Polyanions in Coagulation and Thrombosis: Focus on Polyphosphate and NETs

Neutrophils extracellular traps (NETs) and polyphosphates (polyP) have been recognized as procoagulant polyanions. The review summarizes the activities and regulation of two procoagulant mediators and compares their functions. NETs are composed of DNA and share a phosphate backbone with polyP that is built of phosphate units linked by high energy phospho-anhydride bonds. Both NETs and polyP form insoluble particulate surfaces composed of a DNA/histone meshwork or Ca2+-rich nanoparticles, respectively. The polyanions modulate coagulation involving an array of mechanisms and trigger thrombosis via activation of the factor XII (FXII)-driven procoagulant and proinflammatory contact pathway. This review outlines the current knowledge on NETs and polyP with respect to their procoagulant and prothrombotic nature, strategies for interference of their activities in circulation, as well as the crosstalk between these two molecules. A better understanding of these underlying, cellular mechanisms will shed light on the therapeutic potential of targeting NETs and polyP in coagulation and thrombosis.

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Mesenchymal Stem Cell: A Friend or Foe in Anti-Tumor Immunity

International Journal of Molecular Sciences ◽

10.3390/ijms222212429 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12429

Author(s):

Carl Randall Harrell ◽

Ana Volarevic ◽

Valentin G. Djonov ◽

Nemanja Jovicic ◽

Vladislav Volarevic

Keyword(s):

Stem Cells ◽

Tumor Microenvironment ◽

Tumor Cells ◽

Tumor Immunity ◽

Immune Cells ◽

Therapeutic Potential ◽

Current Knowledge ◽

Cellular Mechanisms ◽

Multipotent Stem Cells ◽

And Function

Mesenchymal stem cells (MSCs) are self-renewable, multipotent stem cells that regulate the phenotype and function of all immune cells that participate in anti-tumor immunity. MSCs modulate the antigen-presenting properties of dendritic cells, affect chemokine and cytokine production in macrophages and CD4+ T helper cells, alter the cytotoxicity of CD8+ T lymphocytes and natural killer cells and regulate the generation and expansion of myeloid-derived suppressor cells and T regulatory cells. As plastic cells, MSCs adopt their phenotype and function according to the cytokine profile of neighboring tumor-infiltrated immune cells. Depending on the tumor microenvironment to which they are exposed, MSCs may obtain pro- and anti-tumorigenic phenotypes and may enhance or suppress tumor growth. Due to their tumor-homing properties, MSCs and their exosomes may be used as vehicles for delivering anti-tumorigenic agents in tumor cells, attenuating their viability and invasive characteristics. Since many factors affect the phenotype and function of MSCs in the tumor microenvironment, a better understanding of signaling pathways that regulate the cross-talk between MSCs, immune cells and tumor cells will pave the way for the clinical use of MSCs in cancer immunotherapy. In this review article, we summarize current knowledge on the molecular and cellular mechanisms that are responsible for the MSC-dependent modulation of the anti-tumor immune response and we discuss different insights regarding therapeutic potential of MSCs in the therapy of malignant diseases.

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Therapeutic Potential of Mesenchymal Stem Cells and Their Secretome in the Treatment of Glaucoma

Stem Cells International ◽

10.1155/2019/7869130 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

C. Randall Harrell ◽

Crissy Fellabaum ◽

Aleksandar Arsenijevic ◽

Bojana Simovic Markovic ◽

Valentin Djonov ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Visual Information ◽

Therapeutic Potential ◽

Current Knowledge ◽

Therapeutic Agents ◽

Dependent Manner ◽

Cellular Mechanisms ◽

Cell Based Therapy ◽

Glaucoma Treatment

Glaucoma represents a group of progressive optic neuropathies characterized by gradual loss of retinal ganglion cells (RGCs), the neurons that conduct visual information from the retina to the brain. Elevated intraocular pressure (IOP) is considered the main reason for enhanced apoptosis of RGCs in glaucoma. Currently used therapeutic agents are not able to repopulate and/or regenerate injured RGCs and, therefore, are ineffective in most patients with advanced glaucoma. Accordingly, several new therapeutic approaches, including stem cell-based therapy, have been explored for the glaucoma treatment. In this review article, we emphasized current knowledge regarding molecular and cellular mechanisms responsible for beneficial effects of mesenchymal stem cells (MSCs) and their secretome in the treatment of glaucoma. MSCs produce neurotrophins and in an exosome-dependent manner supply injured RGCs with growth factors enhancing their survival and regeneration. Additionally, MSCs are able to generate functional RGC-like cells and induce proliferation of retinal stem cells. By supporting integrity of trabecular meshwork, transplanted MSCs alleviate IOP resulting in reduced loss of RGCs. Moreover, MSCs are able to attenuate T cell-driven retinal inflammation providing protection to the injured retinal tissue. In summing up, due to their capacity for neuroprotection and immunomodulation, MSCs and their secretome could be explored in upcoming clinical studies as new therapeutic agents for glaucoma treatment.

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Mesenchymal Stem Cell-Derived Exosomes as New Remedy for the Treatment of Neurocognitive Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms22031433 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1433

Author(s):

Carl Randall Harrell ◽

Ana Volarevic ◽

Valentin Djonov ◽

Vladislav Volarevic

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Therapeutic Potential ◽

Current Knowledge ◽

Experimental Studies ◽

Neurocognitive Disorders ◽

Neural Cells ◽

Cellular Mechanisms ◽

Neural Growth ◽

Neuro Inflammation

Mesenchymal stem cell (MSC)-derived exosomes (MSC-Exo) are nano-sized extracellular vesicles enriched with MSC-sourced neuroprotective and immunomodulatory microRNAs, neural growth factors, and anti-inflammatory cytokines, which attenuate neuro-inflammation, promote neo-vascularization, induce neurogenesis, and reduce apoptotic loss of neural cells. Accordingly, a large number of experimental studies demonstrated MSC-Exo-dependent improvement of cognitive impairment in experimental animals. In this review article, we summarized current knowledge about molecular and cellular mechanisms that were responsible for MSC-Exo-based restoration of cognitive function, emphasizing therapeutic potential of MSC-Exos in the treatment of neurocognitive disorders.

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The Potential of Milk-derived Exosomes for Drug Delivery

Current Drug Delivery ◽

10.2174/1567201817666200817112503 ◽

2020 ◽

Vol 17 ◽

Author(s):

Shuyuan Li ◽

Yue Tang ◽

Yushun Dou

Keyword(s):

Drug Delivery ◽

Oral Delivery ◽

Therapeutic Potential ◽

Current Knowledge ◽

Biological Fluids ◽

Drug Loading ◽

Drug Carriers ◽

Current Application ◽

Therapeutic Benefits ◽

Loading Methods

Background: Exosomes, one of the extracellular vesicles, are widely present in all biological fluids and play an important role in intercellular communication. Because of its hydrophobic lipid bilayer and aqueous hydrophilic core structure, it is considered a possible alternative to liposome drug delivery systems. Not only do they protect the cargo like liposomes during delivery, they are less toxic and better tolerated. However, due to the lack of sources and methods for obtaining enough exosomes, the therapeutic application of exosomes as drug carriers is limited. Methods: A literature search was performed using the ScienceDirect and PubMed electronic databases to obtain information from published literature on milk exosomes related to drug delivery. Results: Here, we briefly reviewed the current knowledge of exosomes, expounded the advantages of milk-derived exosomes over other delivery vectors, including a higher yield, the oral delivery characteristic and additional therapeutic benefits. The purification and drug loading methods of milk exosomes, and the current application of milk exosomes were also introduced. Conclusion: The emergence of milk-derived exosomes is expected to break through the limitations of exosomes as therapeutic carriers of drugs. We hope to raise awareness of the therapeutic potential of milk-derived exosomes as a new drug delivery system.

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Bone morphogenetic proteins, breast cancer, and bone metastases: striking the right balance

Endocrine Related Cancer ◽

10.1530/erc-17-0139 ◽

2017 ◽

Vol 24 (10) ◽

pp. R349-R366 ◽

Cited By ~ 19

Author(s):

Catherine Zabkiewicz ◽

Jeyna Resaul ◽

Rachel Hargest ◽

Wen Guo Jiang ◽

Lin Ye

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Bone Morphogenetic Proteins ◽

Therapeutic Potential ◽

Current Knowledge ◽

Breast Tumour ◽

Cellular Functions ◽

Foetal Development ◽

Key Factor ◽

The Right

Bone morphogenetic proteins (BMPs) belong to the TGF-β super family, and are essential for the regulation of foetal development, tissue differentiation and homeostasis and a multitude of cellular functions. Naturally, this has led to the exploration of aberrance in this highly regulated system as a key factor in tumourigenesis. Originally identified for their role in osteogenesis and bone turnover, attention has been turned to the potential role of BMPs in tumour metastases to, and progression within, the bone niche. This is particularly pertinent to breast cancer, which commonly metastasises to bone, and in which studies have revealed aberrations of both BMP expression and signalling, which correlate clinically with breast cancer progression. Ultimately a BMP profile could provide new prognostic disease markers. As the evidence suggests a role for BMPs in regulating breast tumour cellular function, in particular interactions with tumour stroma and the bone metastatic microenvironment, there may be novel therapeutic potential in targeting BMP signalling in breast cancer. This review provides an update on the current knowledge of BMP abnormalities and their implication in the development and progression of breast cancer, particularly in the disease-specific bone metastasis.

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New agents for thromboprotection

Hämostaseologie ◽

10.5482/hamo-14-11-0060 ◽

2015 ◽

Vol 35 (04) ◽

pp. 338-350 ◽

Cited By ~ 5

Author(s):

L. Labberton ◽

E. Kenne ◽

T. Renné

Keyword(s):

Current Knowledge ◽

Thrombus Formation ◽

Coagulation Cascade ◽

Factor Xii ◽

Bleeding Tendency ◽

New Agents ◽

Mechanistic Basis ◽

Normal Hemostasis ◽

Coagulation Pathway

SummaryBlood coagulation is essential for hemostasis, however excessive coagulation can lead to thrombosis. Factor XII starts the intrinsic coagulation pathway and contact-induced factor XII activation provides the mechanistic basis for the diagnostic aPTT clotting assay. Despite its function for fibrin formation in test tubes, patients and animals lacking factor XII have a completely normal hemostasis. The lack of a bleeding tendency observed in factor XII deficiency states is in sharp contrast to deficiencies of other components of the coagulation cascade and factor XII has been considered to have no function for coagulation in vivo. Recently, experimental animal models showed that factor XII is activated by an inorganic polymer, polyphosphate, which is released from procoagulant platelets and that polyphosphate-driven factor XII activation has an essential role in pathologic thrombus formation. Cumulatively, the data suggest to target polyphosphate, factor XII, or its activated form factor XIIa for anticoagulation. As the factor XII pathway specifically contributes to thrombosis but not to hemostasis, interference with this pathway provides a unique opportunity for safe anticoagulation that is not associated with excess bleeding.The review summarizes current knowledge on factor XII functions, activators and inhibitors.

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Current Knowledge and Future Directions for Improving Subsoiling Quality and Reducing Energy Consumption in Conservation Fields

Agriculture ◽

10.3390/agriculture11070575 ◽

2021 ◽

Vol 11 (7) ◽

pp. 575

Author(s):

Shangyi Lou ◽

Jin He ◽

Hongwen Li ◽

Qingjie Wang ◽

Caiyun Lu ◽

...

Keyword(s):

Energy Consumption ◽

Cover Crops ◽

Current Knowledge ◽

High Energy ◽

Field Application ◽

Research Progress ◽

Monitoring And Control ◽

Future Directions ◽

Tillage Depth ◽

And Control

Subsoiling has been acknowledged worldwide to break compacted hardpan, improve soil permeability and water storage capacity, and promote topsoil deepening and root growth. However, there exist certain factors which limit the wide in-field application of subsoiling machines. Of these factors, the main two are poor subsoiling quality and high energy consumption, especially the undesired tillage depth obtained in the field with cover crops. Based on the analysis of global adoption and benefits of subsoiling technology, and application status of subsoiling machines, this article reviewed the research methods, technical characteristics, and developing trends in five key aspects, including subsoiling shovel design, anti-drag technologies, technologies of tillage depth detection and control, and research on soil mechanical interaction. Combined with the research progress and application requirements of subsoiling machines across the globe, current problems and technical difficulties were analyzed and summarized. Aiming to solve these problems, improve subsoiling quality, and reduce energy consumption, this article proposed future directions for the development of subsoiling machines, including optimizing the soil model in computer simulation, strengthening research on the subsoiling mechanism and comprehensive effect, developing new tillage depth monitoring and control systems, and improving wear-resisting properties of subsoiling shovels.

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Significance of Mast Cell Formed Extracellular Traps in Microbial Defense

Clinical Reviews in Allergy & Immunology ◽

10.1007/s12016-021-08861-6 ◽

2021 ◽

Author(s):

Daniel Elieh Ali Komi ◽

Wolfgang M. Kuebler

Keyword(s):

State Of The Art ◽

Extracellular Dna ◽

Cellular Mechanisms ◽

Extracellular Traps ◽

Synthetic Chemicals ◽

Dna Strands ◽

Associated Proteins ◽

Microbial Defense ◽

And Function ◽

Insight Into

AbstractMast cells (MCs) are critically involved in microbial defense by releasing antimicrobial peptides (such as cathelicidin LL-37 and defensins) and phagocytosis of microbes. In past years, it has become evident that in addition MCs may eliminate invading pathogens by ejection of web-like structures of DNA strands embedded with proteins known together as extracellular traps (ETs). Upon stimulation of resting MCs with various microorganisms, their products (including superantigens and toxins), or synthetic chemicals, MCs become activated and enter into a multistage process that includes disintegration of the nuclear membrane, release of chromatin into the cytoplasm, adhesion of cytoplasmic granules on the emerging DNA web, and ejection of the complex into the extracellular space. This so-called ETosis is often associated with cell death of the producing MC, and the type of stimulus potentially determines the ratio of surviving vs. killed MCs. Comparison of different microorganisms with specific elimination characteristics such as S pyogenes (eliminated by MCs only through extracellular mechanisms), S aureus (removed by phagocytosis), fungi, and parasites has revealed important aspects of MC extracellular trap (MCET) biology. Molecular studies identified that the formation of MCET depends on NADPH oxidase-generated reactive oxygen species (ROS). In this review, we summarize the present state-of-the-art on the biological relevance of MCETosis, and its underlying molecular and cellular mechanisms. We also provide an overview over the techniques used to study the structure and function of MCETs, including electron microscopy and fluorescence microscopy using specific monoclonal antibodies (mAbs) to detect MCET-associated proteins such as tryptase and histones, and cell-impermeant DNA dyes for labeling of extracellular DNA. Comparing the type and biofunction of further MCET decorating proteins with ETs produced by other immune cells may help provide a better insight into MCET biology in the pathogenesis of autoimmune and inflammatory disorders as well as microbial defense.

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A Comprehensive Review of the Ethnotraditional Uses and Biological and Pharmacological Potential of the Genus Mimosa

International Journal of Molecular Sciences ◽

10.3390/ijms22147463 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7463

Author(s):

Ismat Majeed ◽

Komal Rizwan ◽

Ambreen Ashar ◽

Tahir Rasheed ◽

Ryszard Amarowicz ◽

...

Keyword(s):

Web Of Science ◽

Scientific Literature ◽

Therapeutic Potential ◽

Current Knowledge ◽

Folk Medicine ◽

Nutritional Values ◽

Biological Potential ◽

The World ◽

The Future ◽

Pharmacological Potential

The Mimosa genus belongs to the Fabaceae family of legumes and consists of about 400 species distributed all over the world. The growth forms of plants belonging to the Mimosa genus range from herbs to trees. Several species of this genus play important roles in folk medicine. In this review, we aimed to present the current knowledge of the ethnogeographical distribution, ethnotraditional uses, nutritional values, pharmaceutical potential, and toxicity of the genus Mimosa to facilitate the exploitation of its therapeutic potential for the treatment of human ailments. The present paper consists of a systematic overview of the scientific literature relating to the genus Mimosa published between 1931 and 2020, which was achieved by consulting various databases (Science Direct, Francis and Taylor, Scopus, Google Scholar, PubMed, SciELO, Web of Science, SciFinder, Wiley, Springer, Google, The Plant Database). More than 160 research articles were included in this review regarding the Mimosa genus. Mimosa species are nutritionally very important and several species are used as feed for different varieties of chickens. Studies regarding their biological potential have shown that species of the Mimosa genus have promising pharmacological properties, including antimicrobial, antioxidant, anticancer, antidiabetic, wound-healing, hypolipidemic, anti-inflammatory, hepatoprotective, antinociceptive, antiepileptic, neuropharmacological, toxicological, antiallergic, antihyperurisemic, larvicidal, antiparasitic, molluscicidal, antimutagenic, genotoxic, teratogenic, antispasmolytic, antiviral, and antivenom activities. The findings regarding the genus Mimosa suggest that this genus could be the future of the medicinal industry for the treatment of various diseases, although in the future more research should be carried out to explore its ethnopharmacological, toxicological, and nutritional attributes.

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Multiwavelength Observations of Fast Radio Bursts

Universe ◽

10.3390/universe7030076 ◽

2021 ◽

Vol 7 (3) ◽

pp. 76

Author(s):

Luciano Nicastro ◽

Cristiano Guidorzi ◽

Eliana Palazzi ◽

Luca Zampieri ◽

Massimo Turatto ◽

...

Keyword(s):

Radio Burst ◽

High Energy ◽

Medium Size ◽

Radio Bursts ◽

Starting Point ◽

Key Points ◽

Fast Radio Burst ◽

Theoretical Results ◽

Observational Strategy ◽

Shed Light

The origin and phenomenology of the Fast Radio Burst (FRB) remains unknown despite more than a decade of efforts. Though several models have been proposed to explain the observed data, none is able to explain alone the variety of events so far recorded. The leading models consider magnetars as potential FRB sources. The recent detection of FRBs from the galactic magnetar SGR J1935+2154 seems to support them. Still, emission duration and energetic budget challenge all these models. Like for other classes of objects initially detected in a single band, it appeared clear that any solution to the FRB enigma could only come from a coordinated observational and theoretical effort in an as wide as possible energy band. In particular, the detection and localisation of optical/NIR or/and high-energy counterparts seemed an unavoidable starting point that could shed light on the FRB physics. Multiwavelength (MWL) search campaigns were conducted for several FRBs, in particular for repeaters. Here we summarize the observational and theoretical results and the perspectives in view of the several new sources accurately localised that will likely be identified by various radio facilities worldwide. We conclude that more dedicated MWL campaigns sensitive to the millisecond–minute timescale transients are needed to address the various aspects involved in the identification of FRB counterparts. Dedicated instrumentation could be one of the key points in this respect. In the optical/NIR band, fast photometry looks to be the only viable strategy. Additionally, small/medium size radiotelescopes co-pointing higher energies telescopes look a very interesting and cheap complementary observational strategy.

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