Tyrosine Phosphatase Research Articles

PZR suppresses innate immune response to RNA viral infection by inhibiting MAVS activation in interferon signaling mediated by RIG-I and MDA5

RNA viral infections seriously endanger human health. Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2) suppresses innate immunity against influenza A virus, and pharmacological inhibition of SHP2 provokes hepatic innate immunity. SHP2 binds and catalyzes tyrosyl dephosphorylation of protein zero-related (PZR), but the regulatory effect of PZR on innate immune response to viral infection is unclear. In this study, the transcription and protein level of PZR in host cells were found to be decreased with RNA viral infection, and high level of PZR was uncovered to inhibit interferon (IFN) signaling mediated by RIG-I and MDA5. Through localizing in mitochondria, PZR targeted and interacted with MAVS (also known as IPS-1/VISA/Cardif), suppressing the aggregation and activation of MAVS. Specifically, Y263 residue in ITIM is critical for PZR to exert immunosuppression under RNA viral infection. Moreover, the recruited SHP2 by PZR that modified with tyrosine phosphorylation under RNA viral infection might inhibit phosphorylation activation of MAVS. In conclusion, PZR and SHP2 suppress innate immune response to RNA viral infection through inhibiting MAVS activation. This study reveals the regulatory mechanism of PZR-SHP2-MAVS signal axis on IFN signaling mediated by RIG-I and MDA5, which may provide new sight for developing antiviral drugs.

Controling the cytoskeleton during CEACAM3-mediated phagocytosis

Phagocytosis, an innate defense mechanism of multicellular animals, is initiated by specialized surface receptors. A phagocytic receptor expressed by human polymorphonuclear granulocytes, the major professional phagocytes in our body, is one of the fastest evolving human proteins implying a special role in human biology. This receptor, CEACAM3, is a member of the CarcinoEmbryonic Antigen-related Cell Adhesion Molecule (CEACAM) family and dedicated to the immediate recognition and rapid internalization of human-restricted pathogens. In this focused contribution, we will review the special adaptations of this protein, which co-evolves with different species of mucosa-colonizing bacteria. While the extracellular Immunoglobulin-variable (IgV)-like domain recognizes various bacterial adhesins, an Immunoreceptor Tyrosine-based Activation Motif (ITAM)-like sequence in the cytoplasmic tail of CEACAM3 constitutes the central signaling hub to trigger actin rearrangements needed for efficient phagocytosis. A major emphasis of this review will be placed on recent findings, which have revealed the multi-level control of this powerful phagocytic device. As tyrosine phosphorylation and small GTPase activity are central for CEACAM3-mediated phagocytosis, the counterregulation of CEACAM3 activity involves the receptor-type protein tyrosine phosphatase J (PTPRJ) as well as the Rac-GTP scavenging protein Cyri-B. Interference with such negative regulatory circuits has revealed that CEACAM3-mediated phagocytosis can be strongly enhanced. In principle, the knowledge gained by studying CEACAM3 can be applied to other phagocytic systems and opens the door to treatments, which boost the phagocytic capacity of professional phagocytes.

Proteomic analysis of pulmonary arteries and lung tissues from dogs affected with pulmonary hypertension secondary to degenerative mitral valve disease.

In dogs with degenerative mitral valve disease (DMVD), pulmonary hypertension (PH) is a common complication characterized by abnormally elevated pulmonary arterial pressure (PAP). Pulmonary arterial remodeling is the histopathological changes of pulmonary artery that has been recognized in PH. The underlying mechanisms that cause this arterial remodeling are poorly understood. This study aimed to perform shotgun proteomics to investigate changes in protein expression in pulmonary arteries and lung tissues of DMVD dogs with PH compared to normal control dogs and DMVD dogs without PH. Tissue samples were collected from the carcasses of 22 small-sized breed dogs and divided into three groups: control (n = 7), DMVD (n = 7) and DMVD+PH groups (n = 8). Differentially expressed proteins were identified, and top three upregulated and downregulated proteins in the pulmonary arteries of DMVD dogs with PH including SIK family kinase 3 (SIK3), Collagen type I alpha 1 chain (COL1A1), Transforming growth factor alpha (TGF-α), Apoptosis associated tyrosine kinase (AATYK), Hepatocyte growth factor activator (HGFA) and Tyrosine-protein phosphatase non-receptor type 13 (PTPN13) were chosen. Results showed that some of the identified proteins may play a role in the pathogenesis of pulmonary arterial remodeling. This study concluded shotgun proteomics has potential as a tool for exploring candidate proteins associated with the pathogenesis of PH secondary to DMVD in dogs.

Binding Free Energy Calculation Based on the Fragment Molecular Orbital Method and Its Application in Designing Novel SHP-2 Allosteric Inhibitors.

The accurate prediction of binding free energy is a major challenge in structure-based drug design. Quantum mechanics (QM)-based approaches show promising potential in predicting ligand-protein binding affinity by accurately describing the behavior and structure of electrons. However, traditional QM calculations face computational limitations, hindering their practical application in drug design. Nevertheless, the fragment molecular orbital (FMO) method has gained widespread application in drug design due to its ability to reduce computational costs and achieve efficient ab initio QM calculations. Although the FMO method has demonstrated its reliability in calculating the gas phase potential energy, the binding of proteins and ligands also involves other contributing energy terms, such as solvent effects, the 'deformation energy' of a ligand's bioactive conformations, and entropy. Particularly in cases involving ionized fragments, the calculation of solvation free energy becomes particularly crucial. We conducted an evaluation of some previously reported implicit solvent methods on the same data set to assess their potential for improving the performance of the FMO method. Herein, we develop a new QM-based binding free energy calculation method called FMOScore, which enhances the performance of the FMO method. The FMOScore method incorporates linear fitting of various terms, including gas-phase potential energy, deformation energy, and solvation free energy. Compared to other widely used traditional prediction methods such as FEP+, MM/PBSA, MM/GBSA, and Autodock vina, FMOScore showed good performance in prediction accuracies. By constructing a retrospective case study, it was observed that incorporating calculations for solvation free energy and deformation energy can further enhance the precision of FMO predictions for binding affinity. Furthermore, using FMOScore-guided lead optimization against Src homology-2-containing protein tyrosine phosphatase 2 (SHP-2), we discovered a novel and potent allosteric SHP-2 inhibitor (compound 8).

Phogrin Regulates High-Fat Diet-Induced Compensatory Pancreatic β-Cell Growth by Switching Binding Partners.

The receptor protein tyrosine phosphatase phogrin primarily localizes to hormone secretory granules in neuroendocrine cells. Concurrent with glucose-stimulated insulin secretion, phogrin translocates to pancreatic β-cell plasma membranes, where it interacts with insulin receptors (IRs) to stabilize insulin receptor substrate 2 (IRS2) that, in turn, contributes to glucose-responsive β-cell growth. Pancreatic β-cell development was not altered in β-cell-specific, phogrin-deficient mice, but the thymidine incorporation rate decreased in phogrin-deficient islets with a moderate reduction in IRS2 protein expression. In this study, we analyzed the β-cell response to high-fat diet stress and found that the compensatory expansion in β-cell mass was significantly suppressed in phogrin-deficient mice. Phogrin-IR interactions occurred only in high-fat diet murine islets and proliferating β-cell lines, whereas they were inhibited by the intercellular binding of surface phogrin under confluent cell culture conditions. Thus, phogrin could regulate glucose-stimulated compensatory β-cell growth by changing its binding partner from another β-cell phogrin to IR in the same β-cells.

Identification of common and specific fibrosis-related genes in three common chronic kidney diseases

Background Kidney fibrosis is the common final pathway of virtually all advanced forms of chronic kidney disease (CKD) including diabetic nephropathy (DN), IgA nephropathy (IgAN) and membranous nephropathy (MN), with complex mechanism. Comparative gene expression analysis among these types of CKD may shed light on its pathogenesis. Therefore, we conducted this study aiming at exploring the common and specific fibrosis-related genes involved in different types of CKD. Methods Kidney biopsy specimens from patients with different types of CKD and normal control subjects were analyzed using the NanoString nCounter® Human Fibrosis V2 Panel. Genes differentially expressed in all fibrotic DN, IgAN and MN tissues compared to the normal controls were regarded as the common fibrosis-related genes in CKD, whereas genes exclusively differentially expressed in fibrotic DN, IgAN or MN samples were considered to be the specific genes related to fibrosis in DN, IgAN and MN respectively. Quantitative real-time PCR (qRT-PCR) was performed to validate the expression of the selected genes. Results Protein tyrosine phosphatase receptor type C (PTPRC), intercellular cell adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), interleukin 10 receptor alpha (IL10RA) and CC chemokine receptor 2 (CCR2) were identified as the potential common genes for kidney fibrosis in different types of CKD, while peroxisome proliferator-activated receptor alpha (PPARA), lactate oxidase (LOX), secreted phosphoprotein 1 (SPP1) were identified as the specific fibrosis-associated genes for DN, IgAN and MN respectively. qRT-PCR demonstrated that the expression levels of these selected genes were consistent with the NanoString analysis. Conclusions There were both commonalities and differences in the mechanisms of fibrosis in different types of CKD, the commonalities might be used as the common therapeutic targets for kidney fibrosis in CKD, while the differences might be used as the diagnostic markers for DN, IgAN and MN respectively. Inflammation was highly relevant to the pathogenesis of fibrosis. This study provides further insight into the pathophysiology and treatment of fibrotic kidney disease.

Identification and characterization of two immune-related subtypes in human chronic kidney disease

BackgroundImmune response plays a vital role in the initiation and development of chronic kidney disease (CKD). Detailed mechanisms and specific immune-related biomarkers of CKD need further clarification. We aimed to identify and characterize immune-related infiltrates that are implicated in the CKD development using a bioinformatics method. MethodsThe expression profiles of GSE66494 dataset were acquired from the Gene Expression Omnibus (GEO) database. Patients with CKD were divided into low- vs. high-immune subtypes based on their immune score. Based on such analysis, we identified differentially expressed genes (DEGs) of low- and high-immune subtypes. The weight gene co-expression network analysis (WGCNA) was used to identify immune-associated modules between two subtypes. The gene set enriched (GSEA) and variation (GSVA) analyses were correlated with their functional types using the molecular complex detection (MCODE) method. Finally, the immune infiltration landscape between subtypes was revealed using the xCell algorithm. ResultsThe total number of 131 differentially expressed immune-related genes (DEIRGs) were identified between low- vs. high-immune subtypes. Out of them GSEA/GSVA results identified and enriched immune- and inflammation-related pathways. In particular, GSVA results indicated that immune-related pathways were activated in high-immune subgroups. The core DEIRG genes that were identified to be involved in CKD development included: the protein tyrosine phosphatase receptor type C (PTPRC; also known as CD45) regulating cell growth and differentiation, an early activation marker (CD69), co-receptor for T cell receptor (CD8A), and T cell co-stimulatory signal (CD28). These core DEIRD genes were further verified by the GSE96804 dataset. We also found a higher proportion of immune cells infiltrating the high-immune subgroup. Furthermore, the four core genes were positively correlated with most immune cell types. ConclusionAmong 131 DEIRG genes, four genes (PTPRC, CD69, CD8A, and CD28) were identified as potential biomarkers associated with the immune cell infiltration in CKD patients, which may provide a novel insight for immunotherapy for CKD.

Identification and verification of PTPN3 as a novel biomarker in predicting cancer prognosis, immunity, and immunotherapeutic efficacy

BackgroundThe importance of protein tyrosine phosphatase non-receptor type 3 (PTPN3) in controlling multifaceted tumor cell behaviors throughout cancer development has received widespread attention. Nevertheless, little is known about the biological roles of PTPN3 in drug sensitivity, immunotherapeutic effectiveness, tumor immune microenvironment, and cancer prognosis.MethodsThe Cancer Genome Atlas (TCGA) database's RNAseq data were used to examine the expression of PTPN3 in 33 different cancer types. In addition, immunohistochemistry (IHC) was performed to validate the expression of PTPN3 across various cancer types within our clinical cohorts. The features of PTPN3 alterations were demonstrated throughout the cBioPortal database. This study focused on examining the prognostic and clinicopathological importance of PTPN3 through the acquisition of clinical data from the TCGA database. The investigation of PTPN3's probable role in the tumor immune microenvironment was demonstrated by the application of CIBERSORT, ESTIMATE algorithms, and the TISIDB database. Using Spearman's rank correlation coefficient, the relationships between PTPN3 expression and tumor mutation burden (TMB) and microsatellite instability (MSI) were evaluated. To further investigate the putative biological activities and downstream pathways of PTPN3 in various cancers in humans, Gene Set Enrichment Analysis (GSEA) was carried out. In addition, an examination was conducted to explore the associations between PTPN3 and the effectiveness of PD-1/PD-L1 inhibitors, utilizing data extracted from the GEO database.ResultsPTPN3 was abnormally expressed in multiple cancer types and was also strictly associated with the prognosis of cancer patients. IHC was used to investigate and confirm the various expression levels of PTPN3 in various malignancies, including breast cancer, lung cancer, sarcoma, and kidney renal clear cell carcinoma in our clinical cohorts. There is a high correlation between the levels of PTPN3 expression in different cancers and infiltrating immune cells, including mast cells, B cells, regulatory T cells, CD8 + T cells, macrophages, and dendritic cells. Infiltrating immune cells, such as regulatory T cells, CD8 + T cells, macrophages, B cells, dendritic cells, and mast cells, are strongly correlated with PTPN3 expression levels in various tumors. The expression of PTPN3 exhibited a substantial correlation with many immune-related biomolecules and the expression of TMB and MSI in multiple types of cancer. In addition, PTPN3 has demonstrated promise in predicting the therapeutic benefits of PD-1/PD-L1 inhibitors and the susceptibility to anti-cancer medications in the treatment of clinical cancer.ConclusionsOur findings highlight the importance of PTPN3 as a prognostic biomarker and predictor of immunotherapy success in various forms of cancer. Furthermore, PTPN3 appears to have an important role in modifying the tumor immune microenvironment, highlighting its potential as a promising biomarker for prognosis prediction, immunotherapeutic efficacy evaluation, and identification of immune-related characteristics in diverse cancer types.

An in silico analysis of the interaction of marine sponge-derived bioactive compounds with type 2 diabetes mellitus targets DPP-4 and PTP1B

Type 2 diabetes is a medical condition involving elevated blood glucose levels resulting from impaired or improper insulin utilization. As the number of type 2 diabetes cases increases each year, there is an urgent need to develop novel drugs having new targets and/or complementing existing therapeutic protocols. In this regard, marine sponge-derived compounds hold great potential due to their potent biological activity and structural diversity. In this study, a small library of 50 marine sponge-derived compounds were examined for their activity towards type 2 diabetes targets, namely dipeptidyl peptidase-4 (DPP-4) and protein tyrosine phosphatase 1B (PTP1B). The compounds were first subjected to molecular docking on protein models based on their respective co-crystal structures to assess binding free energies (BFE) and conformations. Clustering analysis yielded BFE that ranged from 24.54 kcal/mol to −9.97 kcal/mol for DPP-4, and from −4.98 kcal/mol to −8.67 kcal/mol for PTP1B. Interaction analysis on the top ten compounds with the most negative BFE towards each protein target showed similar intermolecular interactions and key interacting residues as in the previously solved co-crystal structure. These compounds were subjected to absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling to characterize drug-likeness and combining the results from these analyses, (S)-6’-debromohamacanthin B was identified as a potential multi-target inhibitor of DPP-4 and PTP1B, having favorable protein interaction, no Lipinski violations, good gastrointestinal (GI) tract absorption, blood-brain barrier (BBB) penetration, and no predicted toxicity. Finally, the interaction of (S)-6’-debromohamacanthin B with the two proteins was validated using molecular dynamics simulations over 100 ns through RMSD, radius of gyration, PCA, and molecular mechanics Poisson-Boltzmann surface area (MMPBSA) confirming favorable interactions with the respective proteins. Communicated by Ramaswamy H. Sarma

The induction of SHP-1 degradation by TAOK3 ensures the responsiveness of T cells to TCR stimulation.

Thousand-and-one-amino acid kinase 3 (TAOK3) is a serine and threonine kinase that belongs to the STE-20 family of kinases. Its absence reduces T cell receptor (TCR) signaling and increases the interaction of the tyrosine phosphatase SHP-1, a major negative regulator of proximal TCR signaling, with the kinase LCK, a component of the core TCR signaling complex. Here, we used mouse models and human cell lines to investigate the mechanism by which TAOK3 limits the interaction of SHP-1 with LCK. The loss of TAOK3 decreased the survival of naïve CD4+ T cells by dampening the transmission of tonic and ligand-dependent TCR signaling. In mouse T cells, Taok3 promoted the secretion of interleukin-2 (IL-2) in response to TCR activation in a manner that depended on Taok3 gene dosage and on Taok3 kinase activity. TCR desensitization in Taok3-/- T cells was caused by an increased abundance of Shp-1, and pharmacological inhibition of Shp-1 rescued the activation potential of these T cells. TAOK3 phosphorylated threonine-394 in the phosphatase domain of SHP-1, which promoted its ubiquitylation and proteasomal degradation. The loss of TAOK3 had no effect on the abundance of SHP-2, which lacks a residue corresponding to SHP-1 threonine-394. Modulation of SHP-1 abundance by TAOK3 thus serves as a rheostat for TCR signaling and determines the activation threshold of T lymphocytes.

Protein Tyrosine Phosphatase regulation by Reactive Oxygen Species.

Protein Tyrosine Phosphatases (PTPs) help to maintain the balance of protein phosphorylation signals that drive cell division, proliferation, and differentiation. These enzymes are also well-suited to redox-dependent signaling and oxidative stress response due to their cysteine-based catalytic mechanism, which requires a deprotonated thiol group at the active site. This review focuses on PTP structural characteristics, active site chemical properties, and vulnerability to change by reactive oxygen species (ROS). PTPs can be oxidized and inactivated by H2O2 through three non-exclusive mechanisms. These pathways are dependent on the coordinated actions of other H2O2-sensitive proteins, such as peroxidases like Peroxiredoxins (Prx) and Thioredoxins (Trx). PTPs undergo reversible oxidation by converting their active site cysteine from thiol to sulfenic acid. This sulfenic acid can then react with adjacent cysteines to form disulfide bonds or with nearby amides to form sulfenyl-amide linkages. Further oxidation of the sulfenic acid form to the sulfonic or sulfinic acid forms causes irreversible deactivation. Understanding the structural changes involved in both reversible and irreversible PTP oxidation can help with their chemical manipulation for therapeutic intervention. Nonetheless, more information remains unidentified than is presently known about the precise dynamics of proteins participating in oxidation events, as well as the specific oxidation states that can be targeted for PTPs. This review summarizes current information on PTP-specific oxidation patterns and explains how ROS-mediated signal transmission interacts with phosphorylation-based signaling machinery controlled by growth factor receptors and PTPs.

Immunotherapeutic implications of negative regulation by protein tyrosine phosphatases in T cells: the emerging cases of PTP1B and TCPTP.

In the context of inflammation, T cell activation occurs by the concerted signals of the T cell receptor (TCR), co-stimulatory receptors ligation, and a pro-inflammatory cytokine microenvironment. Fine-tuning these signals is crucial to maintain T cell homeostasis and prevent self-reactivity while offering protection against infectious diseases and cancer. Recent developments in understanding the complex crosstalk between the molecular events controlling T cell activation and the balancing regulatory cues offer novel approaches for the development of T cell-based immunotherapies. Among the complex regulatory processes, the balance between protein tyrosine kinases (PTK) and the protein tyrosine phosphatases (PTPs) controls the transcriptional and metabolic programs that determine T cell function, fate decision, and activation. In those, PTPs are de facto regulators of signaling in T cells acting for the most part as negative regulators of the canonical TCR pathway, costimulatory molecules such as CD28, and cytokine signaling. In this review, we examine the function of two close PTP homologs, PTP1B (PTPN1) and T-cell PTP (TCPTP; PTPN2), which have been recently identified as promising candidates for novel T-cell immunotherapeutic approaches. Herein, we focus on recent studies that examine the known contributions of these PTPs to T-cell development, homeostasis, and T-cell-mediated immunity. Additionally, we describe the signaling networks that underscored the ability of TCPTP and PTP1B, either individually and notably in combination, to attenuate TCR and JAK/STAT signals affecting T cell responses. Thus, we anticipate that uncovering the role of these two PTPs in T-cell biology may lead to new treatment strategies in the field of cancer immunotherapy. This review concludes by exploring the impacts and risks that pharmacological inhibition of these PTP enzymes offers as a therapeutic approach in T-cell-based immunotherapies.

Sequence - dynamics - function relationships in protein tyrosine phosphatases.

Protein tyrosine phosphatases (PTPs) are crucial regulators of cellular signaling. Their activity is regulated by the motion of a conserved loop, the WPD-loop, from a catalytically inactive open to a catalytically active closed conformation. WPD-loop motion optimally positions a catalytically critical residue into the active site, and is directly linked to the turnover number of these enzymes. Crystal structures of chimeric PTPs constructed by grafting parts of the WPD-loop sequence of PTP1B onto the scaffold of YopH showed WPD-loops in a wide-open conformation never previously observed in either parent enzyme. This wide-open conformation has, however, been observed upon binding of small molecule inhibitors to other PTPs, suggesting the potential of targeting it for drug discovery efforts. Here, we have performed simulations of both enzymes and show that there are negligible energetic differences in the chemical step of catalysis, but significant differences in the dynamical properties of the WPD-loop. Detailed interaction network analysis provides insight into the molecular basis for this population shift to a wide-open conformation. Taken together, our study provides insight into the links between loop dynamics and chemistry in these YopH variants specifically, and how WPD-loop dynamic can be engineered through modification of the internal protein interaction network.

Molecular recognition of ITIM/ITSM domains with SHP2 and their allosteric effect.

Src homology 2-domain-containing tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase that is widely expressed in a variety of cells and regulates the immune response of T cells through the PD-1 pathway. However, the activation mechanism and allosteric effects of SHP2 remain unclear, hindering the development of small molecule inhibitors. For the first time, in this study, the complex structure formed by the intact PD-1 tail and SHP2 was modeled. The molecular recognition and conformational changes of inactive/active SHP2 versus ITIM/ITSM were compared based on prolonged MD simulations. The relative flexibility of the two SH2 domains during MD simulations contributes to the recruitment of ITIM/ITSM and supports the subsequent conformational change of SHP2. The binding free energy calculation shows that inactive SHP2 has a higher affinity for ITIM/ITSM than active SHP2, mainly because the former's N-SH2 refers to the α-state. In addition, a significant decrease in the contribution to the binding energy of certain residues (e.g., R32, S34, K35, T42, and K55) of conformationally transformed SHP2 contributes to the above result. These detailed changes during conformational transition will provide theoretical guidance for the molecular design of subsequent novel anticancer drugs.

Systematic literature review on early clinical evidence for immune-resolution therapies and potential benefits to patients and healthcare providers.

Several current therapies for autoimmune diseases do not provide sustained remission. Therapies that focus on the restoration of homeostasis within the immune system (i.e., immune resolution) could overcome the limitations of current therapies and provide more durable remission. However, there is no established consensus on appropriate clinical trial designs and endpoints to evaluate such therapies. Therefore, we conducted a systematic literature review (SLR) focusing on five index diseases (asthma, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus [SLE], and ulcerative colitis) to explore published literature on 1) expert opinion on immune-resolution outcomes that should be measured in clinical trials; and 2) quantification of immune resolution in previous clinical trials. The SLR was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Embase and MEDLINE databases were systematically searched (2013-2023) for published English language articles. Conference proceedings (2020-2022) from American Academy of Dermatology, American College of Rheumatology, Digestive Disease Week, European Alliance of Associations for Rheumatology, and European Academy of Dermatology and Venereology were searched to include relevant abstracts. The study protocol was registered in PROSPERO (CRD42023406489). The SLR included 26 publications on 20 trials and 12 expert opinions. Expert opinions generally lacked specific recommendations on the assessment of immune resolution in clinical trials and instead suggested targets or biomarkers for future therapies. The targets included thymic stromal lymphopoietin (TSLP) in asthma; T helper (Th)2 and Th22 cells and their respective cytokines (interleukin [IL]-4R and IL-22) in atopic dermatitis; inhibitory/regulatory molecules involved in T-cell modulation, and protein tyrosine phosphatase, non-receptor type 22 (PTPN22) in rheumatoid arthritis; low-dose IL-2 therapy in SLE; and pro-resolution mediators in ulcerative colitis and asthma. In the interventional studies, direct biomarker assessments of immune resolution were the number/proportion of regulatory T-cells (Treg) and the ratio Th17/Treg in SLE and rheumatoid arthritis; the number of T follicular helper cells (Tfh), Th1, Th2, Th17, and Th22 in atopic dermatitis, rheumatoid arthritis, and SLE; and mucosal proinflammatory gene signatures (tumor necrosis factor [TNF], interleukin 1 alpha [IL1A], regenerating family member 1 alpha [REG1A], IL8, interleukin 1 beta [IL1B], and leukocyte immunoglobulin-like receptors A [LILRA]) in ulcerative colitis. Several studies reported a statistically significant relationship between clinical remission and immune-resolution biomarkers, suggesting a link between T-cell homeostasis, cytokine production, and disease activity in autoimmune diseases. Existing literature does not offer clear guidance on the evaluation of immune resolution in interventional studies. Further research and consensus are needed to assess a treatment's ability to induce long-term remission or low disease activity. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023406489, identifier CRD42023406489.

Upregulation of TCPTP in Macrophages Is Involved in IL-35 Mediated Attenuation of Experimental Colitis.

Ulcerative colitis (UC) is a chronic intestinal inflammatory disease with complex etiology. Interleukin-35 (IL-35), as a cytokine with immunomodulatory function, has been shown to have therapeutic effects on UC, but its mechanism is not yet clear. Therefore, we constructed Pichia pastoris stably expressing IL-35 which enables the cytokines to reach the diseased mucosa, and explored whether upregulation of T-cell protein tyrosine phosphatase (TCPTP) in macrophages is involved in the mechanisms of IL-35-mediated attenuation of UC. After the successful construction of engineered bacteria expressing IL-35, a colitis model was successfully induced by giving BALB/c mice a solution containing 3% dextran sulfate sodium (DSS). Mice were treated with Pichia/IL-35, empty plasmid-transformed Pichia (Pichia/0), or PBS by gavage, respectively. The expression of TCPTP in macrophages (RAW264.7, BMDMs) and intestinal tissues after IL-35 treatment was detected. After administration of Pichia/IL-35, the mice showed significant improvement in weight loss, bloody stools, and shortened colon. Colon pathology also showed that the inflammatory condition of mice in the Pichia/IL-35 treatment group was alleviated. Notably, Pichia/IL-35 treatment not only increases local M2 macrophages but also decreases the expression of inflammatory cytokine IL-6 in the colon. With Pichia/IL-35 treatment, the proportion of M1 macrophages, Th17, and Th1 cells in mouse MLNs were markedly decreased, while Tregs were significantly increased. In vitro experiments, IL-35 significantly promoted the expression of TCPTP in macrophages stimulated with LPS. Similarly, the mice in the Pichia/IL-35 group also expressed more TCPTP than that of the untreated group and the Pichia/0 group.

Association of Protein Tyrosine Phosphatase Receptor Type D and Serine Racemase Genetic Variants with Type 2 Diabetes in Malaysian Indians.

Type 2 diabetes (T2D) candidate genes, protein tyrosine phosphatase receptor type D (PTPRD), and serine racemase (SRR) were suggested by a genome-wide association study (GWAS) in the Chinese population. Association studies have been replicated among East Asian populations. The association of PTPRD and SRR genetic variants with T2D in Southeast Asian populations still needs to be studied. This study aimed to investigate the association of PTPRD and SSR genetic variants with T2D in Malaysian Indian subjects. The single nucleotide polymorphisms (SNPs) of PTPRD (rs649891 and rs17584499) and SRR (rs4523957, rs391300, and rs8081273) were genotyped in 397 T2D and 285 normal Malaysian Indian subjects. The homozygous dominant genotype of rs17584499 is frequent in diabetic patients (56.5%) compared to normal subjects (47.3%). In contrast, the homozygous recessive genotype of rs8081273 is more frequent among normal subjects (12.5%) than diabetic patients (5.6%). The dominant genetic model showed that PTPRD rs17584499 (CC) is a risk factor for T2D (OR = 1.42, P = 0.029), whereas the recessive genetic model showed that SRS SNP rs8081273 was protective for T2D (OR = 0.42, P = 0.003). This study confirmed the association of PTPRD rs17584499 genetic variations with T2D in Malaysian Indians. While the SRR rs8081273 (TT) genotype showed protection against T2D, more investigation in different populations is required to confirm this protection.

Unveiling the potential of marine-derived diterpenes from the order Alcyonacea as promising anti-obesity agents

Metabolic syndrome (MS) represents a global health challenge characterized by various metabolic disorders, including HOMA-IR (insulin resistance), obesity, dyslipidemia, and hypertension. In our pursuit of identifying natural alternatives for the development of effective and safe anti-obesity medications, we examined the potential of the methanolic extract of the Red Sea derived soft coral Sarcophyton glaucum, where serum levels of glucose, insulin, HOMA-IR, lipid profile, fetuin A and B, PTP1Β (Protein tyrosine phosphatase 1B), adropin and omentin were determined. Furthermore, the expression of the UCP1 (Uncoupling protein 1) and PPARGC1A (Peroxisome proliferator–activated receptor-g coactivator-1a) genes have been assessed, to evaluate the anti-obesity potential of S. glaucum organic extract. Our findings demonstrated a significant decrease in glucose, HOMA-IR, cholesterol, triglyceride, LDL-C, fetuin A and B, and PTP1Β levels, accompanied by a significant increase in insulin, HDL-C, adropin, omentin, UCP1, and PPARGC1A expression after treatment with the soft coral extract. These promising outcomes can be attributed to the remarkable ingredients present in the extract, which were further supported by histopathological findings. In addition, a virtual screening protocol including molecular docking (MDock) and Structure-Activity Relationships (SARs) of 27 marine diterpenes was also explored to identify potential PTP1Β inhibitors targeting simultaneously the catalytic site and allosteric site, as well as fetuin A modulators. Moreover, the six most promising predicted marine diterpenes (4, 8, 9, 10, 13 and 14) were investigated for their pharmacokinetic properties, druglike nature and medicinal chemistry friendliness using the SwissADME platform. Of these, four marine diterpenes (4, 8, 9, and 10) were predicted to exhibit the appropriate drug-like properties.

Potential protein tyrosine phosphatase 1B and α-glucosidase inhibitory flavonoids from Erythrina variegata: Experimental and computational results

Erythrina variegata L., a member of the Fabaceae family, is a valuable medicinal plant with a rich history of traditional medicinal uses. However, its potential as an antidiabetic agent has remained largely unexplored. In this study, three isoflavonoid compounds, namely eryvarin M (1), eryvarin H (2), and neobavaisoflavone (3), were isolated from E. variegata. These compounds displayed significant inhibitory effects on both protein tyrosine phosphatase 1B and α-glucosidase enzymes. The specific attachment position of the prenyl group to the isoflavonoid skeleton plays a pivotal role in determining the variation in their activity. Moreover, the results obtained from docking simulations corroborate the experimental findings, confirming the robust binding affinities of these metabolites toward the target proteins. The docking analysis further highlights that these compounds exhibit highly negative values of binding-free energies against proteins, indicative of their favorable binding affinities. In addition, the formation of hydrogen bonds in the binding region contributes to their binding interactions. These findings significantly enhance our understanding of the therapeutic potential of both E. variegata and its isoflavonoids as potential inhibitors for diabetes and related metabolic disorders, shedding light on their promising role in the field of diabetes research.

PRL1 and PRL3 promote macropinocytosis via its lipid phosphatase activity.

PRL1 and PRL3, members of the protein tyrosine phosphatase family, have been associated with cancer metastasis and poor prognosis. Despite extensive research on their protein phosphatase activity, their potential role as lipid phosphatases remains elusive. Methods: We conducted comprehensive investigations to elucidate the lipid phosphatase activity of PRL1 and PRL3 using a combination of cellular assays, biochemical analyses, and protein interactome profiling. Functional studies were performed to delineate the impact of PRL1/3 on macropinocytosis and its implications in cancer biology. Results: Our study has identified PRL1 and PRL3 as lipid phosphatases that interact with phosphoinositide (PIP) lipids, converting PI(3,4)P2 and PI(3,5)P2 into PI(3)P on the cellular membranes. These enzymatic activities of PRLs promote the formation of membrane ruffles, membrane blebbing and subsequent macropinocytosis, facilitating nutrient extraction, cell migration, and invasion, thereby contributing to tumor development. These enzymatic activities of PRLs promote the formation of membrane ruffles, membrane blebbing and subsequent macropinocytosis. Additionally, we found a correlation between PRL1/3 expression and glioma development, suggesting their involvement in glioma progression. Conclusions: Combining with the knowledge that PRLs have been identified to be involved in mTOR, EGFR and autophagy, here we concluded the physiological role of PRL1/3 in orchestrating the nutrient sensing, absorbing and recycling via regulating macropinocytosis through its lipid phosphatase activity. This mechanism could be exploited by tumor cells facing a nutrient-depleted microenvironment, highlighting the potential therapeutic significance of targeting PRL1/3-mediated macropinocytosis in cancer treatment.