scholarly journals LncEGFL7OS regulates human angiogenesis by interacting with MAX at the EGFL7/miR-126 locus

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Qinbo Zhou ◽  
Bo Yu ◽  
Chastain Anderson ◽  
Zhan-Peng Huang ◽  
Jakub Hanus ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Ex Vivo ◽  
Bidirectional Promoter ◽  
Interacting Protein ◽  
Sprouting Angiogenesis ◽  
Pathway Activation ◽  
Opposite Strand ◽  
Ets Factors

In an effort to identify human endothelial cell (EC)-enriched lncRNAs,~500 lncRNAs were shown to be highly restricted in primary human ECs. Among them, lncEGFL7OS, located in the opposite strand of the EGFL7/miR-126 gene, is regulated by ETS factors through a bidirectional promoter in ECs. It is enriched in highly vascularized human tissues, and upregulated in the hearts of dilated cardiomyopathy patients. LncEGFL7OS silencing impairs angiogenesis as shown by EC/fibroblast co-culture, in vitro/in vivo and ex vivo human choroid sprouting angiogenesis assays, while lncEGFL7OS overexpression has the opposite function. Mechanistically, lncEGFL7OS is required for MAPK and AKT pathway activation by regulating EGFL7/miR-126 expression. MAX protein was identified as a lncEGFL7OS-interacting protein that functions to regulate histone acetylation in the EGFL7/miR-126 promoter/enhancer. CRISPR-mediated targeting of EGLF7/miR-126/lncEGFL7OS locus inhibits angiogenesis, inciting therapeutic potential of targeting this locus. Our study establishes lncEGFL7OS as a human/primate-specific EC-restricted lncRNA critical for human angiogenesis.

Abstract 23: Microrna302-367 Sphingosine 1 Phosphate Receptor 1 Pathway Prevents Tumor Growth via Restricting Angiogenesis and Enhancing Vascular Stability

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Jinjiang Pi ◽  
Ting Tao ◽  
Tao Zhuang ◽  
Huimin Sun ◽  
Xiaoli Chen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Growth ◽  
Ex Vivo ◽  
Downstream Target ◽  
Sprouting Angiogenesis ◽  
Pathological Angiogenesis ◽  
Vascular Stability ◽  
Sphingosine 1 Phosphate

Angiogenic hypersprouting and leaky immature vessels of pathological angiogenesis are essential for tumor growth. MicroRNAs have unique therapeutic advantages by targeting multiple pathways of tumor-associated angiogenesis, but the function of individual miRNAs in angiogenesis and tumors has not yet been fully evaluated. Here, we show that miR302-367 elevation in endothelial cells reduces retina sprouting angiogenesis and promotes vascular stability in vivo, ex vivo and in vitro. Erk1/2 are identified as direct targets of miR302-367, and down-regulation of Erk1/2 upon miR302-367 elevation in endothelial cells increases the expression of Klf2 and in turn S1pr1 and its downstream target VE-cadherin, suppressing angiogenesis and improving vascular stability. Conversely, both pharmacological blockade and genetic deletion of S1pr1 in endothelial cells reverse the anti-angiogenic and vascular stabilizing effect of miR302-367 in mice. Pathological angiogenesis in tumors shares features of developmental angiogenesis, and endothelial specific elevation of miR302-367 reduces tumor growth by restricting sprout angiogenesis and decreasing vascular permeability via the same Erk1/2-Klf2-S1pr1 pathways. In conclusion, miR302-367 regulation of an Erk1/2-Klf2-S1pr1 pathway in the endothelium advances our understanding of angiogenesis, meanwhile also provides opportunities for therapeutic intervention of tumor growth.

scholarly journals Lasia spinosa Chemical Composition and Therapeutic Potential: A Literature-Based Review

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Rajib Hossain ◽  
Cristina Quispe ◽  
Jesús Herrera-Bravo ◽  
Md. Shahazul Islam ◽  
Chandan Sarkar ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Human Subjects ◽  
Uterine Cancer ◽  
Safety Data ◽  
Volatile Oil ◽  
Stomach Pain

Lasia spinosa (L.) is used ethnobotanically for the treatment of various diseases, including rheumatoid arthritis, inflammation of the lungs, bleeding cough, hemorrhoids, intestinal diseases, stomach pain, and uterine cancer. This review is aimed at summarizing phytochemistry and pharmacological data with their molecular mechanisms of action. A search was performed in databases such as PubMed, Science Direct, and Google Scholar using the keywords: “Lasia spinosa,” then combined with “ethnopharmacological use,” “phytochemistry,” and “pharmacological activity.” This updated review included studies with in vitro, ex vivo, and in vivo experiments with compounds of known concentration and highlighted pharmacological mechanisms. The research results showed that L. spinosa contains many important nutritional and phytochemical components such as alkanes, aldehydes, alkaloids, carotenoids, flavonoids, fatty acids, ketones, lignans, phenolics, terpenoids, steroids, and volatile oil with excellent bioactivity. The importance of this review lies in the fact that scientific pharmacological evidence supports the fact that the plant has antioxidant, anti-inflammatory, antimicrobial, cytotoxic, antidiarrheal, antihelminthic, antidiabetic, antihyperlipidemic, and antinociceptive effects, while protecting the gastrointestinal system and reproductive. Regarding future toxicological and safety data, more research is needed, including studies on human subjects. In light of these data, L. spinosa can be considered a medicinal plant with effective bioactives for the adjuvant treatment of various diseases in humans.

scholarly journals Nanocurcumin-Loaded UCNPs for Cancer Theranostics: Physicochemical Properties, In Vitro Toxicity, and In Vivo Imaging Studies

Nanomaterials ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 2234
Author(s):  
Anbharasi Lakshmanan ◽  
Roman A. Akasov ◽  
Natalya V. Sholina ◽  
Polina A. Demina ◽  
Alla N. Generalova ◽  
...  
Keyword(s):  
Near Infrared ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Laboratory Animals ◽  
In Vitro Toxicity ◽  
Upconversion Nanoparticles ◽  
Lewis Lung Cancer ◽  
Spectral Bands

Formulation of promising anticancer herbal drug curcumin as a nanoscale-sized curcumin (nanocurcumin) improved its delivery to cells and organisms both in vitro and in vivo. We report on coupling nanocurcumin with upconversion nanoparticles (UCNPs) using Poly (lactic-co-glycolic Acid) (PLGA) to endow visualisation in the near-infrared transparency window. Nanocurcumin was prepared by solvent-antisolvent method. NaYF4:Yb,Er (UCNP1) and NaYF4:Yb,Tm (UCNP2) nanoparticles were synthesised by reverse microemulsion method and then functionalized it with PLGA to form UCNP-PLGA nanocarrier followed up by loading with the solvent-antisolvent process synthesized herbal nanocurcumin. The UCNP samples were extensively characterised with XRD, Raman, FTIR, DSC, TGA, UV-VIS-NIR spectrophotometer, Upconversion spectrofluorometer, HRSEM, EDAX and Zeta Potential analyses. UCNP1-PLGA-nanocurcumin exhibited emission at 520, 540, 660 nm and UCNP2-PLGA-nanocurmin showed emission at 480 and 800 nm spectral bands. UCNP-PLGA-nanocurcumin incubated with rat glioblastoma cells demonstrated moderate cytotoxicity, 60–80% cell viability at 0.12–0.02 mg/mL marginally suitable for therapeutic applications. The cytotoxicity of UCNPs evaluated in tumour spheroids models confirmed UCNP-PLGA-nanocurcumin therapeutic potential. As-synthesised curcumin-loaded nanocomplexes were administered in tumour-bearing laboratory animals (Lewis lung cancer model) and showed adequate contrast to enable in vivo and ex vivo study of UCNP-PLGA-nanocurcumin bio distribution in organs, with dominant distribution in the liver and lungs. Our studies demonstrate promise of nanocurcumin-loaded upconversion nanoparticles for theranostics applications.

scholarly journals The Potential of CRISPR/Cas9 Gene Editing as a Treatment Strategy for Inherited Diseases

2021 ◽  
Vol 9 ◽  
Author(s):  
Sameh A. Abdelnour ◽  
Long Xie ◽  
Abdallah A. Hassanin ◽  
Erwei Zuo ◽  
Yangqing Lu
Keyword(s):  
Therapeutic Potential ◽  
Ex Vivo ◽  
Genetic Diseases ◽  
Patient Specific ◽  
Innovative Technology ◽  
Rna Molecules ◽  
Inherited Diseases ◽  
Genomic Editing

Clustered regularly interspaced short palindromic repeats (CRISPR) is a promising innovative technology for genomic editing that offers scientists the chance to edit DNA structures and change gene function. It has several possible uses consisting of editing inherited deficiencies, treating, and reducing the spread of disorders. Recently, reports have demonstrated the creation of synthetic RNA molecules and supplying them alongside Cas9 into genome of eukaryotes, since distinct specific regions of the genome can be manipulated and targeted. The therapeutic potential of CRISPR/Cas9 technology is great, especially in gene therapy, in which a patient-specific mutation is genetically edited, or in the treating of human disorders that are untreatable with traditional treatments. This review focused on numerous, in vivo, in vitro, and ex vivo uses of the CRISPR/Cas9 technology in human inherited diseases, discovering the capability of this versatile in medicine and examining some of the main limitations for its upcoming use in patients. In addition to introducing a brief impression of the biology of the CRISPR/Cas9 scheme and its mechanisms, we presented the utmost recent progress in the uses of CRISPR/Cas9 technology in editing and treating of human genetic diseases.

scholarly journals Targeted photodynamic therapy selectively kills activated fibroblasts in experimental arthritis

Rheumatology ◽  
2020 ◽  
Vol 59 (12) ◽  
pp. 3952-3960 ◽  
Author(s):  
Daphne N Dorst ◽  
Mark Rijpkema ◽  
Marti Boss ◽  
Birgitte Walgreen ◽  
Monique M A Helsen ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Synovial Fibroblasts ◽  
Knee Joints ◽  
Specific Cell ◽  
Collagen Induced Arthritis ◽  
Targeted Photodynamic Therapy

Abstract Objective In RA, synovial fibroblasts become activated. These cells express fibroblast activation protein (FAP) and contribute to the pathogenesis by producing cytokines, chemokines and proteases. Selective depletion in inflamed joints could therefore constitute a viable treatment option. To this end, we developed and tested a new therapeutic strategy based on the selective destruction of FAP-positive cells by targeted photodynamic therapy (tPDT) using the anti-FAP antibody 28H1 coupled to the photosensitizer IRDye700DX. Methods After conjugation of IRDye700DX to 28H1, the immunoreactive binding and specificity of the conjugate were determined. Subsequently, tPDT efficiency was established in vitro using a 3T3 cell line stably transfected with FAP. The biodistribution of [111In]In-DTPA-28H1 with and without IRDye700DX was assessed in healthy C57BL/6N mice and in C57BL/6N mice with antigen-induced arthritis. The potential of FAP-tPDT to induce targeted damage was determined ex vivo by treating knee joints from C57BL/6N mice with antigen-induced arthritis 24 h after injection of the conjugate. Finally, the effect of FAP-tPDT on arthritis development was determined in mice with collagen-induced arthritis. Results 28H1-700DX was able to efficiently induce FAP-specific cell death in vitro. Accumulation of the anti-FAP antibody in arthritic knee joints was not affected by conjugation with the photosensitizer. Arthritis development was moderately delayed in mice with collagen-induced arthritis after FAP-tPDT. Conclusion Here we demonstrate the feasibility of tPDT to selectively target and kill FAP-positive fibroblasts in vitro and modulate arthritis in vivo using a mouse model of RA. This approach may have therapeutic potential in (refractory) arthritis.

FTY720 Abrogates the Therapeutic Potential of Adoptively Transferred Treg Via Inhibition of IL-2 Induced in Vivo Expansion

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2584-2584
Author(s):  
Anna Maria Wolf ◽  
Kathrin Hochegger ◽  
Robert Zeiser ◽  
Christoph Duerr ◽  
Michael Sixt ◽  
...  
Keyword(s):  
T Cells ◽  
Adoptive Transfer ◽  
Chemokine Receptors ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Effective Means ◽  
Effector T Cells ◽  
Target Tissue

Abstract CD4+CD25+ T cells (Treg) entry into secondary lymphoid organs (SLO) and local expansion after activation is at least in part responsible for their immunosuppressive action. Thus we hypothesized that trapping of adoptively transferred Treg in SLO would be an effective means to tip the balance towards a more immunosuppressive milieu within the LN microenvironment. Systemic application of the sphingosine-phosphate receptor agonist FTY720 has been proven to trap harmful effector T cells in SLO, thereby inhibiting their migration and destruction of target tissue. Here we provide first evidence that selective entrapment of adoptively transferred Treg in inflammatory LN can be achieved by blockade of SP-receptors upon ex vivo exposure of Treg to FTY720 before adoptive transfer. FTY720 exposure did not interfere with proper Treg localization within the T-cell areas of SLO as determined by immunofluorescent microscopy after co-transfer of either FTY720- or solvent exposed and subsequently differentially labelled Treg. However, despite the fact that the in vitro phenotype (including expression of adhesion and chemokine receptors), function (including anergy and suppressive activity) and survival (determined by Annexin/PI staining) of Treg remained unaltered by FTY720, it abrogated their protective effect after adoptive transfer in a murine model of acute experimental glomerulonephritis (determined by quantification of proteinuria and histological analysis) as well as in an acute GvHD model (determined by survival analysis and quantification of the in vivo expansion of luciferase-transgenic effector T cells by bioluminiscence technology). Notably, adoptive transfer of CFSE-labelled Treg revealed a markedly impaired proliferation of Treg in inflammatory SLO when pre-exposed to FTY720 ex vivo. Accordingly, FTY720 blocked Treg-proliferation induced by TCR-stimulation in combination with IL-2 in vitro. In line with this observation, FTY720 completely abolishes IL-2 induced phosphorylation of STAT-5. Thus, SP-1P receptors induce Treg trapping in inflammatory SLO but abrogate their in vivo immunosuppressive potential by inhibition of local Treg expansion.

scholarly journals Unraveling Natural Products’ Role in Osteoarthritis Management—An Overview

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 348 ◽  
Author(s):  
Georgia-Eirini Deligiannidou ◽  
Rafail-Efraim Papadopoulos ◽  
Christos Kontogiorgis ◽  
Anastasia Detsi ◽  
Eugenia Bezirtzoglou ◽  
...  
Keyword(s):  
Natural Products ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Meta Analysis ◽  
Term Treatment ◽  
Naturally Occurring ◽  
Long Term Treatment ◽  
Living Organisms

The natural process of aging gradually causes changes in living organisms, leading to the deterioration of organs, tissues, and cells. In the case of osteoarthritis (OA), the degradation of cartilage is a result of both mechanical stress and biochemical factors. Natural products have already been evaluated for their potential role in the prevention and treatment of OA, providing a safe and effective adjunctive therapeutic approach. This review aimed to assess the therapeutic potential of natural products and their derivatives in osteoarthritis via a systematic search of literature after 2008, including in vitro, in vivo, ex vivo, and animal models, along with clinical trials and meta-analysis. Overall, 170 papers were obtained and screened. Here, we presented findings referring to the preventative and therapeutic potential of 17 natural products and 14 naturally occurring compounds, underlining, when available, the mechanisms implicated. The nature of OA calls to initially focus on the management of symptoms, and, in that context, several naturally occurring compounds have been utilized. Underlying a global need for more sustainable natural sources for treatment, the evidence supporting their chondroprotective potential is still building up. However, arriving at that kind of solution requires more clinical research, targeting the implications of long-term treatment, adverse effects, and epigenetic implications.

scholarly journals mRNA in cancer immunotherapy: beyond a source of antigen

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Lien Van Hoecke ◽  
Rein Verbeke ◽  
Heleen Dewitte ◽  
Ine Lentacker ◽  
Karim Vermaelen ◽  
...  
Keyword(s):  
High Speed ◽  
Tumor Antigens ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Pharmaceutical Formulations ◽  
Building Blocks ◽  
Molecular Medicine ◽  
Medicine Research

AbstractmRNA therapeutics have become the focus of molecular medicine research. Various mRNA applications have reached major milestones at high speed in the immuno-oncology field. This can be attributed to the knowledge that mRNA is one of nature’s core building blocks carrying important information and can be considered as a powerful vector for delivery of therapeutic proteins to the patient.For a long time, the major focus in the use of in vitro transcribed mRNA was on development of cancer vaccines, using mRNA encoding tumor antigens to modify dendritic cells ex vivo. However, the versatility of mRNA and its many advantages have paved the path beyond this application. In addition, due to smart design of both the structural properties of the mRNA molecule as well as pharmaceutical formulations that improve its in vivo stability and selective targeting, the therapeutic potential of mRNA can be considered as endless.As a consequence, many novel immunotherapeutic strategies focus on the use of mRNA beyond its use as the source of tumor antigens. This review aims to summarize the state-of-the-art on these applications and to provide a rationale for their clinical application.

scholarly journals Target-Based Small Molecule Drug Discovery Towards Novel Therapeutics for Inflammatory Bowel Diseases

2021 ◽  
Vol 27 (Supplement_2) ◽  
pp. S38-S62 ◽  
Author(s):  
Yi Li ◽  
Jianping Chen ◽  
Andrew A Bolinger ◽  
Haiying Chen ◽  
Zhiqing Liu ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Therapeutic Potential ◽  
Biological Response ◽  
Mucosal Inflammation ◽  
Interacting Protein ◽  
Iκb Kinase ◽  
Tnf Α ◽  
Inflammatory Bowel

Abstract Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a class of severe and chronic diseases of the gastrointestinal (GI) tract with recurrent symptoms and significant morbidity. Long-term persistence of chronic inflammation in IBD is a major contributing factor to neoplastic transformation and the development of colitis-associated colorectal cancer. Conversely, persistence of transmural inflammation in CD is associated with formation of fibrosing strictures, resulting in substantial morbidity. The recent introduction of biological response modifiers as IBD therapies, such as antibodies neutralizing tumor necrosis factor (TNF)-α, have replaced nonselective anti-inflammatory corticosteroids in disease management. However, a large proportion (~40%) of patients with the treatment of anti-TNF-α antibodies are discontinued or withdrawn from therapy because of (1) primary nonresponse, (2) secondary loss of response, (3) opportunistic infection, or (4) onset of cancer. Therefore, the development of novel and effective therapeutics targeting specific signaling pathways in the pathogenesis of IBD is urgently needed. In this comprehensive review, we summarize the recent advances in drug discovery of new small molecules in preclinical or clinical development for treating IBD that target biologically relevant pathways in mucosal inflammation. These include intracellular enzymes (Janus kinases, receptor interacting protein, phosphodiesterase 4, IκB kinase), integrins, G protein-coupled receptors (S1P, CCR9, CXCR4, CB2) and inflammasome mediators (NLRP3), etc. We will also discuss emerging evidence of a distinct mechanism of action, bromodomain-containing protein 4, an epigenetic regulator of pathways involved in the activation, communication, and trafficking of immune cells. We highlight their chemotypes, mode of actions, structure-activity relationships, characterizations, and their in vitro/in vivo activities and therapeutic potential. The perspectives on the relevant challenges, new opportunities, and future directions in this field are also discussed.

scholarly journals Increased Mesenchymal Stem Cell Functionalization in Three-Dimensional Manufacturing Settings for Enhanced Therapeutic Applications

2021 ◽  
Vol 9 ◽  
Author(s):  
Dimitrios Kouroupis ◽  
Diego Correa
Keyword(s):  
Therapeutic Potential ◽  
Ex Vivo ◽  
Three Dimensional ◽  
Therapeutic Applications ◽  
Cell Based Therapy ◽  
Donor Variability ◽  
Healing Bone ◽  
Preclinical Animal Models

Mesenchymal stem/stromal cell (MSC) exist within their in vivo niches as part of heterogeneous cell populations, exhibiting variable stemness potential and supportive functionalities. Conventional extensive 2D in vitro MSC expansion, aimed at obtaining clinically relevant therapeutic cell numbers, results in detrimental effects on both cellular characteristics (e.g., phenotypic changes and senescence) and functions (e.g., differentiation capacity and immunomodulatory effects). These deleterious effects, added to the inherent inter-donor variability, negatively affect the standardization and reproducibility of MSC therapeutic potential. The resulting manufacturing challenges that drive the qualitative variability of MSC-based products is evident in various clinical trials where MSC therapeutic efficacy is moderate or, in some cases, totally insufficient. To circumvent these limitations, various in vitro/ex vivo techniques have been applied to manufacturing protocols to induce specific features, attributes, and functions in expanding cells. Exposure to inflammatory cues (cell priming) is one of them, however, with untoward effects such as transient expression of HLA-DR preventing allogeneic therapeutic schemes. MSC functionalization can be also achieved by in vitro 3D culturing techniques, in an effort to more closely recapitulate the in vivo MSC niche. The resulting spheroid structures provide spatial cell organization with increased cell–cell interactions, stable, or even enhanced phenotypic profiles, and increased trophic and immunomodulatory functionalities. In that context, MSC 3D spheroids have shown enhanced “medicinal signaling” activities and increased homing and survival capacities upon transplantation in vivo. Importantly, MSC spheroids have been applied in various preclinical animal models including wound healing, bone and osteochondral defects, and cardiovascular diseases showing safety and efficacy in vivo. Therefore, the incorporation of 3D MSC culturing approach into cell-based therapy would significantly impact the field, as more reproducible clinical outcomes may be achieved without requiring ex vivo stimulatory regimes. In the present review, we discuss the MSC functionalization in 3D settings and how this strategy can contribute to an improved MSC-based product for safer and more effective therapeutic applications.

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