Allicin Improves Hepatic Fibrosis by Regulating Notch 1 Pathway

2021 ◽  
Vol 11 (11) ◽  
pp. 2153-2161
Author(s):  
Wenxiang Li ◽  
Yajing Sun ◽  
Zaixing Wang
Keyword(s):  
Liver Function ◽  
Protein Expression ◽  
Hepatic Fibrosis ◽  
Volume Fraction ◽  
Mtor Pathway ◽  
Elisa Assay ◽  
Notch 1 ◽  
Collagen Volume Fraction ◽  
Mtor Protein ◽  
Masson Staining

Aim: To discuss effects and mechanisms of allicin in hepatic fibrosis by vivo study. Materials and methods: Dividing 45 rats into 5 groups. Evaluating pathology and fibrosis by HE and Masson staining, measuring α-SMA, Collage III, Notch 1, p-AKT and p-mTOR protein expression by IHC assay and WB assay; LC 3B protein expression were evaluated by Immunofluorescence. Liver function were measured by Elisa assay. Results: With Allicin supplement, rats’ liver function, pathological and Collagen volume fraction were significantly improved with doses-dependent in liver tissues (P < 0.05, respectively); α-SMA, Collage III, Notch 1, p-AKT and p-mTOR protein expression were significantly suppressed with doses-dependent (P < 0.05, respectively); LC 3B protein expression was significantly increased with doses-dependent (P < 0.05, respectively). Conclusion: Allicin improved hepatic fibrosis by authophagy up regulation via regulation Notrch1/AKT/mTOR pathway by vivo study.

scholarly journals Therapeutic Effect of Biejiaxiaozheng Pills on Carbon Tetrachloride-Induced Hepatic Fibrosis in Rats through the NF-κB/Nrf2 Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Weibin Wu ◽  
Liqiang Li ◽  
Jian Yang ◽  
Pinyu Li ◽  
Yuying Hu ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Function ◽  
Hepatic Fibrosis ◽  
Inflammatory Cytokine ◽  
Nrf2 Pathway ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Commercial Kits ◽  
Plasma Antioxidant ◽  
Masson Staining

Aims. To explore the effects of Biejiaxiaozheng pills on carbon tetrachloride-induced hepatic fibrosis in rats through the NF-κB/Nrf2 pathway and to explore the possible antifibrotic mechanisms of the drug. Material and Method. A rat model of hepatic fibrosis was established via CCl4 induction. Liver function and antioxidant indices were detected using commercial kits. Hematoxylin-eosin and Masson staining were used to detect pathological changes in hepatic tissues. ELISA was used to measure plasma TNF-α, IL-β, and IL-6 levels. RT-PCR was used to measure changes in TNF-α, IL-β, and IL-6 levels in hepatic tissues. Changes in p65, P-p65, Nrf2, and HO-1 protein expression were detected using western blotting. Results. In rats with hepatic fibrosis, Biejiaxiaozheng pills effectively improved liver function, alleviated fibrosis in hepatic tissues, and significantly reduced collagen accumulation. The pills significantly downregulated inflammatory cytokine expression in hepatic tissues by suppressing p65 phosphorylation and reduced plasma inflammatory cytokine levels to some extent. The pills upregulated Nrf2 and HO-1 expression in hepatic tissues, enhanced antioxidant potential, and upregulated plasma antioxidant levels. Conclusion. Biejiaxiaozheng pills improved hepatic fibrosis symptoms and lesions in rats, likely by inhibiting the NF-κB pathway and promoting the Nrf2 pathway.

scholarly journals Sestrin 2 Attenuates Rat Hepatic Stellate Cell (HSC) Activation and Liver Fibrosis via an mTOR/AMPK-Dependent Mechanism

2018 ◽  
Vol 51 (5) ◽  
pp. 2111-2122 ◽  
Author(s):  
Yi-Bing Hu ◽  
Xiao-Ting Ye ◽  
Qing-Qing Zhou ◽  
Rong-Quan Fu
Keyword(s):  
Liver Fibrosis ◽  
Protein Expression ◽  
Hepatic Fibrosis ◽  
Transforming Growth Factor ◽  
Histopathological Examination ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Mrna Levels ◽  
Alpha Smooth Muscle Actin

Background/Aims: Sestrin 2 is associated with the pathophysiology of several diseases. The aim of this study was to investigate the effects and potential mechanisms of Sestrin 2 in rat hepatic stellate cells (HSCs) during liver fibrogenesis. Methods: In this study, Sestrin 2 protein expression was detected in rat HSC-T6 cells challenged with transforming growth factor-β (TGF-β) and in mice treated with carbon tetrachloride (CCl4), a well-known model of hepatic fibrosis. Next, HSC-T6 cells and fibrotic mice were transfected with lentivirus. The mRNA expression levels of markers of liver fibrosis [alpha-smooth muscle actin (α-SMA) and collagen 1A1 (Col1A1)] were analyzed by quantitative reverse transcription–polymerase chain reaction (RT-PCR). Cell death and proliferation were evaluated by the MTT assay, and biochemical markers of liver damage in serum [alanine transaminase (ALT) and aspartate transaminase (AST)] were also measured using a biochemical analyzer. Histopathological examination was used to evaluate the degree of liver fibrosis, and protein expression [phospho-adenosine monophosphate-activated protein kinase (p-AMPK), AMPK, phospho-mammalian target of rapamycin (p-mTOR), and mTOR] was determined by western blotting. Results: We found that Sestrin 2 was elevated in both the HSC-T6 cell and hepatic fibrosis models. In vitro, overexpression of Sestrin 2 attenuated the mRNA levels of α-SMA and Col1A1, suppressed α-SMA protein expression, and modulated HSC-T6 cell proliferation. In vivo, overexpression of Sestrin 2 reduced the ALT and AST levels as well as the α-SMA and Col1A1 protein expression in the CCl4 model of liver fibrosis. Moreover, the degree of liver fibrosis was ameliorated. Interestingly, overexpression of Sestrin 2 increased p-AMPK but decreased p-mTOR protein expression. Conclusion: Our findings indicate that Sestrin 2 may attenuate the activation of HSCs and ameliorate liver fibrosis, most likely via upregulation of AMPK phosphorylation and suppression of the mTOR signaling pathway.

Analysis of Postoperative Liver Function Tests in relation to Residual Liver Volume Fraction in Right Lobe Donors

2004 ◽  
Vol 47 (2) ◽  
pp. 216
Author(s):  
Mikyung Yang ◽  
Mi Sook Gwak ◽  
Yoon Jin Sun ◽  
Soo Joo Choi ◽  
Tae Soo Hahm ◽  
...  
Keyword(s):  
Liver Function ◽  
Volume Fraction ◽  
Liver Volume ◽  
Liver Function Tests ◽  
Function Tests ◽  
Right Lobe

scholarly journals Sedum sarmentosum Total Flavonoids Alleviate Schistosomiasis-Induced Liver Fibrosis by Altering TGF-β1 and Smad7 Expression

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Peng-chun Yang ◽  
Wei-zhe Bai ◽  
Jing Wang ◽  
Cai-hua Yan ◽  
Wei-feng Huang ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Protein Expression ◽  
Hepatic Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Schistosomiasis Japonica ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Tgf Β1 ◽  
Liver Tissues

Objectives. Schistosomiasis is a parasitic disease that affects over 142 million people worldwide. The main causes of death of schistosomiasis include liver granuloma and secondary hepatic cirrhosis resulting from severe fibrosis. Despite intensive research, controlling liver fibrosis associated with schistosomiasis remains challenging. Sedum sarmentosum total flavonoid (SSTF) is a promising agent to reduce liver fibrosis with an unknown mechanism. Thus, the objectives of this study are to validate its effect on the liver fibrosis caused by schistosomiasis and to explore the underlying molecular mechanism. Methods. Sixty male Sprague-Dawley rats were randomly divided into six groups: one group of normal control and five groups of liver fibrosis induced by schistosomiasis japonica with or without SSTF or colchicine treatment, the latter serving as the positive control. Liver tissues from each animal were harvested to observe the degree and grade of hepatic fibrosis. We also measured the expression of transforming growth factor-beta 1 (TGF-β1) and Smad7 using RT-qPCR, Western blot, and immunohistochemistry. Results. Compared with the untreated model group, groups treated with SSTF at all three tested doses had significantly reduced hepatic fibrosis ( P < 0.05 ). Each dose of SSTF also significantly reduced TGF-β1 protein expression and mRNA levels in the liver tissues ( P < 0.05 ). In contrast, the middle and high doses of SSTF significantly increased Smad7 protein expression and mRNA levels ( P < 0.05 ). Immunohistochemistry showed that each dose of SSTF reduced TGF-β1 protein expression ( P < 0.05 ). Conclusion. Our results demonstrated that SSTF alleviated schistosomiasis japonica-induced hepatic fibrosis by inhibiting the TGF-β1/Smad7 pathway.

Hepatoprotective Effects of Saponins from Rhizoma panacis majoris on Hepatic Fibrosis Induced by Carbon Tetrachloride in Rats

2014 ◽  
Vol 568-570 ◽  
pp. 1915-1920
Author(s):  
Ji Hong Zhang ◽  
Meng Qiong Shi ◽  
Hai Bo He ◽  
Cai Hong Bai ◽  
Jun Zhi Wang ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Function ◽  
Antioxidant Capacity ◽  
Hepatic Fibrosis ◽  
Separation And Purification ◽  
Sprague Dawley ◽  
Gene Expressions ◽  
Total Antioxidant ◽  
Hepatoprotective Effects ◽  
Underlying Mechanisms

Saponins from Rhizoma Panacis Majoris (SRPM), the bioactive component in Rhizoma Panacis Majoris, have been used extensively as a remedy for liver injury diseases and achieved good clinical efficacy, but the underlying mechanisms remain poorly understood. The goal of our present study was to further confirm SRPM hepatoprotective effect, and evaluate that whether SRPM attenuate oxidative stress and fibrosis in carbon tetrachloride (CCl4)-induced hepatic injury, based on these results, investigate the probable mechanisms involved. At first, the separation and purification of SRPM were studied. And then, in the animal experiment, the male Sprague-Dawley rats were randomly divided into control, model, l-SRPM and h-SRPM group. Hepatic fibrosis model were made according to our previous studies reported. At the same time, the experimental rats were treated respectively with relative drugs, once a day for 8 weeks. Hepatoprotective effects of SRPM were evaluated by liver function, total antioxidant capacity and total-superoxide dismutase, histopathological observations and the hepatic fibrosis relative gene expressions. In the study, we found that SRPM significantly improved liver function, serum antioxidation level, reversed the upregulated α-SMA and TIMP1 mRNA expressions, and further increased the MMP1 mRNA expression. Our studies indicated that SRPM exerted beneficially hepatoprotective effects on the CCl4 induced hepatic fibrosis, mainly enhancing liver tissue antioxidant capacity, reducing the lipid peroxidation of hepatocyte membranes, and then alleviating hepatic fibrosis and hepatic cell death.

Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

2008 ◽  
Vol 294 (3) ◽  
pp. H1251-H1257 ◽  
Author(s):  
David B. Murray ◽  
Jason D. Gardner ◽  
Gregory L. Brower ◽  
Joseph S. Janicki
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Density ◽  
Volume Fraction ◽  
Volume Overload ◽  
Receptor Antagonism ◽  
Collagen Volume Fraction ◽  
Endothelin 1 ◽  
Mast Cell Density ◽  
Chronic Volume Overload

The objective of this study was to investigate the effect a nonselective endothelin-1 (ET-1) receptor antagonist (bosentan) had on the acute myocardial remodeling process including left ventricular (LV) mast cells and matrix metalloproteinase (MMP) activity secondary to volume overload. Additionally, we investigated the overall functional outcome of preventative endothelin receptor antagonism during 14 days of chronic volume overload. LV tissue from sham-operated (Sham), untreated-fistula (Fist), and bosentan (100 mg·kg−1·day−1)-treated animals (Fist + Bos) was analyzed for mast cell density, MMP activity, and myocardial collagen volume fraction at 1 and 5 days after the creation of an aortocaval fistula. When compared with untreated fistulas, bosentan treatment prevented the marked increase in LV mast cell density at 1 day postfistula (3.1 ± 0.3 vs. 1.3 ± 0.3 LV mast cells/mm2, Fist vs. Fist + Bos, P ≤ 0.01). Additionally, the substantial increase in MMP-2 activation in the untreated fistula at 1 day was prevented following bosentan treatment (1.6 ± 0.3 vs. 0.9 ± 0.1 arbitrary activity units, Fist vs. Fist + Bos, P ≤ 0.01). The marked decrease in collagen volume fraction seen in the Fist group (1.4 ± 0.1 vs. 0.8 ± 0.1% myocardial tissue, Sham vs. Fist, P ≤ 0.01) was significantly attenuated following bosentan treatment at both the 1- and 5-day time points. Lastly, a 2-wk preventative treatment with bosentan resulted in significant attenuation of the increase in LV end-systolic and -diastolic volumes compared with those in untreated fistula hearts. In summary, nonselective ET-1 antagonism prevents the acute increases in cardiac mast cell density and MMP activation induced secondary to chronic volume overload. By preventing these events, ET-1 antagonism was efficacious in attenuating ventricular dilatation and limiting the development of structural and functional deficits in the first 2 wk of chronic volume overload. Accordingly, these results are the first to demonstrate that cardiac mast cells are responsive to the endogenous endothelin system in vivo. Another novel finding from this study is that chronic nonspecific endothelin antagonism may inadvertently potentiate ET-1-mediated signaling.

The Prognostic Role of Jagged-1 Protein Expression In Acute Myeloid Leukemia Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2726-2726 ◽  
Author(s):  
Agnieszka Wierzbowska ◽  
Agnieszka Pluta ◽  
Konrad Stepka ◽  
Magdalena Czemerska ◽  
Barbara Cebula-Obrzut ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Protein Expression ◽  
Hodgkin Lymphoma ◽  
Peripheral Blood ◽  
Univariate Analysis ◽  
Response To Treatment ◽  
Notch 1 ◽  
Hematopoietic Stem

Abstract Abstract 2726 Objectives: Jagged-1 is a member of the Delta/Serrate/Lag-2 (DSL) family of proteins that are ligands for Notch receptors. Aberrant Jagged-1/Notch-1 signaling is posited to promote the development of AML by inducing excessive self-renewal with a concomitant block in cell differentiation. Moreover, Notch-1 signaling has been identified as a critical factor involved in the maintenance of a pool of self-renewing hematopoietic stem cells (HSC) as well as AML stem cells. So far there were no reports on the clinical role of Notch-1 and Jagged-1 expression in AML. In this study we evaluated the expression of Jagged-1 and Notch-1 proteins in AML blasts and CD34+ peripheral blood stem cells (PBSC) collected during mobilization procedures before autologous stem cell transplantation. In addition, in AML patients we correlated the expression of both proteins with known prognostic factors and response to treatment. Methods: The expression of Notch-1 and Jagged-1 proteins was examined in leukemic blasts isolated from bone marrow or peripheral blood of 53 de novo AML patients with median age 57 years (range 21–82). CD34+ collected from 13 lymphoma patients (11 multiple myeloma, 1 Hodgkin lymphoma, 1 non-Hodgkin lymphoma) with median age 57 (range 21–69 years) served as a control. All measurements were carried out using multi-colour flow cytometry. In parallel, the isotype controls were performed for all measurements. Protein expression was assessed as a percentage of Notch-1 and Jagged-1 positive cells. The cut-off 20% was used to subdivide patients into “low-expressers” and “high-expressers” group. Results: We found that the median expression of Jagged-1 was significantly higher in AML blasts (18,2%; range 0,9–62,4%) as compared to CD34+ PBSC (3,0%; range 0,9–21%); p<0.0001. In contrast, the expression of Notch-1 in AML patients (median 1,4%; range 0,1–24,8%) was lower than in the control CD34+ cells (median 3,85%; range 0,7–16%); p<0.004. There was no correlation between Jagged-1 and Notch-1 protein expression in both AML blasts and PBSC. Jagged-1 expression was significantly higher in AML patients with WBC ≤20G/L (median 21,2%) compared to group with WBC >20 G/L (median 9,85%); p<0.004. Consequently, we found the significant negative correlation between Jagged-1 expression and WBC count (p<0.02). Patients with good-risk karyotype according to SWOG classification showed significantly higher expression of Jagged-1 protein as compared to intermediate and poor risk group (medians 21,8% vs. 11,5% respectively; p< 0.02). Thirty two out of 53 AML patients received standard induction chemotherapy with daunorubicine and cytarabine (“3+7”), 21/53 received non-intensive therapy. Nineteen (61%) of intensively treated patients achieved complete remission (CR). We observed that the CR rate in “high-expressers” of Jagged-1 was significantly higher than in the “low-expressers” group (80% vs. 43% respectively; p=0.04). Additionally, a good karyotype and a high expression of Jagged-1 protein were the only factors associated with higher probability of CR (p=0.05, p<0.01, respectively) in univariate analysis. There was no statistical association between the Notch-1 expression and response to treatment, karyotype or tumour size associated risk factors as: WBC, percentage of leukemic blasts in bone marrow and LDH. Moreover, no correlations between Notch-1 and CD34 expression as well as Notch-1 and differentiation markers (CD13, CD14, CD15, CD33) expressions in AML blasts were found. Conclusions: Jagged-1 protein is highly expressed in AML blasts and correlates with better response to standard chemotherapy, favorable karyotype and lower WBC in AML patients. These data clearly demonstrate an important role of Jagged-1 in AML biology. A better understanding of autonomous Jadded-1 signaling in AML may create new options for therapeutic interventions in AML. Disclosures: Robak: Johnson & Johnson: Research Funding.

High Efficiency Of the PDPK1-Inhibitor, BX912, In MCL

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3077-3077
Author(s):  
Grit Hutter ◽  
Yvonne Zimmermann ◽  
Vladimir Giller ◽  
Anna-Katharina Zoellner ◽  
Oliver Weigert ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Expression ◽  
B Cell ◽  
Cell Lines ◽  
Mode Of Action ◽  
High Efficiency ◽  
Cell Receptor ◽  
Mtor Pathway ◽  
B Cell Receptor ◽  
Blue Staining

Abstract Background Mantle cell lymphoma (MCL) is an aggressive lymphoid malignancy with a median survival of 3-5 years. New strategies including proteasome inhibitors, immune modulatory drugs (IMiDs) and mTOR inhibitors achieve high response rate. Emerging data support the clinical efficiency of inhibitors of the B-cell receptor pathway. PDPK1 (3-phosphoinositide dependent protein kinase-1) is an important downstream target of this crucial pathway. Methods MCL cell lines (Granta 519, Jeko-1, Rec-1) were exposed to various PDK1-Inhibitors (OSU-03012, BX912; BX517; GSK2334470; 0,0625-1µM) and cell proliferation was analysed by WST assay. The effect of BX912 was tested on 6 MCL. Cell proliferation (trypanblue staining), induction of apoptosis (Annexin V PE/7-AAD staining) and cell cycle (FACS) were investigated. In MCL cell lines protein expression of the PI3K/Akt/mTOR pathway candidates (Akt, mTOR, eIF4E, PDK) was analysed after 24h BX912 exposure. Combined approaches were evaluated by cell proliferation analysis (WST-assay, trypan blue staining). In an alternative approach PDPK1 expression was downregulated by siRNA and consequently investigated in detail. Results BX912 appeared to be the most potent PDPK1-Inhibitor in the MCL cell lines tested. Sensitivity to BX912 was detected in 4 out of 6 MCL- (IC50: 0,25 -0,75µM). In addition sensitive MCL cells showed strong G2 arrest. In contrast healthy donor lymphocytes did not respond to PDPK1-inhibition. In MCL cell lines response to BX912 correlated with the PDPK1 protein expression status. Treatment with BX912 led to downregulation of PDPK1 protein expression and dephosphorylation of Rictor, Raptor, RSK and eIF4E proteins in the most sensitive to the inhibitor MCL cell line, Z138, suggesting a mode of action of BX912 mainly through the mTOR pathway. Combination of the PDPK1-inhibitors (BX912; OSU-03012, GSK2334470) with each other revealed synergism especially in combinations with GSK2334470 (BX912 and GSK2334470: CI 0,89; OSU-03012 and GSK2334470: CI 0,484; BX912 and OSU-03012: CI: 1,3), substantiating the therapeutic benefit of comprehensive PDPK1 – inhibition in MCL. Combination experiments of BX912 with inhibitors of the B-cell receptor pathway (PI3K, mTOR, PKCß) and the JAK/STAT-pathway (PIM1, JAK1/2) exhibited BX912 and the PI3K-inhibitor, CAL101, as the most potent combination (CI 0,7 -0,91) in MCL cell lines. To uncover the molecular mode of action of this combination, results of protein expression analysis will be shown. Conclusions The PDPK1 inhibitor BX912 shows high efficiency in MCL cells. Our data let suggest PDPK1 inhibition as a new targeted approach in MCL. However further exploration of the underlying molecular mechanisms is warranted to guide the future development of combined treatment approaches. Disclosures: Dreyling: Janssen: Support of IITs, Scientiffic advisory board, Speakers honoraria Other; Hoffmann-La Roche: Support of IITs, Speakers honoraria, Support of IITs, Speakers honoraria Other.

Mechanism of Anti-Hepatic Fibrosis of TGF-β1/Smad Signaling Pathway Affected by Chymase Inhibitors

2020 ◽  
Vol 10 (6) ◽  
pp. 782-788
Author(s):  
Xue-Ji Han ◽  
Ning Chen ◽  
Ming-Shi Yin
Keyword(s):  
Protein Expression ◽  
Mrna Expression ◽  
Hepatic Fibrosis ◽  
Expression Level ◽  
Mrna Expression Level ◽  
Model Group ◽  
Protein Expression Level ◽  
Smad Signaling Pathway ◽  
Chymase Inhibitor ◽  
Liver Tissues

Objective: This study aims to investigate the pathological mechanism of chymase inhibitors (Chy-I) on liver tissue in rats with hepatic fibrosis. Methods: Rats in the model group and chymase inhibitor group were established by using carbon tetrachloride. Rats in the chymase inhibitor group intragastrically received Chy-I (10 mg/kg/d) during the modeling. The pathological changes of rat liver tissues induced by chymase inhibitors were investigated, and the mRNA and protein expression of TGF-β1, Smad3 and Smad7 were observed in rat liver tissues. Results: When compared to the model group, The results presented that the liver tissue pathology of rats had been significantly improved in the Chy-I group. When compared to the normal group, the mRNA expression level and protein expression level of TGF-β1 and Smad3 in liver tissues had significantly increased, but the mRNA expression level and protein expression level of Smad7 significantly decreased (p < 0 05). When compared to the model group, the mRNA expression level and protein expression level of TGF-β1 and Smad3 was significantly downregulated, but the mRNA expression level and protein expression level of Smad7 was significantly upregulated in the Chy-I group. Conclusion:Chy-I plays an active role in blocking hepatic fibrosis in rats by affecting the TGF-β1/Smad signaling pathway in liver tissues through multiple sites.

Changes of Notch-1 Expression in Sinoatrial Node Fat Pad of Canines with Chronic Atrial Fibrillation

2019 ◽  
Vol 9 (7) ◽  
pp. 976-981
Author(s):  
Sun Juan ◽  
Wang Kun ◽  
Ailiman Mahemuti
Keyword(s):  
Atrial Fibrillation ◽  
Protein Expression ◽  
Left Atrium ◽  
Target Genes ◽  
Sinoatrial Node ◽  
Chronic Atrial Fibrillation ◽  
Nerve Plexus ◽  
Sham Operation ◽  
Fat Pad ◽  
Notch 1

Objective: To investigate the changes of Notch-1 protein expression and the changes of Notch-1 and NICD contents in the sinoatrial node fat pad (SAN-FP) nerve plexus of canines with chronic atrial fibrillation in which atrial fibrillation of the left atrium was induced in chronic pacing canines, in order to elucidate the relationship between the Notch signaling pathway of the SAN-FP nerve plexus and the occurrence and development of atrial fibrillation. Methods: Healthy Beagle dogs weighing 18 ± 2.66 kg, aged 7 to 9 years were randomly divided into a sham operation (SO) group (n = 5) and an atrial fibrillation (AF) group (n = 5), respectively. Results: Atrial fibrillation was successfully induced in canines in the AF group by rapid pacing on the left atrium appendage. The scattered nerve plexus was observed in fat cells of the SAN-FP. In contrast with the SO group, Notch-1 protein expression in the AF group was significantly increased (P < 0.05). No significantly statistical differences were observed in the concentration of Notch-1 and NICD between the AF group and the SO group (P > 0.05). In addition, no statistical differences in baseline Notch-1 and NICD concentrations were observed between the AF group and the SO group (P > 0.05). After an 8-week study, the concentrations of Notch-1 and NICD in the AF group were significantly increased compared with the SO group (P < 0.05). Conclusion: During the occurrence and development of AF, Notch-1 was expressed in different phases in the SAN-FP nerve plexus. After combining with ligands, Notch-1 was activated as NICD to affect the downstream target genes.

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