Potent Modulator Research Articles

Seaweed-Derived Bioactive Compounds: Potent Modulators in Breast Cancer Therapy.

Cancer remains a major global health concern, with breast cancer being particularly challenging. To address this, new therapeutic strategies are being explored, including natural alternatives. Seaweeds, rich in bioactive compounds, have gained attention for their therapeutic potential. Traditionally valued for their nutritional content, seaweed-derived compounds such as polysaccharides, polyphenols, sterols, vitamins, minerals, and carotenoids have shown anti-cancer properties. These compounds can modulate key cellular processes like apoptosis, angiogenesis, and inflammation-crucial in cancer progression. Their antioxidant, anti-inflammatory, and immunomodulatory effects make them promising candidates for complementary cancer therapies. Key bioactive components like fucoidans, laminarins, phlorotannins, and carotenoids exhibit anti-proliferative, pro-apoptotic, anti-angiogenic, and anti-metastatic properties. Recent studies focus on the ability of these compounds to induce apoptosis in cancer cells. This review highlights the chemical constituents of various seaweed species with anti-tumor activity, their mechanisms of action, and the potential for integration into cancer treatments. It also addresses challenges in clinical applications and outlines future research directions for leveraging these marine resources in breast cancer therapy.

Scrutinizing the value and implementation of volitional personality development at work

AbstractIn this commentary, we discuss Dupré and Wille's proposal (2024) to consider employees' personality change goals in the work context. We compare volitional personality development to skill development and call for more evidence to determine the benefits for both employees and organizations in this context. We also put forward that a clearer understanding is required of how job demands influence personality traits and of how these demands interact with and shape the integration of potential complementary personality development training modules. In closing, we provide avenues for future research.

Design, Synthesis, and Biological Evaluation of Novel 2-Heteroaryl-oxazolidine-4-one Derivatives as Novel HBV Capsid Assembly Modulators.

Using 2-pyrazole oxazolidine-4-one derivative 1 as the lead compound, a series of novel 2-heteroaryl-oxazolidine-4-one derivatives were designed and synthesized by replacing pyrazole moiety with other heterocycles, including methyl pyrazole, oxazole, thiazole, triazole, and reverse pyrazoles, based on the principle of bioisosterism. The structures of target compounds were established by 1H-NMR, 13C-NMR, and electrospray ionization (ESI)-MS. Majority of these compounds showed moderate to good inhibitory activities against hepatitis B virus (HBV) DNA proliferation with low cytotoxicities. Especially, compound 7g showed the most potent anti-HBV activity with EC50 value of 0.059 µM, accompanied with better selectivity index (SI) value than that of lead compound. Our research revealed the structure-activity relationship (SAR) of these newly designed compounds and compound 7g was identified as the potential HBV capsid assembly modulator.

Nanomaterials as Potential Plant Growth Modulators: Applications, Mechanism of Uptake, and Toxicity: A Comprehensive Review

Nanomaterials as Potential Plant Growth Modulators: Applications, Mechanism of Uptake, and Toxicity: A Comprehensive Review

Moiré Exciton Polaron Engineering via twisted hBN.

Twisted hexagonal boron nitride (thBN) exhibits ferroelectricity due to moiré superlattices with AB/BA domains. These domains possess electric dipoles, leading to a periodic electrostatic potential that can be imprinted onto other materials placed in its proximity. Here we demonstrate the remote imprinting of moiré patterns from thBN onto monolayer MoSe2 and investigate the changes in the exciton properties. We confirm the imprinted moiré patterns on monolayer MoSe2 using Kelvin probe force microscopy (KPFM) and hyperspectral photoluminescence (PL) mapping. By creating a large ferroelectric domain (∼8.7 μm), we achieve unprecedented potential modulation (∼387 ± 52 meV). We observe the formation of exciton-polarons by the ferroelectric moiré domains and investigate the optical property changes induced by the moiré pattern in monolayer MoSe2 by varying the moiré domain size down to ∼110 nm. Our findings highlight the potential of thBN as a platform for controlling the properties of 2D materials for optoelectronic and valleytronic applications.

Discovery of the FXR/CES2 dual modulator LE-77 for the treatment of irinotecan-induced delayed diarrhea

Irinotecan (CPT-11) is a widely utilized topoisomerase I inhibitor in the treatment of colorectal cancer and other malignant tumors. However, severe and even life-threatening dose-limiting toxicity-delayed diarrhea affects the clinical application of CPT-11. The standard treatment for CPT-11-induced delayed diarrhea is prompt use of loperamide (LPA), however LPA can also cause constipation, diarrhea and even intestinal obstruction and has a high failure rate. Carboxylesterase 2 (CES2) is the main enzyme in the intestinal transformation of CPT-11, which can convert CPT-11 into toxic metabolite SN-38 and produce intestinal toxicity. Inhibiting CES2 activity can block the hydrolysis process of CPT-11 in the intestine and reduce SN-38 accumulation. Additionally, Farnesoid X receptor (FXR) agonists have anti-inflammatory, anti-secretory, and protective functions on intestinal barrier integrity that could potentially alleviate diarrhea. In this study, we investigated for the first time the anti-delayed diarrhea effect of FXR agonists, and the first time identified LE-77 as a potent dual modulator that activates FXR and inhibits CES2 through high-throughput screening. In the CPT-11-induced delayed diarrhea model, LE-77 demonstrated a dual modulator mechanism by activating FXR and inhibiting CES2, thereby reducing the accumulation of SN-38 in the intestine, alleviating intestinal inflammation, preserving intestinal mucosal integrity, and ultimately alleviating delayed diarrhea

An In Silico Investigation of the Pathogenic G151R G Protein-Gated Inwardly Rectifying K+ Channel 4 Variant to Identify Small Molecule Modulators

Primary aldosteronism is characterised by the excessive production of aldosterone, which is a key regulator of salt metabolism, and is the most common cause of secondary hypertension. Studies have investigated the association between primary aldosteronism and genetic alterations, with pathogenic mutations being identified. This includes a glycine-to-arginine substitution at position 151 (G151R) of the G protein-activated inward rectifier potassium (K+) channel 4 (GIRK4), which is encoded by the KCNJ5 gene. Mutations in GIRK4 have been found to reduce the selectivity for K+ ions, resulting in membrane depolarisation, the activation of voltage-gated Ca2+ channels, and an increase in aldosterone secretion. As a result, there is an interest in identifying and exploring the mechanisms of action of small molecule modulators of wildtype (WT) and mutant channels. In order to investigate the potential modulation of homotetrameric GIRK4WT and GIRK4G151R channels, homology models were generated. Molecular dynamics (MD) simulations were performed, followed by a cluster analysis to extract starting structures for molecular docking. The central cavity has been previously identified as a binding site for small molecules, including natural compounds. The OliveNetTM database, which consists of over 600 compounds from Olea europaea, was subsequently screened against the central cavity. The binding affinities and interactions of the docked ligands against the GIRK4WT and GIRK4G151R channels were then examined. Based on the results, luteolin-7-O-rutinoside, pheophorbide a, and corosolic acid were identified as potential lead compounds. The modulatory activity of olive-derived compounds against the WT and mutated forms of the GIRK4 channel can be evaluated further in vitro.

Imidazo[2,1-b][1,3]thiazine Derivatives as Potential Modulators of Alpha-Synuclein Amyloid Aggregation.

Insoluble amyloid fibrils accumulate in the intercellular spaces of organs and tissues, leading to various amyloidosis-related disorders in the human body. Specifically, Parkinson's disease is associated with the aggregation of alpha-synuclein. However, current treatments for Parkinson's primarily focus on managing motor symptoms and slowing disease progression. Efforts to prevent and halt the progression of these diseases involve the search for small molecular compounds. In this work, we synthesized imidazo[2,1-b][1,3]thiazines in an atom-economic way by cyclization of 2-alkynylthioimidazoles using 10% AuCl as the catalyst. We identified several compounds with specific functional groups capable of both inhibiting the aggregation of alpha-synuclein and redirecting the fibril formation pathway. The investigation into how these substances function revealed that imidazo[2,1-b][1,3]thiazine derivatives can influence alpha-synuclein aggregation in several ways. They not only inhibit the primary nucleation process and maintain a balance toward nonaggregated protein states but also stabilize smaller oligomeric species of alpha-synuclein and cause the formation of fibrils with unique structures and forms. These imidazo[2,1-b][1,3]thiazines could potentially be used in developing highly efficient, small molecular weight protein aggregation inhibitors.

Integrative bioinformatics analysis of immune activation and gene networks in pediatric septic arthritis

BackgroundPediatric septic arthritis, driven by Staphylococcus aureus, leads to substantial morbidity due to the host’s complex inflammatory response. This study integrates bioinformatics analyses to map the genomic and immune profiles of pediatric septic arthritis, aiming to identify key biomarkers and therapeutic targets. MethodsAn integrative bioinformatics approach was adopted to analyze gene expression datasets from the GEO database, focusing on pediatric septic arthritis. DEGs were identified using GEO2R, and gene co-expression networks were generated via GeneMANIA. STRING database and Cytoscape software facilitated PPI network construction. DAVID enabled functional enrichment analysis to elucidate biological processes and pathways, while iRegulon predicted transcription factor regulation. CIBERSORT provided a detailed profile of immune cell alterations in the condition. ResultsFrom the datasets analyzed, 576 DEGs were extracted, with 35 shared between the two datasets, revealing an innate immunity signature with notable hub genes such as MPO and ELANE, indicative of a pronounced neutrophilic response. Functional enrichment analysis highlighted pathways pertinent to antimicrobial defense and NET formation. Key transcription factors, including PBX1, POLR2A, and STAT3, were identified as potential modulators of these pathways. Immune profiling demonstrated significant shifts in cell populations, with increased plasma cells and reduced CD4+ naïve T cells. ConclusionsThis study elucidates the complex genomic and immunological milieu of pediatric septic arthritis, uncovering potential biomarkers and signaling pathways for targeted therapeutic intervention. These findings underscore the preeminence of innate immune mechanisms in the disease's pathology and offer a foundation for future research to explore diagnostic and treatment innovations. Translation of these bioinformatics discoveries into clinical applications requires further validation and consideration of the limitations inherent to gene expression data and its interpretation.

Large-scale single-nuclei profiling identifies role for ATRNL1 in atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia in humans, yet the molecular basis of AF remains incompletely understood. To determine the cell type-specific transcriptional changes underlying AF, we perform single-nucleus RNA-seq (snRNA-seq) on left atrial (LA) samples from patients with AF and controls. From more than 175,000 nuclei we find that only cardiomyocytes (CMs) and macrophages (MΦs) have a significant number of differentially expressed genes in patients with AF. Attractin Like 1 (ATRNL1) was overexpressed in CMs among patients with AF and localized to the intercalated disks. Further, in both knockdown and overexpression experiments we identify a potent role for ATRNL1 in cell stress response, and in the modulation of the cardiac action potential. Finally, we detect an unexpected expression pattern for a leading AF candidate gene, KCNN3. In sum, we uncover a role for ATRNL1 which may serve as potential therapeutic target for this common arrhythmia.

Generation of Functional Neurons from Mesenchymal Stem Cells Using Neural Differentiator and Engineered Peptide Hydrogel: Potential Therapeutic Lead for Traumatic Brain Injury.

Traumatic brain injuries (TBIs) cause multifaceted disruption in the neural network, initiate huge inflammation processes, and form glial scars that result in severe damage to the brain. Thus, the treatment of TBI is a challenging task. To address this challenge, a newer and innovative approach is extremely important to develop a successful therapeutic strategy. Toward this aim, we hereby report an extremely effective therapeutic strategy. This interesting approach showcased the development and validation of a combination therapy comprising a neuro-regenerative protective peptide hydrogel (SLNAP) and a potent neuro-regenerative chemical modulator (NCM). It is noteworthy to mention that this hydrogel formulation has injectable nature, which allows it to be applied at focal injury site of brain. Remarkably, our results reveal excellent transdifferentiation of human umbilical cord-derived mesenchymal stem cells (hMSCs) into functional neuron upon treatment with this combination therapeutic formulation. The functionality of regenerated neurons was thoroughly checked through observation of active signals generated from those neurons in electrophysiology recording using patch clamp. Further, we also observed that this strategy not only successfully converts hMSCs into neuron but also spontaneously formed neural stem cells (NSCs) like neurosphere. This work also showcased that this multidomain self-assembling peptide hydrogel emerges as an attractive soft-biomaterial due to its capability of slow and sustained release of the drug at the injury site upon topical application. This resulted in significant regeneration of functional neuron at the injury site. Fascinatingly, we found that this combination therapeutic strategy is highly effective in in vivo brain injury model establishing that this could be a potential and highly effective therapeutic strategy for TBI.

Increased alpha power in autistic adults: Relation to sensory behaviors and cortical volume.

Alpha-band (~10 Hz) neural oscillations, crucial for gating sensory information, may offer insights into the atypical sensory experiences characteristic of autism spectrum disorder (ASD). We investigated alpha-band EEG activity in autistic adults (n = 29) compared with a nonautistic group (n = 23) under various stimulus-driven and resting-state conditions. The autistic group showed consistently higher alpha amplitude across all time points. In addition, there was proportionally more suppression of alpha at stimulus onset in the autistic group, and alpha amplitude in this stimulus-onset period correlated with sensory behaviors. Recent research suggests a link between subcortical structures' volume and cortical alpha magnitude. Prompted by this, we explored the association between alpha power and the volume of subcortical structures and total cortical volume in ASD. Our findings indicate a significant correlation with total cortical volume and a group by hippocampal volume interaction, pointing to the potential role of anatomical structural characteristics as potential modulators of cortical alpha oscillations in ASD. Overall, the results highlight altered alpha in autistic individuals as potentially contributing to the heightened sensory symptoms in autistic compared with nonautistic adults.

SPFont: Stroke potential features embedded GAN for Chinese calligraphy font generation

Chinese calligraphy font generation is an extremely challenging problem. Firstly, Chinese calligraphy fonts have complex structures. The accuracy and artistic quality of the generated fonts will be affected by the order and layout of the strokes as well as the relationships between them. Secondly, the number of Chinese characters is large, but existing calligraphy works are scarce. Hence, it is difficult to establish a comprehensive and high-quality Chinese calligraphy dataset. In this paper, we propose an unsupervised calligraphy font generation network SPFont. It is based on a generative adversarial network (GAN) framework. The generator includes a style feature encoder, a content feature encoder, a stroke potential feature fusion module (SPFM) and a decoder. The SPFM module, by overlaying lower-level style and content features, better preserves fine details of the font such as stroke thickness, curve shapes and other characteristics. The SPFM module and the extracted style features are fused and then fed into the decoder, allowing it to consider the influence of style, content and stroke potential simultaneously during the generation process. Experimental results demonstrate that our model generates Chinese calligraphy fonts with higher quality compared to previous methods.

Hydrophobic forces at play: insights into AmelOBP4 and brood volatile interactions in Apis mellifera hygienic behavior

Understanding the intricate processes underlying olfaction necessitates unraveling the complexities of odorant binding protein’s interactions with volatile compounds triggering hygienic behavior in Apis mellifera, This study delves into the intricate processes of olfaction by focusing on the interactions between Apis mellifera Odorant Binding Protein 4 (AmelOBP4) and volatile compounds associated with hygienic behavior, employing a comprehensive computational approach. Molecular docking analyses reveal detailed binding interactions, emphasizing the significance of hydrophobic interactions and specific amino acid residues in stabilizing AmelOBP4-volatile complexes, notably with 2-nonacosanone (-8.4 kcal/mol) and hexacosyl acetate (-8.4 kcal/mol). Molecular dynamics simulations demonstrate sustained stability and principal component analysis affirms structural integrity through restricted global motions. Binding free energy calculations underscore robust interactions, with per-residue free energy decomposition identifying key amino acids contributing significantly to binding affinity. These findings illuminate the pivotal role of hydrophobic interactions and specific residues (Phe 60, Leu 83, Ile 116, Leu 126, and Leu 130) in modulating AmelOBP4-volatile interactions, providing foundational insights into volatile-based applications and potential olfactory response modulation, contributing to our understanding of olfactory processes.

In-Silico discovery of 17alpha-hydroxywithanolide-D as potential neuroprotective allosteric modulator of NMDA receptor targeting Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory impairment, and behavioral alterations. The N-methyl-D-aspartate (NMDA) receptor has emerged as a promising target for AD pharmacotherapy due to its role in the disease’s pathogenesis. This study leverages advanced computational methods to screen 80 active constituents of Withania somnifera (Ashwagandha), a traditional herb known for its neuroprotective effects, against the NMDA receptor, using FDA-approved Ifenprodil as a reference. Our blind virtual screening results demonstrated that all tested compounds could bind to various domains of the NMDA receptor, with binding energies ranging from − 4.1 to -11.9 kcal/mol, compared to Ifenprodil’s -7.8 kcal/mol. Binding preference analysis revealed 7 compounds bound to the A-chain, 37 to the B-chain, 7 to the C-chain, and 29 to the D-chain of the receptor. Notable binding was observed predominantly at the Amino Terminal Domain (ATD) core site, some at the ATD-Ligand Binding Domain (LBD) interface, and a few at the Transmembrane Domain (TMD). Particularly, 17alpha-hydroxywithanolide D, with a binding energy of -11.9 kcal/mol, emerged as a prime candidate for further investigation. Molecular dynamics simulations of this compound revealed key interactions, including direct hydrogen bonding with residues ASP165, ARG431, THR433, LYS466, and TYR476 on the D-chain, as well as additional hydrophobic and water-bridging interactions. These simulations highlighted the compound’s influence on dynamic conformational states of the GluN1b-GluN2B receptor complex, modulating interactions between GluN1b Lys178 and GluN2B Asn184. Furthermore, the compound affected the distance between LBD heterodimers and the tension within the LBD-M30 linker, demonstrating its potential to modulate NMDA receptor activity. This comprehensive study not only underscores the therapeutic promise of Withania somnifera derivatives for AD but also provides a detailed molecular basis for their efficacy, offering valuable insights for targeted drug development and innovative therapeutic strategies against Alzheimer’s disease.

Fabrication of LTA zeolite core and UiO-66 shell structures via surface zeta potential modulation and sequential seeded growth for zeolite/polymer composite membranes

Zeolite-based polymer composites have garnered significant attention for their applications in separation, catalysis, and energy storage, owing to the unique properties of zeolites. The development of core–shell structures provides a promising strategy to enhance these properties, enabling the fine-tuning of zeolite characteristics within composite films. In this study, we present an innovative approach that leverages surface zeta potential differences to facilitate the growth of an organophilic metal–organic framework (MOF) on hydrophilic zeolite surfaces. Specifically, UiO-66 was successfully attached and grown on Linde Type A (LTA) zeolite particles, resulting in the formation of a robust core–shell structure (LTA@UiO-66). This core–shell architecture significantly minimized interfacial voids when embedded into a polyimide (PI, Matrimid® 5218) matrix, yielding composite films (LTA@UiO-66/PI) with superior mechanical integrity and enhanced gas-separation performance. The LTA@UiO-66/PI films demonstrated remarkable ideal selectivity for O2/N2 (10.7) and CO2/CH4 (47), outperforming traditional LTA/PI composites. These enhancements are attributed to the synergistic effects between the LTA core and the UiO-66 shell, which preserve the molecular sieving capability of the zeolite while ensuring strong adhesion and a void-free interface with the polymer matrix. The findings underscore the significant potential of zeolite-based core–shell structures in advancing industrial applications, particularly in the domains of sustainable gas separation and purification technologies.

Accurate Layer-Number Determination of Hexagonal Boron Nitride Using Optical Characterization.

Precise determination of the layer number (N) of hexagonal boron nitride (hBN) is crucial for its integration with other layered materials in applications such as ferroelectric devices and moiré potential modulation. We present a nondestructive method to accurately identify N, combining optical contrast analysis with second harmonic generation (SHG) measurements. By studying the flakes on 90 nm thick SiO2/Si substrates, we demonstrate that red-filtered optical images provide a clear contrast step in N with an uncertainty of ±1 layer, while SHG measurements further reduce the error by distinguishing even and odd layers. We also introduce a real-time detection technique to identify monolayer and few-layer hBN, improving flake identification efficiency. Given the growing interest in twisted hBN interfaces and their integration in van der Waals heterostructures, this method offers a practical approach for future studies.

A cyclic peptide toolkit reveals mechanistic principles of peptidylarginine deiminase IV regulation

Peptidylarginine deiminase IV (PADI4, PAD4) deregulation promotes the development of autoimmunity, cancer, atherosclerosis and age-related tissue fibrosis. PADI4 additionally mediates immune responses and cellular reprogramming, although the full extent of its physiological roles is unexplored. Despite detailed molecular knowledge of PADI4 activation in vitro, we lack understanding of its regulation within cells, largely due to a lack of appropriate systems and tools. Here, we develop and apply a set of potent and selective PADI4 modulators. Using the mRNA-display-based RaPID system, we screen >1012 cyclic peptides for high-affinity, conformation-selective binders. We report PADI4_3, a cell-active inhibitor specific for the active conformation of PADI4; PADI4_7, an inert binder, which we functionalise for the isolation and study of cellular PADI4; and PADI4_11, a cell-active PADI4 activator. Structural studies with PADI4_11 reveal an allosteric binding mode that may reflect the mechanism that promotes cellular PADI4 activation. This work contributes to our understanding of PADI4 regulation and provides a toolkit for the study and modulation of PADI4 across (patho)physiological contexts.

MED12 loss activates endogenous retroelements to sensitise immunotherapy in pancreatic cancer

ObjectivePancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by its lethality and limited treatment options, including the utilisation of checkpoint blockade (ICB) immunotherapy. Epigenetic dysregulation...

Exploring the therapeutic potential of marine actinomycetes: a systems biology-based approach for Alzheimer’s disease treatment

BackgroundThis study addresses the urgent need for novel Alzheimer’s Disease (AD) treatments, focusing on the therapeutic potential of marine Actinomycetes compounds. Current AD therapies provide only symptomatic relief, necessitating a paradigm shift toward more effective interventions.MethodologyNinety-one bioactive compounds were methodically identified from Actinomycetes strains in the Indian Ocean. Rigorous ADME analysis and in silico toxicological screening narrowed the selection to 19 compounds, including Helquinoline, Bonactin, Azamerone, and Arcyriaflavin A. These compounds demonstrated favorable drug-like properties and activity against crucial AD targets. Utilizing network pharmacology, a bioactive-target-disease association network was constructed to unveil intricate relationships between compounds and target proteins in the context of AD. Topological analysis highlighted influential targets such as SRC, MAPK1, EGFR, PRKCA, PRKCD, and CDK2. Protein–Protein Interaction (PPI) mapping revealed interconnected pathways influenced by these compounds.ResultsFocus narrowed to the top 10 pathways associated with key hub–bottleneck genes. The GnRH signaling, EGFR tyrosine kinase inhibitor resistance, and ErbB signaling pathways exhibited remarkable fold enrichment, emphasizing their central roles in AD pathogenesis. The GnRH signaling pathway aligned with endocrine dysregulation in AD, EGFR’s dual role in prion-like propagation and amyloid-β pathology, and ErbB signaling’s multifaceted contributions.ConclusionIn conclusion, this study presents marine Actinomycetes compounds as potential poly-pharmacological modulators in AD. Despite promising results, cautious optimism is warranted, requiring further experimental validation. The identified compounds and pathways offer a novel perspective, laying the groundwork for targeted interventions within the intricate landscape of AD. This research contributes to advancing AD therapeutics within a systems biology framework, introducing innovative approaches to address this complex neurodegenerative disorder.