The discovery of placenta growth factor and its biological activity

De Falco, Sandro Korean Society for Biochemistry and Molecular Bion 2012 Experimental and molecular medicine Vol.44 No.1

Angiogenesis is a complex biological phenomenon crucial for a correct embryonic development and for post-natal growth. In adult life, it is a tightly regulated process confined to the uterus and ovary during the different phases of the menstrual cycle and to the heart and skeletal muscles after prolonged and sustained physical exercise. Conversly, angiogenesis is one of the major pathological changes associated with several complex diseases like cancer, atherosclerosis, arthritis, diabetic retinopathy and age-related macular degeneration. Among the several molecular players involved in angiogenesis, some members of VEGF family, VEGF-A, VEGF-B and placenta growth factor (PlGF), and the related receptors VEGF receptor 1 (VEGFR-1, also known as Flt-1) and VEGF receptor 2 (VEGFR-2, also known as Flk-1 in mice and KDR in human) have a decisive role. In this review, we describe the discovery and molecular characteristics of PlGF, and discuss the biological role of this growth factor in physiological and pathological conditions.

The discovery of placenta growth factor and its biological activity

Sandro De Falco 생화학분자생물학회 2012 Experimental and molecular medicine Vol.44 No.1

Angiogenesis is a complex biological phenomenon crucial for a correct embryonic development and for post-natal growth. In adult life, it is a tightly regulated process confined to the uterus and ovary during the different phases of the menstrual cycle and to the heart and skeletal muscles after prolonged and sustained physical exercise. Conversly, angiogenesis is one of the major pathological changes associated with several complex diseases like cancer, atherosclerosis, arthritis,diabetic retinopathy and age-related macular degeneration. Among the several molecular players involved in angiogenesis, some members of VEGF family,VEGF-A, VEGF-B and placenta growth factor (PlGF), and the related receptors VEGF receptor 1(VEGFR-1, also known as Flt-1) and VEGF receptor 2(VEGFR-2, also known as Flk-1 in mice and KDR in human)have a decisive role. In this review, we describe the discovery and molecular characteristics of PlGF,and discuss the biological role of this growth factor in physiological and pathological conditions.

태반 성장인자의 발견과 생물학적 활성

( Sandro De Falco ) 생화학분자생물학회 (구 한국생화학분자생물학회) 2012 생화학분자생물학회 소식 Vol.32 No.1

REVIEW : Antiangiogenesis therapy: an update after the first decade

( Sandro De Falco ) 대한내과학회 2014 The Korean Journal of Internal Medicine Vol.29 No.1

Angiogenesis is a complex biological phenomenon that forms new blood vessels from the pre-existing vasculature. Aberrant angiogenesis has been implicated in a variety of diseases such as cancer, atherosclerosis, arthritis, obesity, pulmonary hypertension, diabetic retinopathy, and age-related macular degeneration. These conditions collectively affect nearly 10% of the global population. Much effort has focused on identifying new therapeutic agents that inhibit pathological angio-genesis since 1971, when Judah Folkman published the hypothesis that tumor growth is angiogenesis-dependent and that its inhibition may be therapeutic. In 2004, the U.S. Food and Drug Administration approved the first antiangiogenic drug for the treatment of metastatic colon cancer, bevacizumab (Avastin, Genen-tech). This drug is a humanized monoclonal antibody that neutralizes the vascu-lar endothelial growth factor. It is used in combination with chemotherapy, and its use began the era of antiangiogenesis therapy. Several new therapeu-tic agents have been added to the list of approved drugs, and clinical trials of new therapeutic options and antiangiogenic agents are ongoing. This review describes the progress made in the first decade of antiangiogenesis therapy, and addresses both validated and possible targets for future drug development.

Stochastic identification of masonry parameters in 2D finite elements continuum models

Giada Bartolini,Anna De Falco,Filippo Landi Techno-Press 2023 Coupled systems mechanics Vol.12 No.5

The comprehension and structural modeling of masonry constructions is fundamental to safeguard the integrity of built cultural assets and intervene through adequate actions, especially in earthquake-prone regions. Despite the availability of several modeling strategies and modern computing power, modeling masonry remains a great challenge because of still demanding computational efforts, constraints in performing destructive or semi-destructive in-situ tests, and material uncertainties. This paper investigates the shear behavior of masonry walls by applying a plane-stress FE continuum model with the Modified Masonry-like Material (MMLM). Epistemic uncertainty affecting input parameters of the MMLM is considered in a probabilistic framework. After appointing a suitable probability density function to input quantities according to prior engineering knowledge, uncertainties are propagated to outputs relying on gPCE-based surrogate models to considerably speed up the forward problem-solving. The sensitivity of the response to input parameters is evaluated through the computation of Sobol' indices pointing out the parameters more worthy to be further investigated, when dealing with the seismic assessment of masonry buildings. Finally, masonry mechanical properties are calibrated in a probabilistic setting with the Bayesian approach to the inverse problem based on the available measurements obtained from the experimental load-displacement curves provided by shear compression in-situ tests.

Evaluation of Dyeing and UV Protective Properties on Hemp Fabric of Aqueous Extracts from Vegetal Matrices of Different Origin

Daniele Grifoni,Graziana Roscigno,Enrica De Falco,Annapia Vece,Francesca Camilli,Francesco Sabatini,Luca Fibbi,Gaetano Zipoli 한국섬유공학회 2020 Fibers and polymers Vol.21 No.8

Clothes are one of the most effective measures to minimize health hazards due to the current levels of UV radiationon the earth’s surface. Fabrics made of natural fibers and dyed with natural pigments are an excellent means to reduce UVexposure. In this study, the UV protection properties were tested on a vegetal fiber fabric (hemp) dyed with water extractsfrom madder, chestnut, onion, inula, and logwood, at three increasing concentrations. Dyeing extracts were obtained fromdifferent sources: agro-food industry residues (chestnut and onion), spontaneous (inula), and commercial dyeing plants(madder and logwood). The quantitative characterization of water dye extracts was performed to evaluate the amount of dyein pre- and post-dyeing solutions as well as the dye fastened to the fabric. The percentage values of dye fastened to the fabric,in relation to the plant dry weight, were relatively low for all the considered species. The fabric Ultraviolet Protection Factor(UPF) was evaluated using both a laboratory spectrophotometer and a spectroradiometer in outdoor conditions. Aprogressive increase in UPF with the increase of the dye-bath concentration was shown. Chestnut and onion, reaching theminimum protection level (UPF=15) at the highest dye-bath concentration, can be considered the most effective. The UPFpersistence of the fabrics was also evaluated after sun exposure and repeated washing. Colors and UV protective propertiesobtained by the dyeing procedure tested in this research can provide added value to hemp fabric and meet the demands of anexpanding “eco-friendly” market.

Role of placenta growth factor and its receptor flt-1 in rheumatoid inflammation: A link between angiogenesis and inflammation

Yoo, Seung-Ah,Yoon, Hyung-Ju,Kim, Hyun-Sook,Chae, Chi-Bom,De Falco, Sandro,Cho, Chul-Soo,Kim, Wan-Uk Wiley Subscription Services, Inc., A Wiley Company 2009 Vol.60 No.2

<B>Objective</B><P>To investigate the direct effects of placenta growth factor (PlGF) and its specific receptor, flt-1, which are known to mediate angiogenesis, on the inflammatory process of rheumatoid arthritis (RA).</P><B>Methods</B><P>Expression of PlGF and flt-1 in the synovial tissue of RA patients was examined using immunohistochemistry. Enzyme-linked immunosorbent assay was used to determine the concentrations of PlGF, tumor necrosis factor α (TNFα), and interleukin-6 (IL-6) in culture supernatants of either mononuclear cells or synoviocytes. The flt-1 expression level in mononuclear cells was analyzed by flow cytometry. Experimental arthritis was induced in mice either by immunization with type II collagen (CII) or by injection of anti-CII antibody.</P><B>Results</B><P>PlGF was highly expressed in the synovium of RA patients, and its primary source was fibroblast-like synoviocytes (FLS). When stimulated with IL-1β, FLS from RA patients produced higher amounts of PlGF than did FLS from patients with osteoarthritis. Exogenous PlGF specifically increased the production of TNFα and IL-6 in mononuclear cells from RA patients (but not those from healthy controls) via a calcineurin-dependent pathway. The response to PlGF was associated with increased expression of flt-1 on RA monocytes, which could be induced by IL-1β and TNFα. A novel anti–flt-1 hexapeptide, GNQWFI, abrogated the PlGF-induced increase in TNFα and IL-6 production, and also suppressed CII-induced arthritis and serum IL-6 concentrations in mice. Moreover, genetic ablation of PlGF prevented the development of anti-CII antibody–induced arthritis in mice.</P><B>Conclusion</B><P>Our data suggest that enhanced expression of PlGF and flt-1 may contribute to rheumatoid inflammation by triggering production of proinflammatory cytokines. The use of the novel anti–flt-1 peptide, GNQWFI, may be an effective strategy for the treatment of RA.</P>

Cancer-derived exosomal Alu RNA promotes colorectal cancer progression

Magliacane Trotta Sara,Adinolfi Antonio,D’Orsi Luca,Panico Sonia,Mercadante Grazia,Mehlen Patrick,Ambati Jayakrishna,De Falco Sandro,Tarallo Valeria 생화학분자생물학회 2024 Experimental and molecular medicine Vol.56 No.-

Inflammation plays a crucial role in cancer progression, but the relevance of the inflammasome remains unclear. Alu RNA was the first endogenous nucleic acid shown to activate the NLRP3 (nucleotide-binding domain leucine-rich repeat containing 3) inflammasome. Here, we showed that Alu RNA can induce epithelial-to-mesenchymal transition (EMT) through NLRP3 inflammasome activation and IL-1β release in colorectal cancer (CRC) cells. Alu RNA is stored, transported and transferred to CRC cells by exosomes. Exosomal Alu RNA promotes tumorigenesis by inducing invasion, metastasis and EMT via NLRP3 inflammasome activation. Consistent with these data, we found that significantly increased Alu RNA expression correlates with the induction of NLRP3 priming in human CRC patients. Furthermore, the level of Alu RNA in circulating exosomes correlates with CRC progression in a preclinical model. These findings reveal the direct involvement of Alu RNA in cancer pathogenesis, and its presence in CRC cell-derived exosomes could be used as a noninvasive diagnostic biomarker.

Placental Growth Factor-1 and -2 Induce Hyperplasia and Invasiveness of Primary Rheumatoid Synoviocytes

Yoo, Seung-Ah,Park, Ji-Hwan,Hwang, Seong-Hye,Oh, Sang-Min,Lee, Saseong,Cicatiello, Valeria,Rho, Sangchul,De Falco, Sandro,Hwang, Daehee,Cho, Chul-Soo,Kim, Wan-Uk The American Association of Immunologists, Inc. 2015 JOURNAL OF IMMUNOLOGY Vol.194 No.6

<P>Inflammation-mediated oncogenesis has been implicated in a variety of cancer types. Rheumatoid synovial tissues can be viewed as a tumor-like mass, consisting of hyperplastic fibroblast-like synoviocytes (FLSs). FLSs of rheumatoid arthritis (RA) patients have promigratory and invasive characteristics, which may be caused by chronic exposure to genotoxic stimuli, including hypoxia and growth factors. We tested whether a transformed phenotype of RA-FLSs is associated with placental growth factor (PlGF), a representative angiogenic growth factor induced by hypoxia. In this study, we identified <I>PlGF-1</I> and <I>PlGF-2</I> as the major <I>PlGF</I> isoforms in RA-FLSs. Global gene expression profiling revealed that cell proliferation, apoptosis, angiogenesis, and cell migration were mainly represented by differentially expressed genes in RA-FLSs transfected with small interfering RNA for <I>PlGF</I>. Indeed, <I>PlGF</I>-deficient RA-FLSs showed a decrease in cell proliferation, migration, and invasion, but an increase in apoptotic death in vitro. <I>PlGF</I> gene overexpression resulted in the opposite effects. Moreover, exogeneous PlGF-1 and PlGF-2 increased survival, migration, and invasiveness of RA-FLSs by binding their receptors, Flt-1 and neuropilin-1, and upregulating the expression of antiapoptotic molecules, pErk and Bcl2. Knockdown of <I>PlGF</I> transcripts reduced RA-FLS proliferation in a xenotransplantation model. Collectively, in addition to their role for neovascularization, PlGF-1 and -2 promote proliferation, survival, migration, and invasion of RA-FLSs in an autocrine and paracrine manner. These results demonstrated how primary cells of mesenchymal origin acquired an aggressive and transformed phenotype. PlGF and its receptors thus offer new targets for anti-FLS therapy.</P>

Anti–neuropilin-1 peptide inhibition of synoviocyte survival, angiogenesis, and experimental arthritis

Kong, Jin-Sun,Yoo, Seung-Ah,Kim, Jung-Wook,Yang, Seung-Pil,Chae, Chi-Bom,Tarallo, Valeria,Falco, Sandro De,Ryu, Sung-Ho,Cho, Chul-Soo,Kim, Wan-Uk Wiley Subscription Services, Inc., A Wiley Company 2010 Vol.62 No.1

<B>Objective</B><P>To delineate the role of neuropilin-1 (NP-1), a vascular endothelial growth factor receptor (VEGFR), in rheumatoid inflammation and to determine whether blockade of NP-1 could suppress synoviocyte survival and angiogenesis.</P><B>Methods</B><P>VEGF<SUB>111–165</SUB> peptide, which encompasses the NP-1 binding domain of VEGF<SUB>165</SUB>, was generated by cleaving VEGF<SUB>165</SUB> with plasmin. The effect of this peptide on the interaction between VEGF<SUB>165</SUB> and its receptor was determined by <SUP>125</SUP>I-VEGFR binding assay. Assays to determine synoviocyte apoptosis, adhesion, and migration were performed in the presence of VEGF<SUB>165</SUB> and/or the peptide. VEGF<SUB>165</SUB>-induced angiogenesis was assessed by measuring the proliferation, tube formation, and wounding migration of endothelial cells (ECs). Mice were immunized with type II collagen to induce experimental arthritis.</P><B>Results</B><P>VEGF<SUB>111–165</SUB> peptide specifically inhibited the binding of <SUP>125</SUP>I-VEGF<SUB>165</SUB> to NP-1 on rheumatoid synoviocytes and ECs. The peptide eliminated the VEGF<SUB>165</SUB>-mediated increase in synoviocyte survival and activation of p-ERK and Bcl-2. The peptide also completely inhibited a VEGF<SUB>165</SUB>-induced increase in synoviocyte adhesion and migration. In addition, the anti–NP-1 peptide blocked VEGF<SUB>165</SUB>-stimulated proliferation, capillary tube formation, and wounding migration of ECs in vitro. VEGF<SUB>165</SUB>-induced neovascularization in a Matrigel plug in mice was also blocked by treatment with the peptide. Finally, subcutaneous injection of anti–NP-1 peptide suppressed arthritis severity and autoantibody formation in mice with experimental arthritis and inhibited synoviocyte hyperplasia and angiogenesis in arthritic joints.</P><B>Conclusion</B><P>Anti–NP-1 peptide suppressed VEGF<SUB>165</SUB>-induced increases in synoviocyte survival and angiogenesis, and thereby blocked experimental arthritis. Our findings suggest that anti–NP-1 peptide could be useful in alleviating chronic arthritis.</P>