[Show abstract][Hide abstract] ABSTRACT: The role of tuberous sclerosis complex (TSC) in the pathogenesis of pancreatic cancers remains largely unknown. The present study shows that neurogenin 3 directed Cre deletion of Tsc1 gene induces the development of pancreatic acinar carcinoma. By cross-breeding the Neurog3-cre mice with Tsc1loxp/loxp mice, we generated the Neurog3-Tsc1−/− transgenic mice in which Tsc1 gene is deleted and mTOR signaling activated in the pancreatic progenitor cells. All Neurog3-Tsc1−/− mice developed notable adenocarcinoma-like lesions in pancreas starting from the age of 100 days old. The tumor lesions are composed of cells with morphological and molecular resemblance to acinar cells. Metastasis of neoplasm to liver and lung was detected in 5% of animals. Inhibition of mTOR signaling by rapamycin significantly attenuated the growth of the neoplasm. Relapse of the neoplasm occurred within 14 days upon cessation of rapamycin treatment. Our studies indicate that activation of mTOR signaling in the pancreatic progenitor cells may trigger the development of acinar carcinoma. Thus, mTOR may serve as a potential target for treatment of pancreatic acinar carcinoma.
Neoplasia (New York, N.Y.) 11/2014; · 5.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interconversion of white and brown adipocytes occurs between anabolic and catabolic states. The molecular mechanism regulating this phenotypic switch remains largely unknown. This study explores the role of tuberous sclerosis complex 1 (TSC1)-mechanistic target of rapamycin (mTOR) signaling in the conversion of brown to white adipose tissue. A colony of Fabp4-Tsc1-/- mice, in which the Tsc1 gene was specifically deleted by the fatty acid binding protein 4 (FABP4)-Cre, was established. Western blotting and immunostaining demonstrated the absence of TSC1 and activation of ribosomal protein S6 kinase 1, the downstream target of mTOR complex 1 (mTORC1) signaling, in the brown adipose tissues (BAT) of Fabp4-Tsc1-/- mice. Accumulation of lipid droplets in BAT was significantly increased. Levels of brown adipocyte markers were markedly down-regulated, while white adipocyte markers up-regulated. Rapamycin reversed the conversion from BAT to WAT in Fabp4-Tsc1-/- mice. Deletion of Tsc1 gene in cultured brown preadipocytes significantly increased the conversion to white adipocytes. FoxC2 mRNA, the transcriptional factor for brown adipocyte determination, was significantly decreased, while mRNAs for Rb, p107 and RIP140, the transcriptional factors for white adipocyte determination, increased in the BAT of Fabp4-Tsc1-/- mice. Our study demonstrates that TSC1-mTORC1 signaling contributes to the brown-to-white adipocyte phenotypic switch.
[Show abstract][Hide abstract] ABSTRACT: Although ghrelin has been demonstrated to stimulate energy intake and storage through a central mechanism, its effect on hepatic lipid metabolism remains largely uncharacterized. Ghrelin receptor antagonism or gene deletion significantly decreased obesity-associated hepatic steatosis by suppression of de novo lipogenesis, whereas exogenous ghrelin stimulated lipogenesis, leading to hepatic lipid accumulation in mice. The effects of ghrelin were mediated by direct activation of its receptor on hepatocytes. Cultured hepatocytes responded to ghrelin with increased lipid content and expression of lipogenesis-related genes. Ghrelin increased phosphorylation of S6, the downstream target of mammalian target of rapamycin (mTOR) signaling in cultured hepatocytes, whereas ghrelin receptor antagonism reduced hepatic phosphorylation of S6 in db/db mice. Inhibition of mTOR signaling by rapamycin markedly attenuated ghrelin-induced up-regulation of lipogenesis in hepatocytes, whereas activation of hepatic mTOR signaling by deletion of TSC1 increased hepatic lipogenesis. By interacting with peroxisome proliferator-activated receptor-γ (PPARγ), mTOR mediates the ghrelin-induced up-regulation of lipogenesis in hepatocytes. The stimulatory effect of ghrelin on hepatic lipogenesis was significantly attenuated by PPARγ antagonism in cultured hepatocytes and in PPARγ gene-deficient mice. Our study indicates that ghrelin activates its receptor on hepatocytes to promote lipogenesis via a mechanism involving the mTOR-PPARγ signaling pathway.
Proceedings of the National Academy of Sciences 08/2014; · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Resistin is an adipocytokine leading to insulin resistance. Endotoxin/lipopolysaccharide (LPS) has been reported to decrease the expression of resistin mRNA and protein in both lean and db/db obese mice, although the underlying mechanism remains unclear. Several models such as ex vivo culture of adipose tissues, primary rat adipocytes and 3T3-L1 adipocytes were used to further characterize the effect of LPS on the expression of resistin. LPS attenuated both the resistin mRNA and protein in a time- and dose-dependent manner. In the presence of actinomycin D, LPS failed to reduce the half-life of resistin mRNA, suggesting a transcriptional mechanism. The lipid A fraction is crucial for the inhibition of resistin expression induced by LPS. Pharmacological intervention of c-Jun N-terminal kinase (JNK) reversed the inhibitory effect of LPS. LPS down-regulated CCAAT/enhancer-binding protein α (C/EBP-α) and peroxisome proliferator-activated receptor γ (PPAR-γ), while activation of C/EBP-α or PPAR-γ by either over-expressing these transcriptional factors or by rosiglitazone, an agonist of PPAR-γ, blocked the inhibitory effect of LPS on resistin. C/EBP homologous protein (CHOP 10) was up-regulated by LPS, while a CHOP 10 antisense oligonucleotide reversed the decrement of resistin protein induced by LPS. Taken together, these results suggest that LPS inhibits resistin expression through a unique signaling pathway involving TLR4, JNK, CHOP 10, and C/EBP-α/PPAR-γ.
Journal of Molecular Endocrinology 08/2013; · 3.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The actions of peripherally administered nesfatin-1 on glucose homeostasis remain controversial. The aim of this study was to characterize the mechanisms by which peripheral nesfatin-1 regulates glucose metabolism.
The effects of nesfatin-1 on glucose metabolism were examined in mice by continuous infusion of the peptide via osmotic pumps. Changes in AKT phosphorylation and Glut4 were investigated by Western blotting and immnuofluorescent staining. Primary myocytes, adipocytes and hepatocytes were isolated from male mice.
Continuous peripheral infusion of nesfatin-1 altered glucose tolerance and insulin sensitivity in mice fed either normal or high fat diet, while central administration of nesfatin-1 demonstrated no effect. Nesfatin-1 increases insulin secretion in vivo, and in vitro in cultured min6 cells. In addition, nesfatin-1 up-regulates the phosphorylation of AKT in pancreas and min6 islet cells. In mice fed normal diet, peripheral nesfatin-1 significantly increased insulin-stimulated phosphorylation of AKT in skeletal muscle, adipose tissue and liver; similar effects were observed in skeletal muscle and adipose tissue in mice fed high fat diet. At basal conditions and after insulin stimulation, peripheral nesfatin-1 markedly increased GLUT4 membrane translocation in skeletal muscle and adipose tissue in mice fed either diet. In vitro studies showed that nesfatin-1 increased both basal and insulin-stimulated levels of AKT phosphorylation in cells derived from skeletal muscle, adipose tissue and liver.
Our studies demonstrate that nesfatin-1 alters glucose metabolism by mechanisms which increase insulin secretion and insulin sensitivity via altering AKT phosphorylation and GLUT 4 membrane translocation in the skeletal muscle, adipose tissue and liver.
PLoS ONE 08/2013; 8(8):e71513. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ghrelin, a gut hormone with pleiotropic effects, may act as a protective signal in parenchymal cells. We investigated the protective effects of ghrelin on hepatocytes after ischaemia/reperfusion (I/R).
Hepatic injury was assessed by measurement of plasma alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), histological analysis, and TUNEL assay. Effects of exogenous ghrelin and ghrelin receptor gene deletion on I/R induced injury of liver were evaluated.
Ischaemia/reperfusion induced a profound injury to hepatocytes. This was accompanied by elevations in plasma ALT and LDH. Pretreatment with ghrelin significantly reduced elevations in plasma ALT and LDH, and attenuated tissue damage induced by hepatic I/R in mice. Hepatic injury induced by I/R was more pronounced in ghrelin receptor gene null mice. Ghrelin administration blocked the up-regulation of AMP-activated protein kinase (AMPK) activity induced by hepatic I/R.
This study demonstrates that ghrelin contributes to the cytoprotection during hepatic I/R.
Liver international: official journal of the International Association for the Study of the Liver 08/2013; · 4.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Catestatin (CST) is an endogenous neuropeptide with multiple cardiovascular activities. The study is to investigate circulating CST levels in heart failure (HF) patients and to evaluate the role of CST as a biomarker for HF. Plasma CST concentrations were measured by enzyme-linked immunosorbent assay in 228 HF patients and 172 controls. Plasma CST gradually increased in patients from NYHA class I to class IV. No significant differences in CST were found among NYHA I, NYHA II patients and controls. Plasma CST in NYHA III and IV patients was higher compared to other groups. Plasma CST levels in HF patients after treatment were similar to admission, but still higher than controls. In a subgroup analysis among the patients with NYHA class III or IV, patients with ischemic etiology had significantly higher CST. Plasma CST levels were similar between patients with preserved and reduced ejection fraction. Multivariable analysis showed that NYHA classes, the etiology of HF (ischemic or not) and estimated glomerular filtration rate independently predicted plasma LogCST levels (P<0.05). The area under ROC for CST and BNP in moderate to severe HF diagnosis was 0.626 and 0.831 respectively, combining CST and BNP did not improve the accuracy.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Recent studies suggest that urotensin II (UII) and transforming growth factor-β1 (TGF-β1) both have critical roles in vascular remodeling. UII is a recently discovered vasoconstrictive peptide that is involved in the pathogenesis of atherosclerosis, restenosis and hypertension. TGF-β1 is an important factor that has a pivotal role in vascular fibrosis. This study aimed to explore whether TGF-β1 is involved in UII-induced collagen synthesis in rat aortic vascular smooth muscle cells (VSMCs) and examined the effects and mechanisms of UII on collagen synthesis and secretion in VSMCs. METHODS: VSMCs were prepared by the explant culture method. TGF-β1 and collagen I secretions from the cells were determined by enzyme-linked immunosorbent assay (ELISA). The mRNA and protein expressions of TGF-β1, collagen I, Smad2 and Smad3 were determined using Real-time RT-PCR and Western blotting. RESULTS: UII dose-dependently promoted TGF-β1 protein expression and secretion from VSMCs, with maximal effect at 10-8mol/l at 24h for protein expression and 10-7mol/l at 24h for protein secretion (both P<0.01). Moreover, UII dose-dependently promoted Smad2 and Smad3 mRNA expression in VSMCs, with maximal effect at 10-8mol/l for 12h (both P<0.01). The effects of UII were significantly inhibited by its receptor antagonists urantide (10-6mol/l) or SB-710411 (10-6mol/l), and by the mitogen-activated protein kinase (MAPK/ERK) inhibitor PD98059 (10-6mol/l). UII dose-dependently promoted collagen I mRNA expression and protein secretion in VSMCs, with maximal effect at 10-8mol/l at 12h for mRNA expression and 10-6mol/l at 24h for protein secretion (both P<0.01). Collagen synthesis and secretion from VSMCs induced by UII were inhibited significantly by a TGF-β1-specific neutralizing antibody, SB-431542 (an antagonist of the TGF-β1 type II receptor) and PD98059 (all P<0.01). CONCLUSIONS: This study suggests that UII could induce collagen synthesis and secretion through upregulation of TGF-β1 expression and secretion in VSMCs, and that TGF-β1/Smad2/3 signaling might be one of the important pathways by which UII is involved in vascular fibrosis.
[Show abstract][Hide abstract] ABSTRACT: New findings• What is the central question of this study? Does tuberous sclerosis complex 1–mammalian target of rapamycin (mTOR) signalling regulate the synthesis of surfactant proteins A and B and, if so, can this contribute to the postnatal death of Fabp4‐Tsc1cKO mice? • What is the main finding and its importance? Our study reveals a novel mechanism for the regulation of alveolar surfactant proteins. Tuberous sclerosis complex 1–mTOR signalling contributes to the regulation of synthesis of surfactant proteins A and B. Deficiency of tuberous sclerosis complex 1 in alveolar epithelial cells may contribute to the postnatal death of Fabp4‐Tsc1cKO mice.
[Show abstract][Hide abstract] ABSTRACT: Tuberous sclerosis complex 1 (TSC1) forms a heterodimmer with TSC2 to inhibit signaling by the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). The mTORC1 stimulates cell growth by promoting anabolic cellular processes such as gene transcription and protein translation, in response to growth factors and nutrient signals. Originally designed to test the role of TSC1 in adipocyte function, mice in which TSC1 gene was specifically deleted by the fatty acid binding protein 4 (FABP4)-Cre (Fabp4-Tsc1cKO mice) died prematurely within 48 hours after birth. The Fabp4-Tsc1cKO mouse revealed a much smaller phenotype relative to the wildtype littermates. Maternal administration of rapamycin, a classical mTOR inhibitor, significantly increased the survival time of Fabp4-Tsc1cKO mice for up to 23 days. Both macroscopic and microscopic hemorrhages were observed in the lungs of Fabp4-Tsc1cKO mice, while other tissues showed no significant changes. Levels of surfactant proteins A and B demonstrated a significant decrease in the Fabp4-Tsc1cKO mice, which was rescued by maternal injection of rapamycin. Co-localization of FABP4 or TSC1 with surfactant protein B was also detected in neonatal pulmonary tissues. Our study suggests that TSC1-mTORC1 may be critical for the synthesis of surfactant proteins A and B.
[Show abstract][Hide abstract] ABSTRACT: Adventitia is the outer part of the arterial wall where the inflammatory response often occurs. Urotensin II (UII) is a potent vasoconstrictive peptide that also promotes the inflammatory process in patients with cardiovascular disease. Leukotriene C(4) (LTC(4)), a lipid mediator, was recently found to play a role in the inflammatory process in the artery. We hypothesized that the adventitia is one of the resources of LTC(4) and that UII may promote LTC(4) production through the 5-LO (5-lipoxygenase) pathway in adventitial fibroblasts. Rat adventitial fibroblasts were isolated and incubated in serum-free medium with either UII alone or in combination with inhibitors of p38 MAPK, ERK, and UII receptors. The expression of 5-LO was detected using real-time polymerase chain reaction and Western blot. The translocation and binding activity of nuclear factor (NF)-κB were measured using immunofluorescence and electrophoretic mobility shift assay, respectively. The production of LTC(4) was measured by enzyme-linked immunosorbent assay. The results indicated that: (1) adventitial fibroblasts were a source of LTC(4) production; (2) UII increased the expression of the 5-LO mRNA and the protein by NF-κB activation through p38 MAPK and ERK pathways; and (3) UII promoted the LTC(4) release in fibroblasts through the 5-LO pathway by p38 MAPK and ERK activations. The 5-LO pathway mediates LTC(4) production, which may be a new mechanism in the pathogenesis of the vascular adventitial inflammation caused by UII.
[Show abstract][Hide abstract] ABSTRACT: To investigate the effects of hydrogen sulfide (H(2)S) on calcium uptake activity of the rat cardiac sarcoplasmic reticulum (SR) and possible signaling.
Crude SR was isolated after treatment with H(2)S, then SR Ca(2+) uptake and SR Ca(2+)-ATPase (SERCA) activity was measured by the isotopic tracer method. The possible roles of the K(ATP) channel and PI3K/Akt and SR-membrane protein phospholamban (PLB) pathway were analyzed by specific blockers, and target protein activation was assayed by measuring protein phosphorylation.
Exogenous H(2)S lowered Ca(2+) uptake into the SR time or concentration dependently, which was associated with decreased SERCA activity. Inhibiting endogenous H(2)S production by DL-propargylglycine increased SR Ca(2+) uptake and SERCA activity. H(2)S inhibition of PLB phosphorylation was through SERCA activity and was reversed by two PI3K inhibitors, wortmannin and LY294002. Glibenclamide (a K(ATP) channel blocker) blocked the inhibitory effects of H(2)S on PLB and Akt phosphorylation. Pinacidil (a K(ATP) channel opener) reduced the phosphorylation of PLB and reversed the effects of DL-propargylglycine. H(2)S preconditioning increased PLB phosphorylation but did not affect SERCA activity.
Endogenous H(2)S transiently and reversibly inhibits SR Ca(2+) uptake in rat heart SR because of downregulated SERCA activity associated with PLB phosphorylation by the PI3K/Akt or K(ATP) channel. The transient negative regulation of SR Ca(2+) uptake and the L-type Ca(2+) channel contributes to Ca(2+) cycle homeostasis, which might be an important molecular mechanism in ischemic diseases.
Life sciences 08/2012; 91(7-8):271-8. · 2.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The adventitia plays an important role in and is considered to be the initiating site for vascular remodeling. Urotensin II (UII) and angiotensin II (Ang II) are the two most important vascular peptides involved in vascular remodeling in the adventitia. Nevertheless, little is known about their effect on the expression of vascular endothelial growth factor (VEGF). It was hypothesized that both UII and Ang II could induce VEGF expression in adventitial fibroblasts and VEGF may play a role in cell proliferation and collagen I synthesis induced by UII or Ang II.
Growth-arrested adventitial fibroblasts were incubated in serum-free medium with UII and/or Ang II and inhibitors of the mitogen-activated protein kinase (MAPK) pathway or VEGF-neutralizing antibodies. The VEGF expression was evaluated using enzyme-linked immunosorbent assay (ELISA), while the proliferation and collagen I synthesis were detected using methyl thiazol tetrazolium (MTT) assay and ELISA. It was found that: (1) both UII and Ang II could stimulate VEGF expression in adventitial fibroblasts and they had a synergistic effect; (2) MAPK pathway inhibitors could inhibit VEGF secretion induced by UII and/or Ang II; and (3) VEGF-neutralizing antibodies could inhibit UII/Ang II-induced cell proliferation and collagen synthesis in adventitial fibroblasts.
Induction of VEGF expression may be a new mechanism involved in vascular remodeling for UII and Ang II.
[Show abstract][Hide abstract] ABSTRACT: Nesfatin-1, an 82 amino acid peptide derived from the prohormone nucleobindin-2 (NUCB2), is a novel satiety hormone acting through a leptin-independent mechanism in the hypothalamus. The mechanisms by which production of nesfatin-1/NUCB2 is regulated remain unknown.
Nesfatin-1/NUCB2 mRNA and immunoreactivity were examined in gastric tissue and Min-6 cells by RT-PCR and immunofluorescent staining or Western blotting.
Nesfatin-1/NUCB2 is co-localized with pS6K1, the downstream target of mammalian target of rapamycin (mTOR), in gastric X/A like cells. A parallel relationship between gastric mTOR signaling and nesfatin-1/NUCB2 was observed during changes in energy status. Both mTOR activity and gastric nesfatin-1/NUCB2 were down-regulated by fasting, and returned to basal levels with re-feeding. In high fat diet induced obese mice, gastric mTOR signaling and nesfatin-1/NUCB2 were increased. Inhibition of the gastric mTOR signaling by rapamycin attenuated the expression of gastric nesfatin-1/NUCB2 mRNA and protein in both lean and obese mice. Attenuation of mTOR activity by rapamycin or over-expression of TSC1 or TSC2 reduced the expression of nesfatin-1/NUCB2 in Min-6 cells, suggesting a direct effect of mTOR signaling.
Gastric mTOR is a gastric energy sensor whose activity is linked to the regulation of gastric nesfatin-1/NUCB2.
Cellular Physiology and Biochemistry 01/2012; 29(3-4):493-500. · 3.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endogenous hydrogen sulfide is a new neuromodulator which takes part in the regulation of central nervous system physiology and diseases. Whether endogenous hydrogen sulfide in the central nervous system regulates cardiovascular activity is not known. In the present study, we observed the hemodynamic changes of hydrogen sulfide or its precursor by intracerebroventricular injection, and investigate the possible roles of endogenous digitalis like factors and sympathetic activity in the regulation.
Ninety-four Sprague-Dawley rats underwent a right cerebroventricular puncture, then the hydrogen sulfide saturation buffer or its precursor injected by intrcerebroventricular catheter. A heperin-filled catheter was inserted into the right femoral artery or into the left ventricle, and changes of blood pressure or cardiac function recorded by a Powerlab/4S instrument. Phentolamine or metoprolol were pre-injected to observe the possible role in autonomic nerve activity. After rats were sacrificed, plasma was collected and endogenous digitalis-like factors were measured with a commercial radioimmunoassay kit. The aortic, cardiac sarcolemmal vesicles were isolated and the activity of Na(+)-K(+)-ATPase was measured as ouabain-sensitive ATP hydrolysis under maximal velocity conditions by measuring the release of inorganic phosphate from ATP. Unpaired Student's t test for two groups or analysis of variances (ANOVA) for multiple groups were used to compare the differences of the changes.
Intracerebroventricular injection of hydrogen sulfide induced a transient hypotension, then dramatic hypertenive effects in a dose-dependent manner. Bolus injection of L-cysteine or beta- mercaptopyruvate also increased mean arterial pressure (P < 0.01), whereas hydroxylamine-a cystathionine beta synthase inhibitor decreased the arterial pressure (P < 0.01). Hydrogen sulfide and L-cysteine increased mean arterial pressure, left ventricular develop pressure and left-ventricle maximal rate of systolic and diastolic pressure; these functions were decreased by hydroxylamine (P < 0.01). Glibenclamide (a K(ATP) channel blocker) blocked the transient hypotensive effect, phentolamine (an alpha-adrenergic receptor blocker) blocked the hypertensive effect, and metoprolol (a selective beta 1 receptor blocker) blocked the positive inoptropic effect of central nervous system hydrogen sulfide. The endogenous digitalis-like factors in plasma were elevated (P < 0.01) after treatment with L-cysteine, association with decreasing Na(+)-K(+)-ATPase activity in cardiac or aortic sarcolemmal vesicles (P < 0.01). Hydroxylamine injection reduced the endogenous digitalis-like factors level in plasma association with increasing Na(+)-K(+)-ATPase activity in cardiac and aortic sarcolemmal vesicles.
Central nervous system endogenous hydrogen sulfide upregulated mean arterial pressure and cardiac systolic function by activation of sympathetic nerves or release of endogenous digitalis-like factors.
Chinese medical journal 11/2011; 124(21):3468-75. · 1.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endogenous hydrogen sulfide (H(2)S) plays an important role in hypertension. The aim of this study was to investigate the role of erythrocyte and serum H(2)S in patients with untreated essential hypertension.
We recruited 62 patients (age 22 - 74 years) with untreated prehypertension or hypertension, and 64 normotensive subjects (age 18 - 64 years). We assessed the 3-mercaptopyruvate sulphurtransferase (MPST) protein expression in erythrocytes and measured the H(2)S production from erythrocytes and serum H(2)S levels, then analyzed the association of erythrocytic or serum H(2)S content and blood pressure or cardiovascular risk factors (e.g., age, body mass index (BMI) and dyslipidemia). A stepwise regression analysis was used to evaluate the possible relationship of erythrocytic H(2)S in hypertension.
In hypertensive patients, erythrocyte H(2)S production ((111.04 ± 29.20) nmol/min per 10(8) erythrocytes) was higher than that in controls ((78.85 ± 19.38) nmol/min per 10(8) erythrocytes), and serum H(2)S was also higher. The erythrocytic H(2)S production was associated with increased systolic blood pressure (sBP), diastolic blood pressure (dBP), age, BMI, level of C-reactive protein (CRP), as well as triglycerides (TG) and high density lipoprotein cholesterol (HDL-C). Serum H(2)S was not associated with age or CRP. Stepwise regression analysis showed that erythrocytic H(2)S production was correlated with sBP, TG, HDL-C, low density lipoprotein cholesterol (LDL-C) and blood urea nitrogen (BUN) and serum H(2)S was correlated with dBP and TG. Results of receiver-operating characteristic curve analysis suggested that erythrocytic H(2)S production was a more sensitive predictor of hypertension development than serum H(2)S.
Erythrocytic or serum H(2)S production is sensitive predictor of hypertension.
Chinese medical journal 11/2011; 124(22):3693-701. · 1.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The mammalian target of rapamycin (mTOR), an evolutionarily conserved serine-threonine protein kinase, belongs to the phosphoinositide 3-kinase (PI3K)-related kinase family, which contains a lipid kinase-like domain within their C-terminal region. Recent studies have revealed that mTOR as a critical intracellular molecule can sense the extracellular energy status and regulate the cell growth and proliferation in a variety of cells and tissues. This review summarizes our current understanding about the effects of mTOR on cell differentiation and tissue development, with an emphasis on the lineage determination of mesenchymal stem cells. mTOR can promote adipogenesis in white adipocytes, brown adipocytes, and muscle satellite cells, while rapamycin inhibits the adipogenic function of mTOR. mTOR signaling may function to affect osteoblast proliferation and differentiation, however, rapamycin has been reported to either inhibit or promote osteogenesis. Although the precise mechanism remains unclear, mTOR is indispensable for myogenesis. Depending on the cell type, rapamycin has been reported to inhibit, promote, or have no effect on myogenesis.
[Show abstract][Hide abstract] ABSTRACT: The mammalian target of rapamycin (mTOR), an evolutionarily conserved serine-threonine kinase, is an intracellular fuel sensor critical for cellular energy homeostasis. Gastrointestinal endocrine cells play a vital role in the regulation of energy balance by secreting hormones that inform the brain about energy supply. Here we showed the localization of mTOR signaling molecules in more than 90% of gastric ghrelin cells and 36±3% of gastrin cells, while no somatostatin-positive cell showed phospho-S6K1 immunoreactivity. Inhibition of mTOR significantly stimulated expression of gastric ghrelin mRNA and protein, and the concentration of plasma ghrelin (2.06±0.34 ng/ml vs. 12.53±3.9 ng/ml, p<0.05), inhibited gastrin synthesis and secretion (75.01±6.71 pg/ml vs. 54.04±3.65 pg/ml, p<0.05), but had no effect on somatostatin production (165.2±25.07 pg/ml vs. 178.9±29.14 pg/ml, p=0.73). Gastric mTOR is a gastric sensor whose activity is linked to the differential regulation of gastric hormone production and release.
[Show abstract][Hide abstract] ABSTRACT: Adipose-derived stem cells (ADSCs) are mesenchymal stem cells (MSCs) derived from adipose tissue, which have the ability to self-renew and differentiate into many types of tissues. Here we summarize the recent advances in the research of ADSCs, introduce the methods of ADSCs isolation and culture, and discusse the factors regulating the adipo-differentiation and osteo-differentiation of ADSCs. The present review will yield novel insight relevant to the therapeutic intervention of obesity and osteo-tissue engineering.
Sheng li ke xue jin zhan [Progress in physiology] 10/2010; 41(5):341-6.
[Show abstract][Hide abstract] ABSTRACT: To improve a method of a new hydrogen sulfide slow-releasing donor, to observe its cellular toxicity in HepG2 cells and tissue distribution and metabolic pathway after administration of the donor by intraperitoneal injection in ICR mice and to afford experimental evidences for rationally using this donor in hydrogen sulfide research.
We synthesized the new chemical compound which slowly released hydrogen sulfide. After administration of the donor, the cell toxicity was evaluated for cell viability using trypan blue staining in HepG2 cells and lactate dehydrogenase (LDH) activity in culture medium. After administration of this donor by intrasperitoneal injection, we measured the tissue hydrogen sulfide content in the liver, heart, kidney and brain using sensitive-sulfur electrode assay.
We successfully prepared the donor which could release hydrogen sulfide. The releasing ability of the donor solution stored at 4 °C or 20 °C did not change as compared with the freshly-prepared one. Treated at various concentrations of the donor (0.062 5, 0.125, 0.25, 0.5, 1 and 2 mmol/L) for 24 hours in HepG2 cells, the cell viability and LDH leak from the cells were not different as compared with the controls. The donor (2 mmol/L) was administrated everyday and the culture medium was changed every 3 days. After 9 days, the cell viability and LDH leak did not change. Administration of the donor (200 μmol/kg) quickly increased the tissue hydrogen sulfide concentrations in the liver and heart and maintained about 20 min; the hydrogen sulfide level in the kidney elevated and maintained a longer time, then recovered after 2 hours, which implicated that the donor might exclude the kidney; the hydrogen sulfide concentration in the brain did not change in the present study, which suggested that the donor could not pass the blood-brain barrier. Long time (4 weeks) treatment with this compound might induce hepatic or cutaneous injury.
The new chemical compound is a relative stable, slow-releasing donor of hydrogen sulfide with low cellular toxicity, which may be used to study the regulatory role of hydrogen sulfide in the cellular physiological and pathophysiological mechanism of the animal model with acute diseases.
Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 10/2010; 42(5):493-7.