|
1
|
Tlaye KG, Woldeamanuel GG, Wong KCY, Chen L, Zheng R, So PK, Wang X, Nguyen-Hoang L, Zhong M, So HC, Leung BW, Huang Y, Wang Y, Poon LC, Wang CC. Pharmacogenomics and Pharmacokinetics of Aspirin in Preeclampsia Prevention. Circ Res 2025. [PMID: 40329906 DOI: 10.1161/circresaha.124.325699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 04/11/2025] [Accepted: 04/22/2025] [Indexed: 05/08/2025]
Abstract
BACKGROUND It has become evident that some women develop preeclampsia despite aspirin. This study aimed to examine how such aspirin nonresponsiveness develops in high-risk preeclampsia pregnancies by exploring the role of genetic polymorphisms and aspirin metabolism. METHODS The study involved pregnant women who developed preeclampsia despite low-dose aspirin and those who did not. First, we conducted a pharmacogenomic association study exploring the association of potential genetic variants with aspirin nonresponsiveness. Next, we analyzed the rate of enzymatic aspirin hydrolysis in maternal plasma. The extent of placental exposure to acetylsalicylic acid and its bioactive metabolites, that is, salicylic acid and gentisic acid, was determined by liquid chromatography-mass spectrometry. The expressions of AMEs (aspirin metabolizing enzymes), that is, GLYAT (glycine-N-acyltransferase), UGT1A6, CYP2E1, and NAT2 in the placenta, were analyzed by quantitative reverse transcription polymerase chain reaction, immunohistochemistry staining, and ELISA. Finally, the effects of AMEs were further examined on HTR-8/SVneo and human primary cytotrophoblast cells. RESULT Our genetic study showed that single-nucleotide polymorphisms (SNPs) of genes involved in aspirin pharmacokinetics and pharmacodynamics were not associated with aspirin nonresponsiveness in preeclampsia. Rates of aspirin hydrolysis in maternal plasma and the concentrations of acetylsalicylic acid, salicylic acid, and gentisic acid in the placenta did not differ between aspirin-responsive and aspirin-nonresponsive women. Intriguingly, GLYAT was significantly upregulated in the aspirin-nonresponsive placenta and associated with aspirin nonresponsiveness. This overexpression of GLYAT was found to diminish the proangiogenic, anti-inflammatory, and antisenescence effects of salicylic acid in HTR-8/SVneo and human primary cytotrophoblast cells. CONCLUSIONS Our study revealed that maternal genetic factors and plasma aspirin hydrolysis are not among the decisive factors in determining the effectiveness of low-dose aspirin in preventing preeclampsia among high-risk women. Instead, placental GLYAT appears to play a key role by limiting the effect of salicylic acid in the placenta.
Collapse
Affiliation(s)
- Kenean Getaneh Tlaye
- Faculty of Medicine, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin. (K.G.T., G.G.W., L.C., R.Z., X.W., L.N.-H., B.W.L., Y.W., L.C.P., C.C.W.)
| | - Gashaw Garedew Woldeamanuel
- Faculty of Medicine, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin. (K.G.T., G.G.W., L.C., R.Z., X.W., L.N.-H., B.W.L., Y.W., L.C.P., C.C.W.)
| | - Kenneth Chi-Yin Wong
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin. (K.C.-Y.W., H.C.S.)
| | - Lu Chen
- Faculty of Medicine, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin. (K.G.T., G.G.W., L.C., R.Z., X.W., L.N.-H., B.W.L., Y.W., L.C.P., C.C.W.)
| | - Ruqun Zheng
- Faculty of Medicine, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin. (K.G.T., G.G.W., L.C., R.Z., X.W., L.N.-H., B.W.L., Y.W., L.C.P., C.C.W.)
| | - Pui Kin So
- University Research Facility in Life Sciences, The Hong Kong Polytechnic University Hong Kong, Hung Hom (P.K.S.)
| | - Xueqin Wang
- Faculty of Medicine, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin. (K.G.T., G.G.W., L.C., R.Z., X.W., L.N.-H., B.W.L., Y.W., L.C.P., C.C.W.)
| | - Long Nguyen-Hoang
- Faculty of Medicine, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin. (K.G.T., G.G.W., L.C., R.Z., X.W., L.N.-H., B.W.L., Y.W., L.C.P., C.C.W.)
| | - Mei Zhong
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China (M.Z.)
| | - Hon Cheong So
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin. (K.C.-Y.W., H.C.S.)
- Faculty of Medicine, Department of Psychiatry, The Chinese University of Hong Kong, Shatin. (H.C.S.)
| | - Bo Wah Leung
- Faculty of Medicine, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin. (K.G.T., G.G.W., L.C., R.Z., X.W., L.N.-H., B.W.L., Y.W., L.C.P., C.C.W.)
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong (Y.H.)
| | - Yao Wang
- Faculty of Medicine, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin. (K.G.T., G.G.W., L.C., R.Z., X.W., L.N.-H., B.W.L., Y.W., L.C.P., C.C.W.)
| | - Liona C Poon
- Faculty of Medicine, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin. (K.G.T., G.G.W., L.C., R.Z., X.W., L.N.-H., B.W.L., Y.W., L.C.P., C.C.W.)
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China (L.C.P., C.C.W.)
| | - Chi Chiu Wang
- Faculty of Medicine, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin. (K.G.T., G.G.W., L.C., R.Z., X.W., L.N.-H., B.W.L., Y.W., L.C.P., C.C.W.)
- Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, and The Chinese University of Hong Kong-Sichuan University Joint Laboratory for Reproductive Medicine, The Chinese University of Hong Kong, Shatin. (C.C.W.)
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China (L.C.P., C.C.W.)
| |
Collapse
|
|
2
|
Liu Y, Zheng Y, Zhao X, Dong Z, Zhang M, Fang Y, Wang Y, Wang Z, Liu N, Yan P, Ma Y, Yang F, Zheng Y, Zhang W, Yang J, Sun M. Targeting JAML promotes normalization of tumour blood vessels to antagonize tumour progression via FAK/SRC and VEGF/VEGFR2 signalling pathways. Life Sci 2025; 368:123474. [PMID: 39983824 DOI: 10.1016/j.lfs.2025.123474] [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: 09/20/2024] [Revised: 02/06/2025] [Accepted: 02/15/2025] [Indexed: 02/23/2025]
Abstract
BACKGROUND Angiogenesis is a crucial process in tumour growth and metastasis. Junctional adhesion molecule-like protein (JAML) plays an important role in cancer proliferation; however, its expression and role in tumour angiogenesis remains unexplored. METHODS We collected colorectal cancer from Jinan Central Hospital, using immunofluorescence staining to confirm the expression of JAML in vascular endothelial cells of cancer and adjacent tissue. Then we used the endothelial-specific knockout of JAML mice and human umbilical vein endothelial cells (HUVECs) to clarify the role of JAML in vivo and in vitro. RESULT Our findings indicated a significant upregulation of JAML in vascular endothelial cells of colorectal cancer tissues compared to adjacent tissues. Endothelial-specific knockout of JAML effectively inhibited tumour growth through normalization of tumour blood vessels in multiple mice tumour models. The deletion of JAML in endothelial cells facilitated tumour vascular normalization, which was evident from increased pericyte coverage, vessel perfusion and T lymphocytes infiltration, decreased hypoxia, vessel density and leakage in tumour tissues. Further analysis showed that the phosphorylation of FAK/SRC/AKT/ERK pathway and VEGFR2 were suppressed in JAMLendo-/- mice with tumour. CONCLUSION This study concluded that JAML is specifically highly expressed in the vascular endothelial cells of tumour, promoting tumour progression by angiogenesis through the activation of the FAK/SRC/ERK/AKT pathway and VEGF/VEGFR2 pathway. JAML might be a new target for antiangiogenesis and provide valuable insights into the development of novel therapeutic approaches for cancer patients.
Collapse
Affiliation(s)
- Yanan Liu
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, PR China; Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, PR China; Research Center of Translational Medicine, Laboratory Animal Center, Central hospital affiliated to Shandong First Medical University, Jinan, Shandong 250013, PR China
| | - Yawen Zheng
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, PR China
| | - Xinchao Zhao
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, PR China; Department of Clinical Medicine, Shandong First Medical University, Jinan 271016, Shandong, PR China
| | - Zhilin Dong
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, PR China; Department of Clinical Medicine, Shandong First Medical University, Jinan 271016, Shandong, PR China
| | - Mingyan Zhang
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, PR China; Research Center of Translational Medicine, Laboratory Animal Center, Central hospital affiliated to Shandong First Medical University, Jinan, Shandong 250013, PR China
| | - Yuying Fang
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, PR China; Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, PR China; Research Center of Translational Medicine, Laboratory Animal Center, Central hospital affiliated to Shandong First Medical University, Jinan, Shandong 250013, PR China
| | - Yufeng Wang
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, PR China; Research Center of Translational Medicine, Laboratory Animal Center, Central hospital affiliated to Shandong First Medical University, Jinan, Shandong 250013, PR China
| | - Zewen Wang
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, PR China
| | - Ning Liu
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, PR China
| | - Peng Yan
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, PR China
| | - Yuan Ma
- Department of Pathology, Central Hospital affiliated to Shandong First Medical University, Jinan, Shandong 250013, PR China
| | - Fei Yang
- Department of Pathology, Central Hospital affiliated to Shandong First Medical University, Jinan, Shandong 250013, PR China
| | - Yan Zheng
- Research Center of Translational Medicine, Central Hospital affiliated to Shandong First Medical University, Jinan, Shandong 250013, PR China
| | - Wencheng Zhang
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Jianmin Yang
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Meili Sun
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, PR China; Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, PR China.
| |
Collapse
|
|
3
|
Jensen L, Guo Z, Sun X, Jing X, Yang Y, Cao Y. Angiogenesis, signaling pathways, and animal models. Chin Med J (Engl) 2025:00029330-990000000-01523. [PMID: 40254738 DOI: 10.1097/cm9.0000000000003561] [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: 06/14/2024] [Indexed: 04/22/2025] Open
Abstract
ABSTRACT The vasculature plays a critical role in homeostasis and health as well as in the development and progression of a wide range of diseases, including cancer, cardiovascular diseases, metabolic diseases (and their complications), chronic inflammatory diseases, ophthalmic diseases, and neurodegenerative diseases. As such, the growth of the vasculature mediates normal development and physiology, as well as disease, when pathologically induced vessels are morphologically and functionally altered owing to an imbalance of angiogenesis-stimulating and angiogenesis-inhibiting factors. This review offers an overview of the angiogenic process and discusses recent findings that provide additional interesting nuances to this process, including the roles of intussusception and angiovasculogenesis, which may hold promise for future therapeutic interventions. In addition, we review the methodology, including those of in vitro and in vivo assays, which has helped build the vast amount of knowledge on angiogenesis available today and identify important remaining knowledge gaps that should be bridged through future research.
Collapse
Affiliation(s)
- Lasse Jensen
- Department of Health, Medical and Caring Sciences, Unit of Diagnostics and Specialist Medicine, Linköping University, Linköping SE-58183, Sweden
| | - Ziheng Guo
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoting Sun
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vison and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325024, China
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna 17165 , Sweden
| | - Xu Jing
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna 17165 , Sweden
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Yihai Cao
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna 17165 , Sweden
| |
Collapse
|
|
4
|
Luo H, Zhang W, Zeng W, Wang Y, Feng J, Lan Y, Dong X, Liu T, Sun Y, Lu H. OPN3-mediated positive regulation of angiogenesis in HUVECs through VEGFR2 interaction. Commun Biol 2025; 8:529. [PMID: 40164822 PMCID: PMC11958745 DOI: 10.1038/s42003-025-07958-4] [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: 06/03/2024] [Accepted: 03/19/2025] [Indexed: 04/02/2025] Open
Abstract
Many rhodopsin-like G-protein-coupled receptors (Rh-GPCRs) are known to either promote or inhibit angiogenesis. Among these, Opsin 4 and Opsin 5 are specifically involved in vascular development within the eye. Opsin 3 (OPN3), another member of Rh-GPCRs, performs a variety of light-dependent and light-independent functions in extraocular tissue. However, its role in endothelial cells and angiogenesis remains unclear. Here, we found that OPN3 knockdown or knockout in zebrafish impairs embryonic angiogenesis and vascular development. Similarly, silencing OPN3 in human umbilical vein endothelial cells (HUVECs) inhibits cellular proliferation, migration, sprouting, and tube formation, while OPN3 overexpression promotes these cellular processes. Moreover, OPN3 regulates angiogenesis in HUVECs through the VEGFR2-AKT pathway, with OPN3 and VEGFR2 co-localizing at the plasma membrane and forming a physical complex. These findings provide new insights into the non-light-dependent functions of OPN3 in angiogenesis, expanding our understanding of its physiological roles and offering potential therapeutic strategies for angiogenesis-related diseases.
Collapse
Affiliation(s)
- Huanhuan Luo
- School of Public Health, Guizhou Medical University, Guiyang, Guizhou, China
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Wei Zhang
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Wen Zeng
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Yu Wang
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Jianglong Feng
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Yinghua Lan
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Xian Dong
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Ting Liu
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Yan Sun
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Hongguang Lu
- School of Public Health, Guizhou Medical University, Guiyang, Guizhou, China.
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
| |
Collapse
|
|
5
|
Moglad E, Kaur P, Menon SV, Abida, Ali H, Kaur M, Deorari M, Pant K, Almalki WH, Kazmi I, Alzarea SI. ANRIL's Epigenetic Regulation and Its Implications for Cardiovascular Disorders. J Biochem Mol Toxicol 2024; 38:e70076. [PMID: 39620406 DOI: 10.1002/jbt.70076] [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: 04/10/2024] [Revised: 08/13/2024] [Accepted: 11/14/2024] [Indexed: 12/11/2024]
Abstract
Cardiovascular disorders (CVDs) are a major global health concern, but their underlying molecular mechanisms are not fully understood. Recent research highlights the role of long noncoding RNAs (lncRNAs), particularly ANRIL, in cardiovascular development and disease. ANRIL, located in the human genome's 9p21 region, significantly regulates cardiovascular pathogenesis. It controls nearby tumor suppressor genes CDKN2A/B through epigenetic pathways, influencing cell growth and senescence. ANRIL interacts with epigenetic modifiers, leading to altered histone modifications and gene expression changes. It also acts as a transcriptional regulator, impacting key genes in CVD development. ANRIL's involvement in cardiovascular epigenetic regulation suggests potential therapeutic strategies. Manipulating ANRIL and its associated epigenetic modifiers could offer new approaches to managing CVDs and preventing their progression. Dysregulation of ANRIL has been linked to various cardiovascular conditions, including coronary artery disease, atherosclerosis, ischemic stroke, and myocardial infarction. This abstract provides insights from recent research, emphasizing ANRIL's significance in the epigenetic landscape of cardiovascular disorders. By shedding light on ANRIL's role in cellular processes and disease development, the abstract highlights its potential as a therapeutic target for addressing CVDs.
Collapse
Affiliation(s)
- Ehssan Moglad
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam bin Abdulaziz University, Alkharj, Saudi Arabia
| | - Parjinder Kaur
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Mohali, Punjab, India
| | - Soumya V Menon
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Abida
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University, Rafha, Saudi Arabia
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
- Department of Pharmacology, Kyrgyz State Medical College, Bishkek, Kyrgyzstan
| | - Mandeep Kaur
- Department of Sciences, Vivekananda Global University, Jaipur, Rajasthan, India
| | - Mahamedha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Kumud Pant
- Graphic Era (Deemed to be University), Dehradun, Uttarakhand, India
- Graphic Era Hill University, Dehradun, Uttarakhand, India
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf, Saudi Arabia
| |
Collapse
|
|
6
|
Sakini ASA, Hamid AK, Alkhuzaie ZA, Al-Aish ST, Al-Zubaidi S, Tayem AA, Alobi MA, Sakini ASA, Al-Aish RT, Al-Shami K, Hanifa H, Khunda SS. Diabetic macular edema (DME): dissecting pathogenesis, prognostication, diagnostic modalities along with current and futuristic therapeutic insights. Int J Retina Vitreous 2024; 10:83. [PMID: 39468614 PMCID: PMC11514910 DOI: 10.1186/s40942-024-00603-y] [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: 08/04/2024] [Accepted: 10/17/2024] [Indexed: 10/30/2024] Open
Abstract
One of the most common health concerns disturbing people within working years globally is diabetes mellitus (DM). One well-known consequence of DM is vascular damage, which can manifest as macro- and microangiopathy affecting the ocular retina. Therefore, Diabetic macular edema (DME) is a major sight-threatening complication of diabetic retinopathy (DR) worldwide. It is the most prevalent cause of significant vision impairment in diabetic patients. Long-term vision loss can be avoided by following early DME treatment guidelines in everyday life. Hence, there are various therapeutic approaches for DME management. Currently, the first-line treatment for DME is anti-VEGF family drugs, such as ranibizumab, brolucizumab, bevacizumab, and aflibercept. Nevertheless, relapses of the disease, inadequate response, and resistance during anti-VEGF therapy are still seen because of the intricate pathophysiological foundation of the disease. Consequently, there is an excellent requirement for therapeutic approaches to advance and become better at controlling diseases more satisfactorily and require fewer treatments overall. We conducted a thorough literature search in the current review to present a comprehensive overview of the primary data about the current DME therapeutic agents. We also covered the novel advances in DME management and probable future treatments being investigated and developed. This review recommended that Large clinical trials should afford sufficient evidence to support these innovative treatment modalities.
Collapse
Affiliation(s)
| | | | - Zainab A Alkhuzaie
- Clinical Teaching Fellow, College of Medicine, University of Kufa, Al-Najaf, Iraq
| | - Sandra Thair Al-Aish
- Department of Surgery, College of Medicine, University of Baghdad, Baghdad, Iraq
| | - Shahad Al-Zubaidi
- Clinical Teaching Fellow, University of Baghdad, Al-Kindy Medical College, Baghdad, Iraq
| | | | | | | | - Rami Thair Al-Aish
- Department of Surgery, College of Medicine, University of Baghdad, Baghdad, Iraq
| | - Khayry Al-Shami
- Department of Clinical Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, Jordan
| | - Hamdah Hanifa
- Faculty of Medicine, University of Kalamoon, Al-Nabk, Syria.
| | - Sara S Khunda
- Department of Internal Medicine, Baghdad Medical City, Baghdad, Iraq
| |
Collapse
|
|
7
|
Xiao L, Yang Y, Yu J, Li Y, Chen S, Gu Y, Tang C, Yang H, Wang Z, Geng D. Urolithin B inhibits the differentiation of M1 macrophages and relieves the inflammation around the implants under osteoporosis via down-regulating the phosphorylation of VEGFR2. Int Immunopharmacol 2024; 140:112854. [PMID: 39116494 DOI: 10.1016/j.intimp.2024.112854] [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: 05/10/2024] [Revised: 07/24/2024] [Accepted: 07/30/2024] [Indexed: 08/10/2024]
Abstract
The inflammation causes the destroyed osseointegration at the implant-bone interface, significantly increasing the probability of implant loosening in osteoporotic patients. Currently, inhibiting the differentiation of M1 macrophages and the inflammatory response could be a solution to stabilize the microenvironment of implants. Interestingly, some natural products have anti-inflammatory and anti-polarization effects, which could be a promising candidate for stabilizing the implants' microenvironment in osteoporotic patients. This research aims to explore the inhibitory effect of Urolithin B(UB) on macrophage M1 polarization, which ameliorates inflammation, thus alleviating implant instability. We established an osteoporosis mouse model of implant loosening. The mouse tissues were taken out for morphological analysis, staining analysis, and bone metabolic index analysis. In in vitro experiments, RAW264.7 cells were polarized to M1 macrophages using lipopolysaccharide (LPS) and analyzed by immunofluorescence (IF) staining, Western blot (WB), and flow cytometry. The CSP100 plus chip experiments were used to explore the potential mechanisms behind the inhibiting effects of UB. Through observation of these experiments, UB can improve the osseointegration between the implants and femurs in osteoporotic mice and enhance the stability of implants. The UB can inhibit the differentiation of M1 macrophages and local inflammation via inhibiting the phosphorylation of VEGFR2, which can be further proved by the weakened inhibited effects of UB in macrophages with lentivirus-induced overexpression of VEGFR2. Overall, UB can specifically inhibit the activation of VEGFR2, alleviate local inflammation, and improve the stability of implants in osteoporotic mice.
Collapse
Affiliation(s)
- Long Xiao
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China; Orthopaedic Institute, Medical College, Soochow University, Suzhou 215006, Jiangsu, China; Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang 215600, Jiangsu, China
| | - Yunshang Yang
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang 215600, Jiangsu, China
| | - Jingxian Yu
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang 215600, Jiangsu, China
| | - Yajun Li
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang 215600, Jiangsu, China
| | - Shuangshuang Chen
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang 215600, Jiangsu, China
| | - Yong Gu
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang 215600, Jiangsu, China
| | - Cheng Tang
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang 215600, Jiangsu, China
| | - Huilin Yang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China; Orthopaedic Institute, Medical College, Soochow University, Suzhou 215006, Jiangsu, China.
| | - Zhirong Wang
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang 215600, Jiangsu, China.
| | - Dechun Geng
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China; Orthopaedic Institute, Medical College, Soochow University, Suzhou 215006, Jiangsu, China.
| |
Collapse
|
|
8
|
Shou F, Li G, Morshedi M. Long Non-coding RNA ANRIL and Its Role in the Development of Age-Related Diseases. Mol Neurobiol 2024; 61:7919-7929. [PMID: 38443729 DOI: 10.1007/s12035-024-04074-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 02/23/2024] [Indexed: 03/07/2024]
Abstract
ANRIL is known as a lncRNA that has many linear and circular isoforms and its polymorphisms are observed to be associated with the pathogenesis of many diseases including age-related diseases. Age-related diseases including atherosclerosis, ischemic heart disease, and Alzheimer's and Parkinson's disease are the most common cause of mortality in both developed and undeveloped countries and that is why a better understanding of their pathogenesis and underlying mechanisms is necessary for controlling their healthcare burden.In this review, we aim to gather the data of researches which have investigated the role of ANRIL in aging and its related diseases. The conclusions of this paper might give a new insight for decreasing the mortality rate of these diseases.
Collapse
Affiliation(s)
- Feiyan Shou
- Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China
| | - Gang Li
- Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China.
| | - Mohammadamin Morshedi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| |
Collapse
|
|
9
|
Cheng M, Tao X, Wang F, Shen N, Xu Z, Hu Y, Huang P, Luo P, He Q, Zhang Y, Yan F. Underlying mechanisms and management strategies for regorafenib-induced toxicity in hepatocellular carcinoma. Expert Opin Drug Metab Toxicol 2024; 20:907-922. [PMID: 39225462 DOI: 10.1080/17425255.2024.2398628] [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: 04/22/2024] [Accepted: 08/27/2024] [Indexed: 09/04/2024]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) accounts for 85% of liver cancer cases and is the third leading cause of cancer death. Regorafenib is a multi-target inhibitor that dramatically prolongs progression-free survival in HCC patients who have failed sorafenib therapy. However, one of the primary factors limiting regorafenib's clinical utilization is toxicity. Using Clinical Trials.gov and PubMed, we gathered clinical data on regorafenib and conducted a extensive analysis of the medication's adverse reactions and mechanisms. Next, we suggested suitable management techniques to improve regorafenib's effectiveness. AREAS COVERED We have reviewed the mechanisms by which regorafenib-induced toxicity occurs and general management strategies through clinical trials of regorafenib. Furthermore, by examining the literature on regorafenib and other tyrosine kinase inhibition, we summarized the mechanics of the onset of regorafenib toxicity and mechanism-based intervention strategies by reviewing the literature related to regorafenib and other tyrosine kinase inhibition. EXPERT OPINION One of the primary factors restricting regorafenib's clinical utilization and combination therapy is its toxicity reactions. To optimize regorafenib treatment regimens, it is especially important to further understand the specific toxicity mechanisms of regorafenib as a multi-kinase inhibitor.
Collapse
Affiliation(s)
- Mengting Cheng
- College of Pharmaceutical Sciences, Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou, China
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Xinyu Tao
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Fei Wang
- Outpatient Pharmacy, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Nonger Shen
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Zhifei Xu
- College of Pharmaceutical Sciences, Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou, China
| | - Yuhuai Hu
- Department of Pharmacology and Toxicology, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, China
| | - Ping Huang
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
- Zhejiang Provincial Clinical Research Center for malignant tumor, Hangzhou, Zhejiang, People's Republic of China
| | - Peihua Luo
- College of Pharmaceutical Sciences, Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou, China
- Department of Pharmacology and Toxicology, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, China
| | - Qiaojun He
- College of Pharmaceutical Sciences, Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou, China
- Department of Pharmacology and Toxicology, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, China
| | - Yiwen Zhang
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
- Zhejiang Provincial Clinical Research Center for malignant tumor, Hangzhou, Zhejiang, People's Republic of China
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, China
| | - Fangjie Yan
- Department of Pharmacology and Toxicology, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, China
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| |
Collapse
|
|
10
|
Lange M, Babczyk P, Tobiasch E. Exosomes: A New Hope for Angiogenesis-Mediated Bone Regeneration. Int J Mol Sci 2024; 25:5204. [PMID: 38791243 PMCID: PMC11120942 DOI: 10.3390/ijms25105204] [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: 03/26/2024] [Revised: 04/29/2024] [Accepted: 05/08/2024] [Indexed: 05/26/2024] Open
Abstract
Bone is a metabolically dynamic structure that is generally remodeled throughout the lifetime of an individual but often causes problems with increasing age. A key player for bone development and homeostasis, but also under pathological conditions, is the bone vasculature. This complex system of arteries, veins, and capillaries forms distinct structures where each subset of endothelial cells has important functions. Starting with the basic process of angiogenesis and bone-specific blood vessel formation, coupled with initial bone formation, the importance of different vascular structures is highlighted with respect to how these structures are maintained or changed during homeostasis, aging, and pathological conditions. After exemplifying the current knowledge on bone vasculature, this review will move on to exosomes, a novel hotspot of scientific research. Exosomes will be introduced starting from their discovery via current isolation procedures and state-of-the-art characterization to their role in bone vascular development, homeostasis, and bone regeneration and repair while summarizing the underlying signal transduction pathways. With respect to their role in these processes, especially mesenchymal stem cell-derived extracellular vesicles are of interest, which leads to a discussion on patented applications and an update on ongoing clinical trials. Taken together, this review provides an overview of bone vasculature and bone regeneration, with a major focus on how exosomes influence this intricate system, as they might be useful for therapeutic purposes in the near future.
Collapse
Affiliation(s)
- Martin Lange
- Cardiovascular Research Center and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Patrick Babczyk
- Department of Natural Sciences, University Bonn-Rhein-Sieg, D-53559 Rheinbach, Germany
| | - Edda Tobiasch
- Department of Natural Sciences, University Bonn-Rhein-Sieg, D-53559 Rheinbach, Germany
| |
Collapse
|
|
11
|
Su N, Zheng J, Zhang G, Guan J, Gao X, Cheng Z, Xu C, Xie D, Li Y. Molecular characterization of vascular endothelial growth factor b from spotted sea bass (Lateolabrax maculatus) and its potential roles in decreasing lipid deposition. Int J Biol Macromol 2024; 267:131507. [PMID: 38604419 DOI: 10.1016/j.ijbiomac.2024.131507] [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: 02/06/2024] [Revised: 03/15/2024] [Accepted: 04/08/2024] [Indexed: 04/13/2024]
Abstract
Vascular endothelial growth factor B (VEGFB), a member of the VEGF family, exhibits limited angiogenic activity in mammals but plays an unexpected role in targeting lipids to peripheral tissues. However, its role in lipid metabolism in fish is unknown. In this study, the vegfb gene was cloned and characterized from spotted sea bass (Lateolabrax maculatus). It encodes 254 amino acids and possesses the typical characteristics of the Vegfb family, demonstrating high homology with those from other vertebrate species. The vegfb gene exhibits the highest expression levels in the liver, followed by the gills, intestine, and adipose tissues in spotted sea bass. In vivo, high-lipid diets decreased vegfb expression and increased lipid deposition in liver of fish. In vitro, palmitic acid + oleic acid treatment or vegfb knockdown significantly increased TG and TC contents, promoting lipid droplet deposition in hepatocytes. Vegfb overexpression has the opposite effects, inhibiting lipid deposition and downregulating fatty acid transport and adipogenesis genes. In contrast, the vegfb knockdown significantly upregulated the expression levels of c/ebpα, plin2, and dgat1 (P < 0.05). These results demonstrate that Vegfb may play an important role in reducing lipid deposition by regulating fatty acid transport and adipogenesis in the hepatocytes of spotted sea bass.
Collapse
Affiliation(s)
- Ningning Su
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Jun Zheng
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Guanrong Zhang
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Junfeng Guan
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Xin Gao
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Zhiyi Cheng
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Chao Xu
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Dizhi Xie
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Yuanyou Li
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China.
| |
Collapse
|
|
12
|
Shen Y, Hou J, Liu W, Lin Z, Ma L, Xu J, Guo Y. An antitumor fungal polysaccharide from Fomitopsis officinalis by activating immunity and inhibiting angiogenesis. Int J Biol Macromol 2024; 267:131320. [PMID: 38569989 DOI: 10.1016/j.ijbiomac.2024.131320] [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: 09/22/2023] [Revised: 03/19/2024] [Accepted: 03/30/2024] [Indexed: 04/05/2024]
Abstract
Macrofungi, a class of unique natural resources, are gaining popularity owing to their potential therapeutic benefits and edibility. From Fomitopsis officinalis, a medicinal macrofungus with anticancer activity, a homogeneous heteropolysaccharide (FOBP50-1) with a molecular weight of 2.21 × 104 g/mol has been extracted and purified. FOBP50-1 was found to be composed of 3-O-methylfucose, fucose, mannose, glucose, and galactose with a ratio of 1: 6.5: 4.4: 8.1: 18.2. The sugar fragments and structure of FOBP50-1 were investigated, which included →6)-α-d-Galp-(1→, →2,6)-α-d-Galp-(1→, →3)-α-l-Fucp-(1→, α-d-Glcp-(1→, →3)-β-d-Manp-(1→, →6)-β-d-Manp-(1→, 3-O-Me-α-l-Fucp-(1→, according to the UV, FT-IR, GC-MS, and NMR data. Besides the structure elucidation, FOBP50-1 showed promising antitumor activity in the zebrafish assays. The following mechanism examination discovered that FOBP50-1 interacted with TLR-4, PD-1, and VEGF to activate immunity and inhibit angiogenesis according to a series of cell, transgenic zebrafish, and surface plasmon resonance (SPR) experiments. The KD values indicating the association of FOBP50-1 with TLR-4, PD-1, and VEGF, were 4.69 × 10-5, 7.98 × 10-6, 3.04 × 10-6 M, respectively, in the SPR experiments. All investigations have demonstrated that the homogenous fungal polysaccharide FOBP50-1 has the potential to be turned into a tumor immunotherapy agent.
Collapse
Affiliation(s)
- Yongye Shen
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, People's Republic of China
| | - Jiantong Hou
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, People's Republic of China
| | - Wenhui Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, People's Republic of China
| | - Zhen Lin
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, People's Republic of China
| | - Lingling Ma
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, People's Republic of China
| | - Jing Xu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, People's Republic of China.
| | - Yuanqiang Guo
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, People's Republic of China; Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, Hainan Normal University, Haikou, Hainan 571158, People's Republic of China.
| |
Collapse
|
|
13
|
Gougoulakis LS, Rothermundt C, Flynn MC, Jörger M, Todorova MG. Electrodiagnostic Biomarkers in Paraneoplastic Retinopathy. Klin Monbl Augenheilkd 2024; 241:510-524. [PMID: 38653300 DOI: 10.1055/a-2227-3970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2024]
Abstract
OBJECTIVE Paraneoplastic retinopathy (PNR) is a rapid-onset photoreceptor and post-photoreceptor dysfunction triggered by a cross-reaction between antigens expressed by the underlying tumour and retinal proteins. The present study aims to determine the electrodiagnostic biomarkers that support the diagnosis of PNR and evaluate the effect of treatment. METHODS A retrospective observational case-controlled study including 25 patients with suspected PNR, of which 11 patients were diagnosed with PNR. The presence of PNR was confirmed based on clinical examination, supported by colour fundus photography, fundus autofluorescence imaging, optical coherence tomography, fluorescein angiography, retinal vessel oximetry, colour test, full-field electroretinogram (ffERG), on-/off ERG, S-cone ERG, and multifocal ERG (mfERG). The relationships between the clinical symptomatology and the effect of therapy were evaluated. RESULTS All PNR patients (Nr: 11) presented with subjective symptoms of newly reported central vision or visual field deterioration. Posterior segment findings showed a severe patchy-like retinal atrophy, attenuation of the retinal vessels, and a waxy optic disc. Optical coherence tomography revealed a discontinued ISe line, and multiple hyperreflective foci. Retinal vessel oxygen saturation was increased. Multifocal ERG revealed reduced central and paracentral responses and ffERG severely attenuated scotopic-, photopic-, on-/off- and S-cone responses. The colour vision test revealed a tritan-tetartan-weakness. Two of the PNR patients underwent rituximab therapy with no further progression and even recovery of electrodiagnostic responses.In 1 nPNR (non-paraneoplastic retinopathy) patient (total Nr: 14) pseudoxanthoma elasticum-related retinopathy was the reason for impaired vision. In 3 of 13 patients with bronchopulmonary cancer a MEK- and FGFR-inhibitor- drug toxicity was the reason for the visual deterioration. CONCLUSION Careful investigation for signs of central and/or peripheral visual field deterioration must be performed in the presence of history of a co-existing malignancy. The possibility of PNR should be taken into account. The electrodiagnostic biomarkers, suggested in this study, may help to promptly recognise PNR and also to evaluate the effect of implemented therapy.
Collapse
Affiliation(s)
| | - Christian Rothermundt
- Clinic of Medical Oncology and Haematology, Cantonal Hospital St. Gallen, Switzerland
| | - Marie-Claire Flynn
- Clinic of Medical Oncology and Haematology, Cantonal Hospital St. Gallen, Switzerland
| | - Markus Jörger
- Clinic of Medical Oncology and Haematology, Cantonal Hospital St. Gallen, Switzerland
| | - Margarita G Todorova
- Department of Ophthalmology, Cantonal Hospital St. Gallen, Switzerland
- Department of Ophthalmology, University of Zürich, Switzerland
| |
Collapse
|
|
14
|
Corrias G, Lai E, Ziranu P, Mariani S, Donisi C, Liscia N, Saba G, Pretta A, Persano M, Fanni D, Spanu D, Balconi F, Loi F, Deidda S, Restivo A, Pusceddu V, Puzzoni M, Solinas C, Massa E, Madeddu C, Gerosa C, Zorcolo L, Faa G, Saba L, Scartozzi M. Prediction of Response to Anti-Angiogenic Treatment for Advanced Colorectal Cancer Patients: From Biological Factors to Functional Imaging. Cancers (Basel) 2024; 16:1364. [PMID: 38611042 PMCID: PMC11011199 DOI: 10.3390/cancers16071364] [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: 02/25/2024] [Revised: 03/24/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open
Abstract
Colorectal cancer (CRC) is a leading tumor worldwide. In CRC, the angiogenic pathway plays a crucial role in cancer development and the process of metastasis. Thus, anti-angiogenic drugs represent a milestone for metastatic CRC (mCRC) treatment and lead to significant improvement of clinical outcomes. Nevertheless, not all patients respond to treatment and some develop resistance. Therefore, the identification of predictive factors able to predict response to angiogenesis pathway blockade is required in order to identify the best candidates to receive these agents. Unfortunately, no predictive biomarkers have been prospectively validated to date. Over the years, research has focused on biologic factors such as genetic polymorphisms, circulating biomarkers, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and microRNA. Moreover, research efforts have evaluated the potential correlation of molecular biomarkers with imaging techniques used for tumor assessment as well as the application of imaging tools in clinical practice. In addition to functional imaging, radiomics, a relatively newer technique, shows real promise in the setting of correlating molecular medicine to radiological phenotypes.
Collapse
Affiliation(s)
- Giuseppe Corrias
- Department of Radiology, University of Cagliari, 09042 Cagliari, Italy;
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Nicole Liscia
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132 Milan, Italy;
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Daniela Fanni
- Division of Pathology, Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy; (D.F.); (C.G.); (G.F.)
| | - Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Francesca Balconi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Francesco Loi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Simona Deidda
- Colorectal Surgery Unit, A.O.U. Cagliari, Department of Surgical Science, University of Cagliari, 09042 Cagliari, Italy; (S.D.); (A.R.); (L.Z.)
| | - Angelo Restivo
- Colorectal Surgery Unit, A.O.U. Cagliari, Department of Surgical Science, University of Cagliari, 09042 Cagliari, Italy; (S.D.); (A.R.); (L.Z.)
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Cinzia Solinas
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Elena Massa
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Clelia Madeddu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Clara Gerosa
- Division of Pathology, Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy; (D.F.); (C.G.); (G.F.)
| | - Luigi Zorcolo
- Colorectal Surgery Unit, A.O.U. Cagliari, Department of Surgical Science, University of Cagliari, 09042 Cagliari, Italy; (S.D.); (A.R.); (L.Z.)
| | - Gavino Faa
- Division of Pathology, Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy; (D.F.); (C.G.); (G.F.)
| | - Luca Saba
- Department of Radiology, University of Cagliari, 09042 Cagliari, Italy;
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| |
Collapse
|
|
15
|
Farahmand Y, Nabiuni M, Vafaei Mastanabad M, Sheibani M, Mahmood BS, Obayes AM, Asadi F, Davallou R. The exo-microRNA (miRNA) signaling pathways in pathogenesis and treatment of stroke diseases: Emphasize on mesenchymal stem cells (MSCs). Cell Biochem Funct 2024; 42:e3917. [PMID: 38379232 DOI: 10.1002/cbf.3917] [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: 10/25/2023] [Revised: 12/07/2023] [Accepted: 12/17/2023] [Indexed: 02/22/2024]
Abstract
A major factor in long-term impairment is stroke. Patients with persistent stroke and severe functional disabilities have few therapy choices. Long noncoding RNAs (lncRNAs) may contribute to the regulation of the pathophysiologic processes of ischemic stroke as shown by altered expression of lncRNAs and microRNA (miRNAs) in blood samples of acute ischemic stroke patients. On the other hand, multipotent mesenchymal stem cells (MSCs) increase neurogenesis, and angiogenesis, dampen neuroinflammation, and boost brain plasticity to improve functional recovery in experimental stroke models. MSCs can be procured from various sources such as the bone marrow, adipose tissue, and peripheral blood. Under the proper circumstances, MSCs can differentiate into a variety of mature cells, including neurons, astrocytes, and oligodendrocytes. Accordingly, the capability of MSCs to exert neuroprotection and also neurogenesis has recently attracted more attention. Nowadays, lncRNAs and miRNAs derived from MSCs have opened new avenues to alleviate stroke symptoms. Accordingly, in this review article, we examined various studies concerning the lncRNAs and miRNAs' role in stroke pathogenesis and delivered an overview of the therapeutic role of MSC-derived miRNAs and lncRNAs in stroke conditions.
Collapse
Affiliation(s)
- Yalda Farahmand
- School of Medicine, Terhan University of Medical Sciences, Tehran, Iran
| | - Mohsen Nabiuni
- Neurosurgery Department, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Vafaei Mastanabad
- Neurosurgery Department, Faculty of Medicine, Qazvin University of Medical Science, Qazvin, Iran
| | - Mehrnaz Sheibani
- Division of Pediatric Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | | | - Ali Mohammed Obayes
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | - Fatemeh Asadi
- Department of Genetics, Fars Science and Research Branch, Islamic Azad University, Marvdasht, Iran
- Department of Genetics, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran
| | - Rosa Davallou
- Department of Neurology, Sayyad Shirazi Hospital, Golestan University of Medical Siences, Gorgan, Iran
| |
Collapse
|
|
16
|
Chakraborty MP, Das D, Mondal P, Kaul P, Bhattacharyya S, Kumar Das P, Das R. Molecular basis of VEGFR1 autoinhibition at the plasma membrane. Nat Commun 2024; 15:1346. [PMID: 38355851 PMCID: PMC10866885 DOI: 10.1038/s41467-024-45499-2] [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: 06/08/2023] [Accepted: 01/24/2024] [Indexed: 02/16/2024] Open
Abstract
Ligand-independent activation of VEGFRs is a hallmark of diabetes and several cancers. Like EGFR, VEGFR2 is activated spontaneously at high receptor concentrations. VEGFR1, on the other hand, remains constitutively inactive in the unligated state, making it an exception among VEGFRs. Ligand stimulation transiently phosphorylates VEGFR1 and induces weak kinase activation in endothelial cells. Recent studies, however, suggest that VEGFR1 signaling is indispensable in regulating various physiological or pathological events. The reason why VEGFR1 is regulated differently from other VEGFRs remains unknown. Here, we elucidate a mechanism of juxtamembrane inhibition that shifts the equilibrium of VEGFR1 towards the inactive state, rendering it an inefficient kinase. The juxtamembrane inhibition of VEGFR1 suppresses its basal phosphorylation even at high receptor concentrations and transiently stabilizes tyrosine phosphorylation after ligand stimulation. We conclude that a subtle imbalance in phosphatase activation or removing juxtamembrane inhibition is sufficient to induce ligand-independent activation of VEGFR1 and sustain tyrosine phosphorylation.
Collapse
Affiliation(s)
- Manas Pratim Chakraborty
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur, 741246, India
| | - Diptatanu Das
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur, 741246, India
| | - Purav Mondal
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur, 741246, India
| | - Pragya Kaul
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur, 741246, India
| | - Soumi Bhattacharyya
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur, 741246, India
| | - Prosad Kumar Das
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur, 741246, India
| | - Rahul Das
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur, 741246, India.
- Centre for Advanced Functional Materials, Indian Institute of Science Education and Research Kolkata, Mohanpur campus, Mohanpur, 741246, India.
| |
Collapse
|
|
17
|
Li F, Lin Y, Li R, Shen X, Xiang M, Xiong G, Zhang K, Xia T, Guo J, Miao Z, Liao Y, Zhang X, Xie L. Molecular targeted therapy for metastatic colorectal cancer: current and evolving approaches. Front Pharmacol 2023; 14:1165666. [PMID: 37927605 PMCID: PMC10622804 DOI: 10.3389/fphar.2023.1165666] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 10/02/2023] [Indexed: 11/07/2023] Open
Abstract
Colorectal cancer (CRC) represents 10% of all cancer types, making it the third leading cause of cancer-related deaths globally. Metastasis is the primary factor causing mortality in CRC patients. Approximately 22% of CRC-related deaths have metastasis present at diagnosis, with approximately 70% of these cases recurring. Recently, with the application of novel targeted drugs, targeted therapy has become the first-line option for individualized and comprehensive treatment of CRC. The management of these patients remains a significant medical challenge. The most prevalent targeted therapies for CRC in clinical practice focus on anti-vascular endothelial growth factor and its receptor, epidermal growth factor receptor (EGFR), and multi-target kinase inhibitors. In the wake of advancements in precision diagnosis and widespread adoption of second-generation sequencing (NGS) technology, rare targets such as BRAF V600E mutation, KRAS mutation, HER2 overexpression/amplification, and MSI-H/dMMR in metastatic colorectal cancer (mCRC) are increasingly being discovered. Simultaneously, new therapeutic drugs targeting these mutations are being actively investigated. This article reviews the progress in clinical research for developing targeted therapeutics for CRC, in light of advances in precision medicine and discovery of new molecular target drugs.
Collapse
Affiliation(s)
- Furong Li
- Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Yanping Lin
- Department of Gastroenterology and Internal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Rong Li
- Department of Gastroenterology and Internal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Xin Shen
- Department of Gastroenterology and Internal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Mengying Xiang
- Department of Gastroenterology and Internal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Guangrui Xiong
- Department of Gastroenterology and Internal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Ke Zhang
- Department of Gastroenterology and Internal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Tingrong Xia
- Department of Gastroenterology and Internal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Jiangyan Guo
- Department of Pathology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Zhonghui Miao
- Department of Gastroenterology and Internal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Yedan Liao
- Department of Gastroenterology and Internal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Xuan Zhang
- Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Lin Xie
- Department of Gastroenterology and Internal Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| |
Collapse
|
|
18
|
Yang Y, Zhong J, Cui D, Jensen LD. Up-to-date molecular medicine strategies for management of ocular surface neovascularization. Adv Drug Deliv Rev 2023; 201:115084. [PMID: 37689278 DOI: 10.1016/j.addr.2023.115084] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 08/30/2023] [Accepted: 09/04/2023] [Indexed: 09/11/2023]
Abstract
Ocular surface neovascularization and its resulting pathological changes significantly alter corneal refraction and obstruct the light path to the retina, and hence is a major cause of vision loss. Various factors such as infection, irritation, trauma, dry eye, and ocular surface surgery trigger neovascularization via angiogenesis and lymphangiogenesis dependent on VEGF-related and alternative mechanisms. Recent advances in antiangiogenic drugs, nanotechnology, gene therapy, surgical equipment and techniques, animal models, and drug delivery strategies have provided a range of novel therapeutic options for the treatment of ocular surface neovascularization. In this review article, we comprehensively discuss the etiology and mechanisms of corneal neovascularization and other types of ocular surface neovascularization, as well as emerging animal models and drug delivery strategies that facilitate its management.
Collapse
Affiliation(s)
- Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Junmu Zhong
- Department of Ophthalmology, Longyan First Hospital Affiliated to Fujian Medical University, Longyan 364000, Fujian Province, China
| | - Dongmei Cui
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen 518040, Guangdong Province, China
| | - Lasse D Jensen
- Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine, Unit of Cardiovascular Medicine, Linköping University, Linköping, Sweden.
| |
Collapse
|
|
19
|
Go EJ, Yang H, Lee SJ, Yang HG, Shin JA, Lee WS, Lim HS, Chon HJ, Kim C. PB101, a VEGF- and PlGF-targeting decoy protein, enhances antitumor immunity and suppresses tumor progression and metastasis. Oncoimmunology 2023; 12:2259212. [PMID: 37744990 PMCID: PMC10515676 DOI: 10.1080/2162402x.2023.2259212] [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: 05/11/2023] [Accepted: 09/11/2023] [Indexed: 09/26/2023] Open
Abstract
Antiangiogenic therapy is a recognized method for countering the immunosuppressive tumor microenvironment (TME) and improving anti-tumor immunity. PB101 is a glycosylated decoy receptor that binds to VEGF-A and PlGF with high affinity, based on the VEGFR1 backbone. Here, we elucidated PB101-induced remodeling of tumor angiogenesis and immunity, which enhances anti-PD-L1 immune checkpoint blockade. PB101 inhibited tumor growth by suppressing angiogenesis and enhancing CD8+ T cell infiltration into the tumors. PB101 induced robust reprogramming of antitumor immunity and activates intratumoral CD8+ T cells. Anti-tumor efficacy of PB101 is mostly dependent on CD8+ T cells and IFN-γ. PB101 reprograms tumor immunity in a manner distinct from that of the conventional VEGF decoy receptor, VEGF-trap. With its potent immune-modulating capability, PB101 synergizes with an anti-PD-L1, triggering strengthened antitumor immunity. Combining PB101 and anti-PD-L1 could establish durable protective immunity against tumor recurrence and metastasis. The findings of this study offer scientific rationales for further clinical development of PB101, particularly when used in combination with immune checkpoint inhibitors, as a potential treatment for advanced cancers.
Collapse
Affiliation(s)
- Eun-Jin Go
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University School of Medicine, Seongnam, Gyeonggi-do, Republic of Korea
| | - Hannah Yang
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University School of Medicine, Seongnam, Gyeonggi-do, Republic of Korea
| | - Seung Joon Lee
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University School of Medicine, Seongnam, Gyeonggi-do, Republic of Korea
| | - Hyun Gul Yang
- Panolos Bioscience, Inc, Hwaseong-si, Republic of Korea
| | - Jin A. Shin
- Panolos Bioscience, Inc, Hwaseong-si, Republic of Korea
| | - Won Suk Lee
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University School of Medicine, Seongnam, Gyeonggi-do, Republic of Korea
| | - Hye Seong Lim
- Panolos Bioscience, Inc, Hwaseong-si, Republic of Korea
| | - Hong Jae Chon
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University School of Medicine, Seongnam, Gyeonggi-do, Republic of Korea
| | - Chan Kim
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, Republic of Korea
- Laboratory of Translational Immuno-Oncology, CHA University School of Medicine, Seongnam, Gyeonggi-do, Republic of Korea
| |
Collapse
|
|
20
|
Moon BH, Kim Y, Kim SY. Twenty Years of Anti-Vascular Endothelial Growth Factor Therapeutics in Neovascular Age-Related Macular Degeneration Treatment. Int J Mol Sci 2023; 24:13004. [PMID: 37629185 PMCID: PMC10454953 DOI: 10.3390/ijms241613004] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/10/2023] [Accepted: 08/13/2023] [Indexed: 08/27/2023] Open
Abstract
Neovascular age-related macular degeneration (nAMD) is the primary disastrous retinal disease that leads to blindness in the elderly population. In the early 2000s, nAMD resulted in irreversible vision loss and blindness with no available treatment options. However, there have been breakthrough advances in the drug development of anti-angiogenic biological agents over the last two decades. The primary target molecule for treating nAMD is the vascular endothelial growth factor (VEGF), and there are currently several anti-VEGF drugs such as bevacizumab, ranibizumab, and aflibercept, which have made nAMD more manageable than before, thus preventing vision loss. Nevertheless, it should be noted that these anti-VEGF drugs for nAMD treatment are not effective in more than half of the patients, and even those who initially gain visual improvements lose their vision over time, along with potential deterioration in the geography of atrophy. As a result, there have been continuous endeavors to improve anti-VEGF agents through better efficacy, fewer doses, expanded intervals, and additional targets. This review describes past and current anti-VEGF therapeutics used to treat nAMD and outlines future directions to improve the effectiveness and safety of anti-VEGF agents.
Collapse
Affiliation(s)
- Bo-Hyun Moon
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - Younghwa Kim
- Department of Paramedicine, Kyungil University, Gyeongsan-si 38428, Gyeongbuk, Republic of Korea
| | - Soo-Young Kim
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298, USA
| |
Collapse
|
|
21
|
Cao Y, Langer R, Ferrara N. Targeting angiogenesis in oncology, ophthalmology and beyond. Nat Rev Drug Discov 2023; 22:476-495. [PMID: 37041221 DOI: 10.1038/s41573-023-00671-z] [Citation(s) in RCA: 122] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/24/2023] [Indexed: 04/13/2023]
Abstract
Angiogenesis is an essential process in normal development and in adult physiology, but can be disrupted in numerous diseases. The concept of targeting angiogenesis for treating diseases was proposed more than 50 years ago, and the first two drugs targeting vascular endothelial growth factor (VEGF), bevacizumab and pegaptanib, were approved in 2004 for the treatment of cancer and neovascular ophthalmic diseases, respectively. Since then, nearly 20 years of clinical experience with anti-angiogenic drugs (AADs) have demonstrated the importance of this therapeutic modality for these disorders. However, there is a need to improve clinical outcomes by enhancing therapeutic efficacy, overcoming drug resistance, defining surrogate markers, combining with other drugs and developing the next generation of therapeutics. In this Review, we examine emerging new targets, the development of new drugs and challenging issues such as the mode of action of AADs and elucidating mechanisms underlying clinical benefits; we also discuss possible future directions of the field.
Collapse
Affiliation(s)
- Yihai Cao
- Department of Microbiology, Tumour and Cell Biology, Karolinska Institute, Stockholm, Sweden.
| | - Robert Langer
- David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Napoleone Ferrara
- Department of Pathology, University of California San Diego, La Jolla, CA, USA.
- Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA.
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
| |
Collapse
|
|
22
|
Yu J, Zhuang A, Gu X, Hua Y, Yang L, Ge S, Ruan J, Chai P, Jia R, Fan X. Nuclear PD-L1 promotes EGR1-mediated angiogenesis and accelerates tumorigenesis. Cell Discov 2023; 9:33. [PMID: 36977660 PMCID: PMC10050073 DOI: 10.1038/s41421-023-00521-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 01/10/2023] [Indexed: 03/30/2023] Open
Abstract
Targeting programmed cell death protein ligand 1 (PD-L1) remains one of the most essential immunotherapies in cancer1,2. PD-L1 has been detected in the nucleus in multiple malignancies, playing an oncogenic role independent of immune checkpoint regulation3-5. Howbeit, the regulatory function of nuclear PD-L1 (nPD-L1) remains to be fully understood. Here, we report that nPD-L1 is an endogenous accelerator for cancer angiogenesis. First, we found that an abundant proportion of PD-L1 was distributed within the nucleus of uveal melanoma samples, which is associated with an unfavorable outcome. Moreover, the capacity of promoting angiogenesis was largely attenuated in the nPD-L1-deficient cells both in vivo and in vitro. Mechanistically, nPD-L1 facilitates p-STAT3 binding to the promoter of early growth response-1 (EGR1), resulting in the activation of EGR1-mediated angiogenesis. Therapeutically, the inhibition of histone deacetylase 2 restores the normal acetylation level of PD-L1, blocking its nuclear translocation and thereby attenuating tumor angiogenesis. Conclusively, we reveal that nPD-L1 promotes angiogenesis in malignancies, and provide a novel anti-vascularization strategy through blocking aberrant PD-L1 nuclear translocation for tumor therapy.
Collapse
Affiliation(s)
- Jie Yu
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Ai Zhuang
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Xiang Gu
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yu Hua
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Ludi Yang
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Shengfang Ge
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Jing Ruan
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Peiwei Chai
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
| | - Renbing Jia
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
| | - Xianqun Fan
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
| |
Collapse
|
|
23
|
Kremer V, Oppelaar JJ, Gimbel T, Koziarek S, Ganzevoort W, van Pampus MG, van den Born BJ, Vogt L, de Groot C, Boon RA. Neuro-oncological Ventral Antigen 2 Regulates Splicing of Vascular Endothelial Growth Factor Receptor 1 and Is Required for Endothelial Function. Reprod Sci 2023; 30:678-689. [PMID: 35927413 PMCID: PMC9988812 DOI: 10.1007/s43032-022-01044-4] [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: 04/01/2022] [Accepted: 07/16/2022] [Indexed: 11/24/2022]
Abstract
Pre-eclampsia (PE) affects 2-8% of pregnancies and is responsible for significant morbidity and mortality. The maternal clinical syndrome (defined by hypertension, proteinuria, and organ dysfunction) is the result of endothelial dysfunction. The endothelial response to increased levels of soluble FMS-like Tyrosine Kinase 1 (sFLT1) is thought to play a central role. sFLT1 is released from multiple tissues and binds VEGF with high affinity and antagonizes VEGF. Expression of soluble variants of sFLT1 is a result of alternative splicing; however, the mechanism is incompletely understood. We hypothesize that neuro-oncological ventral antigen 2 (NOVA2) contributes to this. NOVA2 was inhibited in human umbilical vein endothelial cells (HUVECs) and multiple cellular functions were assessed. NOVA2 and FLT1 expression in the placenta of PE, pregnancy-induced hypertension, and normotensive controls was measured by RT-qPCR. Loss of NOVA2 in HUVECs resulted in significantly increased levels of sFLT1, but did not affect expression of membrane-bound FLT1. NOVA2 protein was shown to directly interact with FLT1 mRNA. Loss of NOVA2 was also accompanied by impaired endothelial functions such as sprouting. We were able to restore sprouting capacity by exogenous VEGF. We did not observe statistically significant regulation of NOVA2 or sFLT1 in the placenta. However, we observed a negative correlation between sFLT1 and NOVA2 expression levels. In conclusion, NOVA2 was found to regulate FLT1 splicing in the endothelium. Loss of NOVA2 resulted in impaired endothelial function, at least partially dependent on VEGF. In PE patients, we observed a negative correlation between NOVA2 and sFLT1.
Collapse
Affiliation(s)
- Veerle Kremer
- Department of Physiology, Amsterdam Cardiovascular Sciences, VU Medical Center, Amsterdam UMC, Amsterdam, The Netherlands.,Department of Medical Chemistry, Academic Medical Center, Amsterdam UMC, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences, Microcirculation, Amsterdam, The Netherlands
| | - Jetta J Oppelaar
- Department of Internal Medicine, Section of Nephrology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
| | - Theresa Gimbel
- Institute of Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany.,German Centre for Cardiovascular Research DZHK, Partner Site Frankfurt Rhein/Main, Frankfurt am Main, Germany
| | - Susanne Koziarek
- Institute of Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany.,German Centre for Cardiovascular Research DZHK, Partner Site Frankfurt Rhein/Main, Frankfurt am Main, Germany
| | - Wessel Ganzevoort
- Department of Obstetrics and Gynecology, Amsterdam Reproduction & Development, Amsterdam UMC University of Amsterdam, Amsterdam, The Netherlands
| | | | - Bert-Jan van den Born
- Department of Internal Medicine, Section of Vascular Medicine, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences, Atherosclerosis and Ischemic Syndromes, Amsterdam, The Netherlands
| | - Liffert Vogt
- Amsterdam Cardiovascular Sciences, Microcirculation, Amsterdam, The Netherlands.,Department of Internal Medicine, Section of Nephrology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
| | - Christianne de Groot
- Department of Obstetrics and Gynaecology, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands
| | - Reinier A Boon
- Department of Physiology, Amsterdam Cardiovascular Sciences, VU Medical Center, Amsterdam UMC, Amsterdam, The Netherlands. .,Institute of Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany. .,German Centre for Cardiovascular Research DZHK, Partner Site Frankfurt Rhein/Main, Frankfurt am Main, Germany. .,Amsterdam UMC, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.
| |
Collapse
|
|
24
|
Jia W, Tian H, Jiang J, Zhou L, Li L, Luo M, Ding N, Nice EC, Huang C, Zhang H. Brain-Targeted HFn-Cu-REGO Nanoplatform for Site-Specific Delivery and Manipulation of Autophagy and Cuproptosis in Glioblastoma. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2205354. [PMID: 36399643 DOI: 10.1002/smll.202205354] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/16/2022] [Indexed: 06/16/2023]
Abstract
Durable glioblastoma multiforme (GBM) management requires long-term chemotherapy after surgery to eliminate remaining cancerous tissues. Among chemotherapeutics, temozolomide is considered as the first-line drug for GBM therapy, but the treatment outcome is not satisfactory. Notably, regorafenib, an oral multi-kinase inhibitor, has been reported to exert a markedly superior effect on GBM suppression compared with temozolomide. However, poor site-specific delivery and bioavailability significantly restrict the efficient permeability of regorafenib to brain lesions and compromise its treatment efficacy. Therefore, human H-ferritin (HFn), regorafenib, and Cu2+ are rationally designed as a brain-targeted nanoplatform (HFn-Cu-REGO NPs), fulfilling the task of site-specific delivery and manipulating autophagy and cuproptosis against GBM. Herein, HFn affords a preferential accumulation capacity to GBM due to transferrin receptor 1 (TfR1)-mediated active targeting and pH-responsive delivery behavior. Moreover, regorafenib can inhibit autophagosome-lysosome fusion, resulting in lethal autophagy arrest in GBM cells. Furthermore, Cu2+ not only facilitates the encapsulation of regorafenib to HFn through coordination interaction but also disturbs copper homeostasis for triggering cuproptosis, resulting in a synergistical effect with regorafenib-mediated lethal autophagy arrest against GBM. Therefore, this work may broaden the clinical application scope of Cu2+ and regorafenib in GBM treatment via modulating autophagy and cuproptosis.
Collapse
Affiliation(s)
- Wenhui Jia
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Hailong Tian
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Jingwen Jiang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Li Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Lei Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, P. R. China
| | - Maochao Luo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Ning Ding
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, P. R. China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China
| | - Haiyuan Zhang
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, 434023, China
| |
Collapse
|
|
25
|
Cao Y. Blood vessels in fat tissues and vasculature-derived signals in controlling lipid metabolism and metabolic disease. Chin Med J (Engl) 2022; 135:2647-2652. [PMID: 36382988 PMCID: PMC9943976 DOI: 10.1097/cm9.0000000000002406] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Indexed: 11/17/2022] Open
Affiliation(s)
- Yihai Cao
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 65 Stockholm, Sweden
- Hong Kong Centre for Cerebro-Cardiovascular Health Engineering, Hong Kong, China
| |
Collapse
|
|
26
|
Yang Y, Cao Y. The impact of VEGF on cancer metastasis and systemic disease. Semin Cancer Biol 2022; 86:251-261. [PMID: 35307547 DOI: 10.1016/j.semcancer.2022.03.011] [Citation(s) in RCA: 131] [Impact Index Per Article: 43.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 03/08/2022] [Accepted: 03/15/2022] [Indexed: 01/27/2023]
Abstract
Metastasis is the leading cause of cancer-associated mortality and the underlying mechanisms of cancer metastasis remain elusive. Both blood and lymphatic vasculatures are essential structures for mediating distal metastasis. The vasculature plays multiple functions, including accelerating tumor growth, sustaining the tumor microenvironment, supplying growth and invasive signals, promoting metastasis, and causing cancer-associated systemic disease. VEGF is one of the key angiogenic factors in tumors and participates in the initial stage of tumor development, progression and metastasis. Consequently, VEGF and its receptor-mediated signaling pathways have become one of the most important therapeutic targets for treating various cancers. Today, anti-VEGF-based antiangiogenic drugs (AADs) are widely used in the clinic for treating different types of cancer in human patients. Despite nearly 20-year clinical experience with AADs, the impact of these drugs on cancer metastasis and systemic disease remains largely unknown. In this review article, we focus our discussion on tumor VEGF in cancer metastasis and systemic disease and mechanisms underlying AADs in clinical benefits.
Collapse
Affiliation(s)
- Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Yihai Cao
- Department of Microbiology, Tumor and Cell Biology, Biomedicum, Karolinska Institute, 171 77 Stockholm, Sweden.
| |
Collapse
|
|
27
|
Barta P, Kamaraj R, Kucharova M, Novy Z, Petrik M, Bendova K, Hajduch M, Pavek P, Trejtnar F. Preparation, In Vitro Affinity, and In Vivo Biodistribution of Receptor-Specific 68Ga-Labeled Peptides Targeting Vascular Endothelial Growth Factor Receptors. Bioconjug Chem 2022; 33:1825-1836. [PMID: 36197842 DOI: 10.1021/acs.bioconjchem.2c00272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
As angiogenesis plays a key role in tumor growth and metastasis, the angiogenic process has attracted scientific interest as a target for diagnostic and therapeutic agents. Factors influencing angiogenesis include the vascular endothelial growth factor (VEGF) family and the two associated receptor types (VEGFR-1 and VEGFR-2). VEGFR-1/-2 detection and quantification in cancer lesions are essential for tumor process management. As a result of the advantageous pharmacokinetics and image contrast, peptides radiolabeled with PET emitters have become interesting tools for the visualization of VEGFR-1/-2-positive tumors. In this study, we prepared 68Ga-labeled peptides containing 15 (peptide 1) and 23 (peptide 2) amino acids as new PET tracers for tumor angiogenic process imaging. METHODS The peptides were conjugated with NODAGA-tris(t-Bu ester) and subsequently radiolabeled with [68Ga]Ga-chloride. The prepared [68Ga]Ga-NODAGA-peptide 1 and [68Ga]Ga-NODAGA-peptide 2 were tested for radiochemical purity and saline/plasma stability. Consequently, the binding affinity toward VEGFRs was assessed in vitro on human glioblastoma and kidney carcinoma cells. The found peptide receptor affinity was compared with the calculated values in the PROtein binDIng enerGY prediction (PRODIGY) server. Finally, the biodistribution study was performed on BALB/c female mice to reveal the basic pharmacokinetic behavior of radiopeptides. RESULTS The in vitro affinity testing of [68Ga]Ga-NODAGA-peptides 1 and 2 showed retained receptor binding as characterized by equilibrium dissociation constant (KD) values in the range of 0.5-1.2 μM and inhibitory concentration 50% (IC50) values in the range of 3.0-5.6 μM. Better binding properties of peptide 2 to VEGFR-1/-2 were found in the PRODIGY server. The biodistribution study on mice showed remarkable accumulation of both peptides in the kidneys and urinary bladder with a short half-life after intravenous application. The in vitro plasma stability of [68Ga]Ga-NODAGA-peptide 2 was superior to that of [68Ga]Ga-NODAGA-peptide 1. CONCLUSIONS The obtained results demonstrated a high radiolabeling yield with no need for purification and preserved binding potency of 68Ga-labeled peptides 1 and 2 toward VEGFRs in cancer cells. The peptide-receptor protein interaction assessed in protein-peptide docking determined the strongest interaction of peptide 2 with domain 2 of VEGFR-2 in addition to a more acceptable plasma stability (t1/2 = 120 min) than that for peptide 1. We found both radiolabeled peptides very potent in their receptor binding, which makes them suitable imaging agents. The rapid transition of the radiopeptides into the urinary tract indicates suitable pharmacokinetic characteristics.
Collapse
Affiliation(s)
- Pavel Barta
- Faculty of Pharmacy in Hradec Kralove, Department of Biophysics and Physical Chemistry, Charles University, Hradec Kralove 500 05, Czech Republic
| | - Rajamanikkam Kamaraj
- Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Charles University, Hradec Kralove 500 05, Czech Republic
| | - Monika Kucharova
- Faculty of Pharmacy in Hradec Kralove, Department of Biophysics and Physical Chemistry, Charles University, Hradec Kralove 500 05, Czech Republic
| | - Zbynek Novy
- Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacky University Olomouc, Olomouc 779 00, Czech Republic
| | - Milos Petrik
- Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacky University Olomouc, Olomouc 779 00, Czech Republic
| | - Katerina Bendova
- Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacky University Olomouc, Olomouc 779 00, Czech Republic
| | - Marian Hajduch
- Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacky University Olomouc, Olomouc 779 00, Czech Republic
| | - Petr Pavek
- Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Charles University, Hradec Kralove 500 05, Czech Republic
| | - Frantisek Trejtnar
- Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Charles University, Hradec Kralove 500 05, Czech Republic
| |
Collapse
|
|
28
|
Zhu M, Niu Q, Zhang J, Yu Y, Wang H, Zhu T, Wang G, Yang L, Yin Y, Li P. Amorphous selenium nanodots alleviate non-alcoholic fatty liver disease via activating VEGF receptor 1 to further inhibit phosphorylation of JNK/p38 MAPK pathways. Eur J Pharmacol 2022; 932:175235. [PMID: 36049560 DOI: 10.1016/j.ejphar.2022.175235] [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: 07/12/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 12/01/2022]
Abstract
In clinic, there is still no unified standard for the treatment of non-alcoholic fatty liver disease (NAFLD), and the development of effective novel drugs to alleviate NAFLD remains a challenge. This study aimed to explore the effect and mechanism of amorphous selenium nanodots (A SeNDs) in alleviating NAFLD. Model rats with NAFLD were induced by the high-fat diet (HFD). Histomorphology was used to observe liver tissue, automatic biochemical analyzer was used to analyze liver function indicators, and ELISA kit was used to detect the effect of A SeNDs on oxidative stress and inflammatory factors in NAFLD rats. The results exhibited that A SeNDs could reduce hepatocyte steatosis, liver index, blood lipid level, and transaminase level in NAFLD rats. Furthermore, A SeNDs could relieve the oxidative stress and inflammatory reaction and maintain liver tissue structure in NAFLD rats. Mechanistically, A SeNDs (0.3 mg/kg/day) inhibit the phosphorylation of JNK/p38 MAPK pathways after activating vascular endothelial growth factor receptor 1 (VEGFR1) in the liver of rats with NAFLD to allay oxidative stress and inflammatory response and improves hepatic structure and liver function. Therefore, it should be an important method to mitigate NAFLD by supplementing A SeNDs to normalize hepatic structure and liver function.
Collapse
Affiliation(s)
- Moli Zhu
- School of Pharmacy, Xinxiang Medical University, Xinxiang, 453000, China; Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, 453000, China
| | - Qianqian Niu
- School of Pharmacy, Xinxiang Medical University, Xinxiang, 453000, China
| | - Jie Zhang
- School of Pharmacy, Xinxiang Medical University, Xinxiang, 453000, China
| | - Yanan Yu
- School of Pharmacy, Xinxiang Medical University, Xinxiang, 453000, China
| | - Huanhuan Wang
- School of Pharmacy, Xinxiang Medical University, Xinxiang, 453000, China
| | - Tiantian Zhu
- School of Pharmacy, Xinxiang Medical University, Xinxiang, 453000, China
| | - Ge Wang
- Basic Medical College, Xinxiang Medical University, Xinxiang, 453000, China
| | - Lin Yang
- Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, 453000, China.
| | - Yaling Yin
- Basic Medical College, Xinxiang Medical University, Xinxiang, 453000, China.
| | - Peng Li
- School of Pharmacy, Xinxiang Medical University, Xinxiang, 453000, China.
| |
Collapse
|
|
29
|
Placental growth factor stabilizes VEGF receptor-2 protein in retinal pigment epithelial cells by downregulating glycogen synthase kinase 3 activity. J Biol Chem 2022; 298:102378. [PMID: 35970387 PMCID: PMC9478399 DOI: 10.1016/j.jbc.2022.102378] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 08/04/2022] [Accepted: 08/06/2022] [Indexed: 11/24/2022] Open
Abstract
Placental growth factor (PlGF) belongs to the vascular endothelial growth factor (VEGF) family of proteins that participate in angiogenesis and vasculogenesis. Anti-VEGF therapy has become the standard treatment for ocular angiogenic disorders in ophthalmological practice. However, there is emerging evidence that anti-VEGF treatment may increase the risk of atrophy of the retinal pigment epithelium (RPE), which is important for the homeostasis of retinal tissue. Whereas the cytoprotective role of VEGF family molecules, particularly that of VEGF A (VEGFA) through its receptor VEGF receptor-2 (VEGFR-2), has been recognized, the physiological role of PlGF in the retina is still unknown. In this study, we explored the role of PlGF in the RPE using PlGF-knockdown RPE cells generated by retrovirus-based PlGF-shRNA transduction. We show that VEGFA reduced apoptosis induced by serum starvation in RPE cells, whereas the antiapoptotic effect of VEGFA was abrogated by VEGFR-2 knockdown. Furthermore, PlGF knockdown increased serum starvation–induced cell apoptosis and unexpectedly reduced the protein level of VEGFR-2 in the RPE. The antiapoptotic effect of VEGFA was also diminished in PlGF-knockdown RPE cells. In addition, we found that glycogen synthase kinase 3 activity was involved in proteasomal degradation of VEGFR-2 in RPE cells and inactivated by PlGF via AKT phosphorylation. Overall, the present data demonstrate that PlGF is crucial for RPE cell viability and that PlGF supports VEGFA/VEGFR-2 signaling by stabilizing the VEGFR-2 protein levels through glycogen synthase kinase 3 inactivation.
Collapse
|
|
30
|
Ling M, Lai X, Quan L, Li F, Lang L, Fu Y, Feng S, Yi X, Zhu C, Gao P, Zhu X, Wang L, Shu G, Jiang Q, Wang S. Knockdown of VEGFB/VEGFR1 Signaling Promotes White Adipose Tissue Browning and Skeletal Muscle Development. Int J Mol Sci 2022; 23:ijms23147524. [PMID: 35886871 PMCID: PMC9315609 DOI: 10.3390/ijms23147524] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 07/04/2022] [Accepted: 07/06/2022] [Indexed: 02/01/2023] Open
Abstract
It has been demonstrated that vascular endothelial growth factor B (VEGFB) and vascular endothelial growth factor receptor 1 (VEGFR1) play a vital role in regulating vascular biological function. However, the role of VEGFB and VEGFR1 in regulating fat deposition and skeletal muscle growth remains unclear. Therefore, this study was conducted to investigate the effects of VEGFB and VEGFR1 on fat deposition and skeletal muscle growth in mice. Our results showed that knockdown of VEGFB decreased body weight and iWAT index, stimulated the browning of mice iWAT with increased expression of UCP1, decreased the diameters of adipocytes, and elevated energy expenditure. In contrast, knockdown of VEGFB increased gastrocnemius (GAS) muscle index with increased proliferation of GAS muscle by expression of PCNA and Cyclin D1. Meanwhile, knockdown of endothelial VEGFR1 induced the browning of iWAT with increased expression of UCP1 and decreased diameters of adipocytes. By contrast, knockdown of endothelial VEGFR1 inhibited GAS muscle differentiation with decreased expression of MyoD. In conclusion, these results suggested that the loss of VEGFB/VEGFR1 signaling is associated with enhanced browning of inguinal white adipose tissue and skeletal muscle development. These results provided new insights into the regulation of skeletal muscle growth and regeneration, as well as fat deposition, suggesting the potential application of VEGFB/VEGFR1 as an intervention for the restriction of muscle diseases and obesity and related metabolic disorders.
Collapse
Affiliation(s)
- Mingfa Ling
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Xumin Lai
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Lulu Quan
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Fan Li
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Limin Lang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Yiming Fu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Shengchun Feng
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Xin Yi
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Canjun Zhu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Ping Gao
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Xiaotong Zhu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Lina Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Gang Shu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Qingyan Jiang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Songbo Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (X.L.); (L.Q.); (F.L.); (L.L.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Correspondence: ; Tel.: +86-135-7051-8681
| |
Collapse
|
|
31
|
Fursova AZ, Derbeneva AS, Vasilyeva MS, Niculich IF, Tarasov MS, Gamza YA, Chubar NV, Gusarevich OG, Dmitrieva EI, Kozhevnikova OS, Kolosova NG, Elizarova AA. [New findings on pathogenetic mechanisms in the development of age-related macular degeneration]. Vestn Oftalmol 2022; 138:120-130. [PMID: 35488571 DOI: 10.17116/oftalma2022138021120] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Age-related macular degeneration (AMD) is a complex multifactorial disease that occurs due to disfunction and degeneration of retinal pigment epithelium (RPE) and choriocapillaris, as well as death of photoreceptors. The exact pathogenetic mechanism remains uncertain. The aging process is the main and the clearest risk factor of AMD. In the development of this condition, a special role belongs to the secretory phenotype of aging spreading from one cell to another and mediated by the secretion and release of growth factors, cytokines, chemokines, proteases, and other molecules. Another major contributor is oxidative stress caused by violations in the recirculation of vitamin A in the vision cycle and accompanied by accumulation of lipofuscin, which mediates the formation of iron-based oxidants that are toxic for mitochondria. Furthermore, prolonged oxidative stress and constant light exposure induce the development of inflammation in the retina. Accumulation of metabolic products and cellular defects with age can induce an inflammatory reaction that amplifies the damage. The inflammatory processes including innate immune response, activation of microglia and parainflammation that occur locally in the vascular membrane, pigment epithelium and neuroretina are very significant contributors to the age-related changes, their progression, and the development of advanced stages of AMD. Various growth factors play a special role in the development of choroidal neovascularization (CNV). Vascular endothelial growth factor A (VEGF-A) has traditionally been considered the main factor of neoangiogenesis and, consequently, the main therapeutic target, but in recent years various studies have determined the role of other factors - VEGF-B, C, D, PGF, Gal-1, angiopoietins. This article describes the main underlying mechanisms in the development of choroidal neovascularization including retinal aging, impaired metabolic activity, mitochondrial dysfunction, inflammatory reactions and genetic variations, as well as the role of various growth factors.
Collapse
Affiliation(s)
- A Zh Fursova
- Novosibirsk State Medical University, Novosibirsk, Russia.,Novosibirsk State Regional Clinical Hospital, Novosibirsk, Russia.,Federal Research Center Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - A S Derbeneva
- Novosibirsk State Medical University, Novosibirsk, Russia.,Novosibirsk State Regional Clinical Hospital, Novosibirsk, Russia.,Federal Research Center Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - M S Vasilyeva
- Novosibirsk State Regional Clinical Hospital, Novosibirsk, Russia
| | - I F Niculich
- Novosibirsk State Medical University, Novosibirsk, Russia.,Novosibirsk State Regional Clinical Hospital, Novosibirsk, Russia
| | - M S Tarasov
- Novosibirsk State Medical University, Novosibirsk, Russia.,Novosibirsk State Regional Clinical Hospital, Novosibirsk, Russia.,Federal Research Center Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Yu A Gamza
- Novosibirsk State Medical University, Novosibirsk, Russia.,Novosibirsk State Regional Clinical Hospital, Novosibirsk, Russia
| | - N V Chubar
- Novosibirsk State Medical University, Novosibirsk, Russia.,Novosibirsk State Regional Clinical Hospital, Novosibirsk, Russia
| | - O G Gusarevich
- Novosibirsk State Medical University, Novosibirsk, Russia
| | - E I Dmitrieva
- Novosibirsk State Medical University, Novosibirsk, Russia
| | - O S Kozhevnikova
- Federal Research Center Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - N G Kolosova
- Federal Research Center Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - A A Elizarova
- Novosibirsk State Medical University, Novosibirsk, Russia
| |
Collapse
|
|
32
|
Mirzaeinia S, Zeinali S, Budisa N, Karbalaei-Heidari HR. Targeted Codelivery of Prodigiosin and Simvastatin Using Smart BioMOF: Functionalization by Recombinant Anti-VEGFR1 scFv. Front Bioeng Biotechnol 2022; 10:866275. [PMID: 35402395 PMCID: PMC8987009 DOI: 10.3389/fbioe.2022.866275] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 02/28/2022] [Indexed: 11/18/2022] Open
Abstract
Biological metal-organic frameworks (BioMOFs) are hybrid compounds in which metal nodes are linked to biocompatible organic ligands and have potential for medical application. Herein, we developed a novel BioMOF modified with an anti-VEGFR1 scFv antibody (D16F7 scFv). Our BioMOF is co-loaded with a combination of an anticancer compound and a lipid-lowering drug to simultaneously suppress the proliferation, growth rate and metastases of cancer cells in cell culture model system. In particular, Prodigiosin (PG) and Simvastatin (SIM) were co-loaded into the newly synthesized Ca-Gly BioMOF nanoparticles coated with maltose and functionalized with a recombinant maltose binding protein-scFv fragment of anti-VEGFR1 (Ca-Gly-Maltose-D16F7). The nanoformulation, termed PG + SIM-NP-D16F7, has been shown to have strong active targeting behavior towards VEGFR1-overexpresing cancer cells. Moreover, the co-delivery of PG and SIM not only effectively inhibits the proliferation of cancer cells, but also prevents their invasion and metastasis. The PG + SIM-NP-D16F7 nanocarrier exhibited stronger cytotoxic and anti-metastatic effects compared to mono-treatment of free drugs and drug-loaded nanoparticles. Smart co-delivery of PG and SIM on BioMOF nanoparticles had synergistic effects on growth inhibition and prevented cancer cell metastasis. The present nanoplatform can be introduced as a promising tool for chemotherapy compared with mono-treatment and/or non-targeted formulations.
Collapse
Affiliation(s)
- Somayyeh Mirzaeinia
- Molecular Biotechnology Lab, Department of Biology, Faculty of Science, Shiraz University, Shiraz, Iran
| | - Sedighe Zeinali
- Department of Nanochemical Engineering, School of Advanced Technologies, Nanotechnology Research Institute, Shiraz University, Shiraz, Iran
| | - Nediljko Budisa
- Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB, Canada
- Institut für Chemie, Technische Universität Berlin, Berlin, Germany
| | - Hamid Reza Karbalaei-Heidari
- Molecular Biotechnology Lab, Department of Biology, Faculty of Science, Shiraz University, Shiraz, Iran
- Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB, Canada
| |
Collapse
|
|
33
|
She K, Su J, Wang Q, Liu Y, Zhong X, Jin X, Zhao Q, Xiao J, Li R, Deng H, Lu F, Yang Y, Wei Y. Delivery of nVEGFi using AAV8 for the treatment of neovascular age-related macular degeneration. Mol Ther Methods Clin Dev 2022; 24:210-221. [PMID: 35141350 PMCID: PMC8800040 DOI: 10.1016/j.omtm.2022.01.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 01/05/2022] [Indexed: 11/01/2022]
Abstract
Inhibition of vascular endothelial growth factor (VEGF) is the standard therapy for neovascular age-related macular degeneration (nAMD). However, anti-VEGF agents used in the clinic require repeated injections, causing adverse effects. Gene therapy could provide sustained anti-VEGF levels after a single injection, thereby drastically decreasing the treatment burden and improving visual outcomes. In this study, we developed a novel VEGF Trap, nVEGFi, containing domains 1 and 2 of VEGFR1 and domain 3 of VEGFR2 fused to the Fc portion of human IgG. The nVEGFi had a higher expression level than aflibercept under the same expression cassettes of adeno-associated virus (AAV)8 in vitro and in vivo. nVEGFi was found to be noninferior to aflibercept in binding and blocking VEGF in vitro. AAV8-mediated expression of nVEGFi was maintained for at least 12 weeks by subretinal delivery in C57BL/6J mice. In a mouse laser-induced choroidal neovascularization (CNV) model, 4 × 108 genome copies of AAV8-nVEGFi exhibited a significantly increased reduction in the CNV area compared with AAV8-aflibercept (78.1% vs. 63.9%, p < 0.05), while causing no structural or functional changes to the retina. In conclusion, this preclinical study showed that subretinal injection of AAV8-nVEGFi was long lasting, well tolerated, and effective for nAMD treatment, supporting future translation to the clinic.
Collapse
Affiliation(s)
- Kaiqin She
- Department of Ophthalmology, West China Hospital, Sichuan University, No.37, Guoxue Xiang, Chengdu, Sichuan 610041, China.,State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, China
| | - Jing Su
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, China
| | - Qingnan Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, China
| | - Yi Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, China
| | - Xiaomei Zhong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, China
| | - Xiu Jin
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, China
| | - Qinyu Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, China
| | - Jianlu Xiao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, China
| | - Ruiting Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, China
| | - Hongxin Deng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, China
| | - Fang Lu
- Department of Ophthalmology, West China Hospital, Sichuan University, No.37, Guoxue Xiang, Chengdu, Sichuan 610041, China
| | - Yang Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, China
| | - Yuquan Wei
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, China
| |
Collapse
|
|
34
|
Xu X, Mu L, Li L, Liang J, Zhang S, Jia L, Yang X, Dai Y, Zhang J, Wang Y, Niu S, Xia G, Yang Y, Zhang Y, Cao Y, Zhang H. Imaging and tracing the pattern of adult ovarian angiogenesis implies a strategy against female reproductive aging. SCIENCE ADVANCES 2022; 8:eabi8683. [PMID: 35020427 PMCID: PMC8754302 DOI: 10.1126/sciadv.abi8683] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Robust angiogenesis is continuously active in ovaries to remodel the ovary-body connections in mammals, but understanding of this unique process remains elusive. Here, we performed high-resolution, three-dimensional ovarian vascular imaging and traced the pattern of ovarian angiogenesis and vascular development in the long term. We found that angiogenesis was mainly active on ovarian follicles and corpus luteum and that robust angiogenesis constructs independent but temporary vascular networks for each follicle. Based on the pattern of ovarian angiogenesis, we designed an angiogenesis-blocking strategy by axitinib administration to young females, and we found that the temporary suppression of angiogenesis paused ovarian development and kept the ovarian reserve in the long term, leading to postponed ovarian senescence and an extension of the female reproductive life span. Together, by uncovering the detailed model of physiological ovarian angiogenesis, our experiments suggest a potential approach to delay female reproductive aging through the manipulation of angiogenesis.
Collapse
Affiliation(s)
- Xueqiang Xu
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Lu Mu
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Lingyu Li
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Jing Liang
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Shuo Zhang
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Longzhong Jia
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Xuebing Yang
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Yanli Dai
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Jiawei Zhang
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Yibo Wang
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Shudong Niu
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Guoliang Xia
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Yan Zhang
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Yihai Cao
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm 171 77, Sweden
| | - Hua Zhang
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
- Corresponding author.
| |
Collapse
|
|
35
|
Martín-Estal I, Castorena-Torres F. Gestational Diabetes Mellitus and Energy-Dense Diet: What Is the Role of the Insulin/IGF Axis? Front Endocrinol (Lausanne) 2022; 13:916042. [PMID: 35813659 PMCID: PMC9259869 DOI: 10.3389/fendo.2022.916042] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/24/2022] [Indexed: 01/02/2023] Open
Abstract
Gestational diabetes mellitus (GDM), is one of the most important pregnancy complications affecting approximately 15% of pregnant women. It is related to several gestational adverse outcomes in the fetus, e.g., macrosomia, shoulder dystocia, stillbirth, neonatal hypoglycemia, and respiratory distress. Women with GDM have a high risk of developing type 2 diabetes in the future. The pathogenesis of GDM is not completely understood; nevertheless, two factors could contribute to its development: β-cell dysfunction and failure in insulin secretion in response to insulin resistance induced by gestation. Both processes, together with the physiological activities of the insulin-like growth factors (IGFs), play a crucial role in glucose transport to the fetus and hence, fetal growth and development. IGFs (both IGF-1 and IGF-2) and their binding proteins (IGFBPs) regulate glucose metabolism and insulin sensitivity. Maternal nutritional status determines the health of the newborn, as it has substantial effects on fetal growth and development. Maternal obesity and an energy-dense diet can cause an increase in insulin and IGF-1 serum levels, producing metabolic disorders, such as insulin resistance, GDM, and high birth weight (> 4,000 g) due to a higher level of body fat. In this way, in GDM pregnancies there is an increase in IGF-1 and IGF-2 serum levels, and a decrease in IGFBP-1 and 4 serum levels, suggesting the crucial role of the insulin/IGF system in this gestational outcome. Here, the present review tries to elucidate the role that energy-dense diets and the insulin/IGF-1 signaling pathway perform in GDM pregnancies.
Collapse
|
|
36
|
Cationic, anionic and neutral polysaccharides for skin tissue engineering and wound healing applications. Int J Biol Macromol 2021; 192:298-322. [PMID: 34634326 DOI: 10.1016/j.ijbiomac.2021.10.013] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/25/2021] [Accepted: 10/03/2021] [Indexed: 12/17/2022]
Abstract
Today, chronic wound care and management can be regarded as a clinically critical issue. However, the limitations of current approaches for wound healing have encouraged researchers and physicians to develop more efficient alternative approaches. Advances in tissue engineering and regenerative medicine have resulted in the development of promising approaches that can accelerate wound healing and improve the skin regeneration rate and quality. The design and fabrication of scaffolds that can address the multifactorial nature of chronic wound occurrence and provide support for the healing process can be considered an important area requiring improvement. In this regard, polysaccharide-based scaffolds have distinctive properties such as biocompatibility, biodegradability, high water retention capacity and nontoxicity, making them ideal for wound healing applications. Their tunable structure and networked morphology could facilitate a number of functions, such as controlling their diffusion, maintaining wound moisture, absorbing a large amount of exudates and facilitating gas exchange. In this review, the wound healing process and the influential factors, structure and properties of carbohydrate polymers, physical and chemical crosslinking of polysaccharides, scaffold fabrication techniques, and the use of polysaccharide-based scaffolds in skin tissue engineering and wound healing applications are discussed.
Collapse
|
|
37
|
Meena R, Nangia A, Sharma S, Chandra J. Serum Levels of Vascular Endothelial Growth Factor and Its Receptor in Newly Diagnosed Paediatric Acute Lymphoblastic Leukemia. Indian J Hematol Blood Transfus 2021; 37:586-592. [PMID: 34744342 PMCID: PMC8523739 DOI: 10.1007/s12288-021-01413-0] [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: 11/10/2020] [Accepted: 02/09/2021] [Indexed: 10/22/2022] Open
Abstract
Autocrine and paracrine loop involving vascular endothelial growth factor (VEGF) and its receptor have been described in haematological malignancies. However, scarce literature is present on angiogenesis in paediatric acute lymphoblastic leukemia (ALL) with studies showing controversial results. The aim was to study serum levels of VEGF and its receptors in paediatric ALL at the time of diagnosis and at the end of induction phase and to compare these levels with clinico-haematological parameters in these patients. Serum VEGF, VEGFR-1 and VEGFR-2 levels were measured by enzyme-linked immunoabsorbant assay at diagnosis (day 0) and at the end of induction phase (day 35) in 30 newly diagnosed paediatric ALL patients and in 10 healthy controls. Median s-VEGF was significantly lower at day 0 as compared to day 35 (196.15 vs. 606.75 pg/ml: p < 0.001). s-VEGFR-1 levels were detectable only in 7 patients at day 0 and were below detection level at day 35 in all patients. Median s-VEGFR-2 at day 0 was significantly lower as compared to day 35 (17,577.5 vs. 20,507.5 pg/ml; p = 0.005). Median VEGF-R1 showed an inverse relationship with VEGF-R2 but was statistically insignificant. All patients were in remission at the end of induction. Thus, leukemic infiltration of bone marrow affects angiogenesis and reduces pro-angiogenic markers VEGF and VEGFR-2 in serum possibly due to increased local consumption by blasts. A successful induction leads to clearing of blasts causing restoration of normal hematopoiesis with normalization of VEGF and VEGFR-2 levels.
Collapse
Affiliation(s)
- Rachana Meena
- Department of Pathology, Lady Hardinge Medical College, New Delhi, India
| | - Anita Nangia
- Department of Pathology, Lady Hardinge Medical College, New Delhi, India
| | - Sunita Sharma
- Department of Pathology, Lady Hardinge Medical College, New Delhi, India
| | - Jagdish Chandra
- Department of Paediatrics, Lady Hardinge Medical College, New Delhi, India
| |
Collapse
|
|
38
|
Cheong LY, Xu A. Intercellular and inter-organ crosstalk in browning of white adipose tissue: molecular mechanism and therapeutic complications. J Mol Cell Biol 2021; 13:466-479. [PMID: 34185049 PMCID: PMC8530522 DOI: 10.1093/jmcb/mjab038] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/27/2021] [Accepted: 05/11/2021] [Indexed: 12/26/2022] Open
Abstract
Adipose tissue (AT) is highly plastic and heterogeneous in response to environmental and nutritional changes. The development of heat-dissipating beige adipocytes in white AT (WAT) through a process known as browning (or beiging) has garnered much attention as a promising therapeutic strategy for obesity and its related metabolic complications. This is due to its inducibility in response to thermogenic stimulation and its association with improved metabolic health. WAT consists of adipocytes, nerves, vascular endothelial cells, various types of immune cells, adipocyte progenitor cells, and fibroblasts. These cells contribute to the formation of beige adipocytes through the release of protein factors that significantly influence browning capacity. In addition, inter-organ crosstalk is also important for beige adipocyte biogenesis. Here, we summarize recent findings on fat depot-specific differences, secretory factors participating in intercellular and inter-organ communications that regulate the recruitment of thermogenic beige adipocytes, as well as challenges in targeting beige adipocytes as a potential anti-obese therapy.
Collapse
Affiliation(s)
- Lai Yee Cheong
- The State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Aimin Xu
- The State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China.,Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
| |
Collapse
|
|
39
|
New epigenetic players in stroke pathogenesis: From non-coding RNAs to exosomal non-coding RNAs. Biomed Pharmacother 2021; 140:111753. [PMID: 34044272 PMCID: PMC8222190 DOI: 10.1016/j.biopha.2021.111753] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/22/2021] [Accepted: 05/19/2021] [Indexed: 12/17/2022] Open
Abstract
Non-coding RNAs (ncRNAs) have critical role in the pathophysiology as well as recovery after ischemic stroke. ncRNAs, particularly microRNAs, and the long non-coding RNAs (lncRNAs) are critical for angiogenesis and neuroprotection, and they have been suggested to be therapeutic, diagnostic and prognostic tools in cerebrovascular diseases, including stroke. Moreover, exosomes have been considered as nanocarriers capable of transferring various cargos, such as lncRNAs and miRNAs to recipient cells, with prominent inter-cellular roles in the mediation of neuro-restorative events following strokes and neural injuries. In this review, we summarize the pathogenic role of ncRNAs and exosomal ncRNAs in the stroke.
Collapse
|
|
40
|
Jia JD, Jiang WG, Luo X, Li RR, Zhao YC, Tian G, Li YN. Vascular endothelial growth factor B inhibits insulin secretion in MIN6 cells and reduces Ca 2+ and cyclic adenosine monophosphate levels through PI3K/AKT pathway. World J Diabetes 2021; 12:480-498. [PMID: 33889292 PMCID: PMC8040075 DOI: 10.4239/wjd.v12.i4.480] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/25/2021] [Accepted: 03/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Type 2 diabetes (T2D) is characterized by insufficient insulin secretion caused by defective pancreatic β-cell function or insulin resistance, resulting in an increase in blood glucose. However, the mechanism involved in this lack of insulin secretion is unclear. The level of vascular endothelial growth factor B (VEGF-B) is significantly increased in T2D patients. The inactivation of VEGF-B could restore insulin sensitivity in db/db mice by reducing fatty acid accumulation. It is speculated that VEGF-B is related to pancreatic β-cell dysfunction and is an important factor affecting β-cell secretion of insulin. As an in vitro model of normal pancreatic β-cells, the MIN6 cell line can be used to analyze the mechanism of insulin secretion and related biological effects.
AIM To study the role of VEGF-B in the insulin secretion signaling pathway in MIN6 cells and explore the effect of VEGF-B on blood glucose regulation.
METHODS The MIN6 mouse pancreatic islet β-cell line was used as the model system. By administering exogenous VEGF-B protein or knocking down VEGF-B expression in MIN6 cells, we examined the effects of VEGF-B on insulin secretion, Ca2+ and cyclic adenosine monophosphate (cAMP) levels, and the insulin secretion signaling pathway.
RESULTS Exogenous VEGF-B inhibited the secretion of insulin and simultaneously reduced the levels of Ca2+ and cAMP in MIN6 cells. Exogenous VEGF-B also reduced the expression of phospholipase C gamma 1 (PLCγ1), phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase (AKT), and other proteins in the insulin secretion pathway. Upon knockdown of VEGF-B, MIN6 cells exhibited increased insulin secretion and Ca2+ and cAMP levels and upregulated expression of PLCγ1, PI3K, AKT, and other proteins.
CONCLUSION VEGF-B can regulate insulin secretion by modulating the levels of Ca2+ and cAMP. VEGF-B involvement in insulin secretion is related to the expression of PLCγ1, PI3K, AKT, and other signaling proteins. These results provide theoretical support and an experimental basis for the study of VEGF-B in the pathogenesis of T2D.
Collapse
Affiliation(s)
- Jing-Dan Jia
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264003, Shandong Province, China
| | - Wen-Guo Jiang
- Department of Pharmacy, Binzhou Medical University, Yantai 264003, Shandong Province, China
| | - Xu Luo
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264003, Shandong Province, China
| | - Rong-Rong Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264003, Shandong Province, China
| | - Yu-Chi Zhao
- Department of Surgery, Yantaishan Hospital, Yantai 264001, Shandong Province, China
| | - Geng Tian
- Department of Pharmacy, Binzhou Medical University, Yantai 264003, Shandong Province, China
| | - Ya-Na Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264003, Shandong Province, China
| |
Collapse
|
|
41
|
Tyczyńska M, Kędzierawski P, Karakuła K, Januszewski J, Kozak K, Sitarz M, Forma A. Treatment Strategies of Gastric Cancer-Molecular Targets for Anti-angiogenic Therapy: a State-of-the-art Review. J Gastrointest Cancer 2021; 52:476-488. [PMID: 33761051 PMCID: PMC8131337 DOI: 10.1007/s12029-021-00629-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2021] [Indexed: 12/19/2022]
Abstract
Purpose Recent studies have suggested that molecular targets for the anti-angiogenic therapy might constitute a basis for additional therapy in gastric cancer treatment. A vast number of molecules, receptors, pathways, specific interactions, and thus strategies that target gastric cancer angiogenesis specifically have been reported in numerous research articles and clinical trials. Methods We conducted a systematic literature review of molecularly targeted treatment strategies in gastric cancer on the following databases—PubMed, Google Scholar, and Scopus—on September 20, 2020. Multiple articles and evaluations were searched for studies reporting newly found and promising molecular anti-angiogenic therapy pathways. Eventually, 39 articles regarding the anti-angiogenic therapy in gastric cancer were included in the final analysis. Results As a consequence of the release of the pro-angiogenic molecules from the tumour cells, gastric cancer presents high angiogenic capability. Therefore, potential schemes for future treatment strategies include the decrease of the process ligands as well as the expression of their receptors. Moreover, the increase in the angiogenic inhibitor levels and direct aim for the inner walls of the endothelial cells appear as a promising therapeutic strategy. Beyond that, angiogenesis process inhibition seems to indirectly exaggerate the effects of chemotherapy in the considered patients. Conclusions The anti-angiogenic treatment in gastric cancer patients evaluates its significance especially in the early stages of the malignancy. The studies conducted so far show that most of the meaningful angiogenic factors and receptors with the potential molecular pathways should be further evaluated since they could potentially play a substantial role in future therapies.
Collapse
Affiliation(s)
- Magdalena Tyczyńska
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland
| | - Paweł Kędzierawski
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland
| | - Kaja Karakuła
- Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin, Gluska Street 1, 20-439 Lublin, Poland
| | - Jacek Januszewski
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland
| | - Krzysztof Kozak
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland
| | - Monika Sitarz
- Department of Conservative Dentistry with Endodontics, Medical University of Lublin, 20-090 Lublin, Poland
| | - Alicja Forma
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland
| |
Collapse
|
|
42
|
Fischer AW, Jaeckstein MY, Gottschling K, Heine M, Sass F, Mangels N, Schlein C, Worthmann A, Bruns OT, Yuan Y, Zhu H, Chen O, Ittrich H, Nilsson SK, Stefanicka P, Ukropec J, Balaz M, Dong H, Sun W, Reimer R, Scheja L, Heeren J. Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation. Cell Metab 2021; 33:547-564.e7. [PMID: 33357458 DOI: 10.1016/j.cmet.2020.12.001] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 10/02/2020] [Accepted: 11/30/2020] [Indexed: 12/13/2022]
Abstract
In response to cold exposure, thermogenic adipocytes internalize large amounts of fatty acids after lipoprotein lipase-mediated hydrolysis of triglyceride-rich lipoproteins (TRL) in the capillary lumen of brown adipose tissue (BAT) and white adipose tissue (WAT). Here, we show that in cold-exposed mice, vascular endothelial cells in adipose tissues endocytose substantial amounts of entire TRL particles. These lipoproteins subsequently follow the endosomal-lysosomal pathway, where they undergo lysosomal acid lipase (LAL)-mediated processing. Endothelial cell-specific LAL deficiency results in impaired thermogenic capacity as a consequence of reduced recruitment of brown and brite/beige adipocytes. Mechanistically, TRL processing by LAL induces proliferation of endothelial cells and adipocyte precursors via beta-oxidation-dependent production of reactive oxygen species, which in turn stimulates hypoxia-inducible factor-1α-dependent proliferative responses. In conclusion, this study demonstrates a physiological role for TRL particle uptake into BAT and WAT and establishes endothelial lipoprotein processing as an important determinant of adipose tissue remodeling during thermogenic adaptation.
Collapse
Affiliation(s)
- Alexander W Fischer
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Michelle Y Jaeckstein
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kristina Gottschling
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Markus Heine
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Frederike Sass
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nils Mangels
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Schlein
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anna Worthmann
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Oliver T Bruns
- Helmholtz Pioneer Campus, Helmholtz Zentrum München, Neuherberg, Germany
| | - Yucheng Yuan
- Department of Chemistry, Brown University, Providence, RI, USA
| | - Hua Zhu
- Department of Chemistry, Brown University, Providence, RI, USA
| | - Ou Chen
- Department of Chemistry, Brown University, Providence, RI, USA
| | - Harald Ittrich
- Department of Diagnostic and Interventional Radiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan K Nilsson
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
| | - Patrik Stefanicka
- Department of Otorhinolaryngology - Head and Neck Surgery, Comenius University, Bratislava, Slovakia
| | - Jozef Ukropec
- Institute of Experimental Endocrinology, Biomedical Research Center at the Slovak Academy of Sciences, Bratislava, Slovakia
| | - Miroslav Balaz
- Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland
| | - Hua Dong
- Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland
| | - Wenfei Sun
- Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland
| | - Rudolf Reimer
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Ludger Scheja
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Joerg Heeren
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| |
Collapse
|
|
43
|
Hua L, Li J, Feng B, Jiang D, Jiang X, Luo T, Che L, Xu S, Lin Y, Fang Z, Wu D, Zhuo Y. Dietary Intake Regulates White Adipose Tissues Angiogenesis via Liver Fibroblast Growth Factor 21 in Male Mice. Endocrinology 2021; 162:6054191. [PMID: 33369618 PMCID: PMC7814301 DOI: 10.1210/endocr/bqaa244] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Indexed: 11/19/2022]
Abstract
Obesity and related metabolic disorders have become epidemic diseases. Intermittent fasting has been shown to promote adipose tissue angiogenesis and have an anti-obesity feature; however, the mechanisms of how intermittent fasting modulates adipose tissues angiogenesis are poorly understood. We investigated the effect of fasting on vascular endothelial growth factor (VEGF) levels in white adipose tissues (WAT) and the function of fibroblast growth factor 21 (FGF21) in 1-time fasting and long-term intermittent fasting-induced VEGF expression. In the current study, fasting induced a selective and drastic elevation of VEGF levels in WAT, which did not occur in interscapular brown adipose tissue and liver. The fasting-induced Vegfa expression occurred predominantly in mature adipocytes, but not in the stromal vascular fraction in epididymal WAT and inguinal WAT (iWAT). Furthermore, a single bolus of recombinant mouse FGF21 injection increased VEGF levels in WAT. Long-term intermittent fasting for 16 weeks increased WAT angiogenesis, iWAT browning, and improved insulin resistance and inflammation, but the effect was blunted in FGF21 liver-specific knockout mice. In summary, these data suggest that FGF21 is a potent regulator of VEGF levels in WAT. The interorgan FGF21 signaling-induced WAT angiogenesis by VEGF could be a potential new therapeutic target in combination with obesity-related metabolic disorders.
Collapse
Affiliation(s)
- Lun Hua
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Jing Li
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Bin Feng
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Dandan Jiang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Xuemei Jiang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Ting Luo
- Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Lianqiang Che
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Shengyu Xu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Yan Lin
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Zhengfeng Fang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - De Wu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu, China
- Correspondence: Yong Zhuo, 211 Huimin Road, Wenjiang District, Chengdu, PR China, 611130. ; De Wu, 211 Huimin Road, Wenjiang District, Chengdu, PR China, 611130.
| | - Yong Zhuo
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
- Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu, China
- Correspondence: Yong Zhuo, 211 Huimin Road, Wenjiang District, Chengdu, PR China, 611130. ; De Wu, 211 Huimin Road, Wenjiang District, Chengdu, PR China, 611130.
| |
Collapse
|
|
44
|
Samaee SM, Atashbar Kangarloei B, Noori F, Estévez A. An Endeavor to Find Starter Feed Alternatives and Techniques for Zebrafish First-Feeding Larvae: The Effects on Viability, Morphometric Traits, Digestive Enzymes, and Expression of Growth-Related Genes. Zebrafish 2021; 18:73-91. [PMID: 33538651 DOI: 10.1089/zeb.2020.1928] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Low and variable growth and survival rates (SR) of 6-10 days postfertilization zebrafish larvae are a problem. This problem seems to be linked to starter feed characteristics. This study is an attempt to find alternatives to address these requests. For this, larvae were fed fresh and lyophilized microalgae (Chlorella, Scenedesmus, and Haematococcus), egg yolk (YOLK), lyophilized Artemia nauplii (LAN), and a combination of them. The lowest SR was observed in algae-fed larvae. All died on day 11 showing an emaciated appearance, similar to starved larvae. The highest SR was observed in YOLK- and LAN-fed larvae, which also showed an elongated anterior part of the body. Negative correlations of SR with vegfaa (vascular endothelial growth factor) and morphometric traits with igf2a (insulin-like growth factor) were also found and supported by changes at the molecular level. The presence of algae in the digestive tract of the larvae and the observation of fecal droppings indicate that the algae have an appropriate size and are palatable. The increase in the digestive enzyme activity shows the larval effort to digest the algae. The fact that the algae-fed larvae died even before the larvae were kept in starvation indicates the dramatic amount of energy that the larvae spent in microalgae digestion. Although both YOLK- and LAN-fed larvae had the highest SR, LAN group started to feed on Artemia nauplii sooner. This can be linked to the delayed growth in YOLK-fed larvae and an accelerated growth in the case of LAN-fed group. LAN is an expensive feed with negative effects on water quality, whereas YOLK is a cheap and nutritionally balanced feed with fine granular texture that contributes to a larval SR similar to LAN without affecting water quality. In conclusion, microalgae cannot be considered a suitable starter food for zebrafish, whereas LAN and YOLK can be considered good starter feeds.
Collapse
Affiliation(s)
| | - Behrooz Atashbar Kangarloei
- Department of Ecology and Resource Assessment, Artemia and Aquaculture Research Institute, Urmia University, Urmia, Iran
| | - Farzaneh Noori
- Department of Biology and Aquaculture, Artemia and Aquaculture Research Institute, Urmia University, Urmia, Iran
| | | |
Collapse
|
|
45
|
Tomita K, Saito Y, Suzuki T, Imbaby S, Hattori K, Matsuda N, Hattori Y. Vascular endothelial growth factor contributes to lung vascular hyperpermeability in sepsis-associated acute lung injury. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2020; 393:2365-2374. [PMID: 32696151 PMCID: PMC7371837 DOI: 10.1007/s00210-020-01947-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 07/13/2020] [Indexed: 12/26/2022]
Abstract
Vascular endothelial growth factor (VEGF) is a prime regulator of vascular permeability. Acute lung injury (ALI) is characterized by high-permeability pulmonary edema in addition to refractory hypoxemia and diffuse pulmonary infiltrates. In this study, we examined whether VEGF can be implicated as a pulmonary vascular permeability factor in sepsis-associated ALI. We found that a great increase in lung vascular leak occurred in mice instilled intranasally with lipopolysaccharide (LPS), as assessed by IgM levels in bronchoalveolar lavage fluid. Treatment with the VEGF-neutralizing monoclonal antibody bevacizumab significantly reduced this hyperpermeability response, suggesting active participation of VEGF in non-cardiogenic lung edema associated with LPS-induced ALI. However, this was not solely attributable to excessive levels of intrapulmonary VEGF. Expression levels of VEGF were significantly reduced in lung tissues from mice with both intranasal LPS administration and cecal ligation and puncture (CLP)-induced sepsis, which may stem from decreases in non-endothelial cells-dependent VEGF production in the lungs. In support of this assumption, stimulation with LPS and interferon-γ (IFN-γ) significantly increased VEGF in human pulmonary microvascular endothelial cells (HPMECs) at mRNA and protein levels. Furthermore, a significant rise in plasma VEGF levels was observed in CLP-induced septic mice. The increase in VEGF released from HPMECs after LPS/IFN-γ challenge was completely blocked by either specific inhibitor of mitogen-activated protein kinase (MAPK) subgroups. Taken together, our results indicate that VEGF can contribute to the development of non-cardiogenic lung edema in sepsis-associated ALI due to increased VEGF secretion from pulmonary vascular endothelial cells through multiple MAPK-dependent pathways.
Collapse
Affiliation(s)
- Kengo Tomita
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
- Medical Environment Engineering Group, Center for Environmental Engineering, Shimizu Corporation, Institute of Technology, Tokyo, 135-0044, Japan
| | - Yuna Saito
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
- Center for Clinical Training, Juntendo University Urayasu Hospital, Urayasu, 279-0021, Japan
| | - Tokiko Suzuki
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
- J-Pharma Co., Ltd., Yokohama, 230-0046, Japan
| | - Samar Imbaby
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
- Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt
| | - Kohshi Hattori
- Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital, Tokyo, 113-8655, Japan
| | - Naoyuki Matsuda
- Department of Emergency and Critical Care Medicine, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Yuichi Hattori
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan.
- Advanced Research Promotion Center, Health Sciences University of Hokkaido, Tobetsu, 061-0293, Japan.
| |
Collapse
|
|
46
|
Hong HK, Park YJ, Kim DK, Ryoo NK, Ko YJ, Park KH, Kim HM, Woo SJ. Preclinical Efficacy and Safety of VEGF-Grab, a Novel Anti-VEGF Drug, and Its Comparison to Aflibercept. Invest Ophthalmol Vis Sci 2020; 61:22. [PMID: 33196778 PMCID: PMC7671872 DOI: 10.1167/iovs.61.13.22] [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: 11/30/2019] [Accepted: 10/05/2020] [Indexed: 12/27/2022] Open
Abstract
Purpose VEGF-Grab is a novel anti-vascular endothelial growth factor (VEGF) candidate drug with higher affinity to both VEGF and placental growth factor (PlGF) compared to aflibercept. We investigated the preclinical efficacy of VEGF-Grab for ophthalmic therapy and compared it to that of aflibercept. Methods The in vitro anti-VEGF efficacy of VEGF-Grab was determined using VEGF-induced cell proliferation/migration and tube formation assays. The in vivo antiangiogenic efficacy of intravitreal injection of either VEGF-Grab or aflibercept was evaluated using murine models of ocular angiogenesis: mouse oxygen-induced retinopathy (OIR) and rat laser-induced choroidal neovascularization (CNV). The in vivo retinal toxicity in the mouse eye resulting from the injection of either drug was evaluated with light and electron microscopy. Results VEGF-Grab showed greater inhibition of VEGF-induced cell proliferation/migration than aflibercept, but it showed comparable inhibition of tube formation in vitro. In the in vivo OIR model, VEGF-Grab showed a comparable suppression of retinal neovascularization compared to aflibercept. Additionally, VEGF-Grab showed an efficacy similar to that of aflibercept in terms of CNV inhibition in the laser-induced CNV model. Histology and transmission electron microscopy showed no significant signs of toxicity in the mouse retina at 7 and 30 days following the intravitreal injection of VEGF-Grab or aflibercept. Conclusions Compared to aflibercept, VEGF-Grab presented comparable in vivo antiangiogenic efficacy and superior in vitro anti-VEGF activity. The retinal safety profiles were comparable for the two drugs. Considering its known higher binding affinity to VEGF and PlGF compared to aflibercept, VEGF-Grab could be a potential candidate drug for neovascular retinal diseases and an alternative to aflibercept.
Collapse
Affiliation(s)
- Hye Kyoung Hong
- Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Young Joo Park
- Department of Ophthalmology, Kangwon National University Hospital, Chuncheon, Korea
| | - Duk Ki Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
| | - Na-Kyung Ryoo
- Department of Ophthalmology, Veterans Health Service Medical Center, Seoul, Korea
| | - You-Jin Ko
- Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Kyu Hyung Park
- Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ho Min Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
- Center for Biomolecular & Cellular Structure, Institute for Basic Science, Daejeon, Korea
| | - Se Joon Woo
- Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam, Korea
| |
Collapse
|
|
47
|
Chen J, Hendriks M, Chatzis A, Ramasamy SK, Kusumbe AP. Bone Vasculature and Bone Marrow Vascular Niches in Health and Disease. J Bone Miner Res 2020; 35:2103-2120. [PMID: 32845550 DOI: 10.1002/jbmr.4171] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/21/2020] [Accepted: 08/05/2020] [Indexed: 12/20/2022]
Abstract
Bone vasculature and bone marrow vascular niches supply oxygen, nutrients, and secrete angiocrine factors required for the survival, maintenance, and self-renewal of stem and progenitor cells. In the skeletal system, vasculature creates nurturing niches for bone and blood-forming stem cells. Blood vessels regulate hematopoiesis and drive bone formation during development, repair, and regeneration. Dysfunctional vascular niches induce skeletal aging, bone diseases, and hematological disorders. Recent cellular and molecular characterization of the bone marrow microenvironment has provided unprecedented insights into the complexity, heterogeneity, and functions of the bone vasculature and vascular niches. The bone vasculature is composed of distinct vessel subtypes that differentially regulate osteogenesis, hematopoiesis, and disease conditions in bones. Further, bone marrow vascular niches supporting stem cells are often complex microenvironments involving multiple different cell populations and vessel subtypes. This review provides an overview of the emerging vascular cell heterogeneity in bone and the new roles of the bone vasculature and associated vascular niches in health and disease. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Collapse
Affiliation(s)
- Junyu Chen
- Tissue and Tumor Microenvironments Group, The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Michelle Hendriks
- Institute of Clinical Sciences, Imperial College London, London, UK
- MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Alexandros Chatzis
- Tissue and Tumor Microenvironments Group, The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Saravana K Ramasamy
- Institute of Clinical Sciences, Imperial College London, London, UK
- MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Anjali P Kusumbe
- Tissue and Tumor Microenvironments Group, The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| |
Collapse
|
|
48
|
Ngo MT, Harley BAC. Angiogenic biomaterials to promote therapeutic regeneration and investigate disease progression. Biomaterials 2020; 255:120207. [PMID: 32569868 PMCID: PMC7396313 DOI: 10.1016/j.biomaterials.2020.120207] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/08/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023]
Abstract
The vasculature is a key component of the tissue microenvironment. Traditionally known for its role in providing nutrients and oxygen to surrounding cells, the vasculature is now also acknowledged to provide signaling cues that influence biological outcomes in regeneration and disease. These cues come from the cells that comprise vasculature, as well as the dynamic biophysical and biochemical properties of the surrounding extracellular matrix that accompany vascular development and remodeling. In this review, we illustrate the larger role of the vasculature in the context of regenerative biology and cancer progression. We describe cellular, biophysical, biochemical, and metabolic components of vascularized microenvironments. Moreover, we provide an overview of multidimensional angiogenic biomaterials that have been developed to promote therapeutic vascularization and regeneration, as well as to mimic elements of vascularized microenvironments as a means to uncover mechanisms by which vasculature influences cancer progression and therapy.
Collapse
Affiliation(s)
- Mai T Ngo
- Dept. Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Brendan A C Harley
- Dept. Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA; Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
| |
Collapse
|
|
49
|
Ria R, Melaccio A, Racanelli V, Vacca A. Anti-VEGF Drugs in the Treatment of Multiple Myeloma Patients. J Clin Med 2020; 9:E1765. [PMID: 32517267 PMCID: PMC7355441 DOI: 10.3390/jcm9061765] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/29/2020] [Accepted: 06/03/2020] [Indexed: 02/07/2023] Open
Abstract
The interaction between the bone marrow microenvironment and plasma cells plays an essential role in multiple myeloma progression and drug resistance. The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway in vascular endothelial cells activates and promotes angiogenesis. Moreover, VEGF activates and promotes vasculogenesis and vasculogenic mimicry when it interacts with VEGF receptors expressed in precursor cells and inflammatory cells, respectively. In myeloma bone marrow, VEGF and VEGF receptor expression are upregulated and hyperactive in the stromal and tumor cells. It has been demonstrated that several antiangiogenic agents can effectively target VEGF-related pathways in the preclinical phase. However, they are not successful in treating multiple myeloma, probably due to the vicarious action of other cytokines and signaling pathways. Thus, the simultaneous blocking of multiple cytokine pathways, including the VEGF/VEGFR pathway, may represent a valid strategy to treat multiple myeloma. This review aims to summarize recent advances in understanding the role of the VEGF/VEGFR pathway in multiple myeloma, and mainly focuses on the transcription pathway and on strategies that target this pathway.
Collapse
Affiliation(s)
- Roberto Ria
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy; (A.M.); (V.R.); (A.V.)
| | | | | | | |
Collapse
|
|
50
|
Soyama H, Miyamoto M, Matsuura H, Iwahashi H, Kakimoto S, Ishibashi H, Sakamoto T, Hada T, Suminokura J, Takano M. Rapid decrease in serum VEGF-A levels may be a worse prognostic biomarker for patients with platinum-resistant recurrent ovarian cancer treated with bevacizumab and gemcitabine. Cancer Chemother Pharmacol 2020; 85:941-947. [PMID: 32279102 DOI: 10.1007/s00280-020-04070-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 04/02/2020] [Indexed: 12/27/2022]
Abstract
PURPOSE The aim of this study was to investigate the association between changes in the levels of vascular endothelial growth factors (VEGFs) after treatment with bevacizumab and gemcitabine (Bev-Gem) and the clinical outcome. METHODS Platinum-resistant ovarian cancer patients treated with Bev-Gem therapy at our hospital between 2014 and 2018 were identified. Serum VEGF levels at the first and second treatment cycle were measured by ELISA. All patients were categorized into two groups-patients with > 50% decrease in serum VEGF-A levels (Group A) and patients with < 50% decrease serum VEGF-A levels (Group B). The association between clinical outcome and serum VEGF levels was investigated between the two groups. RESULTS Among 18 patients, 10 were in Group A and 8 in Group B. Group A exhibited a lower response rate (0% vs.75% p < 0.01) and clinical benefit rate (60% vs.100% p = 0.02) than Group B. The median serum VEGF-A level of Group A before the first cycle of Bev-Gem therapy was higher than that in Group B (61.2 vs. 3.7 pg/mL, p < 0.01). Group A exhibited worse PFS (7 vs., 10 months, p < 0.01) and OS (17 vs. 26 months, p = 0.04) than Group B. There were more patients with > 10% increase in serum VEGF-B levels in Group A than in Group B (p < 0.01). CONCLUSION The rapid decrease in VEGF-A levels and the resultant increase in serum VEGF-B levels might be associated with an unfavorable clinical outcome. Large-scale studies are needed to further examine these results.
Collapse
Affiliation(s)
- Hiroaki Soyama
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Morikazu Miyamoto
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan.
| | - Hiroko Matsuura
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Hideki Iwahashi
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Soichiro Kakimoto
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Hiroki Ishibashi
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Takahiro Sakamoto
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Taira Hada
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Jin Suminokura
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| | - Masashi Takano
- Departments of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Saitama, 359-8513, Japan
| |
Collapse
|