 weeks to evaluate tissue morphology.
The irradiation dose volume distributions were significantly different between single and dual field irradiation groups (t=4.177, P=0.002), although dose volume histogramin (DVH) indicated the equal maximal dose in parotid glands. Saliva flow rates from IR side decreased dramatically at all time points in IR groups, especially in dual field irradiation group. The radiation caused changes of white blood cell count in blood, lactate dehydrogenase and amylase in serum, calcium, potassium and amylase in saliva. Morphologically, more severe radiation damage was found in irradiated parotid glands from dual field irradiation group than that from single field irradiation group.
Data from this large animal model demonstrated that the radiation damage from the dual field irradiation was more severe than that of the single field irradiation at the same dose, suggesting that dose-volume distribution is an important factor in evaluation of the radiobiology of parotid glands.
PMCID: PMC3735788  PMID: 20690500
irradiation damage; miniature pig; parotid gland

Results 1-12 (12)