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1.
Tolerogenic Immunotherapy: Targeting DC Surface Receptors to Induce Antigen-Specific Tolerance.
Castenmiller, C, Keumatio-Doungtsop, BC, van Ree, R, de Jong, EC, van Kooyk, Y
Frontiers in immunology. 2021;:643240
Abstract
Dendritic cells (DCs) are well-established as major players in the regulation of immune responses. They either induce inflammatory or tolerogenic responses, depending on the DC-subtype and stimuli they receive from the local environment. This dual capacity of DCs has raised therapeutic interest for their use to modify immune-activation via the generation of tolerogenic DCs (tolDCs). Several compounds such as vitamin D3, retinoic acid, dexamethasone, or IL-10 and TGF-β have shown potency in the induction of tolDCs. However, an increasing interest exists in defining tolerance inducing receptors on DCs for new targeting strategies aimed to develop tolerance inducing immunotherapies, on which we focus particular in this review. Ligation of specific cell surface molecules on DCs can result in antigen presentation to T cells in the presence of inhibitory costimulatory molecules and tolerogenic cytokines, giving rise to regulatory T cells. The combination of factors such as antigen structure and conformation, delivery method, and receptor specificity is of paramount importance. During the last decades, research provided many tools that can specifically target various receptors on DCs to induce a tolerogenic phenotype. Based on advances in the knowledge of pathogen recognition receptor expression profiles in human DC subsets, the most promising cell surface receptors that are currently being explored as possible targets for the induction of tolerance in DCs will be discussed. We also review the different strategies that are being tested to target DC receptors such as antigen-carbohydrate conjugates, antibody-antigen fusion proteins and antigen-adjuvant conjugates.
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2.
Human cell receptors: potential drug targets to combat COVID-19.
Raghav, PK, Kalyanaraman, K, Kumar, D
Amino acids. 2021;(6):813-842
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Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) has announced that COVID-19 is a pandemic having a higher spread rate rather than the mortality. Identification of a potential approach or therapy against COVID-19 is still under consideration. Therefore, it is essential to have an insight into SARS-CoV-2, its interacting partner, and domains for an effective treatment. The present study is divided into three main categories, including SARS-CoV-2 prominent receptor and its expression levels, other interacting partners, and their binding domains. The first section focuses primarily on coronaviruses' general aspects (SARS-CoV-2, SARS-CoV, and the Middle East Respiratory Syndrome Coronaviruses (MERS-CoV)) their structures, similarities, and mode of infections. The second section discusses the host receptors which includes the human targets of coronaviruses like dipeptidyl peptidase 4 (DPP4), CD147, CD209L, Angiotensin-Converting Enzyme 2 (ACE2), and other miscellaneous targets (type-II transmembrane serine proteases (TTSPs), furin, trypsin, cathepsins, thermolysin, elastase, phosphatidylinositol 3-phosphate 5-kinase, two-pore segment channel, and epithelium sodium channel C-α subunit). The human cell receptor, ACE2 plays an essential role in the Renin-Angiotensin system (RAS) pathway and COVID-19. Thus, this section also discusses the ACE2 expression and risk of COVID-19 infectivity in various organs and tissues such as the liver, lungs, intestine, heart, and reproductive system in the human body. Absence of ACE2 protein expression in immune cells could be used for limiting the SARS-CoV-2 infection. The third section covers the current available approaches for COVID-19 treatment. Overall, this review focuses on the critical role of human cell receptors involved in coronavirus pathogenesis, which would likely be used in designing target-specific drugs to combat COVID-19.
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Allosteric targeting of the FFA2 receptor (GPR43) restores responsiveness of desensitized human neutrophils.
Frei, R, Nordlohne, J, Hüser, U, Hild, S, Schmidt, J, Eitner, F, Grundmann, M
Journal of leukocyte biology. 2021;(4):741-751
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Abstract
The G protein-coupled free fatty acid receptor 2 (FFA2R) is highly expressed on neutrophils and was previously described to regulate neutrophil activation. Allosteric targeting of G protein-coupled receptors (GPCRs) is increasingly explored to create distinct pharmacology compared to endogenous, orthosteric ligands. The consequence of allosteric versus orthosteric FFA2R activation for neutrophil response, however, is currently largely elusive. Here, different FFA2R desensitization profiles in human neutrophils following allosteric or orthosteric activation are reported. Using a set of neutrophil functional assays to measure calcium flux, pERK1/2, chemotaxis, cellular degranulation, and oxidative burst together with holistic and pathway-unbiased whole cell sensing based on dynamic mass redistribution, it is found that the synthetic positive allosteric modulator agonist 4-CMTB potently activates neutrophils and simultaneously alters FFA2R responsiveness toward the endogenous, orthosteric agonist propionic acid (C3) after homologous and heterologous receptor desensitization. Stimulation with C3 or the hierarchically superior chemokine receptor activator IL-8 led to strong FFA2R desensitization and rendered neutrophils unresponsive toward repeated stimulation with C3. In contrast, stimulation with allosteric 4-CMTB engaged a distinct composition of signaling pathways as compared to orthosteric receptor activation and was able to activate neutrophils that underwent homologous and heterologous desensitization with C3 and IL-8, respectively. Moreover, allosteric FFA2R activation could re-sensitize FFA2 toward the endogenous agonist C3 after homologous and heterologous desensitization. Given the fact that receptor desensitization is critical in neutrophils to sense and adapt to their current environment, these findings are expected to be useful for the discovery of novel pharmacological mechanisms to modulate neutrophil responsiveness therapeutically.
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Hypermethylated promoters of genes UNC5D and KCNA1 as potential novel diagnostic biomarkers in colorectal cancer.
Uhan, S, Zidar, N, Tomažič, A, Hauptman, N
Epigenomics. 2020;(19):1677-1688
Abstract
Aim: Identification of aberrant hypermethylation in promoter regions of candidate genes to discover potential biomarkers for colorectal cancer. Materials & Methods: Genes BMP2, IRF4, KCNA1, LRRC7, NRG3, SLC27A6 and UNC5D were pre-selected in a bioinformatics study for their hypermethylation status in colorectal cancer. Methylation analysis was performed on 202 cancer tissue specimens to validate candidate genes. Results: Genes KCNA1 and UNC5D displayed methylation in 95.3 and 99.7% of The Cancer Genome Atlas dataset samples and in 96 and 98% of our experimentally tested samples, respectively. Conclusion:KCNA1 and UNC5D promoter hypermethylation holds diagnostic biomarker potential in patients with early colorectal cancer.
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A simple and rapid pipeline for identification of receptor-binding sites on the surface proteins of pathogens.
Mertinková, P, Kulkarni, A, Káňová, E, Bhide, K, Tkáčová, Z, Bhide, M
Scientific reports. 2020;(1):1163
Abstract
Ligand-receptor interactions play a crucial role in the plethora of biological processes. Several methods have been established to reveal ligand-receptor interface, however, the majority of methods are time-consuming, laborious and expensive. Here we present a straightforward and simple pipeline to identify putative receptor-binding sites on the pathogen ligands. Two model ligands (bait proteins), domain III of protein E of West Nile virus and NadA of Neisseria meningitidis, were incubated with the proteins of human brain microvascular endothelial cells immobilized on nitrocellulose or PVDF membrane, the complex was trypsinized on-membrane, bound peptides of the bait proteins were recovered and detected on MALDI-TOF. Two peptides of DIII (~916 Da and ~2003 Da) and four peptides of NadA (~1453 Da, ~1810 Da, ~2051 Da and ~2433 Da) were identified as plausible receptor-binders. Further, binding of the identified peptides to the proteins of endothelial cells was corroborated using biotinylated synthetic analogues in ELISA and immunocytochemistry. Experimental pipeline presented here can be upscaled easily to map receptor-binding sites on several ligands simultaneously. The approach is rapid, cost-effective and less laborious. The proposed experimental pipeline could be a simpler alternative or complementary method to the existing techniques used to reveal amino-acids involved in the ligand-receptor interface.
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The Evolving Complexity of Treating Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-2 (HER2)-Negative Breast Cancer: Special Considerations in Older Breast Cancer Patients-Part I: Early-Stage Disease.
Sammons, S, Sedrak, MS, Kimmick, GG
Drugs & aging. 2020;(5):331-348
Abstract
The median age for breast cancer diagnosis is 62 years, but a disproportionate number of patients are over the age of 75 years and the majority of those have hormone receptor-positive, human epidermal growth factor receptor-2 (HER2)-negative cancers. This review provides a logical algorithm to guide providers through the many complicated issues involved in adjuvant systemic therapy decisions in older patients with hormone receptor-positive, HER2-negative breast cancer. For this subtype of breast cancer, the mainstay of treatment is surgery and adjuvant endocrine therapy with tamoxifen or an aromatase inhibitor (AI). Adjuvant chemotherapy is added to the treatment regimen when the benefits of treatment are deemed to outweigh the risks, making the risk-benefit discussion particularly important in older women. Traditional tools for cancer risk assessment and genomic expression profiles (GEPs) are under-utilized in older patients, but yield equally useful information about cancer prognosis as they do in younger patients. Additionally, there are tools that estimate life-limiting toxicity risk from chemotherapy and life expectancy, which are both important issues in the risk-benefit discussion. For very low-risk cancers, such as non-invasive and small lymph node (LN)-negative cancers, the benefits of any adjuvant therapy is likely outweighed by the risks, but endocrine therapy might be considered to prevent future new breast cancers. For invasive tumors that are > 5 mm (T1b or larger) or involve LNs, adjuvant endocrine therapy is recommended. Generally, AIs should be included, though tamoxifen is effective and should be offered when AIs are not tolerated. Bone-preserving agents and high-dose vitamin D are options to preserve bone density or treat osteoporosis, especially in older women who are taking AIs. Where the risk-reducing benefit from adjuvant chemotherapy outweighs the toxicity risk, adjuvant chemotherapy should be considered. Adjuvant chemotherapy has similar benefits in older and younger patients and standard regimens are preferred. Several exciting clinic trials are underway and have included older patients, including those adding molecularly targeted agents, cyclin-dependent kinase (CDK) 4/6 inhibitors and everolimus, to endocrine therapy in the adjuvant setting. The high incidence of breast cancer in older women should drive us to design clinical trials for this population and emphasize their inclusion in ongoing trials as much as possible.
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Receptor-Like Kinases Sustain Symbiotic Scrutiny.
Chiu, CH, Paszkowski, U
Plant physiology. 2020;(4):1597-1612
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Abstract
Plant receptor-like kinases (RLKs) control the initiation, development, and maintenance of symbioses with beneficial mycorrhizal fungi and nitrogen-fixing bacteria. Carbohydrate perception activates symbiosis signaling via Lysin-motif RLKs and subsequently the common symbiosis signaling pathway. As the receptors activated are often also immune receptors in multiple species, exactly how carbohydrate identities avoid immune activation and drive symbiotic outcome is still not fully understood. This may involve the coincident detection of additional signaling molecules that provide specificity. Because of the metabolic costs of supporting symbionts, the level of symbiosis development is fine-tuned by a range of local and mobile signals that are activated by various RLKs. Beyond early, precontact symbiotic signaling, signal exchanges ensue throughout infection, nutrient exchange, and turnover of symbiosis. Here, we review the latest understanding of plant symbiosis signaling from the perspective of RLK-mediated pathways.
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Platelet Apoptosis Can Be Triggered Bypassing the Death Receptors.
Leytin, V, Gyulkhandanyan, AV, Freedman, J
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2019;:1076029619853641
Abstract
In nucleated cells, the extrinsic pathway of the programmed cell death (apoptosis) is triggered by interaction of death ligands of the tumor necrosis factor superfamily with the death receptors on external cell surface membrane. In this review, we present evidence that, in contrast to nucleated cells, apoptosis in anucleate platelets can be induced through bypassing the death receptors, using instead specific receptors on the platelet surface mediating platelet activation, aggregation, and blood coagulation. These platelet surface receptors include the protease-activated receptor 1 of thrombin and glycoproteins IIbIIIa and Ibα, receptors of fibrinogen, and von Willebrand factor. The pro-apoptotic BH3 mimetic ABT-737 and calcium ionophore A23187 also trigger platelet apoptosis without using death receptors. These agents induce the intrinsic pathway of platelet apoptosis by direct targeting mitochondrial and extra-mitochondrial apoptotic responses.
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Soluble CD163 correlates with lipid metabolic adaptations in type 1 diabetes patients during ketoacidosis.
Svart, M, Rittig, N, Møller, N, Møller, HJ, Gronbaek, H
Journal of diabetes investigation. 2019;(1):67-72
Abstract
INTRODUCTION Diabetic ketoacidosis (DKA) is associated with inflammation and increased lipolysis. The macrophage activation marker, soluble CD163 (sCD163), is associated with obesity, non-alcoholic fatty liver disease and type 2 diabetes. We aimed to investigate whether sCD163 correlates with key elements of lipolysis in type 1 diabetes patients during mild DKA. MATERIALS AND METHODS We investigated nine patients with type 1 diabetes twice during: (i) euglycemic control conditions and a bolus of saline; and (ii) hyperglycemic ketotic conditions induced by lipopolysaccharide administration combined with insulin deprivation. Blood samples, indirect calorimetry, palmitate tracer and adipose tissue biopsies were used to investigate lipid metabolism. RESULTS We observed a significant increase in plasma sCD163 levels after lipopolysaccharide exposure (P < 0.001). Concentrations of sCD163 were positively correlated with plasma concentrations of free fatty acids, palmitate rate of appearance and lipid oxidation rates, and negatively correlated to the expression of G0/G1 switch 2 gene messenger ribonucleic acid content in adipose tissue (P < 0.01 for all). Furthermore, sCD163 levels correlated positively with plasma peak concentrations of cortisol, glucagon, tumor necrosis factor-α, interleukin-6 and interleukin-10 (P < 0.01 for all). Data on lipolysis and inflammation have previously been published. CONCLUSIONS Macrophage activation assessed by sCD163 might play an important role in DKA, as it correlates strongly with important components of lipid metabolism including free fatty acids, palmitate, lipid oxidation, G0/G1 switch 2 gene and pro-inflammatory cytokines during initial steps of DKA. These results are novel and add important knowledge to the field of DKA.
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Clinical, genetic, and molecular characterization of hyperphosphatasia with mental retardation: a case report and literature review.
Abi Farraj, L, Khatoun, WD, Abou Chebel, N, Wakim, V, Dawali, K, Ghassibe-Sabbagh, M
Diagnostic pathology. 2019;(1):123
Abstract
BACKGROUND Hyperphosphatasia with mental retardation syndrome (HPMRS) is a recessive disorder characterized by high blood levels of alkaline phosphatase together with typical dysmorphic signs such as cleft palate, intellectual disability, cardiac abnormalities, and developmental delay. Genes involved in the glycosylphosphatidylinositol pathway and known to be mutated in HPMRS have never been characterized in the Lebanese population. CASE PRESENTATION Herein, we describe a pair of monozygotic twins presenting with severe intellectual disability, distinct facial dysmorphism, developmental delay, and increased alkaline phosphatase level. Two individuals underwent whole exome sequencing followed by Sanger sequencing to confirm the co-segregation of the mutation in the consanguineous family. A biallelic loss of function mutation in PGAP3 was detected. Both patients were homozygous for the c.203delC (p.C68LfsX88) mutation and the parents were carriers confirming the founder effect of the mutation. High ALP serum levels confirmed the molecular diagnosis. CONCLUSION Our findings have illustrated the genomic profile of PGAP3-related HPMRS which is essential for targeted molecular and genetic testing. Moreover, we found previously unreported clinical findings such as hypodontia and skin hyperpigmentation. These features, together with the novel mutation expand the phenotypic and genotypic spectrum of this rare recessive disorder.