Synthesis of Arginase Inhibitors: An Overview

Pharmaceutics, Journal Year: 2025, Volume and Issue: 17(1), P. 117 - 117

Published: Jan. 16, 2025

Arginase (ARG) is a binuclear manganese-containing metalloenzyme that can convert L-arginine to L-ornithine and urea plays key role in the cycle. It also mediates different cellular functions processes such as proliferation, senescence, apoptosis, autophagy, inflammatory responses various cell types. In mammals, there are two isoenzymes, ARG-1 ARG-2; they functionally similar, but their coding genes, tissue distribution, subcellular localization, molecular regulation distinct. recent decades, abnormal expression of or ARG-2 has been reported be increasingly linked variety diseases, including cardiovascular disease, bowel Alzheimer's cancer. Therefore, considering current relevance this topic need address growing demand for new more potent ARG inhibitors context review was conceived. We will provide an overview all classes developed so far compounds synthetic, natural, semisynthetic origin. For first time, synthesis protocol optimized reaction conditions each molecule, those patent applications, described. its inhibitory activity terms IC50 towards specifying type assay conducted.

Language: Английский

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Optimization of citrulline production from a Bacillus subtilis BH-01 isolated from raw buffalo milk

BMC Microbiology, Journal Year: 2025, Volume and Issue: 25(1)

Published: Feb. 10, 2025

Abstract The main purpose of this study was to optimize the L-citrulline production process using Plackett-Burman and Box-Behnken designs. L-citrulline-producing bacterium BH-01 isolated from raw buffalo milk. isolate tested for probiotic activities such as tolerance simulated gastric intestinal juices, antagonistic activity against six antibiotic-resistant bacteria, temperature tolerance. arginine deiminase (ADI) were optimized statistical bacterial molecularly identified Bacillus subtilis strain AUMC B-498 (accession number PP574248.1). exhibited resistance at pH 2.0 bile salt 0.5% a two-hour exposure period. It could inhibit growth Escherichia coli , Klebsiella pneumonia Serratia sp., Staphylococcus aureus methicillin - resistant (MRSA), Streptococcus pneumoniae. From results optimization, design temperature, L-arginine, incubation period, peptone most effective factors among eight selected variables. Based on these, used required maximize citrulline production. maximum 632.5 µg/L, ADI 1.42 U/mL. Therefore, Buffalo milk might be promising candidate in food, biotechnological, pharmaceutical applications due its dual functionality characteristics.

Language: Английский

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Differential Expression of ARG1 and MRC2 in Retinal Müller Glial Cells During Autoimmune Uveitis

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 288 - 288

Published: Feb. 14, 2025

Retinal Müller glial cells (RMG) play a crucial role in retinal neuroinflammation, including autoimmune uveitis. Increasing evidence supports their function as active modulators of immune responses and potential atypical antigen-presenting (APCs). To further investigate this hypothesis, we conducted differential proteome analysis primary equine RMG from healthy controls horses with recurrent uveitis (ERU), spontaneous model This identified 310 proteins abundance. Among these, the Major Histocompatibility Complex (MHC) class II enzyme Arginase 1 (ARG1) were significantly enriched uveitis-affected horses, whereas Mannose Receptor C-type 2 (MRC2) its interactor Thrombospondin (THBS1) more abundant RMG. The detection MHC RMG, consistent previous studies, validates robustness our approach. Furthermore, identification ARG1 MRC2, together THBS1, provides new insights into immunomodulatory properties Immunohistochemical analyses confirmed proteomic findings revealed spatial distribution MRC2. MRC2 are thus markers for neuroinflammatory or physiological milieu highlight differences particularly antigen presentation.

Language: Английский

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Not All Neuroinflammation Is Created Equal: The Dual Nature of Astrogliosis

Biological Psychiatry, Journal Year: 2025, Volume and Issue: 97(8), P. 758 - 760

Published: March 27, 2025

Language: Английский

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Metabolomic reprogramming of the tumor microenvironment by dual arginase inhibitor OATD-02 boosts anticancer immunity

Published: April 1, 2025

Metabolic reprogramming within the tumor microenvironment (TME) plays a central role in cancer progression and immune evasion, with L-arginine metabolism emerging as key regulatory axis. Arginase overexpression depletes intratumoral L-arginine, thus suppressing T-cell proliferation while fuelling growth through polyamine biosynthesis. OATD-02, novel dual arginase (ARG1/ARG2) inhibitor, reprograms by restoring availability reducing levels of polyamines, thereby shifting TME toward more immunostimulatory state. Unlike ARG1-selective inhibitors limited intracellular uptake, OATD-02 effectively inhibits both extracellular arginases, addressing major limitation first-generation inhibitors. To visualize pharmacodynamic effects dosing mice spatial resolution, we employed MALDI mass spectrometry imaging (MALDI-MSI), enabling direct mapping metabolic changes tissues. In preclinical models, treatment led to widespread accumulation concomitant depletion polyamines resulted shifts that correlated increased cell infiltration an improved response checkpoint blockade. These findings underscore inhibition reshaping overcoming suppression fitness cells fight cancer. The caused significantly enhanced antitumor responses, tumors, expansion CD8⁺ T draining lymph nodes, systemic upregulation activation markers. translated into substantial survival benefit CT26 model, particularly when combined anti-PD-1 therapy, where blockade efficacy relieving constraints affecting tumor-infiltrating lymphocytes. By leveraging unique capabilities MALDI-MSI, this study provides high-resolution insights mechanism action reinforcing its potential next-generation metabolic-immunotherapeutic agent. observed reprogramming, coupled prolonged survival, supports clinical development promising strategy for enhancing immunotherapy efficacy. is currently undergoing evaluation phase I/II trial (NCT05759923), which will further elucidate safety therapeutic impact. highlight arginase-targeted therapies value MALDI-MSI powerful tool tracking responses therapy.

Language: Английский

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Genome-wide association study of plasma amino acids and Mendelian randomization for cardiometabolic traits

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 25, 2025

Plasma amino acids (AAs) have emerged as promising biomarkers for metabolic disorders, yet their causality remains unclear. We aimed to investigate the genetic determinants of AA levels in a cohort 10,333 individuals and causal effects on cardiometabolic traits using Mendelian randomization (MR). 20 AAs were quantified capillary electrophoresis mass spectrometry. Genome-wide association studies conducted BOLT-LMM heritability estimation via LDSC analysis. Causal 11 examined two-sample MR analyses. identified 85 locus-metabolite associations across 43 genes 18 AAs, including 44 novel loci linked genes. Heritability was estimated at 16%. analysis demonstrated cystine positively associate with systolic blood pressure (SBP) (β = 0.056, SE 0.010), while serine indicated protective SBP - 0.040, 0.011), diastolic BP 0.044, coronary artery disease (odds ratio 0.888, 0.028). potentially associated robust between several traits. These findings reinforce importance potential therapeutic targets health.

Language: Английский

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Functional Role of Granulocytic Myeloid-Derived Suppressor Cells in CAR-T Therapy: Insights from Single- Cell RNA Sequencing in Multiple Myeloma

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: May 7, 2025

Immunotherapies, including chimeric antigen receptor T-cell (CAR-T) therapy, represent a pivotal approach in the treatment of multiple myeloma (MM). However, complex immunosuppressive tumor microenvironment (TME) poses significant challenges to their efficacy. Among cells MM TME, granulocytic myeloid-derived suppressor (G-MDSCs) are predominant; however, functions remain incompletely understood. In this study, comprehensive analysis G-MDSCs was conducted using single-cell transcriptomic data from seven patients before and post CAR-T therapy. The pathological activation roles were identified, these features found be potentially linked patient prognosis. Functional enrichment revealed that key modulators immune responses within TME. GSEA suggested regulate via IFN-α/γ signaling pathway. Furthermore, may facilitate evasion by promoting cell proliferation through IGF1-IGF1R axis inhibiting T other SIRPA-CD47 A risk prediction model based on differentially expressed genes demonstrated high prognostic accuracy (AUC = 0.94) validated Kaplan-Meier survival analysis. Additionally, PTGS1 identified as marker associated with high-risk groups, suggesting its potential therapeutic adjunct target improve outcomes. Further vitro experiments exert expression. This study provides new insights into role TME highlights strategies enhance therapy

Language: Английский

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Metabolomic Insights into the Predictive Landscape of Neoadjuvant Immunochemotherapy in Gastric Cancer: Towards Precision Medicine with Machine Learning

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: May 14, 2025

Neoadjuvant Immunochemotherapy (NAIC) shows promising application prospects in the treatment of (Gastric Cancer, GC) patients. However, differences between individual patients and issue resistance significantly affect whether could truly benefit from this treatment. This study conducted metabolomic analysis 369 plasma samples 108 gastric cancer following NAIC to characterize their metabolic profiles for more accurate therapeutic efficacy prediction. Machine learning was used build a GC response prediction model 21-PM based on expression levels baseline metabolites. Two monitoring models, 11-MMI 13-MMP, were developed using R-specific metabolites imaging histology outcomes, respectively. In conclusion, outcomes offered strong evidence advancement precision medicine by exposing landscape after efficiently creating models that independently predict monitor

Language: Английский

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Evolving therapeutic strategies for severe fever with thrombocytopenia syndrome: from past to future

Therapeutic Advances in Infectious Disease, Journal Year: 2025, Volume and Issue: 12

Published: May 1, 2025

Severe fever with thrombocytopenia syndrome (SFTS) is a hemorrhagic caused by Bandavirus dabieense . SFTS was first identified in China 2009 and has been reported since then neighboring countries regions. The clinical manifestations of include fever, thrombocytopenia, leukocytopenia are often accompanied gastrointestinal symptoms bleeding. In severe cases, patients experience life-threatening immune damage cytokine storms. Despite nearly 15 years its discovery, no effective vaccine approved. However, significant progress achieved elucidating the mechanisms host responses, implementation various therapeutic agents. This article provides comprehensive review commonly utilized treatments supported current evidence. Favipiravir advantages over ribavirin terms viral clearance prognosis. Conventional immunomodulators like interferon, intravenous immunoglobulin, glucocorticoids have limited effects may even worsen conditions, whereas novel such as tocilizumab ruxolitinib shown potential for improving Prophylactic platelet transfusions neither prevent bleeding nor improve outcomes. Additionally, plasma exchange, calcium channel blockers, arginine can laboratory values expedite clearance. future, screening Food Drug Administration-approved drugs conducting multiomics analyses lead to discovery new options.

Language: Английский

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DIA-based quantitative proteomic insight of lamb meat quality: tenderness and amino acid profile under different grazing intensities

LWT, Journal Year: 2024, Volume and Issue: unknown, P. 117285 - 117285

Published: Dec. 1, 2024

Language: Английский

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