-
Journal of Virology Feb 2023Rabies virus (RABV) is a prototypical neurotropic virus that causes rabies in human and animals with an almost 100% mortality rate. Once RABV enters the central nervous...
Rabies virus (RABV) is a prototypical neurotropic virus that causes rabies in human and animals with an almost 100% mortality rate. Once RABV enters the central nervous system, no treatment is proven to prevent death. RABV glycoprotein (G) interacts with cell surface receptors and then enters cells via clathrin-mediated endocytosis (CME); however, the key host factors involved remain largely unknown. Here, we identified transferrin receptor 1 (TfR1), a classic receptor that undergoes CME, as an entry factor for RABV. TfR1 interacts with RABV G and is involved in the endocytosis of RABV. An antibody against TfR1 or the TfR1 ectodomain soluble protein significantly blocked RABV infection in HEK293 cells, N2a cells, and mouse primary neuronal cells. We further found that the endocytosis of TfR1 is coupled with the endocytosis of RABV and that TfR1 and RABV are transported to early and late endosomes. Our results suggest that RABV hijacks the transport pathway of TfR1 for entry, thereby deepening our understanding of the entry mechanism of RABV. For most viruses, cell entry involves engagement with many distinct plasma membrane components, each of which is essential. After binding to its specific receptor(s), rabies virus (RABV) enters host cells through the process of clathrin-mediated endocytosis. However, whether the receptor-dependent clathrin-mediated endocytosis of RABV requires other plasma membrane components remain largely unknown. Here, we demonstrate that transferrin receptor 1 (TfR1) is a functional entry factor for RABV infection. The endocytosis of RABV is coupled with the endocytosis of TfR1. Our results indicate that RABV hijacks the transport pathway of TfR1 for entry, which deepens our understanding of the entry mechanism of RABV.
Topics: Animals; Humans; Mice; Clathrin; HEK293 Cells; Rabies; Rabies virus; Receptors, Transferrin; Virus Internalization; Cell Line; Endocytosis
PubMed: 36779762
DOI: 10.1128/jvi.01612-22 -
Expert Opinion on Biological Therapy May 2021: Recent advances in immuno-oncology and bioengineering have rekindled the interest in monoclonal antibody (mAb)-based immunotherapies for malignancies. Crucial for...
: Recent advances in immuno-oncology and bioengineering have rekindled the interest in monoclonal antibody (mAb)-based immunotherapies for malignancies. Crucial for their success is the identification of tumor antigens (TAs) that can serve as targets. B7-H3, a member of the B7 ligand family, represents such a TA. Although its exact functions and receptor(s) remain unclear, B7-H3 has predominantly a pro-tumorigenic effect mainly by suppressing the anti-tumor functions of T-cells.: Initially we present a historical perspective on TA-specific antibodies for diagnosis and treatment of malignancies. Following a description of the TA requirements to be an attractive antibody-based immunotherapy target, we show that B7-H3 fulfills these criteria. We discuss its structure and functions. In a review and pooled analysis, we describe the limited B7-H3 expression in normal tissues and estimate B7-H3 expression frequency in tumors, tumor-associated vasculature and cancer initiating cells (CICs). Lastly, we discuss the association of B7-H3 expression in tumors with poor prognosis.: B7-H3 is an attractive target for mAb-based cancer immunotherapy. B7-H3-targeting strategies are expected to be highly effective and - importantly - safe. To fully exploit the diagnostic and therapeutic potential of B7-H3, its expression in pre-malignant lesions, serum, metastases, and CICs requires further investigation.
Topics: Antibodies, Monoclonal; Antigens, Neoplasm; B7 Antigens; Humans; Immunotherapy; Neoplasms
PubMed: 33301369
DOI: 10.1080/14712598.2021.1862791 -
Stress (Amsterdam, Netherlands) Nov 2020There is evidence that plasma cortisol concentration can be either increased or decreased in patients with depression and related anxiety and stress-related disorders;... (Review)
Review
There is evidence that plasma cortisol concentration can be either increased or decreased in patients with depression and related anxiety and stress-related disorders; the exact pathophysiological mechanisms of this state are not almost clear. Several distinct theories were proposed and mechanisms, which could lead to decreased glucocorticoid signaling and/or levels, were described. However, there is a possible drawback in almost all the theories proposed: insufficient attention to the inflammatory process, which is undoubtedly present in several stress-related disorders, including post-traumatic stress disorder (PTSD). Previous studies only briefly mentioned the presence of an inflammatory reaction's signs in PTSD, without giving it due importance, although recognizing that it can affect the course of the disease. With that, the state of biochemical changes, characterized by the low glucocorticoids, glucocorticoid receptor's resistance and the signs of the persistent inflammation (with the high levels of circulating cytokines) might be observed not only in PTSD but in coronary heart diseases and systemic chronic inflammatory diseases (rheumatoid arthritis) as well. That is why the present review aims to depict the pathophysiological mechanisms, which lead to a decrease in glucocorticoids in PTSD due to the action of inflammatory stimuli. We described changes in the glucocorticoid system and inflammatory reaction as parts of an integral system, where glucocorticoids and the glucocorticoid receptor reside at the apex of a regulatory network that blocks several inflammatory pathways, while decreased glucocorticoid signaling and/or level leads to unchecked inflammatory reactions to promote pathologies such as PTSD. LAY SUMMARY This review emphasizes the importance of inflammatory reaction in the development of puzzling conditions sometimes observed in severe diseases including post-traumatic stress disorder - the decreased levels of glucocorticoids in the blood. Following the classical concepts, one would expect an increase in glucocorticoid hormones, since they are part of the feedback mechanism in the immune system, which reduces stress and inflammation. However, low levels of glucocorticoid hormones are also observed. Thus, this review describes potential mechanisms, which can lead to the development of such a state.
Topics: Glucocorticoids; Humans; Inflammation; Receptors, Glucocorticoid; Stress Disorders, Post-Traumatic; Stress, Psychological
PubMed: 32401103
DOI: 10.1080/10253890.2020.1766020 -
Neurological Sciences : Official... Apr 2024Immunoglobulin G (IgG) autoantibodies can lead to the formation of autoimmune diseases through Fab and/or Fc-mediated interactions with host molecules as well as... (Review)
Review
Immunoglobulin G (IgG) autoantibodies can lead to the formation of autoimmune diseases through Fab and/or Fc-mediated interactions with host molecules as well as activated T cells. The neonatal Fc receptor (FcRn) binds at acidic pH IgG and albumin, and the mechanism for prolonging serum IgG half-life is making IgG re-entry into circulation by prompting it not to be degraded by lysosomes and back to the cell surface. Given the FcRn receptor's essential role in IgG homeostasis, one of the strategies to promote the quick degradation of endogenous IgG is to suppress the function of FcRn, which is beneficial to the treatment of IgG-driven autoimmune disorders like myasthenia gravis (MG), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), stiff person syndrome, and immune thrombocytopenia (ITP). We elaborately read the literature about efgartigimod and systematically reviewed the research progress and clinical application of this novel FcRn inhibitor in autoimmune diseases. Efgartigimod is the firstly FcRn antagonist developed and was approved on 17 December 2021 by the United States for the therapy of acetylcholine receptor-positive MG. In January 2022, efgartigimod received its second regulatory approval in Japan. In addition, the market authorization application in Europe was submitted and validated in August 2021. China's National Medical Products Administration officially accepted the marketing application of efgartigimod on July 13, 2022. To suppress the function of FcRn, which is beneficial to the treatment of IgG-driven autoimmune disorders like MG, CIDP, ITP, and stiff person syndrome. We review the rationale, clinical evidence, and future perspectives of efgartigimod for the treatment of autoimmune disease.
PubMed: 38644454
DOI: 10.1007/s10072-024-07460-5 -
International Journal of Molecular... Jul 2022The P2X7 receptor (P2X7R) is an ATP-gated membrane ion channel that is expressed by multiple cell types. Following activation by extracellular ATP, the P2X7R mediates a... (Review)
Review
The P2X7 receptor (P2X7R) is an ATP-gated membrane ion channel that is expressed by multiple cell types. Following activation by extracellular ATP, the P2X7R mediates a broad range of cellular responses including cytokine and chemokine release, cell survival and differentiation, the activation of transcription factors, and apoptosis. The P2X7R is made up of three P2X7 subunits that contain specific domains essential for the receptor's varied functions. Alternative splicing produces P2X7 isoforms that exclude one or more of these domains and assemble in combinations that alter P2X7R function. The modification of the structure and function of the P2X7R may adversely affect cellular responses to carcinogens and pathogens, and alternatively spliced (AS) P2X7 isoforms have been associated with several cancers. This review summarizes recent advances in understanding the structure and function of AS P2X7 isoforms and their associations with cancer and potential role in modulating the inflammatory response.
Topics: Adenosine Triphosphate; Cytokines; Humans; Neoplasms; Protein Isoforms; Receptors, Purinergic P2X7
PubMed: 35897750
DOI: 10.3390/ijms23158174 -
Current Problems in Cardiology Jan 2024Low-density lipoprotein (LDL) and oxidized LDL (oxLDL) are major contributors to atherogenesis, as endogenous antigens, via several receptors such as LOX 1. A PubMed... (Review)
Review
Low-density lipoprotein (LDL) and oxidized LDL (oxLDL) are major contributors to atherogenesis, as endogenous antigens, via several receptors such as LOX 1. A PubMed search was conducted in order to identify relevant articles regarding LOX-1's role in the atherosclerosis, diagnosis, prognostic use and molecules that could be used for therapy. The references of the manuscripts obtained were also reviewed, in order to find additional relevant bibliography. LOX-1 is a lectin-like pattern recognition receptor, mostly expressed in endothelial cells (ECs) which can bind a variety of molecules, including oxLDL and C-reactive protein (CRP). LOX-1 plays a key role in oxLDL's role as a causative agent of atherosclerosis through several pathologic mechanisms, such as oxLDL deposition in the subintima, foam cell formation and endothelial dysfunction. Additionally, LOX-1 acts a scavenger receptor for oxLDL in macrophages and can be responsible for oxLDL uptake, when stimulated. Serum LOX-1 (sLOX-1) has emerged as a new, potential biomarker for diagnosis of acute coronary syndromes, and it seems promising for use along with other common biomarkers in everyday clinical practice. In a therapeutic perspective, natural as well as synthetic molecules exert anti-LOX-1 properties and attain the receptor's pathophysiological effects, thus extensive research is ongoing to further evaluate molecules with therapeutic potential. However, most of these molecules need further trials in order to properly assess their safety and efficacy for clinical use. The aim of this review is to investigate LOX-1 role in atherogenesis and explore its potential as diagnostic tool and therapeutic target.
Topics: Humans; Endothelial Cells; Scavenger Receptors, Class E; Atherosclerosis
PubMed: 37802161
DOI: 10.1016/j.cpcardiol.2023.102117 -
Journal of Virology May 2023Arthritogenic alphaviruses, including chikungunya virus (CHIKV), preferentially target joint tissues and cause chronic rheumatic disease that adversely impacts the...
Arthritogenic alphaviruses, including chikungunya virus (CHIKV), preferentially target joint tissues and cause chronic rheumatic disease that adversely impacts the quality of life of patients. Viruses enter target cells via interaction with cell surface receptor(s), which determine the viral tissue tropism and pathogenesis. Although MXRA8 is a recently identified receptor for several clinically relevant arthritogenic alphaviruses, its detailed role in the cell entry process has not been fully explored. We found that in addition to its localization on the plasma membrane, MXRA8 is present in acidic organelles, endosomes, and lysosomes. Moreover, MXRA8 is internalized into cells without a requirement for its transmembrane and cytoplasmic domains. Confocal microscopy and live cell imaging revealed that MXRA8 interacts with CHIKV at the cell surface and then enters cells along with CHIKV particles. At the moment of membrane fusion in the endosomes, many viral particles are still colocalized with MXRA8. These findings provide insight as to how MXRA8 functions in alphavirus internalization and suggest possible targets for antiviral development. The globally distributed arthritogenic alphaviruses have infected millions of humans and induce rheumatic disease, such as severe polyarthralgia/polyarthritis, for weeks to years. Alphaviruses infect target cells through receptor(s) followed by clathrin-mediated endocytosis. MXRA8 was recently identified as an entry receptor that shapes the tropism and pathogenesis for multiple arthritogenic alphaviruses, including chikungunya virus (CHIKV). Nonetheless, the exact functions of MXRA8 during the process of viral cell entry remain undetermined. Here, we have provided compelling evidence for MXRA8 as a bona fide entry receptor that mediates the uptake of alphavirus virions. Small molecules that disrupt MXRA8-dependent binding of alphaviruses or internalization steps could serve as a platform for unique classes of antiviral drugs.
Topics: Humans; Chikungunya virus; Virus Internalization; Membrane Fusion; Quality of Life; Chikungunya Fever; Rheumatic Diseases
PubMed: 37133449
DOI: 10.1128/jvi.01557-22 -
Journal of Medicinal Chemistry Sep 2020One of the three subtypes of the peroxisome proliferator-activated receptor (PPAR) functioning as a transcription factor is the PPARβ or PPARδ. PPARδ is crucial to... (Review)
Review
One of the three subtypes of the peroxisome proliferator-activated receptor (PPAR) functioning as a transcription factor is the PPARβ or PPARδ. PPARδ is crucial to pathophysiological processes, including metabolic disorders, liver diseases, and cardiovascular diseases. In the past, the clinical development of PPARδ-selective agonist drugs has been stalled due to potential safety-related issues. Despite the elusiveness of such a drug, efforts continue in developing drugs that target PPARδ due to advances in the knowledge of the PPARδ receptor's structure and functions. While several preclinical and clinical studies are reported on PPARδ agonists, there is limited data with no clinical evidence available for PPARδ-selective antagonists. In this review, we mainly focus on the challenges of PPARδ selectivity and the medicinal chemistry of most active agonists discovered by different pharmaceutical companies and institutes. With this in mind, we also provide an update on the development status of PPARδ agonists that are undergoing clinical trials and their therapeutic promise for the treatment of various diseases.
Topics: Animals; Chemistry, Pharmaceutical; Humans; Molecular Structure; Organic Chemicals; PPAR delta; Structure-Activity Relationship
PubMed: 32539376
DOI: 10.1021/acs.jmedchem.9b01882 -
European Journal of Medicinal Chemistry Feb 2020In the last few decades, considerable progress has been made in anticancer agents development, and several new anticancer agents of natural and synthetic origin have... (Review)
Review
In the last few decades, considerable progress has been made in anticancer agents development, and several new anticancer agents of natural and synthetic origin have been produced. Among heterocyclic compounds, thiazole, a 5-membered unique heterocyclic motif containing sulphur and nitrogen atoms, serves as an essential core scaffold in several medicinally important compounds. Thiazole nucleus is a fundamental part of some clinically applied anticancer drugs, such as dasatinib, dabrafenib, ixabepilone, patellamide A, and epothilone. Recently, thiazole-containing compounds have been successfully developed as possible inhibitors of several biological targets, including enzyme-linked receptor(s) located on the cell membrane, (i.e., polymerase inhibitors) and the cell cycle (i.e., microtubular inhibitors). Moreover, these compounds have been proven to exhibit high effectiveness, potent anticancer activity, and less toxicity. This review presents current research on thiazoles and elucidates their biological importance in anticancer drug discovery. The findings may aid researchers in the rational design of more potent and bio-target specific anticancer drug molecules.
Topics: Animals; Antineoplastic Agents; Cell Proliferation; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Enzymes; Humans; Molecular Structure; Thiazoles
PubMed: 31926469
DOI: 10.1016/j.ejmech.2019.112016 -
Frontiers in Nephrology 2023Insulin is a hormone that is composed of 51 amino acids and structurally organized as a hexamer comprising three heterodimers. Insulin is the central hormone involved in... (Review)
Review
Insulin is a hormone that is composed of 51 amino acids and structurally organized as a hexamer comprising three heterodimers. Insulin is the central hormone involved in the control of glucose and lipid metabolism, aiding in processes such as body homeostasis and cell growth. Insulin is synthesized as a large preprohormone and has a leader sequence or signal peptide that appears to be responsible for transport to the endoplasmic reticulum membranes. The interaction of insulin with the kidneys is a dynamic and multicenter process, as it acts in multiple sites throughout the nephron. Insulin acts on a range of tissues, from the glomerulus to the renal tubule, by modulating different functions such as glomerular filtration, gluconeogenesis, natriuresis, glucose uptake, regulation of ion transport, and the prevention of apoptosis. On the other hand, there is sufficient evidence showing the insulin receptor's involvement in renal functions and its responsibility for the regulation of glucose homeostasis, which enables us to understand its contribution to the insulin resistance phenomenon and its association with the progression of diabetic kidney disease.
PubMed: 37675359
DOI: 10.3389/fneph.2023.1133352