Background
This review focuses on exosomes derived from various cancer cells. The review discusses the possibility of differentiating macrophages in alternatively activated anti-inflammatory ...pro-tumorigenic M2 macrophage phenotypes and classically activated pro-inflammatory, anti-tumorigenic M1 macrophage phenotypes in the tumor microenvironment (TME). The review is divided into two main parts, as follows: (1) role of exosomes in alternatively activating M2-like macrophages-breast cancer-derived exosomes, hepatocellular carcinoma (HCC) cell-derived exosomes, lung cancer-derived exosomes, prostate cancer-derived exosomes, Oral squamous cell carcinoma (OSCC)—derived exosomes, epithelial ovarian cancer (EOC)—derived exosomes, Glioblastoma (GBM) cell-derived exosomes, and colorectal cancer-derived exosomes, (2) role of exosomes in classically activating M1-like macrophages, oral squamous cell carcinoma-derived exosomes, breast cancer-derived exosomes, Pancreatic-cancer derived modified exosomes, and colorectal cancer-derived exosomes, and (3) exosomes and antibody-dependent cellular cytotoxicity (ADCC). This review addresses the following subjects: (1) crosstalk between cancer-derived exosomes and recipient macrophages, (2) the role of cancer-derived exosome payload(s) in modulating macrophage fate of differentiation, and (3) intracellular signaling mechanisms in macrophages regarding the exosome’s payload(s) upon its uptake and regulation of the TME.
Evidence
Under the electron microscope, nanoscale exosomes appear as specialized membranous vesicles that emerge from the endocytic cellular compartments. Exosomes harbor proteins, growth factors, cytokines, lipids, miRNA, mRNA, and DNAs. Exosomes are released by many cell types, including reticulocytes, dendritic cells, B-lymphocytes, platelets, mast cells, and tumor cells. It is becoming clear that exosomes can impinge upon signal transduction pathways, serve as a mediator of signaling crosstalk, thereby regulating cell-to-cell wireless communications.
Conclusion
Based on the vesicular cargo, the molecular constituents, the exosomes have the potential to change the fate of macrophage phenotypes, either M1, classically activated macrophages, or M2, alternatively activated macrophages. In this review, we discuss and describe the ability of tumor-derived exosomes in the mechanism of macrophage activation and polarization.
Macrophages are critical mediators of the innate immune response against foreign pathogens, including bacteria, physical stress, and injury. Therefore, these cells play a key role in the ..."inflammatory pathway" which in turn can lead to an array of diseases and disorders such as autoimmune neuropathies and myocarditis, inflammatory bowel disease, atherosclerosis, sepsis, arthritis, diabetes, and angiogenesis. Recently, more studies have focused on the macrophages inflammatory diseases since the discovery of the two subtypes of macrophages, which are differentiated on the basis of their phenotype and distinct gene expression pattern. Of these, M1 macrophages are pro-inflammatory and responsible for inflammatory signaling, while M2 are anti-inflammatory macrophages that participate in the resolution of the inflammatory process, M2 macrophages produce anti-inflammatory cytokines, thereby contributing to tissue healing. Many studies have shown the role of these two subtypes in the inflammatory pathway, and their emergence appears to decide the fate of inflammatory signaling and disease progression. As a next step in directing the pro-inflammatory response toward the anti-inflammatory type after an insult by a foreign pathogen (e. g., bacterial lipopolysaccharide), investigators have identified many natural compounds that have the potential to modulate M1 to M2 macrophages. In this review, we provide a focused discussion of advances in the identification of natural therapeutic molecules with anti-inflammatory properties that modulate the phenotype of macrophages from M1 to M2.
Background and objective
Coronavirus disease (COVID-19) is an ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to the incessant spread of the disease with ...substantial morbidity and mortality rates, there is an urgent demand for effective therapeutics and vaccines to control and diminish this pandemic. A critical step in the crosstalk between the virus and the host cell is the binding of SARS-CoV-2 spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of the host cells. Hence, inhibition of this interaction could be a promising strategy to combat the SARS-CoV-2 infection.
Methods
Docking and Molecular Dynamics (MD) simulation studies revealed that designed peptide maintains their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2.
Results
We have designed a novel peptide that could inhibit SARS-CoV-2 spike protein interaction with ACE2, thereby blocking the cellular entry of the virus.
Conclusion
Our findings suggest that computationally developed inhibitory peptide may be developed as an anti-SARS-CoV-2 agent for the treatment of SARS-CoV-2 infection. We further plan to pursue the peptide in cell-based assays and eventually for clinical trials.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Human coronavirus NL63 (HCoV-NL63) mainly affects young children and immunocompromised patients, causing morbidity and mortality in a subset of patients. Since no specific treatment is available, ...this study aims to explore the anti-SARS-CoV-2 agents including favipiravir and remdesivir for treating HCoV-NL63 infection. We first successfully modelled the 3D structure of HCoV-NL63 RNA-dependent RNA polymerase (RdRp) based on the experimentally solved SARS-CoV-2 RdRp structure. Molecular docking indicated that favipiravir has similar binding affinities to SARS-CoV-2 and HCoV-NL63 RdRp with LibDock scores of 75 and 74, respectively. The LibDock scores of remdesivir to SARS-CoV-2 and HCoV-NL63 were 135 and 151, suggesting that remdesivir may have a higher affinity to HCoV-NL63 compared to SARS-CoV-2 RdRp. In cell culture models infected with HCoV-NL63, both favipiravir and remdesivir significantly inhibited viral replication and production of infectious viruses. Overall, remdesivir compared to favipiravir is more potent in inhibiting HCoV-NL63 in cell culture. Importantly, there is no evidence of resistance development upon long-term exposure to remdesivir. Furthermore, combining favipiravir or remdesivir with the clinically used antiviral cytokine interferon-alpha resulted in synergistic effects. These findings provided a proof-of-concept that anti-SARS-CoV-2 drugs, in particular remdesivir, have the potential to be repurposed for treating HCoV-NL63 infection.
Inflammation is set off when innate immune cells detect infection or tissue injury. Tight control of the severity, duration, and location of inflammation is an absolute requirement for an appropriate ...balance between clearance of injured tissue and pathogens versus damage to host cells. Impeding the risk associated with the imbalance in the inflammatory response requires precise identification of potential therapeutic targets involved in provoking the inflammation. Toll-like receptors (TLRs) primarily known for the pathogen recognition and subsequent immune responses are being investigated for their pathogenic role in various chronic diseases. A mammalian homologue of Drosophila Toll receptor 4 (TLR4) was shown to induce the expression of genes involved in inflammatory responses. Signaling pathways via TLR4 activate various transcription factors like Nuclear factor kappa-light-chain-enhancer (NF-κB), activator protein 1 (AP1), Signal Transducers and Activators of Transcription family of transcription factors (STAT1) and Interferon regulatory factors (IRF's), which are the key players regulating the inflammatory response. Inhibition of these targets and their upstream signaling molecules provides a potential therapeutic approach to treat inflammatory diseases. Here we review the therapeutic targets involved in TLR-4 signaling pathways that are critical for suppressing chronic inflammatory disorders.
•Tight control of the severity, duration and location of inflammation is an absolute requirement for an appropriate balance between clearance of injured tissue and pathogens versus damage to host cells.•Potential therapeutic targets involved in provoking the inflammation include Toll-like receptors (TLRs) and their downstream signaling molecules responsible for their critical role in various chronic inflammatory diseases.•Signaling pathways via TLR4 activate various transcription factors like NF-κB, AP1, STAT1, and IRFs. Inhibition of these targets and their upstream signaling molecules provide a potential therapeutic approach to treat inflammatory diseases.•In this article, we have highlighted the already known inflammatory signaling players and discussed about the recent advancements in discovery of potential targets within the major TLR-4 mediated pathway.•SiR4 activs like nuclear factor kappa-light-chain-enhancer (NF-κB), activator protein 1 (AP1), signal transducers and activators of tran(STAT1) and nterferon regulatory factors (IRF's),
The outbreak of the coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2 triggered a global pandemic where control is needed through therapeutic and preventive ...interventions. This study aims to identify natural compounds that could affect the fusion between the viral membrane (receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 spike protein) and the human cell receptor angiotensin-converting enzyme 2. Accordingly, we performed the enzyme-linked immunosorbent assay-based screening of 10 phytochemicals that already showed numerous positive effects on human health in several epidemiological studies and clinical trials. Among these phytochemicals, epigallocatechin gallate, a polyphenol and a major component of green tea, could effectively inhibit the interaction between the receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 spike protein and the human cell receptor angiotensin-converting enzyme 2. Alternately,
in silico
molecular docking studies of epigallocatechin gallate and angiotensin-converting enzyme 2 indicated a binding score of −7.8 kcal/mol and identified a hydrogen bond between R393 and angiotensin-converting enzyme 2, which is considered as a key interacting residue involved in binding with the severe acute respiratory syndrome coronavirus 2 spike protein receptor-binding domain, suggesting the possible blocking of interaction between receptor-binding domain and angiotensin-converting enzyme 2. Furthermore, epigallocatechin gallate could attenuate severe acute respiratory syndrome coronavirus 2 infection and replication in Caco-2 cells. These results shed insight into identification and validation of severe acute respiratory syndrome coronavirus 2 entry inhibitors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Atherosclerosis is a chronic inflammatory disease arising due to an imbalance in lipid metabolism and maladaptive immune response driven by the accumulation of cholesterol‐laden macrophages in the ...artery wall. Interactions between monocytes/macrophages and endothelial cells play an essential role in the pathogenesis of atherosclerosis. In our current study, nitric oxide synthase 1 (NOS1)‐derived nitric oxide (NO) has been identified as a regulator of macrophage and endothelial cell interaction. Oxidized LDL (OxLDL) activates NOS1, which results in the expression of CD40 ligand in macrophages. OxLDL‐stimulated macrophages produce some soluble factors which increase the CD40 receptor expression in endothelial cells. This increases the interaction between the macrophages and endothelial cells, which leads to an increase in the inflammatory response. Inhibition of NOS1‐derived NO might serve as an effective strategy to reduce foam cell formation and limit the extent of atherosclerotic plaque expansion.
Toll/interleukin‐1 like receptors (TLRs) are membrane‐spanning proteins crucially involved in innate immunity. On activation, the cytoplasmic toll/interleukin‐1 receptor (TIR) domains of these ...receptors undergo homo‐ or heterodimerization.
Brucella sp. are bacterial pathogens that affect the immune system by suppressing the TLR signaling pathway. They enact this by encoding a TIR domain–containing protein, TcpB, which suppresses NF‐κB activation and proinflammatory cytokine secretion mediated by TLR4 receptors. TcpB has been shown to target the Mal‐mediated pathway to suppress TLR signaling. The recent identification of its mechanism of interference with TLR4 signaling involving Mal prompted us to further study the structural aspects of TcpB binding with TLR4 and Mal. Our triprotein model displays the overall scaffolding role of TcpB in anchoring TLR4 and Mal thereby inhibiting their interaction leading to the attenuation of the TLR4 pathway.
This novel work describes the structural aspects of Brucella TcpB binding to Mal and toll/interleukin‐1 like receptor 4 (TLR4), thereby inhibiting the TLR4 pathway. We understand that this study is the first of its kind and would throw light on how scaffolding by TcpB leads to the inhibition of TLR4‐Mal interaction critical for downstream inflammatory signaling.
TIRAP in the Mechanism of Inflammation Rajpoot, Sajjan; Wary, Kishore K; Ibbott, Rachel ...
Frontiers in immunology,
07/2021, Letnik:
12
Journal Article
Recenzirano
Odprti dostop
The Toll-interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP) represents a key intracellular signalling molecule regulating diverse immune responses. Its capacity to function as an ...adaptor molecule has been widely investigated in relation to Toll-like Receptor (TLR)-mediated innate immune signalling. Since the discovery of TIRAP in 2001, initial studies were mainly focused on its role as an adaptor protein that couples Myeloid differentiation factor 88 (MyD88) with TLRs, to activate MyD88-dependent TLRs signalling. Subsequent studies delineated TIRAP's role as a transducer of signalling events through its interaction with non-TLR signalling mediators. Indeed, the ability of TIRAP to interact with an array of intracellular signalling mediators suggests its central role in various immune responses. Therefore, continued studies that elucidate the molecular basis of various TIRAP-protein interactions and how they affect the signalling magnitude, should provide key information on the inflammatory disease mechanisms. This review summarizes the TIRAP recruitment to activated receptors and discusses the mechanism of interactions in relation to the signalling that precede acute and chronic inflammatory diseases. Furthermore, we highlighted the significance of TIRAP-TIR domain containing binding sites for several intracellular inflammatory signalling molecules. Collectively, we discuss the importance of the TIR domain in TIRAP as a key interface involved in protein interactions which could hence serve as a therapeutic target to dampen the extent of acute and chronic inflammatory conditions.
Modulation of prostate stromal cells (PrSCs) within tumor tissues is gaining attention for the treatment of solid tumors. Using our original in vitro coculture system, we previously reported that ...leucinostatin (LCS)‐A, a peptide mycotoxin, inhibited prostate cancer DU‐145 cell growth through reduction of insulin‐like growth factor 1 (IGF‐I) expression in PrSCs. To further obtain additional bioactive compounds from LCS‐A, we designed and synthesized a series of LCS‐A derivatives as compounds that target PrSCs. Among the synthesized LCS‐A derivatives, LCS‐7 reduced IGF‐I expression in PrSCs with lower toxicity to PrSCs and mice than LCS‐A. As LCS‐A has been suggested to interact with mitochondrial adenosine triphosphate (ATP) synthase, a docking study was performed to elucidate the mechanism of reduced IGF‐I expression in the PrSCs. As expected, LCS‐A and LCS‐7 directly interacted with mitochondrial ATP synthase, and like LCS‐A and LCS‐7, other mitochondrial ATP synthase inhibitors also reduced the expression of IGF‐I by PrSCs. Furthermore, LCS‐A and LCS‐7 significantly decreased the growth of mouse xenograft tumors. Based on these data, we propose that the mitochondrial ATP synthases–IGF‐I axis of PrSCs plays a critical role on cancer cell growth and inhibition could be a potential anticancer target for prostate cancer.
What's new?
The secretion by prostate stromal cells (PrSCs) of insulin‐like growth factor‐1 (IGF‐I) fuels prostate cancer (PC) cell proliferation. IGF‐I expression by PC cells can be reduced by leucinostatin‐A (LCS‐A), a fungal nanopeptide. Here, the authors investigated a panel of synthetic LCS‐A compounds and identified a derivative, LCS‐7, that specifically reduces IGF‐I expression in PrSCs. Docking analyses show that LCS‐7 interacts directly with mitochondrial ATP synthase to reduce IGF‐I expression. In a mouse xenograft model, LCS‐7 significantly inhibited prostate tumor growth. The findings open the path to mitochondrial ATP synthase–IGF‐I axis targeting as a novel therapeutic strategy against prostate cancer.
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