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Bioengineered JMJD3-PROTAC targeted epigenetic immunotherapy strategy for diabetic periodontitis.

OBJECTIVES: This study aimed to develop and evaluate a targeted nanotherapeutic system to degrade the nonenzymatic form of JMJD3 and thereby restore immune balance and tissue repair in diabetic periodontitis. METHODS: A pH/reactive oxygen species (ROS)-responsive nanoplatform (P-PLGA@MM) was engineered using diselenium-bonded poly(lactic-co-glycolic acid) (PLGA) loaded with a JMJD3-targeting proteolysis-targeting chimera (PROTAC) and camouflaged with macrophage membranes. In vitro and in vivo models of diabetic periodontitis were used to assess cellular uptake, JMJD3 degradation, anti-inflamm…

Targeting Bruton's Tyrosine Kinase in CLL: Selectivity, Resistance Mechanisms, and Emerging Therapeutic Strategies.

Kinases are highly explored drug targets due to their central role in cell growth, differentiation, and cell death, as well as their relatio … summary of the design of irreversible inhibitors, reversible inhibitors, and Proteolysis-targeting chimera (PROTAC) degraders targeting BTK. We will include crystal structures of compounds bound to BTKWT and provide a review of how the design of these inhibitors and PROTACs leads to a more selective inhibition and degradation of BTK. With the emergence o …

Collective dynamics and synchronization of coupled hair-bundle models with elastic and viscous interactions.

Despite extensive studies of single hair-bundle dynamics, comparatively little attention has been paid to the collective dynamics arising in … chronization, the network exhibits a variety of complex collective states, including non-stationary chimera patterns and clustered dynamics with distinct dynamical behaviors. Finally, we establish the occurrence of coherence resonance in the network, showing that an intermediate level of noise can enhance temporal regularity in the absence of external per …

Effect of ligands and HIV latency-reversing agents on estrogen receptor α in CD4+ T cells.

The estrogen receptor (ER) is hypothesized to directly influence HIV transcription and latency but is also critical for immune signaling. However, the mechanisms of action of the ER in immune cells in the context of HIV are limited, and relevant to HIV cure strategies, the influence of latency reversal agents (LRAs) on the ER pathway are unknown. We evaluated (a) the effect of estrogen (E2) on the nuclear translocation of ERα in CD4+ T cells; (b) the ability of Fulvestrant, a selective estrogen receptor degrader (SERD), and ARV-471, a potent, PROteolysis TArgeting Chimera (PROTAC) selective ER…

AI-driven discovery of dual antiaging and anti-AD therapeutics via PROTAC target deconvolution of a super-enhancer-regulated axis.

The lack of safe, durable therapeutics that act against both biological aging and Alzheimer's disease is an unmet clinical need. To bridge t … ognition, suppresses neuroinflammation, and alleviates senescence phenotypes. Proteolysis targeting chimera (PROTAC)-guided chemoproteomic deconvolution next pinpointed the histone acetyltransferase p300 as MLT's target. Integrated Cleavage Under Targets and Tagmentation, single-cell RNA sequencing, and spatial transcriptomics revealed that MLT-bound p300 …

Recent advances in targeting LRRK2 for Parkinson's disease treatment.

Parkinson's disease (PD) is a neurodegenerative disease with severe movement problems. Current treatments mainly focus on symptom management … mune system. We also discuss targeted therapies such as kinase inhibitors and Proteolysis targeting chimera and the application of using the LRRK2 protein to diagnose PD and develop bioassay designs. Finally, we mention the clinical trials conducted and the challenges and safety required.

Late-stage Tyrosine ortho-C(sp2)-H Alkenylation for Macrocyclic Peptide SuFEx Proximity Labeling and Targeted Degradation.

Cyclic peptides hold great promise in drug discovery due to their conformational stability, proteolytic resistance, and ability to disrupt p … ared with its linear counterpart. We further developed a covalent cyclic peptide-lysosome targeting chimera (CCP-TAC) that selectively degrades PD-L1, remodels the tumor immune microenvironment, and exhibits favorable biosafety in vivo. Together, these findings establish tyrosine-directed C─H functionalization as a versatile platform for multifunctional c …

Synthesis of Two Versions of Carbon-14-Labeled ARV-110: An Androgen Receptor PROTAC Degrader for Prostate Cancer.

N-((1R,4R)-4-(3-Chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (ARV-110) is a proteolysis-targeting chimera (PROTAC) designed against the androgen receptor (AR), which shows great potential for treating AR-dependent diseases, such as prostate cancer. To support preclinical safety evaluations as well as studies of drug metabolism and pharmacokinetics, two versions of carbon-14-labeled ARV-110 were synthesized: N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6…

Ferroptosis-associated transcriptional factors in neurological diseases: molecular mechanisms and therapeutic prospects.

Ferroptosis, a newly discovered type of regulatory cell death with iron-dependent accumulation of lipid peroxides, is widely discussed in a … in patients with Alzheimer's disease supports this notion. Future research on proteolysis-targeting chimera (PROTAC) and gene therapy holds promise for optimization of neurological disease treatment.

Activation of lysosomal iron triggers ferroptosis in cancer.

Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death referred to as ferroptosis1-3. Identifying … kills primary sarcoma and pancreatic ductal adenocarcinoma cells. It acts as a lipolysis-targeting chimera (LIPTAC), preferentially targeting iron-rich CD44high cell-subpopulations7,8 associated with the metastatic disease and drug resistance9,10. Furthermore, we demonstrate that fentomycin also depletes CD44high cells in vivo and reduces intranodal tumo …

Discovery and engineering of the antibody response to a prominent skin commensal.

The ubiquitous skin colonist Staphylococcus epidermidis elicits a CD8+ T cell response pre-emptively, in the absence of an infection1. Howev … ts mice against a lethal challenge. A similar strain of S. epidermidis expressing an Aap-SpyCatcher chimera can be conjugated with recombinant immunogens; the resulting labelled commensal elicits high antibody titres under conditions of physiologic colonization, including a robust IgA response in the nasal and pulmonary mucosa. Thus, immunity to a common …

Early Circulating Edema Factor in Inhalational Anthrax Infection: Does It Matter?

Anthrax toxins are critical virulence factors of Bacillus anthracis and Bacillus cereus strains that cause anthrax-like disease, composed of a common binding factor, the protective antigen (PA), and two enzymatic proteins, lethal factor (LF) and edema factor (EF). While PA is required for endocytosis and activity of EF and LF, several studies showed that these enzymatic factors disseminate within the body in the absence of PA after intranasal infection. In an effort to understand the impact of EF in the absence of PA, we used a fluorescent EF chimera to facilitate the study of endocytosis in d…

Fixed Time-Point Analysis Reveals Repetitive Mild Traumatic Brain Injury Effects on Resting State Functional Magnetic Resonance Imaging Connectivity and Neuro-Spatial Protein Profiles.

Repetitive mild traumatic brain injuries (rmTBIs) are serious trauma events responsible for the development of numerous neurodegenerative disorders. A major challenge in developing diagnostics and treatments for the consequences of rmTBI is the fundamental knowledge gaps of the molecular mechanisms responsible for neurodegeneration. It is both critical and urgent to understand the neuropathological and functional consequences of rmTBI to develop effective therapeutic strategies. Using the Closed-Head Impact Model of Engineered Rotational Acceleration, or CHIMERA, we measured neural changes fol…

Diverse contribution of amniogenic somatopleural cells to cardiovascular development: With special reference to thyroid vasculature.

BACKGROUND: The somatopleure serves as the primordium of the amnion, an extraembryonic membrane surrounding the embryo. Recently, we have reported that amniogenic somatopleural cells (ASCs) not only form the amnion but also migrate into the embryo and differentiate into cardiomyocytes and vascular endothelial cells. However, detailed differentiation processes and final distributions of these intra-embryonic ASCs (hereafter referred to as iASCs) remain largely unknown. RESULTS: By quail-chick chimera analysis, we here show that iASCs differentiate into various cell types including cardiomyocyt…

Rational Engineering of a Sub-Picomolar HIV-1 Blocker.

With the aim of rationally devising a refined and potent HIV-1 blocker, the cDNA of CCL5 5p12 5m, an extremely potent CCR5 antagonist, was f … ifferent CCR5 conformational populations. Within the mechanism of HIV-1 entry, the CCL5 5p12 5m-C37 chimera may fit as a powerful blocker in several instances. In its possible consideration for systemic therapy or pre-exposure prophylaxis, this protein design represents an interesting lead in the combat of HIV-1 infection.

MHC Class I on murine hematopoietic APC selects Type A IEL precursors in the thymus.

TCRαβ+ CD8α+ CD8β- intestinal intraepithelial lymphocytes (CD8αα IEL) are gut T cells that maintain barrier surface homeostasis. Most CD8αα … t to define a CD80/86 negative, MHCI positive APC that supports the development to the IEL lineage. Chimera studies showed that MHCI needs to be expressed on hematopoietic APC for selection. As thymic hematopoietic APC are heterogeneous in their expression of MHCI and costimulatory molecules, we identified four thymic APC types that were CD80/86neg/low an …

Intrinsic positional memory guides target-specific axon regeneration in the zebrafish vagus nerve.

Regeneration after peripheral nerve damage requires that axons re-grow to the correct target tissues in a process called target-specific reg … find a robust capacity for target-specific, functional re-growth. We then develop a new single-cell chimera injury model for precise manipulation of axon-environment interactions and find that (1) the guidance mechanism used during regeneration is distinct from the nerve's developmental guidance mechanism, (2) target selection is specified by neurons' int …

Proteasomal and lysosomal degradation for specific and durable suppression of immunotherapeutic targets.

Cancer immunotherapy harness the body's immune system to eliminate cancer, by using a broad panel of soluble and membrane proteins as therapeutic targets. Immunosuppression signaling mediated by ligand-receptor interaction may be blocked by monoclonal antibodies, but because of repopulation of the membrane via intracellular organelles, targets must be eliminated in whole cells. Targeted protein degradation, as exemplified in proteolysis targeting chimera (PROTAC) studies, is a promising strategy for selective inhibition of target proteins. The recently reported use of lysosomal targeting molec…

Development of the multi-epitope chimeric antigen rqTSA-25 from Taenia saginata for serological diagnosis of bovine cysticercosis.

Bovine cysticercosis is a worldwide distributed zoonosis caused by the larval form of Taenia saginata present in bovine muscles. The diagnos … nosis using enzyme-linked immunosorbent assay. We generated and evaluated a new recombinant protein chimera derived from the fusion of different peptides. We selected three distinct regions of T. saginata and predicted six peptides with antigenic potential (EP2-EP7). These peptides were analyzed individually and selected for generating a new chimeric reco …

Экстринальный протеин тиросин Фосфатаза, неприемник 22, способствует изнурению клеток CD8 T и способствует стойкости хронического черепно-лимфоцитного заражения.

Генетический вариант белкового тиросина фосфатазы нерецептора 22 (PTPN22) связан с широким кругом аутоиммунных заболеваний; однако причины, лежащие в его основе среди населения в целом, до сих пор не до конца понятны. Последние данные свидетельствуют о важной роли аутоиммунной восприимчивости генетических вариантов в обеспечении устойчивости к определенным патогенам. В этом исследовании мы изучили роль PTPN22 в стойкой инфекции у мышей, не имеющих PTPN22, зараженных клоном лимфоцита хориомингита 13. Мы обнаружили, что отсутствие PTPN22 у мышей привело к расчистке вирусов через 30 дней после ин

Совпадение в аннотации оригинала
A genetic variant of the protein tyrosine phosphatase non-receptor 22 (PTPN22) is associated with a wide range of autoimmune diseases; howev … d CD4 T cell numbers and functionality and reduced exhausted phenotype. Moreover, mixed bone marrow chimera studies demonstrated no differences in virus-specific CD8 T cell accumulation and function between the PTPN22+/+ and PTPN22-/- compartments, showing that the effects of PTPN22 on CD8 T cells are T cell-extrinsic. Together, these findings identify a …