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【Objective】 To investigate the protection of astragaloside IV from high glucose induced podocyte injury and mitochondrial dysfunction and its molecular mechanisms. 【Methods】 The model of podocyte injury induced by high glucose (30 mmol/L glucose) was established, and the model cells were treated with low, medium and high doses of astragaloside IV respectively; cell activity was detected by CCK-8. Apoptosis was detected by TUNEL staining. Mitochondrial membrane potential was detected by JC-1 fluorescence probe. ATP content was detected by the kit. The expression levels of apoptosis and podocyte injury related proteins and Notch pathway related proteins were detected by Western blotting. 【Results】 Compared with the control group, cell activity was decreased, apoptosis level was increased (P<0.05), anti-apoptotic protein (Bcl2) expression was decreased, and apoptosis protein (Bax, cleaved-caspase 9, cleaved-caspase 3) expressions were increased (all P<0.05) in HG group. Compared with HG group, HG+AS-IV improved cell activity and apoptosis level induced by high glucose (P<0.05), increased expression of anti-apoptotic protein (Bcl2), and decreased expressions of apoptotic protein (Bax, cleaved-caspase 9, and cleaved-caspase 3) (all P<0.05). Compared with the control group, mitochondrial dysfunction occurred in HG group, JC-1 monomer content increased, and ATP content decreased (all P<0.05). Compared with HG group, HG+AS-IV improved mitochondrial dysfunction, increased JC-1 polymer content and ATP content (P<0.05). In addition, compared with the control group, the expression of Notch pathway-related protein was decreased in HG group (P<0.05). Compared with HG group, Notch pathway-related protein expression was increased in HG+AS-IV group (all P<0.05). Molecular docking results showed that AS-IV could bind Notch1. 【Conclusion】 Astragaloside IV can improve podocyte injury and mitochondrial dysfunction induced by high glucose, possibly by inhibiting Notch pathway activation.
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Ischemic stroke is a major public health problem worldwide. Although the circadian clock is involved in the process of ischemic stroke, the exact mechanism of the circadian clock in regulating angiogenesis after cerebral infarction remains unclear. In the present study, we determined that environmental circadian disruption (ECD) increased the stroke severity and impaired angiogenesis in the rat middle cerebral artery occlusion model, by measuring the infarct volume, neurological tests, and angiogenesis-related protein. We further report that Bmal1 plays an irreplaceable role in angiogenesis. Overexpression of Bmal1 promoted tube-forming, migration, and wound healing, and upregulated the vascular endothelial growth factor (VEGF) and Notch pathway protein levels. This promoting effect was reversed by the Notch pathway inhibitor DAPT, according to the results of angiogenesis capacity and VEGF pathway protein level. In conclusion, our study reveals the intervention of ECD in angiogenesis in ischemic stroke and further identifies the exact mechanism by which Bmal1 regulates angiogenesis through the VEGF-Notch1 pathway.
Subject(s)
Rats , Animals , Vascular Endothelial Growth Factor A/pharmacology , Brain Ischemia/metabolism , Ischemic Stroke , Signal Transduction , ARNTL Transcription Factors/pharmacology , Neovascularization, Physiologic/physiologyABSTRACT
@#AIM: To investigate the effects of intravitreal injection of triamcinolone acetonide(TA)on angiogenesis and Notch pathway in photochemistry induced branch retinal vein occlusion(BRVO)model in rats. <p>METHODS: BRVO model rats were induced by photochemistry induction and randomly divided into BRVO model group and TA(1, 7, 21)d groups; at the same time, blank control group was set for comparison. The intraocular pressure of rats was measured by ophthalmotonometer; the condition of rat fundus was observed fluorescein fundus color photography(FFA)and optical coherence tomography(OCT); retinal angiogenesis related factors vascular endothelial growth factor(VEGF)and vascular endothelial growth factor receptor 2(VEGFR2), the protein expressions of Notch pathway important factors Notch 1, Jagged 1 and DLL4 were detected in rat retina by Western blotting(WB). <p>RESULTS: In the normal control group, the fundus vessels were arranged neatly and in a clear state. In the BRVO model group, edema appeared in the fundus, the retina turned white, the arrangement of blood vessels was disordered, the optic disc pit was disappeared, retinal vessels were in the state of vasoconstriction. In TA 1, 7 and 21d groups, edema gradually decreased, blood vessels expansion and bending gradually slowed down, and the optic disc pit was restored. Compared with the blank control group, the intraocular pressure of BRVO model group increased, the thickness of the retina increased at the injured site and 250μm far from injured site, the protein expressions of VEGF, VEGFR2, Notch1 and Jagged1 increased, the protein expression of DLL4 protein was decreased(<i>P</i><0.05). Compared with the BRVO model group, in TA 1d group, the retinal thickness decreased at 250μm far from injured site, the protein expressions of VEGFR2, Notch1 and Jagged1 decreased, the protein expression of DLL4 protein increased; in TA 7d group, the retinal thickness was decreased at the injured site and 250μm far from injured site, the protein expressions of VEGFR2, Notch1 and Jagged1 decreased, the protein expression of DLL4 protein increased; the intraocular pressure of TA 21d group decreased, the thickness of the retina decreased at the injured site and 250μm far from injured site, the protein expressions of VEGF, VEGF R2, Notch1 and Jagged1 decreased, the protein expression of DLL4 protein increased(<i>P</i><0.05). <p>CONCLUSION: Vitreous injection of TA may inhibit angiogenesis by regulating Notch pathway to inhibit the activation of VEGF, thus achieving the retinal protection in BRVO rats.
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@#AIM: To investigate the effects of intravitreal injection of triamcinolone acetonide(TA)on angiogenesis and Notch pathway in photochemistry induced branch retinal vein occlusion(BRVO)model in rats. <p>METHODS: BRVO model rats were induced by photochemistry induction and randomly divided into BRVO model group and TA(1, 7, 21)d groups; at the same time, blank control group was set for comparison. The intraocular pressure of rats was measured by ophthalmotonometer; the condition of rat fundus was observed fluorescein fundus color photography(FFA)and optical coherence tomography(OCT); retinal angiogenesis related factors vascular endothelial growth factor(VEGF)and vascular endothelial growth factor receptor 2(VEGFR2), the protein expressions of Notch pathway important factors Notch 1, Jagged 1 and DLL4 were detected in rat retina by Western blotting(WB). <p>RESULTS: In the normal control group, the fundus vessels were arranged neatly and in a clear state. In the BRVO model group, edema appeared in the fundus, the retina turned white, the arrangement of blood vessels was disordered, the optic disc pit was disappeared, retinal vessels were in the state of vasoconstriction. In TA 1, 7 and 21d groups, edema gradually decreased, blood vessels expansion and bending gradually slowed down, and the optic disc pit was restored. Compared with the blank control group, the intraocular pressure of BRVO model group increased, the thickness of the retina increased at the injured site and 250μm far from injured site, the protein expressions of VEGF, VEGFR2, Notch1 and Jagged1 increased, the protein expression of DLL4 protein was decreased(<i>P</i><0.05). Compared with the BRVO model group, in TA 1d group, the retinal thickness decreased at 250μm far from injured site, the protein expressions of VEGFR2, Notch1 and Jagged1 decreased, the protein expression of DLL4 protein increased; in TA 7d group, the retinal thickness was decreased at the injured site and 250μm far from injured site, the protein expressions of VEGFR2, Notch1 and Jagged1 decreased, the protein expression of DLL4 protein increased; the intraocular pressure of TA 21d group decreased, the thickness of the retina decreased at the injured site and 250μm far from injured site, the protein expressions of VEGF, VEGF R2, Notch1 and Jagged1 decreased, the protein expression of DLL4 protein increased(<i>P</i><0.05). <p>CONCLUSION: Vitreous injection of TA may inhibit angiogenesis by regulating Notch pathway to inhibit the activation of VEGF, thus achieving the retinal protection in BRVO rats.
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Systemic sclerosis (SSc) is an autoimmune disorder characterized by the fibrosis of skin, heart, lung, and kidney as well. Excessive activation of fibroblasts is associated with higher expression of Notch1 and/or Notch3 genes. The constitutive expression of NOTCH genes was described in epithelial cells: epidermal keratinocytes, hair follicle cells and sebaceous glands. The NOTCH signalling pathway may be involved in the development of fibrosis, myofibroblast formation and the process of epithelial-mesenchymal transition. Activation of the NOTCH pathway leads to morphological, phenotypic and functional changes in epithelial cells. Furthermore, inhibition of Notch signalling prevent the development of fibrosis in different models, among them, bleomycin-induced fibrosis and in the Task-1 mause model. Molecular mechanisms, including the role of NOTCH signaling pathway, associated with fibrosis in SSc have not been completely recognized.
Subject(s)
Epithelial Cells , Epithelial-Mesenchymal Transition , Fibroblasts , Fibrosis , Hair Follicle , Heart , Keratinocytes , Kidney , Lung , Myofibroblasts , Scleroderma, Systemic , Sebaceous Glands , Skin , Transforming Growth Factor betaABSTRACT
Asthma is a chronic airway inflammation caused by a variety of factors, involving a variety of cells and cellular components, which is often accompanied by airway hyperresponsiveness and airway remodeling. At present, asthma has become a common chronic respiratory disease. There exists close relationship between the asthma and signaling pathways. MAPK, PI3K/Akt, NF-κB, TGF-β, Notch and Wnt pathways related to the asthma were extensively studied currently. Traditional Chinese medicine shows advantages in the treatment of chronic diseases such as asthma. In order to explain the advantages of traditional Chinese medicine in the treatment of asthma and develop new asthma drugs originated from traditional Chinese medicine, the role of traditional Chinese medicine in the intervention of related signaling pathways of asthma was reviewed. In addition, the relationship between signaling pathway and pathogenesis (airway inflammation, airway hyperresponsive, and airway remodeling) were also discussed.
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Objective • To investigate the crosstalk between receptor activator of nuclear factor-κB ligand (RANKL) / receptor activator of nuclear factor-κB (RANK) system and Notch signaling pathways. Methods • Mouse osteoclast precursor cell line RAW264.7 was cultured and stimulated by RANKL (35 ng/L). Real-time PCR and Western blotting analysis were used to determine the expressions of Notch signaling molecules in RANKL-stimulated RAW264.7 cells. Small interfering RNA (siRNA) transfection was used to inhibit the expression of Notch1, Dll1 and Dll3 in Notch signaling pathways, then the mRNA and protein expressions of Rank were detected using real-time PCR and Western blotting analysis, respectively. Results • The expressions of Notch1, Jagged1 and Jagged2 were down-regulated while the expression of Dll4 was up-regulated after RANKL stimulation. The stimulation also inhibited the expression of Hes1 and Hey1. After siRNA transfection, the mRNA expressions of Notch1, Dll1 and Dll3 were suppressed by 71% (P=0.000), 53% (P=0.015) and 70% (P=0.000), respectively. The mRNA and protein expressions of Rank were up-regulated after Notch1 inhibition (P=0.003, P=0.000). Conclusion • The data infers that the impact of Notch1 on RANKL/RANK system might play a key role in bone resorption conducted by osteoclast.
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Objective To investigate the expression of Notch pathway in the kidney of diabetic nephropathy (DN) rats and the intervention effect of Chinese materia medica (CMM) for dispersing blood stasis and dredging collateral. Methods Sixty male Sprague-Dawley rats, in which ten rats were randomly selected as control group (n = 10), and the other rats were fed with high glucose and high fat diet combined with low-dose streptozotocin (STZ) ip injection as DN models. The model rats were randomly divided into model group, irbesartan group, and Huayu Tongluo Granles (HTG) group. The rats in each group were ig administered with corresponding drugs. At the end of the 16 weeks, the 24 h urinary protein was detected. The expression of Notch1, Jagged1, and Hey1 mRNA and protein in renal tissue was detected by real-time PCR, and immunohistochemical staining and western blotting assay, respectively. Results Compared with the control group, 24 h urinary protein, the mRNA and protein expression of Notch1, Jagged1, and Hey1 in model group was significantly increased (P < 0.01). Compared with the model group, 24 h urinary protein and Notch1, Jagged1, Hey1 mRNA, and protein expression of HTG group and irbesartan group was significantly decreased (P < 0.01). Conclusion CMM for dispersing blood stasis and dredging collateral can reduce 24 h urinary protein in DN rats and inhibit the high expression of Notch1, Jagged1, and Hey1 in the kidney tissue of DN rats, which may be one of the main ways to reduce proteinuria excretion.
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Objective@#To investigate the effect of different mechanical loading on the expression of Notch-1, Notch-3, Jagged-1 and Delta-like-1 in growing rabbits' condylar cartilage.@*Methods@#Sixty-four ten-days-old rabbits were randomly divided into experimental and control groups. The rabbits in the experimental groups were fed on a powder diet, while the control groups were fed on a solid diet. The animals were sacrificed after 2, 4, 6 and 8 weeks. Notch-1, Notch-3, Jagged-1 and Delta-like-1 gene and protein expressions were examined by HE, immunohistochemistry, Western blotting and quantitative real-time PCR.@*Results@#At 2, 4, 6, 8 weeks, the anterior part of condylar cartilage in solid diet groups ([318.1±4.3], [342.4±2.6], [364.2±3.2], [380.7±6.0] mm, respectively) were thicker than those in powder diet groups ([275.4±2.6], [301.1±2.0], [322.3±3.3], [366.5±8.4] mm, respectively) (P<0.05). There was no significant difference between the two groups in the middle part (P>0.05). From 2 to 6 weeks, the posterior part of cartilage in solid diet groups ([444.1±1.5], [451.1±0.3], [476.4±5.7] mm, respectively) was thinner than those in power diet groups ([470.4±2.7], [494.3±2.9], [512.3±5.7] mm, respectively) (P<0.05). At 6 weeks, there were more mRNA expressions of Notch-3, Jagged-1 and Delta-like-1 in solid diet group than in power diet group (P<0.05). The Notch-1 protein could be found in all layers of condylar cartilage, especially in the surface of hypertrophic zone. The expressions of Notch-1, Notch-3, and Delta-like-1 protein were increased from 2 to 6 weeks, and decreased at 8 weeks. In solid diet groups, the protein expressions of Notch-1 (at 2, 4, 6, 8 weeks), Notch-3 (at 2, 4, 6 weeks), Jagged-1 (at 2, 4, 6 weeks) and Delta-like-1 (at 4, 6, 8 weeks) were greater than in power diet groups (P<0.05).@*Conclusions@#Low masticatory loading may delay or inhibit the development of condylar cartilage and its growing factors such as Notch-1, Notch-3, Jagged-1 and Delta-like-1. Appropriate masticatory loading plays an important role in normal development of the condyle.
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Objective:Cancer stem cells (CSCs) are resistant to chemotherapy. Our study aimed to investigate the stem cell-like proper-ties of doxorubicin-resistant osteosarcoma cell line 143B and its correlation with Notch signaling. Methods:We generated doxorubicin-resistant osteosarcoma cells by treating them with 2μm doxorubicin. Stem cell-like properties such as morphology change, Stro-1/CD117 double positive ratio, stem cell-related gene expression, sphere formation efficiency, and EMT character were assessed on day 5 after doxorubicin withdrawal. Notch receptor and its target genes were examined using qPCR and Western blot analysis. The stem cell-like properties of doxorubicin-resistant osteosarcoma cells were assessed when pretreated with Notch inhibitor or vehicle. The an-ti-tumor effect of Notch inhibitor was tested using a xenograft model. Results:Doxorubicin-resistant osteosarcoma cells were enriched in Stro-1+/CD117+cells, which showed obvious increased expression of stem cell-related genes, and exhibited enhanced spheroid for-mation and evident mesenchymal characteristics unlike doxorubicin-sensitive cells. qPCR and Western blot assays showed that Notch intracellular domain 1 (NICD1) and target genes Hes1 and Hey1 were upregulated in doxorubicin-resistant osteosarcoma stem cells compared with those in vehicle cells. Furthermore, pretreatment with a γ-secretase inhibitor (GSI) to prevent Notch signaling en-hanced chemo-sensitivity and inhibited doxorubicin-enriched osteosarcoma stem cell activity in vitro. Finally, the Notch inhibitor pre-vented tumor growth in mice xenograft models. Conclusion: Doxorubicin induced the enrichment of osteosarcoma stem-like cells through Notch signaling, and inactivation of Notch could be useful for overcoming drug resistance and eliminating osteosarcoma.
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Objective To analyze the relationship between Notch signaling pathway and levels of lymphocytes and cytokines in children with juvenile idiopathic arthritis (JIA),and to explore its role in the pathogenesis of JIA.Methods Thirty-five pediatric patients with JIA [males 20 cases,females 15 cases;aged (6.5 ±4.0) years old,(0.83-15.00 years old)] and 15 healthy children [males 6 cases,females 9 cases;aged (5.0 ± 2.9) years old,(1.0-11.0 years old)] from November 2015 to February 2016 in Guangzhou Women and Children's Medical Center were included in the study.The JIA group were divided into the systemonset JIA(So-JIA) group (22 cases) and psoriatic JIA(p-JIA) group (13 cases,polyarthritis 7 cases and oligoarthritis 6 cases).The expressions of Notch signaling's receptor,ligand and target gene mRNA in peripheral blood monouclear cells (PBMC) from the JIA group and the control group were determined by quantitative real-time PCR.The levels of cytokines interleukin (IL)-1 β,IL-10,IL-6,IL-17,IL-4 and transforming growth factor-β (TGF-β) were detected by enzyme-linked immunosorbent assay.Results Compared with the healthy control group,the Notch2 receptors (1.6 ± 3.2 vs.0.4 ± 0.3) expression level,Jagged1 ligand (44.0 ± 79.0 vs.11.3 ± 1.2) expression levels and the levels of target gene HES1(0.4 ±0.3 vs.0.1 ± 0.1) mRNA in the JIA group showed a significant increase,and the differences were all statistically significant (all P ＜0.05).Compared with the healthy control group,the JIA group showed an increased level of IL-1β [(182.22 ± 309.13) ng/L vs.(54.71 ± 20.33) ng/L],IL-10 [(32.99 ± 34.28) ng/L vs.(22.68 ±4.56) ng/L],IL-6 [(100.48 ±305.57) ng/L vs.(13.98 ±2.78) ng/L],IL-17 [(9.11 ± 17.57) ng/L vs.(2.42 ±0.29) ng/L] and TGF-β [(14.37 ±9.33) ng/L vs.(5.49 ±4.49) ng/L],and there were statistically significant differences (all P ＜ 0.05).The expression level of HES1 mRNA was positively correlated with STAT3 mRNA in the So-JIA group (r =0.573,P ＜0.05).The expression level of HES1 mRNA was positively correlated with CD3 + T(r =0.528),CD19 + B (r =0.480),CD3 + CD4 + TH(r =0.457) and CD16 + CD56 + NK (r =0.598) cell absolute count in the So-JIA group (all P ＜0.05).The expression level of HES1 mRNA was positively correlated with CD3 + T cell absolute count in the p-JIA group (r =0.577,P ＜ 0.05).Conclusion Imbalance between Notch pathway and lymphocytes and cytokines in children with JIA may play an important role in the pathogenesis of JIA.
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AIM: To observe the inhibitory effect of recombinant human endostatin (rhES) on plaque angio-genesis, and to explore the regulatory mechanism of Dll4 /Notch pathway in the anti-angiogenic effect of rhES.METH-ODS: Male Wistar rats were randomized into 3 groups: normal control group (N group), atherosclerotic model group (AS group), and rhES treated group (AS +rhES group).The rats in N group were fed a normal diet, while the remaining 2 groups were established to atherosclerotic rat model via high-cholesterol diet, intraperitoneal injection of vitamin D3 and aor-tic balloon injury.The rats in AS +rhES group received intraperitoneal injection of rhES.The blood total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), C-reactive protein (CRP), interleukin-1 (IL-1) and troponin I (TnI) were measured.The atherosclerotic abdominal aortas were taken for pathological observation.Immu-nohistochemical staining was used to measure the density of neovessels in the plaques, which were marked by CD31.The protein levels of Dll4 and Notch1 in the aortas were analyzed by Western blot.RESULTS: The levels of blood TC, TG, LDL-C, CRP and IL-1 in AS group and AS +rhES group were much higher than those in N group (P <0.05), and no sta-tistical difference between AS group and AS +rhES group was observed.The expression of CD31 in AS group was the high-est among all groups.Compared with AS group, the density of neovessels in the plaques of AS +rhES group decreased sig-nificantly (P <0.05).The protein expression of Dll4 and Notch1 in AS group was lower than that in N group (P <0.05). Compared with AS group, the protein expression of Dll4 and Notch1 increased significantly (P <0.05).CONCLUSION:rhES has the ability to inhibit plaque angiogenesis in rats.The activation of Dll4 /Notch pathway may be the mechanism of rhES in inhibiting plaque angiogenesis.
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[ ABSTRACT] AIM:To investigate the role of the Notch pathway in Toll-like receptor 4 ( TLR4 )-mediated in-flammatory response in renal ischemia reperfusion injury ( IRI) in rats.METHODS: A total of 75 male sprague-Dawley rats were randomly divided into sham operation group , IRI group and DAPT treatment group .Blood samples and the kid-neys were obtained at 6 h, 12 h, 24 h, 48 h and 72 h after reperfusion .The concentrations of blood urea nitrogen ( BUN) and serum creatinine (Scr) were measured.The serum levels of tumor necrosis factor-α(TNF-α) and interleukin-6 (IL-6) were detected by ELISA, and the expression of Notch1, TLR4 and NF-κB p65 in the renal tissues was assessed by im-munohistochemistry and Western blot .RESULTS: The serum levels of BUN, Scr, TNF-αand IL-6 in IRI group were markedly increased as compared with sham group (P<0.05).The protein levels of Notch1, TLR4 and NF-κB p65 in re-nal tubular epithelial cells in IRI group was significantly enhanced as compared with sham group ( P<0.05 ) .In DAPT group, the serum levels of BUN, Scr, TNF-αand IL-6 were significantly reduced compared with IRI group (P<0.05), and the protein levels of Notch1, TLR4 and NF-κB p65 were apparently less than those in IRI group (P<0.05).CON-CLUSION:Significant changes of renal function , a rise of serum inflammatory factor including TNF-αand IL-6 and en-hanced expression of Notch 1, TLR4 and NF-κB p65 in the renal tissue occurred in the rats with IRI .γ-Secretase inhibitor DAPT attenuates TLR4-mediated inflammatory response in the renal IRI through the inhibition of Notch 1 and down-regula-tion of NF-κB.
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Aim To investigate the expression of Notch pathway and Nephrin in angiotensin Ⅱ ( AngⅡ)-stimulated mice podocyte. Methods Mice podo-cyte was stimulated by AngⅡ, and then was treated with valsartan. The levels of Notch1, Notch intracellu-lar domain 1 ( NICD1 ) , Hes1 and Nephrin were deter-mined by immunofluorescence, Western blot and Real-time PCR. Results AngⅡincreased Notch1, NICD1 and Hes1 expression, and decreased Nephrin expres-sion in a time-dependent manner ( P<0. 01 ) . Valsar-tan inhibited AngⅡ-induced activation of Notch path-way and enhanced Nephrin level ( P <0. 01 ) . Con-clusion AngⅡdecreases Nephrin expression in podo-cyte by activating Notch pathway.
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Objective To investigate the effect and mechanism of dibenzazepines ( DBZ ) injection on pulmonary hypertension in rat. Methods Rat models of pulmonary hypertension were established, and 30 male rats were randomly divided into 3 groups: normal control group with saline injection, pulmonary hypertension model control group with hypoxia treatment and saline injection, DBZ group with hypoxia treatment and DBZ injection. The right ventricular pressure was determined by ultrasound cardiogram.Pulmonary arterial remodeling was detected by HE staining.Proliferation cell nuclear antigen and CCK-8 in pulmonary arterial smooth muscle cells were detected by Western blotting. Results The right ventricular pressure of pulmonary hypertension group was significantly increased compared with normal control group [(4.60±0.16) kPa vs. (3.37±0.18) kPa(P<0.01)].After hypoxia treatment, pulmonary arterial remodeling and proliferation of pulmonary arterial smooth muscle cells of the rats of pulmonary hypertension group were augmented remarkably. Rats from DBZ group showed reductions in right ventricular pressure, amelioration in pulmonary arterial remodeling and suppression in proliferation of pulmonary arterial smooth muscle cells. The proliferation of rat pulmonary artery smooth muscle cells decreased significantly in DBZ treated group [(2.073±0.064) vs.(4.392±0.013)] compared with model control group (P<0.05). Conclusion Notch pathway takes part in the process of pulmonary hypertension, and DBZ injection can significantly suppress the proliferation of pulmonary artery smooth muscle cells with a protective effect on pulmonary hypertension.
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@#As one of the first-line antipsychotic drugs, olanzapine(OLA)inducing insulin resistance and metabolic disorder has become a serious clinical concern. This study aimed at investigating the effect of OLA on white adipose tissue(WAT)beiging as a potential mechanism behind its metabolism-disturbing effects. C57BL6/J mice were orally administered with low and high-dose OLA(4, 8 mg/kg, once daily)for 28 consecutive days; body weight and food intake were recorded every other day. Mice were subjected to glucose-tolerance test(GTT)and a cohort from each group was challenged with cold stress for 36 h before sacrifice. The perirenal, epididymal and inguinal WAT were carefully dissected, weighed and processed separately for hematoxylin-eosin staining, UCP-1 immunohistochemical and Western blot analysis. The results showed that OLA induced significant impairment in basal heat generation and glucose regulation. There were fewer beige adipocytes in the inguinal WAT after OLA treatment. The beiging of inguinal WAT in response to cold stress was significantly inhibited in OLA-treated mice. Mechanistically, OLA induced the activation of mTOR-Notch pathway, as evidenced by a significant increase in phosphorylated mammalian target of rapamycin(p-mTOR)and intracellular domain of Notch1(N1ICD)expression. Together, our study reveals that the inhibitory effects on WAT beiging may explain the propensity of OLA to induce metabolic disturbance, and mTOR-Notch pathway activation could play key roles in this effect. Future validation and elucidation of these novel findings are expected to provide novel insights into the metabolic risks of OLA and related second generation antipsychotics, which may lead to innovative intervention strategies in the clinic.
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La vía de señalización NOTCH es un mecanismo de señalización célula-célula conservado evolutivamente entre las especies, el cual es indispensable para un correcto desarrollo embrionario, mediando una variedad de procesos celulares como proliferación, diferenciación, apoptosis, transformación epitelio- mesénquimal, migración, angiogénesis, mantenimiento de células madre y definición de destino celular. Varios genes componentes de esta vía han sido implicados en el desarrollo de estructuras craneofaciales. El 80% de los pacientes con síndrome de Alagille, presentan mutaciones en el gen que codifica para el receptor Jagged1 (Jag1), acompañado de hipoplasia del tercio medio facial y de craneosinostosis esporádica. Ratones con mutaciones homocigotas en el gen Jagged2 (Jag2) presentan paladar hendido, como resultado de fusiones ectópicas entre la lengua y los procesos palatinos. Por otro lado, mutaciones inducidas en el gen Hes1 generan defectos en el desarrollo de estructuras craneofaciales, derivadas de las células de la cresta neural craneal (CCNC) que incluyen: paladar hendido, agenesia del hueso frontal, malformación de base craneal y disminución en el tamaño del maxilar superior e inferior. Recientes estudios han evidenciado alteraciones durante la morfogénesis dental de ratones mutantes Jagged2-/-, acompañada de defectos en la citodiferenciación de ameloblastos y deficiente deposición de matriz de esmalte. Estos estudios muestran cómo la vía de señalización NOTCH está implicada en el desarrollo de una variedad de estructuras craneofaciales como paladar, dientes, maxilares y cráneo. Por esta razón, el propósito del presente artículo es presentar una revisión de las diferentes funciones de la vía NOTCH durante el desarrollo de estas estructuras craneofaciales, y de las alteraciones resultantes cuando existen mutaciones en algunos genes componentes de la vía NOTCH, como Jagged2, Jagged1, Hes1, Notch1 y Notch2.
Subject(s)
Receptors, NotchABSTRACT
Purpose To investigate effect of valsartan on expression of Notch pathway and production of extracellular matrix. Methods Urine protein and production of extracellular matrix were measured after diabetic mice were treated with valsartan. The levels of Jag-ged1, Notch1, Notch intracellular domain 1 (NICD1), transforming growth factor-β1 (TGF-β1), TypeⅣcollagen and Laminin were determinated by immunohistochemistry, Western blot and real-time PCR. Results Valsartan suppressed urine protein and production of extracellular matrix in diabetic mice (P<0. 05). Valsartan also inhibits overexpression of Jagged1, Notch1, NICD1, TGF-β1, Type Ⅳ collagen and Laminin in glomerular tissues of diabetic mice (P<0. 05 or P<0. 01). Conclusion Valsartan inhibits activa-tion of Notch pathway in glomerular tissues of diabetic mice, inhibits production of extracellular matrix in glomerulus and delays glomer-ulosclerosis.