2.Role of orphan G protein-coupled receptor 55 in diabetic gastroparesis in mice.
Xu-Hong LIN ; ; Dan-Dan WEI ; Hui-Chao WANG ; Bin WANG ; Chun-Yang BAI ; Ya-Qiang WANG ; Guo-En LI ; Hui-Ping LI ; Xue-Qun REN
Acta Physiologica Sinica 2014;66(3):332-340
The aim of the present study was to explore the role of orphan G protein-coupled receptor 55 (GPR55) in diabetic gastroparesis (DG). Streptozotocin (STZ) was used to mimic the DG model, and the body weight and blood glucose concentration were tested 4 weeks after STZ injection (i.p.). Electrogastrogram and phenolsulfonphthalein test were used for detecting gastric emptying. Motilin (MTL), gastrin (GAS), vasoactive intestinal peptide (VIP), and somatostatin (SS) levels in plasma were determined using radioimmunology. Real-time PCR and Western blot were applied to identify the expression of GPR55 in gastric tissue, and immunohistochemistry was used to detect the distribution. The effect of lysophosphatidylinositol (LPI), an agonist of GPR55, was observed. STZ mice showed increased blood glucose concentration, lower body weight, decreased amplitude of slow wave, and delayed gastric emptying. LPI antagonized these effects of STZ. Compared to the control group, STZ caused significant decreases of MTL and GAS levels (P < 0.01), as well as increases of SS and VIP levels (P < 0.01). The changes of these hormones induced by STZ were counteracted when using LPI. GPR55 located in mice stomach, and it was up-regulated in DG. Although LPI showed no effects on the distribution and expression of GPR55 in normal mice, it could inhibit STZ-induced GPR55 up-regulation. These results suggest GPR55 is involved in the regulation of gastric movement of DG, and may serve as a new target of DG treatment. LPI, an agonist of GPR55, can protect against STZ-induced DG, and the mechanism may involve the change of GPR55 expression and modification of gastrointestinal movement regulating hormones.
Animals
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Diabetes Mellitus, Experimental
;
metabolism
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pathology
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Gastroparesis
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metabolism
;
pathology
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Lysophospholipids
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pharmacology
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Mice
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Receptors, Cannabinoid
;
metabolism
3.Netrin-3 Suppresses Diabetic Neuropathic Pain by Gating the Intra-epidermal Sprouting of Sensory Axons.
Weiping PAN ; Xueyin HUANG ; Zikai YU ; Qiongqiong DING ; Liping XIA ; Jianfeng HUA ; Bokai GU ; Qisong XIONG ; Hualin YU ; Junbo WANG ; Zhenzhong XU ; Linghui ZENG ; Ge BAI ; Huaqing LIU
Neuroscience Bulletin 2023;39(5):745-758
Diabetic neuropathic pain (DNP) is the most common disabling complication of diabetes. Emerging evidence has linked the pathogenesis of DNP to the aberrant sprouting of sensory axons into the epidermal area; however, the underlying molecular events remain poorly understood. Here we found that an axon guidance molecule, Netrin-3 (Ntn-3), was expressed in the sensory neurons of mouse dorsal root ganglia (DRGs), and downregulation of Ntn-3 expression was highly correlated with the severity of DNP in a diabetic mouse model. Genetic ablation of Ntn-3 increased the intra-epidermal sprouting of sensory axons and worsened the DNP in diabetic mice. In contrast, the elevation of Ntn-3 levels in DRGs significantly inhibited the intra-epidermal axon sprouting and alleviated DNP in diabetic mice. In conclusion, our studies identified Ntn-3 as an important regulator of DNP pathogenesis by gating the aberrant sprouting of sensory axons, indicating that Ntn-3 is a potential druggable target for DNP treatment.
Mice
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Animals
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Diabetes Mellitus, Experimental/metabolism*
;
Axons/physiology*
;
Diabetic Neuropathies
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Sensory Receptor Cells/metabolism*
;
Neuralgia/metabolism*
4.Tu-Xian Decoction ameliorates diabetic cognitive impairment by inhibiting DAPK-1.
Danyang WANG ; Bin YAN ; An WANG ; Qing SUN ; Junyi PANG ; Yangming CUI ; Guoqing TIAN
Chinese Journal of Natural Medicines (English Ed.) 2023;21(12):950-960
Tu-Xian decoction (TXD), a traditional Chinese medicine (TCM) formula, has been frequently administered to manage diabetic cognitive impairment (DCI). Despite its widespread use, the mechanisms underlying TXD's protective effects on DCI have yet to be fully elucidated. As a significant regulator in neurodegenerative conditions, death-associated protein kinase-1 (DAPK-1) serves as a focus for understanding the action of TXD. This study was designed to whether TXD mediates its beneficial outcomes by inhibiting DAPK-1. To this end, a diabetic model was established using Sprague-Dawley (SD) rats through a high-fat, high-sugar (HFHS) diet regimen, followed by streptozotocin (STZ) injection. The experimental cohort was stratified into six groups: Control, Diabetic, TC-DAPK6, high-dose TXD, medium-dose TXD, and low-dose TXD groups. Following a 12-week treatment period, various assessments-including blood glucose levels, body weight measurements, Morris water maze (MWM) testing for cognitive function, brain magnetic resonance imaging (MRI), and histological analyses using hematoxylin-eosin (H&E), and Nissl staining-were conducted. Protein expression in the hippocampus was quantified through Western blotting analysis. The results revealed that TXD significantly improved spatial learning and memory abilities, and preserved hippocampal structure in diabetic rats. Importantly, TXD administration led to a down-regulation of proteins indicative of neurological damage and suppressed DAPK-1 activity within the hippocampal region. These results underscore TXD's potential in mitigating DCIvia DAPK-1 inhibition, positioning it as a viable therapeutic candidate for addressing this condition. Further investigation into TXD's molecular mechanisms may elucidate new pathways for the treatment of DCI.
Animals
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Rats
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Brain/metabolism*
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Cognitive Dysfunction/drug therapy*
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Diabetes Mellitus, Experimental/metabolism*
;
Hippocampus
;
Rats, Sprague-Dawley
5.Expressions of adiponectin and its receptors in the retina of normal and type 1 diabetic mice.
Journal of Southern Medical University 2012;32(11):1543-1547
OBJECTIVETo investigate the expression of adiponectin and its receptors (AdipoRs) in the retina of normal mice and mice with type 1 diabetes mellitus (T1DM).
METHODSC57BL/6 mice were randomly divided into control group and streptozotocin-induced T1DM group. Two months after the modeling, the total protein and adiponectin protein expression in the retina and choroid were measured using BCA method and enzyme-linked immunosorbent assay, respectively. Quantitative RT-PCR was performed to detect the mRNA expressions of AdipoRs in the retina and choroid, and Western blotting was employed to examine the protein expressions of AdipoRs in the retina.
RESULTSAdiponectin and AdipoRs proteins were expressed in the retina and choroid in normal mice. The expressions of adiponectin and AdipoR1 were up-regulated in the retina of mice with T1DM while AdipoR2 expression exhibited no significant changes.
CONCLUSIONAdiponectin and AdipoR1 may play an important role in the evolvement of type 1 diabetic retinopathy.
Adiponectin ; metabolism ; Animals ; Diabetes Mellitus, Experimental ; metabolism ; Diabetes Mellitus, Type 1 ; metabolism ; Diabetic Retinopathy ; metabolism ; pathology ; Male ; Mice ; Mice, Inbred C57BL ; Receptors, Adiponectin ; metabolism ; Retina ; metabolism
6.Conjugated linoleic acid improves glucose and lipid metabolism in diabetic mice.
Jun XIA ; Mingyue ZHENG ; Lingjie LI ; Xufeng HOU ; Weisen ZENG
Journal of Southern Medical University 2019;39(6):740-746
OBJECTIVE:
To analyze the effect of conjugated linoleic acid (CLA) on glucose and lipid metabolism in obese diabetic (db/db) mice.
METHODS:
db/db mice were randomized for treatment with saline or CLA mixture administered intragastrically. The changes in body weight, dietary intake, water intake, oral glucose tolerance, triglyceride and total cholesterol were recorded after the treatments. HE staining and oil red O staining were used to assess liver pathologies and fatty acid content. The expression levels of PPARα, PPARγ, CD36, CHREBP and SREBP-1c were detected using real-time PCR and Western blotting. HepG2 cells were treated with CLA and linoleic acid and the expressions of PPARα, ACC, P-ACC, and CD36 were detected; the level of acetyl-CoA in the cell supernatant was detected using ELISA.
RESULTS:
CLA treatment obviously reduced the dietary and water intake of db/db mice, effectively reduced the body weight and decreased serum triglyceride and cholesterol levels ( < 0.05). CLA significantly reduced fasting blood glucose, increased glucose tolerance, reduced the accumulation of lipid droplets in the liver and improved lipid metabolism in db/db mice. The mice showed significantly increased expression of PPARα ( < 0.05) and lowered CD36 expression ( < 0.001) in the liver after CLA treatment. Cellular experiments showed that CLA significantly up-regulated PPARα ( < 0.001) and P-ACC and decreased the expression of CD36 ( < 0.01). ELISA showed that acetyl-CoA was significantly up-regulated in the cells after CLA treatment ( < 0.01).
CONCLUSIONS
The mixture of two conjugated linoleic acid isomers can reduce fasting blood glucose, increase glucose tolerance and improve glycolipid metabolism in db/db mice by enhancing the expression of PPARα, increasing P-ACC and inhibiting CD36 expression.
Animals
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Diabetes Mellitus, Experimental
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Glucose
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Linoleic Acids, Conjugated
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Lipid Metabolism
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Liver
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Mice
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Triglycerides
7.Effects of insulin treatment on intracellular lipid content in livers and insulin resistance in type 2 diabetic rats.
Yong-bo WANG ; Lu-lu CHEN ; Min ZHOU ; Bao-ping WANG
Chinese Journal of Hepatology 2005;13(6):451-454
OBJECTIVETo study effects of insulin treatment on intracellular lipid content in livers and insulin resistance of type 2 diabetic rats.
METHODSType 2 diabetic rats were induced by injecting streptozotocin (25 mg/kg) and fat rich food. Then according to the results of the oral glucose tolerance test (OGTT) and glucose-induced insulin secretion test (IST), the rats were divided into two groups: control group (DC) and insulin treated group (DI). Normal rats (NC) served as controls. The treatment of each group with either NPH insulin (4 approximately 6 U . kg-1. d-1), or saline continued for 4 weeks. Body weight, OGTT, IST, blood lipids, intracellular lipids in liver and liver histology were studied. The insulin sensitivity index (ISI) was applied to assess the status of insulin resistance.
RESULTSBlood lipid and intracellular lipids in livers in the DC were higher than those in NC (t = 2.59 approximately 15.77, P < 0.05) and the ISI was lower (t = 3.16, P < 0.05), with many fatty droplets appearing in the livers. In comparison to DC, DI showed that blood lipids were decreased, but lipids in livers were markedly increased (TG, TC, FFA increased 55.7%, 19.87%, 22.2%, respectively), and fatty droplets in hepatocytes were larger, but the ISI did not change significantly.
CONCLUSIONInsulin treatment can make blood glucose normal, increase the intracellular lipid content in the liver, and not increase the insulin resistance significantly.
Animals ; Diabetes Mellitus, Experimental ; drug therapy ; metabolism ; Diabetes Mellitus, Type 2 ; drug therapy ; metabolism ; Insulin ; therapeutic use ; Insulin Resistance ; Lipid Metabolism ; Liver ; metabolism ; Male ; Rats ; Rats, Wistar
8.Nucleolus expression in diabetic cardiomyopathy.
Li SUN ; Xin HE ; Juan WANG ; Bimei JIANG ; Zhongyi TONG ; Yanjuan LIU ; Yuanbin LI ; Xianzhong XIAO
Journal of Central South University(Medical Sciences) 2014;39(10):1056-1060
OBJECTIVE:
To investigate the nucleolus expression in the diabetic cardiomyopathy.
METHODS:
The rats were divided into a control group and a type II diabetic cardiomyopathy group (model group). In the model group, rats were fed with high-fat and high-sugar food (rats were intravenously injected with 60 mg/kg chain urea with cephalosporins in the 5th and 6th weeks in mice). The level of blood glucose was determined at the end of 8th week and the level of fasting blood glucose was examined at the end of 20th week. The ratio of the heart mass and body mass was calculated, and the pathological changes in myocardial morphology were observed. The immunohistochemical method and Western blot were used to detect the expression level of myocardial nucleolin.
RESULTS:
The level of fasting blood glucose was significantly increased in the diabetic model group than that in the control group (P<0.05). Rats in the model group were found hypertrophic cardic cells, with fracture, dissolusion, and disordered arrangement. Immunohistochemical staining and Western blot showed the protein levels of myocardial nucleolin in the model group were obviously higher than those in the control group (P<0.05).
CONCLUSION
Nucleolin may play a role in the pathogenesis and development of the diabetic cardiomyopathy.
Animals
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Blood Glucose
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Diabetes Mellitus, Experimental
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metabolism
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Diabetic Cardiomyopathies
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metabolism
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Myocardium
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pathology
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Phosphoproteins
;
metabolism
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RNA-Binding Proteins
;
metabolism
;
Rats
9.Study on pancreas of type 1 diabetic mice induced by MLD-STZ using proteomics.
Miao GENG ; Hong-yan CHEN ; Jian-hua WANG ; Ya-zhuo HU ; Gang ZHANG
Chinese Journal of Applied Physiology 2011;27(3):357-361
OBJECTIVETo get a better understanding of the mechanisms underlying type 1 diabetes mellitus, the differentially expressed pancreatic proteins from multiple low-dose streptozotocin (MLD-SIZ) mouse and normal mouse were analyzed and compared.
METHODS20 male rats were separated into 2 groups (n=10): model mice treated with MLD-STZ and normal mice,differences of pancreatic proteome among in the two groups of mice, were analyzed by two dimensional polyacryamide gel electrophoresis (2DE). Protein quantification was analyzed and the differentially expressed spots were identified using mass spectrometry and MASCOT database searching.
RESULTSCompared with control group, 23 proteins had changed significantly in the model group, 8 proteins expression were up-regulated, 15 proteins expressions down-regulated significantly. Using MALDI-TOF-MS, 15 proteins with significant change were identified by peptide fingerprinting map and the results were searched in MASCOT database. The function analyzed showed that proteins with change were associated with metabolic, anti-oxidant, structural, catalytic enzymes and chaperone, et al.
CONCLUSIONType 1 diabetes is probably exerted via multi-target and multi-path mechanism. The proteins with significant change are newly target for type 1 diabetes early diagnosis and treatment.
Animals ; Diabetes Mellitus, Experimental ; physiopathology ; Diabetes Mellitus, Type 1 ; chemically induced ; metabolism ; physiopathology ; Male ; Mice ; Pancreas ; metabolism ; Proteins ; metabolism ; Proteomics ; methods ; Streptozocin
10.Jujuboside A ameliorates tubulointerstitial fibrosis in diabetic mice through down-regulating the YY1/TGF-β1 signaling pathway.
Yang-Yang LIU ; Lin LI ; Bei JI ; Shi-Long HAO ; Xiao-Feng KUANG ; Xin-Yun CAO ; Jia-Yu YUAN ; Zhen-Zhou JIANG ; Si-Tong QIAN ; Chu-Jing WEI ; Jing XU ; Xiao-Xing YIN ; Qian LU ; Ting-Ting YANG
Chinese Journal of Natural Medicines (English Ed.) 2022;20(9):656-668
Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus, which is characterized in renal tubulointerstitial fibrosis (TIF). The current study was designed to investigate the protective effect of Jujuboside A (Ju A) on TIF in type 2 diabetes (T2DM) mice, and explore its underlying anti-fibrosis mechanism. A mouse T2DM model was established using high fat diet (HFD) feeding combined with intraperitoneal injection of streptozotocin (STZ). Then, diabetic mice were treated with Ju A (10, 20 and 40 mg·kg-1·d-1, i.g.) for 12 weeks. Results showed that administration of Ju A not only down-regulated fasting blood glucose (FBG) levels, but also improved hyperlipidemia and renal function in diabetic mice. Moreover, the reduced ECM accumulation was observed in the renal cortex of Ju A treated diabetic mice, while the TIF progression was also attenuated by Ju A through blocking the epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells (RTECs). Further mechanism studies showed that Ju A treatment effectively down-regulated the protein expression and subsequent nuclear translocation of Yin Yang 1 (YY1) in the renal cortex of diabetic mice, and reduced the levels of transforming growth factor-β1 (TGF-β1) in the serum and renal cortex of Ju A treated mice. According to invitro studies, the up-regulated YY1/TGF-β1 signaling pathway was restored by Ju A in high glucose (HG) cultured HK-2 cells. Taken together, these findings demonstrated that Ju A can ameliorate the TIF of DN through down-regulating the YY1/TGF-β1 signaling pathway.
Animals
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Blood Glucose
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Diabetes Mellitus, Experimental/metabolism*
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Diabetes Mellitus, Type 2/drug therapy*
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Diabetic Nephropathies/metabolism*
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Fibrosis
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Mice
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Saponins
;
Signal Transduction
;
Streptozocin
;
Transforming Growth Factor beta1/metabolism*