P2RX7 at the Host-Pathogen Interface of Infectious Diseases

SUMMARY The P2X7 receptor (P2RX7) is an important molecule that functions as a danger sensor, detecting extracellular nucleotides from injured cells and thus signaling an inflammatory program to nearby cells. It is expressed in immune cells and plays important roles in pathogen surveillance and cell-mediated responses to infectious organisms. There is an abundance of literature on the role of P2RX7 in inflammatory diseases and the role of these receptors in host-pathogen interactions. Here, we describe the current knowledge of the role of P2RX7 in the host response to a variety of pathogens, including viruses, bacteria, fungi, protozoa, and helminths. We describe in vitro and in vivo evidence for the critical role these receptors play in mediating and modulating immune responses. Our observations indicate a role for P2X7 signaling in sensing damage-associated molecular patterns released by nearby infected cells to facilitate immunopathology or protection. In this review, we describe how P2RX7 signaling can play critical roles in numerous cells types in response to a diverse array of pathogens in mediating pathogenesis and immunity to infectious agents.

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The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations

Nature Communications ◽

10.1038/s41467-021-24418-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Brianna J. Klein ◽

Anagha Deshpande ◽

Khan L. Cox ◽

Fan Xuan ◽

Mohamad Zandian ◽

...

Keyword(s):

Critical Role ◽

Cellular Transformation ◽

Acute Leukemias ◽

Hematopoietic Stem ◽

Nucleosome Core ◽

Stem And Progenitor Cells ◽

Transforming Activity

AbstractChromosomal translocations of the AF10 (or MLLT10) gene are frequently found in acute leukemias. Here, we show that the PZP domain of AF10 (AF10PZP), which is consistently impaired or deleted in leukemogenic AF10 translocations, plays a critical role in blocking malignant transformation. Incorporation of functional AF10PZP into the leukemogenic CALM-AF10 fusion prevents the transforming activity of the fusion in bone marrow-derived hematopoietic stem and progenitor cells in vitro and in vivo and abrogates CALM-AF10-mediated leukemogenesis in vivo. Crystallographic, biochemical and mutagenesis studies reveal that AF10PZP binds to the nucleosome core particle through multivalent contacts with the histone H3 tail and DNA and associates with chromatin in cells, colocalizing with active methylation marks and discriminating against the repressive H3K27me3 mark. AF10PZP promotes nuclear localization of CALM-AF10 and is required for association with chromatin. Our data indicate that the disruption of AF10PZP function in the CALM-AF10 fusion directly leads to transformation, whereas the inclusion of AF10PZP downregulates Hoxa genes and reverses cellular transformation. Our findings highlight the molecular mechanism by which AF10 targets chromatin and suggest a model for the AF10PZP-dependent CALM-AF10-mediated leukemogenesis.

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Antimalarial drugs—are they beneficial in rheumatic and viral diseases?—considerations in COVID-19 pandemic

Clinical Rheumatology ◽

10.1007/s10067-021-05805-5 ◽

2021 ◽

Author(s):

Bogna Grygiel-Górniak

Keyword(s):

Connective Tissue ◽

Viral Infections ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Antiviral Drugs ◽

In Vivo Studies ◽

Viral Diseases ◽

Cardiac Complications

AbstractThe majority of the medical fraternity is continuously involved in finding new therapeutic schemes, including antimalarial medications (AMDs), which can be useful in combating the 2019-nCoV: coronavirus disease (COVID-19). For many decades, AMDs have been widely used in the treatment of malaria and various other anti-inflammatory diseases, particularly to treat autoimmune disorders of the connective tissue. The review comprises in vitro and in vivo studies, original studies, clinical trials, and consensus reports for the analysis, which were available in medical databases (e.g., PubMed). This manuscript summarizes the current knowledge about chloroquine (CQ)/hydroxychloroquine (HCQ) and shows the difference between their use, activity, recommendation, doses, and adverse effects on two groups of patients: those with rheumatic and viral diseases (including COVID-19). In the case of connective tissue disorders, AMDs are prescribed for a prolonged duration in small doses, and their effect is observed after few weeks, whereas in the case of viral infections, they are prescribed in larger doses for a short duration to achieve a quick saturation effect. In rheumatic diseases, AMDs are well tolerated, and their side effects are rare. However, in some viral diseases, the effect of AMDs is questionable or not so noticeable as suggested during the initial prognosis. They are mainly used as an additive therapy to antiviral drugs, but recent studies have shown that AMDs can diminish the efficacy of some antiviral drugs and may cause respiratory, kidney, liver, and cardiac complications.

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Role of Cathepsin S in Periodontal Inflammation and Infection

Mediators of Inflammation ◽

10.1155/2017/4786170 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

S. Memmert ◽

A. Damanaki ◽

A. V. B. Nogueira ◽

S. Eick ◽

M. Nokhbehsaim ◽

...

Keyword(s):

Periodontal Diseases ◽

Interleukin 1 ◽

Critical Role ◽

Gingival Tissue ◽

Cathepsin S ◽

Protein Levels ◽

Periodontal Inflammation

Cathepsin S is a cysteine protease and regulator of autophagy with possible involvement in periodontitis. The objective of this study was to investigate whether cathepsin S is involved in the pathogenesis of periodontal diseases. Human periodontal fibroblasts were cultured under inflammatory and infectious conditions elicited by interleukin-1β and Fusobacterium nucleatum, respectively. An array-based approach was used to analyze differential expression of autophagy-associated genes. Cathepsin S was upregulated most strongly and thus further studied in vitro at gene and protein levels. In vivo, gingival tissue biopsies from rats with ligature-induced periodontitis and from periodontitis patients were also analyzed at transcriptional and protein levels. Multiple gene expression changes due to interleukin-1β and F. nucleatum were observed in vitro. Both stimulants caused a significant cathepsin S upregulation. A significantly elevated cathepsin S expression in gingival biopsies from rats with experimental periodontitis was found in vivo, as compared to that from control. Gingival biopsies from periodontitis patients showed a significantly higher cathepsin S expression than those from healthy gingiva. Our findings provide original evidence that cathepsin S is increased in periodontal cells and tissues under inflammatory and infectious conditions, suggesting a critical role of this autophagy-associated molecule in the pathogenesis of periodontitis.

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Heparan sulfate side chains have a critical role in the inhibitory effects of perlecan on vascular smooth muscle cell response to arterial injury

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00654.2013 ◽

2014 ◽

Vol 307 (3) ◽

pp. H337-H345 ◽

Cited By ~ 6

Author(s):

Lara Gotha ◽

Sang Yup Lim ◽

Azriel B. Osherov ◽

Rafael Wolff ◽

Beiping Qiang ◽

...

Keyword(s):

Smooth Muscle ◽

Critical Role ◽

Arterial Injury ◽

Side Chains ◽

Wild Type ◽

Injury Response ◽

Migratory Response

Perlecan is a proteoglycan composed of a 470-kDa core protein linked to three heparan sulfate (HS) glycosaminoglycan chains. The intact proteoglycan inhibits the smooth muscle cell (SMC) response to vascular injury. Hspg2Δ3/Δ3 (MΔ3/Δ3) mice produce a mutant perlecan lacking the HS side chains. The objective of this study was to determine differences between these two types of perlecan in modifying SMC activities to the arterial injury response, in order to define the specific role of the HS side chains. In vitro proliferative and migratory activities were compared in SMC isolated from MΔ3/Δ3 and wild-type mice. Proliferation of MΔ3/Δ3 SMC was 1.5× greater than in wild type ( P < 0.001), increased by addition of growth factors, and showed a 42% greater migratory response than wild-type cells to PDGF-BB ( P < 0.001). In MΔ3/Δ3 SMC adhesion to fibronectin, and collagen types I and IV was significantly greater than wild type. Addition of DRL-12582, an inducer of perlecan expression, decreased proliferation and migratory response to PDGF-BB stimulation in wild-type SMC compared with MΔ3/Δ3. In an in vivo carotid artery wire injury model, the medial thickness, medial area/lumen ratio, and macrophage infiltration were significantly increased in the MΔ3/Δ3 mice, indicating a prominent role of the HS side chain in limiting vascular injury response. Mutant perlecan that lacks HS side chains had a marked reduction in the inhibition of in vitro SMC function and the in vivo arterial response to injury, indicating the critical role of HS side chains in perlecan function in the vessel wall.

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The State of the Art and Prospects for Osteoimmunomodulatory Biomaterials

Materials ◽

10.3390/ma14061357 ◽

2021 ◽

Vol 14 (6) ◽

pp. 1357

Author(s):

Andreea-Mariana Negrescu ◽

Anisoara Cimpean

Keyword(s):

Foreign Bodies ◽

Structural Characteristics ◽

Critical Role ◽

Fibrous Tissue ◽

Bioactive Molecules ◽

New Bone Formation ◽

Recent Developments

The critical role of the immune system in host defense against foreign bodies and pathogens has been long recognized. With the introduction of a new field of research called osteoimmunology, the crosstalk between the immune and bone-forming cells has been studied more thoroughly, leading to the conclusion that the two systems are intimately connected through various cytokines, signaling molecules, transcription factors and receptors. The host immune reaction triggered by biomaterial implantation determines the in vivo fate of the implant, either in new bone formation or in fibrous tissue encapsulation. The traditional biomaterial design consisted in fabricating inert biomaterials capable of stimulating osteogenesis; however, inconsistencies between the in vitro and in vivo results were reported. This led to a shift in the development of biomaterials towards implants with osteoimmunomodulatory properties. By endowing the orthopedic biomaterials with favorable osteoimmunomodulatory properties, a desired immune response can be triggered in order to obtain a proper bone regeneration process. In this context, various approaches, such as the modification of chemical/structural characteristics or the incorporation of bioactive molecules, have been employed in order to modulate the crosstalk with the immune cells. The current review provides an overview of recent developments in such applied strategies.

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Dual oxidase 1 limits the IFNγ-associated antitumor effect of macrophages

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000622 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000622

Author(s):

Lydia Meziani ◽

Marine Gerbé de Thoré ◽

Pauline Hamon ◽

Sophie Bockel ◽

Ruy Andrade Louzada ◽

...

Keyword(s):

Antitumor Effect ◽

Therapeutic Strategy ◽

Critical Role ◽

Tumor Development ◽

Intratumoral Injection ◽

Histocompatibility Complex ◽

Dual Oxidase

BackgroundMacrophages play pivotal roles in tumor progression and the response to anticancer therapies, including radiotherapy (RT). Dual oxidase (DUOX) 1 is a transmembrane enzyme that plays a critical role in oxidant generation.MethodsSince we found DUOX1 expression in macrophages from human lung samples exposed to ionizing radiation, we aimed to assess the involvement of DUOX1 in macrophage activation and the role of these macrophages in tumor development.ResultsUsing Duox1−/− mice, we demonstrated that the lack of DUOX1 in proinflammatory macrophages improved the antitumor effect of these cells. Furthermore, intratumoral injection of Duox1−/− proinflammatory macrophages significantly enhanced the antitumor effect of RT. Mechanistically, DUOX1 deficiency increased the production of proinflammatory cytokines (IFNγ, CXCL9, CCL3 and TNFα) by activated macrophages in vitro and the expression of major histocompatibility complex class II in the membranes of macrophages. We also demonstrated that DUOX1 was involved in the phagocytotic function of macrophages in vitro and in vivo. The antitumor effect of Duox1−/− macrophages was associated with a significant increase in IFNγ production by both lymphoid and myeloid immune cells.ConclusionsOur data indicate that DUOX1 is a new target for macrophage reprogramming and suggest that DUOX1 inhibition in macrophages combined with RT is a new therapeutic strategy for the management of cancers.

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An in vitro approach for demonstrating the critical role of serum albumin in the detoxication of the carbamate carbaryl at in vivo toxicologically relevant concentrations

Archives of Toxicology ◽

10.1007/s00204-006-0142-9 ◽

2006 ◽

Vol 81 (2) ◽

pp. 113-119 ◽

Cited By ~ 18

Author(s):

Miguel A. Sogorb ◽

Carlos Álvarez-Escalante ◽

Victoria Carrera ◽

Eugenio Vilanova

Keyword(s):

Serum Albumin ◽

Critical Role

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Review: The endless nutritional and pharmaceutical benefits of the Himalayan gold, Cordyceps; Current knowledge and prospective potentials

Biofarmasi Journal of Natural Product Biochemistry ◽

10.13057/biofar/f180204 ◽

2020 ◽

Vol 18 (2) ◽

Author(s):

Waill Elkhateeb ◽

Ghoson Daba

Keyword(s):

Current Knowledge ◽

Health Benefits ◽

Chemical Compounds ◽

Food Supplement ◽

In Vivo Studies ◽

Protective Agent ◽

Global Marketplace

Abstract. Elkhateeb WA, Daba GM. 2020. Review: The endless nutritional and pharmaceutical benefits of the Himalayan gold, Cordyceps; Current knowledge and prospective potentials. Biofarmasi J Nat Prod Biochem 18: 70-77. As a traditional medicine, Cordyceps has long been used in Asian nations for maintaining vivacity and boosting immunity. Numerous publications on various bioactivities of Cordyceps have been investigated in both in-vitro as well as in vivo studies. Nevertheless, the role of Cordyceps is still arguable whether it acts as food supplement for health benefits or a real healing drug that can be prescribed in medicine. The Cordyceps industry has developed greatly and offers thousands of products, commonly available in a global marketplace. In this review, focus will be on introducing the ecology of Cordyceps and their classification. Moreover, elucidation of the richness of extracts originated from this mushroom in nutritional components was presented, with description of the chemical compounds of Cordyceps and its well-known compounds such as cordycepin, and cordycepic acid. Furthermore, highlights on natural growth and artificial cultivation of famous Cordyceps species were presented. The health benefits and reported bioactivities of Cordyceps species as promising antimicrobial, anticancer, hypocholesterolemic, antioxidant, antiviral, anti-inflammatory, organ protective agent, and enhancer for organ function were presented.

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NUSAP1 Promotes Gastric Cancer Progression Through Regulation of Yap Stability

10.21203/rs.3.rs-33883/v1 ◽

2020 ◽

Author(s):

Hui Guo ◽

Jianping Zou ◽

Ling Zhou ◽

Yan He ◽

Miao Feng ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Target Genes ◽

Hippo Pathway ◽

Critical Role ◽

Xenograft Model ◽

Migration And Invasion

Abstract Background:Nucleolar and spindle associated protein (NUSAP1) is involved in tumor initiation, progression and metastasis. However, there are limited studies regarding the role of NUSAP1 in gastric cancer (GC). Methods: The expression profile and clinical significance of NUSAP1 in GC were analysed in online database using GEPIA, Oncomine and KM plotter, which was further confirmed in clinical specimens.The functional role of NUSAP1 were detected utilizing in vitro and in vivo assays. Western blotting, qRT-PCR, the cycloheximide-chase, immunofluorescence staining and Co-immunoprecipitaion (Co-IP) assays were performed to explore the possible molecular mechanism by which NUSAP1 stabilizes YAP protein. Results:In this study, we found that the expression of NUSAP1 was upregulated in GC tissues and correlates closely with progression and prognosis. Additionally, abnormal NUSAP1 expression promoted malignant behaviors of GC cells in vitro and in a xenograft model. Mechanistically, we discovered that NUSAP1 physically interacts with YAP and furthermore stabilizes YAP protein expression, which induces the transcription of Hippo pathway downstream target genes. Furthermore, the effects of NUSAP1 on GC cell growth, migration and invasion were mainly mediated by YAP. Conclusions:Our data demonstrates that the novel NUSAP1-YAP axis exerts an critical role in GC tumorigenesis and progression, and therefore could provide a novel therapeutic target for GC treatment.

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The Emerging Role of Neutrophil Extracellular Traps in Arterial, Venous and Cancer-Associated Thrombosis

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.786387 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yilu Zhou ◽

Weimin Tao ◽

Fuyi Shen ◽

Weijia Du ◽

Zhendong Xu ◽

...

Keyword(s):

Current Knowledge ◽

Neutrophil Extracellular Traps ◽

Vital Role ◽

Extracellular Traps ◽

Protein Components ◽

Cancer Associated Thrombosis ◽

Coagulation Pathway

Neutrophils play a vital role in the formation of arterial, venous and cancer-related thrombosis. Recent studies have shown that in a process known as NETosis, neutrophils release proteins and enzymes complexed to DNA fibers, collectively called neutrophil extracellular traps (NETs). Although NETs were originally described as a way for the host to capture and kill bacteria, current knowledge indicates that NETs also play an important role in thrombosis. According to recent studies, the destruction of vascular microenvironmental homeostasis and excessive NET formation lead to pathological thrombosis. In vitro experiments have found that NETs provide skeletal support for platelets, red blood cells and procoagulant molecules to promote thrombosis. The protein components contained in NETs activate the endogenous coagulation pathway to promote thrombosis. Therefore, NETs play an important role in the formation of arterial thrombosis, venous thrombosis and cancer-related thrombosis. This review will systematically summarize and explain the study of NETs in thrombosis in animal models and in vivo experiments to provide new targets for thrombosis prevention and treatment.

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