scholarly journals Efficacy of SPG-ODN 1826 Nanovehicles in Inducing M1 Phenotype through TLR-9 Activation in Murine Alveolar J774A.1 Cells: Plausible Nano-Immunotherapy for Lung Carcinoma

2021 ◽  
Vol 22 (13) ◽  
pp. 6833
Author(s):  
Mohammed F. Aldawsari ◽  
Ahmed Alalaiwe ◽  
El-Sayed Khafagy ◽  
Ahmed Al Saqr ◽  
Saad M. Alshahrani ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Alveolar Macrophages ◽  
Transcriptional Activation ◽  
Critical Role ◽  
Prokaryotic Genome ◽  
Endosomal Trafficking ◽  
Cpg Odn ◽  
Tem Analysis ◽  
Enhanced Expression ◽  
Average Size

Alveolar macrophages are the first line of defense against intruding pathogens and play a critical role in cancer immunology. The Toll-like receptor (TLR) family mediates an important role in recognizing and mounting an immune response against intruding microbes. TLR-9 is a member of the intracellular TLR family, which recognizes unmethylated CG motifs from the prokaryotic genome. Upon its activation, TLR-9 triggers downstream of the MyD-88-dependent transcriptional activation of NF-κB, and subsequently results in abundant inflammatory cytokines expression that induces a profound inflammatory milieu. The present exploratory investigation aimed at elucidating the potency of schizophyllan for entrapping ODN 1826 (SPG-ODN 1826)-mediated stimulation of TLR-9 in provoking an inflammatory-type response in murine alveolar macrophages. Schizophyllan (SPG), a representative of the β-glucan family, was used in the present study as a nanovehicle for endosomal trafficking of CpG ODN 1826. TEM analysis of SPG-ODN 1826 nanovehicles revealed that the prepared nanovehicles are spherical and have an average size of about 100 nm. Interestingly, SPG-ODN 1826 nanovehicles were competent in delivering their therapeutic payload within endosomes of murine alveolar macrophage (J774A.1) cells. Exposure of these nanovehicles within LPS stimulated J774A.1, resulted in a significant provocation of reactive oxygen species (ROS) (p < 0.01) in comparison to CpG ODN 1826 alone. Moreover, the formulated nanovehicles succeeded in generating a profound Th1-based cytokine profile constituted by enhanced expression of IFN-γ (p < 0.001) and IL-1β (p < 0.001) inflammatory cytokines. These findings clearly indicated the immunostimulatory potential of SPG-ODN 1826 nanovehicles for inducing the Th1-type phenotype, which would certainly assist in skewing M2 phenotype into the much-desired M1 type during lung cancer.

scholarly journals Alpha 1 Antitrypsin-Deficient Macrophages Have Impaired Efferocytosis of Apoptotic Neutrophils

2020 ◽  
Vol 11 ◽  
Author(s):  
Jungnam Lee ◽  
Yuanqing Lu ◽  
Regina Oshins ◽  
Jesse West ◽  
Craig G. Moneypenny ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Alveolar Macrophages ◽  
Critical Role ◽  
Neutrophil Accumulation ◽  
Antitrypsin Deficiency ◽  
Main Driver ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Chemotactic Factors ◽  
Alpha 1 Antitrypsin ◽  
Underlying Mechanisms

Alpha 1 antitrypsin deficiency (AATD) is an autosomal co-dominant disorder characterized by a low level of circulating AAT, which significantly reduces protection for the lower airways against proteolytic burden caused by neutrophils. Neutrophils, which are terminally differentiated innate immune cells and play a critical role to clear pathogens, accumulate excessively in the lung of AATD individuals. The neutrophil burden in AATD individuals increases the risk for early-onset destructive lung diseases by producing neutrophil products such as reactive oxygen radicals and various proteases. The level of AAT in AATD individuals is not sufficient to inhibit the activity of neutrophil chemotactic factors such as CXCL-8 and LTB4, which could lead to alveolar neutrophil accumulation in AATD individuals. However, as neutrophils have a short lifespan, and apoptotic neutrophils are rapidly cleared by alveolar macrophages that outnumber the apoptotic neutrophils in the pulmonary alveolus, the increased chemotaxis activity does not fully explain the persistent neutrophil accumulation and the resulting chronic inflammation in AATD individuals. Here, we propose that the ability of alveolar macrophages to clear apoptotic neutrophils is impaired in AATD individuals and it could be the main driver to cause neutrophil accumulation in their lung. This study demonstrates that Z-AAT variant significantly increases the expression of pro-inflammatory cytokines including CXCL-8, CXCL1, LTB4, and TNFα in LPS-treated macrophages. These cytokines play a central role in neutrophil recruitment to the lung and in clearance of apoptotic neutrophils by macrophages. Our result shows that LPS treatment significantly reduces the efferocytosis ability of macrophages with the Z-AAT allele by inducing TNFα expression. We incubated monocyte-derived macrophages (MDMs) with apoptotic neutrophils and found that after 3 h of co-incubation, the expression level of CXCL-8 is reduced in M-MDMs but increased in Z-MDMs. This result shows that the expression of inflammatory cytokines could be increased by impaired efferocytosis. It indicates that the efferocytosis ability of macrophages plays an important role in regulating cytokine expression and resolving inflammation. Findings from this study would help us better understand the multifaceted effect of AAT on regulating neutrophil balance in the lung and the underlying mechanisms.

scholarly journals Functional Attributes of Myco-Synthesized Silver Nanoparticles from Endophytic Fungi: A New Implication in Biomedical Applications

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 473
Author(s):  
Prabu Kumar Seetharaman ◽  
Rajkuberan Chandrasekaran ◽  
Rajiv Periakaruppan ◽  
Sathishkumar Gnanasekar ◽  
Sivaramakrishnan Sivaperumal ◽  
...  
Keyword(s):  
Silver Nanoparticles ◽  
Culture Filtrate ◽  
Morphological Changes ◽  
Xrd Analysis ◽  
Penicillium Oxalicum ◽  
Breast Cancer Cell Lines ◽  
Face Centered Cubic ◽  
Tem Analysis ◽  
X Ray ◽  
Average Size

To develop a benign nanomaterial from biogenic sources, we have attempted to formulate and fabricate silver nanoparticles synthesized from the culture filtrate of an endophytic fungus Penicillium oxalicum strain LA-1 (PoAgNPs). The synthesized PoAgNPs were exclusively characterized through UV–vis absorption spectroscopy, Fourier Transform Infra-Red spectroscopy (FT-IR), X-ray powder diffraction (XRD), and Transmission Electron Microscopy (TEM) with energy dispersive X-ray spectroscopy (EDX). The synthesized nanoparticles showed strong absorbance around 430 nm with surface plasmon resonance (SPR) and exhibited a face-centered cubic crystalline nature in XRD analysis. Proteins presented in the culture filtrate acted as reducing, capping, and stabilization agents to form PoAgNPs. TEM analysis revealed the generation of polydispersed spherical PoAgNPs with an average size of 52.26 nm. The PoAgNPs showed excellent antibacterial activity against bacterial pathogens. The PoAgNPs induced a dose-dependent cytotoxic activity against human adenocarcinoma breast cancer cell lines (MDA-MB-231), and apoptotic morphological changes were observed by dual staining. Additionally, PoAgNPs demonstrated better larvicidal activity against the larvae of Culex quinquefasciatus. Moreover, the hemolytic test indicated that the as-synthesized PoAgNPs are a safe and biocompatible nanomaterial with versatile bio-applications.

scholarly journals Squalene Stimulates a Key Innate Immune Cell to Foster Wound Healing and Tissue Repair

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Cristina Sánchez-Quesada ◽  
Alicia López-Biedma ◽  
Estefania Toledo ◽  
José J. Gaforio
Keyword(s):  
Wound Healing ◽  
Inflammatory Cytokines ◽  
Tissue Repair ◽  
Immune Cell ◽  
Critical Role ◽  
Virgin Olive Oil ◽  
Skin Damage ◽  
Macrophage Response ◽  
Anti Inflammatory ◽  
Minor Compounds

Anti-inflammatory effects of virgin olive oil (VOO) have been described recently, along with its wound healing effect. One of the main minor compounds found in VOO is squalene (SQ), which also possesses preventive effects against skin damage and anti-inflammatory properties. The inflammatory response is involved in wound healing and manages the whole process by macrophages, among others, as the main innate cells with a critical role in the promotion and resolution of inflammation for tissue repair. Because of that, this work is claimed to describe the role that squalene exerts in the immunomodulation of M1 proinflammatory macrophages, which are the first cells implicate in recent injuries. Pro- and anti-inflammatory cytokines were analysed using TPH1 cell experimental model. SQ induced an increase in the synthesis of anti-inflammatory cytokines, such as IL-10, IL-13, and IL-4, and a decrease in proinflammatory signals, such as TNF-α and NF-κB in M1 proinflammatory macrophages. Furthermore, SQ enhanced remodelling and repairing signals (TIMP-2) and recruitment signals of eosinophils and neutrophils, responsible for phagocytosis processes. These results suggest that SQ is able to promote wound healing by driving macrophage response in inflammation. Therefore, squalene could be useful at the resolution stage of wound healing.

scholarly journals Reading and Function of a Histone Code Involved in Targeting Corepressor Complexes for Repression

2005 ◽  
Vol 25 (1) ◽  
pp. 324-335 ◽  
Author(s):  
Ho-Geun Yoon ◽  
Youngsok Choi ◽  
Philip A. Cole ◽  
Jiemin Wong
Keyword(s):  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Hormone Receptors ◽  
Critical Role ◽  
Pericentric Heterochromatin ◽  
Histone Code ◽  
Stable Association ◽  
And Function

ABSTRACT A central question in histone code theory is how various codes are recognized and utilized in vivo. Here we show that TBL1 and TBLR1, two WD-40 repeat proteins in the corepressor SMRT/N-CoR complexes, are functionally redundant and essential for transcriptional repression by unliganded thyroid hormone receptors (TR) but not essential for transcriptional activation by liganded TR. TBL1 and TBLR1 bind preferentially to hypoacetylated histones H2B and H4 in vitro and have a critical role in targeting the corepressor complexes to chromatin in vivo. We show that targeting SMRT/N-CoR complexes to the deiodinase 1 gene (D1) requires at least two interactions, one between unliganded TR and SMRT/N-CoR and the other between TBL1/TBLR1 and hypoacetylated histones. Neither interaction alone is sufficient for the stable association of the corepressor complexes with the D1 promoter. Our data support a feed-forward working model in which deacetylation exerted by initial unstable recruitment of SMRT/N-CoR complexes via their interaction with unliganded TR generates a histone code that serves to stabilize their own recruitment. Similarly, we find that targeting of the Sin3 complex to pericentric heterochromatin may also follow this model. Our studies provide an in vivo example that a histone code is not read independently but is recognized in the context of other interactions.

scholarly journals Mediator subunit MED1 is required for E2A-PBX1–mediated oncogenic transcription and leukemic cell growth

2021 ◽  
Vol 118 (6) ◽  
pp. e1922864118 ◽  
Author(s):  
Yu-Ling Lee ◽  
Keiichi Ito ◽  
Wen-Chieh Pi ◽  
I-Hsuan Lin ◽  
Chi-Shuen Chu ◽  
...  
Keyword(s):  
Cell Growth ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Critical Role ◽  
Gene Activation ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Specific Gene ◽  
Aberrant Expression ◽  
Transcriptional Machinery

The chimeric transcription factor E2A-PBX1, containing the N-terminal activation domains of E2A fused to the C-terminal DNA-binding domain of PBX1, results in 5% of pediatric acute lymphoblastic leukemias (ALL). We recently have reported a mechanism for RUNX1-dependent recruitment of E2A-PBX1 to chromatin in pre-B leukemic cells; but the subsequent E2A-PBX1 functions through various coactivators and the general transcriptional machinery remain unclear. The Mediator complex plays a critical role in cell-specific gene activation by serving as a key coactivator for gene-specific transcription factors that facilitates their function through the RNA polymerase II transcriptional machinery, but whether Mediator contributes to aberrant expression of E2A-PBX1 target genes remains largely unexplored. Here we show that Mediator interacts directly with E2A-PBX1 through an interaction of the MED1 subunit with an E2A activation domain. Results of MED1 depletion by CRISPR/Cas9 further indicate that MED1 is specifically required for E2A-PBX1–dependent gene activation and leukemic cell growth. Integrated transcriptome and cistrome analyses identify pre-B cell receptor and cell cycle regulatory genes as direct cotargets of MED1 and E2A-PBX1. Notably, complementary biochemical analyses also demonstrate that recruitment of E2A-PBX1 to a target DNA template involves a direct interaction with DNA-bound RUNX1 that can be further stabilized by EBF1. These findings suggest that E2A-PBX1 interactions with RUNX1 and MED1/Mediator are of functional importance for both gene-specific transcriptional activation and maintenance of E2A-PBX1–driven leukemia. The MED1 dependency for E2A-PBX1–mediated gene activation and leukemogenesis may provide a potential therapeutic opportunity by targeting MED1 in E2A-PBX1+ pre-B leukemia.

scholarly journals Synthesis of Silver Nanoparticles from Anagalis arvensis and Their Biomedical Applications

2018 ◽  
Author(s):  
Mohib Shah ◽  
Natasha Anwar ◽  
Samreen Saleem ◽  
Iqbal Munir ◽  
Niaz Ali Shah ◽  
...  
Keyword(s):  
Silver Nanoparticles ◽  
Reducing Power ◽  
Spherical Shape ◽  
Artemia Salina ◽  
Maximum Activity ◽  
Tem Analysis ◽  
Synthesis Of Nanoparticles ◽  
The Stability ◽  
Average Size ◽  
Biological Methods

Background. Nanotechnology is promising field for generating new applications. A green synthesis of nanoparticles through biological methods using plant extract have a reliable and ecofriendly approach to improve our global environment. Methods. Silver nanoparticles (AgNPs) were synthesized using aqueous extract of Anagalis arvensis L and silver nitrate and were physicochemically characterized. Results. The stability of AgNPs toward acidity, alkalinity, salinity and temperature showed that they remained stable at room temperature for more than two months. The SEM and TEM analysis of the AgNPs showed that they have a uniform spherical shape with an average size in the range of 40&ndash;78 nm. Further 1-Dibhenyl-2-Picrylhydrazl radical in Anagalis arvensis L.mediated AgNPs showed a maximum activity of 98% at concentration of 200&mu;g/mL. Hydrogen peroxide scavenging assay in Anagalis arvensis L. mediated AgNPs showed a maximum activity of 85% at concentration of 200&mu;g/mL. Reducing power of Anagalis arvensis L.Ag NPs exhibited a higher activity of 330 &mu;g/mL at concentration of 200 &mu;g/mL. These NPs have cytotoxic effects against brine shrimp (Artemia salina) nauplii with a value of 53% LD 178.04&mu;g/mL. Conclusion. The AgNPs synthesized using&nbsp;Anagalis arvensis L. extract demonstrate a broad range of applications.

scholarly journals Enhanced expression of the complement regulatory protein, membrane inhibitor of reactive lysis (CD59), is regulated at the level of transcription

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 968-977
Author(s):  
MH Holguin ◽  
CB Martin ◽  
JH Weis ◽  
CJ Parker
Keyword(s):  
Protein Expression ◽  
Blot Analysis ◽  
Interleukin 1 ◽  
Critical Role ◽  
Regulatory Protein ◽  
Calcium Ionophore ◽  
Cytolytic Activity ◽  
Host Cells ◽  
Rna Expression ◽  
Enhanced Expression

The membrane inhibitor of reactive lysis (MIRL) is an 18-Kd glycosyl phosphatidylinositol anchored membrane glycoprotein that inhibits the cytolytic activity of complement. MIRL is expressed by all hematopoietic elements and by a wide variety of nonhematopoietic tissues. A deficiency of MIRL is primarily responsible for the greater sensitivity of the erythrocytes of paroxysmal nocturnal hemoglobinuria to complement mediated lysis. Because of its critical role in protecting host cells from injury by complement, we hypothesized that mechanisms exist that allow MIRL expression to be regulated. To investigate this hypothesis, both MIRL RNA and MIRL protein expression were analyzed following exposure of K562 erythroleukemia cells to a variety of potential stimulants. Incubation with dexamethasone, calcium ionophore, lipopolysaccharide, interleukin 1, tumor necrosis factor, hemin, and cyclic AMP had no effect on MIRL expression. However, incubation with phorbol 12-myristate 13 acetate (PMA), induced a marked increase in MIRL RNA as determined by Northern blot analysis. This enhanced expression of MIRL RNA was associated with an increase in MIRL protein expression as determined by immunoprecipitation of metabolically labeled proteins, Western blot analysis, and immunobinding assay. Enhanced MIRL RNA expression was first detected after 8 hours and increased through 24 hours of observation. Inhibitors of either protein synthesis or transcription abrogated the PMA-induced enhancement of MIRL RNA expression. Together, these results are consistent with a model in which PMA induces synthesis of a trans acting protein that enhances transcription of the MIRL gene.

scholarly journals Silver Nanoparticles Formation by Jatropha integerrima and LC/MS-QTOF-Based Metabolite Profiling

Nanomaterials ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 2400
Author(s):  
Afrah E. Mohammed ◽  
Lamya Ahmed Al-Keridis ◽  
Ishrat Rahman ◽  
Modhi O. Alotaibi ◽  
Rasha Saad Suliman ◽  
...  
Keyword(s):  
Silver Nanoparticles ◽  
Laser Scanning ◽  
Antibacterial Effect ◽  
Therapeutic Potential ◽  
Laser Scanning Microscopy ◽  
Ultrastructural Changes ◽  
Confocal Laser ◽  
Synthesis Methods ◽  
Tem Analysis ◽  
Average Size

The broad application of metal nanoparticles in different fields encourages scientists to find alternatives to conventional synthesis methods to reduce negative environmental impacts. Herein, we described a safe method for preparing silver nanoparticles (J-AgNPs) using Jatropha integerrima leaves extract as a reducing agent and further characterize its physiochemical and pharmacological properties to identify its therapeutic potential as a cytotoxic and antimicrobial agent. The biogenic synthesized J-AgNPs were physiochemically characterized by ultraviolet-visible spectroscopy, dynamic light scattering (DLS), transmission electron microscope (TEM), and energy-dispersive X-ray spectroscopy. HPLC-DAD, followed by LC/MS and the Fourier-transform infrared spectroscopy (FTIR), was applied to detect the biomolecules of J. integerrima involved in the fabrication of NPs. Furthermore, J-AgNPs and the ampicillin-nanocomposite conjugate were investigated for their potential antibacterial effects against four clinical isolates. Finally, cytotoxic effects were also investigated against cancer and normal cell lines, and their mechanism was assessed using TEM analysis and confocal laser scanning microscopy (LSM). Ag ions were reduced to spherical J-AgNPs, with a zeta potential of −34.7 mV as well as an average size of 91.2 and 22.8 nm as detected by DLS and TEM, respectively. HPLC GC/MC analysis identified five biomolecules, and FTIR suggested the presence of proteins besides polyphenolic molecules; together, these molecules could be responsible for the reduction and capping processes during NP formation. Additionally, J-AgNPs displayed a strong antibacterial effect, although the ampicillin conjugated form had a very weak antibacterial effect. Furthermore, the NPs caused a reduction in cell viability of all the treated cells by initiating ultrastructural changes and apoptosis, as identified by TEM and LSM analysis. Therefore, J-AgNPs can be formed using the leaf extract from the J. integerrima plant. Furthermore, J-AgNPs may serve as a candidate for further biochemical and pharmacological testing to identify its therapeutic value.

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