• AKI
• CKD
• hypertension
• hypertension and cardiorenal disorders
• immunology
• kidney transplantation

• TKI-PPP Health∼Holland

• Adenosine diphosphate (ADP)
• Adenosine-5’-triphosphate (ATP)
• And pars plana vitrectomy
• Apoptosis
• Rhegmatogenous retinal detachment (RRD)

• JP17K11455 Japan Society for the Promotion of Science
• 2020 Japanese Ophthalmological Society Council Award

• ATP-induced cell death
• Breast cancer
• Prognostic model
• mRNA
• miRNA

• BzATP
• P2X7 receptor knockout mice
• P2X7 receptors
• endogenous progenitors
• ependymal cells
• purinergic signaling
• regeneration
• spinal cord injury

• ATP
• P2x7
• cancer
• immunity
• purinergic
• tumor microenvironment

• Age-related macular degeneration
• Macrophage
• Microglia
• P2X7
• Retina
• Uveitis

• P2X7
• microglia
• photoreceptors
• retinopathy
• sodium iodate

• MOST 110-2314-B-567 - 003 - MY3; NSCCMOH-145-61 Ministry of Science and Technology, Taiwan
• NTUHYL109.S010 National Taiwan University

We have previously showed that plasma membrane cholesterol and GM1 ganglioside content are responsible for the opposite sensitivity of mouse leukemic T cells to ATP. We also reported that the sensitivity of CD4⁺ and CD8⁺ T cells to ATP depends on their stage of differentiation. Here, we show that CD4⁺ and CD8⁺ T cells from B6 mice express different levels of membrane GM1 and P2X7 but similar levels of cholesterol. Thus, in CD4⁺ T cells, membrane cholesterol content negatively correlated with ATP/P2X7-induced CD62L shedding but positively correlated with pore formation, phosphatidylserine externalization, and cell death. By contrast, in CD8⁺ T cells, cholesterol, GM1, and P2X7 levels negatively correlated with all these ATP/P2X7-induced cellular responses. The relationship between cholesterol and P2X7-induced cellular responses was confirmed by modulating cholesterol levels either ex vivo or through a high-fat diet. Membrane cholesterol enrichment ex vivo led to a significant reduction in all P2X7-induced cellular responses in T cells. Importantly, diet-induced hypercholesterolemia in B6 mice was also associated with decreased sensitivity to ATP in CD4⁺ and CD8⁺ T cells, highlighting the relationship between cholesterol intake and the amplitudes of P2X7-induced cellular responses in T cells.

• P2X7 receptor
• T-cell subsets
• cholesterol
• high fat diet

• P2X7 receptor
• apoptosis
• endocrine disruptors
• lung toxicity
• mitochondrial alterations
• placental toxicity
• skin toxicity

• Apoptotic platelets
• P2X1 receptor
• P2X7 receptor
• Platelets
• extracellular vesicles

ATP, one of the signaling molecules most commonly secreted in the nervous system and capable of stimulating multiple pathways, binds to the ionotropic purinergic receptors, in particular, the P2X₇ receptor (P2X₇R) and stimulates neuronal cell death. Given this effect of purinergic receptors on the viability of dopaminergic neurons model cells and that Ras GTPases control Erk1/2-regulated mitogen-activated cell proliferation and survival, we have investigated the role of the small GTPases of the Ras superfamily, together with their regulatory and effector molecules as the potential molecular intermediates in the P2X₇R-regulated cell death of SN4741 dopaminergic neurons model cells. Here, we demonstrate that the neuronal response to purinergic stimulation involves the Calmodulin/RasGRF1 activation of the small GTPase Ras and Erk1/2. We also demonstrate that tyrosine phosphatase PTPRβ and other tyrosine phosphatases regulate the small GTPase activation pathway and neuronal viability. Our work expands the knowledge on the intracellular responses of dopaminergic cells by identifying new participating molecules and signaling pathways. In this sense, the study of the molecular circuitry of these neurons is key to understanding the functional effects of ATP, as well as considering the importance of these cells in Parkinson’s Disease.

• Erk1/2
• P2X7 receptor
• Parkinson’s
• Ras GTPase
• dopaminergic neurons
• hPTPRβ

• Calcium
• Cation channel
• NLRP3 inflammasome
• P2X7 receptor
• Purino-receptor

• Colorectal cancer
• P13/Akt
• P2X7 receptor
• Proliferation

• Animals
• Antineoplastic Agents/pharmacology
• Calcium Signaling
• Cell Movement
• Cell Proliferation/drug effects
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/enzymology
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Epithelial-Mesenchymal Transition/drug effects
• Gene Expression Regulation, Neoplastic
• Glycogen Synthase Kinase 3 beta/metabolism
• HCT116 Cells
• Humans
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Invasiveness
• Phosphatidylinositol 3-Kinase/metabolism
• Phosphoinositide-3 Kinase Inhibitors/pharmacology
• Phosphorylation
• Proto-Oncogene Proteins c-akt/metabolism
• Purinergic P2X Receptor Agonists/pharmacology
• Purinergic P2X Receptor Antagonists/pharmacology
• Receptors, Purinergic P2X7/drug effects
• Receptors, Purinergic P2X7/genetics
• Receptors, Purinergic P2X7/metabolism
• Tumor Burden
• Xenograft Model Antitumor Assays
• Mice

Background: Bisphenol A (BPA), a reprotoxic and endocrine-disrupting chemical, has been substituted by alternative bisphenols such as bisphenol F (BPF) and bisphenol S (BPS) in the plastic industry. Despite their detection in placenta and amniotic fluids, the effects of bisphenols on human placental cells have not been characterized. Our objective was to explore in vitro and to compare the toxicity of BPA to its substitutes BPF and BPS to highlight their potential risks for placenta and then pregnancy. Methods: Human placenta cells (JEG-Tox cells) were incubated with BPA, BPF, and BPS for 72 h. Cell viability, cell death, and degenerative P2X7 receptor and caspases activation, and chromatin condensation were assessed using microplate cytometry and fluorescence microscopy. Results: Incubation with BPA, BPF, or BPS was associated with P2X7 receptor activation and chromatin condensation. BPA and BPF induced more caspase-1, caspase-9, and caspase-3 activation than BPS. Only BPF enhanced caspase-8 activity. Conclusions: BPA, BPF, and BPS are all toxic to human placental cells, with the P2X7 receptor being a common key element. BPA substitution by BPF and BPS does not appear to be a safe alternative for human health, particularly for pregnant women and their fetuses.

• P2X7 receptor
• apoptosis
• bisphenol A
• bisphenol F
• bisphenol S
• human placental toxicity
• inflammasome

• connexin
• cytokines
• epithelial-mesenchymal transition
• gap junction intercellular communication
• hemichannels
• immune system
• inflammasome
• pannexin
• purinergic system
• tumor microenvironment

• Adenosine Triphosphate/metabolism
• Animals
• Cell Communication/immunology
• Cell Communication/physiology
• Connexins/physiology
• Cytokines/immunology
• Epithelial-Mesenchymal Transition/physiology
• Gap Junctions/physiology
• Humans
• Immunity, Innate
• Inflammasomes/immunology
• Models, Biological
• Neoplasm Invasiveness/pathology
• Neoplasm Invasiveness/physiopathology
• Neoplasm Metastasis/pathology
• Neoplasm Metastasis/physiopathology
• Neoplasms/pathology
• Neoplasms/physiopathology
• Neoplasms/therapy
• Tumor Escape
• Tumor Microenvironment/immunology
• Tumor Microenvironment/physiology

• Atractylodes lancea (Thunb) D.C
• LC-MS/MS
• bile duct
• cancer

• P2RX7
• infection
• inflammasome
• inflammatory
• purinergic

• Alarmins/immunology
• Animals
• Bacteria/immunology
• Fungi/immunology
• Helminths/immunology
• Host-Pathogen Interactions/immunology
• Host-Pathogen Interactions/physiology
• Humans
• Inflammation/immunology
• Parasites/immunology
• Receptors, Purinergic P2X7/immunology
• Signal Transduction/immunology
• Viruses/immunology

• K08 AI120806 NIAID NIH HHS
• R01 DA052255 NIDA NIH HHS
• R21 AI152833 NIAID NIH HHS
• HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)

• ATP
• Bone metabolism diseases
• Osteoblasts
• Osteoclasts
• P2X7 receptor

P2X purinergic receptors are extracellular ATP-gated ion channel receptors present on the cell plasma membrane. P2X receptors have been found in Metazoa, fungi, amoebas, and in plants. In mammals, P2X7 is expressed by a large number of cell types and is involved in inflammation and immunity. Remarkably, P2X7 does not desensitize as other P2X do, a feature linked to a “C-cysteine anchor” intra-cytoplasmic motif encoded by exon 11. Another specific feature of P2X7 is its C-terminal cytoplasmic ballast domain (exon 13) which contains a zinc (Zn) coordinating cysteine motif and a GDP-binding region. To determine the origin of P2X7, we analyzed and compared sequences and protein motifs of the C-terminal intra-cytoplasmic region across all main groups of Metazoa. We identified proteins with typical ballast domains, sharing a remarkably conserved Zn-coordinating cysteine motif. Apart from vertebrates, these ballast domains were not associated with a typical P2X architecture. These results strongly suggest that P2X7 resulted from the fusion of a P2X gene, highly similar to P2X4, with an exon encoding a ballast domain. Our work brings new evidence on the origin of the P2X7 purinergic receptor and identifies the Zn-coordinating cysteine domain as the fundamental feature of the ancient ballast fold.

• NANOR-like proteins
• P2X7
• ballast domain
• evolution
• purinercic receptors

• ASC
• ATP
• Caspase-1
• Grouper
• Immune
• Interaction

• Adenosine Triphosphate/immunology
• Animals
• Bass/genetics
• Bass/immunology
• CARD Signaling Adaptor Proteins/genetics
• CARD Signaling Adaptor Proteins/immunology
• Caspase 1/genetics
• Caspase 1/immunology
• Cloning, Molecular
• Fish Diseases/immunology
• Gene Expression Regulation
• Immunity, Innate
• Phylogeny
• Signal Transduction/immunology

• P2X7
• alternative splicing
• heteromer
• single nucleotide polymorphism

• Apoptosis
• Bax
• Bcl-2
• Leishmania
• Macrophage
• Transgenic
• miRNA

• Enteric glial cells
• GFAP
• Ischemia and reperfusion
• P2X7 receptor
• S100β

• Apoptosis
• Caspases
• Extracellular ATP
• Immune response
• Paralichthys olivaceus
• Teleost

• Adenosine Triphosphate/pharmacology
• Animals
• Apoptosis/drug effects
• Apoptosis/physiology
• Caspase 2/genetics
• Caspase 2/physiology
• Caspase 3/genetics
• Caspase 3/physiology
• Caspase 6/genetics
• Caspase 6/physiology
• Caspase 8/genetics
• Caspase 8/physiology
• Fish Proteins/genetics
• Fish Proteins/physiology
• Flounder/genetics
• Flounder/immunology
• Gene Expression Regulation/drug effects
• Genes/drug effects
• Immunity, Innate/drug effects
• Immunity, Innate/immunology
• Lipopolysaccharides/pharmacology
• Phylogeny
• Real-Time Polymerase Chain Reaction/veterinary
• Sequence Alignment/veterinary
• Sequence Analysis, DNA/veterinary

• 31572645 the National Natural Science Foundation of China
• NA the University Yong Talent Cultivation Program provided by Tianjin Municipal Education Commission
• 52XC1503 the Science Promotion Program for Young Scholars provided by Tianjin Normal University
• 18JCZDJC33600 the Natural Science Foundation of Tianjin
• the Natural Science Foundation of Tianjin

• T lymphocyte
• naive T lymphocyte
• purinergic signaling

Microglia are ramified cells that exhibit highly motile processes, which continuously survey the brain parenchyma and react to any insult to the CNS homeostasis. Although microglia have long been recognized as a crucial player in generating and maintaining inflammatory responses in the CNS, now it has become clear, that their function are much more diverse, particularly in the healthy brain. The innate immune response and phagocytosis represent only a little segment of microglia functional repertoire that also includes maintenance of biochemical homeostasis, neuronal circuit maturation during development and experience-dependent remodeling of neuronal circuits in the adult brain. Being equipped by numerous receptors and cell surface molecules microglia can perform bidirectional interactions with other cell types in the CNS. There is accumulating evidence showing that neurons inform microglia about their status and thus are capable of controlling microglial activation and motility while microglia also modulate neuronal activities. This review addresses the topic: how microglia communicate with other cell types in the brain, including fractalkine signaling, secreted soluble factors and extracellular vesicles. We summarize the current state of knowledge of physiological role and function of microglia during brain development and in the mature brain and further highlight microglial contribution to brain pathologies such as Alzheimer’s and Parkinson’s disease, brain ischemia, traumatic brain injury, brain tumor as well as neuropsychiatric diseases (depression, bipolar disorder, and schizophrenia).

• cytokines
• extracellular vesicles
• fractalkine
• microglia
• neurodegeneration
• neuroinflammation
• neuron

A previous report has shown that regulatory T cells (Treg) were markedly more sensitive to adenosine-5′-triphosphate (ATP) than conventional T cells (Tconv). Another one has shown that Tregs and CD45RB^low Tconvs, but not CD45RB^high Tconvs, displayed similar high sensitivity to ATP. We have previously reported that CD45RB^low Tconvs expressing B220/CD45RABC molecules in a pre-apoptotic stage are resistant to ATP stimulation due to the loss of P2X7 receptor (P2X7R) membrane expression. To gain a clearer picture on T-cell sensitivity to ATP, we have quantified four different cellular activities triggered by ATP in mouse T cells at different stages of activation/differentiation, in correlation with levels of P2X7R membrane expression. P2X7R expression significantly increases on Tconvs during differentiation from naive CD45RB^highCD44^low to effector/memory CD45RB^lowCD44^high stage. Maximum levels of upregulation are reached on recently activated CD69⁺ naive and memory Tconvs. Ectonucleotidases CD39 and CD73 expression levels increase in parallel with those of P2X7R. Recently activated CD69⁺ CD45RB^highCD44^low Tconvs, although expressing high levels of P2X7R, fail to cleave homing receptor CD62L after ATP treatment, but efficiently form pores and externalize phosphatidylserine (PS). In contrast, naive CD45RB^highCD44^low Tconvs cleave CD62L with high efficiency although they express a lower level of P2X7, thus suggesting that P2X7R levels are not a limiting factor for signaling ATP-induced cellular responses. Contrary to common assumption, P2X7R-mediated cellular activities in mouse Tconvs are not triggered in an all-or-none manner, but depend on their stage of activation/differentiation. Compared to CD45RB^low Tconvs, CD45RB^lowFoxp3⁺ Tregs show significantly higher levels of P2X7R membrane expression and of sensitivity to ATP as evidenced by their high levels of CD62L shedding, pore formation and PS externalization observed after ATP treatment. In summary, the different abilities of ATP-treated Tconvs to form pore or cleave CD62L depending on their activation and differentiation state suggests that P2X7R signaling varies according to the physiological role of T convs during antigen activation in secondary lymphoid organs or trafficking to inflammatory sites.

• CD39
• CD62L shedding
• CD73
• P2X7
• cell death
• phosphatidyslerine exposure
• pore formation
• regulatory T lymphocyte

• P2X7 receptor
• Polymorphism
• Spinal tuberculosis
• Susceptibility

• ATP
• Colitis, regulatory T cells
• P2X7 receptor

• Animals
• Colitis/chemically induced
• Colitis/genetics
• Colitis/immunology
• Colitis/pathology
• Female
• Immunity, Mucosal
• Inflammation/chemically induced
• Inflammation/genetics
• Inflammation/immunology
• Inflammation/pathology
• Inflammatory Bowel Diseases/chemically induced
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/pathology
• Intestinal Mucosa/immunology
• Intestinal Mucosa/pathology
• Mice
• Mice, Knockout
• Oxazolone/adverse effects
• Oxazolone/pharmacology
• Receptors, Purinergic P2X7/genetics
• Receptors, Purinergic P2X7/immunology
• T-Lymphocytes/immunology
• T-Lymphocytes/pathology
• Trinitrobenzenesulfonic Acid/toxicity

• Brain tumor
• Elevated extracellular ATP
• Glioma cells
• Ionotropic purinergic receptor P2X(7)
• Microglia
• P2X(7)R antagonist

The P2X7 receptor is expressed in both anterior and posterior segments of the eyeball. In the ocular surface, the P2X7 receptor is activated in case of external aggressions: preservatives and surfactants induce the activation of P2X7 receptors, leading to either apoptosis, inflammation, or cell proliferation. In the retina, the key endogenous actors of age-related macular degeneration, diabetic retinopathy, and glaucoma act through P2X7 receptors’ activation and/or upregulation of P2X7 receptors’ expression. Different therapeutic strategies aimed at the P2X7 receptor exist. P2X7 receptor antagonists, such as divalent cations and Brilliant Blue G (BBG) could be used to target either the ocular surface or the retina, as long as polyunsaturated fatty acids may exert their effects through the disruption of plasma membrane lipid rafts or saffron that reduces the response evoked by P2X7 receptor stimulation. Treatments against P2X7 receptor activation are proposed by using either eye drops or food supplements.

• P2X7 receptor
• modulation
• ocular
• stress
• therapeutic target

• cytokines
• extracellular ATP
• immunopathology
• influenza
• purinergic receptor

• Animals
• Body Weight
• Cytokines/analysis
• Disease Models, Animal
• Host-Pathogen Interactions
• Lung/pathology
• Macrophages/immunology
• Mice
• Mice, Knockout
• Neutrophils/immunology
• Orthomyxoviridae/pathogenicity
• Orthomyxoviridae Infections/pathology
• Orthomyxoviridae Infections/virology
• Receptors, Purinergic P2X7/metabolism
• Survival Analysis

• HHSN272201400008C NIAID NIH HHS

• Ancient DNA
• Genetic drift
• Innate immune response
• Natural selection

• Blood cells
• Heterologous expression
• P2X receptors
• P2X1del receptors
• Patch clamp

• Drug delivery
• Engineered peptides
• Nanoscaffold
• Neural tissue engineering
• Self-assembly

Leishmania spp. are intracellular parasitic protozoa responsible for a group of neglected tropical diseases, endemic in 98 countries around the world, called leishmaniasis. These parasites have a complex digenetic life cycle requiring a susceptible vertebrate host and a permissive insect vector, which allow their transmission. The clinical manifestations associated with leishmaniasis depend on complex interactions between the parasite and the host immune system. Consequently, leishmaniasis can be manifested as a self-healing cutaneous affliction or a visceral pathology, being the last one fatal in 85–90% of untreated cases. As a result of a long host–parasite co-evolutionary process, Leishmania spp. developed different immunomodulatory strategies that are essential for the establishment of infection. Only through deception and manipulation of the immune system, Leishmania spp. can complete its life cycle and survive. The understanding of the mechanisms associated with immune evasion and disease progression is essential for the development of novel therapies and vaccine approaches. Here, we revise how the parasite manipulates cell death and immune responses to survive and thrive in the shadow of the immune system.

• Leishmania
• acquired immunity
• apoptosis
• immunomodulation
• innate immunity

• Central nervous system injuries
• Microglia
• Receptor

• Animals
• Central Nervous System/immunology
• Humans
• Microglia/physiology
• Receptors, Cell Surface/metabolism
• Receptors, Chemokine/metabolism
• Receptors, Pattern Recognition/metabolism
• Receptors, Purinergic/metabolism
• Trauma, Nervous System/immunology

• NS45048 NINDS NIH HHS
• R01 NS062157 NINDS NIH HHS
• P01 NS059806 NINDS NIH HHS
• NS36736 NINDS NIH HHS
• NS59806 NINDS NIH HHS
• R01 NS056118 NINDS NIH HHS
• NS62157 NINDS NIH HHS
• R01 NS036736 NINDS NIH HHS
• R01 NS045048 NINDS NIH HHS

• Animals
• Clinical Trials as Topic
• Disease Models, Animal
• Drug Design
• Gene Expression Regulation/drug effects
• Humans
• Molecular Targeted Therapy
• Polymorphism, Genetic
• Purinergic P2X Receptor Antagonists/pharmacology
• Receptors, Purinergic P2X7/drug effects
• Receptors, Purinergic P2X7/genetics
• Receptors, Purinergic P2X7/metabolism
• Signal Transduction/drug effects

During embryonic development of Artemia sinica, environmental stresses induce the embryo diapause phenomenon, required to resist apoptosis and regulate cell cycle activity. The small ubiquitin-related modifier-1 (SUMO), a reversible post-translational protein modifier, plays an important role in embryo development. SUMO regulates multiple cellular processes, including development and other biological processes. The molecular mechanism of diapause, diapause termination and the role of As-sumo-1 in this processes and in early embryo development of Artemia sinica still remains unknown. In this study, the complete cDNA sequences of the sumo-1 homolog, sumo ligase homolog, caspase-1 homolog and cyclin B homolog from Artemia sinica were cloned. The mRNA expression patterns of As-sumo-1, sumo ligase, caspase-1, cyclin B and the location of As-sumo-1 were investigated. SUMO-1, p53, Mdm2, Caspase-1, Cyclin B and Cyclin E proteins were analyzed during different developmental stages of the embryo of A. sinica. Small interfering RNA (siRNA) was used to verify the function of sumo-1 in A. sinica. The full-length cDNA of As-sumo-1 was 476 bp, encoding a 92 amino acid protein. The As-caspases-1 cDNA was 966 bp, encoding a 245 amino-acid protein. The As-sumo ligase cDNA was 1556 bp encoding, a 343 amino acid protein, and the cyclin B cDNA was 739 bp, encoding a 133 amino acid protein. The expressions of As-sumo-1, As-caspase-1 and As-cyclin B were highest at the 10 h stage of embryonic development, and As-sumo ligase showed its highest expression at 0 h. The expression of As-SUMO-1 showed no tissue or organ specificity. Western blotting showed high expression of As-SUMO-1, p53, Mdm2, Caspase-1, Cyclin B and Cyclin E at the 10 h stage. The siRNA caused abnormal development of the embryo, with increased malformation and mortality. As-SUMO-1 is a crucial regulation and modification protein resumption of embryonic diapause and early embryo development of A. sinica.

• Amino Acid Sequence
• Animals
• Artemia/classification
• Artemia/embryology
• Artemia/genetics
• Artemia/metabolism
• Base Sequence
• Caspase 1/chemistry
• Caspase 1/genetics
• Caspase 1/metabolism
• Cloning, Molecular
• Computational Biology
• Cyclin B/chemistry
• Cyclin B/genetics
• Cyclin B/metabolism
• Gene Expression Regulation, Developmental
• Molecular Sequence Data
• Phylogeny
• RNA Interference
• SUMO-1 Protein/chemistry
• SUMO-1 Protein/genetics
• SUMO-1 Protein/metabolism
• Sequence Alignment

• Caspase-1
• Inflammasome
• Interleukin-1β
• P2X(7) receptor antagonists
• Pro-inflammatory cytokines
• Purinergic receptor
• Toll like receptor (TLR)