Target For Agents Research Articles

Multifunctional Microflowers for Precise Optoacoustic Localization and Intravascular Magnetic Actuation In Vivo.

Efficient drug delivery remains a significant challenge in modern medicine and pharmaceutical research. Micrometer-scale robots have recently emerged as a promising solution to enhance the precision of drug administration through remotely controlled navigation within microvascular networks. Real-time tracking is crucial for accurate guidance and confirmation of target arrival. However, deep-tissue monitoring of microscopic structures in vivo is limited by the sensitivity and spatiotemporal resolution of current bioimaging techniques. In this study, biocompatible microrobots are synthesized by incorporating indocyanine green and iron oxide nanoparticles onto copper phosphate microflowers using a layer-by-layer approach, enhancing optoacoustic contrast and enabling magnetic navigation. Magnetic control of these particles under optoacoustic guidance is demonstrated in vivo. Furthermore, super-resolution optoacoustic imaging, achieved through individual particle tracking, is shown to enable the characterization of microvascular structures and quantification of blood flow. The combination of the microflowers' high carrying capacity, in vivo actuation, and high-resolution tracking capabilities opens new opportunities for precise microvascular targeting and localized administration of theranostic agents via intravascular routes.

A novel agent targeting APRIL: A new hope for elderly patients of IgA nephropathy

A novel agent targeting APRIL: A new hope for elderly patients of IgA nephropathy

Real-world safety of maribavir: a retrospective study based on signal detection in the FDA adverse event reporting system.

Maribavir is a novel antiviral agent targeting cytomegalovirus through inhibition of the UL97 protein kinase, exhibiting a distinct mechanism of action. However, limited data are available on its safety profile post-marketing. This study aimed to evaluate the adverse events (AEs) associated with maribavir using the Food and Drug Administration's Adverse Event Reporting System (FAERS), providing insights to inform clinical practice. We conducted a retrospective analysis of maribavir-related adverse event reports from the FAERS database, spanning the fourth quarter of 2021 to the second quarter of 2024. Signal detection was performed using four statistical methods: the proportional reporting ratio, reporting odds ratio, Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker. A total of 1372 reports associated with maribavir were identified. Seven significant signals emerged at the system organ class level. At the preferred term level, 76 adverse events (AEs) demonstrated positive signals, including novel events such as pleural effusion, hypersomnia, and anosmia, alongside signals related to ear disorders. The majority of AEs were reported within the first month of maribavir use. This study identified several new adverse event signals for maribavir, offering healthcare professionals a deeper understanding of its safety profile, which may guide safer clinical usage.

NGF-TrkA Axis Enhances PDGF-C-Mediated Angiogenesis in Osteosarcoma via miR-29b-3p Suppression: A Potential Therapeutic Strategy Using Larotrectinib.

Angiogenesis plays a critical role in osteosarcoma (OS) growth and metastasis. While nerve growth factor (NGF) is implicated in cancer progression, its role in OS angiogenesis remains unclear. This study explored NGF's effects on angiogenesis and the underlying molecular mechanisms. Analysis of GEO (GSE16088) data identified five angiogenesis markers significantly upregulated in OS tissues. In vitro experiments demonstrated that NGF enhanced HUVEC tube formation by upregulating platelet-derived growth factor C (PDGF-C) expression and suppressing microRNA-29b-3p (miR-29b-3p). The results of tube formation assays confirmed that NGF stimulation significantly increased the angiogenic capacity of MG63/NGF cells compared to MG63 cells. Furthermore, larotrectinib, a TrkA inhibitor, effectively reduced the migration and invasion abilities of MG63/NGF cells in a dose-dependent manner. These findings suggest that the NGF-TrkA axis promotes PDGF-C-mediated angiogenesis by inhibiting miR-29b-3p signaling. Larotrectinib could serve as a potential therapeutic agent targeting NGF-mediated angiogenesis in OS, offering a promising avenue for treatment.

Rapid identification of bacterial select agents using loop-mediated isothermal amplification

BackgroundPoint of need diagnostics provide efficient testing capability for remote or austere locations, decreasing the time to answer by minimizing travel or sample transport requirements. Loop-mediated isothermal amplification (LAMP) is an appealing technology for point-of-need diagnostics due to its rapid analysis time and minimal instrumentation requirements.MethodsHere, we designed and optimized nine LAMP assays that are sensitive and specific to targeted bacterial select agents including Bacillus anthracis, Francisella tularensis, Yersinia pestis, and Brucella spp. Evaluation of each assay determined preliminary limit of detection (LOD) with LOD confirmed across 60 replicates (≥ 95% positivity rate). Testing across a robust set of strains of the target agent, common DNA agents, and near-neighbors documented sensitivity and specificity for independent assays.ResultsSpecifically, all assays were 100% specific and sensitive except for Y. pestis Caf1 (90% inclusive across Y. pestis strains).ConclusionHere, we optimized assay turn-around-time, decreasing a standard 60 min traditional polymerase chain reaction (PCR) to 30 min using LAMP with positive results in as little as 5–10 min. Incorporating point of need sample processing and evaluating the potential inhibitory impact of sample matrices such as whole blood and soil would be needed to enable this test system for use on field-forward clinical and environmental sample testing.

Characterization of Clostridium perfringens Phage Endolysin PlyDolk21.

Background:Clostridium perfringens is a significant cause of food poisoning. Broad-spectrum antibiotics, commonly used to control C. perfringens, are becoming less effective due to the rise of antibiotic-resistant strains, necessitating alternative control strategies. Methods: A C. perfringens-infecting bacteriophage, Dolk21, and its endolysin, PlyDolk21, were isolated and characterized. The lytic activity of PlyDolk21 was assessed in comparison to its catalytic domain alone. Both PlyDolk21 and its cell wall binding domain (CBD) were evaluated in beef and milk for their antimicrobial activity and cell wall binding activity, respectively. Results: While phage Dolk21 was specific to certain C. perfringens strains, PlyDolk21 exhibited lytic activity against all C. perfringens strains tested. The full-length PlyDolk21 showed stronger lytic activity compared to its catalytic domain alone. PlyDolk21_CBD successfully bound to C. perfringens in vitro and in foods. Additionally, PlyDolk21 effectively reduced the viable cell counts of C. perfringens by 3-log in beef soup and milk samples. Conclusions: This study demonstrates that PlyDolk21 and its CBD hold potential as a biocontrol and detection agent targeting C. perfringens in various food matrices.

Cyclophilin A Regulates Tripartite Motif 5 Alpha Restriction of HIV-1.

The peptidyl-prolyl isomerase A (PPIA), also known as cyclophilin A (CYPA), is involved in multiple steps of the HIV-1 replication cycle. CYPA regulates the restriction of many host factors by interacting with the CYPA-binding loop on the HIV-1 capsid (CA) surface. TRIM5 (tripartite motif protein 5) in primates is a key species-specific restriction factor defining the HIV-1 pandemic. The incomplete adaptation of HIV-1 to humans is due to the different utilization of CYPA by pandemic and non-pandemic HIV-1. The enzymatic activity of CYPA on the viral core is likely an important reason for regulating the TRIM5 restriction activity. Thus, the HIV-1 capsid and its CYPA interaction may serve as new targets for future anti-AIDS therapeutic agents. This article will describe the species-specificity of the restriction factor TRIM5, understand the role of CYPA in regulating restriction factors in retroviral infection, and discuss important future research issues.

Advancing Prognosis in Behçet's Uveitis: The Role of Biologic Therapies

Behçet’s disease (BD) is a chronic, multi-system inflammatory disease with potentially devastating ocular involvement. Uveitis remains one of the leading causes of blindness in BD patients. The usual remedies, mainly corticosteroids and immunosuppressants, do not effectively work long term and/or stop relapses. New medicines have changed treatment. New therapies for Behçet’s uveitis may just address the cause of the disease process. This paper analyses the continuous evolution of biologics and their contribution towards improving prognosis; specifically it examines tumour necrosis factor (TNF) inhibitors, interleukin (IL) antagonists, and other monoclonal antibodies. Drugs like infliximab and adalimumab have been quite helpful in controlling inflammation, preventing relapses, and saving sight. These agents target immune pathways to ameliorate the systemic and ocular manifestations of BD, and they have a better safety profile than traditional agents. Rising proof points out that IL-17 and IL-1 inhibitors may also work, opening the choice of therapy for resistant cases. Even though they have made progress, there is still a lot of work to do and overcome optimization biologics challenges related to the patient, cost, and adverse effects. This review highlights the value of personalized treatments, offering key recommendations for the use of biologics in their overall management approach depending on the severity. Also, real-world studies and head-to-head trials will help refine therapeutic algorithms in the future directions. Doctors may use biologic therapies to greatly enhance the quality of life and the visual outcome in Behçet’s uveitis. It is an important step toward precision medicine in BD.

LFA-1: A potential key player in microglia-mediated neuroprotection against oxygen-glucose deprivation in vitro.

For the last 38 years, all neuroprotective agents for patients with ischemic stroke have failed in clinical trials. The innate immune system, particularly microglia, is a much-discussed target for neuroprotective agents. Promising results for neuroprotection by inhibition of integrins with drugs such as natalizumab in animal stroke models have not been translated into clinical practice. Our present study reveals the relevance of a β2 integrin, lymphocyte function-associated antigen-1 (LFA-1), as a potential key player in protecting neuronal cell death after oxygen-glucose deprivation in organotypic hippocampal cell cultures. In addition, we identified microglial cells as effector cells for LFA-1-mediated neuroprotection. The counterpart of LFA-1 on microglia is unclear, but we show strong expression of ICAM-5 in hippocampal neurons, suggesting a critical role for direct crosstalk between microglia and neurons for neuronal survival under oxygen-glucose deprivation. The enigma of neuroprotection after ischemic stroke remains to be solved, and our findings highlight the continuing importance and lack of understanding of integrin-mediated pathways after ischemic stroke and the need for further intensive research.

Repurposing FDA-Approved Drugs for Eumycetoma Treatment: Homology Modeling and Computational Screening of CYP51 Inhibitors.

Eumycetoma, a chronic fungal infection caused by Madurella mycetomatis, is a neglected tropical disease characterized by tumor-like growths that can lead to permanent disability and deformities if untreated. Predominantly affecting regions in Africa, South America, and Asia, it imposes significant physical, social, and economic burdens. Current treatments, including antifungal drugs like itraconazole, often show variable efficacy, with severe cases necessitating surgical intervention or amputation. Drug discovery for eumycetoma faces challenges due to limited understanding of the disease's molecular mechanisms and the lack of 3D structures for key targets such as Madurella mycetomatis CYP51, a well-known target for azoles' antifungal agents. To address these challenges, this study employed computational approaches, including homology modeling, virtual screening, free energy calculations, and molecular dynamics simulations, to repurpose FDA-approved drugs as potential treatments for eumycetoma targeting Madurella mycetomatis CYP51. To this end, a library of 2619 FDA-approved drugs was screened, identifying three promising candidates: montelukast, vilanterol, and lidoflazine. These compounds demonstrated favorable binding affinities, strong interactions with critical residues of the homology model of Madurella mycetomatis CYP51, and stability in molecular dynamics simulations, offering potential for further investigation as effective therapeutic options for eumycetoma.

SurfR: Riding the wave of RNA-seq data with a comprehensive bioconductor package to identify surface protein-coding genes.

Proteins at the cell surface connect signaling networks and largely determine a cell's capacity to communicate and interact with its environment. In particular, variations in transcriptomic profiles are often observed between healthy and diseased cells, leading to distinct sets of cell-surface proteins. For these reasons, cell-surface proteins may act as biomarkers for the detection of cells of interest in tissues or body fluids, are often the target of pharmaceutical agents, and hold significant promise in the clinical practice for diagnosis, prognosis, treatment development, and evaluation of therapy response. Therefore, implementing robust methods to identify condition-specific cell-surface proteins is of pivotal importance to advance biomedical research. We developed SurfR, an R/Bioconductor package providing a streamlined end-to-end workflow for computationally identifying surface protein-coding genes from expression data. Our user-friendly, comprehensive workflow performs systematic expression data retrieval from public databases, differential gene expression across conditions, integration of datasets, enrichment analysis, identification of targetable proteins on a condition of interest, and data visualization. SurfR is released under GNU-GPL-v3.0 License. Source code, documentation, examples, and tutorials are available through Bioconductor (http://www.bioconductor.org/packages/SurfR). RMD notebooks with the use cases code described in the manuscript can be found on GitHub (https://github.com/auroramaurizio/SurfR_UseCases).

Ultrafine fiber-mediated transvascular interventional photothermal therapy using indocyanine green for precision embolization treatment.

Photothermal treatment has attracted immense interest as a promising approach for biomedical applications such as cancer ablation, yet its effectiveness is often limited by insufficient laser penetration and challenges in achieving efficient targeting of photothermal agents. Here we developed a transvascular interventional photothermal therapy (Ti-PTT), which employed a small-sized microcatheter (outer diameter: 0.60 mm, 1.8 Fr) equipped with an ultrafine optical fiber (diameter: 100 μm) capable of simultaneously delivering photothermal agents while performing 808 nm laser irradiation via an endovascular route. Specifically, we employed two types of indocyanine green (ICG)-based photothermal agents, i.e. ICG solution serving as a purely photothermal agent and ICG-ethiodized oil (ICG-EO) emulsion acting as a radiopaque photothermal embolic agent. Using the customized microcatheter with the ICG solution, both proximal and distal embolization were able to be performed in a rat liver model. Compared to the ICG solution, the ICG-EO emulsion dramatically enhanced the ICG retention time, enabling a photothermally triggered precision vascular blockade to induce local embolization of large tissue volumes in a rat kidney model with an unfavorable ICG leakage rate. The Ti-PTT paves the way to broadening the potential applications of photothermal therapy through combination with clinical intervention-based approaches.

Altered metabolic function induced by Aβ-oligomers and PSEN1 mutations in iPSC-derived astrocytes.

Altered energy metabolism in Alzheimer's disease (AD) is a major pathological hallmark implicated in the early stages of the disease process. Astrocytes play a central role in brain homeostasis and are implicated in multiple neurodegenerative diseases. Although numerous studies have investigated global changes in brain metabolism, redox status, gene expression and epigenetic markers in AD, the intricate interplay between different metabolic processes, particularly in astrocytes, remains poorly understood. Numerous studies have implicated amyloid-β and the amyloid-β precursor in the development and progression of AD. To determine the effects of amyloid-β peptides or the impact of amyloid-β precursor protein processing on astrocyte metabolism, we differentiated astrocytes from induced pluripotent stem cells derived from people with early onset familial AD and controls. This study demonstrates that familial AD-derived astrocytes exhibit significantly more changes in their metabolism including glucose uptake, glutamate uptake and lactate release, with increases in oxidative and glycolytic metabolism compared to acute amyloid-β exposure. In addition to changes in major metabolic pathways including glutamate, purine and arginine metabolism and the citric acid cycle, we demonstrate evidence of gliosis in familial AD astrocytes highlighting a potential pathological hallmark. This suggests that chronic alterations in metabolism may occur very early in the disease process and present significant risk factors for disease progression for patients with early onset AD. These findings may also reveal important drivers of disease in late onset dementia and highlights key targets for potential diagnostic features and therapeutic agents in the future.

When a principal sets a target level and agents reaching it receive a bonus

When a principal sets a target level and agents reaching it receive a bonus

Design, Synthesis, and Anticancer Activity of Drug-like Iron Chelators/G-Quadruplex Binders as Synergic Dual Targeting Agents.

Iron homeostasis is strictly related to numerous physiological pathways including cell cycle progression and cell growth. The newest anticancer strategies focus on either depleting the cells with a suitable chelator or increasing their loading by administering iron complexes to induce ferroptosis. Iron depletion inhibits cell proliferation, while iron overload induces the damage of guanine nucleobases in G-quadruplex structures via ROS generation, leading to genome instability. Here, we demonstrated that designing a molecular chimera embodying structural requirements for both iron chelation and G-quadruplex binding can result in dual-targeting compounds endowed with synergistic anticancer effects. We designed, synthesized, and tested a library of such compounds through biophysical and biological experiments. Compound 16 emerged as a lead candidate and a pharmacological tool able to chelate iron and stabilize G-quadruplexes in human leukemia Jurkat cells. Notably, it also localizes in the cell nucleus, serving as an intrinsically fluorescent nuclear tracer for the labile iron pool.

A novel platinum(II) complex with a berberine derivative as a potential antitumor agent targeting G-quadruplex DNA.

G-quadruplexes are considered attractive targets for various human diseases, including cancer therapy, owing to their potential therapeutic applications. Understanding the interaction between ligands and G-quadruplexes is crucial for the development of novel anticancer agents. In this study, we designed a novel platinum(II) complex (Pt1), with a berberine derivative (L) serving as a bioactive ligand. The structures of both ligand L and Pt1 were fully characterized using NMR, ESI-MS, and IR. UV-visible spectroscopy, fluorescence spectroscopy, circular dichroism spectroscopy, electrostatic surface potential, frontier molecular orbital and molecular docking experiments were employed to investigate the interaction between Pt1 and G-quadruplexes. The results suggested that Pt1 interacted favorably with G-quadruplex DNA over double-stranded DNA (DS26). Among them, Pt1 interacts with the bcl-2 G-quadruplex with a binding affinity of 17.9 μM and did not induce conformational changes in the topology of the bcl-2 G-quadruplex. Moreover, we evaluated its antiproliferative activities on tumor cells (HeLa, A549 and T24), which demonstrated that Pt1 inhibited tumor cell proliferation and induced HeLa cell apoptosis. Overall, this study offers novel insights for the development of promising platinum(II) antitumor agents based on G-quadruplex structures.

A New Frontier of Hope: Highlighting the Promising Potential of Spliceosome Inhibitor E7107 in Treating SF3B1 Mutant Uveal Melanoma

Dear editor This letter highlights the promising nature of spliceosome inhibitor E7107 in SF3B1 mutant uveal melanoma and warrants future research to establish its clinical application, safety, and efficacy for these patients. Uveal melanoma originates from the melanocyte of the uvea and has a metastasis rate of about 25-34% within a span of ten years leading to poor prognosis and a death rate of 80% at 1 year following metastasis.1 This shows the horrible nature of these melanomas and demand for an inevitable urge of definitive treatment options for these patients. However, unfortunately, the treatment options are very limited and poor. Various prognostic factors have been identified for uveal melanoma including mutations in genes encoding BRCA-1 associated protein (BAP1) being worst, splicing factor 3b subunit 1 (SF3B1) being intermediate, and eukaryotic translation initiating factor 1A X-linked (EIF1AX) being best prognostic factor.2,3A large percentage of about 15%-35% of uveal melanomas have SF3B1 mutations which make it an important prognostic feature however there is no well-established pharmacological agent targeting or utilizing this major prognostic mutation as a therapeutic fortune. A recently introduced protein Tebetafusp though showed prolonged survival in metastatic carcinoma but available only for metastatic uveal melanoma

Synthesis and antifungal evaluation of new azole derivatives containing 1,2,3-triazole.

Invasive fungal infections caused by C. albicans are becoming increasingly serious and there is an urgent need for exploring new antifungal drugs. In the present work, a series of new azole derivatives containing a 1,2,3-triazole moiety have been prepared, and in vitro antifungal activity have been evaluated. The results revealed that most compounds showed excellent antifungal activity against C. albicans SC5314 and drug-resistant SC5314-FR. In particular, compounds 4h, 4j, 4l, 4s and 4w exhibited better antifungal activity than FLC. The preliminary mechanism study indicated that 4s could damage the integrity of the cell structure, increase the permeability of the cell membrane, and cause the leakage of cell contents of C. albicans. The molecular docking study indicated that 4s showed an obvious binding site with the target CYP51 (PDB ID: 5TL8). Therefore, 4s could be considered as a new antifungal agent targeting CYP51 for further study.

Salicylalazine: A novel therapeutic agent targeting TLR4/NLRP3/GSDMD-mediated pyroptosis in rheumatoid arthritis.

Joint pain and functional impairment are hallmarks of arthritis, a painful inflammatory disease. Salicylalazine (SAZ), an anti-inflammatory compound, has demonstrated promise in modulating inflammation, thereby being selected in the current study to unveil its anti-arthritic potential. The aim behind this study was to assess the anti-arthritic properties of salicylalazine via evaluating its impact on paw volume, arthritic scores, oxidative stress indicators, and significant inflammatory mediators. The arthritic potential of SAZ was estimated first through the formaldehyde (FA) model to screen the most effective dose of SAZ, followed by the Complete Freund's adjuvant (CFA) model. Over a 28-day period, we monitored parameters such as paw edema, arthritic index, body weight, flexion pain, mobility, and stance score. Oxidative stress markers (GSH, CAT, SOD, MDA), serological markers (CRP, RF, anti-CCP), and gene expression of key inflammatory mediators (TLR4, MyD88, NFκB, NLRP3, ASC, IL-1β, IL-18, caspase-1, GSDMD) were assessed. SAZ treatment led to a substantial decrease in paw volume in both arthritis models, with the most pronounced effects observed on day 10 for the formaldehyde model and day 28 for the CFA model (p<0.001). Additionally, SAZ helped to restore the body's weight and considerably relieved the flexion pain, which led to improvements in both mobility and stance. Moreover, SAZ substantially raised the levels of antioxidant enzymes (GSH, CAT, SOD) and decreased MDA levels, suggesting a reduction in oxidative stress. Also with SAZ, there was a substantial (p<0.001) decrease in the expression of pyroptotic mediators. Serological markers of inflammation, including CRP, RF, and anti-CCP levels, were also restored by SAZ administration. In a nutshell, SAZ achieved significant anti-arthritic benefits, most likely via the modulation of the TLR4/NLRP3/GSDMD-mediated pyroptosis pathway, lowering oxidative stress, and improvement of clinical findings. Taking into consideration these findings, it seems that SAZ has the potential to be an effective treatment alternative for the management of arthritis.

Novel insights toward diagnosis and treatment of glioneuronal and neuronal tumors in young adults.

Aim: Glioneuronal and neuronal tumors are rare primary central nervous system malignancies with heterogeneous features. Due to the rarity of these malignancies diagnosis and treatment remains a clinical challenge. Methods: Here we performed a narrative review aimed to investigate theprincipal issues concerning the diagnosis, pathology, and clinical management of glioneuronal tumors. Results: Diagnostic criteria have been recently overturned thanks to a better characterization on a histological and molecular biology level. The study of genomic alterations occurring within these tumors has allowed us to identify potential therapeutic targets including BRAF, FGFR, and PDGFRA. Conclusion: Techniques allowing molecular sequencing DNA methylation assessment of the disease are essential diagnostic tools. Targeting agents should be included in the therapeutic armamentarium after loco-regional treatment failure.