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Patel S, Yang E, Milne TJ, Hussaini H, Cooper PR, Friedlander LT. Angiogenic effects of Type 2 diabetes on the dental pulp. Int Endod J 2025; 58:434-448. [PMID: 39652136 DOI: 10.1111/iej.14181] [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: 08/01/2024] [Revised: 10/17/2024] [Accepted: 11/24/2024] [Indexed: 01/03/2025]
Abstract
AIM To investigate the influence of type 2 diabetes (T2D) and hyperglycaemia on blood vessels and angiogenic markers in the dental pulp. METHODOLOGY Extracted non-carious permanent molar teeth were collected from patients with well-controlled T2D (n = 10) and non-T2D (controls) (n = 10). The pulp was examined qualitatively using haematoxylin and eosin and Van Gieson stains. Immunohistochemistry (IHC) identified the primary receptor for VEGF, VEGFR2, and the endothelial cell marker CD34. Primary human dental pulp cell (hDPC) lines (n = 3) were established from tissue explants and cells were grown in media containing 5.5 mM D-glucose (control), 12.5 mM (prediabetes) and 25 mM (T2D) D-glucose under normoxic conditions for 24, 48 and 72 h. Assays for metabolic activity (PrestoBlue) and cell viability (Crystal Violet staining) assessed the hDPC response to hyperglycaemia. The expression of angiogenic genes VEGFA, KDR, FLT-1, ANGPT1, ANGPT2, TIE1 and TEK were analysed using quantitative real-time polymerase chain reaction. ELISAs were used to quantify the level of expressed protein for VEGFA, ANG1, ANG2, TIE1, and TIE2 in the media. Data analyses were performed using GraphPad Prism and anova tests at p < .05. RESULTS Blood vessels in T2D samples had thicker walls and stained strongly for elastin and collagen compared with non-T2D samples. VEGFR2 protein was not seen in any T2D samples but consistently detected in healthy specimens. Culturing healthy cells in high glucose (25 mM) significantly reduced cell viability at 24 h compared to the control (p = .005) and 12.5 mM glucose (p = .001) but the metabolic activity was not greatly affected by glucose and time. VEGFA mRNA and VEGFA protein expression were detected in the hDPCs in the presence of hyperglycaemia over time; however, the primary receptor, VEGFR2/KDR, was not detected. Genes for the ANG1 and ANG2 and their receptors were expressed at all glucose concentrations but hyperglycaemia upregulated ANG2 mRNA. Proteins for all growth factors were detected in the media however proteins for TIE1 and TIE2 receptors were not. CONCLUSION T2D and hyperglycaemia may impair the angiogenic response in the pulp similar to other body site. The scarcity of VEGFR2 and increased expression of ANG2 in response to hyperglycaemia suggests that VEGF and ANG-Tie1/Tie2 signalling may be compromised.
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Affiliation(s)
- S Patel
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - E Yang
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - T J Milne
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - H Hussaini
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - P R Cooper
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - L T Friedlander
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
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Elayat G, Selim A. Angiogenesis in breast cancer: insights and innovations. Clin Exp Med 2024; 24:178. [PMID: 39105831 PMCID: PMC11303414 DOI: 10.1007/s10238-024-01446-5] [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: 04/13/2024] [Accepted: 07/19/2024] [Indexed: 08/07/2024]
Abstract
This review explores the pivotal role of angiogenesis in breast cancer progression and treatment. It covers biomarkers, imaging techniques, therapeutic approaches, resistance mechanisms, and clinical implications. Key topics include Vascular Endothelial Growth Factors, angiopoietins, microRNA signatures, and circulating endothelial cells as biomarkers, along with Magnetic Resonance Imaging, Computed Tomography Angiography, Ultrasound, and Positron Emission Tomography for imaging. Therapeutic strategies targeting VEGF, tyrosine kinase inhibitors, and the intersection of angiogenesis with immunotherapy are discussed. Challenges such as resistance mechanisms and personalized medicine approaches are addressed. Clinical implications, prognostic value, and the future direction of angiogenesis-targeted therapies are highlighted. The article concludes with reflections on the transformative potential of understanding angiogenesis.
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Affiliation(s)
- Ghada Elayat
- Department of Natural Science, Middlesex University, Hendon, London, UK.
- Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
| | - Abdel Selim
- Histopathology Department, King's College Hospital, Denmark Hill, London, UK
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Ding Y, Li H, Cao S, Yu Y. Effects of catechin on the malignant biological behavior of gastric cancer cells through the PI3K/Akt signaling pathway. Toxicol Appl Pharmacol 2024; 490:117036. [PMID: 39009138 DOI: 10.1016/j.taap.2024.117036] [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: 05/14/2024] [Revised: 07/11/2024] [Accepted: 07/11/2024] [Indexed: 07/17/2024]
Abstract
Catechin is a kind of flavonoids, mainly derived from the plant Camellia sinensis. It has a strong antioxidant effect, and it also has significant therapeutic effects on anti-cancer, anti-diabetes, and anti-infection. This study was intended to look at how catechin affected the malignant biological activity of gastric cancer cells. We used databases to predict the targets of catechin and the pathogenic targets of gastric cancer. Venn diagram was used to find the intersection genes, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were performed on intersection genes. Using the STRING database, the Protein-Protein Interaction (PPI) network was built. The top 8 genes were screened by Cytoscape 3.9.1, then their binding was verified by molecular docking. The proliferation ability, cell cycle, apoptosis and migration of gastric cancer cells were detected, as well as the protein expression levels of PI3K, p-AKT, and AKT and the mRNA expression levels of AKT1, VEGFA, EGFR, HRAS, and HSP90AA1 in gastric cancer cells. Our research revealed that different concentrations of catechin could effectively inhibit the proliferation and migration of gastric cancer cells, regulate the cell cycle, and promote the death of these cells, and it's possible that the PI3K/Akt pathway was crucial in mediating this impact. Moreover, adding the PI3K/Akt pathway agonist significantly reduced the promoting effect of catechin on the apoptosis of gastric cancer cells. This study suggested that catechin was a potential drug for the treatment of gastric cancer.
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Affiliation(s)
- Ye Ding
- Henan Key Laboratory of Helicobacter Pylori & Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China; Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Hao Li
- Henan Key Laboratory of Helicobacter Pylori & Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China; Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Saisai Cao
- Henan Key Laboratory of Helicobacter Pylori & Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China; Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yong Yu
- Henan Key Laboratory of Helicobacter Pylori & Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China; Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
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Agarwal S, Srivastava VK, Arshad Z, Sharma P, Prakash R. Effect of Dopamine as a Vascular Endothelial Growth Factor Antagonist on the Development of Acute Lung Injury in Sepsis Patients. Cureus 2024; 16:e64102. [PMID: 39114208 PMCID: PMC11305694 DOI: 10.7759/cureus.64102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/08/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Sepsis is a dysregulated host immune response stemming from a systemic inflammatory response to microbial invasion, encompassing bacteria, viruses, and other pathogens. The vascular endothelial growth factor (VEGF) was initially identified for its potent induction of endothelial permeability. Studies have proposed a therapeutic role of dopamine in mitigating VEGF-induced permeability, shedding light on its potential in acute respiratory distress syndrome (ARDS) management. MAIN OBJECTIVE To determine the effect of dopamine as an inhibitor of VEGF and to prevent the progression of sepsis to acute lung injury (ALI) and ARDS. METHODS A total of 154 critical care unit patients with a diagnosis of sepsis were randomized into two groups: Group I (control group) and Group II (Study group). Both received standard treatment, as per ICU protocol. In addition, the study group (Group II) received a dopamine infusion of 2 micrograms/kg/min. Baseline routine investigation, procalcitonin, and chest X-ray were done. Day one and day seven blood samples were stored for analysis of VEGF levels. Murray's score and sequential organ failure assessment (SOFA) score (organ dysfunction) were calculated from day one to day seven. RESULTS VEGF levels on day seven were significantly lower in the study group compared to the control group (p<0.05). The PaO2/FiO2 ratio at day seven was significantly increased in the study group than in the control group, indicating an improvement in oxygenation status in the study group. There was a mean ICU stay of 9.3 days in the study group versus 11.6 days in the control group (p<0.05). The SOFA score showed a significant improvement in the study group from day five onwards, indicating a therapeutic effect of dopamine on organ dysfunction in sepsis. CONCLUSION Dopamine reduces VEGF and lung injury mediated by increased endothelial permeability.
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Affiliation(s)
- Shivam Agarwal
- Anesthesiology and Critical Care, King George's Medical University, Lucknow, IND
| | - Vinod K Srivastava
- Anesthesiology and Critical Care, King George's Medical University, Lucknow, IND
| | - Zia Arshad
- Anesthesiology and Critical Care, King George's Medical University, Lucknow, IND
| | - Pallavi Sharma
- Anesthesiology and Critical Care, King George's Medical University, Lucknow, IND
| | - Ravi Prakash
- Anesthesiology and Critical Care, King George's Medical University, Lucknow, IND
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Gatti DM, Tyler AL, Mahoney JM, Churchill GA, Yener B, Koyuncu D, Gurcan MN, Niazi MKK, Tavolara T, Gower A, Dayao D, McGlone E, Ginese ML, Specht A, Alsharaydeh A, Tessier PA, Kurtz SL, Elkins KL, Kramnik I, Beamer G. Systems genetics uncover new loci containing functional gene candidates in Mycobacterium tuberculosis-infected Diversity Outbred mice. PLoS Pathog 2024; 20:e1011915. [PMID: 38861581 PMCID: PMC11195971 DOI: 10.1371/journal.ppat.1011915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 06/24/2024] [Accepted: 04/17/2024] [Indexed: 06/13/2024] Open
Abstract
Mycobacterium tuberculosis infects two billion people across the globe, and results in 8-9 million new tuberculosis (TB) cases and 1-1.5 million deaths each year. Most patients have no known genetic basis that predisposes them to disease. Here, we investigate the complex genetic basis of pulmonary TB by modelling human genetic diversity with the Diversity Outbred mouse population. When infected with M. tuberculosis, one-third develop early onset, rapidly progressive, necrotizing granulomas and succumb within 60 days. The remaining develop non-necrotizing granulomas and survive longer than 60 days. Genetic mapping using immune and inflammatory mediators; and clinical, microbiological, and granuloma correlates of disease identified five new loci on mouse chromosomes 1, 2, 4, 16; and three known loci on chromosomes 3 and 17. Further, multiple positively correlated traits shared loci on chromosomes 1, 16, and 17 and had similar patterns of allele effects, suggesting these loci contain critical genetic regulators of inflammatory responses to M. tuberculosis. To narrow the list of candidate genes, we used a machine learning strategy that integrated gene expression signatures from lungs of M. tuberculosis-infected Diversity Outbred mice with gene interaction networks to generate scores representing functional relationships. The scores were used to rank candidates for each mapped trait, resulting in 11 candidate genes: Ncf2, Fam20b, S100a8, S100a9, Itgb5, Fstl1, Zbtb20, Ddr1, Ier3, Vegfa, and Zfp318. Although all candidates have roles in infection, inflammation, cell migration, extracellular matrix remodeling, or intracellular signaling, and all contain single nucleotide polymorphisms (SNPs), SNPs in only four genes (S100a8, Itgb5, Fstl1, Zfp318) are predicted to have deleterious effects on protein functions. We performed methodological and candidate validations to (i) assess biological relevance of predicted allele effects by showing that Diversity Outbred mice carrying PWK/PhJ alleles at the H-2 locus on chromosome 17 QTL have shorter survival; (ii) confirm accuracy of predicted allele effects by quantifying S100A8 protein in inbred founder strains; and (iii) infection of C57BL/6 mice deficient for the S100a8 gene. Overall, this body of work demonstrates that systems genetics using Diversity Outbred mice can identify new (and known) QTLs and functionally relevant gene candidates that may be major regulators of complex host-pathogens interactions contributing to granuloma necrosis and acute inflammation in pulmonary TB.
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Affiliation(s)
- Daniel M. Gatti
- The Jackson Laboratory, Bar Harbor, Maine, United States of America
| | - Anna L. Tyler
- The Jackson Laboratory, Bar Harbor, Maine, United States of America
| | | | | | - Bulent Yener
- Rensselaer Polytechnic Institute, Troy, New York, United States of America
| | - Deniz Koyuncu
- Rensselaer Polytechnic Institute, Troy, New York, United States of America
| | - Metin N. Gurcan
- Wake Forest University School of Medicine, Winston Salem, North Carolina, United States of America
| | - MK Khalid Niazi
- Wake Forest University School of Medicine, Winston Salem, North Carolina, United States of America
| | - Thomas Tavolara
- Wake Forest University School of Medicine, Winston Salem, North Carolina, United States of America
| | - Adam Gower
- Clinical and Translational Science Institute, Boston University, Boston, Massachusetts, United States of America
| | - Denise Dayao
- Tufts University Cummings School of Veterinary Medicine, North Grafton, Massachusetts, United States of America
| | - Emily McGlone
- Tufts University Cummings School of Veterinary Medicine, North Grafton, Massachusetts, United States of America
| | - Melanie L. Ginese
- Tufts University Cummings School of Veterinary Medicine, North Grafton, Massachusetts, United States of America
| | - Aubrey Specht
- Tufts University Cummings School of Veterinary Medicine, North Grafton, Massachusetts, United States of America
| | - Anas Alsharaydeh
- Texas Biomedical Research Institute, San Antonio, Texas, United States of America
| | - Philipe A. Tessier
- Department of Microbiology and Immunology, Laval University School of Medicine, Quebec, Canada
| | - Sherry L. Kurtz
- Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America
| | - Karen L. Elkins
- Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America
| | - Igor Kramnik
- National Emerging Infectious Diseases Laboratories, Boston University, Boston, Massachusetts, United States of America
| | - Gillian Beamer
- Texas Biomedical Research Institute, San Antonio, Texas, United States of America
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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.
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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.
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Egorikhina MN, Rubtsova YP, Linkova DD, Charykova IN, Farafontova EA, Aleinik DY. Specifics of Cryopreservation of Hydrogel Biopolymer Scaffolds with Encapsulated Mesenchymal Stem Cells. Polymers (Basel) 2024; 16:247. [PMID: 38257046 PMCID: PMC10820988 DOI: 10.3390/polym16020247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/29/2023] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
The demand for regenerative medicine products is growing rapidly in clinical practice. Unfortunately, their use has certain limitations. One of these, which significantly constrains the widespread distribution and commercialization of such materials, is their short life span. For products containing suspensions of cells, this issue can be solved by using cryopreservation. However, this approach is rarely used for multicomponent tissue-engineered products due to the complexity of selecting appropriate cryopreservation protocols and the lack of established criteria for assessing the quality of such products once defrosted. Our research is aimed at developing a cryopreservation protocol for an original hydrogel scaffold with encapsulated MSCs and developing a set of criteria for assessing the quality of their functional activity in vitro. The scaffolds were frozen using two alternative types of cryocontainers and stored at either -40 °C or -80 °C. After cryopreservation, the external state of the scaffolds was evaluated in addition to recording the cell viability, visible changes during subsequent cultivation, and any alterations in proliferative and secretory activity. These observations were compared to those of scaffolds cultivated without cryopreservation. It was shown that cryopreservation at -80 °C in an appropriate type of cryocontainer was optimal for the hydrogels/adipose-derived stem cells (ASCs) tested if it provided a smooth temperature decrease during freezing over a period of at least three hours until the target values of the cryopreservation temperature regimen were reached. It was shown that evaluating a set of indicators, including the viability, the morphology, and the proliferative and secretory activity of the cells, enables the characterization of the quality of a tissue-engineered construct after its withdrawal from cryopreservation, as well as indicating the effectiveness of the cryopreservation protocol.
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Affiliation(s)
| | | | - Daria D. Linkova
- Federal State Budgetary Educational Institution of Higher Education, Privolzhsky Research Medical University of the Ministry of Health of the Russian Federation (FSBEI HE PRMU MOH), 603600 Nizhny Novgorod, Russia; (M.N.E.); (Y.P.R.); (I.N.C.); (D.Y.A.)
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Yasmin R, Thakur S, Blotra A, Sahu A, Vasudevan K, Reza MA, Doley R. Proteome analysis of Daboia russelii venom, a medically important snake from the Indian sub-continent. Toxicon 2024; 237:107532. [PMID: 38030094 DOI: 10.1016/j.toxicon.2023.107532] [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: 09/20/2023] [Revised: 10/31/2023] [Accepted: 11/21/2023] [Indexed: 12/01/2023]
Abstract
Daboia russelii is a category-I medically important snake throughout the Indian sub-continent contributing to majority of snakebite incidences in this part of the world. As such, extensive studies on its venom composition and search of efficient and appropriate interventions for its treatment become crucial. In this study, the proteome of Daboia russelii venom from Tanore, Rajshahi, Bangladesh was profiled using a combination of chromatographic and mass spectrometric techniques. A total of 37 different proteins belonging to 11 different snake venom protein families were detected. Proteomics analysis revealed the presence of major phospholipase A2 toxins. Daboiatoxin (both A and B subunits), the main lethal PLA2 toxin in the venom of Daboia siamensis (Myanmar viper) which is neurotoxic, myotoxic and cytotoxic was detected. Presence of Daboxin P, which is a major protein in the venom of Indian Daboia russelii with strong anticoagulant activity, was also observed. Inconsistent distribution of such lethal toxins in the venom of same species calls for more investigations of snake venoms from lesser explored regions and formulation of better alternatives to the current antivenom therapy for efficient treatment.
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Affiliation(s)
- Rafika Yasmin
- Molecular Toxinology Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Assam, 784028, India
| | - Susmita Thakur
- Molecular Toxinology Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Assam, 784028, India
| | - Avni Blotra
- Laboratory for the Conservation of Endangered Species, CSIR-Centre for Cellular and Molecular Biology, Hyderabad, 500048, India
| | - Alka Sahu
- Laboratory for the Conservation of Endangered Species, CSIR-Centre for Cellular and Molecular Biology, Hyderabad, 500048, India
| | - Karthikeyan Vasudevan
- Laboratory for the Conservation of Endangered Species, CSIR-Centre for Cellular and Molecular Biology, Hyderabad, 500048, India
| | - Md Abu Reza
- Molecular Biology and Protein Science Laboratory, Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, 6205, Bangladesh
| | - Robin Doley
- Molecular Toxinology Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Assam, 784028, India.
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9
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Gatti DM, Tyler AL, Mahoney JM, Churchill GA, Yener B, Koyuncu D, Gurcan MN, Niazi M, Tavolara T, Gower AC, Dayao D, McGlone E, Ginese ML, Specht A, Alsharaydeh A, Tessier PA, Kurtz SL, Elkins K, Kramnik I, Beamer G. Systems genetics uncover new loci containing functional gene candidates in Mycobacterium tuberculosis-infected Diversity Outbred mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.21.572738. [PMID: 38187647 PMCID: PMC10769337 DOI: 10.1101/2023.12.21.572738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Mycobacterium tuberculosis, the bacillus that causes tuberculosis (TB), infects 2 billion people across the globe, and results in 8-9 million new TB cases and 1-1.5 million deaths each year. Most patients have no known genetic basis that predisposes them to disease. We investigated the complex genetic basis of pulmonary TB by modelling human genetic diversity with the Diversity Outbred mouse population. When infected with M. tuberculosis, one-third develop early onset, rapidly progressive, necrotizing granulomas and succumb within 60 days. The remaining develop non-necrotizing granulomas and survive longer than 60 days. Genetic mapping using clinical indicators of disease, granuloma histopathological features, and immune response traits identified five new loci on mouse chromosomes 1, 2, 4, 16 and three previously identified loci on chromosomes 3 and 17. Quantitative trait loci (QTLs) on chromosomes 1, 16, and 17, associated with multiple correlated traits and had similar patterns of allele effects, suggesting these QTLs contain important genetic regulators of responses to M. tuberculosis. To narrow the list of candidate genes in QTLs, we used a machine learning strategy that integrated gene expression signatures from lungs of M. tuberculosis-infected Diversity Outbred mice with gene interaction networks, generating functional scores. The scores were then used to rank candidates for each mapped trait in each locus, resulting in 11 candidates: Ncf2, Fam20b, S100a8, S100a9, Itgb5, Fstl1, Zbtb20, Ddr1, Ier3, Vegfa, and Zfp318. Importantly, all 11 candidates have roles in infection, inflammation, cell migration, extracellular matrix remodeling, or intracellular signaling. Further, all candidates contain single nucleotide polymorphisms (SNPs), and some but not all SNPs were predicted to have deleterious consequences on protein functions. Multiple methods were used for validation including (i) a statistical method that showed Diversity Outbred mice carrying PWH/PhJ alleles on chromosome 17 QTL have shorter survival; (ii) quantification of S100A8 protein levels, confirming predicted allele effects; and (iii) infection of C57BL/6 mice deficient for the S100a8 gene. Overall, this work demonstrates that systems genetics using Diversity Outbred mice can identify new (and known) QTLs and new functionally relevant gene candidates that may be major regulators of granuloma necrosis and acute inflammation in pulmonary TB.
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Affiliation(s)
- D M Gatti
- The Jackson Laboratory, Bar Harbor, ME
| | - A L Tyler
- The Jackson Laboratory, Bar Harbor, ME
| | | | | | - B Yener
- Rensselaer Polytechnic Institute, Troy, NY
| | - D Koyuncu
- Rensselaer Polytechnic Institute, Troy, NY
| | - M N Gurcan
- Wake Forest University School of Medicine, Winston Salem, NC
| | - Mkk Niazi
- Wake Forest University School of Medicine, Winston Salem, NC
| | - T Tavolara
- Wake Forest University School of Medicine, Winston Salem, NC
| | - A C Gower
- Clinical and Translational Science Institute, Boston University, Boston, MA
| | - D Dayao
- Tufts University Cummings School of Veterinary Medicine, North Grafton, MA
| | - E McGlone
- Tufts University Cummings School of Veterinary Medicine, North Grafton, MA
| | - M L Ginese
- Tufts University Cummings School of Veterinary Medicine, North Grafton, MA
| | - A Specht
- Tufts University Cummings School of Veterinary Medicine, North Grafton, MA
| | - A Alsharaydeh
- Texas Biomedical Research Institute, San Antonio, TX
| | - P A Tessier
- Department of Microbiology and Immunology, Laval University School of Medicine, Quebec, Canada
| | - S L Kurtz
- Center for Biologics, Food and Drug Administration, Bethesda, MD
| | - K Elkins
- Center for Biologics, Food and Drug Administration, Bethesda, MD
| | - I Kramnik
- NIEDL, Boston University, Boston, MA
| | - G Beamer
- Texas Biomedical Research Institute, San Antonio, TX
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Liang S, Zheng Z, Li Y, Yang Y, Qin L, Zhao Z, Wang L, Wang H. A review of platelet-rich plasma for enteric fistula management. Front Bioeng Biotechnol 2023; 11:1287890. [PMID: 38033816 PMCID: PMC10685294 DOI: 10.3389/fbioe.2023.1287890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 11/02/2023] [Indexed: 12/02/2023] Open
Abstract
Enteric fistula (EF), a serious complication after abdominal surgery, refers to unnatural communication between the gastrointestinal tract and the skin or other hollow organs. It is associated with infection, massive fluid/electrolyte loss, and malnutrition, resulting in an unhealed course. Despite advances in surgical techniques, wound care, infection control, and nutritional support, EF remains associated with considerable morbidity and mortality. Autologous platelet-rich plasma (PRP) containing elevated platelet concentrations has been proposed to promote healing in many tissues. However, the mechanism of action of PRP in EF treatment remains unclear owing to its complicated clinical manifestations. In this review, we summarized the clinical approaches, outlined the principal cytokines involved in the healing effects, and discussed the advantages of PRP for EF therapy. In addition, we defined the mechanism of autologous PRP in EF management, which is essential for further developing EF therapies.
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Affiliation(s)
- Shuang Liang
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
- Department of Clinical Laboratory, Zhangdian District People’s Hospital of Zibo City, Zibo, China
| | - Zhiqiang Zheng
- Department of Emergency Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yaxin Li
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yuanming Yang
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lifeng Qin
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhen Zhao
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Licun Wang
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Haiyan Wang
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
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11
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Giannotti L, Di Chiara Stanca B, Spedicato F, Nitti P, Damiano F, Demitri C, Calabriso N, Carluccio MA, Palermo A, Siculella L, Stanca E. Progress in Regenerative Medicine: Exploring Autologous Platelet Concentrates and Their Clinical Applications. Genes (Basel) 2023; 14:1669. [PMID: 37761809 PMCID: PMC10530962 DOI: 10.3390/genes14091669] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 08/17/2023] [Accepted: 08/22/2023] [Indexed: 09/29/2023] Open
Abstract
The goal of regenerative medicine is to achieve tissue regeneration. In the past, commonly used techniques included autologous or allogeneic transplantation and stem cell therapy, which have limitations, such as a lack of donor sites in the case of autologous transplantation and the invasiveness of stem cell harvesting. In recent years, research has, therefore, focused on new and less invasive strategies to achieve tissue regeneration. A step forward in this direction has been made with the development of autologous platelet concentrates (APCs), which are derived from the patient's own blood. They can be classified into three generations: platelet-rich plasma (PRP), platelet-rich fibrin (PRF), and concentrated growth factors (CGFs). These APCs have different structural characteristics, depending on the distinctive preparation method, and contain platelets, leukocytes, and multiple growth factors, including those most involved in regenerative processes. The purpose of this review is to clarify the most used techniques in the field of regenerative medicine in recent years, comparing the different types of APCs and analyzing the preparation protocols, the composition of the growth factors, the level of characterization achieved, and their clinical applications to date.
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Affiliation(s)
- Laura Giannotti
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; (L.G.); (B.D.C.S.); (F.S.); (F.D.); (E.S.)
| | - Benedetta Di Chiara Stanca
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; (L.G.); (B.D.C.S.); (F.S.); (F.D.); (E.S.)
| | - Francesco Spedicato
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; (L.G.); (B.D.C.S.); (F.S.); (F.D.); (E.S.)
| | - Paola Nitti
- Department of Engineering for Innovation, University of Salento, 73100 Lecce, Italy; (P.N.); (C.D.)
| | - Fabrizio Damiano
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; (L.G.); (B.D.C.S.); (F.S.); (F.D.); (E.S.)
| | - Christian Demitri
- Department of Engineering for Innovation, University of Salento, 73100 Lecce, Italy; (P.N.); (C.D.)
| | - Nadia Calabriso
- National Research Council (CNR), Institute of Clinical Physiology (IFC), 73100 Lecce, Italy; (N.C.); (M.A.C.)
| | - Maria Annunziata Carluccio
- National Research Council (CNR), Institute of Clinical Physiology (IFC), 73100 Lecce, Italy; (N.C.); (M.A.C.)
| | - Andrea Palermo
- Implant Dentistry College of Medicine and Dentistry, Birmingham B4 6BN, UK;
| | - Luisa Siculella
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; (L.G.); (B.D.C.S.); (F.S.); (F.D.); (E.S.)
| | - Eleonora Stanca
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; (L.G.); (B.D.C.S.); (F.S.); (F.D.); (E.S.)
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12
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Cartmel B, Li F, Zhou Y, Gottlieb L, Lu L, Mszar R, Harrigan M, Ligibel JA, Gogoi R, Schwartz PE, Risch HA, Irwin ML. Randomized trial of exercise on cancer-related blood biomarkers and survival in women with ovarian cancer. Cancer Med 2023; 12:15492-15503. [PMID: 37269192 PMCID: PMC10417064 DOI: 10.1002/cam4.6187] [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: 10/13/2022] [Revised: 04/13/2023] [Accepted: 05/21/2023] [Indexed: 06/04/2023] Open
Abstract
BACKGROUND In randomized trials in women with breast cancer, exercise has been shown to have beneficial effects on cancer-related circulating biomarkers that may impact survival. Such studies are lacking for ovarian cancer. METHODS This secondary analysis of a published randomized controlled trial examined the impact of a 6-month exercise intervention versus attention-control on change in prespecified circulating biomarkers (cancer antigen 125 (CA-125), C-reactive protein (CRP), insulin-like growth factor-1(IGF-1), insulin and leptin) in a subset of participants who provided a fasting blood draw (N = 104/144) at enrollment and at 6 months. Change in biomarkers between study arms was compared using a linear mixed effects model analysis. An exploratory analysis of the exercise intervention versus attention-control on all-cause mortality included all (N = 144) participants. All statistical tests were two-sided. RESULTS Participants included in the biomarker analysis were 57.0 ± 8.8 (mean ± SD) years old and 1.6 ± 0.9 years post-diagnosis. Adherence to the exercise intervention was 176.4 ± 63.5 min/week. Post intervention IGF-1 (group difference in change: -14.2 (-26.1 to -2.3) ng/mL (least squared means (95% CI))) and leptin (-8.9 (-16.5 to -1.4) ng/mL) were significantly reduced in the exercise group (N = 53) compared to those in attention-control (N = 51). No group difference in change was seen for CA-125 (p = 0.54), CRP (p = 0.95), or insulin (p = 0.37). With median follow-up of 70 months [range 6.6-105.4 months], 50/144 (34.7%) (exercise group; 24/74 (32.4%) versus attention-control group; 26/70 (37.1%)) participants died with no between group difference in overall survival (p = 0.99). CONCLUSIONS Further studies are needed to determine the clinical significance of exercise-induced changes in cancer-related circulating biomarkers in women with ovarian cancer.
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Affiliation(s)
- Brenda Cartmel
- Department of Chronic Disease EpidemiologyYale School of Public HealthNew HavenConnecticutUSA
- Yale Cancer CenterNew HavenConnecticutUSA
| | - Fang‐yong Li
- Department of BiostatisticsYale School of Public HealthNew HavenConnecticutUSA
| | - Yang Zhou
- Department of Chronic Disease EpidemiologyYale School of Public HealthNew HavenConnecticutUSA
- Yale Cancer CenterNew HavenConnecticutUSA
| | - Linda Gottlieb
- Department of Chronic Disease EpidemiologyYale School of Public HealthNew HavenConnecticutUSA
| | - Lingeng Lu
- Department of Chronic Disease EpidemiologyYale School of Public HealthNew HavenConnecticutUSA
- Yale Cancer CenterNew HavenConnecticutUSA
| | - Reed Mszar
- Department of Chronic Disease EpidemiologyYale School of Public HealthNew HavenConnecticutUSA
| | - Maura Harrigan
- Department of Chronic Disease EpidemiologyYale School of Public HealthNew HavenConnecticutUSA
| | - Jennifer A. Ligibel
- Department of Medical OncologyDana‐Farber Cancer InstituteBostonMassachusettsUSA
| | - Radhika Gogoi
- Gynecologic Oncology, Women and Children's InstituteGeisinger Health SystemDanvillePennsylvaniaUSA
- Present address:
Department of Obstetrics & GynecologyWayne State UniversityDetroitMichiganUSA
| | - Peter E. Schwartz
- Yale Cancer CenterNew HavenConnecticutUSA
- Section of Medical Oncology, Department of Internal MedicineYale School of MedicineNew HavenConnecticutUSA
| | - Harvey A. Risch
- Department of Chronic Disease EpidemiologyYale School of Public HealthNew HavenConnecticutUSA
- Yale Cancer CenterNew HavenConnecticutUSA
| | - Melinda L. Irwin
- Department of Chronic Disease EpidemiologyYale School of Public HealthNew HavenConnecticutUSA
- Yale Cancer CenterNew HavenConnecticutUSA
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13
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Fraidakis M, Giannakakis G, Anifantaki A, Skouradaki M, Tsakoumi P, Bitzopoulou P, Kourpa S, Zervakis A, Kakouri P. Intraovarian Platelet-Rich Plasma Injections: Safety and Thoughts on Efficacy Based on a Single Centre Experience With 469 Women. Cureus 2023; 15:e38674. [PMID: 37288228 PMCID: PMC10243509 DOI: 10.7759/cureus.38674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/06/2023] [Indexed: 06/09/2023] Open
Abstract
BACKGROUND Ovarian rejuvenation is an innovative procedure intended to restore ovarian fertility and development during the climacteric and has been used to enhance fertility in women with premature ovarian insufficiency (POI). This retrospective study was conducted to determine the effects of an intraovarian platelet-rich plasma (PRP) injection on ovarian stimulation outcomes in women referred to an in vitro fertilisation centre. Methods-Population: This was a retrospective observational study, and the inclusion criteria included women of reproductive age with at least one ovary with a history of infertility, hormonal abnormalities, an absence of a menstrual cycle, and premature ovarian failure. During the patient's first consultation, a detailed reproductive history was recorded, a pelvic scan for ovarian size was conducted, and hormonal analysis for follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH), estradiol (E2), and luteinizing hormone (LH) was conducted. RESULTS In the study, 469 women with a history of infertility, hormonal abnormalities, an absence of a menstrual cycle, and premature ovarian failure had hormonal levels recorded up to four months after treatment, and these were included in the study. The volume of peripheral blood required to prepare 6-8 mL of PRP for administration was 40-60 mL. The initial concentration of platelets in the peripheral blood sample was about 25000/µL, whereas the prepared PRP had a concentration of 900.000/µL. A volume of approximately 2-4 mL per ovary, depending on the ovarian volume, was used for the intraovarian injection. PRP intervention had significant effects on FSH concentration at the α = 0.05 level. Statistically significant increases in normal values of FSH and E2were observed for months three and four after the PRP intervention for all age groups. CONCLUSIONS The results of our observational study revealed that a PRP intraovarian injection is associated with improved ovarian tissue and function. Future randomised clinical trials are needed to shed light on the use of PRP in ovarian rejuvenation before offering it routinely in clinical practice.
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Affiliation(s)
| | - Giorgios Giannakakis
- Biomedicine Laboratory, Foundation for Research and Technology-Hellas, Heraklion, GRC
| | | | | | | | | | - Sofia Kourpa
- Maternity Unit, Crete Fertility Centre, Heraklion, GRC
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14
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Maffulli N, Cuozzo F, Migliorini F, Oliva F. The tendon unit: biochemical, biomechanical, hormonal influences. J Orthop Surg Res 2023; 18:311. [PMID: 37085854 PMCID: PMC10120196 DOI: 10.1186/s13018-023-03796-4] [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: 01/17/2023] [Accepted: 04/12/2023] [Indexed: 04/23/2023] Open
Abstract
The current literature has mainly focused on the biology of tendons and on the characterization of the biological properties of tenocytes and tenoblasts. It is still not understood how these cells can work together in homeostatic equilibrium. We put forward the concept of the "tendon unit" as a morpho-functional unit that can be influenced by a variety of external stimuli such as mechanical stimuli, hormonal influence, or pathological states. We describe how this unit can modify itself to respond to such stimuli. We evidence the capability of the tendon unit of healing itself through the production of collagen following different mechanical stimuli and hypothesize that restoration of the homeostatic balance of the tendon unit should be a therapeutic target.
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Affiliation(s)
- Nicola Maffulli
- Barts and the London School of Medicine and Dentistry, Centre for Sports and Exercise Medicine, Mile End Hospital, Queen Mary University of London, 275 Bancroft Road, London, E1 4DG, England
- School of Pharmacy and Bioengineering, Keele University Faculty of Medicine, Thornburrow Drive, Stoke On Trent, England
- Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081, Baronissi, SA, Italy
| | - Francesco Cuozzo
- Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081, Baronissi, SA, Italy
| | - Filippo Migliorini
- Department of Orthopaedic, Trauma, and Reconstructive Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany.
- Department of Orthopaedic and Trauma Surgery, Eifelklinik St. Brigida, 52152, Simmerath, Germany.
| | - Francesco Oliva
- Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081, Baronissi, SA, Italy
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15
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Palermo A, Giannotti L, Di Chiara Stanca B, Ferrante F, Gnoni A, Nitti P, Calabriso N, Demitri C, Damiano F, Batani T, Lungherini M, Carluccio MA, Rapone B, Qorri E, Scarano A, Siculella L, Stanca E, Rochira A. Use of CGF in Oral and Implant Surgery: From Laboratory Evidence to Clinical Evaluation. Int J Mol Sci 2022; 23:15164. [PMID: 36499489 PMCID: PMC9736623 DOI: 10.3390/ijms232315164] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/22/2022] [Accepted: 12/01/2022] [Indexed: 12/03/2022] Open
Abstract
Edentulism is the condition of having lost natural teeth, and has serious social, psychological, and emotional consequences. The need for implant services in edentulous patients has dramatically increased during the last decades. In this study, the effects of concentrated growth factor (CGF), an autologous blood-derived biomaterial, in improving the process of osseointegration of dental implants have been evaluated. Here, permeation of dental implants with CGF has been obtained by using a Round up device. These CGF-coated dental implants retained a complex internal structure capable of releasing growth factors (VEGF, TGF-β1, and BMP-2) and matrix metalloproteinases (MMP-2 and MMP-9) over time. The CGF-permeated implants induced the osteogenic differentiation of human bone marrow stem cells (hBMSC) as confirmed by matrix mineralization and the expression of osteogenic differentiation markers. Moreover, CGF provided dental implants with a biocompatible and biologically active surface that significantly improved adhesion of endothelial cells on CGF-coated implants compared to control implants (without CGF). Finally, data obtained from surgical interventions with CGF-permeated dental implants presented better results in terms of optimal osseointegration and reduced post-surgical complications. These data, taken together, highlight new and interesting perspectives in the use of CGF in the dental implantology field to improve osseointegration and promote the healing process.
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Affiliation(s)
- Andrea Palermo
- College of Medicine and Dentistry Birmingham, University of Birmingham, Birmingham B4 6BN, UK
| | - Laura Giannotti
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy
| | - Benedetta Di Chiara Stanca
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy
| | | | - Antonio Gnoni
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Paola Nitti
- Department of Engineering for Innovation, Campus Ecotekne, University of Salento, Via per Monteroni, 73100 Lecce, Italy
| | - Nadia Calabriso
- National Research Council (CNR) Institute of Clinical Physiology (IFC), 73100 Lecce, Italy
| | - Christian Demitri
- Department of Engineering for Innovation, Campus Ecotekne, University of Salento, Via per Monteroni, 73100 Lecce, Italy
| | - Fabrizio Damiano
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy
| | | | | | | | - Biagio Rapone
- Interdisciplinary Department of Medicine, Aldo Moro University of Bari, 70121 Bari, Italy
| | - Erda Qorri
- Faculty of Medical Science, Albanian University, Bulevardi Zogu I, 1001 Tirana, Albania
| | - Antonio Scarano
- Department of Oral Science, Nano and Biotechnology and CeSi-Met, University of Chieti-Pescara, 66100 Chieti, Italy
| | - Luisa Siculella
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy
| | - Eleonora Stanca
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy
| | - Alessio Rochira
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy
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16
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Ghori A, Prinz V, Nieminen-Kehlä M, Bayerl SH, Kremenetskaia I, Riecke J, Krechel H, Broggini T, Scherschinski L, Licht T, Keshet E, Vajkoczy P. Vascular Endothelial Growth Factor Augments the Tolerance Towards Cerebral Stroke by Enhancing Neurovascular Repair Mechanism. Transl Stroke Res 2022; 13:774-791. [PMID: 35175562 PMCID: PMC9391249 DOI: 10.1007/s12975-022-00991-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 12/05/2021] [Accepted: 01/26/2022] [Indexed: 11/30/2022]
Abstract
The breakdown of the blood-brain barrier (BBB) is a critical event in the development of secondary brain injury after stroke. Among the cellular hallmarks in the acute phase after stroke are a downregulation of tight-junction molecules and the loss of microvascular pericyte coverage and endothelial sealing. Thus, a rapid repair of blood vessel integrity and re-stabilization of the BBB is considered an important strategy to reduce secondary brain damage. However, the mechanisms underlying BBB disruption remain poorly understood. Especially, the role of VEGF in this context remains inconclusive. With the conditional and reversible VEGF expression systems, we studied the time windows of deleterious and beneficial VEGF actions on blood vessel integrity in mice. Using genetic systems for gain of function and loss of function experiments, we activated and inhibited VEGF signaling prior and simultaneously to ischemic stroke onset. In both scenarios, VEGF seems to play a vital role in containing the stroke-induced damage after cerebral ischemia. We report that the transgenic overexpression of VEGF (GOF) prior to the stroke stabilizes the vasculature and prevents blood-brain barrier disruption in young and aged animals after stroke. Whereas inhibition of signals for endogenous VEGF (LOF) prior to stroke results in bigger infarction with massive brain swelling and enhanced BBB permeability, furthermore, activating or blocking VEGF signaling after ischemic stroke onset had comparable effects on BBB repair and cerebral edema. VEGF can function as an anti-permeability factor, and a VEGF-based therapy in the context of stroke prevention and recovery has an enormous potential.
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Affiliation(s)
- Adnan Ghori
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Vincent Prinz
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | | | - Simon. H. Bayerl
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Irina Kremenetskaia
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Jana Riecke
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Hanna Krechel
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Thomas Broggini
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Lea Scherschinski
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
| | - Tamar Licht
- Department of Developmental Biology and Cancer Research, Hebrew University Hadassah Medical School, 91120 Jerusalem, Israel
| | - Eli Keshet
- Department of Developmental Biology and Cancer Research, Hebrew University Hadassah Medical School, 91120 Jerusalem, Israel
| | - Peter Vajkoczy
- Department of Neurosurgery, Universitätsmedizin Charité, 10117 Berlin, Germany
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Lipid nanoparticle-encapsulated VEGFa siRNA facilitates cartilage formation by suppressing angiogenesis. Int J Biol Macromol 2022; 221:1313-1324. [PMID: 36108749 DOI: 10.1016/j.ijbiomac.2022.09.065] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/04/2022] [Accepted: 09/07/2022] [Indexed: 12/18/2022]
Abstract
Cartilage is an important tissue that is widely found in joints, ears, nose and other organs. The limited capacity to regenerate makes cartilage reconstruction an urgent clinical demand. Due to the avascular nature of cartilage, we hypothesized that inhibition of vascularization contributes to cartilage formation. Here, we used VEGFa siRNA to inhibit the infiltration of the local vascular system. Optimized lipid nanoparticles were prepared by microfluidics for the delivery of siRNA. Then, we constructed a tissue engineering scaffold. Both seed cells and VEGFa siRNA-LNPs were loaded in a GELMA hydrogel. Subcutaneous implantation experiments in nude mice indicate that this is a promising strategy for cartilage reconstruction. The regenerated cartilage was superior, with significant upregulation of SOX9, COL-II and ACAN. This is attributed to an environment deficient in oxygen and nutrients, which facilitates cartilage formation by upregulating HIF-1α and FOXO transcription factors. In conclusion, a GelMA/Cells+VEGFa siRNA-LNPs scaffold was constructed to achieve superior cartilage regeneration.
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18
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Lai Y, Lin C, Lin X, Wu L, Zhao Y, Shao T, Lin F. Comprehensive Analysis of Molecular Subtypes and Hub Genes of Sepsis by Gene Expression Profiles. Front Genet 2022; 13:884762. [PMID: 36035194 PMCID: PMC9412106 DOI: 10.3389/fgene.2022.884762] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 06/10/2022] [Indexed: 11/15/2022] Open
Abstract
Background: Sepsis is a systemic inflammatory response syndrome (SIRS) with heterogeneity of clinical symptoms. Studies further exploring the molecular subtypes of sepsis and elucidating its probable mechanisms are urgently needed. Methods: Microarray datasets of peripheral blood in sepsis were downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were identified. Weighted gene co-expression network analysis (WGCNA) analysis was conducted to screen key module genes. Consensus clustering analysis was carried out to identify distinct sepsis molecular subtypes. Subtype-specific pathways were explored using gene set variation analysis (GSVA). Afterward, we intersected subtype-related, dramatically expressed and module-specific genes to screen consensus DEGs (co-DEGs). Enrichment analysis was carried out to identify key pathways. The least absolute shrinkage and selection operator (LASSO) regression analysis was used for screen potential diagnostic biomarkers. Results: Patients with sepsis were classified into three clusters. GSVA showed these DEGs among different clusters in sepsis were assigned to metabolism, oxidative phosphorylation, autophagy regulation, and VEGF pathways, etc. In addition, we identified 40 co-DEGs and several dysregulated pathways. A diagnostic model with 25-gene signature was proven to be of high value for the diagnosis of sepsis. Genes in the diagnostic model with AUC values more than 0.95 in external datasets were screened as key genes for the diagnosis of sepsis. Finally, ANKRD22, GPR84, GYG1, BLOC1S1, CARD11, NOG, and LRG1 were recognized as critical genes associated with sepsis molecular subtypes. Conclusion: There are remarkable differences in and enriched pathways among different molecular subgroups of sepsis, which may be the key factors leading to heterogeneity of clinical symptoms and prognosis in patients with sepsis. Our current study provides novel diagnostic and therapeutic biomarkers for sepsis molecular subtypes.
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Affiliation(s)
- Yongxing Lai
- Department of Geriatric Medicine, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Fujian Provincial Center for Geriatrics, Fujian Provincial Hospital, Fuzhou, China
| | - Chunjin Lin
- Department of Geriatric Medicine, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Fujian Provincial Center for Geriatrics, Fujian Provincial Hospital, Fuzhou, China
| | - Xing Lin
- Department of Geriatric Medicine, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Fujian Provincial Center for Geriatrics, Fujian Provincial Hospital, Fuzhou, China
| | - Lijuan Wu
- Department of Geriatric Medicine, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Fujian Provincial Center for Geriatrics, Fujian Provincial Hospital, Fuzhou, China
| | - Yinan Zhao
- Department of Geriatric Medicine, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Fujian Provincial Center for Geriatrics, Fujian Provincial Hospital, Fuzhou, China
| | - Tingfang Shao
- Department of Geriatric Medicine, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Fujian Provincial Center for Geriatrics, Fujian Provincial Hospital, Fuzhou, China
| | - Fan Lin
- Department of Geriatric Medicine, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Fujian Provincial Center for Geriatrics, Fujian Provincial Hospital, Fuzhou, China
- *Correspondence: Fan Lin,
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19
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Al-Farsi H, Al-Azwani I, Malek JA, Chouchane L, Rafii A, Halabi NM. Discovery of new therapeutic targets in ovarian cancer through identifying significantly non-mutated genes. J Transl Med 2022; 20:244. [PMID: 35619151 PMCID: PMC9134657 DOI: 10.1186/s12967-022-03440-5] [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: 01/26/2022] [Accepted: 05/13/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Mutated and non-mutated genes interact to drive cancer growth and metastasis. While research has focused on understanding the impact of mutated genes on cancer biology, understanding non-mutated genes that are essential to tumor development could lead to new therapeutic strategies. The recent advent of high-throughput whole genome sequencing being applied to many different samples has made it possible to calculate if genes are significantly non-mutated in a specific cancer patient cohort. METHODS We carried out random mutagenesis simulations of the human genome approximating the regions sequenced in the publicly available Cancer Growth Atlas Project for ovarian cancer (TCGA-OV). Simulated mutations were compared to the observed mutations in the TCGA-OV cohort and genes with the largest deviations from simulation were identified. Pathway analysis was performed on the non-mutated genes to better understand their biological function. We then compared gene expression, methylation and copy number distributions of non-mutated and mutated genes in cell lines and patient data from the TCGA-OV project. To directly test if non-mutated genes can affect cell proliferation, we carried out proof-of-concept RNAi silencing experiments of a panel of nine selected non-mutated genes in three ovarian cancer cell lines and one primary ovarian epithelial cell line. RESULTS We identified a set of genes that were mutated less than expected (non-mutated genes) and mutated more than expected (mutated genes). Pathway analysis revealed that non-mutated genes interact in cancer associated pathways. We found that non-mutated genes are expressed significantly more than mutated genes while also having lower methylation and higher copy number states indicating that they could be functionally important. RNAi silencing of the panel of non-mutated genes resulted in a greater significant reduction of cell viability in the cancer cell lines than in the non-cancer cell line. Finally, as a test case, silencing ANKLE2, a significantly non-mutated gene, affected the morphology, reduced migration, and increased the chemotherapeutic response of SKOV3 cells. CONCLUSION We show that we can identify significantly non-mutated genes in a large ovarian cancer cohort that are well-expressed in patient and cell line data and whose RNAi-induced silencing reduces viability in three ovarian cancer cell lines. Targeting non-mutated genes that are important for tumor growth and metastasis is a promising approach to expand cancer therapeutic options.
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Affiliation(s)
| | | | - Joel A Malek
- Genomics Core, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, Doha, Qatar
| | - Lotfi Chouchane
- Genetic Intelligence Laboratory, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, Doha, Qatar
| | - Arash Rafii
- Genetic Intelligence Laboratory, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, Doha, Qatar.
| | - Najeeb M Halabi
- Genetic Intelligence Laboratory, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, Doha, Qatar.
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20
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Quantitative changes in iris vasculature and blood flow in patients with different refractive errors. Graefes Arch Clin Exp Ophthalmol 2022; 260:3123-3129. [DOI: 10.1007/s00417-022-05632-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 03/01/2022] [Accepted: 03/10/2022] [Indexed: 11/04/2022] Open
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21
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Chen Z, Miao D, Zhang L, Zhong L, Liu N, Chen Y. Efficacy of concentrated growth factor with low-level laser for the regeneration of interdental papilla defects. Odontology 2022; 110:795-804. [PMID: 35290532 DOI: 10.1007/s10266-022-00702-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 03/03/2022] [Indexed: 11/26/2022]
Abstract
Gingival "black triangle" is common in clinical which due to interdental papilla recession. The cause of the loss of papilla is multi-factorial and it may be caused by the absorption of interdental alveolar bone or abnormal tooth position. Besides, it is a common complication after orthodontics and implant surgery. Recession of gingival papilla influences interdental plaque control, increasing food impaction and alveolar bone absorption, causing aesthetic and pronunciation problems. Thus, the way of reducing or eliminating the gingival "black triangle" has become one of the most essential problems for dentists. Concentrated growth factor (CGF) and low-level-laser therapy have been widely used, respectively, and CGF was considered as the only self-substance which has soft tissue regeneration function. This study aims to evaluate the efficacy of regenerating interdental papilla by Liquid phase concentrated growth factor (LPCGF) injection with low-level-laser therapy (LLLT).
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Affiliation(s)
- Ziling Chen
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Department of Periodontology, College of Stomatology, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Di Miao
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Department of Periodontology, College of Stomatology, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Le Zhang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Department of Periodontology, College of Stomatology, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Liangqiuyue Zhong
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Department of Periodontology, College of Stomatology, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Na Liu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
- Department of Periodontology, College of Stomatology, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Yue Chen
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
- Department of Periodontology, College of Stomatology, Xi'an Jiaotong University, Xi'an, People's Republic of China.
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22
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Liu P, Zhang Q, Mi J, Wang S, Xu Q, Zhuang D, Chen W, Liu C, Zhang L, Guo J, Wu X. Exosomes derived from stem cells of human deciduous exfoliated teeth inhibit angiogenesis in vivo and in vitro via the transfer of miR-100-5p and miR-1246. Stem Cell Res Ther 2022; 13:89. [PMID: 35241153 PMCID: PMC8895508 DOI: 10.1186/s13287-022-02764-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 12/29/2021] [Indexed: 12/14/2022] Open
Abstract
Background Anti-angiogenic therapy has been shown to be a promising strategy for anti-tumor treatment. Increasing evidence indicates that tumor angiogenesis is affected by exosomes that are secreted by mesenchymal stem cells (MSCs), but whether exosomes derived from MSCs suppress or promote angiogenesis remain paradoxical. The purpose of this study focused on understanding the potential role of exosomes derived from stem cells of human deciduous exfoliated teeth (SHED-Exos) in regulating angiogenesis and the underlying molecular mechanism. Methods Exosomes were isolated from supernatants of SHED cells using an exosome purification kit and were characterized by transmission electron microscopy, nanoparticle tracking analysis and western blot analysis. Cell Counting Kit-8, flow cytometric assays, western blots, wound healing and transwell migration assays were performed to characterize the roles of SHED-Exos on cell proliferation, apoptosis and migration of human umbilical vein endothelial cells (HUVECs). The anti-angiogenic activity of SHED-Exos was assessed via a tube formation assay of endothelial cells and angiogenesis-related factors were analyzed by western blotting. In vivo, we used the chick chorioallantoic membrane (CAM) assay and an oral squamous cell carcinoma (OSCC) xenograft transplantation model with nude mice that received multi-point injections at three-day intervals to evaluate the effects on angiogenesis. Furthermore, the sequencing of microRNAs (miRNAs) in SHED-Exos was performed to investigate the underlying anti-angiogenic mechanism. Results The results showed that SHED-Exos inhibit cell proliferation and migration and induce apoptosis in HUVECs. SHED-Exos suppress the tube-like structure formation of HUVECs in vitro. SHED-Exos downregulate several angiogenesis-related factors, including VEGFA, MMP-9 and ANGPT1. In vivo, the chick CAM assay verified that treatment with SHED-Exos inhibits micro-vascular formation, and importantly, significantly reduces the micro-vascular formation of tumors generated from xenografted OSCC cells, which was associated with the inhibition of tumor growth in vivo. Mechanistically, our data suggested that SHED-Exos are enriched with miR-100-5p and miR-1246 and are transferred to endothelial cells, which results in decreased tube formation via the down-regulation of VEGFA expression. Conclusions These results demonstrate that SHED-Exos inhibit angiogenesis in vitro and in vivo, which suggests that SHED-Exos could potentially serve as a novel and effective therapeutic approach for anti-angiogenic treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02764-9.
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Affiliation(s)
- Panpan Liu
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China.,Department of Pediatrics Dentistry and Preventive Dentistry, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China
| | - Qun Zhang
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China
| | - Jun Mi
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China
| | - Shuangshuang Wang
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China
| | - Qiuping Xu
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China.,Savaid Stomatology School of Hangzhou Medical College, Ningbo Stomatology Hospital, Ningbo, China
| | - Dexuan Zhuang
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China
| | - Wenqian Chen
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China.,Savaid Stomatology School of Hangzhou Medical College, Ningbo Stomatology Hospital, Ningbo, China
| | - Chang Liu
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China.,Savaid Stomatology School of Hangzhou Medical College, Ningbo Stomatology Hospital, Ningbo, China
| | - Liwei Zhang
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China.,Savaid Stomatology School of Hangzhou Medical College, Ningbo Stomatology Hospital, Ningbo, China
| | - Jing Guo
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China. .,Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China. .,Savaid Stomatology School of Hangzhou Medical College, Ningbo Stomatology Hospital, Ningbo, China.
| | - Xunwei Wu
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China. .,Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. .,Savaid Stomatology School of Hangzhou Medical College, Ningbo Stomatology Hospital, Ningbo, China.
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23
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Van Petten de Vasconcelos Azevedo F, Lopes DS, Zóia MAP, Correia LIV, Saito N, Fonseca BB, Polloni L, Teixeira SC, Goulart LR, de Melo Rodrigues Ávila V. A New Approach to Inhibiting Triple-Negative Breast Cancer: In Vitro, Ex Vivo and In Vivo Antiangiogenic Effect of BthTx-II, a PLA 2-Asp-49 from Bothrops jararacussu Venom. Biomolecules 2022; 12:258. [PMID: 35204758 PMCID: PMC8961627 DOI: 10.3390/biom12020258] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/28/2021] [Accepted: 01/05/2022] [Indexed: 12/10/2022] Open
Abstract
Phospholipases A2 (PLA2) represent a superfamily of enzymes widely distributed in living organisms, with a broad spectrum of pharmacological activities and therapeutic potential. Anti-angiogenic strategies have become one of the main tools in fighting cancer. In this sense, the present work reports the inhibition of tumor angiogenesis induced by Asp-49 BthTX-II using in vitro, ex vivo and in vivo approaches. We demonstrate that BthTx-II inhibited cell adhesion, proliferation, and migration of human umbilical vein endothelial cells (HUVEC), as well as caused a reduction in the levels of endothelial growth factor (VEGF) during in vitro angiogenesis assays. BthTx-II was also able to inhibit the sprouting angiogenic process, by the ex vivo germination assay of the aortic ring; in addition, this toxin inhibited the migration and proliferation of HUVEC in co-culture with triple-negative breast cancer cells (e.g., MDA-MB-231 cells). Finally, in vivo tumor suppression and anti-angiogenic activities were analyzed using MDA-MB-231 cells with Matrigel injected into the chorioallantoic membrane of chicken embryo (CAM) for 7 days treatment with BthTx-II, showing a considerable reduction in vessel caliber, on the size and weight of tumors. Together, these results suggest an important antiangiogenic and antitumor role for BthTx-II, as a potential prototype for the development of new tools and antitumor drugs in cancer therapy.
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Affiliation(s)
- Fernanda Van Petten de Vasconcelos Azevedo
- Laboratory of Biochemistry and Animal Toxins, Institute of Biotechnology, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil; (L.I.V.C.); (L.P.)
- Laboratory of Nanobiotechnology, Institute of Biotechnology, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil; (M.A.P.Z.); (N.S.); (L.R.G.)
| | - Daiana Silva Lopes
- Multidisciplinary Institute of Health, Federal University of Bahia, Vitoria da Conquista, Salvador 40170-110, BA, Brazil;
| | - Mariana Alves Pereira Zóia
- Laboratory of Nanobiotechnology, Institute of Biotechnology, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil; (M.A.P.Z.); (N.S.); (L.R.G.)
| | - Lucas Ian Veloso Correia
- Laboratory of Biochemistry and Animal Toxins, Institute of Biotechnology, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil; (L.I.V.C.); (L.P.)
- Laboratory of Nanobiotechnology, Institute of Biotechnology, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil; (M.A.P.Z.); (N.S.); (L.R.G.)
| | - Natieli Saito
- Laboratory of Nanobiotechnology, Institute of Biotechnology, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil; (M.A.P.Z.); (N.S.); (L.R.G.)
| | | | - Lorena Polloni
- Laboratory of Biochemistry and Animal Toxins, Institute of Biotechnology, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil; (L.I.V.C.); (L.P.)
| | - Samuel Cota Teixeira
- Department of Immunology, Biomedical Sciences Institute, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil;
| | - Luiz Ricardo Goulart
- Laboratory of Nanobiotechnology, Institute of Biotechnology, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil; (M.A.P.Z.); (N.S.); (L.R.G.)
| | - Veridiana de Melo Rodrigues Ávila
- Laboratory of Biochemistry and Animal Toxins, Institute of Biotechnology, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil; (L.I.V.C.); (L.P.)
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Scondotto G, Sultana J, Vadalà M, Avitabile T, Cillino S, Foti SS, Labbate L, Longo A, Mirabelli E, Puzo MR, Rapisarda C, Ibanez Toro P, Trombetta CJ, Trifirò G, Virgili G. Assessment of intravitreal anti-VEGF drugs and dexamethasone for retinal diseases in real world setting: A multi-centre prospective study from Southern Italy. Eur J Ophthalmol 2022; 32:3064-3073. [PMID: 35075918 DOI: 10.1177/11206721211073402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Describe drug utilisation and clinical outcomes of intravitreal anti-VEGF drug and dexamethasone use in the real-world setting in Southern Italy using data from multi-centre study of retinal disease. Clinical data of retinal disease patients treated with anti-VEGF drugs and dexamethasone implant in 6 out-patient ophthalmology centres from Southern Italy were collected by means of an electronic case report form. Patients receiving at least one intravitreal injection/implant of the study drugs were followed for up to two years and described in terms of demographics and clinical characteristics. Drug utilisation patterns were described. A sign-rank test was used to compare clinical data on visual acuity and other ophthalmic parameters from baseline at different follow-up times for each indication. Data from 1327 patients was collected. Most patients were diagnosed with age-related macular degeneration (AMD) (660, 49.7%), followed by diabetic macular oedema (423, 31.9%), retinal vein occlusion (164, 12.3%), and myopic choroidal neovascularization (80, 6.0%). Patients were followed for a median of 10.3 months (interquartile range: 3.6 - 24.7 months). Mean patient age was 69.7 (±10.9) years and 54.2% were males. Ranibizumab (55.4%) and aflibercept (27.5%) were the most commonly used drugs. Baseline visual acuity significantly improved by about 0.05 to 0.1 logMAR at all follow-up times for AMD and RVO but less consistently for the other diseases. Intravitreal ranibizumab use accounted for half of all treatment for retinal diseases in a Southern Italian out-patient setting. Patients treated with anti-VEGF drugs for AMD and RVO in Southern Italy experienced significant improvement in VA.
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Affiliation(s)
- Giulia Scondotto
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, 18980University of Messina, Messina, Italy
| | - Janet Sultana
- Pharmacy Department, Mater Dei Hospital, Malta.,College of Medicine and Health, University of Exeter, Exeter, Malta
| | - Maria Vadalà
- Institute of European and Mediterranean Science and Technology (IEMEST), Palermo, Italy
| | - Teresio Avitabile
- Department of Ophthalmology, A. O. U. Policlinic-Vittorio Emanuele, Catania, Italy
| | - Salvatore Cillino
- Department of Biomedicine, Neuroscience and Advanced Diagnostic, Ophthalmology Section, University of Palermo, Palermo, Italy
| | - Saveria Serena Foti
- Academic spin-off "INSPIRE - Innovative Solutions For Medical Prediction And Big Data Integration In Real World Setting" - Azienda Ospedaliera Universitaria "G. Martino" Messina, Italy
| | - Luca Labbate
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, 18980University of Messina, Messina, Italy
| | - Antonio Longo
- Department of Ophthalmology, A. O. U. Policlinic-Vittorio Emanuele, Catania, Italy
| | - Eliana Mirabelli
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, 18980University of Messina, Messina, Italy
| | - Maria Rosalia Puzo
- Assistance and Pharmaceutical Services Office, Personal Policies Department, Basilicata Region, Potenza, Italy
| | - Carlo Rapisarda
- Department of Ophthalmology, A. O. U. Policlinic-Vittorio Emanuele, Catania, Italy
| | - Patricia Ibanez Toro
- Assistance and Pharmaceutical Services Office, Personal Policies Department, Basilicata Region, Potenza, Italy
| | - Costantino J Trombetta
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, 18980University of Messina, Messina, Italy
| | - Gianluca Trifirò
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Gianni Virgili
- Department of Neuroscience, Psychology, Drug Research and Clinical Health, University of Florence, Florence, Italy.,Centre for Public Health, Queen's University of Belfast (UK), Belfast, UK
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25
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Mima A. Hypoxia-inducible factor-prolyl hydroxylase inhibitors for renal anemia in chronic kidney disease: Advantages and disadvantages. Eur J Pharmacol 2021; 912:174583. [PMID: 34678238 DOI: 10.1016/j.ejphar.2021.174583] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/18/2021] [Accepted: 10/18/2021] [Indexed: 12/17/2022]
Abstract
Anemia is a common feature and complication of chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) and recombinant human erythropoietin have been used widely in renal anemia treatment. Recently, hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) that may improve the treatment of renal anemia patients were launched. Previous studies indicated that HIF-PHIs may decrease hepcidin levels and modulate iron metabolism, thereby increasing total iron-binding capacity and reducing the need for iron supplementation. Furthermore, HIF-PHIs can reduce inflammation and oxidative stress in CKD. Recombinant erythropoietin has become a routine treatment for patients with CKD and end-stage renal disease with relatively few adverse effects. However, higher doses of recombinant erythropoietin have been demonstrated to be an independent predictor of mortality in patients under hemodialysis. Phase III clinical trials of HIF-PHIs in patients with anemia and dialysis-dependent CKD have shown their efficacy and safety in both non-dialysis and dialysis CKD patients. However, HIFα binds to specific hypoxia-response elements in the vascular endothelial growth factor or retinoic acid-related orphan receptor gamma t (RORγt) promoter, which may be involved in the progression of cancer, psoriasis, and rheumatoid arthritis. In this paper, we have summarized the mechanism, clinical application, and clinical trials of HIF-PHIs in the treatment of renal anemia and aimed to provide an overview of the new drugs in clinical practice, as well as reconsider the advantages and disadvantages of HIF-PHIs and ESAs. Presently, there are not enough clinical studies examining the effects of long-term administration of HIF-PHIs. Therefore, further studies will be needed.
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Affiliation(s)
- Akira Mima
- Department of Nephrology, Osaka Medical and Pharmaceutical University, Osaka, Japan.
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Mederos N, Jankovic J, Gomez RGH, Dunet V, Cristina V. Intracranial response to a combination of bevacizumab and epirubicin for an adenoid cystic carcinoma of the external auditory canal: A case report and review of the literature. CURRENT PROBLEMS IN CANCER: CASE REPORTS 2021. [DOI: 10.1016/j.cpccr.2021.100130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Zhang H, Ding L, Shi X, Mei W, Huang Z, Zhang L, Li X, Xu B, Zhang L, Wang P. Imperatorin alleviated NLR family pyrin domain-containing 3 inflammasome cascade-induced synovial fibrosis and synovitis in rats with knee osteoarthritis. Bioengineered 2021; 12:12954-12964. [PMID: 34847824 PMCID: PMC8809955 DOI: 10.1080/21655979.2021.2012949] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 11/25/2021] [Accepted: 11/26/2021] [Indexed: 01/09/2023] Open
Abstract
We aimed to clarify the therapeutic effects of imperatorin (IMP) on knee osteoarthritis (KOA). Thirty 3-month-old SD male rats were randomly divided into Normal, monosodium iodoacetate (MIA) and MIA+IMP groups. Their synovial tissues were subjected to histopathological analysis. Primary synovial fibroblasts obtained from additional normal rats were treated by lipopolysaccharide (LPS) and then IMP. The mRNA and protein expressions of factors related to synovitis and synovial fibrosis were detected by qRT-PCR and Western blotting, respectively. The concentrations of inflammatory factors IL-1β and IL-18 were measured by ELISA. IMP reduced HIF-1α, NLR family pyrin domain-containing 3 inflammasome expression and IL-1β, IL-18 production in synovial fibroblasts induced by LPS. IMP also downregulated synovial fibrosis markers. In vitro study revealed that MIA-induced synovitis and synovial fibrosis were relieved by IMP. IMP relieves the inflammation associated with synovitis and synovial fibrosis. It reduces the production of pro-inflammatory mediators and cytokines and inhibits TGF-β1, TIMP-1 and VEGF expressions that promote synovial fibrosis.
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Affiliation(s)
- Haosheng Zhang
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, NanjingJiangsu Province, China
- Department of Orthopedics, Zhenjiang Hospital Affiliated to Nanjing University of Chinese Medicine, ZhenjiangJiangsu Province, China
| | - Liang Ding
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, NanjingJiangsu Province, China
- Department of Orthopedics, Jiangsu Province Hospital of Chinese Medicine, NanjingJiangsu Province, China
| | - Xiaoqing Shi
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, NanjingJiangsu Province, China
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, NanjingJiangsu Province, China
- Department of Orthopedics, Jiangsu Province Hospital of Chinese Medicine, NanjingJiangsu Province, China
| | - Wei Mei
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, NanjingJiangsu Province, China
- Department of Orthopedics, Jiangsu Province Hospital of Chinese Medicine, NanjingJiangsu Province, China
| | - Zhengquan Huang
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, NanjingJiangsu Province, China
- Department of Orthopedics, Jiangsu Province Hospital of Chinese Medicine, NanjingJiangsu Province, China
| | - Li Zhang
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, NanjingJiangsu Province, China
- Department of Orthopedics, Jiangsu Province Hospital of Chinese Medicine, NanjingJiangsu Province, China
| | - Xiaochen Li
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, NanjingJiangsu Province, China
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, NanjingJiangsu Province, China
- Department of Orthopedics, Jiangsu Province Hospital of Chinese Medicine, NanjingJiangsu Province, China
| | - Bo Xu
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, NanjingJiangsu Province, China
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, NanjingJiangsu Province, China
- Department of Orthopedics, Jiangsu Province Hospital of Chinese Medicine, NanjingJiangsu Province, China
| | - Li Zhang
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, NanjingJiangsu Province, China
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, NanjingJiangsu Province, China
- Department of Orthopedics, Jiangsu Province Hospital of Chinese Medicine, NanjingJiangsu Province, China
| | - Peimin Wang
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, NanjingJiangsu Province, China
- Department of Orthopedics, Jiangsu Province Hospital of Chinese Medicine, NanjingJiangsu Province, China
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Catar R, Moll G, Kamhieh-Milz J, Luecht C, Chen L, Zhao H, Ernst L, Willy K, Girndt M, Fiedler R, Witowski J, Morawietz H, Ringdén O, Dragun D, Eckardt KU, Schindler R, Zickler D. Expanded Hemodialysis Therapy Ameliorates Uremia-Induced Systemic Microinflammation and Endothelial Dysfunction by Modulating VEGF, TNF-α and AP-1 Signaling. Front Immunol 2021; 12:774052. [PMID: 34858433 PMCID: PMC8632537 DOI: 10.3389/fimmu.2021.774052] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 10/20/2021] [Indexed: 12/15/2022] Open
Abstract
Abstract Systemic chronic microinflammation and altered cytokine signaling, with adjunct cardiovascular disease (CVD), endothelial maladaptation and dysfunction is common in dialysis patients suffering from end-stage renal disease and associated with increased morbidity and mortality. New hemodialysis filters might offer improvements. We here studied the impact of novel improved molecular cut-off hemodialysis filters on systemic microinflammation, uremia and endothelial dysfunction. Human endothelial cells (ECs) were incubated with uremic serum obtained from patients treated with two different hemodialysis regimens in the Permeability Enhancement to Reduce Chronic Inflammation (PERCI-II) crossover clinical trial, comparing High-Flux (HF) and Medium Cut-Off (MCO) membranes, and then assessed for their vascular endothelial growth factor (VEGF) production and angiogenesis. Compared to HF membranes, dialysis with MCO membranes lead to a reduction in proinflammatory mediators and reduced endothelial VEGF production and angiogenesis. Cytokine multiplex screening identified tumor necrosis factor (TNF) superfamily members as promising targets. The influence of TNF-α and its soluble receptors (sTNF-R1 and sTNF-R2) on endothelial VEGF promoter activation, protein release, and the involved signaling pathways was analyzed, revealing that this detrimental signaling was indeed induced by TNF-α and mediated by AP-1/c-FOS signaling. In conclusion, uremic toxins, in particular TNF-signaling, promote endothelial maladaptation, VEGF expression and aberrant angiogenesis, which can be positively modulated by dialysis with novel MCO membranes. Translational Perspective and Graphical Abstract Systemic microinflammation, altered cytokine signaling, cardiovascular disease, and endothelial maladaptation/dysfunction are common clinical complications in dialysis patients suffering from end-stage renal disease. We studied the impact of novel improved medium-cut-off hemodialysis filters on uremia and endothelial dysfunction. We can show that uremic toxins, especially TNF-signaling, promote endothelial maladaptation, VEGF expression and aberrant angiogenesis, which can be positively modulated by dialysis with novel improved medium-cut-off membranes.
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Affiliation(s)
- Rusan Catar
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Guido Moll
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
- Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Julian Kamhieh-Milz
- Institute of Transfusion Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Christian Luecht
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Lei Chen
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Hongfan Zhao
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Lucas Ernst
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Kevin Willy
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
- Department of Cardiology, University Hospital Münster, Münster, Germany
| | - Matthias Girndt
- Department of Internal Medicine II, Martin-Luther-University Halle, Halle, Germany
| | - Roman Fiedler
- Department of Internal Medicine II, Martin-Luther-University Halle, Halle, Germany
| | - Janusz Witowski
- Department of Pathophysiology, Poznan University of Medical Sciences, Poznan, Poland
| | - Henning Morawietz
- Division of Vascular Endothelium and Microcirculation, Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Olle Ringdén
- Division of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm, Sweden
| | - Duska Dragun
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Kai-Uwe Eckardt
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Ralf Schindler
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Daniel Zickler
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
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van der Merwe M, van Niekerk G, Fourie C, du Plessis M, Engelbrecht AM. The impact of mitochondria on cancer treatment resistance. Cell Oncol (Dordr) 2021; 44:983-995. [PMID: 34244972 DOI: 10.1007/s13402-021-00623-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 06/24/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The ability of cancer cells to develop treatment resistance is one of the primary factors that prevent successful treatment. Although initially thought to be dysfunctional in cancer, mitochondria are significant players that mediate treatment resistance. Literature indicates that cancer cells reutilize their mitochondria to facilitate cancer progression and treatment resistance. However, the mechanisms by which the mitochondria promote treatment resistance have not yet been fully elucidated. CONCLUSIONS AND PERSPECTIVES Here, we describe various means by which mitochondria can promote treatment resistance. For example, mutations in tricarboxylic acid (TCA) cycle enzymes, i.e., fumarate hydratase and isocitrate dehydrogenase, result in the accumulation of the oncometabolites fumarate and 2-hydroxyglutarate, respectively. These oncometabolites may promote treatment resistance by upregulating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, inhibiting the anti-tumor immune response, or promoting angiogenesis. Furthermore, stromal cells can donate intact mitochondria to cancer cells after therapy to restore mitochondrial functionality and facilitate treatment resistance. Targeting mitochondria is, therefore, a feasible strategy that may dampen treatment resistance. Analysis of tumoral DNA may also be used to guide treatment choices. It will indicate whether enzymatic mutations are present in the TCA cycle and, if so, whether the mutations or their downstream signaling pathways can be targeted. This may improve treatment outcomes by inhibiting treatment resistance or promoting the effectiveness of anti-angiogenic agents or immunotherapy.
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Affiliation(s)
- Michelle van der Merwe
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa.
| | - Gustav van Niekerk
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Carla Fourie
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Manisha du Plessis
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Anna-Mart Engelbrecht
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
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30
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Analysis of CGF Biomolecules, Structure and Cell Population: Characterization of the Stemness Features of CGF Cells and Osteogenic Potential. Int J Mol Sci 2021; 22:ijms22168867. [PMID: 34445573 PMCID: PMC8396261 DOI: 10.3390/ijms22168867] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/12/2021] [Accepted: 08/15/2021] [Indexed: 01/08/2023] Open
Abstract
Concentrated Growth Factors (CGF) represent new autologous (blood-derived biomaterial), attracting growing interest in the field of regenerative medicine. In this study, the chemical, structural, and biological characterization of CGF was carried out. CGF molecular characterization was performed by GC/MS to quantify small metabolites and by ELISA to measure growth factors and matrix metalloproteinases (MMPs) release; structural CGF characterization was carried out by SEM analysis and immunohistochemistry; CGF has been cultured, and its primary cells were isolated for the identification of their surface markers by flow cytometry, Western blot, and real-time PCR; finally, the osteogenic differentiation of CGF primary cells was evaluated through matrix mineralization by alizarin red staining and through mRNA quantification of osteogenic differentiation markers by real-time PCR. We found that CGF has a complex inner structure capable of influencing the release of growth factors, metabolites, and cells. These cells, which could regulate the production and release of the CGF growth factors, show stem features and are able to differentiate into osteoblasts producing a mineralized matrix. These data, taken together, highlight interesting new perspectives for the use of CGF in regenerative medicine.
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31
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Wewers TM, Schulz A, Nolte I, Pavenstädt H, Brand M, Di Marco GS. Circulating Soluble Fms-like Tyrosine Kinase in Renal Diseases Other than Preeclampsia. J Am Soc Nephrol 2021; 32:1853-1863. [PMID: 34155060 PMCID: PMC8455271 DOI: 10.1681/asn.2020111579] [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] [Received: 11/10/2020] [Accepted: 04/20/2021] [Indexed: 02/04/2023] Open
Abstract
Soluble Fms-like tyrosine kinase (sFlt-1/sVEGFR1) is a naturally occurring antagonist of vascular endothelial growth factor (VEGF). Despite being a secreted, soluble protein lacking cytoplasmic and transmembrane domains, sFlt-1 can act locally and be protective against excessive microenvironmental VEGF concentration or exert autocrine functions independently of VEGF. Circulating sFlt-1 may indiscriminately affect endothelial function and the microvasculature of distant target organs. The clinical significance of excess sFlt-1 in kidney disease was first shown in preeclampsia, a major renal complication of pregnancy. However, circulating sFlt-1 levels appear to be increased in various diseases with varying degrees of renal impairment. Relevant clinical associations between circulating sFlt-1 and severe outcomes (e.g., endothelial dysfunction, renal impairment, cardiovascular disease, and all-cause mortality) have been observed in patients with CKD and after kidney transplantation. However, sFlt-1 appears to be protective against renal dysfunction-associated aggravation of atherosclerosis and diabetic nephropathy. Therefore, in this study, we provide an update on sFlt-1 in several kidney diseases other than preeclampsia, discuss clinical findings and experimental studies, and briefly consider its use in clinical practice.
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Affiliation(s)
- Theresa M. Wewers
- Department of Internal Medicine D, University Hospital Muenster, Muenster, Germany,Small Animal Hospital, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Annika Schulz
- Department of Internal Medicine D, University Hospital Muenster, Muenster, Germany
| | - Ingo Nolte
- Small Animal Hospital, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Hermann Pavenstädt
- Department of Internal Medicine D, University Hospital Muenster, Muenster, Germany
| | - Marcus Brand
- Department of Internal Medicine D, University Hospital Muenster, Muenster, Germany
| | - Giovana S. Di Marco
- Department of Internal Medicine D, University Hospital Muenster, Muenster, Germany,Correspondence: Giovana S. Di Marco, Albert-Schweitzer-Campus 1, Building A14, 48149 Münster, Germany.
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32
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Kreimendahl F, Kniebs C, Tavares Sobreiro AM, Schmitz-Rode T, Jockenhoevel S, Thiebes AL. FRESH bioprinting technology for tissue engineering - the influence of printing process and bioink composition on cell behavior and vascularization. J Appl Biomater Funct Mater 2021; 19:22808000211028808. [PMID: 34282976 DOI: 10.1177/22808000211028808] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The rapid and tailored biofabrication of natural materials is of high interest for the field of tissue engineering and regenerative medicine. Scaffolds require both high biocompatibility and tissue-dependent mechanical strength to function as basis for tissue-engineered implants. Thus, natural hydrogels such as fibrin are promising but their rapid biofabrication remains challenging. Printing of low viscosity and slow polymerizing solutions with good spatial resolution can be achieved by freeform reversible embedding of suspended hydrogels (FRESH) bioprinting of cell-laden natural hydrogels. In this study, fibrin and hyaluronic acid were used as single components as well as blended ink mixtures for the FRESH bioprinting. Rheometry revealed that single materials were less viscous than the blended bioink showing higher values for viscosity over a shear rate of 10-1000 s-1. While fibrin showed viscosities between 0.1624 and 0.0017 Pa·s, the blended ink containing fibrin and hyaluronic acid were found to be in a range of 0.1-1 Pa·s. In 3D vascularization assays, formation of vascular structures within the printed constructs was investigated indicating that the printing process did not harm cells and allowed formation of vasculature comparable to moulded control samples. Best values for vascularization were achieved in bioinks consisting of 1.0% fibrin-0.5% hyaluronic acid. The vascular structure area and length were three times higher compared to other tested bioinks, and structure volume as well as number of branches revealed almost four times higher values. In this study, we combined the benefits of the FRESH printing technique with in vitro vascularization, showing that it is possible to achieve a mechanically stable small-scale hydrogel construct incorporating vascular network formation.
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Affiliation(s)
- Franziska Kreimendahl
- Department of Biohybrid and Medical Textiles (BioTex), Institute of Applied Medical Engineering, Helmholtz Institute Aachen, RWTH Aachen University, Aachen, Germany.,Faculty of Science and Engineering, Aachen-Maastricht Institute for Biobased Materials, Maastricht University, Brightlands Chemelot Campus, Geleen, The Netherlands
| | - Caroline Kniebs
- Department of Biohybrid and Medical Textiles (BioTex), Institute of Applied Medical Engineering, Helmholtz Institute Aachen, RWTH Aachen University, Aachen, Germany.,Faculty of Science and Engineering, Aachen-Maastricht Institute for Biobased Materials, Maastricht University, Brightlands Chemelot Campus, Geleen, The Netherlands
| | - Ana Margarida Tavares Sobreiro
- Department of Biohybrid and Medical Textiles (BioTex), Institute of Applied Medical Engineering, Helmholtz Institute Aachen, RWTH Aachen University, Aachen, Germany
| | - Thomas Schmitz-Rode
- Department of Biohybrid and Medical Textiles (BioTex), Institute of Applied Medical Engineering, Helmholtz Institute Aachen, RWTH Aachen University, Aachen, Germany
| | - Stefan Jockenhoevel
- Department of Biohybrid and Medical Textiles (BioTex), Institute of Applied Medical Engineering, Helmholtz Institute Aachen, RWTH Aachen University, Aachen, Germany.,Faculty of Science and Engineering, Aachen-Maastricht Institute for Biobased Materials, Maastricht University, Brightlands Chemelot Campus, Geleen, The Netherlands
| | - Anja Lena Thiebes
- Department of Biohybrid and Medical Textiles (BioTex), Institute of Applied Medical Engineering, Helmholtz Institute Aachen, RWTH Aachen University, Aachen, Germany.,Faculty of Science and Engineering, Aachen-Maastricht Institute for Biobased Materials, Maastricht University, Brightlands Chemelot Campus, Geleen, The Netherlands
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33
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Zeng H, Peng F, Wang J, Meng R, Zhang J. Effects of Fruquintinib on the Pluripotency Maintenance and Differentiation Potential of Mouse Embryonic Stem Cells. Cell Reprogram 2021; 23:180-190. [PMID: 34077681 DOI: 10.1089/cell.2020.0100] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Mouse embryonic stem cells (mESCs) can maintain self-renewal and differentiate into any cell type of the three primary germ layers. The vascular endothelial growth factor (VEGF) is involved in the regulation of mESC differentiation and induces the activation of a series of kinase responses and several cell signaling pathways by binding to its respective transmembrane receptors, vascular endothelial growth factor receptor VEGFR1, and VEGFR2. Fruquintinib is a selective inhibitor of VEGFRs, and we used it to investigate the effects on the maintenance of pluripotency and differentiation potential of mESCs in this study. Our results showed that fruquintinib-treated cells expressed higher levels of pluripotent markers, including Oct4, Nanog, Sox2, and Esrrb under serum and leukemia inhibitory factor (LIF) condition, whereas the expression of phosphorylated Erk1/2 was restricted. Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (MEK) signaling inhibitor (PD0325901) and glycogen synthase kinase 3 (GSK3) signaling inhibitor (CHIR99021) (also known as 2i) enable cells to maintain naive pluripotency with LIF, and fruquintinib can also promote cells to maintain naive pluripotent state even under serum/LIF condition, whereas VEGF addition limits the pluripotency characteristics in serum/LIF mESCs. Furthermore, fruquintinib could inhibit the three-germ layer establishment in embryoid body formation and maintain the undifferentiated characteristics of mESCs, indicating that fruquintinib could promote the maintenance of naive pluripotency and inhibit early differentiation programs.
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Affiliation(s)
- Hanyi Zeng
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Fanke Peng
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Jiachen Wang
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Ru Meng
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Jun Zhang
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
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34
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Calabriso N, Stanca E, Rochira A, Damiano F, Giannotti L, Di Chiara Stanca B, Massaro M, Scoditti E, Demitri C, Nitti P, Palermo A, Siculella L, Carluccio MA. Angiogenic Properties of Concentrated Growth Factors (CGFs): The Role of Soluble Factors and Cellular Components. Pharmaceutics 2021; 13:pharmaceutics13050635. [PMID: 33946931 PMCID: PMC8146902 DOI: 10.3390/pharmaceutics13050635] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/25/2021] [Accepted: 04/27/2021] [Indexed: 12/21/2022] Open
Abstract
Blood-derived concentrated growth factors (CGFs) represent a novel autologous biomaterial with promising applications in regenerative medicine. Angiogenesis is a key factor in tissue regeneration, but the role played by CGFs in vessel formation is not clear. The purpose of this study was to characterize the angiogenic properties of CGFs by evaluating the effects of its soluble factors and cellular components on the neovascularization in an in vitro model of angiogenesis. CGF clots were cultured for 14 days in cell culture medium; after that, CGF-conditioned medium (CGF-CM) was collected, and soluble factors and cellular components were separated and characterized. CGF-soluble factors, such as growth factors (VEGF and TGF-β1) and matrix metalloproteinases (MMP-2 and -9), were assessed by ELISA. Angiogenic properties of CGF-soluble factors were analyzed by stimulating human cultured endothelial cells with increasing concentrations (1%, 5%, 10%, or 20%) of CGF-CM, and their effect on cell migration and tubule-like formation was assessed by wound healing and Matrigel assay, respectively. The expression of endothelial angiogenic mediators was determined using qRT-PCR and ELISA assays. CGF-derived cells were characterized by immunostaining, qRT-PCR and Matrigel assay. We found that CGF-CM, consisting of essential pro-angiogenic factors, such as VEGF, TGF-β1, MMP-9, and MMP-2, promoted endothelial cell migration; tubule structure formation; and endothelial expression of multiple angiogenic mediators, including growth factors, chemokines, and metalloproteinases. Moreover, we discovered that CGF-derived cells exhibited features such as endothelial progenitor cells, since they expressed the CD34 stem cell marker and endothelial markers and participated in the neo-angiogenic process. In conclusion, our results suggest that CGFs are able to promote endothelial angiogenesis through their soluble and cellular components and that CGFs can be used as a biomaterial for therapeutic vasculogenesis in the field of tissue regeneration.
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Affiliation(s)
- Nadia Calabriso
- National Research Council (CNR), Campus Ecotekne, Institute of Clinical Physiology (IFC), University of Salento, Via per Monteroni, 73100 Lecce, Italy; (N.C.); (M.M.); (E.S.)
| | - Eleonora Stanca
- Laboratory of Molecular Biology, Department of Biological and Environmental Sciences and Technologies, Campus Ecotekne, University of Salento, Via per Monteroni, 73100 Lecce, Italy; (E.S.); (A.R.); (F.D.); (L.G.); (B.D.C.S.)
| | - Alessio Rochira
- Laboratory of Molecular Biology, Department of Biological and Environmental Sciences and Technologies, Campus Ecotekne, University of Salento, Via per Monteroni, 73100 Lecce, Italy; (E.S.); (A.R.); (F.D.); (L.G.); (B.D.C.S.)
| | - Fabrizio Damiano
- Laboratory of Molecular Biology, Department of Biological and Environmental Sciences and Technologies, Campus Ecotekne, University of Salento, Via per Monteroni, 73100 Lecce, Italy; (E.S.); (A.R.); (F.D.); (L.G.); (B.D.C.S.)
| | - Laura Giannotti
- Laboratory of Molecular Biology, Department of Biological and Environmental Sciences and Technologies, Campus Ecotekne, University of Salento, Via per Monteroni, 73100 Lecce, Italy; (E.S.); (A.R.); (F.D.); (L.G.); (B.D.C.S.)
| | - Benedetta Di Chiara Stanca
- Laboratory of Molecular Biology, Department of Biological and Environmental Sciences and Technologies, Campus Ecotekne, University of Salento, Via per Monteroni, 73100 Lecce, Italy; (E.S.); (A.R.); (F.D.); (L.G.); (B.D.C.S.)
| | - Marika Massaro
- National Research Council (CNR), Campus Ecotekne, Institute of Clinical Physiology (IFC), University of Salento, Via per Monteroni, 73100 Lecce, Italy; (N.C.); (M.M.); (E.S.)
| | - Egeria Scoditti
- National Research Council (CNR), Campus Ecotekne, Institute of Clinical Physiology (IFC), University of Salento, Via per Monteroni, 73100 Lecce, Italy; (N.C.); (M.M.); (E.S.)
| | - Christian Demitri
- Department of Engineering for Innovation, Campus Ecotekne, University of Salento, Via per Monteroni, 73100 Lecce, Italy; (C.D.); (P.N.)
| | - Paola Nitti
- Department of Engineering for Innovation, Campus Ecotekne, University of Salento, Via per Monteroni, 73100 Lecce, Italy; (C.D.); (P.N.)
| | - Andrea Palermo
- Implant Dentistry College of Medicine and Dentistry Birmingham, University of Birmingham, Birmingham B4 6BN, UK;
| | - Luisa Siculella
- Laboratory of Molecular Biology, Department of Biological and Environmental Sciences and Technologies, Campus Ecotekne, University of Salento, Via per Monteroni, 73100 Lecce, Italy; (E.S.); (A.R.); (F.D.); (L.G.); (B.D.C.S.)
- Correspondence: (L.S.); (M.A.C.)
| | - Maria Annunziata Carluccio
- National Research Council (CNR), Campus Ecotekne, Institute of Clinical Physiology (IFC), University of Salento, Via per Monteroni, 73100 Lecce, Italy; (N.C.); (M.M.); (E.S.)
- Correspondence: (L.S.); (M.A.C.)
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Tejada MÁ, Santos-Llamas AI, Fernández-Ramírez MJ, Tarín JJ, Cano A, Gómez R. A Reassessment of the Therapeutic Potential of a Dopamine Receptor 2 Agonist (D2-AG) in Endometriosis by Comparison against a Standardized Antiangiogenic Treatment. Biomedicines 2021; 9:biomedicines9030269. [PMID: 33800198 PMCID: PMC8001569 DOI: 10.3390/biomedicines9030269] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/25/2021] [Accepted: 03/02/2021] [Indexed: 12/26/2022] Open
Abstract
Dopamine receptor 2 agonists (D2-ags) have been shown to reduce the size of tumors by targeting aberrant angiogenesis in pathological tissue. Because of this, the use of a D2-ag was inferred for endometriosis treatment. When assayed in mouse models however, D2-ags have been shown to cause a shift of the immature vessels towards a more mature phenotype but not a significant reduction in the amount of vascularization and size of lesions. These has raised concerns on whether the antiangiogenic effects of these compounds confer a therapeutic value for endometriosis. In the belief that antiangiogenic effects of D2-ags in endometriosis were masked due to non-optimal timing of pharmacological interventions, herein we aimed to reassess the antiangiogenic therapeutic potential of D2-ags in vivo by administering compounds at a timeframe in which vessels in the lesions are expected to be more sensitive to antiangiogenic stimuli. To prove our point, immunodeficient (NU/NU) mice were given a D2-ag (cabergoline), anti-VEGF (CBO-P11) or vehicle (saline) compounds (n = 8 per group) starting 5 days after implantation of a fluorescently labeled human lesion. The effects on the size of the implants was estimated by monitoring the extent of fluorescence emitted by the lesion during the three-week treatment period. Subsequently mice were sacrificed and lesions excised and fixed for quantitative immunohistochemical/immunofluorescent analysis of angiogenic parameters. Lesion size, vascular density and innervation were comparable in D2-ag and anti-VEGF groups and significantly decreased when compared to control. These data suggest that D2-ags are as powerful as standard antiangiogenic compounds in interfering with angiogenesis and lesion size. Our preliminary study opens the way to further exploration of the mechanisms beneath the antiangiogenic effects of D2-ags for endometriosis treatment in humans.
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Affiliation(s)
- Miguel Á. Tejada
- Research Unit on Women’s Health-Institute of Health Research, INCLIVA, 46010 Valencia, Spain; (A.I.S.-L.); (J.J.T.)
- Correspondence: (M.Á.T.); (A.C.); (R.G.)
| | - Ana I. Santos-Llamas
- Research Unit on Women’s Health-Institute of Health Research, INCLIVA, 46010 Valencia, Spain; (A.I.S.-L.); (J.J.T.)
| | - María José Fernández-Ramírez
- Department of Obstetrics and Gynecology, Hospital Clínico Universitario, 46010 Valencia, Spain;
- Department of Pediatrics and Obstetrics and Gynecology, University of Valencia, 46010 Valencia, Spain
| | - Juan J. Tarín
- Research Unit on Women’s Health-Institute of Health Research, INCLIVA, 46010 Valencia, Spain; (A.I.S.-L.); (J.J.T.)
- Department of Cellular Biology, Functional Biology, and Physical Anthropology, University of Valencia, 46100 Burjassot, Spain
| | - Antonio Cano
- Research Unit on Women’s Health-Institute of Health Research, INCLIVA, 46010 Valencia, Spain; (A.I.S.-L.); (J.J.T.)
- Department of Pediatrics and Obstetrics and Gynecology, University of Valencia, 46010 Valencia, Spain
- Correspondence: (M.Á.T.); (A.C.); (R.G.)
| | - Raúl Gómez
- Research Unit on Women’s Health-Institute of Health Research, INCLIVA, 46010 Valencia, Spain; (A.I.S.-L.); (J.J.T.)
- Department of Pathology, University of Valencia, 46010 Valencia, Spain
- Correspondence: (M.Á.T.); (A.C.); (R.G.)
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Eiamsitrakoon T, Tharabenjasin P, Pabalan N, Jarjanazi H, Tasanarong A. Influence of polymorphisms in the vascular endothelial growth factor gene on allograft rejection after kidney transplantation: a meta-analysis. F1000Res 2021; 10:90. [PMID: 35284063 PMCID: PMC8905004 DOI: 10.12688/f1000research.27800.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/25/2021] [Indexed: 11/20/2022] Open
Abstract
Background: Reported associations of allograft rejection in kidney transplant patients with VEGF single nucleotide polymorphisms (SNPs) have been inconsistent between studies, which prompted a meta-analysis to obtain more precise estimates. Methods: Using the PICO elements, kidney transplant patients (P) were compared by genotype data between rejectors (I) and non-rejectors (C) in order to determine the risk of allograft rejection (O) attributed to the VEGF SNPs. Literature search of four databases yielded seven articles. To calculate risks for allograft rejection, four SNPs were examined. Using the allele-genotype model we compared the variant ( var) with the wild-type ( wt) and heterozygous ( var- wt) alleles. Meta-analysis treatments included outlier and subgroup analyses, the latter was based on ethnicity (Indians/Caucasians) and rejection type (acute/chronic). Multiple comparisons were corrected with the Bonferroni test. Results: Five highly significant outcomes (P a < 0.01) survived Bonferroni correction, one of which showed reduced risk for the var allele (OR 0.61, 95% CI 0.45-0.82). The remaining four indicated increased risk for the wt allele where the chronic rejection (OR 2.10, 95% CI 1.36-3.24) and Indian (OR 1.44, 95% CI 1.13-1.84) subgroups were accorded susceptibility status. Conclusions: Risk associations for renal allograft rejection were increased and reduced on account of the wt and var alleles, respectively. These findings could render the VEGF polymorphisms useful in the clinical genetics of kidney transplantation.
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Affiliation(s)
- Thanee Eiamsitrakoon
- Chulabhorn International College of Medicine, Thammasat University, Rangsit, Pathumthani, 12121, Thailand
| | - Phuntila Tharabenjasin
- Chulabhorn International College of Medicine, Thammasat University, Rangsit, Pathumthani, 12121, Thailand
| | - Noel Pabalan
- Chulabhorn International College of Medicine, Thammasat University, Rangsit, Pathumthani, 12121, Thailand
| | - Hamdi Jarjanazi
- Environmental Monitoring and Reporting Branch, Ontario Ministry of the Environment, Conservation and Parks, Toronto, Ontario, M5T 3L9, Canada
| | - Adis Tasanarong
- Nephrology Unit, Faculty of Medicine, Thammasat University, Rangsit, Pathumthani, 12121, Thailand
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Tandulwadkar S, Karthick MS. Combined Use of Autologous Bone Marrow-derived Stem Cells and Platelet-rich Plasma for Ovarian Rejuvenation in Poor Responders. J Hum Reprod Sci 2020; 13:184-190. [PMID: 33311903 PMCID: PMC7727891 DOI: 10.4103/jhrs.jhrs_130_19] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 04/26/2020] [Indexed: 12/30/2022] Open
Abstract
Background: The management of poor responders is still a challenge in modern-assisted reproductive technology. Several researches are showing encouraging results with autologous bone marrow-derived stem cells (ABMDSCs) and platelet-rich plasma (PRP) individually. Hence, we decided to study the synergistic effect of ABMDSCs with PRP. Aims and Objective: The aim of the study was to assess the safety and efficacy of intraovarian instillation of ABMDSCs combined with PRP in poor responders. Design: This was an interventional pilot study. Study Period: January 2017 to January 2019. Materials and Methods: We designed a pilot study using Patient-oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) Group 3 and 4 poor responder patients (n = 20). The study group underwent laparoscopic/transvaginal intraovarian instillation of ABMDSCs combined with PRP and the outcome was analyzed – primary outcome – antral follicular count (AFC) and mature MII oocytes and secondary outcome – Anti-Mullerian hormone (AMH) levels and number of Grade A and B embryos frozen on day 3. The Wilcoxon signed-rank test and Pearson correlation were used for the statistical analysis and P < 0.05 was considered statistically significant. Results: After 6 weeks of intraovarian instillation ABMDSCs mixed with PRP, patients were reassessed for AFC and AMH and their response to subsequent controlled ovarian stimulation (COS) cycle was observed. Statistically significant improvement was seen in AFC, MII oocytes, and Grade A and Grade B embryos. AMH was also increased in some patients, but the result was not statistically significant. Conclusion: Our results suggest that intraovarian instillation of ABMDSCs combined with PRP is safe and it optimized the recruitment of existing dormant primordial follicles to improve oocyte yield and hence the number and quality of embryos after COS in POSEIDON Group 3 and 4 poor responders.
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Affiliation(s)
- Sunita Tandulwadkar
- Ruby Hall IVF and Endoscopy Center, Ruby Hall Clinic and Solo Stem Cells, Pune, Maharashtra, India
| | - M Selva Karthick
- Ruby Hall IVF and Endoscopy Center, Ruby Hall Clinic and Solo Stem Cells, Pune, Maharashtra, India
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Tran-Nguyen TM, Le KT, Nguyen LGT, Tran TLT, Hoang-Thai PC, Tran TL, Tan SL, Tran-Van H. Third-degree burn mouse treatment using recombinant human fibroblast growth factor 2. Growth Factors 2020; 38:282-290. [PMID: 34415815 DOI: 10.1080/08977194.2021.1967342] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Fibroblast growth factor 2 (FGF-2) is a multifunctional protein that has major roles in wound healing, tissue repair, and regeneration. This therapeutic protein is widely used for burn treatment because it can stimulate cell proliferation and differentiation, angiogenesis, and extracellular matrix remodeling. In this study, we developed a simple method using a controlled heated brass rod to create a homogenous third-degree burn murine model and evaluated the treatment using recombinant human FGF-2 (rhFGF-2). The results indicated that the wound area was 0.83 ± 0.05 cm2 and wound depth was 573.42 ± 147.82 μm. Mice treated with rhFGF-2 showed higher rates of wound closure, granulation tissue formation, angiogenesis, and re-epithelialization than that of phosphate-buffered saline (PBS)-treated group. In conclusion, our lab-made rhFGF-2 could be a potentially therapeutic protein for burn treatment as well as a bioequivalent drug for other commercial applications using FGF-2.
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Affiliation(s)
- Thu-Minh Tran-Nguyen
- Faculty of Biology and Biotechnology, University of Science, Ho Chi Minh City, Vietnam
- Institute of Drug Quality Control, Ho Chi Minh City, Vietnam
| | - Khanh-Thien Le
- Faculty of Biology and Biotechnology, University of Science, Ho Chi Minh City, Vietnam
- Vietnam National University, Ho Chi Minh City, Vietnam
| | - Le-Giang Thi Nguyen
- Faculty of Biology and Biotechnology, University of Science, Ho Chi Minh City, Vietnam
- Vietnam National University, Ho Chi Minh City, Vietnam
| | - Thanh-Loan Thi Tran
- Department of Histology - Embryology and Pathology, University of Medicine and Pharmacy at HCMC, Ho Chi Minh City, Vietnam
| | | | - Thuoc Linh Tran
- Faculty of Biology and Biotechnology, University of Science, Ho Chi Minh City, Vietnam
- Vietnam National University, Ho Chi Minh City, Vietnam
| | - Sik-Loo Tan
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Hieu Tran-Van
- Faculty of Biology and Biotechnology, University of Science, Ho Chi Minh City, Vietnam
- Vietnam National University, Ho Chi Minh City, Vietnam
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Chen H, Xiao H, Gan H, Zhang L, Wang L, Li S, Wang D, Li T, Zhai X, Zhao J. Hypoxia-inducible Factor 2α Exerts Neuroprotective Effects by Promoting Angiogenesis via the VEGF/Notch Pathway after Intracerebral Hemorrhage Injury in Rats. Neuroscience 2020; 448:206-218. [PMID: 32736070 DOI: 10.1016/j.neuroscience.2020.07.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 06/15/2020] [Accepted: 07/06/2020] [Indexed: 10/23/2022]
Abstract
Angiogenesis after intracerebral hemorrhage (ICH) injury can effectively alleviate brain damage and improve neurological function. Hypoxia-inducible factor 2α (HIF-2α) is an important angiogenic regulator and exhibits protective effects in several neurological diseases; however, its role in ICH has not yet been reported. Hence, in the present study, we explored whether HIF-2α reduces ICH injury by promoting angiogenesis. In addition, we explored the role of the vascular endothelial growth factor (VEGF)/Notch pathway in HIF-2α-mediated angiogenesis. We injected 50 μL of autologous blood taken from the femoral artery into the right striatum of healthy male adult Sprague-Dawley rats to create an autologous-blood-induced rat model of ICH. Lentiviral vectors were injected to both overexpress and knock down HIF-2α expression. VEGF receptor 2 (VEGFR2) and Notch-specific inhibitors were injected intraperitoneally to block VEGFR2- and Notch-mediated signaling after lentiviral injections. Our data showed that HIF-2α overexpression reduced neurological-damage scores and brain-water content, suggesting it had a protective effect on ICH injury. In addition, overexpression of HIF-2α promoted angiogenesis, increased focal cerebral blood flow (CBF), and reduced neuronal damage, whereas HIF-2α knockdown resulted in the opposite effects. Furthermore, we found that HIF-2α-mediated angiogenesis was blocked by a Notch-specific inhibitor. Likewise, the HIF-2α-mediated increase in phospho-VEGFR-2, cleaved-Notch1 and Notch1 expression was reversed via a VEGFR2-specific inhibitor. Taken together, our results indicate that HIF-2α promotes angiogenesis via the VEGF/Notch pathway to attenuate ICH injury. Moreover, our findings may contribute to the development of a novel strategy for alleviating ICH injury via HIF-2α-mediated upregulation of angiogenesis.
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Affiliation(s)
- Hui Chen
- Department of Neurosurgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Han Xiao
- Department of Neurosurgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Hui Gan
- Department of Neurosurgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Li Zhang
- Department of Neurosurgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Lu Wang
- Department of Neurosurgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Siyu Li
- Department of Cardiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Difei Wang
- Department of Neurosurgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Tiegang Li
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Meteria Medica, Peking Union Medical College and Chinese Academy of Sciences, Beijing 100050, China
| | - Xuan Zhai
- Department of Neurosurgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing 400010, China.
| | - Jing Zhao
- Department of Pathophysiology, Chongqing Medical University, Chongqing 400016, China; Institute of Neuroscience, Chongqing Medical University, Chongqing 400016, China.
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Piard C, Luthcke R, Kamalitdinov T, Fisher J. Sustained delivery of vascular endothelial growth factor from mesoporous calcium-deficient hydroxyapatite microparticles promotes in vitro angiogenesis and osteogenesis. J Biomed Mater Res A 2020; 109:1080-1087. [PMID: 32918524 DOI: 10.1002/jbm.a.37100] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 05/13/2020] [Accepted: 05/21/2020] [Indexed: 01/05/2023]
Abstract
Promoting the growth of blood vessels within engineered tissues remains one of the main challenge in bone tissue engineering. One way to improve angiogenesis is the use of vascular endothelial growth factor (VEGF) as it holds the ability to increase the formation of a vascular network. In the present study, collagen scaffolds with VEGF-releasing hydroxyapatite particles were fabricated, in order to engineer a material both capable of presenting an osteoconductive surface and delivering an angiogenic growth factor in a localized and sustained manner, in order to enhance osteogenesis as well as angiogenesis. To this end, we developed microparticles and characterize their size, chemical properties and Ca/P ratio to validate the formation of hydroxyapatite. We then evaluated the osteogenic potential of HAp when cultured with mesenchymal stem cells and compare it to commercially available hydroxyapatite (SBp). Finally, we characterized the encapsulation and release of VEGF in the HAp and assess the angiogenic potential of the VEGF-HAp when cultured with endothelial cells. We demonstrated the successful fabrication of calcium deficient hydroxyapatite microparticles (CDHAp), with biological properties closer to the bone than stoichiometric, commercially available hydroxyapatite. This CDHAp exhibited a well-defined 3D network of crystalline nanoplates forming mesoporous and hollow structures. The high specific area created by those structures enabled the loading of VEGF with high efficiency when compared to the loading efficiency of SBp. Furthermore, their biological performances were evaluated in vitro. Our results indicate that VEGF-CDHAp can be used to improve both osteogenesis and angiogenesis in vitro.
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Affiliation(s)
- Charlotte Piard
- Fischell Department of Bioengineering, University of Maryland, Maryland, USA
| | - Rachel Luthcke
- Fischell Department of Bioengineering, University of Maryland, Maryland, USA
| | - Timur Kamalitdinov
- Fischell Department of Bioengineering, University of Maryland, Maryland, USA
| | - John Fisher
- Fischell Department of Bioengineering, University of Maryland, Maryland, USA.,Center for Engineering Complex Tissues, University of Maryland, Maryland, USA
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Hu Z, Zhao G, Gou W, Cheng H. Myricitrin inhibits vascular endothelial growth factor-induced angiogenesis of human umbilical vein endothelial cells and mice. Biomed Pharmacother 2020; 130:110726. [PMID: 34321178 DOI: 10.1016/j.biopha.2020.110726] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 08/31/2020] [Accepted: 09/02/2020] [Indexed: 11/25/2022] Open
Abstract
In the present study, the protective effects of myricitrin against vascular endothelial growth factor (VEGF)-induced angiogenesis of vascular endothelial cells were characterized. Cells were induced with 50 ng/mL VEGF in the presence or absence of various concentrations of myricitrin for 24 h. Myricitrin treatment significantly reduced cell proliferation by more than 50 %. Cells treated with myricitrin showed significantly increased caspase 3/7 activity and apoptosis in a dose-dependent manner. Treatment with 1, 10, or 100 μM myricitrin significantly reduced matrix metalloproteinase (MMP) activity by 23.3 %, 46.2 %, or 64.3 %, respectively. Myricitrin significantly reduced MMP1 and MMP2 mRNA expression. Similarly, treatment with 1, 10, or 100 μM myricitrin reduced MMP1 protein expression by 10.5 %, 31.6 %, or 52.6 %, respectively, and MMP2 protein expression by 10.9 %, 28.2 %, or 43.5 %, respectively. Cells treated with myricitrin showed significant inhibition of cell migration as well as capillary tube and sprouting formation. Myricitrin treatment significantly reduced the VEGF level. Immune-deficient nude mice bearing U251 xenograft tumors were used to investigate the antiangiogenic effects of myricitrin in vivo. The results demonstrated that myricitrin treatment in vivo significantly inhibited U251 cell xenograft tumor growth, as confirmed by the decreases in tumor volume and tumor weight. VEGF expression is a key proangiogenic factor. Myricitrin treatment significantly reduced mRNA and protein VEGF expression. Taken together, these results indicate that myricitrin is a potential inhibitor of VEGF-induced angiogenesis.
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Affiliation(s)
- Zhipeng Hu
- Department of Vascular Surgery, The General Hospital of NingXia Medical University, Yinchuan, 750004, China
| | - Gang Zhao
- Department of Vascular Surgery, The General Hospital of NingXia Medical University, Yinchuan, 750004, China
| | - Wei Gou
- Department of Vascular Surgery, The General Hospital of NingXia Medical University, Yinchuan, 750004, China
| | - Hua Cheng
- Department of Medical Cardiology, The General Hospital of NingXia Medical University, Yinchuan, 750004, China.
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Akyol E, Lotery A. Gene, Cell and Antibody-Based Therapies for the Treatment of Age-Related Macular Degeneration. Biologics 2020; 14:83-94. [PMID: 32982165 PMCID: PMC7494004 DOI: 10.2147/btt.s252581] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 08/04/2020] [Indexed: 12/30/2022]
Abstract
Here we discuss antibody, cell and gene-based therapies that are currently available and under investigation for both wet and dry age-related macular degeneration (AMD). We initially discuss ocular anatomy, AMD modelling as well as the underlying pathophysiology of AMD. The antibody-based trials which have revolutionised the management of wet AMD are reviewed. The latest concepts in antibody therapy for wet AMD such as the port delivery systems, bispecific antibodies, designed ankyrin repeat protein (DARPINs) and brolucizumab are explored. Furthermore, the antibody-based trials targeting the complement pathway to reduce progression of geographic atrophy (GA) in dry AMD are discussed. Stem cell therapy and gene therapy are novel treatment modalities with no established clinical use in wet or dry AMD. Here, we discuss their efficacy so far in clinical trials. Their benefits and risk in the treatment of both wet and dry AMD are evaluated.
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Affiliation(s)
- Engin Akyol
- Clinical Neurosciences Research Group, Faculty of Medicine, University of Southampton, Southampton General Hospital, SouthamptonSO16 6YD, UK
| | - Andrew Lotery
- Clinical Neurosciences Research Group, Faculty of Medicine, University of Southampton, Southampton General Hospital, SouthamptonSO16 6YD, UK
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Liu J, Tan X, Zhao W, Liu J, Xing X, Fan G, Zhang P, Zhang Z, Zhong Y, Kong D. In Vitro and In Vivo Antimetastatic Effects of ZSTK474 on Prostate Cancer DU145 Cells. Curr Cancer Drug Targets 2020; 19:321-329. [PMID: 30205797 DOI: 10.2174/1568009618666180911101310] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 03/15/2018] [Accepted: 06/22/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND The lethality of prostate cancer is mainly due to metastasis. Inhibition of metastasis is expected to be a promising approach for prostate cancer therapy. Phosphatidylinositol 3-kinase (PI3K)/Akt pathway is reported to be closely involved in cell growth, migration, etc. Objective: The study investigated the antimetastatic activities of pan-PI3K inhibitor ZSTK474 on DU145 cells. METHODS 1. The In vitro effect of ZSTK474 on the migration, invasion and adhesion of DU145 cells was determined with Transwell migration assay and wound healing assay, Tranwell invasion assay and adhesion assay, respectively. 2. In vitro effect of ZSTK474 on the signal proteins in DU145 cells was determined with Western blot analysis and ELISA. 3. Moreover, the In vivo antimetastatic effect of ZSTK474 was evaluated with MicroCT and histology analysis. RESULTS ZSTK474 potently attenuated the capability of migration, invasion and adhesion of DU145 cells, negatively regulated Girdin, Integrinβ1 and matrix metalloproteinases (MMPs). In addition, the expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF), which are known to be related to angiogenesis and metastasis, was also inhibited. Oral administration of ZSTK474 (200 mg/kg) ameliorated in vivo bone metastasis of DU145 cells, with improved bone structure and bone mineral density (BMD). Tissue staining indicated a reduction in metastatic DU145 cells and osteoclasts in the bones of ZSTK474-treated mice, compared with the non-treated group. CONCLUSION Our result demonstrated the antimetastatic activity of ZSTK474 on prostate cancer DU145 cells, suggesting the potential application in prostate cancer patients.
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Affiliation(s)
- Jie Liu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.,Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Xiao Tan
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.,Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.,State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Wennan Zhao
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.,Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Jing Liu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.,Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.,State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Xiaoxue Xing
- State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Guanwei Fan
- State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Ping Zhang
- Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Zhe Zhang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Yuxu Zhong
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Dexin Kong
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.,Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
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Zhao J, Li D, Tang H, Tang L. Association of vascular endothelial growth factor polymorphisms with polycystic ovarian syndrome risk: a meta-analysis. Reprod Biol Endocrinol 2020; 18:18. [PMID: 32164758 PMCID: PMC7069028 DOI: 10.1186/s12958-020-00577-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 02/24/2020] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Polycystic ovarian syndrome (PCOS) is a multi-gene hereditary disorder caused by the interaction of certain gene variation with environmental factors. Previous studies have shown that vascular endothelial growth factor (VEGF) gene polymorphisms are associated with the risk of polycystic ovarian syndrome. However, the results of these studies remain controversial. We performed the present meta-analysis aiming to further investigate the potential relationship between VEGF polymorphisms and susceptibility to PCOS. METHODS The following databases were systematically searched: PubMed, EMBASE, Web of Science (WOS), China National Knowledge Infrastructure (CNKI), and Wanfang Databases. The correlation between VEGF polymorphisms and PCOS risk was assessed by calculating pooled odds ratios (ORs) and their 95% confidence intervals (95% CIs). Subgroup analyses stratified by ethnicity and source of control were also conducted. Besides, trial sequential analysis (TSA) was done to verify the reliability of the pooled results. RESULTS 10 relevant case-control studies were incorporated in this meta-analysis, involving 1347 PCOS cases and 1378 controls. The VEGF rs2010963 polymorphism was associated with decreased PCOS risk in the whole population and the Asian populations. The VEGF rs3025039 polymorphism was associated with decreased PCOS susceptibility and the Asian populations, but increased risk of PCOS was observed among the Caucasian populations. In addition, the results of trial sequential analysis (TSA) showed the negative correlation between rs2010963 and PCOS risk, obtained by our meta-analysis, was stable and reliable. CONCLUSION Overall, different VEGF gene polymorphisms may exert different effects on PCOS susceptibility. The VEGF rs2010963 polymorphism decreases PCOS susceptibility in both the whole population and the Asian populations, and VEGF rs3025039 polymorphism causes lower PCOS susceptibility in the whole population and the Asian populations but higher in the Caucasian populations.
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Affiliation(s)
- Jiahui Zhao
- Department of Reproductive Medicine, Lianyungang Maternal and Child Health Hospital, NO.669 Qindongmen Road, Lianyungang, 222001, Jiangsu Province, China
| | - Da Li
- Department of Vascular Surgery, the First People's Hospital of Lianyungang, NO.182 North Tongguan Road, Lianyungang, Jiangsu Province, 222002, China
| | - Huaiyun Tang
- Department of Reproductive Medicine, Lianyungang Maternal and Child Health Hospital, NO.669 Qindongmen Road, Lianyungang, 222001, Jiangsu Province, China
| | - Lisha Tang
- Department of Reproductive Medicine, Lianyungang Maternal and Child Health Hospital, NO.669 Qindongmen Road, Lianyungang, 222001, Jiangsu Province, China.
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A Rationale for the Use of Clotted Vertebral Bone Marrow to Aid Tissue Regeneration Following Spinal Surgery. Sci Rep 2020; 10:4115. [PMID: 32139727 PMCID: PMC7058026 DOI: 10.1038/s41598-020-60934-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 02/19/2020] [Indexed: 12/25/2022] Open
Abstract
Vertebral body bone marrow aspirate (V-BMA), easily accessible simultaneously with the preparation of the site for pedicle screw insertion during spinal procedures, is becoming an increasingly used cell therapy approach in spinal surgery. However, the main drawbacks for V-BMA use are the lack of a standardized procedure and of a structural texture with the possibility of diffusion away from the implant site. The aim of this study was to evaluate, characterize and compare the biological characteristics of MSCs from clotted V-BMA and MSCs from whole and concentrate V-BMAs. MSCs from clotted V-BMA showed the highest cell viability and growth factors expression (TGF-β, VEGF-A, FGF2), the greatest colony forming unit (CFU) potency, cellular homogeneity, ability to differentiate towards the osteogenic (COL1AI, TNFRSF11B, BGLAP) and chondrogenic phenotype (SOX9) and the lowest ability to differentiate toward the adipogenic lineage (ADIPOQ) in comparison to all the other culture conditions. Additionally, results revealed that MSCs, differently isolated, expressed different level of HOX and TALE signatures and that PBX1 and MEIS3 were down-regulated in MSCs from clotted V-BMA in comparison to concentrated one. The study demonstrated for the first time that the cellular source inside the clotted V-BMA showed the best biological properties, representing an alternative and advanced cell therapy approach for patients undergoing spinal surgery.
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Bao C, Yang Z, Li Q, Cai Q, Li H, Shu B. Aerobic Endurance Exercise Ameliorates Renal Vascular Sclerosis in Aged Mice by Regulating PI3K/AKT/mTOR Signaling Pathway. DNA Cell Biol 2020; 39:310-320. [PMID: 31971826 DOI: 10.1089/dna.2019.4966] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Renal vascular sclerosis caused by aging plays an important role in the occurrence and development of chronic kidney disease. Clinical studies have confirmed that endurance exercise is able to delay the aging of skeletal muscle and brain tissue. However, to date, few studies have assessed whether endurance exercise is able to improve the occurrence of renal vascular sclerosis caused by natural aging and its related mechanisms. In this study, we investigated the protective effect of aerobic endurance exercise on renal vascular sclerosis in aged mice and its effect on the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. The results suggested that aerobic endurance exercise preserved kidney morphology and renal function. Glomerular basement membrane thickness was evidently increased, podocyte foot processes were effaced in aged mice, and aerobic endurance exercise significantly ameliorated the overall lesion range. The protein expression of vascular endothelial growth factor (VEGF) and JG12 was lower in the senile control group (OC group). The protein expression of VEGF and JG12 was significantly increased after aerobic endurance exercise. Furthermore, aerobic endurance exercise resulted in downregulation of Bax, Caspase 3, IL-6, and senescent cells and upregulation of Bcl-2. The upregulation of PI3K and its downstream signal molecules AKT and mTOR after aerobic endurance exercise was further observed. Our observations indicated that aerobic endurance exercise may inhibit renal vascular sclerosis in aged mice by regulating the PI3K/AKT/mTOR signaling pathway.
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Affiliation(s)
- Chuncha Bao
- Department of Rehabilitation Medicine, University-Town Hospital, Chongqing Medical University, Chongqing, China
| | - Zhong Yang
- Department of Clinical Blood Teaching and Research, Army Medical University, Chongqing, China
| | - Qian Li
- Department of Rehabilitation Medicine, University-Town Hospital, Chongqing Medical University, Chongqing, China
| | - Qiyan Cai
- Department of Histology and Embryology, Army Medical University, Chongqing, China
| | - Hongli Li
- Department of Histology and Embryology, Army Medical University, Chongqing, China
| | - Bin Shu
- Department of Rehabilitation Medicine, University-Town Hospital, Chongqing Medical University, Chongqing, China
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Yaman S, Çukadar N, Baran F, Uyanık FB, Kılınç M, Mert T. Monoklonal antikorlardan bevacizumab'ın deneysel inflamatuar ağrı modelinde antianjiyogenik etkisi. CUKUROVA MEDICAL JOURNAL 2019. [DOI: 10.17826/cumj.532813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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48
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Sun W, He G, Zhang M, Zhao Y, Yu H, Li Y, Wu W, Ji T. 99mTc-3PRGD 2 SPECT Predicts the Outcome of Endostar and Cisplatin Therapy in Xenograft Animals. Dose Response 2019; 17:1559325819882544. [PMID: 31673250 PMCID: PMC6804356 DOI: 10.1177/1559325819882544] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 08/03/2019] [Accepted: 08/11/2019] [Indexed: 11/16/2022] Open
Abstract
Aims: Our study was designed to investigate the usefulness of 99mTc-3PRGD2 single-photon emission computed tomography (SPECT) for noninvasively monitoring the response of integrin αvβ3 expression to antiangiogenic treatment with endostar and cisplatin in xenograft animals. Methods: 99mTc-3PRGD2 SPECT imaging was performed at days 0, 7, 14, and 21. Tumors were harvested at all imaging time points for Western blotting and histopathological analysis. Result: In 99mTc-3PRGD2 SPECT imaging, the radioactivity accumulation of NaCl group rised gradually in the first half and dispersed on day 21 due to the necrosis of the tumor. While the radioactivity accumulation of treated groups gradually decreased throughout the course. The downtrend of tumor to nontumor ratio in endostar-treated group was more remarkable than cisplatin-treated group. The expression of intergrin αvβ3 of treated groups was lower than NaCl group from day 14. The expression of intergrin αvβ3 of endostar-treated group was significantly lower than cisplatin-treated group from baseline onward. Conclusion: It’s demonstrated that the 99mTc-3PRGD2 could noninvasively visualize and semiquantify tumor angiogenesis in the xenograft model and monitor the response to the antiangiogenic therapy of endostar and cisplatin effectively. It also can predict the outcome of endostar and cisplatin therapy in xenograft animals.
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Affiliation(s)
- Wei Sun
- Institute of Pediatrics, First Hospital, Jilin University, Changchun, Jilin, China
| | - Guifu He
- Department of Nuclear Medicine, Jilin Provincial Tumor Hospital, Changchun, Jilin, China
| | - Mingming Zhang
- Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Yi Zhao
- Department of Nuclear Medicine, Jilin Provincial Tumor Hospital, Changchun, Jilin, China
| | - Hongmei Yu
- Department of Blood Transfusion, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China
| | - Yi Li
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, Jilin University, Changchun, Jilin, China
| | - Wei Wu
- Department of Nuclear Medicine, Jilin Provincial Tumor Hospital, Changchun, Jilin, China
| | - Tiefeng Ji
- Department of Radiology, First Hospital, Jilin University, Changchun, Jilin, China
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49
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Lu RM, Chiu CY, Liu IJ, Chang YL, Liu YJ, Wu HC. Novel human Ab against vascular endothelial growth factor receptor 2 shows therapeutic potential for leukemia and prostate cancer. Cancer Sci 2019; 110:3773-3787. [PMID: 31578782 PMCID: PMC6890446 DOI: 10.1111/cas.14208] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 09/25/2019] [Accepted: 09/25/2019] [Indexed: 12/15/2022] Open
Abstract
Vascular endothelial growth factor receptor 2 (VEGFR2) is highly expressed in tumor‐associated endothelial cells, where it modulates tumor‐promoting angiogenesis, and it is also found on the surface of tumor cells. Currently, there are no Ab therapeutics targeting VEGFR2 approved for the treatment of prostate cancer or leukemia. Therefore, development of novel efficacious anti‐VEGFR2 Abs will benefit cancer patients. We used the Institute of Cellular and Organismic Biology human Ab library and affinity maturation to develop a fully human Ab, anti‐VEGFR2‐AF, which shows excellent VEGFR2 binding activity. Anti‐VEGFR2‐AF bound Ig‐like domain 3 of VEGFR2 extracellular region to disrupt the interaction between VEGF‐A and VEGFR2, neutralizing downstream signaling of the receptor. Moreover, anti‐VEGFR2‐AF inhibited capillary structure formation and exerted Ab‐dependent cell‐mediated cytotoxicity and complement‐dependent cytotoxicity in vitro. We found that VEGFR2 is expressed in PC‐3 human prostate cancer cell line and associated with malignancy and metastasis of human prostate cancer. In a PC‐3 xenograft mouse model, treatment with anti‐VEGFR2‐AF repressed tumor growth and angiogenesis as effectively and safely as US FDA‐approved anti‐VEGFR2 therapeutic, ramucirumab. We also report for the first time that addition of anti‐VEGFR2 Ab can enhance the efficacy of docetaxel in the treatment of a prostate cancer mouse model. In HL‐60 human leukemia‐xenografted mice, anti‐VEGFR2‐AF showed better efficacy than ramucirumab with prolonged survival and reduced metastasis of leukemia cells to ovaries and lymph nodes. Our findings suggest that anti‐VEGFR2‐AF has strong potential as a cancer therapy that could directly target VEGFR2‐expressing tumor cells in addition to its anti‐angiogenic action.
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Affiliation(s)
- Ruei-Min Lu
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Chiung-Yi Chiu
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - I-Ju Liu
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Yu-Ling Chang
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Yaw-Jen Liu
- Research and Development Center, United Biopharma Inc., Hsinshu, Taiwan
| | - Han-Chung Wu
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
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50
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Caruana A, Savina D, Macedo JP, Soares SC. From Platelet-Rich Plasma to Advanced Platelet-Rich Fibrin: Biological Achievements and Clinical Advances in Modern Surgery. Eur J Dent 2019; 13:280-286. [PMID: 31509878 PMCID: PMC6777161 DOI: 10.1055/s-0039-1696585] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
In the past 20 years, the platelet concentrates have evolved from first-generation products, i.e., platelet-rich plasma (PRP) and plasma rich in growth factors to the second-generation products such as leukocyte-platelet-rich fibrin (L-PRF) and advanced platelet-rich fibrin (A-PRF). These autologous products with a higher leukocyte inclusion and flexible fibrin mesh act as a scaffold to increase cellular migration in the angiogenic, osteogenic, and antimicrobial potential of these biomaterials in tissue regeneration. In the second-generation platelet concentrates, the protocols are easier, cheaper, and faster with an entire physiological fibrin matrix, resulting in a tridimensional mesh, not as rigid as one of the first generations. This allows the slow release of molecules over a longer period of time and triggers the healing and regenerative process at the site of injury. The potential of A-PRF to mimic the physiology and immunology of wound healing is also due to the high concentration of growth factors released as follows: vascular endothelial growth factor, platelet-derived growth factor, transforming growth factor-β, and anti-inflammatory cytokines that stimulate tissue cicatrization, vessels formation, and bone cell proliferation and differentiation. Furthermore, the number of neutrophils and monocytes/macrophages is higher releasing important chemotactic molecules such as chemokine ligand-5 and eotaxin. Thus, L-PRF and A-PRF have been used, especially in implantology, periodontology, and maxillofacial surgery. Future clinical applications include tissue regeneration/grafts, ulcers/skin necrosis in the diabetic patient and others, plastic surgery, and even musculoskeletal lesions.
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Affiliation(s)
- Andrea Caruana
- Faculty of Health Sciences, School of Dentistry, Fernando Pessoa University, Porto, Portugal
| | - Daniele Savina
- Faculty of Health Sciences, School of Dentistry, Fernando Pessoa University, Porto, Portugal
| | - José Paulo Macedo
- Faculty of Health Sciences, School of Dentistry, Fernando Pessoa University, Porto, Portugal
| | - Sandra Clara Soares
- Biomedical Research Center, Fernando Pessoa Energy, Environment and Health Research Unit, Faculty of Health Sciences, Fernando Pessoa University, Porto, Portugal
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