|
1
|
Uba AI. Computer-Aided Design of VEGFR-2 Inhibitors as Anticancer Agents: A Review. J Mol Recognit 2025; 38:e3104. [PMID: 39389566 DOI: 10.1002/jmr.3104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 08/01/2024] [Accepted: 09/03/2024] [Indexed: 10/12/2024]
Abstract
Due to its intricate molecular and structural characteristics, vascular endothelial growth factor receptor 2 (VEGFR-2) is essential for the development of new blood vessels in various pathological processes and conditions, especially in cancers. VEGFR-2 inhibitors have demonstrated significant anticancer effects by blocking many signaling pathways linked to tumor growth, metastasis, and angiogenesis. Several small compounds, including the well-tolerated sunitinib and sorafenib, have been approved as VEGFR-2 inhibitors. However, the widespread side effects linked to these VEGFR-2 inhibitors-hypertension, epistaxis, proteinuria, and upper respiratory infection-motivate researchers to search for new VEGFR-2 inhibitors with better pharmacokinetic profiles. The key molecular interactions required for the interaction of the small molecules with the protein target to produce the desired pharmacological effects are identified using computer-aided drug design (CADD) methods such as pharmacophore and QSAR modeling, structure-based virtual screening, molecular docking, molecular dynamics (MD) simulation coupled with MM/PB(GB)SA, and other computational strategies. This review discusses the applications of these methods for VEGFR-2 inhibitor design. Future VEGFR-2 inhibitor designs may be influenced by this review, which focuses on the current trends of using multiple screening layers to design better inhibitors.
Collapse
Affiliation(s)
- Abdullahi Ibrahim Uba
- Department of Molecular Biology and Genetics, Istanbul AREL University, Istanbul, Turkey
| |
Collapse
|
|
2
|
Syaj S, Saeed A. Profile of Fruquintinib in the Management of Advanced Refractory Metastatic Colorectal Cancer: Design, Development and Potential Place in Therapy. Drug Des Devel Ther 2024; 18:5203-5210. [PMID: 39568782 PMCID: PMC11577260 DOI: 10.2147/dddt.s388577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 11/09/2024] [Indexed: 11/22/2024] Open
Abstract
Colorectal cancer (CRC) is a prevalent and deadly cancer, with metastatic CRC (mCRC) often leading to poor outcomes despite advancements in screening and chemotherapy. Anti-angiogenic agents targeting vascular endothelial growth factor (VEGF) pathways have become essential in mCRC treatment. Bevacizumab, a VEGF inhibitor, was the first agent used in this context. However, drug resistance prompted the development of more selective inhibitors, such as fruquintinib, a tyrosine kinase inhibitor (TKI) that targets VEGFR-1, -2, and -3. Fruquintinib has shown promise in clinical trials, particularly for third-line mCRC treatment. The Phase III FRESCO trial in China demonstrated its efficacy, significantly improving overall survival (OS) and progression-free survival (PFS) compared to placebo, with manageable safety concerns like hypertension and hand-foot skin reactions. The FRESCO-2 trial extended these findings to European and North American populations, leading to a recent FDA approval for previously treated mCRC patients. The pharmacodynamic profile of fruquintinib includes potent inhibition of VEGFR, angiogenesis, and lymphangiogenesis. It has shown synergistic effects when combined with other treatments like chemotherapy and immune checkpoint inhibitors (ICIs). Current research focuses on exploring fruquintinib's combination with ICIs, such as PD-1 inhibitors, to enhance treatment efficacy, especially in microsatellite stable (MSS) CRC. Ongoing trials are investigating Fruquintinib's potential in combination with other therapies and its use in earlier lines of treatment. While promising, further studies are required to optimize its place in therapy and identify predictive biomarkers for better patient selection.
Collapse
Affiliation(s)
- Sebawe Syaj
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Anwaar Saeed
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| |
Collapse
|
|
3
|
Wang WG, Jiang XF, Zhang C, Zhan XP, Cheng JG, Tao LM, Xu WP, Li Z, Zhang Y. Avermectin induced vascular damage in zebrafish larvae: association with mitochondria-mediated apoptosis and VEGF/Notch signaling pathway. JOURNAL OF HAZARDOUS MATERIALS 2024; 477:135376. [PMID: 39111175 DOI: 10.1016/j.jhazmat.2024.135376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/21/2024] [Accepted: 07/28/2024] [Indexed: 08/17/2024]
Abstract
Avermectin is a highly effective insecticide that has been widely used in agriculture since the 1990s. In recent years, the safety of avermectin for non-target organisms has received much attention. The vasculature is important organs in the body and participate in the composition of other organs. However, studies on the vascular safety of avermectin are lacking. The vasculature of zebrafish larvae is characterized by ease of observation and it is a commonly used model for vascular studies. Therefore, zebrafish larvae were used to explore the potential risk of avermectin on the vasculature. The results showed that avermectin induced vascular damage throughout the body of zebrafish larvae, including the head, eyes, intestine, somite, tail and other vasculature. The main forms of damage are reduction in vascular diameter, vascular area and vascular abundance. Meanwhile, avermectin induced a decrease in the number of endothelial cells and apoptosis within the vasculature. In addition, vascular damage may be related to impairment of mitochondrial function and mitochondria-mediated apoptosis. Finally, exploration of the molecular mechanisms revealed abnormal alterations in the expression of genes related to the VEGF/Notch signaling pathway. Therefore, the VEGF/Notch signaling pathway may be an important mechanism for avermectin-induced vascular damage in zebrafish larvae. This study demonstrates the vascular toxicity of avermectin in zebrafish larvae and reveals the possible molecular mechanism, which would hopefully draw more attention to the safety of avermectin in non-target organisms.
Collapse
Affiliation(s)
- Wei-Guo Wang
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Xu-Feng Jiang
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Cheng Zhang
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, United States
| | - Xiu-Ping Zhan
- Shanghai Agricultural Technology Extension Center, Shanghai 201103, China
| | - Jia-Gao Cheng
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Li-Ming Tao
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Wen-Ping Xu
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Zhong Li
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Yang Zhang
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
| |
Collapse
|
|
4
|
Jiwaganont P, Roytrakul S, Thaisakun S, Sukumolanan P, Petchdee S. Investigation of coagulation and proteomics profiles in symptomatic feline hypertrophic cardiomyopathy and healthy control cats. BMC Vet Res 2024; 20:292. [PMID: 38970022 PMCID: PMC11225243 DOI: 10.1186/s12917-024-04170-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 07/01/2024] [Indexed: 07/07/2024] Open
Abstract
BACKGROUND Hypertrophic cardiomyopathy (HCM) is a crucial heart disease in cats. The clinical manifestations of HCM comprise pulmonary edema, dyspnea, syncope, arterial thromboembolism (ATE), and sudden cardiac death. D-dimer and prothrombin time (PT) are powerful biomarkers used to assess coagulation function. Dysregulation in these two biomarkers may be associated with HCM in cats. This study aims to assess D-dimer levels, PT, and proteomic profiling in healthy cats in comparison to cats with symptomatic HCM. RESULTS Twenty-nine client-owned cats with HCM were enrolled, including 15 healthy control and 14 symptomatic HCM cats. The D-dimer concentration and PT were examined. Proteomic analysis was conducted by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry and liquid chromatography-tandem mass spectrometry (LC-MS/MS). In symptomatic cats, D-dimer levels were statistically significantly higher (mean ± SEM: 372.19 ng/ml ± 58.28) than in healthy cats (mean ± SEM: 208.54 ng/ml ± 10.92) with P-value of less than 0.01, while PT was statistically significantly lower in symptomatic cats (mean ± SEM: 9.8 s ± 0.15) compared to healthy cats (mean ± SEM: 11.08 s ± 0.23) with P-value of less than 0.0001. The proteomics analysis revealed upregulation of integrin subunit alpha M (ITGAM), elongin B (ELOB), and fibrillin 2 (FBN2) and downregulation of zinc finger protein 316 (ZNF316) and ectonucleoside triphosphate diphosphohydrolase 8 (ENTPD8) in symptomatic HCM cats. In addition, protein-drug interaction analysis identified the Ras signaling pathway and PI3K-Akt signaling pathway. CONCLUSIONS Cats with symptomatic HCM have higher D-dimer and lower PT than healthy cats. Proteomic profiles may be used as potential biomarkers for the detection and management of HCM in cats. The use of D-dimer as a biomarker for HCM detection and the use of proteomic profiling for a better understanding of disease mechanisms remain to be further studied in cats.
Collapse
Affiliation(s)
- Palin Jiwaganont
- Graduate School, Veterinary Clinical Studies Program, Faculty of Veterinary Medicine, Kasetsart University, Kamphaeng Saen, Nakorn Pathom, Thailand
| | - Sittiruk Roytrakul
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Siriwan Thaisakun
- Functional Proteomics Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Pratch Sukumolanan
- Graduate School, Veterinary Clinical Studies Program, Faculty of Veterinary Medicine, Kasetsart University, Kamphaeng Saen, Nakorn Pathom, Thailand
| | - Soontaree Petchdee
- Department of Large Animal and Wildlife Clinical Sciences, Faculty of Veterinary Medicine, Kasetsart University, Kamphaeng Saen, Nakorn Pathom, Thailand.
| |
Collapse
|
|
5
|
Mohanty S, Suklabaidya S, Lavorgna A, Ueno T, Fujisawa JI, Ngouth N, Jacobson S, Harhaj EW. The tyrosine kinase KDR is essential for the survival of HTLV-1-infected T cells by stabilizing the Tax oncoprotein. Nat Commun 2024; 15:5380. [PMID: 38918393 PMCID: PMC11199648 DOI: 10.1038/s41467-024-49737-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 06/18/2024] [Indexed: 06/27/2024] Open
Abstract
Human T-cell leukemia virus type 1 (HTLV-1) infection is linked to the development of adult T-cell leukemia/lymphoma (ATLL) and the neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax oncoprotein regulates viral gene expression and persistently activates NF-κB to maintain the viability of HTLV-1-infected T cells. Here, we utilize a kinome-wide shRNA screen to identify the tyrosine kinase KDR as an essential survival factor of HTLV-1-transformed cells. Inhibition of KDR specifically induces apoptosis of Tax expressing HTLV-1-transformed cell lines and CD4 + T cells from HAM/TSP patients. Furthermore, inhibition of KDR triggers the autophagic degradation of Tax resulting in impaired NF-κB activation and diminished viral transmission in co-culture assays. Tax induces the expression of KDR, forms a complex with KDR, and is phosphorylated by KDR. These findings suggest that Tax stability is dependent on KDR activity which could be exploited as a strategy to target Tax in HTLV-1-associated diseases.
Collapse
Affiliation(s)
- Suchitra Mohanty
- Department of Microbiology and Immunology, Penn State College School of Medicine, Hershey, PA, USA
| | - Sujit Suklabaidya
- Department of Microbiology and Immunology, Penn State College School of Medicine, Hershey, PA, USA
| | - Alfonso Lavorgna
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Millipore-Sigma, Rockville, MD, USA
| | - Takaharu Ueno
- Department of Microbiology, Kansai Medical University, Osaka, Japan
| | | | - Nyater Ngouth
- Viral Immunology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Steven Jacobson
- Viral Immunology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Edward W Harhaj
- Department of Microbiology and Immunology, Penn State College School of Medicine, Hershey, PA, USA.
| |
Collapse
|
|
6
|
Yuki S, Yamazaki K, Sunakawa Y, Taniguchi H, Bando H, Shiozawa M, Nishina T, Yasui H, Kanazawa A, Ando K, Horita Y, Goto M, Okano N, Moriwaki T, Satoh T, Tsuji A, Yamashita K, Asano C, Abe Y, Nomura S, Yoshino T. Plasma Angiogenic Factors as Predictors of the Efficacy of Second-line Chemotherapy Combined with Angiogenesis Inhibitors in Metastatic Colorectal Cancer: Results From the GI-SCREEN CRC-Ukit Study. Clin Colorectal Cancer 2024; 23:147-159.e7. [PMID: 38331650 DOI: 10.1016/j.clcc.2024.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 01/12/2024] [Accepted: 01/13/2024] [Indexed: 02/10/2024]
Abstract
BACKGROUND The significance of angiogenic factors as predictors of second-line (2L) chemotherapy efficacy when combined with angiogenesis inhibitors for metastatic colorectal cancer (mCRC) remains unestablished. PATIENTS AND METHODS In this multicenter prospective observational study, 17 angiogenic factors were analyzed in plasma samples collected at pretreatment and progression stages using a Luminex multiplex assay. Patients who received chemotherapy plus bevacizumab (BEV group), FOLFIRI plus ramucirumab (RAM group), or FOLFIRI plus aflibercept (AFL group) as the 2L treatment were included. Interactions between pretreatment and treatment groups for progression-free survival (PFS), overall survival (OS), and response rate (RR) were assessed using the propensity-score weighted Cox proportional hazards model. RESULTS From February 2018 to September 2020, 283 patients were analyzed in the 2L cohort. A strong interaction was observed for PFS between BEV and RAM with HGF, sNeuropilin-1, sVEGFR-1, and sVEGFR-3. Interactions for RR between the BEV and RAM groups were observed for sNeuropilin-1 and sVEGFR-1. Contrarily, OS, PlGF, sVEGFR-1, and sVEGFR-3 differentiated the treatment effect between BEV and AFL. Plasma samples were evaluable for dynamic analysis in 203 patients. At progression, VEGF-A levels significantly decreased in the BEV group and increased in the RAM and AFL groups. CONCLUSION The pretreatment plasma sVEGFR-1 and sVEGFR-3 levels could be predictive biomarkers for distinguishing BEV and RAM when combined with chemotherapy in 2L mCRC treatment. Based on the VEGF-A dynamics at progression, selecting RAM or AFL for patients with significantly elevated VEGF-A levels may be a 2L treatment strategy, with BEV considered for the third-line treatment. CLINICAL TRIAL NUMBER UMIN000028616.
Collapse
Affiliation(s)
- Satoshi Yuki
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan.
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Yu Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Hiroya Taniguchi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Hideaki Bando
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Manabu Shiozawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Hisateru Yasui
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Akiyoshi Kanazawa
- Department of Surgery, Shimane Prefectural Central Hospital, Izumo, Japan
| | - Koji Ando
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yosuke Horita
- Department of Gastroenterological Oncology, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Masahiro Goto
- Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Takatsuki, Japan
| | - Naohiro Okano
- Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka, Japan
| | - Toshikazu Moriwaki
- Department of Gastroenterology, University of Tsukuba Hospital, Tsukuba, Japan
| | - Taroh Satoh
- Center for Cancer Genomics and Precision Medicine Osaka University Hospital, Osaka, Japan
| | - Akihito Tsuji
- Department of Clinical Oncology, Faculty of Medicine, Kagawa University, Takamatsu, Japan
| | - Kaname Yamashita
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Chiharu Asano
- Institute of Health Science Innovation for Medical Care, Hokkaido University Hospital, Sapporo, Japan
| | - Yukiko Abe
- Board member, G&G Science Co., Ltd., Fukushima, Japan
| | - Shogo Nomura
- Department of Biostatistics and Bioinformatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| |
Collapse
|
|
7
|
Sobczuk P, Cholewiński M, Rutkowski P. Recent advances in tyrosine kinase inhibitors VEGFR 1-3 for the treatment of advanced metastatic melanoma. Expert Opin Pharmacother 2024; 25:501-510. [PMID: 38607407 DOI: 10.1080/14656566.2024.2342403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 04/09/2024] [Indexed: 04/13/2024]
Abstract
INTRODUCTION Increasing evidence from preclinical and clinical studies suggests the role of vascular endothelial growth factor (VEGF) signaling in melanoma progression, response to therapy, and overall survival. Moreover, the discovery of the potential involvement of the VEGF pathway in resistance to immunotherapy has led to new clinical trials with VEGFR inhibitors. AREAS COVERED We have reviewed recent literature, mainly published within the last 5 years, on VEGFR-targeted treatments for advanced melanoma, including mucosal, acral, and uveal melanoma. The VEGFR inhibitors were used as a single therapy or combined with either immunotherapy or chemotherapy, and they were employed in treatment for KIT-mutated cutaneous melanoma and for patients with brain metastases. EXPERT OPINION Trials involving monotherapy have been unsuccessful in demonstrating meaningful efficacy. Despite some activity, the combination of VEGFR-targeting tyrosine kinase inhibitors (TKIs) with immune checkpoint inhibitors (ICI) in patients with ICI-resistant melanoma, the combination did not significantly improve outcomes compared to anti-PD-1 monotherapy in the first-line settings. On the contrary, some patients with mucosal, acral or KIT-mutant melanoma may benefit from TKI-based therapies. Further studies focused on biomarker discovery and randomized trials are necessary to better understand the role of VEGFR1-3 as a therapeutic target in melanoma.
Collapse
Affiliation(s)
- Paweł Sobczuk
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Skłodowska-Curie National Research institute of Oncology in Warsaw, Warsaw, Poland
| | - Michał Cholewiński
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Skłodowska-Curie National Research institute of Oncology in Warsaw, Warsaw, Poland
- Faculty of Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Rutkowski
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Skłodowska-Curie National Research institute of Oncology in Warsaw, Warsaw, Poland
| |
Collapse
|
|
8
|
Simkin J, Aloysius A, Adam M, Safaee F, Donahue RR, Biswas S, Lakhani Z, Gensel JC, Thybert D, Potter S, Seifert AW. Tissue-resident macrophages specifically express Lactotransferrin and Vegfc during ear pinna regeneration in spiny mice. Dev Cell 2024; 59:496-516.e6. [PMID: 38228141 PMCID: PMC10922778 DOI: 10.1016/j.devcel.2023.12.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 05/30/2023] [Accepted: 12/21/2023] [Indexed: 01/18/2024]
Abstract
The details of how macrophages control different healing trajectories (regeneration vs. scar formation) remain poorly defined. Spiny mice (Acomys spp.) can regenerate external ear pinnae tissue, whereas lab mice (Mus musculus) form scar tissue in response to an identical injury. Here, we used this dual species system to dissect macrophage phenotypes between healing modes. We identified secreted factors from activated Acomys macrophages that induce a pro-regenerative phenotype in fibroblasts from both species. Transcriptional profiling of Acomys macrophages and subsequent in vitro tests identified VEGFC, PDGFA, and Lactotransferrin (LTF) as potential pro-regenerative modulators. Examining macrophages in vivo, we found that Acomys-resident macrophages secreted VEGFC and LTF, whereas Mus macrophages do not. Lastly, we demonstrate the requirement for VEGFC during regeneration and find that interrupting lymphangiogenesis delays blastema and new tissue formation. Together, our results demonstrate that cell-autonomous mechanisms govern how macrophages react to the same stimuli to differentially produce factors that facilitate regeneration.
Collapse
Affiliation(s)
- Jennifer Simkin
- Department of Biology, University of Kentucky, Lexington, KY 40506, USA; Department of Orthopaedic Surgery, LSU Health-New Orleans, New Orleans, LA 70112, USA.
| | - Ajoy Aloysius
- Department of Biology, University of Kentucky, Lexington, KY 40506, USA
| | - Mike Adam
- Department of Pediatrics, University of Cincinnati Children's Hospital Medical Center, Division of Developmental Biology, Cincinnati, OH 45229, USA
| | - Fatemeh Safaee
- Department of Biology, University of Kentucky, Lexington, KY 40506, USA
| | - Renée R Donahue
- Department of Biology, University of Kentucky, Lexington, KY 40506, USA
| | - Shishir Biswas
- Department of Biology, University of Kentucky, Lexington, KY 40506, USA
| | - Zohaib Lakhani
- Department of Orthopaedic Surgery, LSU Health-New Orleans, New Orleans, LA 70112, USA
| | - John C Gensel
- Department of Physiology, University of Kentucky, Lexington, KY 40506, USA; Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40506, USA
| | - David Thybert
- European Bioinformatics Institute (EMBL-EBI), Cambridge, UK
| | - Steven Potter
- Department of Pediatrics, University of Cincinnati Children's Hospital Medical Center, Division of Developmental Biology, Cincinnati, OH 45229, USA
| | - Ashley W Seifert
- Department of Biology, University of Kentucky, Lexington, KY 40506, USA; Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40506, USA.
| |
Collapse
|
|
9
|
Cowan DB, Wu H, Chen H. Epsin Endocytic Adaptor Proteins in Angiogenic and Lymphangiogenic Signaling. Cold Spring Harb Perspect Med 2024; 14:a041165. [PMID: 37217282 PMCID: PMC10759987 DOI: 10.1101/cshperspect.a041165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Circulating vascular endothelial growth factor (VEGF) ligands and receptors are central regulators of vasculogenesis, angiogenesis, and lymphangiogenesis. In response to VEGF ligand binding, VEGF receptor tyrosine kinases initiate the chain of events that transduce extracellular signals into endothelial cell responses such as survival, proliferation, and migration. These events are controlled by intricate cellular processes that include the regulation of gene expression at multiple levels, interactions of numerous proteins, and intracellular trafficking of receptor-ligand complexes. Endocytic uptake and transport of macromolecular complexes through the endosome-lysosome system helps fine-tune endothelial cell responses to VEGF signals. Clathrin-dependent endocytosis remains the best understood means of macromolecular entry into cells, although the importance of non-clathrin-dependent pathways is increasingly recognized. Many of these endocytic events rely on adaptor proteins that coordinate internalization of activated cell-surface receptors. In the endothelium of both blood and lymphatic vessels, epsins 1 and 2 are functionally redundant adaptors involved in receptor endocytosis and intracellular sorting. These proteins are capable of binding both lipids and proteins and are important for promoting curvature of the plasma membrane as well as binding ubiquitinated cargo. Here, we discuss the role of epsin proteins and other endocytic adaptors in governing VEGF signaling in angiogenesis and lymphangiogenesis and discuss their therapeutic potential as molecular targets.
Collapse
Affiliation(s)
- Douglas B Cowan
- Vascular Biology Program, Boston Children's Hospital, and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Hao Wu
- Vascular Biology Program, Boston Children's Hospital, and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Hong Chen
- Vascular Biology Program, Boston Children's Hospital, and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA
| |
Collapse
|
|
10
|
Kazemi-Lomedasht F, Taghizadeh-Hesary F, Faal Z, Behdani M. Targeted Delivery of Diphtheria Toxin into VEGFR1/VEGFR2 Overexpressing Cells Induces Anti-angiogenesis Activity. Curr Protein Pept Sci 2024; 25:567-576. [PMID: 39044556 DOI: 10.2174/0113892037292385240222074908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 01/28/2024] [Accepted: 02/01/2024] [Indexed: 07/25/2024]
Abstract
BACKGROUND Vascular Endothelial Growth Factor Receptors (VEGFR1 and VEGFR2) are tyrosine kinase receptors expressed on endothelial cells and tumor vessels and play an important role in angiogenesis. In this study, three repeats of VEGFR1 and VEGFR2 binding peptide (VGB3) were genetically fused to the truncated diphtheria toxin (TDT), and its in vitro activity was evaluated. METHODS The recombinant construct (TDT-triVGB3) was expressed in bacteria cells and purified with nickel affinity chromatography. The binding capacity and affinity of TDT-triVGB3 were evaluated using the enzyme-linked immunosorbent assay. The inhibitory activity of TDT-triVGB3 on viability, migration, and tube formation of human endothelial cells was evaluated using MTT, migration, and tube formation assays. RESULTS TDT-triVGB3 selectively detected VEGFR1 and VEGFR2 with high affinity in an enzyme- linked immunosorbent assay and significantly inhibited viability, migration, and tube formation of human endothelial cells. CONCLUSION The developed TDT-triVGB3 is potentially a novel agent for targeting VEGFR1/ VEGFR2 over-expressing cancer cells.
Collapse
Affiliation(s)
- Fatemeh Kazemi-Lomedasht
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Farzad Taghizadeh-Hesary
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Clinical Oncology Department, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Faal
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Mahdi Behdani
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| |
Collapse
|
|
11
|
Hlophe YN, Joubert AM. Vascular endothelial growth
factor‐C
in activating vascular endothelial growth factor receptor‐3 and chemokine receptor‐4 in melanoma adhesion. J Cell Mol Med 2022; 26:5743-5754. [DOI: 10.1111/jcmm.17571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 08/27/2022] [Accepted: 09/12/2022] [Indexed: 11/19/2022] Open
Affiliation(s)
- Yvette N. Hlophe
- Department of Physiology University of Pretoria Pretoria South Africa
| | - Anna M. Joubert
- Department of Physiology University of Pretoria Pretoria South Africa
| |
Collapse
|
|
12
|
Yu L, Wang Y, He Y, Zhong H, Ge S, Zou Y, Lai Y, Xu Q, Gao J, Liu W, Guo W. Combination of apatinib with apo-IDO1 inhibitor for the treatment of colorectal cancer. Int Immunopharmacol 2022; 112:109233. [PMID: 36126409 DOI: 10.1016/j.intimp.2022.109233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/03/2022] [Accepted: 09/02/2022] [Indexed: 11/05/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world. Recently, many clinical studies have demonstrated the therapeutic potential of immune checkpoint therapy combined with inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) in colon cancer. Compound B37, identified in our previous experiment, is an apo-form indoleamine-2,3-dioxygenase 1 inhibitor (apo-IDO1 inhibitor), which has been shown to significantly suppress tumor growth combined with an anti-PD1 antibody. We speculated whether this apo-IDO inhibitor (B37) combined with a VEGFR2 inhibitor (apatinib) would further improve its anti-tumor activity. Therefore, a syngeneic mouse colon cancer model (mouse colon cancer cell line CT26) was established to investigate the anti-tumor activity of B37 combined with apatinib. As expected, the combination of B37 and apatinib (VEGFR2 inhibitor) improved the therapeutic effect compared with apo-IDO1 inhibitor and apatinib monotherapy, as shown by the reduced growth of transplanted tumors, weakened proliferation, and increased apoptosis of cancer cells. Specifically, there was a 24.8% reduction in tumor volume using apatinib and 31.3% reduction using B37. The combination-treated group showed remarkable inhibition of tumor growth (52.2%). For tumor weight, there was a 29.2% reduction in the apatinib-treated group and 35.0% reduction in the B37-treated group. The combination-treated group showed a 56.3% reduction. Moreover, the combination therapy reprogrammed the immune microenvironment by increasing infiltration of CD4+ and CD8+ T cells, decreasing the ratio of regulatory T cells, and promoting the killing ability of T cells manifested by elevated expression of IFN-γ and granzyme B in the combination-treated group. Our study indicates that the combination of apo-IDO1 inhibitor and apatinib is a promising strategy for CRC therapy.
Collapse
Affiliation(s)
- Longbo Yu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China
| | - Yuanyuan Wang
- The First People's Hospital of Lianyungang, Lianyungang, PR China
| | - Yingxue He
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China
| | - Haiqing Zhong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China
| | - Shushan Ge
- China State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China
| | - Yi Zou
- China State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China
| | - Yisheng Lai
- China State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China
| | - Qiang Xu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China
| | - Jian Gao
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China.
| | - Wen Liu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China; Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing 210093, PR China.
| | - Wenjie Guo
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China.
| |
Collapse
|
|
13
|
Fu YH, Hou YD, Duan YZ, Sun XY, Chen SQ. Gastroprotective effect of an active ingredients group of Lindera reflexa Hemsl. On Ethanol-Induced gastric ulcers in Rats: Involvement of VEGFR2/ERK and TLR-2/Myd88 signaling pathway. Int Immunopharmacol 2022; 107:108673. [PMID: 35259712 DOI: 10.1016/j.intimp.2022.108673] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 02/07/2022] [Accepted: 02/27/2022] [Indexed: 12/12/2022]
|
|
14
|
Nguyen T, Mueller S, Malbari F. Review: Neurological Complications From Therapies for Pediatric Brain Tumors. Front Oncol 2022; 12:853034. [PMID: 35480100 PMCID: PMC9035987 DOI: 10.3389/fonc.2022.853034] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/15/2022] [Indexed: 11/29/2022] Open
Abstract
Surgery, chemotherapy and radiation have been the mainstay of pediatric brain tumor treatment over the past decades. Recently, new treatment modalities have emerged for the management of pediatric brain tumors. These therapies range from novel radiotherapy techniques and targeted immunotherapies to checkpoint inhibitors and T cell transfer therapies. These treatments are currently investigated with the goal of improving survival and decreasing morbidity. However, compared to traditional therapies, these novel modalities are not as well elucidated and similarly has the potential to cause significant short and long-term sequelae, impacting quality of life. Treatment complications are commonly mediated through direct drug toxicity or vascular, infectious, or autoimmune mechanisms, ranging from immune effector cell associated neurotoxicity syndrome with CART-cells to neuropathy with checkpoint inhibitors. Addressing treatment-induced complications is the focus of new trials, specifically improving neurocognitive outcomes. The aim of this review is to explore the pathophysiology underlying treatment related neurologic side effects, highlight associated complications, and describe the future direction of brain tumor protocols. Increasing awareness of these neurologic complications from novel therapies underscores the need for quality-of-life metrics and considerations in clinical trials to decrease associated treatment-induced morbidity.
Collapse
Affiliation(s)
- Thien Nguyen
- Department of Pediatrics, University of San Francisco, San Francisco, CA, United States
- *Correspondence: Thien Nguyen,
| | - Sabine Mueller
- Department of Neurology, Neurosurgery and Pediatrics, University of San Francisco, San Francisco, CA, United States
| | - Fatema Malbari
- Division of Neurology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| |
Collapse
|
|
15
|
Soleimanizadeh M, Jalali Javaran M, Bagheri A, Behdani M. Apoplastic Production of Recombinant AntiVEGF Protein Using Plant-Virus Transient Expression Vector. Mol Biotechnol 2022; 64:1013-1021. [PMID: 35332419 DOI: 10.1007/s12033-022-00483-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 03/17/2022] [Indexed: 11/26/2022]
Abstract
Targeting of vascular endothelial growth factor (VEGF) using AntiVEGF can be a promising approach for angiogenesis inhibition and cancer therapy. In this study, we direct AntiVEGF recombinant protein accumulation to cucurbit plant apoplast using a suitable signal (Pr1b) sequence. After assembling the target gene construct and cloning into the expression vector, we infected the plants with the resulting pZYMV-AntiVEGF viral vector. Transcription of the target gene was confirmed with RT-PCR assays. The apoplast-targeted AntiVEGF recombinant protein was detected in infected plants by Dot-blot, western blot, and ELISA analysis. AntiVEGF protein accumulation in the apoplast resulted in levels of 1.2% of TSP (Total Soluble Protein) that demonstrated a two-order increase compared to the cytoplasm-targeted protein. After purification of AntiVEGF protein using aqueous two-phase system (ATPS), purified protein was analyzed with MTT assay. Our results reveal that production of biologically active and correctly processed apoplast-targeted AntiVEGF recombinant protein is possible in plant apoplast. The low level of cytoplasm-targeted AntiVEGF recombinant protein might result from the degradation of improperly folded protein.
Collapse
Affiliation(s)
- Mojgan Soleimanizadeh
- Department of Horticultural Science, Faculty of Agriculture and Natural Resources, University of Hormozgan, Bandar Abbas, Iran.
| | | | - Abdolreza Bagheri
- Department of Biotechnology and Plant Breeding, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Mahdi Behdani
- Venom & Biotherapeutics Molecules Lab, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| |
Collapse
|
|
16
|
Maliszewski D, Drozdowska D. Recent Advances in the Biological Activity of s-Triazine Core Compounds. Pharmaceuticals (Basel) 2022; 15:221. [PMID: 35215333 PMCID: PMC8875733 DOI: 10.3390/ph15020221] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/05/2022] [Accepted: 02/10/2022] [Indexed: 12/18/2022] Open
Abstract
An effective strategy for successful chemotherapy relies on creating compounds with high selectivity against cancer cells compared to normal cells and relatively low cytotoxicity. One such approach is the discovery of critical points in cancer cells, i.e., where specific enzymes that are potential therapeutic targets are generated. Triazine is a six-membered heterocyclic ring compound with three nitrogen replacing carbon-hydrogen units in the benzene ring structure. The subject of this review is the symmetrical 1,3,5-triazine, known as s-triazine. 1,3,5-triazine is one of the oldest heterocyclic compounds available. Because of its low cost and high availability, it has attracted researcher attention for novel synthesis. s-Triazine has a weak base, it has much weaker resonance energy than benzene, therefore, nucleophilic substitution is preferred to electrophilic substitution. Heterocyclic bearing a symmetrical s-triazine core represents an interesting class of compounds possessing a wide spectrum of biological properties such as anti-cancer, antiviral, fungicidal, insecticidal, bactericidal, herbicidal and antimicrobial, antimalarial agents. They also have applications as dyes, lubricants, and analytical reagents. Hence, the group of 1,3,5-triazine derivatives has developed over the years. Triazine is not only the core amongst them, but is also a factor increasing the kinetic potential of the entire derivatives. Modifying the structure and introducing new substituents makes it possible to obtain compounds with broad inhibitory activity on processes such as proliferation. In some cases, s-triazine derivatives induce cell apoptosis. In this review we will present currently investigated 1,3,5-triazine derivatives with anti-cancer activities, with particular emphasis on their inhibition of enzymes involved in the process of tumorigenesis.
Collapse
Affiliation(s)
- Dawid Maliszewski
- Department of Organic Chemistry, Medical University of Bialystok, 15-222 Białystok, Poland
| | - Danuta Drozdowska
- Department of Organic Chemistry, Medical University of Bialystok, 15-222 Białystok, Poland
| |
Collapse
|
|
17
|
Plasma Levels and Diagnostic Utility of VEGF in a Three-Year Follow-Up of Patients with Breast Cancer. J Clin Med 2021; 10:jcm10225452. [PMID: 34830735 PMCID: PMC8624052 DOI: 10.3390/jcm10225452] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/19/2021] [Accepted: 11/17/2021] [Indexed: 12/28/2022] Open
Abstract
Breast cancer is the most common malignancy in women globally. The increasing worldwide incidence of this type of cancer illustrates the challenge it represents for healthcare providers. Therefore, new tumor markers are constantly being sought. The aim of this study was to assess plasma concentrations and the diagnostic power of VEGF in 100 patients with early-stage breast cancer, both before and after surgical treatment and during a three-year follow-up. The control groups included 50 subjects with benign breast tumors (fibroadenoma) and 50 healthy women. The VEGF concentration was determined using enzyme-linked immunosorbent assay (ELISA) and the CA 15-3 concentration was determined by chemiluminescent microparticle immunoassay (CMIA). We observed significantly higher preoperative plasma concentrations of VEGF and CA 15-3 in patients with breast cancer. VEGF, similar to CA 15-3, demonstrated high diagnostic utility in the assessment of the long-term efficacy of surgical removal of the tumor. Determinations of VEGF had the highest diagnostic usefulness in the detection of breast cancer recurrence (SE 40%, SP 92%, PPV 67%, NPV 79%). Additionally, the highest values of SE, NPV and AUC were observed during the combined analysis with CA 15-3 (60%; 84%; 0.7074, respectively). Our study suggests a promising diagnostic utility of VEGF in the early stages of breast cancer and in the evaluation of the efficacy of the surgical treatment of breast cancer as well as the detection of breast cancer recurrence, particularly in a combined analysis with CA 15-3 as a new diagnostic panel.
Collapse
|
|
18
|
Ma L, Li W, Zhang Y, Qi L, Zhao Q, Li N, Lu Y, Zhang L, Zhou F, Wu Y, He Y, Yu H, He Y, Wei B, Wang H. FLT4/VEGFR3 activates AMPK to coordinate glycometabolic reprogramming with autophagy and inflammasome activation for bacterial elimination. Autophagy 2021; 18:1385-1400. [PMID: 34632918 DOI: 10.1080/15548627.2021.1985338] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Macrophages rapidly undergo glycolytic reprogramming in response to macroautophagy/autophagy, inflammasome activation and pyroptosis for the clearance of bacteria. Identification the key molecules involved in these three events will provide critical potential therapeutic applications. Upon S. typhimurium infection, FLT4/VEGFR3 and its ligand VEGFC were inducibly expressed in macrophages, and FLT4 signaling inhibited CASP1 (caspase 1)-dependent inflammasome activation and pyroptosis but enhanced MAP1LC3/LC3 activation for elimination of the bacteria. Consistently, FLT4 mutants lacking the extracellular ligand-binding domain increased production of the proinflammatory metabolites such as succinate and lactate, and reduced antimicrobial metabolites including citrate and NAD(P)H in macrophages and liver upon infection. Mechanistically, FLT4 recruited AMP-activated protein kinase (AMPK) and phosphorylated Y247 and Y441/442 in the PRKAA/alpha subunit for AMPK activation. The AMPK agonist AICAR could rescue glycolytic reprogramming and inflammasome activation in macrophages expressing the mutant FLT4, which has potential translational application in patients carrying Flt4 mutations to prevent recurrent infections. Collectively, we have elucidated that the FLT4-AMPK module in macrophages coordinates glycolytic reprogramming, autophagy, inflammasome activation and pyroptosis to eliminate invading bacteria.
Collapse
Affiliation(s)
- Li Ma
- State Key Laboratory of Cell Biology, Cas Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Weiyun Li
- State Key Laboratory of Cell Biology, Cas Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.,School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China
| | - Yanbo Zhang
- State Key Laboratory of Cell Biology, Cas Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.,Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Linlin Qi
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Qi Zhao
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Na Li
- State Key Laboratory of Cell Biology, Cas Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Yao Lu
- State Key Laboratory of Cell Biology, Cas Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Luqing Zhang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Cam-Su Genomic Resources Center, Soochow University, Suzhou, China
| | - Fei Zhou
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Cam-Su Genomic Resources Center, Soochow University, Suzhou, China
| | - Yichun Wu
- State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Shanghai Key Laboratory of Molecular Andrology, Cas Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Yongning He
- State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Shanghai Key Laboratory of Molecular Andrology, Cas Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Hongxiu Yu
- Institutes of Biomedical Science, Fudan University, Shanghai, China
| | - Yulong He
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Cam-Su Genomic Resources Center, Soochow University, Suzhou, China
| | - Bin Wei
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.,School of Life Sciences, Shanghai University, Shanghai, China.,School of Medicine, Cancer Center, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Hongyan Wang
- State Key Laboratory of Cell Biology, Cas Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.,School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.,Bio-Research Innovation Center Suzhou, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Suzhou, Jiangsu, China
| |
Collapse
|
|
19
|
Molecular Mechanisms of Neuroimmune Crosstalk in the Pathogenesis of Stroke. Int J Mol Sci 2021; 22:ijms22179486. [PMID: 34502395 PMCID: PMC8431165 DOI: 10.3390/ijms22179486] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/26/2021] [Accepted: 08/28/2021] [Indexed: 12/21/2022] Open
Abstract
Stroke disrupts the homeostatic balance within the brain and is associated with a significant accumulation of necrotic cellular debris, fluid, and peripheral immune cells in the central nervous system (CNS). Additionally, cells, antigens, and other factors exit the brain into the periphery via damaged blood–brain barrier cells, glymphatic transport mechanisms, and lymphatic vessels, which dramatically influence the systemic immune response and lead to complex neuroimmune communication. As a result, the immunological response after stroke is a highly dynamic event that involves communication between multiple organ systems and cell types, with significant consequences on not only the initial stroke tissue injury but long-term recovery in the CNS. In this review, we discuss the complex immunological and physiological interactions that occur after stroke with a focus on how the peripheral immune system and CNS communicate to regulate post-stroke brain homeostasis. First, we discuss the post-stroke immune cascade across different contexts as well as homeostatic regulation within the brain. Then, we focus on the lymphatic vessels surrounding the brain and their ability to coordinate both immune response and fluid homeostasis within the brain after stroke. Finally, we discuss how therapeutic manipulation of peripheral systems may provide new mechanisms to treat stroke injury.
Collapse
|
|
20
|
Serdaroğlu G, Şahin N, Üstün E, Tahir MN, Arıcı C, Gürbüz N, Özdemir İ. PEPPSI type complexes: Synthesis, x-ray structures, spectral studies, molecular docking and theoretical investigations. Polyhedron 2021. [DOI: 10.1016/j.poly.2021.115281] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
|
|
21
|
Zhang S, Li X, Liu W, Zhang X, Huang L, Li S, Yang M, Zhao P, Yang J, Fei P, Zhu X, Yang Z. Whole-Exome Sequencing Identified DLG1 as a Candidate Gene for Familial Exudative Vitreoretinopathy. Genet Test Mol Biomarkers 2021; 25:309-316. [PMID: 33945310 DOI: 10.1089/gtmb.2021.0013] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Purpose: Familial exudative vitreoretinopathy (FEVR) is a blinding retinal vascular disease. Clinically, FEVR is characterized by incomplete vascularization of the peripheral retina and pathological neovascularization. Only about 50% of FEVR cases can be explained by known FEVR disease gene variations. This study aimed to identify novel genes associated with the FEVR phenotype and explore their pathogenic mechanisms. Materials and Methods: Exome sequencing analyses were conducted on one Chinese family with FEVR whose affected members did not exhibit pathogenic variants in the known FEVR genes (verified using Sanger sequencing analysis). Functions of the affected proteins were evaluated using reporter assays. Western blot analysis was used to detect mutant protein expression and the genes' pathogenic mechanisms. Results: A rare novel heterozygous variant in DLG1 (c.1792A>G; p.S598G) was identified. The amino acid residues surrounding the identified variant are highly conserved among vertebrates. A luciferase reporter assay revealed that the mutant DLG1 protein DLG1-S598G lost its ability to activate Wnt signaling. Moreover, a knockdown (KD) of DLG1 in human primary retinal endothelial cells impaired tube formation. Mechanistically, DLG1 KD led to a reduction in phosphorylated VEGFR2, an essential receptor for the angiogenic potency that signals the vascular endothelial growth factor molecule. Conclusions: The data reported here demonstrate that DLG1 is a novel candidate gene for FEVR.
Collapse
Affiliation(s)
- Shanshan Zhang
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Xiao Li
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Wenjing Liu
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Xiang Zhang
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lulin Huang
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Shujin Li
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.,Chengdu Institute of Biology, Sichuan Translational Medicine Research Hospital, Chinese Academy of Sciences, Chengdu, China
| | - Mu Yang
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.,Chengdu Institute of Biology, Sichuan Translational Medicine Research Hospital, Chinese Academy of Sciences, Chengdu, China
| | - Peiquan Zhao
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiyun Yang
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Ping Fei
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xianjun Zhu
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.,Chengdu Institute of Biology, Sichuan Translational Medicine Research Hospital, Chinese Academy of Sciences, Chengdu, China
| | - Zhenglin Yang
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.,Chengdu Institute of Biology, Sichuan Translational Medicine Research Hospital, Chinese Academy of Sciences, Chengdu, China
| |
Collapse
|
|
22
|
Wei R, Wu Q, Ai N, Wang L, Zhou M, Shaw C, Chen T, Ye RD, Ge W, Siu SW, Kwok HF. A novel bioengineered fragment peptide of Vasostatin-1 exerts smooth muscle pharmacological activities and anti-angiogenic effects via blocking VEGFR signalling pathway. Comput Struct Biotechnol J 2021; 19:2664-2675. [PMID: 34093983 PMCID: PMC8131715 DOI: 10.1016/j.csbj.2021.05.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/30/2021] [Accepted: 05/01/2021] [Indexed: 12/14/2022] Open
Abstract
Chromogranin A (CgA) is a hydrophilic glycoprotein released by post-ganglionic sympathetic neurons. CgA consists of a single peptide chain containing numerous paired basic residues, which are typical cleavage sites in prohormones to generate bioactive peptides. It is recognized as a diagnostic and prognostic serum marker for neuroendocrine tumours. Vasostatin-1 is one of the most conserved regions of CgA and has diverse inhibitory biological activities. In this study, a novel peptide fragment that contains three typical functional structures of Vasostatin-1 was synthesized. This unique bioengineered Vasostatin-1 Derived Peptide (named V1DP) includes a highly conserved domain between vertebrate species in its N-terminal region, comprising a disulphide bridge formed by two cysteine residues at amino acid positions 17 and 38, respectively. Besides, V1DP contains two significant tripeptide recognition sequences: the amino acid triplets, RGD and KGD. Our data demonstrated that V1DP could induce a dose-dependent relaxation of rat arterial smooth muscle and also increase the contraction activity of rat uterus smooth muscle. More importantly, we found that V1DP inhibits cancer cell proliferation, modulate the HUVEC cell migration, and exhibit anti-angiogenesis effect both in vitro and in vivo. We further investigated the actual mechanism of V1DP, and our results confirmed that V1DP involves inhibiting the vascular endothelial growth factor receptor (VEGFR) signalling. We docked V1DP to the apo structures of VEGFR2 and examined the stability of the peptide in the protein pockets. Our simulation and free energy calculations results indicated that V1DP can bind to the catalytic domain and regulatory domain pockets, depending on whether the conformational state of the protein is JM-in or JM-out. Taken together, our data suggested that V1DP plays a role as the regulator of endothelial cell function and smooth muscle pharmacological homeostasis. V1DP is a water-soluble and biologically stable peptide and could further develop as an anti-angiogenic drug for cancer treatment.
Collapse
Affiliation(s)
- Ran Wei
- CCZU-JITRI Joint Bio-X Lab, School of Pharmacy & School of Medicine, Changzhou University, Changzhou, China; Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR
- Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, China
| | - Qiushuang Wu
- Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, China
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR; MoE Frontiers Science Center for Precision Oncology, University of Macau, Avenida de Universidade, Taipa, Macau SAR, China
| | - Nana Ai
- Centre of Reproduction, Development and Aging (CRDA), Faculty of Health Sciences, Avenida de Universidade, University of Macau, Macau SAR, China
| | - Lei Wang
- Natural Drug Discovery Group, School of Pharmacy, Queen’s University Belfast, Northern Ireland, United Kingdom
| | - Mei Zhou
- Natural Drug Discovery Group, School of Pharmacy, Queen’s University Belfast, Northern Ireland, United Kingdom
| | - Chris Shaw
- Natural Drug Discovery Group, School of Pharmacy, Queen’s University Belfast, Northern Ireland, United Kingdom
| | - Tianbao Chen
- Natural Drug Discovery Group, School of Pharmacy, Queen’s University Belfast, Northern Ireland, United Kingdom
| | - Richard Dequan Ye
- School of Life and Health Sciences, The Chinese University of Hong Kong (Shenzhen), Shenzhen, China
| | - Wei Ge
- Centre of Reproduction, Development and Aging (CRDA), Faculty of Health Sciences, Avenida de Universidade, University of Macau, Macau SAR, China
| | - Shirley W.I. Siu
- Department of Computer and Information Science, Faculty of Science and Technology University of Macau, Avenida de Universidade, Taipa, Macau SAR, China
| | - Hang Fai Kwok
- Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, China
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR; MoE Frontiers Science Center for Precision Oncology, University of Macau, Avenida de Universidade, Taipa, Macau SAR, China
- Corresponding author at: Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, China.
| |
Collapse
|
|
23
|
Cheng QN, Yang X, Wu JF, Ai WB, Ni YR. Interaction of non‑parenchymal hepatocytes in the process of hepatic fibrosis (Review). Mol Med Rep 2021; 23:364. [PMID: 33760176 PMCID: PMC7986015 DOI: 10.3892/mmr.2021.12003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 03/02/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatic fibrosis (HF) is the process of fibrous scar formation caused by chronic liver injury of different etiologies. Previous studies have hypothesized that the activation of hepatic stellate cells (HSCs) is the central process in HF. The interaction between HSCs and surrounding cells is also crucial. Additionally, hepatic sinusoids capillarization, inflammation, angiogenesis and fibrosis develop during HF. The process involves multiple cell types that are highly connected and work in unison to maintain the homeostasis of the hepatic microenvironment, which serves a key role in the initiation and progression of HF. The current review provides novel insight into the intercellular interaction among liver sinusoidal endothelial cells, HSCs and Kupffer cells, as well as the hepatic microenvironment in the development of HF.
Collapse
Affiliation(s)
- Qi-Ni Cheng
- Medical College, China Three Gorges University, Yichang, Hubei 443002, P.R. China
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, Yichang, Hubei 443002, P.R. China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, Hubei 443002, P.R. China
| | - Xue Yang
- Medical College, China Three Gorges University, Yichang, Hubei 443002, P.R. China
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, Yichang, Hubei 443002, P.R. China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, Hubei 443002, P.R. China
| | - Jiang-Feng Wu
- Medical College, China Three Gorges University, Yichang, Hubei 443002, P.R. China
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, Yichang, Hubei 443002, P.R. China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, Hubei 443002, P.R. China
- The People's Hospital of China Three Gorges University, Yichang, Hubei 443000, P.R. China
| | - Wen-Bing Ai
- The Yiling Hospital of Yichang, Yichang, Hubei 443100, P.R. China
| | - Yi-Ran Ni
- Medical College, China Three Gorges University, Yichang, Hubei 443002, P.R. China
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, Yichang, Hubei 443002, P.R. China
| |
Collapse
|
|
24
|
Li F, Xu J, Liu S. Cancer Stem Cells and Neovascularization. Cells 2021; 10:cells10051070. [PMID: 33946480 PMCID: PMC8147173 DOI: 10.3390/cells10051070] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/19/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) refer to a subpopulation of cancer cells responsible for tumorigenesis, metastasis, and drug resistance. Increasing evidence suggests that CSC-associated tumor neovascularization partially contributes to the failure of cancer treatment. In this review, we discuss the roles of CSCs on tumor-associated angiogenesis via trans-differentiation or forming the capillary-like vasculogenic mimicry, as well as the roles of CSCs on facilitating endothelial cell-involved angiogenesis to support tumor progression and metastasis. Furthermore, we discuss the underlying regulation mechanisms, including the intrinsic signals of CSCs and the extrinsic signals such as cytokines from the tumor microenvironment. Further research is required to identify and verify some novel targets to develop efficient therapeutic approaches for more efficient cancer treatment through interfering CSC-mediated neovascularization.
Collapse
Affiliation(s)
- Fengkai Li
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Fudan University, Shanghai 200032, China; (F.L.); (J.X.)
- Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, Fudan University, Shanghai 200032, China
- The International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Jiahui Xu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Fudan University, Shanghai 200032, China; (F.L.); (J.X.)
- Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, Fudan University, Shanghai 200032, China
- The International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Fudan University, Shanghai 200032, China; (F.L.); (J.X.)
- Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, Fudan University, Shanghai 200032, China
- The International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Correspondence: ; Tel.: +86-21-34771023
| |
Collapse
|
|
25
|
Banerjee A, Mukherjee S, Maji BK. Efficacy of Coccinia grandis against monosodium glutamate induced hepato-cardiac anomalies by inhibiting NF-kB and caspase 3 mediated signalling in rat model. Hum Exp Toxicol 2021; 40:1825-1851. [PMID: 33887972 DOI: 10.1177/09603271211010895] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Since prehistoric times Coccinia grandis has been used as traditional medicine for various diseases including diabetes, dyslipidemia, metabolic and digestive disorders. Although the rationality of efficacy as natural antioxidants with different bioactive compounds in Coccinia grandis against monosodium glutamate (MSG) induced hepato-cardiac damage remains to be disclosed. Six different solvent extracts of the leaves of Coccinia grandis were chosen to evaluate in vitro antioxidant and free radical (FR)-scavenging activity. Due to high antioxidant content and FR-scavenging property of ethanol extract of Coccinia grandis leaves (EECGL) and presence of different bioactive compounds in EECGL was further tested to evaluate in vivo hepato-protective and cardio-protective efficacy against MSG-induced anomalies. MSG-induced dyslipidemia, increased cell toxicity markers altered functional status and histopathological peculiarities of target organs were blunted by EECGL. Additionally, MSG incited increase level of interleukin (IL)-6, tumour necrosis factor (TNF)-α, IL-1β which activates nuclear factor kappa-B (NF-kB) guided inflammation via down regulation of IL-10; impaired redox-homeostasis subsequently promoted inflammation associated oxidative stress (OS) and increased vascular endothelial growth factor (VEGF) which provoked microvascular proliferation related cellular damage. On the contrary, increased lipid peroxidation and nitric oxide promotes reduced cell viability, deoxyribonucleic acid damage and apoptosis via activation of caspase 3. EECGL significantly reduced MSG-induced inflammation mediated OS and apoptosis via inhibition of pro-inflammatory factors and pro-apoptotic mediators to protect liver and heart. Therefore, it can be suggested that EECGL contributed competent scientific information to validate the demands for its use to treat MSG-induced hepato-cardiac OS mediated inflammation and apoptosis from natural origin.
Collapse
Affiliation(s)
- Arnab Banerjee
- Department of Physiology (UG & PG), 212035Serampore College, Hooghly, West Bengal, India
| | - Sandip Mukherjee
- Department of Physiology (UG & PG), 212035Serampore College, Hooghly, West Bengal, India
| | - Bithin Kumar Maji
- Department of Physiology (UG & PG), 212035Serampore College, Hooghly, West Bengal, India
| |
Collapse
|
|
26
|
A supramolecular complex of hydrazide-pillar[5]arene and bisdemethoxycurcumin with potential anti-cancer activity. Bioorg Chem 2021; 110:104764. [PMID: 33657507 DOI: 10.1016/j.bioorg.2021.104764] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 01/21/2021] [Accepted: 02/20/2021] [Indexed: 10/22/2022]
Abstract
Pillar[5]arene complexes of the naturally occurring compound bisdemethoxycurcumin (BDMC) were acquired for improving the water solubility and stability of BDMC. As a family member of curcuminoid compounds, BDMC has many interesting therapeutic properties. However, its low aqueous solubility and stability resulted in poor availability and restricted the clinical efficacy. Pillar[5]arenes with hydrophilic ends and a hydrophobic cavity could include with BDMC based on size matching. The synthesized hydrazide-pillar[5]arene (HP5A) and BDMC had a strong host-guest interaction with a 1:1 binding stoichiometry. Furthermore, the HP5A ⊃ BDMC complex could self-assemble into well-defined fibers in water/ethanol solution. This supramolecular complex worked well in vitro for inhibiting the proliferation of hepatoma carcinoma cells HepG2. Remarkably, this method of complexation with pillar[5]arenes visibly reduced the undesirable side effects on normal cells without weakening the anti-cancer activity of the drugs. We expected that the obtained host-guest complex and fibrous assembly would provide a promising platform for delivering drugs with low water solubility.
Collapse
|
|
27
|
Bui K, Hong YK. Ras Pathways on Prox1 and Lymphangiogenesis: Insights for Therapeutics. Front Cardiovasc Med 2020; 7:597374. [PMID: 33263009 PMCID: PMC7688453 DOI: 10.3389/fcvm.2020.597374] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 10/12/2020] [Indexed: 12/12/2022] Open
Abstract
Over the past couple of decades, lymphatics research has accelerated and gained a much-needed recognition in pathophysiology. As the lymphatic system plays heavy roles in interstitial fluid drainage, immune surveillance and lipid absorption, the ablation or excessive growth of this vasculature could be associated with many complications, from lymphedema to metastasis. Despite their growing importance in cancer, few anti-lymphangiogenic therapies exist today, as they have yet to pass phase 3 clinical trials and acquire FDA approval. As such, many studies are being done to better define the signaling pathways that govern lymphangiogenesis, in hopes of developing new therapeutic approaches to inhibit or stimulate this process. This review will cover our current understanding of the Ras signaling pathways and their interactions with Prox1, the master transcriptional switch involved in specifying lymphatic endothelial cell fate and lymphangiogenesis, in hopes of providing insights to lymphangiogenesis-based therapies.
Collapse
Affiliation(s)
| | - Young-Kwon Hong
- Department of Surgery, Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| |
Collapse
|
|
28
|
Jozaghi Y, Zafereo M, Williams MD, Gule-Monroe MK, Wang J, Grubbs EG, Vaporciyan A, Hu MI, Busaidy N, Dadu R, Waguespack SG, Subbiah V, Cabanillas M. Neoadjuvant selpercatinib for advanced medullary thyroid cancer. Head Neck 2020; 43:E7-E12. [PMID: 33169506 PMCID: PMC7756223 DOI: 10.1002/hed.26527] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/22/2020] [Accepted: 10/22/2020] [Indexed: 01/21/2023] Open
Abstract
Background Targeted kinase inhibitors have been increasingly utilized in the treatment of advanced medullary thyroid cancer (MTC) over the last decade. Recently, highly potent next generation selective RET inhibitors have been clinically validated, and selpercatinib was recently Food and Drug Administration (FDA)‐approved for advanced MTC. The advent of highly selective, potent RET inhibitors is broadening the treatment options for patients with RET‐mutated cancers. Methods We report the first published case of neoadjuvant selpercatinib followed by surgery for a patient with initially unresectable, widely metastatic, RET‐mutated MTC who was treated on a single patient protocol. Results After greater than 50% RECIST response, the patient underwent complete surgical resection followed by selpercatinib resumption. He remains locoregionally disease‐free 21 months after starting therapy with stable metastatic disease (after initial partial response); and calcitonin/CEA continue to decline. Conclusion This novel treatment strategy for locoregionally advanced RET‐mutated MTC warrants further study in clinical trials.
Collapse
Affiliation(s)
- Yelda Jozaghi
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| | - Mark Zafereo
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| | - Michelle D Williams
- Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| | - Maria K Gule-Monroe
- Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| | - Jennifer Wang
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| | - Elizabeth G Grubbs
- Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| | - Ara Vaporciyan
- Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| | - Mimi I Hu
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| | - Naifa Busaidy
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| | - Ramona Dadu
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| | - Steven G Waguespack
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| | - Vivek Subbiah
- Department of Investigational Cancer Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| | - Maria Cabanillas
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| |
Collapse
|
|
29
|
Wang X, Che X, Yu Y, Cheng Y, Bai M, Yang Z, Guo Q, Xie X, Li D, Guo M, Hou K, Guo W, Qu X, Cao L. Hypoxia-autophagy axis induces VEGFA by peritoneal mesothelial cells to promote gastric cancer peritoneal metastasis through an integrin α5-fibronectin pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:221. [PMID: 33081836 PMCID: PMC7576728 DOI: 10.1186/s13046-020-01703-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 09/07/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Peritoneal metastasis (PM) is an important pathological process in the progression of gastric cancer (GC). The metastatic potential of tumor and stromal cells is governed by hypoxia, which is a key molecular feature of the tumor microenvironment. Mesothelial cells also participate in this complex and dynamic process. However, the molecular mechanisms underlying the hypoxia-driven mesothelial-tumor interactions that promote peritoneal metastasis of GC remain unclear. METHODS We determined the hypoxic microenvironment in PM of nude mice by immunohistochemical analysis and screened VEGFA by human growth factor array kit. The crosstalk mediated by VEGFA between peritoneal mesothelial cells (PMCs) and GC cells was determined in GC cells incubated with conditioned medium prepared from hypoxia-treated PMCs. The association between VEGFR1 and integrin α5 and fibronectin in GC cells was enriched using Gene Set Enrichment Analysis and KEGG pathway enrichment analysis. In vitro and xenograft mouse models were used to evaluate the impact of VEGFA/VEGFR1 on gastric cancer peritoneal metastasis. Confocal microscopy and immunoprecipitation were performed to determine the effect of hypoxia-induced autophagy. RESULTS Here we report that in the PMCs of the hypoxic microenvironment, SIRT1 is degraded via the autophagic lysosomal pathway, leading to increased acetylation of HIF-1α and secretion of VEGFA. Under hypoxic conditions, VEGFA derived from PMCs acts on VEGFR1 of GC cells, resulting in p-ERK/p-JNK pathway activation, increased integrin α5 and fibronectin expression, and promotion of PM. CONCLUSIONS Our findings have elucidated the mechanisms by which PMCs promote PM in GC in hypoxic environments. This study also provides a theoretical basis for considering autophagic pathways or VEGFA as potential therapeutic targets to treat PM in GC.
Collapse
Affiliation(s)
- Xiaoxun Wang
- Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, 110001, Liaoning, China
| | - Xiaofang Che
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Yang Yu
- Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, 110001, Liaoning, China
| | - Yu Cheng
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Ming Bai
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Zichang Yang
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Qiqiang Guo
- Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, 110001, Liaoning, China
| | - Xiaochen Xie
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, 110001, China
| | - Danni Li
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Min Guo
- Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, 110001, Liaoning, China
| | - Kezuo Hou
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Wendong Guo
- Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, 110001, Liaoning, China
| | - Xiujuan Qu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China. .,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China.
| | - Liu Cao
- Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, 110001, Liaoning, China.
| |
Collapse
|
|
30
|
Zhu G, Zhao M, Han Q, Tan Y, Sun YU, Bouvet M, Singh SR, Ye J, Hoffman RM. Pazopanib Inhibits Tumor Growth, Lymph-node Metastasis and Lymphangiogenesis of an Orthotopic Mouse of Colorectal Cancer. Cancer Genomics Proteomics 2020; 17:131-139. [PMID: 32108035 DOI: 10.21873/cgp.20173] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 11/27/2019] [Accepted: 12/03/2019] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND/AIM Pazopanib (PAZ) can inhibit tumor progression, but whether PAZ inhibits lymph node metastasis and lymphangiogenesis in colorectal cancer is still unknown. The aim of the present study was to determine the efficacy of PAZ on tumor growth, lymph node metastasis and lymphangiogenesis in an orthotopic nude mouse model in colorectal cancer. MATERIALS AND METHODS CT-26-green fluorescence protein (GFP)-expressing mouse colon cancer cells were injected into nude mice to establish a subcutaneous colorectal cancer model and were treated with saline and PAZ. Additionals subcutaneous tumors were harvested and cut into 5 mm3 fragments, then tumor fragments were implanted orthotopically in the cecum to establish an orthotopic colorectal-cancer nude mouse model. Orthotopic mice were randomized into two groups for the treatment with saline and PAZ, respectively. Tumor width, length and mouse body weight was measured twice a week. The Fluor Vivo imaging system was used to image the GFP. Hematoxylin & eosin staining and immunohistochemical staining was used for histological analysis. RESULTS PAZ inhibited the growth of subcutaneous colorectal cancer, as wells as orthotopic transplanted colorectal cancer tumors. PAZ suppressed lymph node metastasis and lymphangiogenesis in the orthotopic colon cancer model. No significant changes were observed in the body weight between the control and the mice treated with PAZ. CONCLUSION PAZ can inhibit the growth of colorectal cancer and inhibit lymph node metastasis and lymphangiogenesis in orthotopic colon cancer nude mouse models.
Collapse
Affiliation(s)
- Guangwei Zhu
- AntiCancer, Inc., San Diego, CA, U.S.A.,Department of Surgery, University of California, San Diego, CA, U.S.A.,Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, P.R. China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, P.R. China
| | - Ming Zhao
- AntiCancer, Inc., San Diego, CA, U.S.A
| | | | | | - Y U Sun
- AntiCancer, Inc., San Diego, CA, U.S.A.,Department of Surgery, University of California, San Diego, CA, U.S.A
| | - Michael Bouvet
- Department of Surgery, University of California, San Diego, CA, U.S.A
| | - Shree Ram Singh
- Basic Research Laboratory, National Cancer Institute, Frederick, MD, U.S.A.
| | - Jianxin Ye
- Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, P.R. China .,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, P.R. China
| | - Robert M Hoffman
- AntiCancer, Inc., San Diego, CA, U.S.A. .,Department of Surgery, University of California, San Diego, CA, U.S.A
| |
Collapse
|
|
31
|
Suzuki S, Mori A, Fukui A, Ema Y, Nishiwaki K. Lidocaine inhibits vascular endothelial growth factor-A-induced angiogenesis. J Anesth 2020; 34:857-864. [PMID: 32734387 DOI: 10.1007/s00540-020-02830-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 07/18/2020] [Indexed: 12/18/2022]
Abstract
PURPOSE Angiogenesis is closely related to the pathophysiology of diseases such as cancer or ischemia. Here, we investigated the effect of lidocaine at clinically effective blood concentrations on vascular endothelial growth factor A (VEGF-A)-induced angiogenesis. In addition, we aimed to clarify the mechanisms by which lidocaine could inhibit angiogenesis. METHODS Angiogenesis was analyzed using commercially available in vitro assay kits in human umbilical vein endothelial cells (HUVECs)/normal human dermal fibroblast co-culture systems. The effects of lidocaine on cytotoxicity, VEGF-induced cell migration, and VEGF-induced cell proliferation were examined in HUVECs using lactate dehydrogenase cytotoxic, Boyden chamber, and WST-8 assays, respectively. The VEGF signaling pathway via VEGF receptor 2 (VEGFR-2) was analyzed by western blotting. RESULTS Lidocaine elicited a significant dose-dependent, angiogenesis-inhibitory effect at a concentration range of 1-10 μg/ml. At this concentration range, cell death was not observed. Lidocaine, at a concentration of 10 μg/ml, significantly inhibited cell proliferation but not cell migration, induced by VEGF-A in HUVECs. Furthermore, lidocaine, in a dose-dependent manner, significantly inhibited the VEGF-A-induced phosphorylation of VEGFR-2 at 3 and 10 μg/ml. CONCLUSION We demonstrated that lidocaine has an anti-angiogenesis effect on clinically effective blood concentrations without causing cell death. This finding could represent a new avenue for future research into anesthesia, cancer-related analgesia, and revascularization therapy.
Collapse
Affiliation(s)
- Shogo Suzuki
- Department of Anesthesiology, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Atsushi Mori
- Department of Perioperative Management System, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Aya Fukui
- Department of Anesthesiology, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Yoshiaki Ema
- Department of Anesthesiology, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Kimitoshi Nishiwaki
- Department of Anesthesiology, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
| |
Collapse
|
|
32
|
Fang Y, Kaszuba T, Imoukhuede PI. Systems Biology Will Direct Vascular-Targeted Therapy for Obesity. Front Physiol 2020; 11:831. [PMID: 32760294 PMCID: PMC7373796 DOI: 10.3389/fphys.2020.00831] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 06/22/2020] [Indexed: 12/12/2022] Open
Abstract
Healthy adipose tissue expansion and metabolism during weight gain require coordinated angiogenesis and lymphangiogenesis. These vascular growth processes rely on the vascular endothelial growth factor (VEGF) family of ligands and receptors (VEGFRs). Several studies have shown that controlling vascular growth by regulating VEGF:VEGFR signaling can be beneficial for treating obesity; however, dysregulated angiogenesis and lymphangiogenesis are associated with several chronic tissue inflammation symptoms, including hypoxia, immune cell accumulation, and fibrosis, leading to obesity-related metabolic disorders. An ideal obesity treatment should minimize adipose tissue expansion and the advent of adverse metabolic consequences, which could be achieved by normalizing VEGF:VEGFR signaling. Toward this goal, a systematic investigation of the interdependency of vascular and metabolic systems in obesity and tools to predict personalized treatment ranges are necessary to improve patient outcomes through vascular-targeted therapies. Systems biology can identify the critical VEGF:VEGFR signaling mechanisms that can be targeted to regress adipose tissue expansion and can predict the metabolic consequences of different vascular-targeted approaches. Establishing a predictive, biologically faithful platform requires appropriate computational models and quantitative tissue-specific data. Here, we discuss the involvement of VEGF:VEGFR signaling in angiogenesis, lymphangiogenesis, adipogenesis, and macrophage specification – key mechanisms that regulate adipose tissue expansion and metabolism. We then provide useful computational approaches for simulating these mechanisms, and detail quantitative techniques for acquiring tissue-specific parameters. Systems biology, through computational models and quantitative data, will enable an accurate representation of obese adipose tissue that can be used to direct the development of vascular-targeted therapies for obesity and associated metabolic disorders.
Collapse
Affiliation(s)
- Yingye Fang
- Imoukhuede Systems Biology Laboratory, Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO, United States
| | - Tomasz Kaszuba
- Imoukhuede Systems Biology Laboratory, Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO, United States
| | - P I Imoukhuede
- Imoukhuede Systems Biology Laboratory, Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO, United States
| |
Collapse
|
|
33
|
Hadanny A, Efrati S. The Hyperoxic-Hypoxic Paradox. Biomolecules 2020; 10:biom10060958. [PMID: 32630465 PMCID: PMC7355982 DOI: 10.3390/biom10060958] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/20/2020] [Accepted: 06/22/2020] [Indexed: 12/12/2022] Open
Abstract
Effective metabolism is highly dependent on a narrow therapeutic range of oxygen. Accordingly, low levels of oxygen, or hypoxia, are one of the most powerful inducers of gene expression, metabolic changes, and regenerative processes, including angiogenesis and stimulation of stem cell proliferation, migration, and differentiation. The sensing of decreased oxygen levels (hypoxia) or increased oxygen levels (hyperoxia), occurs through specialized chemoreceptor cells and metabolic changes at the cellular level, which regulate the response. Interestingly, fluctuations in the free oxygen concentration rather than the absolute level of oxygen can be interpreted at the cellular level as a lack of oxygen. Thus, repeated intermittent hyperoxia can induce many of the mediators and cellular mechanisms that are usually induced during hypoxia. This is called the hyperoxic-hypoxic paradox (HHP). This article reviews oxygen physiology, the main cellular processes triggered by hypoxia, and the cascade of events triggered by the HHP.
Collapse
Affiliation(s)
- Amir Hadanny
- The Sagol Center for Hyperbaric Medicine and Research, Shamir (Assaf-Harofeh) Medical Center, Zerifin 70300, Israel;
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel
- The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat-Gan 5290002, Israel
- Correspondence: ; Tel.: +972-544707381; Fax: +972-8-9779748
| | - Shai Efrati
- The Sagol Center for Hyperbaric Medicine and Research, Shamir (Assaf-Harofeh) Medical Center, Zerifin 70300, Israel;
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel
- The Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 6997801, Israel
| |
Collapse
|
|
34
|
Hadanny A, Efrati S. The Hyperoxic-Hypoxic Paradox. Biomolecules 2020; 10:biom10060958. [PMID: 32630465 DOI: 10.3390/biom1006095] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/20/2020] [Accepted: 06/22/2020] [Indexed: 05/21/2023] Open
Abstract
Effective metabolism is highly dependent on a narrow therapeutic range of oxygen. Accordingly, low levels of oxygen, or hypoxia, are one of the most powerful inducers of gene expression, metabolic changes, and regenerative processes, including angiogenesis and stimulation of stem cell proliferation, migration, and differentiation. The sensing of decreased oxygen levels (hypoxia) or increased oxygen levels (hyperoxia), occurs through specialized chemoreceptor cells and metabolic changes at the cellular level, which regulate the response. Interestingly, fluctuations in the free oxygen concentration rather than the absolute level of oxygen can be interpreted at the cellular level as a lack of oxygen. Thus, repeated intermittent hyperoxia can induce many of the mediators and cellular mechanisms that are usually induced during hypoxia. This is called the hyperoxic-hypoxic paradox (HHP). This article reviews oxygen physiology, the main cellular processes triggered by hypoxia, and the cascade of events triggered by the HHP.
Collapse
Affiliation(s)
- Amir Hadanny
- The Sagol Center for Hyperbaric Medicine and Research, Shamir (Assaf-Harofeh) Medical Center, Zerifin 70300, Israel
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel
- The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat-Gan 5290002, Israel
| | - Shai Efrati
- The Sagol Center for Hyperbaric Medicine and Research, Shamir (Assaf-Harofeh) Medical Center, Zerifin 70300, Israel
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel
- The Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 6997801, Israel
| |
Collapse
|
|
35
|
Chen J, Du F, Dang Y, Li X, Qian M, Feng W, Qiao C, Fan D, Nie Y, Wu K, Xia L. Fibroblast Growth Factor 19-Mediated Up-regulation of SYR-Related High-Mobility Group Box 18 Promotes Hepatocellular Carcinoma Metastasis by Transactivating Fibroblast Growth Factor Receptor 4 and Fms-Related Tyrosine Kinase 4. Hepatology 2020; 71:1712-1731. [PMID: 31529503 DOI: 10.1002/hep.30951] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 09/04/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS The poor prognosis of patients with hepatocellular carcinoma (HCC) is mainly attributed to its high rate of metastasis and recurrence. However, the molecular mechanisms underlying HCC metastasis need to be elucidated. The SRY-related high-mobility group box (SOX) family proteins, which are a group of highly conserved transcription factors, play important roles in cancer initiation and progression. Here, we report on a role of SOX18, a member of the SOX family, in promoting HCC invasion and metastasis. APPROACH AND RESULTS The elevated expression of SOX18 was positively correlated with poor tumor differentiation, higher tumor-node-metastasis (TNM) stage, and poor prognosis. Overexpression of SOX18 promoted HCC metastasis by up-regulating metastasis-related genes, including fibroblast growth factor receptor 4 (FGFR4) and fms-related tyrosine kinase 4 (FLT4). Knockdown of both FGFR4 and FLT4 significantly decreased SOX18-mediated HCC invasion and metastasis, whereas the stable overexpression of FGFR4 and FLT4 reversed the decrease in cell invasion and metastasis that was induced by inhibition of SOX18. Fibroblast growth factor 19 (FGF19), which is the ligand of FGFR4, up-regulated SOX18 expression. A mechanistic investigation indicated that the up-regulation of SOX18 that was mediated by the FGF19-FGFR4 pathway relied on the phosphorylated (p)-fibroblast growth factor receptor substrate 2/p-glycogen synthase kinase 3 beta/β-catenin pathway. SOX18 knockdown significantly reduced FGF19-enhanced HCC invasion and metastasis. Furthermore, BLU9931, a specific FGFR4 inhibitor, significantly reduced SOX18-mediated HCC invasion and metastasis. In human HCC tissues, SOX18 expression was positively correlated with FGF19, FGFR4, and FLT4 expression, and patients that coexpressed FGF19/SOX18, SOX18/FGFR4, or SOX18/FLT4 had the worst prognosis. CONCLUSIONS We defined a FGF19-SOX18-FGFR4 positive feedback loop that played a pivotal role in HCC metastasis, and targeting this pathway may be a promising therapeutic option for the clinical management of HCC.
Collapse
Affiliation(s)
- Jie Chen
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Feng Du
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Yunzhi Dang
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Xiaowei Li
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Meirui Qian
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Weibo Feng
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Chenyang Qiao
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Daiming Fan
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Yongzhan Nie
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Kaichun Wu
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Limin Xia
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| |
Collapse
|
|
36
|
Oplawski M, Dziobek K, Zmarzły N, Grabarek B, Halski T, Januszyk P, Kuś-Kierach A, Adwent I, Dąbruś D, Kiełbasiński K, Boroń D. Expression Profile of VEGF-C, VEGF-D, and VEGFR-3 in Different Grades of Endometrial Cancer. Curr Pharm Biotechnol 2020; 20:1004-1010. [PMID: 31333122 DOI: 10.2174/1389201020666190718164431] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/22/2019] [Accepted: 07/08/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF)-C, -D, and VEGF receptor-3 are proteins characterized as crucial for tumor lymphangiogenesis. It is accompanied by angiogenesis during wound healing, but also in the neoplastic process. The research studies have shown that the lymphatic system plays a key role in the progression of carcinogenesis. OBJECTIVE The aim of this study was to evaluate changes in the expression of VEGF-C, VEGF-D and VEGFR-3 in different grades of endometrial cancer (G1-G3). METHODS The study included 45 patients diagnosed with endometrial cancer (G1=17; G2=15; G3=13) and 15 patients without neoplastic changes. The expression of VEGF-C, VEGF-D, and VEGFR-3 was assessed using microarray technique and immunohistochemistry. Statistical analysis was performed using the one-way ANOVA and Tukey's post-hoc test. RESULTS Statistically significant changes in the expression at the transcriptome level were found only in the case of VEGF-C (G1 vs. C, fold change - FC = -1.15; G2 vs. C, FC = -2.33; G3 vs. C, FC = - 1.68). However, VEGF-D and VEGFR-3 were expressed at the protein level. Analysis of VEGF-D expression showed that the optical density of the reaction product in G1 reached 101.7, while the values in G2 and G3 were 142.7 and 184.4, respectively. For VEGF-R3, the optical density of the reaction product reached the following levels: 72 in control, 118.77 in G1, 145.8 in G2, and 170.9 in G3. CONCLUSION An increase in VEGF-D and VEGFR-3 levels may indicate that VEGF-D-dependent processes are intensified along with the dedifferentiation of tumor cells. The lack of VEGF-C expression in endometrial cancer samples may suggest that this tumor is characterized by a different mechanism of metastasis than EMT. Our study emphasizes that when analyzing the metastatic potential of cancer, the expression of more than one factor should be taken into account.
Collapse
Affiliation(s)
- Marcin Oplawski
- Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Cracow, Poland
| | - Konrad Dziobek
- Center of Oncology, M. Sklodowska-Curie Memorial Institute, Cracow Branch, Warsaw, Poland
| | - Nikola Zmarzły
- Katowice School of Technology, The University of Science and Art in Katowice, Katowice, Poland.,Department of Molecular Biology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Katowice, Poland
| | - Beniamin Grabarek
- Center of Oncology, M. Sklodowska-Curie Memorial Institute, Cracow Branch, Warsaw, Poland.,Katowice School of Technology, The University of Science and Art in Katowice, Katowice, Poland
| | - Tomasz Halski
- Faculty of Health Science, Public Higher Medical Professional School in Opole, Opole, Poland
| | - Piotr Januszyk
- Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Cracow, Poland
| | - Agnieszka Kuś-Kierach
- Faculty of Health Science, Public Higher Medical Professional School in Opole, Opole, Poland
| | - Iwona Adwent
- Faculty of Health Science, Public Higher Medical Professional School in Opole, Opole, Poland
| | - Dariusz Dąbruś
- Faculty of Health Science, Public Higher Medical Professional School in Opole, Opole, Poland
| | | | - Dariusz Boroń
- Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Cracow, Poland.,Katowice School of Technology, The University of Science and Art in Katowice, Katowice, Poland.,Faculty of Health Science, Public Higher Medical Professional School in Opole, Opole, Poland
| |
Collapse
|
|
37
|
Niimi K, Kohara M, Sedoh E, Fukumoto M, Shibata S, Sawano T, Tashiro F, Miyazaki S, Kubota Y, Miyazaki JI, Inagaki S, Furuyama T. FOXO1 regulates developmental lymphangiogenesis by upregulating CXCR4 in the mouse-tail dermis. Development 2020; 147:dev.181545. [PMID: 31852686 DOI: 10.1242/dev.181545] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 12/10/2019] [Indexed: 12/27/2022]
Abstract
Lymphangiogenesis plays important roles in normal fetal development and postnatal growth. However, its molecular regulation remains unclear. Here, we have examined the function of forkhead box protein O1 (FOXO1) transcription factor, a known angiogenic factor, in developmental dermal lymphangiogenesis using endothelial cell-specific FOXO1-deficient mice. FOXO1-deficient mice showed disconnected and dilated lymphatic vessels accompanied with increased proliferation and decreased apoptosis in the lymphatic capillaries. Comprehensive DNA microarray analysis of the causes of in vivo phenotypes in FOXO1-deficient mice revealed that the gene encoding C-X-C chemokine receptor 4 (CXCR4) was the most drastically downregulated in FOXO1-deficient primary lymphatic endothelial cells (LECs). CXCR4 was expressed in developing dermal lymphatic capillaries in wild-type mice but not in FOXO1-deficient dermal lymphatic capillaries. Furthermore, FOXO1 suppression impaired migration toward the exogenous CXCR4 ligand, C-X-C chemokine ligand 12 (CXCL12), and coordinated proliferation in LECs. These results suggest that FOXO1 serves an essential role in normal developmental lymphangiogenesis by promoting LEC migration toward CXCL12 and by regulating their proliferative activity. This study provides valuable insights into the molecular mechanisms underlying developmental lymphangiogenesis.
Collapse
Affiliation(s)
- Kenta Niimi
- Group of Neurobiology, Division of Health Science, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan.,Kagawa Prefectural University of Health Sciences, Hara 281-1, Mure, Takamatsu, Kagawa 761-0123, Japan
| | - Misaki Kohara
- Group of Neurobiology, Division of Health Science, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan
| | - Eriko Sedoh
- Kagawa Prefectural University of Health Sciences, Hara 281-1, Mure, Takamatsu, Kagawa 761-0123, Japan
| | - Moe Fukumoto
- Group of Neurobiology, Division of Health Science, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan
| | - Satoshi Shibata
- Group of Neurobiology, Division of Health Science, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan
| | - Toshinori Sawano
- Group of Neurobiology, Division of Health Science, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan
| | - Fumi Tashiro
- Department of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan
| | - Satsuki Miyazaki
- Department of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan
| | - Yoshiaki Kubota
- Department of Anatomy, Keio University School of Medicine, 35-Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Jun-Ichi Miyazaki
- Department of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan
| | - Shinobu Inagaki
- Group of Neurobiology, Division of Health Science, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan
| | - Tatsuo Furuyama
- Kagawa Prefectural University of Health Sciences, Hara 281-1, Mure, Takamatsu, Kagawa 761-0123, Japan
| |
Collapse
|
|
38
|
Chiumia D, Hankele AK, Groebner AE, Schulke K, Reichenbach HD, Giller K, Zakhartchenko V, Bauersachs S, Ulbrich SE. Vascular Endothelial Growth Factor A and VEGFR-1 Change during Preimplantation in Heifers. Int J Mol Sci 2020; 21:ijms21020544. [PMID: 31952188 PMCID: PMC7014046 DOI: 10.3390/ijms21020544] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 01/08/2020] [Accepted: 01/09/2020] [Indexed: 02/06/2023] Open
Abstract
Vascular endothelial growth factor A (VEGFA) plays a critical angiogenic role in the endometrium of placentalia during preimplantation. The role of VEGFA and its receptors is not fully characterised in bovine reproduction. We analysed the mRNA expression of VEGFA isoforms 121, 165 and 189, and VEGF receptors 1 and 2 in three experimental settings (A, B and C). We compared intercaruncular endometrium of cyclic to pregnant heifers at Days 12, 15 and 18 post insemination (Day 0), and between Day 15 and Day 18 conceptuses (A). We further compared caruncular versus intercaruncular endometrium at Day 15 (B), and endometrium of heifers carrying embryos originating from somatic cell nuclear transfer (SCNT) versus in vitro fertilisation (IVF) at Day 18 (C). Endometrial VEGFA protein was localised and quantified. Pregnant heifers displayed lower intercaruncular endometrial mRNA expression of VEGFA-121 (p = 0.045) and VEGFA-189 (p = 0.009) as well as lower VEGFA protein abundance (p < 0.001) at Day 15. The VEGFA protein was localised in intercaruncular luminal, glandular epithelium and in tunica muscularis of blood vessels. At Day 15, caruncular endometrium displayed higher VEGFA mRNA expression than intercaruncular endometrium (p < 0.05). Intercaruncular endometrial VEGFA protein at Day 18 was higher in abundance in SCNT than in IVF (p = 0.038). Therefore, during preimplantation in cattle, there may be a need for timely physiological reduction in intercaruncular endometrial VEGFA expression in favour of the caruncular area to facilitate a gradient towards the implantation sites. A higher expression of VEGFA in SCNT may predispose for later placentation abnormalities frequently observed following SCNT.
Collapse
Affiliation(s)
- Daniel Chiumia
- ETH Zurich, Animal Physiology, Institute of Agricultural Sciences, 8092 Zurich, Switzerland; (D.C.); (A.-K.H.)
| | - Anna-Katharina Hankele
- ETH Zurich, Animal Physiology, Institute of Agricultural Sciences, 8092 Zurich, Switzerland; (D.C.); (A.-K.H.)
| | - Anna E. Groebner
- Physiology Weihenstephan, Technical University of Munich, 85354 Freising, Germany; (A.E.G.); (K.S.)
| | - Katy Schulke
- Physiology Weihenstephan, Technical University of Munich, 85354 Freising, Germany; (A.E.G.); (K.S.)
| | - Horst-Dieter Reichenbach
- Bavarian State Research Center for Agriculture, Institute of Animal Breeding, 85586 Poing, Grub, Germany;
| | - Katrin Giller
- ETH Zurich, Animal Nutrition, Institute of Agricultural Sciences, 8092 Zurich, Switzerland;
| | - Valeri Zakhartchenko
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians University, 81377 Munich, Germany; (V.Z.); (S.B.)
| | - Stefan Bauersachs
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians University, 81377 Munich, Germany; (V.Z.); (S.B.)
- Vetsuisse Faculty Zurich, University of Zurich, Eschikon 27, AgroVet-Strickhof, 8315 Lindau (ZH), Switzerland
| | - Susanne E. Ulbrich
- ETH Zurich, Animal Physiology, Institute of Agricultural Sciences, 8092 Zurich, Switzerland; (D.C.); (A.-K.H.)
- Physiology Weihenstephan, Technical University of Munich, 85354 Freising, Germany; (A.E.G.); (K.S.)
- Correspondence: ; Tel.: +41-44-632-27-21
| |
Collapse
|
|
39
|
Gao B, Wang X, Wang M, Ren XK, Guo J, Xia S, Zhang W, Feng Y. From single to a dual-gene delivery nanosystem: coordinated expression matters for boosting the neovascularization in vivo. Biomater Sci 2020; 8:2318-2328. [DOI: 10.1039/c9bm02000d] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
A dual-gene delivery system with coordinated expression function boosted the neovascularization.
Collapse
Affiliation(s)
- Bin Gao
- School of Chemical Engineering and Technology
- Tianjin University
- Tianjin 300350
- China
| | - Xiaoyu Wang
- School of Chemical Engineering and Technology
- Tianjin University
- Tianjin 300350
- China
| | - Meiyu Wang
- School of Chemical Engineering and Technology
- Tianjin University
- Tianjin 300350
- China
| | - Xiang-kui Ren
- School of Chemical Engineering and Technology
- Tianjin University
- Tianjin 300350
- China
- Collaborative Innovation Center of Chemical Science and Chemical Engineering (Tianjin)
| | - Jintang Guo
- School of Chemical Engineering and Technology
- Tianjin University
- Tianjin 300350
- China
- Collaborative Innovation Center of Chemical Science and Chemical Engineering (Tianjin)
| | - Shihai Xia
- Department of Hepatopancreatobiliary and Splenic Medicine
- Affiliated Hospital
- Logistics University of People's Armed Police Force
- Tianjin 300162
- China
| | - Wencheng Zhang
- Department of Physiology and Pathophysiology
- Logistics University of Chinese People's Armed Police Force
- Tianjin 300309
- China
| | - Yakai Feng
- School of Chemical Engineering and Technology
- Tianjin University
- Tianjin 300350
- China
- Collaborative Innovation Center of Chemical Science and Chemical Engineering (Tianjin)
| |
Collapse
|
|
40
|
VEGF/Flk1 Mechanism is Involved in Roxarsone Promotion of Rat Endothelial Cell Growth and B16F10 Xenograft Tumor Angiogenesis. Sci Rep 2019; 9:17417. [PMID: 31758020 PMCID: PMC6874592 DOI: 10.1038/s41598-019-53870-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 11/06/2019] [Indexed: 01/08/2023] Open
Abstract
The potential angiogenic effect of roxarsone, a feed additive widely used to promote animal growth worldwide, was demonstrated recently. We explored the mechanism of vascular endothelial growth factor (VEGF) and its receptor (VEGFR) in roxarsone promotion of rat vascular endothelial cells (ECs) and B16F10 mouse xenografts. ECs were treated with 0.1–50 μM roxarsone or with roxarsone plus 10 ng/mL VEGF, VEGFR1 (Flt1), or VEGFR2 (Flk1) antibodies for 12–48 h to examine their role in cell growth promotion. Small interfering RNA (siRNA) targeting Vegf, Flt1, and Flk1 were transfected in the ECs, and we measured the expression level, cell proliferation, migration, and tube formation ability. The siRNA targeting Vegf or Flk1 were injected intratumorally in the B16F10 xenografts of mice that received 25 mg/kg roxarsone orally. Cell viability and VEGF expression following roxarsone treatment were significantly higher than that of the control (P < 0.05), peaking following treatment with 1.0 μM roxarsone. Compared to roxarsone alone, the VEGF antibody decreased cell promotion by roxarsone (P < 0.05), and the Flk1 antibody greatly reduced cell viability compared to the Flt1 antibody (P < 0.01). Roxarsone and Flk1 antibody co-treatment increased supernatant VEGF significantly, while cellular VEGF was obviously decreased (P < 0.01), whereas there was no significant difference following Flt1 antibody blockade. The siRNA against Vegf or Flk1 significantly attenuated the roxarsone promotion effects on EC proliferation, migration, and tube-like formation (P < 0.01), whereas the siRNA against Flt1 effected no obvious differences. Furthermore, the RNA interference significantly weakened the roxarsone-induced increase in xenograft weight and volume, and VEGF and Flk1 expression. Roxarsone promotion of rat EC growth, migration, and tube-like formation in vitro and of B16F10 mouse xenograft model tumor growth and angiogenesis involves a VEGF/Flk1 mechanism.
Collapse
|
|
41
|
Ruffolo C, Toffolatti L, Massani M, Pozza A, Campo Dell'Orto M, Saadeh LM, Ferrara F, Benvenuti S, Dei Tos AP, Bassi N, Kotsafti A, Scarpa M. Interferon-Gamma and Tumor Necrosis Factor-Related Weak Inducer of Apoptosis Expression in Neoangiogenesis in Colorectal Polypoid Lesions. Eur Surg Res 2019; 60:186-195. [PMID: 31597147 DOI: 10.1159/000502786] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 08/19/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND Interferon gamma (IFNγ) and tumor necrosis factor-related weak inducer of apoptosis (TWEAK) molecules seem to have a potential effect on angiogenic factors such as vascular endothelial growth factor (VEGF). The aim of this study was to assess a possible interplay between IFNγ and TWEAK cytokines and VEGF machinery in the different steps of colorectal carcinogenesis. METHODS A total of 92 subjects with colonic adenoma or cancer who underwent screening colonoscopy or surgery were prospectively enrolled. Polypoid lesion tissue samples were collected and frozen. Real-time reverse transcription polymerase chain reaction for IFNγ, TWEAK, and VEGF-A mRNA expression was performed. Immunoassays for VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, and VEGFR-3 were also performed. Nonparametric statistics, receiver operating characteristic curve analysis, and logistic multiple regression analysis were used. RESULTS IFNγ and TWEAK mRNA expression was higher in patients with T2 or more advanced colorectal cancer than in those with adenomas or T1 cancer (p < 0.001 and p = 0.01, respectively). IFNγ and TWEAK mRNA expression levels directly correlated with VEGF-A mRNA expression levels (rho = 0.44, p < 0.001 and rho = 0.29, p = 0.004, respectively). On the contrary, IFNγ and TWEAK mRNA expression levels inversely correlated with VEGF-C protein levels (rho = -0.29, p = 0.04 and rho = -0.31, p = 0.03, respectively). Similarly, IFNγ and TWEAK mRNA expression levels inversely correlated with VEGFR2 protein levels (rho = -0.38, p = 0.033 and rho = -0.40, p = 0.025, respectively). CONCLUSION This study showed that in colorectal polypoid lesions, IFNγ and TWEAK expressions are directly correlated to VEGF-A expression but inversely correlated with VEGFR2 levels, suggesting a possible feedback mechanism in the regulation of VEGF-A expression.
Collapse
Affiliation(s)
- Cesare Ruffolo
- General Surgery Unit, University Hospital of Padova, Padova, Italy
| | | | - Marco Massani
- Department of Surgery, Cà Foncello Regional Hospital, Treviso, Italy
| | - Anna Pozza
- Department of Surgery, Cà Foncello Regional Hospital, Treviso, Italy
| | | | - Luca M Saadeh
- General Surgery Unit, University Hospital of Padova, Padova, Italy
| | - Francesco Ferrara
- Gastroenterology Unit (IV), Cà Foncello Regional Hospital, Treviso, Italy
| | - Stefano Benvenuti
- Gastroenterology Unit (IV), Cà Foncello Regional Hospital, Treviso, Italy
| | | | - Nicolò Bassi
- Department of Surgery, Cà Foncello Regional Hospital, Treviso, Italy
| | - Andromachi Kotsafti
- Laboratory of Advanced Translational Research, Veneto Institute of Oncology (IOV-IRCCS), Padova, Italy
| | - Marco Scarpa
- General Surgery Unit, University Hospital of Padova, Padova, Italy,
| |
Collapse
|
|
42
|
Maliken BD, Kanisicak O, Karch J, Khalil H, Fu X, Boyer JG, Prasad V, Zheng Y, Molkentin JD. Gata4-Dependent Differentiation of c-Kit +-Derived Endothelial Cells Underlies Artefactual Cardiomyocyte Regeneration in the Heart. Circulation 2019; 138:1012-1024. [PMID: 29666070 PMCID: PMC6125755 DOI: 10.1161/circulationaha.118.033703] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Supplemental Digital Content is available in the text. Background: Although c-Kit+ adult progenitor cells were initially reported to produce new cardiomyocytes in the heart, recent genetic evidence suggests that such events are exceedingly rare. However, to determine if these rare events represent true de novo cardiomyocyte formation, we deleted the necessary cardiogenic transcription factors Gata4 and Gata6 from c-Kit–expressing cardiac progenitor cells. Methods: Kit allele–dependent lineage tracing and fusion analysis were performed in mice following simultaneous Gata4 and Gata6 cell type–specific deletion to examine rates of putative de novo cardiomyocyte formation from c-Kit+ cells. Bone marrow transplantation experiments were used to define the contribution of Kit allele–derived hematopoietic cells versus Kit lineage–dependent cells endogenous to the heart in contributing to apparent de novo lineage-traced cardiomyocytes. A Tie2CreERT2 transgene was also used to examine the global impact of Gata4 deletion on the mature cardiac endothelial cell network, which was further evaluated with select angiogenesis assays. Results: Deletion of Gata4 in Kit lineage–derived endothelial cells or in total endothelial cells using the Tie2CreERT2 transgene, but not from bone morrow cells, resulted in profound endothelial cell expansion, defective endothelial cell differentiation, leukocyte infiltration into the heart, and a dramatic increase in Kit allele–dependent lineage-traced cardiomyocytes. However, this increase in labeled cardiomyocytes was an artefact of greater leukocyte-cardiomyocyte cellular fusion because of defective endothelial cell differentiation in the absence of Gata4. Conclusions: Past identification of presumed de novo cardiomyocyte formation in the heart from c-Kit+ cells using Kit allele lineage tracing appears to be an artefact of labeled leukocyte fusion with cardiomyocytes. Deletion of Gata4 from c-Kit+ endothelial progenitor cells or adult endothelial cells negatively impacted angiogenesis and capillary network integrity.
Collapse
Affiliation(s)
- Bryan D Maliken
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | - Onur Kanisicak
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | - Jason Karch
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | - Hadi Khalil
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | | | - Justin G Boyer
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.).,Howard Hughes Medical Institute, Cincinnati Children's Hospital Research Foundation, OH (J.G.B., J.D.M)
| | - Vikram Prasad
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | - Yi Zheng
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | - Jeffery D Molkentin
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.).,Howard Hughes Medical Institute, Cincinnati Children's Hospital Research Foundation, OH (J.G.B., J.D.M)
| |
Collapse
|
|
43
|
Deng Y, Li X. Fruquintinib and its use in the treatment of metastatic colorectal cancer. Future Oncol 2019; 15:2571-2576. [PMID: 31407939 DOI: 10.2217/fon-2018-0454] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Fruquintinib is a potent, highly selective and orally active inhibitor of VEGFR1, 2, 3 tyrosine kinases. It inhibits VEGF-induced VEGFR2 phosphorylation, endothelial cell proliferation and tubule formation. Currently, it has been approved for the treatment of metastatic colorectal cancer in patients who have failed at least two prior systemic antineoplastic therapies in China. However, it is not approved outside China, and there is another similar small molecular VEGFR multitarget drug approved in China, USA, Europe, etc. Here, we summarize the mechanism characteristics and clinical development of fruquintinib supporting its use in the treatment of metastastic colorectal cancer as well as explorations in other tumor types.
Collapse
Affiliation(s)
- Yanhong Deng
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal & Pelvic Floor Diseases, Guangzhou, Guangdong, PR China
| | - Xiaomin Li
- Medical Affair, Lilly Suzhou Pharmaceutical Co., Ltd, Suzhou, Jiangsu, PR China
| |
Collapse
|
|
44
|
Vastrad C, Vastrad B. Investigation into the underlying molecular mechanisms of non-small cell lung cancer using bioinformatics analysis. GENE REPORTS 2019. [DOI: 10.1016/j.genrep.2019.100394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
|
|
45
|
Di Stasi R, De Rosa L, Diana D, Fattorusso R, D'Andrea LD. Human Recombinant VEGFR2D4 Biochemical Characterization to Investigate Novel Anti-VEGFR2D4 Antibodies for Allosteric Targeting of VEGFR2. Mol Biotechnol 2019; 61:513-520. [PMID: 31025286 DOI: 10.1007/s12033-019-00181-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
VEGF-A/VEGFR2 complex is the major signaling pathway involved in angiogenesis and the inhibition of this axis retards tumor growth and inflammatory disorders progression, reducing vessel sprouting. Signaling by VEGFR2 requires receptor dimerization and a well-defined orientation of monomers in the active dimer. The extracellular portion of receptor is composed of seven Ig-like domains, of which D2-3 are the ligand binding domains, while D4 and D7, establishing homotypic contacts, allosterically regulate receptor activity. The allosteric targeting of VEGFR2 represents a promising alternative to study neovascular disorders overcoming drawbacks related to competition with VEGF. In this work, we expressed in bacterial host domain 4 of VEGFR2 (VEGFR2D4). After protein refolding, we characterized the purified domain and administered it in mice for monoclonal antibodies production. One of them, mAbD4, was tested in ELISA assays, showing a nanomolar affinity for VEGFR2D4. Finally, the methodology here described could contribute to the development of antibodies which can allosterically bind VEGFR2 and therefore to be used for imaging purposes or to modulate receptor signaling.
Collapse
Affiliation(s)
- Rossella Di Stasi
- Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134, Napoli, Italy
| | - Lucia De Rosa
- Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134, Napoli, Italy
| | - Donatella Diana
- Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134, Napoli, Italy
| | - Roberto Fattorusso
- Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Università della Campania "L. Vanvitelli", Via Vivaldi, 43, 81100, Caserta, Italy
| | - Luca D D'Andrea
- Istituto di Biostrutture e Bioimmagini, CNR, Via Nizza 52, 10126, Torino, Italy.
| |
Collapse
|
|
46
|
Parveen A, Subedi L, Kim HW, Khan Z, Zahra Z, Farooqi MQ, Kim SY. Phytochemicals Targeting VEGF and VEGF-Related Multifactors as Anticancer Therapy. J Clin Med 2019; 8:E350. [PMID: 30871059 PMCID: PMC6462934 DOI: 10.3390/jcm8030350] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 02/27/2019] [Accepted: 03/06/2019] [Indexed: 02/06/2023] Open
Abstract
The role of vascular endothelial growth factor (VEGF) in cancer cells is not limited to angiogenesis; there are also multiple factors, such as neuropilins (non-tyrosine kinases receptors), tyrosine kinases receptors, immunodeficiencies, and integrins, that interact with VEGF signaling and cause cancer initiation. By combating these factors, tumor progression can be inhibited or limited. Natural products are sources of several bioactive phytochemicals that can interact with VEGF-promoting factors and inhibit them through various signaling pathways, thereby inhibiting cancer growth. This review provides a deeper understanding of the relation and interaction of VEGF with cancer-promoting factors and phytochemicals in order to develop multi-targeted cancer prevention and treatment.
Collapse
Affiliation(s)
- Amna Parveen
- Department of Pharmacognosy, Faculty of Pharmaceutical Science, Government College University, Faisalabad, Faisalabad 38000, Pakistan.
- College of Pharmacy, Gachon University, No. 191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.
| | - Lalita Subedi
- College of Pharmacy, Gachon University, No. 191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.
| | - Heung Wan Kim
- College of Pharmacy, Gachon University, No. 191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.
| | - Zahra Khan
- College of Pharmacy, Gachon University, No. 191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.
| | - Zahra Zahra
- Institute of Environmental Sciences and Engineering, School of Civil and Environmental Engineering, National University of Sciences and Technology, Sector H-12, Islamabad 44000, Pakistan.
| | | | - Sun Yeou Kim
- College of Pharmacy, Gachon University, No. 191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.
- Gachon Institute of Pharmaceutical Science, Gachon University, No. 191 Hambakmoe-ro, Yeonsu-gu, Incheon 21936, Korea.
| |
Collapse
|
|
47
|
Meng X, Duan C, Pang H, Chen Q, Han B, Zha C, Dinislam M, Wu P, Li Z, Zhao S, Wang R, Lin L, Jiang C, Cai J. DNA damage repair alterations modulate M2 polarization of microglia to remodel the tumor microenvironment via the p53-mediated MDK expression in glioma. EBioMedicine 2019; 41:185-199. [PMID: 30773478 PMCID: PMC6442002 DOI: 10.1016/j.ebiom.2019.01.067] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 01/16/2019] [Accepted: 01/17/2019] [Indexed: 12/25/2022] Open
Abstract
Background DNA damage repair (DDR) alterations are important events in cancer initiation, progression, and therapeutic resistance. However, the involvement of DDR alterations in glioma malignancy needs further investigation. This study aims to characterize the clinical and molecular features of gliomas with DDR alterations and elucidate the biological process of DDR alterations that regulate the cross talk between gliomas and the tumor microenvironment. Methods Integrated transcriptomic and genomic analyses were undertaken to conduct a comprehensive investigation of the role of DDR alterations in glioma. The prognostic DDR-related cytokines were identified from multiple datasets. In vivo and in vitro experiments validated the role of p53, the key molecule of DDR, regulating M2 polarization of microglia in glioma. Findings DDR alterations are associated with clinical and molecular characteristics of glioma. Gliomas with DDR alterations exhibit distinct immune phenotypes, and immune cell types and cytokine processes. DDR-related cytokines have an unfavorable prognostic implication for GBM patients and are synergistic with DDR alterations. Overexpression of MDK mediated by p53, the key transcriptional factor in DDR pathways, remodels the GBM immunosuppressive microenvironment by promoting M2 polarization of microglia, suggesting a potential role of DDR in regulating the glioma microenvironment. Interpretation Our work suggests that DDR alterations significantly contribute to remodeling the glioma microenvironment via regulating the immune response and cytokine pathways. Fund This study was supported by: 1. The National Key Research and Development Plan (No. 2016YFC0902500); 2. National Natural Science Foundation of China (No. 81702972, No. 81874204, No. 81572701, No. 81772666); 3. China Postdoctoral Science Foundation (2018M640305); 4. Special Fund Project of Translational Medicine in the Chinese-Russian Medical Research Center (No. CR201812); 5. The Research Project of the Chinese Society of Neuro-oncology, CACA (CSNO-2016-MSD12); 6. The Research Project of the Health and Family Planning Commission of Heilongjiang Province (2017–201); and 7. Harbin Medical University Innovation Fund (2017LCZX37, 2017RWZX03).
Gliomas with DNA damage repair alterations had distinct genomic variation spectrum. DDR alterations exhibit distinct immune phenotypes, cytokine processes and immune cell types in glioma. DDR-related cytokines in GME have an unfavorable prognostic implication for GBM patients. P53-mediated midkine expression derived from glioma cells promotes M2 polarization of microglia.
Collapse
Affiliation(s)
- Xiangqi Meng
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
| | - Chunbin Duan
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
| | - Hengyuan Pang
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Qun Chen
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Bo Han
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
| | - Caijun Zha
- Department of Laboratory Diagnosis, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Magafurov Dinislam
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neurosurgical department, Bashkir State Medical University, Ufa 450008, Russia
| | - Pengfei Wu
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
| | - Ziwei Li
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
| | - Shihong Zhao
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Ruijia Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
| | - Lin Lin
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
| | - Chuanlu Jiang
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China.
| | - Jinquan Cai
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China.
| |
Collapse
|
|
48
|
Breslin JW, Yang Y, Scallan JP, Sweat RS, Adderley SP, Murfee WL. Lymphatic Vessel Network Structure and Physiology. Compr Physiol 2018; 9:207-299. [PMID: 30549020 PMCID: PMC6459625 DOI: 10.1002/cphy.c180015] [Citation(s) in RCA: 202] [Impact Index Per Article: 28.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The lymphatic system is comprised of a network of vessels interrelated with lymphoid tissue, which has the holistic function to maintain the local physiologic environment for every cell in all tissues of the body. The lymphatic system maintains extracellular fluid homeostasis favorable for optimal tissue function, removing substances that arise due to metabolism or cell death, and optimizing immunity against bacteria, viruses, parasites, and other antigens. This article provides a comprehensive review of important findings over the past century along with recent advances in the understanding of the anatomy and physiology of lymphatic vessels, including tissue/organ specificity, development, mechanisms of lymph formation and transport, lymphangiogenesis, and the roles of lymphatics in disease. © 2019 American Physiological Society. Compr Physiol 9:207-299, 2019.
Collapse
Affiliation(s)
- Jerome W. Breslin
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Ying Yang
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Joshua P. Scallan
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Richard S. Sweat
- Department of Biomedical Engineering, Tulane University, New Orleans, LA
| | - Shaquria P. Adderley
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - W. Lee Murfee
- Department of Biomedical Engineering, University of Florida, Gainesville, FL
| |
Collapse
|
|
49
|
Engineered systems to study the synergistic signaling between integrin-mediated mechanotransduction and growth factors (Review). Biointerphases 2018; 13:06D302. [DOI: 10.1116/1.5045231] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
|
|
50
|
Liao X, Li H, Liu Z, Liao S, Li Q, Liang C, Huang Y, Xie M, Wei J, Li Y. Clinical efficacy and safety of apatinib in patients with advanced colorectal cancer as the late-line treatment. Medicine (Baltimore) 2018; 97:e13635. [PMID: 30558053 PMCID: PMC6320137 DOI: 10.1097/md.0000000000013635] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
There is currently no standard therapeutic regimen available for patients with advanced colorectal cancer in whom the disease continues to progress after 2 or more lines of chemotherapy. The purpose of this study is to investigate the efficacy and safety of apatinib in patients with advanced colorectal cancer for whom at least two lines of prior chemotherapy had failed.Twenty seven patients with advanced colorectal cancer who had failed at least 2 lines chemotherapy were treated with apatinib (500 mg/day). As a comparison control, 26 advanced colorectal cancer patients with comparable clinical baseline characteristics including age, sex, Eastern Cooperative Oncology Group (ECOG) score, pathological type, carcinoembryonic antigen (CEA) level, tumor location, number and location(s) of metastasis, and previous chemotherapies were subject to observation. Survival analyses were performed via the Kaplan-Meier method. The toxicity were evaluated in all patients this study according to the National Cancer Institute Common Toxicity Criteria 4 (NCI CTC version 4.0).A total of 53 well-matched patients with advanced colorectal cancer were retrospectively analyzed. The median follow-up time was 6.0 months (2.0-16.0 months). The median PFS was significantly longer for apatinib group than for observation group (2.0 vs. 1.1 months; HR = 3.88; 95% confidence interval [CI], 1.91-7.88; P < .001). However, there was no significant difference between the 2 groups for median OS (5.0 vs. 4.0 months; HR = 1.03; 95% CI, 0.56-1.90; P = .914). The disease control rate of the apatinib group was significantly better than that of the observation group (70.4% vs 26.9%, P = .002). There was no significant difference in the overall remission rate between the 2 groups (3.7% vs 0%, P = .322). Advanced colorectal cancer patients with 2 or fewer metastatic sites experienced longer PFS than those with more than 2 sites. High ECOG scores, cancer localization to the right side of colon and lymph node metastasis were associated with increased risk of death and all remained independent factors affecting OS. The most common grade 3/4 treatment-related adverse events were hypertension and hand-foot skin syndrome.Apatinib treatment for patients with advanced colorectal cancer who had failed chemotherapy achieved better disease control and prolonged PFS relative to untreated controls. The toxicity was manageable.
Collapse
Affiliation(s)
| | | | | | | | - Qian Li
- Department of First Chemotherapy
| | | | - Yu Huang
- Department of First Chemotherapy
| | | | - Junbao Wei
- Department of Therapeutic Radiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | | |
Collapse
|