scholarly journals Angiostatic activity of the antitumor cytokine interleukin-21

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4940-4947 ◽  
Author(s):  
Karolien Castermans ◽  
Sebastien P. Tabruyn ◽  
Rong Zeng ◽  
Judy R. van Beijnum ◽  
Cheryl Eppolito ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Angiogenesis ◽  
Chorioallantoic Membrane ◽  
Antitumor Immune Response ◽  
In Vivo Studies ◽  
Type I ◽  
Stat3 Phosphorylation ◽  
Interleukin 21

Abstract Interleukin-21 (IL-21) is a recently described immunoregulatory cytokine. It has been identified as a very potent immunotherapeutic agent in several cancer types in animal models, and clinical studies are ongoing. IL-21 belongs to the type I cytokine family of which other members, ie, IL-2, IL-15, and IL-4, have been shown to exert activities on vascular endothelial cells (ECs). We hypothesized that IL-21, in addition to inducing the antitumor immune response, also inhibits tumor angiogenesis. In vitro experiments showed a decrease of proliferation and sprouting of activated ECs after IL-21 treatment. We found that the IL-21 receptor is expressed on vascular ECs. Furthermore, in vivo studies in the chorioallantoic membrane of the chick embryo and in mouse tumors demonstrated that IL-21 treatment disturbs vessel architecture and negatively affects vessel outgrowth. Our results also confirm the earlier suggested angiostatic potential of IL-2 in vitro and in vivo. The angiostatic effect of IL-21 is confirmed by the decrease in expression of angiogenesis-related genes. Interestingly, IL-21 treatment of ECs leads to a decrease of Stat3 phosphorylation. Our research shows that IL-21 is a very powerful antitumor compound that combines the induction of an effective antitumor immune response with inhibition of tumor angiogenesis.

scholarly journals Characterization of Weissella viridescens UCO-SMC3 as a Potential Probiotic for the Skin: Its Beneficial Role in the Pathogenesis of Acne Vulgaris

2021 ◽  
Vol 9 (7) ◽  
pp. 1486
Author(s):  
Marcela Espinoza-Monje ◽  
Jorge Campos ◽  
Eduardo Alvarez Villamil ◽  
Alonso Jerez ◽  
Stefania Dentice Maidana ◽  
...  
Keyword(s):  
Immune Response ◽  
Oral Treatment ◽  
Acne Vulgaris ◽  
Topical Administration ◽  
In Vivo Studies ◽  
Mice Model ◽  
Cutibacterium Acnes ◽  
Snail Helix Aspersa

Previously, we isolated lactic acid bacteria from the slime of the garden snail Helix aspersa Müller and selected Weissella viridescens UCO-SMC3 because of its ability to inhibit in vitro the growth of the skin-associated pathogen Cutibacterium acnes. The present study aimed to characterize the antimicrobial and immunomodulatory properties of W. viridescens UCO-SMC3 and to demonstrate its beneficial effect in the treatment of acne vulgaris. Our in vitro studies showed that the UCO-SMC3 strain resists adverse gastrointestinal conditions, inhibits the growth of clinical isolates of C. acnes, and reduces the adhesion of the pathogen to keratinocytes. Furthermore, in vivo studies in a mice model of C. acnes infection demonstrated that W. viridescens UCO-SMC3 beneficially modulates the immune response against the skin pathogen. Both the oral and topical administration of the UCO-SCM3 strain was capable of reducing the replication of C. acnes in skin lesions and beneficially modulating the inflammatory response. Of note, orally administered W. viridescens UCO-SMC3 induced more remarkable changes in the immune response to C. acnes than the topical treatment. However, the topical administration of W. viridescens UCO-SMC3 was more efficient than the oral treatment to reduce pathogen bacterial loads in the skin, and effects probably related to its ability to inhibit and antagonize the adhesion of C. acnes. Furthermore, a pilot study in acne volunteers demonstrated the capacity of a facial cream containing the UCO-SMC3 strain to reduce acne lesions. The results presented here encourage further mechanistic and clinical investigations to characterize W. viridescens UCO-SMC3 as a probiotic for acne vulgaris treatment.

scholarly journals Isopsoralen Enhanced Osteogenesis by Targeting AhR/ERα

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2600 ◽  
Author(s):  
Luna Ge ◽  
Yazhou Cui ◽  
Kai Cheng ◽  
Jinxiang Han
Keyword(s):  
Osteoblast Differentiation ◽  
Estrogen Receptor Alpha ◽  
Biological Effects ◽  
Hormone Deficiency ◽  
In Vivo Studies ◽  
Osteogenic Potential ◽  
Type I ◽  
Dependent Manner

Isopsoralen (IPRN), one of the main effective ingredients in Psoralea corylifolia Linn, has a variety of biological effects, including antiosteoporotic effects. In vivo studies show that IPRN can increase bone strength and trabecular bone microstructure in a sex hormone deficiency-induced osteoporosis model. However, the mechanism underlying this osteogenic potential has not been investigated in detail. In the present study, we investigated the molecular mechanism of IPRN-induced osteogenesis in MC3T3-E1 cells. Isopsoralen promoted osteoblast differentiation and mineralization, increased calcium nodule levels and alkaline phosphatase (ALP) activity and upregulated osteoblast markers, including ALP, runt-related transcription factor 2 (RUNX2), and collagen type I alpha 1 chain (COL1A1). Furthermore, IPRN limited the nucleocytoplasmic shuttling of aryl hydrocarbon receptor (AhR) by directly binding to AhR. The AhR target gene cytochrome P450 family 1 subfamily A member 1 (CYP1A1) was also inhibited in vitro and in vivo. This effect was inhibited by the AhR agonists indole-3-carbinol (I3C) and 3-methylcholanthrene (3MC). Moreover, IPRN also increased estrogen receptor alpha (ERα) expression in an AhR-dependent manner. Taken together, these results suggest that IPRN acts as an AhR antagonist and promotes osteoblast differentiation via the AhR/ERα axis.

scholarly journals A novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252233
Author(s):  
Michael I. Dorrell ◽  
Heidi R. Kast-Woelbern ◽  
Ryan T. Botts ◽  
Stephen A. Bravo ◽  
Jacob R. Tremblay ◽  
...  
Keyword(s):  
Side Effects ◽  
Tumor Angiogenesis ◽  
Clinical Success ◽  
Low Cost ◽  
Chorioallantoic Membrane ◽  
Cellular Interactions ◽  
Compensatory Mechanisms ◽  
Chick Chorioallantoic Membrane

Tumor angiogenesis is critical for the growth and progression of cancer. As such, angiostasis is a treatment modality for cancer with potential utility for multiple types of cancer and fewer side effects. However, clinical success of angiostatic monotherapies has been moderate, at best, causing angiostatic treatments to lose their early luster. Previous studies demonstrated compensatory mechanisms that drive tumor vascularization despite the use of angiostatic monotherapies, as well as the potential for combination angiostatic therapies to overcome these compensatory mechanisms. We screened clinically approved angiostatics to identify specific combinations that confer potent inhibition of tumor-induced angiogenesis. We used a novel modification of the ex ovo chick chorioallantoic membrane (CAM) model that combined confocal and automated analyses to quantify tumor angiogenesis induced by glioblastoma tumor onplants. This model is advantageous due to its low cost and moderate throughput capabilities, while maintaining complex in vivo cellular interactions that are difficult to replicate in vitro. After screening multiple combinations, we determined that glioblastoma-induced angiogenesis was significantly reduced using a combination of bevacizumab (Avastin®) and temsirolimus (Torisel®) at doses below those where neither monotherapy demonstrated activity. These preliminary results were verified extensively, with this combination therapy effective even at concentrations further reduced 10-fold with a CI value of 2.42E-5, demonstrating high levels of synergy. Thus, combining bevacizumab and temsirolimus has great potential to increase the efficacy of angiostatic therapy and lower required dosing for improved clinical success and reduced side effects in glioblastoma patients.

scholarly journals Anti-Inflammatory Fibronectin-AgNP for Regulation of Biological Performance and Endothelial Differentiation Ability of Mesenchymal Stem Cells

2021 ◽  
Vol 22 (17) ◽  
pp. 9262
Author(s):  
Huey-Shan Hung ◽  
Kai-Bo Chang ◽  
Cheng-Ming Tang ◽  
Tian-Ren Ku ◽  
Mei-Lang Kung ◽  
...  
Keyword(s):  
Stem Cells ◽  
Immune Response ◽  
Silver Nanoparticles ◽  
Mesenchymal Stem Cells ◽  
Superior Performance ◽  
In Vivo Studies ◽  
Vascular Regeneration ◽  
Anti Inflammatory

The engineering of vascular regeneration still involves barriers that need to be conquered. In the current study, a novel nanocomposite comprising of fibronectin (denoted as FN) and a small amount of silver nanoparticles (AgNP, ~15.1, ~30.2 or ~75.5 ppm) was developed and its biological function and biocompatibility in Wharton’s jelly-derived mesenchymal stem cells (MSCs) and rat models was investigated. The surface morphology as well as chemical composition for pure FN and the FN-AgNP nanocomposites incorporating various amounts of AgNP were firstly characterized by atomic force microscopy (AFM), UV-Visible spectroscopy (UV-Vis), and Fourier-transform infrared spectroscopy (FTIR). Among the nanocomposites, FN-AgNP with 30.2 ppm silver nanoparticles demonstrated the best biocompatibility as assessed through intracellular ROS production, proliferation of MSCs, and monocytes activation. The expression levels of pro-inflammatory cytokines, TNF-α, IL-1β, and IL-6, were also examined. FN-AgNP 30.2 ppm significantly inhibited pro-inflammatory cytokine expression compared to other materials, indicating superior performance of anti-immune response. Mechanistically, FN-AgNP 30.2 ppm significantly induced greater expression of vascular endothelial growth factor (VEGF) and stromal-cell derived factor-1 alpha (SDF-1α) and promoted the migration of MSCs through matrix metalloproteinase (MMP) signaling pathway. Besides, in vitro and in vivo studies indicated that FN-AgNP 30.2 ppm stimulated greater protein expressions of CD31 and von Willebrand Factor (vWF) as well as facilitated better endothelialization capacity than other materials. Furthermore, the histological tissue examination revealed the lowest capsule formation and collagen deposition in rat subcutaneous implantation of FN-AgNP 30.2 ppm. In conclusion, FN-AgNP nanocomposites may facilitate the migration and proliferation of MSCs, induce endothelial cell differentiation, and attenuate immune response. These finding also suggests that FN-AgNP may be a potential anti-inflammatory surface modification strategy for vascular biomaterials.

Angiogenic oligosaccharides of hyaluronan enhance the production of collagens by endothelial cells

1993 ◽  
Vol 105 (1) ◽  
pp. 213-218
Author(s):  
P. Rooney ◽  
M. Wang ◽  
P. Kumar ◽  
S. Kumar
Keyword(s):  
Endothelial Cells ◽  
Polyacrylamide Gel Electrophoresis ◽  
Chorioallantoic Membrane ◽  
Type I ◽  
Aortic Endothelial Cells ◽  
Type Viii ◽  
High Degree ◽  
Bovine Type

The present study demonstrates a relationship between angiogenic oligosaccharides of hyaluronan (HA) and the production of collagens during the process of angiogenesis in vivo and in vitro. The addition of angiogenic oligosaccharides of HA to the chorioallantoic membrane of the chick embryo induced a deposition of collagen fibrils. The treatment of sub-confluent cultures of bovine aortic endothelial cells with the same oligosaccharides (1 microgram/ml) increased the uptake of [3H]proline by approximately 60%. SDS-polyacrylamide gel electrophoresis of treated cultures demonstrated the enhanced synthesis of type I and type VIII collagens. The production of type VIII collagen was confirmed by western blotting and immunocytochemistry using antibodies to sheep and bovine type VIII collagen. Type VIII collagen is a short chain collagen that has a high degree of homology to cartilage-specific type X collagen. The biological functions of type VIII and type X collagens are unknown. We have suggested that the two collagens play a role in the process of angiogenesis.

scholarly journals Recruitment of Immune Effector Cells against Glioblastoma-Multiforme by a MHC-Chlorotoxin Chimeric Protein

2016 ◽  
Vol 43 (S4) ◽  
pp. S1-S1
Author(s):  
O. Cohen-Inbar
Keyword(s):  
Immune Response ◽  
Glioblastoma Multiforme ◽  
Cytotoxic T Cells ◽  
Chimeric Protein ◽  
Human Leukocyte ◽  
In Vivo Studies ◽  
Great Promise ◽  
Single Chain

Glioblastoma Multiforme is the most common malignant primary brain tumor, having a mean overall survival <2 years. The lack of an efficient immune response against the tumor have been attributed to its immunosuppressive capabilities and an immunosuppressing local environment. Aim: We set out to design a chimeric molecule that recognizes and binds tissue inducible metalloproteinase known to be induced in GBM cells (MMP-2) on one end. Its other end, the effector domain, mobilizes and recruits cytotoxic T-cells to mount an effective anti-tumor reaction. Methods: The targeting moiety is the small 36-amino acids Chlorotoxin, derived from the venom of the Israeli Yellow scorpion. The effector end is a single chain HLA-A2 (Human leukocyte antigen subtype A2) covalently bound to phosphoprotein-65 derived from the cytomegalovirus, to which most of the human population has developed a specific immune response. Results: The molecular construct was cloned and expressed in E.coli. The protein product was isolated, purified, and then folded in vitro. Various activity assays employed demonstrated retained activity of each domain, including flow-cytometry, intracellular staining, fluorescence immunohistochemistry, radiolabeled toxicity assays etc. Initial in-vivo studies show great promise. Conclusions: We present a proof of concept study for a new immunotherapy approach to battle GBM. A molecular construct which contains a non-antibody compact and highly specific targeting domain, combined with the ability to recruit anti-CMV T-cell lymphocyte population. The recruitment of potent memory CTL’s to the tumor’s milieu may prove resistant to the previously described local immunosuppressive environment brought about by the tumor.

Cellular and humoral responses to collagen–polyvinylpyrrolidone administered during short and long periods in humans

2003 ◽  
Vol 81 (11) ◽  
pp. 1029-1035 ◽  
Author(s):  
Janette Furuzawa-Carballeda ◽  
Emilio Rojas ◽  
Mahara Valverde ◽  
Irma Castillo ◽  
Lino Diaz de León ◽  
...  
Keyword(s):  
Dna Damage ◽  
Type I Collagen ◽  
Cellular Damage ◽  
In Vivo Studies ◽  
Type I ◽  
Healthy Donors ◽  
Collagen Antibodies ◽  
Humoral Responses

Collagen, particularly type I, and its related derivatives have been extensively employed in many areas of pharmacology. The present study was performed to determine the safety of collagen–polyvinylpyrrolidone (collagen–PVP) by in vitro and in vivo studies. Sera and peripheral blood cells from healthy donors without treatment and patients treated with collagen–PVP were evaluated. We observed that the biodrug does not stimulate lymphoproliferation or DNA damage in vitro, nor does it induce human anti-porcine type I collagen or anti-collagen–PVP antibodies in vivo. Furthermore, no hepatic or renal metabolic dysfunctions were observed when collagen–PVP was administered by intradermal or intramuscular routes in short- or long-term treatments. In conclusion, the present work shows that no cellular damage or immunological adverse effects (cellular and humoral) occurred during collagen–PVP treatment, even after more than 400 weeks of consecutive administrations.Key words: collagen–polyvinylpyrrolidone, DNA damage, collagen antibodies, hypertrophic scar.

A novel nano-structured porous polycaprolactone scaffold improves hyaline cartilage repair in a rabbit model compared to a collagen type I/III scaffold: in vitro and in vivo studies

2011 ◽  
Vol 20 (6) ◽  
pp. 1192-1204 ◽  
Author(s):  
Bjørn Borsøe Christensen ◽  
Casper Bindzus Foldager ◽  
Ole Møller Hansen ◽  
Asger Albæk Kristiansen ◽  
Dang Quang Svend Le ◽  
...  
Keyword(s):  
Cartilage Repair ◽  
Collagen Type ◽  
Hyaline Cartilage ◽  
Rabbit Model ◽  
Collagen Type I ◽  
In Vivo Studies ◽  
Type I

scholarly journals Engineering the indigoidine-synthesising enzyme BpsA for diverse applications in biotechnology

2021 ◽  
Author(s):  
◽  
Alistair Brown
Keyword(s):  
Substrate Specificity ◽  
Culture Media ◽  
Protein Domain ◽  
In Vivo Studies ◽  
Blue Pigment ◽  
Carrier Protein ◽  
Type I ◽  
Phosphopantetheinyl Transferase

<p>Non-ribosomal peptide synthetases (NRPSs) are large, modular enzymes that synthesise bioactive peptides using an assembly line architecture, wherein each module is responsible for the incorporation of a monomer into the growing chain. Present in both fungi and bacteria, NRPSs are responsible for a wide variety of secondary metabolites and bioactive compounds including siderophores, antibiotics, anti-cancer compounds and immunosuppressants. For functionality, NRPSs require the attachment of a phosphopantetheine moiety to their peptidyl carrier protein domains. This reaction is catalysed by a phosphopantetheinyl transferase (PPTase).  The NRPS blue pigment synthetase A (BpsA) is unusual in that it is comprised of only a single module. BpsA contains an adenylation domain that recognises and sequentially binds two molecules of L-glutamine, an oxidation domain that is believed to oxidise each glutamine monomer, a peptidyl carrier protein domain that binds the phosphopantetheine moiety, and a thioesterase domain that cyclises each glutamine and releases the final bicyclic product from the enzyme. This final product is a blue pigment called indigoidine, and its synthesis from two molecules of L-glutamine is powered by ATP. Comparatively to other NRPSs BpsA is easy to manipulate and work with both in vitro and in vivo. Here, the ability to easily detect synthesis of indigoidine was utilised to provide a versatile reporter to detect a variety of biochemical activities.  PPTases are essential enzymes that are promising drug targets in the clinically important bacteria Pseudomonas aeruginosa and Mycobacterium tuberculosis. BpsA can be purified in the inactive apo form, which then requires a PPTase to activate it to enable indigoidine synthesis. Here it was shown that mixing BpsA, a PPTase, the enzymatic substrates, and a potential inhibitor enables screening for PPTase inhibition by monitoring the rate or extent of indigoidine synthesis. This method was optimised and used to screen commercial drug libraries against two PPTases, PcpS from P. aeruginosa and PptT from M. tuberculosis. Several novel inhibitors were identified and pilot in vivo studies were performed. M. tuberculosis also possesses a second essential PPTase called TB-AcpS, which has very narrow substrate specificity and cannot post-translationally modify BpsA. In an attempt to widen the substrate specificity a combination of rational engineering and directed evolution was employed. These attempts did not yield significant improvements in the ability of TB-AcpS to activate modified BpsA, however they did yield mutants that were more effective substrates for other type I PPTases.  The easily detectable nature of indigoidine also enabled application of BpsA as a reporter for a range of different substrates. Particularly effective was development of a commercially applicable method using BpsA to quantify L-glutamine in a range of conditions, including cell culture media and blood. The assay developed offers several advantages over currently available kits. BpsA was also used to detect and quantify ATP, and this was applied to monitor adenylation reactions. Finally, the ability of BpsA to synthesise indigoidine-like compounds from glutamine analogues was explored.</p>

scholarly journals Complex Regional Pain Syndrome Type I, a Debilitating and Poorly Understood Syndrome. Possible Role for Pulsed Electromagnetic Fields: A Narrative Review

2017 ◽  
Vol 6 (20;6) ◽  
pp. E807-E822 ◽  
Author(s):  
Francesca Veronesi
Keyword(s):  
Inflammatory Cytokines ◽  
Pain Syndrome ◽  
In Vitro Studies ◽  
In Vivo Studies ◽  
Type I ◽  
Pulsed Electromagnetic Fields ◽  
Syndrome Type ◽  
Pulsed Electromagnetic

Background: Complex regional pain syndrome type I (CRPS-I), also called algodystrophy, is a complex syndrome characterized by limb pain, edema, allodynia, hyperalgesia and functional impairment of bone with a similar clinical picture of osteoporosis, including an increased release of various pro-inflammatory neuropeptides and cytokines. Several treatments have been proposed for CRPS-I, but due to the poor outcome of conventional drugs and the invasiveness of some techniques, expectations are now directed towards new resources that could be more effective and less invasive. Objective: In the light of preclinical evidence, which underlined pulsed electromagnetic fields’ (PEMFs) properties on osteoblasts (OBs), osteoclasts (OCs), and pathologies with an inflammatory profile, the present review aims to investigate whether there is a rationale for the use of PEMFs, as a combined approach, in CRPS-I. Study Design: This review analyzed the 44 in vitro and in vivo studies published in the last decade that focused on 2 main aspects of CRPS-I: local osteoporosis (OP) and inflammation. Setting: Not applicable. Methods: This review includes in vitro and in vivo studies found with a PubMed and Web of Knowledge database search by 2 independent authors. The limits of the search were the publication date between January 1, 2006, and January 1, 2016, and English language. In detail, the search strategy was based on: 1) CRPS-I or algodystrophy; 2) OP, OCs, and OBs; and 3) inflammatory aspects. Results: The included studies looked at the relationship between PEMFs and OCs (2 in vitro studies), osteoporotic animal models (8 in vivo studies), OBs (20 in vitro studies), inflammatory cytokines, and reactive oxygen species. They also tried to define the molecular cell pathways involved (5 in vivo and 9 in vitro studies on inflammatory models). It was observed that PEMFs increased OC apoptosis, OB viability, bone protein and matrix calcification, antioxidant protein, and the levels of adenosine receptors, while it decreased the levels of pro-inflammatory cytokines. Limitations: Data from clinical trials are scarce; moreover, experimental conditions and PEMF parameters are not standardized. Conclusions: The present review underlined the rationale for the use of PEMFs in the complex contest of CRPS-I syndrome, in combination with conventional drugs.

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