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Li M, Song J, Niu X, Mo F, Xie X, Li X, Yin Y, Wang T, Song X, Liu J, Lv P. Baicalein ameliorates cognitive decline induced by chronic cerebral hypoperfusion through the SIRT1-mediated Notch1 pathway to improve angiogenesis and suppress neuroinflammation. Front Aging Neurosci 2025; 17:1521353. [PMID: 40290868 PMCID: PMC12021866 DOI: 10.3389/fnagi.2025.1521353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 03/26/2025] [Indexed: 04/30/2025] Open
Abstract
Introduction The potential for therapeutic strategies that promote angiogenesis and suppress neuroinflammation to ameliorate cognitive decline induced by chronic cerebral hypoperfusion (CCH) has led to their recognition as promising therapeutic targets for vascular dementia (VD). The SIRT1-mediated Notch1 signaling pathway is important in regulating angiogenesis and neuroinflammation. Previous studies have demonstrated that baicalein alleviates cognitive decline in rats with CCH. Nevertheless, it remains unclear whether baicalein can stimulate angiogenesis in the context of VD and whether this cognitive protective effect is achieved by regulating the SIRT1-mediated Notch1 pathway. The aim of this study was to investigate the impact and the underlying mechanism of baicalein on angiogenesis and neuroinflammation in rats with CCH. Methods Adult Sprague-Dawley (SD) rats were administered baicalein or a SIRT1 inhibitor. Cognitive function was assessed by the Morris water maze (MWM) test, and angiogenesis was assessed by immunohistochemical analysis of microvascular density (MVD) and the number of CD31+/5-bromo-2'-deoxyuridine (BrdU)+ cells. Neuroinflammation and apoptosis were assessed by immunohistochemistry for GFAP, Iba-1, NEUN/cleaved caspase-3, and ELISA analysis for TNF-α and IL-1β. Additionally, Western blotting was employed to evaluate the expression of the SIRT1-mediated Notch1 pathway. Results The results demonstrated that baicalein ameliorated memory and learning deficits in rats following CCH by promoting angiogenesis and suppressing neuroinflammation. However, this protective effect could be reversed by inhibiting SIRT1. Baicalein was observed to up-regulate the expression of SIRT1 and down-regulate the Notch1-related molecules. Discussion The SIRT1-related pathway plays a crucial role in regulating angiogenesis and neuroinflammation. Moreover, baicalein exerts a neuroprotective effect against cognitive decline through the SIRT1-mediated Notch1 pathway, which in turn improves angiogenesis and suppresses neuroinflammation.
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Affiliation(s)
- Meixi Li
- Postdoctoral Innovation Practice Base of Hebei General Hospital, Shijiazhuang, Hebei, China
- Postdoctoral Research Station of Biology, Hebei Normal University, Shijiazhuang, Hebei, China
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, China
- Hebei Key Laboratory of Cerebral Networks and Cognitive Disorders, Hebei General Hospital, Shijiazhuang, Hebei, China
- Department of Rehabilitation, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Jiaxi Song
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, China
- Hebei Key Laboratory of Cerebral Networks and Cognitive Disorders, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Xiaoli Niu
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, China
- Hebei Key Laboratory of Cerebral Networks and Cognitive Disorders, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Feng Mo
- Department of Neurosurgery, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Xiaohua Xie
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, China
- Hebei Key Laboratory of Cerebral Networks and Cognitive Disorders, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Xiuqin Li
- Department of Geriatrics, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Yu Yin
- Department of Rehabilitation, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Tianjun Wang
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, China
- Hebei Key Laboratory of Cerebral Networks and Cognitive Disorders, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Xiujuan Song
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jingze Liu
- Postdoctoral Research Station of Biology, Hebei Normal University, Shijiazhuang, Hebei, China
- Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Peiyuan Lv
- Postdoctoral Innovation Practice Base of Hebei General Hospital, Shijiazhuang, Hebei, China
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, China
- Hebei Key Laboratory of Cerebral Networks and Cognitive Disorders, Hebei General Hospital, Shijiazhuang, Hebei, China
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Senchukova MA. Issues of origin, morphology and clinical significance of tumor microvessels in gastric cancer. World J Gastroenterol 2021; 27:8262-8282. [PMID: 35068869 PMCID: PMC8717017 DOI: 10.3748/wjg.v27.i48.8262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 07/02/2021] [Accepted: 12/07/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) remains a serious oncological problem, ranking third in the structure of mortality from malignant neoplasms. Improving treatment outcomes for this pathology largely depends on understanding the pathogenesis and biological characteristics of GC, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers. It is known that the main cause of death from malignant neoplasms and GC, in particular, is tumor metastasis. Given that angiogenesis is a critical process for tumor growth and metastasis, it is now considered an important marker of disease prognosis and sensitivity to anticancer therapy. In the presented review, modern concepts of the mechanisms of tumor vessel formation and the peculiarities of their morphology are considered; data on numerous factors influencing the formation of tumor microvessels and their role in GC progression are summarized; and various approaches to the classification of tumor vessels, as well as the methods for assessing angiogenesis activity in a tumor, are highlighted. Here, results from studies on the prognostic and predictive significance of tumor microvessels in GC are also discussed, and a new classification of tumor microvessels in GC, based on their morphology and clinical significance, is proposed for consideration.
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Affiliation(s)
- Marina A Senchukova
- Department of Oncology, Orenburg State Medical University, Orenburg 460021, Russia
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Wei G, Liu Y, Ji X, Li Q, Xing Y, Xue Y, Liu H. Micro-morphological feature visualization, auto-classification, and evolution quantitative analysis of tumors by using SR-PCT. Cancer Med 2021; 10:2319-2331. [PMID: 33682368 PMCID: PMC7982622 DOI: 10.1002/cam4.3796] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 02/05/2021] [Accepted: 02/06/2021] [Indexed: 11/15/2022] Open
Abstract
Tissue micro‐morphological abnormalities and interrelated quantitative data can provide immediate evidences for tumorigenesis and metastasis in microenvironment. However, the multiscale three‐dimensional nondestructive pathological visualization, measurement, and quantitative analysis are still a challenging for the medical imaging and diagnosis. In this work, we employed the synchrotron‐based X‐ray phase‐contrast tomography (SR‐PCT) combined with phase‐and‐attenuation duality phase retrieval to reconstruct and extract the volumetric inner‐structural characteristics of tumors in digesting system, helpful for tumor typing and statistic calculation of different tumor specimens. On the basis of the feature set including eight types of tumor micro‐lesions presented by our SR‐PCT reconstruction with high density resolution, the AlexNet‐based deep convolutional neural network model was trained and obtained the 94.21% of average accuracy of auto‐classification for the eight types of tumors in digesting system. The micro‐pathomophological relationship of liver tumor angiogenesis and progression were revealed by quantitatively analyzing the microscopic changes of texture and grayscale features screened by a machine learning method of area under curve and principal component analysis. The results showed the specific path and clinical manifestations of tumor evolution and indicated that these progressions of tumor lesions rely on its inflammation microenvironment. Hence, this high phase‐contrast 3D pathological characteristics and automatic analysis methods exhibited excellent recognizable and classifiable for micro tumor lesions.
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Affiliation(s)
- Gong‐Xiang Wei
- School of Physics and Optoelectronic EngineeringShandong University of TechnologyZiboChina
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence DiseasesFirst Affiliated Hospital of Xinjiang Medical UniversityUrumqiChina
| | - Yun‐Yan Liu
- School of Physics and Optoelectronic EngineeringShandong University of TechnologyZiboChina
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence DiseasesFirst Affiliated Hospital of Xinjiang Medical UniversityUrumqiChina
| | - Xue‐Wen Ji
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence DiseasesFirst Affiliated Hospital of Xinjiang Medical UniversityUrumqiChina
- Hepatobiliary SurgeryFirst Affiliated HospitalXinjiang Medical UniversityUrumqiChina
| | - Qiao‐Xin Li
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence DiseasesFirst Affiliated Hospital of Xinjiang Medical UniversityUrumqiChina
- Department of PathologyFirst Affiliated HospitalXinjiang Medical UniversityUrumqiChina
| | - Yan Xing
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence DiseasesFirst Affiliated Hospital of Xinjiang Medical UniversityUrumqiChina
- Imaging CenterFirst Affiliated HospitalXinjiang Medical UniversityUrumqiChina
| | - Yan‐Ling Xue
- SSRFShanghai Advanced Research InstituteChinese Academy of SciencesShanghaiChina
| | - Hui‐Qiang Liu
- School of Physics and Optoelectronic EngineeringShandong University of TechnologyZiboChina
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence DiseasesFirst Affiliated Hospital of Xinjiang Medical UniversityUrumqiChina
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Li F, Meng G, Tan B, Chen Z, Ji Q, Wang X, Liu C, Niu S, Li Y, Liu Y. Relationship between HER2 expression and tumor interstitial angiogenesis in primary gastric cancer and its effect on prognosis. Pathol Res Pract 2020; 217:153280. [PMID: 33253925 DOI: 10.1016/j.prp.2020.153280] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/31/2020] [Accepted: 11/01/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Her2-positive gastric cancer is a unique subtype of disease, requiring different diagnosis and treatment strategies and methods. Neoplasms are significantly correlated with the occurrence, invasion and metastasis of tumors. The purpose of this study was to explore the correlation between HER2 amplification and tumor interstitial angiogenesis in patients with gastric cancer. METHODS The data of 1121 patients with gastric cancer were retrospectively analyzed, and the amplification of HER2 was detected by immunohistochemistry (IHC) and FISH. CD34 IHC was used to label MVD. We analyzed the factors affecting HER2 amplification, the difference in MVD under different HER2 states, the factors related to 5-year survival rate of patients, and predicted the independent factors affecting 5-year survival rate of gastric cancer patients. RESULTS We found 115 cases with HER2 positive rate of 10.26 %. HER2 amplification was more likely in gastric cancer patients with more than 5.2 cm tumor diameter, Lauren intestinal type, tubular adenocarcinoma, and the depth of infiltration at stage T2, (P < 0.05). Gender, age, tumor location, number of lymph node metastasis, distant metastasis, clinical stage, nerve invasion and vascular tumor thrombi were not the factors affecting HER2 amplification of gastric cancer (P > 0.05). MVD count of HER2-positive gastric cancer was significantly higher than that of HER2-negative gastric cancer, (P < 0.05). The 5-year overall survival rate of 1121 patients with gastric cancer was 51.92 %. HER2 amplification, high MVD count, large tumor size, tubular adenocarcinoma, Lauren intestinal type, deep tumor infiltration, numerous lymph node metastases and late clinical stage are all associated with low 5-year survival rate, indicating poor prognosis in gastric cancer patients, (P < 0.05). The 5-year survival rate of gastric cancer patients was not correlated with gender, age, tumor location, distant metastasis, nerve invasion and vascular cancer plug, (P > 0.05). Multivariate analysis showed that Lauren classification, Infiltrating depth, Nodal status, Clinical stage, HER2 expression, MVD count were independent factors affecting the prognosis of gastric cancer patients, (P < 0.05). CONCLUSION HER2 overexpression was not only closely related to gastric cancer neovascularization, but also an independent predictor of prognosis of gastric cancer. In clinical treatment, anti-HER2 targeted therapy and anti-angiogenesis drugs can be adopted to achieve effective treatment.
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Affiliation(s)
- Fang Li
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Guiqing Meng
- Department of Pathology Gastroscopy, Pingxiang General Hospital, Pingxiang, Xingtai, China
| | - Bibo Tan
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zihao Chen
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Qiang Ji
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaoxiao Wang
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chang Liu
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Shuyao Niu
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yong Li
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
| | - Yueping Liu
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
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Xu N, Meng H, Liu T, Feng Y, Qi Y, Zhang D, Wang H. Stent-Jailing Technique Reduces Aneurysm Recurrence More Than Stent-Jack Technique by Causing Less Mechanical Forces and Angiogenesis and Inhibiting TGF-β/Smad2,3,4 Signaling Pathway in Intracranial Aneurysm Patients. Front Physiol 2019; 9:1862. [PMID: 30670979 PMCID: PMC6331523 DOI: 10.3389/fphys.2018.01862] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 12/11/2018] [Indexed: 11/13/2022] Open
Abstract
Background: Stent-jailing and stent-jack are used for stent-assisted coil embolism (SCE) in intracranial aneurysm (IA) therapy, and cause different incidences of IA recurrence. Angiogenesis strongly correlates with aneurysm accumulation. Stent-jack causes higher mechanical forces in cerebral vessels than stent-jailing. Mechanical forces, as well as TGF-β/Smad2,3,4 signaling pathway, may play an important factor in IA recurrence by affecting angiogenesis. Methods: We explored the effects of stent-jailing or stent-jack technique on IA recurrence by investigating mechanical forces, TGF-β/Smad2,3,4 signaling pathway and the incidence of angiogenesis in IA patients. One-hundred-eighty-one IA patients were assigned into stent-jailing (n = 93) and stent-jacket groups (n = 88). The clinical outcome was evaluated using Glasgow Outcome Score (GOS) and aneurysm occlusion grades. The percentage of CD34+EPCs (releasing pro-angiogenic cytokines) in peripheral blood was measured by flow cytometer. Endothelial cells were separated from cerebral aneurysm and malformed arteries via immunomagnetic cell sorting. Angiogenesis was measured by microvessel density (MVD) using anti-CD34 monoclonal antibody staining before using the stent, immediately after surgery and 2 years later. Meanwhile, the mechanical forces in cerebral vessels were determined by measuring endothelial shear stress (ESS) via a computational method. TGF-β and Smad2,3,4 were measured by real-time qPCR and Western Blot. Tube formation analysis was performed to test the relationship between angiogenesis and TGF-β, and the effects of different techniques on angiogenesis. Results: After a 2-year follow-up, 85 and 81 patients from stent-jailing and stent-jack groups, respectively, completed the experiment. Stent-jailing technique improved GOS and reduced aneurysm occlusion grades higher than the stent-jack technique (P < 0.05). The counts of CD34+EPCs and MVD values in the stent-jailing group were lower than the stent-jack group (P < 0.05). ESS values in sent-jailing group were lower than the stent-jack group (P < 0.05), and positively correlated with MVD values (P < 0.05). TGF-β and Smad2,3,4 levels in sent-jailing group were also lower than the stent-jack group (P < 0.05). TGF-β was associated with angiogenesis incidence and stent-jack caused angiogenesis incidence more than stent-jailing. Conclusion: Stent-jailing technique reduces IA recurrence more than stent-jack by causing less mechanical forces, angiogenesis and inhibiting TGF-β/Smad2,3,4 signaling in IA patients.
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Affiliation(s)
- Ning Xu
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Hao Meng
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Tianyi Liu
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Yingli Feng
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Yuan Qi
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Donghuan Zhang
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Honglei Wang
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
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Zheng XW, Shan CS, Xu QQ, Wang Y, Shi YH, Wang Y, Zheng GQ. Buyang Huanwu Decoction Targets SIRT1/VEGF Pathway to Promote Angiogenesis After Cerebral Ischemia/Reperfusion Injury. Front Neurosci 2018; 12:911. [PMID: 30564092 PMCID: PMC6288378 DOI: 10.3389/fnins.2018.00911] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 11/20/2018] [Indexed: 12/11/2022] Open
Abstract
Background: Ischemia stroke is known as the major cause of morbidity and mortality. Buyang Huanwu Decoction (BHD), a classical traditional Chinese medicine (TCM) formula, has been used to prevent and treat stoke for hundreds of years. The purpose of present study is to investigate the effects of BHD on angiogenesis in rats after cerebral ischemia/reperfusion (I/R) injury targeting Silent information regulator 1 (SIRT1) / Vascular endothelial growth factor (VEGF) pathway. Methods: The cerebral I/R injury model was induced by middle cerebral artery occlusion (MCAO). Adult Sprag-Dawley (SD) rats were randomly divided into five groups: sham group, normal saline (NS) group, BHD group, BHD+EX527 (SIRT1 specific inhibitor) group, and NS+EX527 group. Each group was divided into the subgroups according to 1, 3, 7, or 14 days time-point after cerebral ischemia/reperfusion, respectively. Neurological function score (NFS) was evaluated by the Rogers scale; microvascular density (MVD) in brain tissue around infarction area was observed by immunofluorescence; and the expression of SIRT1 and VEGF was assessed by Western Blot and Quantitative Real-time-PCR. Results: BHD can significantly improve NFS (P < 0.05), increase the MVD in the boundary ischemic area (P < 0.01) and elevate the expression of protein and mRNA of SIRT1 and VEGF following I/R injury (P < 0.01). In contrast, treatment with EX527 reversed the BHD-induced improvements in NFS (P < 0.01) and decreased the MVD (P < 0.01) and the expression of SIRT1 and VEGF (P < 0.05). Conclusion: BHD exerts neuroprotection targeting angiogenesis through the up-regulation of SIRT1/VEGF pathway against cerebral ischemic injury in rats.
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Affiliation(s)
- Xia-Wei Zheng
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chun-Shuo Shan
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qing-Qing Xu
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yong Wang
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yi-Hua Shi
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yan Wang
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guo-Qing Zheng
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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