Mater Today Bio. 2025 Jan 23;31:101482. doi: 10.1016/j.mtbio.2025.101482. eCollection 2025 Apr.

ABSTRACT

Vital pulp therapy is critically important for the long-term preservation of teeth with pulpitis. However, the anti-inflammatory effects of pulp-capping materials used in clinics remain unsatisfactory. Pulpitis is tightly connected with oxidative stresses; therefore, scavenging excessive reactive oxygen species (ROS) is a prospective treatment. Here a thermosensitive and injectable hydrogel that forms in situ was developed. By using poly(d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide)-based triblock copolymer (PPP) as a scaffold to carry Prussian blue nanoparticles (PBNPs), with effective ROS scavenging capability via multiple enzyme-like activities, such as superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD)activities. The developed PBNPs@PPP demonstrated anti-oxidative stress and anti-inflammation capabilities in vitro. As a direct pulp capping material, PBNPs@PPP suppressed inflammation progression in pulpitis in rats while also reducing cell necrosis and inflammatory cell infiltration in pulp tissue. RNA sequencing analyses showed that the functions of PBNPs@PPP were highly involved in anti-inflammatory pathways. Through experimental verification, it was found that PBNPs@PPP suppressed inflammation progression in pulpitis by inhibiting the NF-κB/NLRP3 pathway, which reduced the transmission of downstream inflammation pathways. Overall, use of this PBNPs@PPP hydrogel has potential to be a new, safe and efficient strategy for vital pulp therapy to treat pulpitis.

PMID:39944531 | PMC:PMC11815288 | DOI:10.1016/j.mtbio.2025.101482

eGastroenterology. 2024 Apr 3;2(2):e100055. doi: 10.1136/egastro-2023-100055. eCollection 2024 Apr.

ABSTRACT

Inflammatory bowel disease (IBD) is characterised by chronic inflammation in the gastrointestinal tract, with unclear aetiology but with known factors contributing to the disease, including genetics, immune responses, environmental factors and dysbiosis of the gut microbiota. Existing pharmacotherapies mainly target the inflammatory symptoms of disease, but recent research has highlighted the capacity for microbial-accessible carbohydrates that confer health benefits (ie, prebiotics) to selectively stimulate the growth of beneficial gut bacteria for improved IBD management. However, since prebiotics vary in source, chemical composition and microbiota effects, there is a clear need to understand the impact of prebiotic selection on IBD treatment outcomes. This review subsequently explores and contrasts the efficacy of prebiotics from various sources (β-fructans, galacto-oligosaccharides, xylo-oligosaccharides, resistant starch, pectin, β-glucans, glucomannans and arabinoxylans) in mitigating IBD symptomatology, when used as either standalone or adjuvant therapies. In preclinical animal colitis models, prebiotics have revealed type-dependent effects in positively modulating gut microbiota composition and subsequent attenuation of disease indicators and proinflammatory responses. While prebiotics have demonstrated therapeutic potential in animal models, clinical evidence for their precise efficacy remains limited, stressing the need for further investigation in human patients with IBD to facilitate their widespread clinical translation as microbiota-targeting IBD therapies.

PMID:39944472 | PMC:PMC11731074 | DOI:10.1136/egastro-2023-100055

Infect Dis Model. 2025 Jan 10;10(2):571-590. doi: 10.1016/j.idm.2024.12.015. eCollection 2025 Jun.

ABSTRACT

Emerging infectious diseases and climate change are two of the major challenges in 21st century. Although over the past decades, highly-resolved mathematical models have contributed in understanding dynamics of infectious diseases and are of great aid when it comes to finding suitable intervention measures, they may need substantial computational effort and produce significant CO2 emissions. Two popular modeling approaches for mitigating infectious disease dynamics are agent-based and population-based models. Agent-based models (ABMs) offer a microscopic view and are thus able to capture heterogeneous human contact behavior and mobility patterns. However, insights on individual-level dynamics come with high computational effort that scales with the number of agents. On the other hand, population-based models (PBMs) using e.g. ordinary differential equations (ODEs) are computationally efficient even for large populations due to their complexity being independent of the population size. Yet, population-based models are restricted in their granularity as they assume a (to some extent) homogeneous and well-mixed population. To manage the trade-off between computational complexity and level of detail, we propose spatial- and temporal-hybrid models that use ABMs only in an area or time frame of interest. To account for relevant influences to disease dynamics, e.g., from outside, due to commuting activities, we use population-based models, only adding moderate computational costs. Our hybridization approach demonstrates significant reduction in computational effort by up to 98% - without losing the required depth in information in the focus frame. The hybrid models used in our numerical simulations are based on two recently proposed models, however, any suitable combination of ABM and PBM could be used, too. Concluding, hybrid epidemiological models can provide insights on the individual scale where necessary, using aggregated models where possible, thereby making a contribution to green computing.

PMID:39944375 | PMC:PMC11815675 | DOI:10.1016/j.idm.2024.12.015

Plants (Basel). 2025 Feb 6;14(3):493. doi: 10.3390/plants14030493.

ABSTRACT

Ultraviolet radiation (UV) represents a significant abiotic stress, affecting green plants. Phenolic compounds have been suggested as components involved in plant photoprotective adaptation. We used a unique combination of experimental (LED lighting and leaf tagging) and analytical (unbiased, or untargeted, metabolomics) approaches to study the effects of high (approximating mid-summer) and low (approximating winter) levels of UVA on the expression of phenolic compounds. These consisted of river red gum (Eucalyptus camaldulensis ssp. camaldulensis) of five provenances. The geographically separated provenances used in our study spanned the lowest and highest latitudes of the range of this subspecies. The concentrations of gallotannins and ellagitannins (i.e., hydrolysable tannins) increased most under high levels of UVA, but responses only differed slightly among provenances. The most substantial changes in the composition of phenolic compounds were associated with leaf age. Overall, 3-month-old (herein, termed 'young') leaves had substantially different phenolic compositions to 6- and 12-month-old ('old') leaves. Hydrolysable tannins were more abundant in young leaves, whereas pedunculagin, catechin, and kaempferol galloyl glucoses were more abundant in old leaves. High levels of UVA altered the expression of phenolic compounds, but our experimental saplings were unlikely to experience photoinhibition because they were not exposed to high levels of light and low temperatures, nor were they nitrogen-limited. We expect that changes in phenolic compounds would have been more pronounced if we had induced photoinhibition.

PMID:39943055 | DOI:10.3390/plants14030493

Plants (Basel). 2025 Feb 5;14(3):470. doi: 10.3390/plants14030470.

ABSTRACT

Global food insecurity and environmental degradation highlight the urgent need for more sustainable agricultural solutions. Plant synthetic biology emerges as a promising yet risky avenue to develop such solutions. While synthetic biology offers the potential for enhanced crop traits, it also entails risks of extensive environmental damage. This review highlights the complexities and risks associated with plant synthetic biology, while presenting the potential of multiscale mathematical modeling to assess and mitigate those risks effectively. Despite its potential, applying multiscale mathematical models in plants remains underutilized. Here, we advocate for integrating technological advancements in agricultural data analysis to develop a comprehensive understanding of crops across biological scales. By reviewing common modeling approaches and methodologies applicable to plants, the paper establishes a foundation for creating and utilizing integrated multiscale mathematical models. Through modeling techniques such as parameter estimation, bifurcation analysis, and sensitivity analysis, researchers can identify mutational targets and anticipate pleiotropic effects, thereby enhancing the safety of genetically engineered species. To demonstrate the potential of this approach, ongoing efforts are highlighted to develop an integrated multiscale mathematical model for maize (Zea mays L.), engineered through synthetic biology to enhance resilience against Striga (Striga spp.) and drought.

PMID:39943032 | DOI:10.3390/plants14030470

Plants (Basel). 2025 Jan 29;14(3):404. doi: 10.3390/plants14030404.

ABSTRACT

Urban afforestation is increasingly regarded as a key strategy for fostering biodiversity to restore and enhance the ecosystem services needed to counteract the effects of climate change in built-up areas. In Italy, several experimental afforestation projects have been launched as part of the National Recovery and Resilience Plan (NRRP), focusing on cities or metropolitan areas such as Milan, Rome, Pistoia and Campobasso. These projects follow a multidisciplinary approach, integrating botanists, foresters, urban planners, landscape architects and remote sensing specialists. The goal is to address the challenging complexity of urban forest restoration through reforestation and afforestation actions. Key innovations include the integration of transdisciplinary methodologies (landscape analysis, landscape design, forest and plant ecology) with the application of advanced remote sensing technologies and participatory community engagement frameworks to address ecological and social challenges. Experimental plots have been set up across various urban areas, testing a range of planting schemes to maximise climate change resilience and ensure long-term ecological sustainability. Emphasis has been placed on selecting drought-tolerant and thermophilic species that are better adapted to widespread warming and local urban heat islands. 'Biodiversity strips' with perennial flowers for insects, shrubs with berries for birds and nests for wild bees and vertebrates have been set up to enhance biodiversity in new afforestation areas. Advanced monitoring tools, such as Light Detection and Ranging (LiDAR) and multi-sensor drones, have been employed alongside field observations to assess forest growth, species survival, structural complexity and biodiversity enhancement over time. Historical analyses of landscape patterns and ecological connectivity over the past 200 years, along with evaluations of afforestation projects from the last 70 years, have provided critical insights into the successes and challenges of previous interventions, serving as a guide for future efforts. By focusing on ecological connectivity, the integration of afforested areas into the urban matrix, and citizen engagement, the current project aims to align urban forestry efforts with sustainable development goals. This comprehensive project framework addresses environmental restoration and the social and aesthetic impacts on local communities, contributing to the overall resilience and well-being of urban and peri-urban ecosystems.

PMID:39942966 | DOI:10.3390/plants14030404

Molecules. 2025 Feb 3;30(3):668. doi: 10.3390/molecules30030668.

ABSTRACT

A recent analysis compared the proteome of (i) blood clots seen in two diseases-sepsis and long COVID-when blood was known to have clotted into an amyloid microclot form (as judged by staining with the fluorogenic amyloid stain thioflavin T) with (ii) that of those non-amyloid clots considered to have formed normally. Such fibrinaloid microclots are also relatively resistant to fibrinolysis. The proteins that the amyloid microclots contained differed markedly both from the soluble proteome of typical plasma and that of normal clots, and also between the diseases studied (an acute syndrome in the form of sepsis in an ITU and a chronic disease represented by Long COVID). Many proteins in the amyloid microclots were low in concentration in plasma and were effectively accumulated into the fibres, whereas many other abundant plasma proteins were excluded. The proteins found in the microclots associated with the diseases also tended to be themselves amyloidogenic. We here ask effectively the inverse question. This is: can the clot proteome tell us whether the clots associated with a particular disease contained proteins that are observed uniquely (or are highly over-represented) in known amyloid clots relative to normal clots, and thus were in fact amyloid in nature? The answer is in the affirmative in a variety of major coagulopathies, viz., venous thromboembolism, pulmonary embolism, deep vein thrombosis, various cardiac issues, and ischaemic stroke. Galectin-3-binding protein and thrombospondin-1 seem to be especially widely associated with amyloid-type clots, and the latter has indeed been shown to be incorporated into growing fibrin fibres. These may consequently provide useful biomarkers with a mechanistic basis.

PMID:39942772 | DOI:10.3390/molecules30030668

Foods. 2025 Feb 3;14(3):485. doi: 10.3390/foods14030485.

ABSTRACT

The Bacillus cereus group frequently contaminates milk and dairy products. Some members of this group can produce the heat-stable pre-formed toxin cereulide, which causes emetic foodborne intoxication. This study characterised emetic B. cereus group isolates from raw cow's milk in the biochemical, genetic, and toxigenic aspects. Of the 158 B. cereus group isolates derived from 99 raw milk samples, 7 (4.43%) harboured cereulide synthetase A (cesA), which encodes a cereulide synthetase associated with the emetic phenotype. Heat-treated culture filtrates from the cesA-positive isolates demonstrated cytotoxicity to HepG2 and Caco-2 cells, resulting in cell viabilities of 32.22-36.57% and 44.41-47.08%, respectively. The cytotoxicity levels were comparable to those of the reference emetic strain, F4810/72 (alternately termed AH187). Genome analysis of a representative isolate, CSB98, revealed the complete ces gene cluster with additional virulence factors such as non-haemolytic enterotoxin, haemolysins and phospholipases, suggesting that the isolate could be both emetic and diarrhoeagenic. CSB98 exhibited a closer relationship to the type strain of B. paranthracis than to that of B. cereus sensu stricto (ATCC 14579). The genomes of CSB98 and AH187 were indistinguishable through OrthoANI analysis, but 13 variants were identified via SNP calling. These results affirm genetic conservation among the emetic traits.

PMID:39942077 | DOI:10.3390/foods14030485

Cancers (Basel). 2025 Jan 28;17(3):445. doi: 10.3390/cancers17030445.

ABSTRACT

BACKGROUND: Previous studies have described sex-specific patient subtyping in glioblastoma. The cluster labels associated with these "legacy data" were used to train a predictive model capable of recapitulating this clustering in contemporary contexts.

METHODS: We used robust ensemble machine learning to train a model using gene microarray data to perform multi-platform predictions including RNA-seq and potentially scRNA-seq.

RESULTS: The engineered feature set was composed of many previously reported genes that are associated with patient prognosis. Interestingly, these well-known genes formed a predictive signature only for female patients, and the application of the predictive signature to male patients produced unexpected results.

CONCLUSIONS: This work demonstrates how annotated "legacy data" can be used to build robust predictive models capable of multi-target predictions across multiple platforms.

PMID:39941811 | DOI:10.3390/cancers17030445

Int J Mol Sci. 2025 Feb 6;26(3):1369. doi: 10.3390/ijms26031369.

ABSTRACT

Coronary artery disease (CAD) is linked to atherosclerosis plaque formation. In pro-inflammatory conditions, human Natural Killer (NK) cell frequencies in blood or plaque decrease; however, NK cells are underexplored in CAD pathogenesis, inflammatory mechanisms, and CAD comorbidities, such as human cytomegalovirus (HCMV) infection and diabetes. Analysis of PBMC CITE-seq data from sixty-one CAD patients revealed higher blood NK cell SPON2 expression in CAD patients with higher stenosis severity. Conversely, NK cell SPON2 expression was lower in pro-inflammatory atherosclerosis plaque tissue with an enriched adaptive NK cell gene signature. In CAD patients with higher stenosis severity, peripheral blood NK cell SPON2 expression was lower in patients with high HCMV-induced adaptive NK cell frequencies and corresponded to lower PBMC TGFβ transcript expression with dependency on diabetes status. These results suggest that high NK cell SPON2 expression is linked to atherosclerosis pro-homeostatic status and may have diagnostic and prognostic implications in cardiovascular disease.

PMID:39941136 | DOI:10.3390/ijms26031369

Int J Mol Sci. 2025 Jan 29;26(3):1181. doi: 10.3390/ijms26031181.

ABSTRACT

When the protective mechanisms of the gastroesophageal mucosa are overwhelmed by injurious factors, the structural and functional mucosal integrity is compromised, resulting in a wide spectrum of disorders. Poliprotect has recently been shown to be non-inferior to standard-dose omeprazole for the treatment of endoscopy-negative patients with heartburn and/or epigastric pain or burning. Here, we provide preclinical data describing the mechanism of action of the Poliprotect formulation, a 100% natural, biodegradable, and environmental friendly medical device according to EU 2017/745 and containing UVCB (unknown or variable composition, complex-reaction products, or biological materials) substances of botanical and mineral origin, according to the REACH and European Chemical Agency definitions. Different in vitro assays demonstrated the capability of Poliprotect to adhere to mucus-secreting gastric cells and concomitantly deliver a local barrier with buffering and antioxidant activity. In studies conducted in accordance with systems biology principles, we evaluated the effects of this barrier on human gastric cells exposed to acidic stress. Biological functions identified via Ingenuity Pathway Analysis highlighted the product's ability to create a microenvironment that supports the mucosal structural and functional integrity, promotes healing, and restores a balanced mucosal inflammatory status. Additionally, transepithelial electrical resistance and an Ussing chamber showed the product's capability of preserving the integrity of the gastric and esophageal epithelial barriers when exposed to an acid solution. Two in vivo models of erosive gastropathy further highlighted its topical protection against ethanol- and drug-induced mucosal injury. Overall, our findings sustain the feasibility of a paradigm shift in therapeutics R&D by depicting a very innovative and desirable mode of interaction with the human body based on the emerging biophysical, rather than the pharmacological properties of these therapeutic agents.

PMID:39940951 | DOI:10.3390/ijms26031181

Int J Mol Sci. 2025 Jan 28;26(3):1129. doi: 10.3390/ijms26031129.

ABSTRACT

The escalating impact of abiotic stress on crop productivity requires innovative strategies to ensure sustainable agriculture. This review examines the promising role of biostimulants in mitigating the adverse effects of abiotic stress on crops. Biostimulants, ranging from simple organic compounds to complex living microorganisms, have demonstrated significant potential in enhancing plant resilience, stress tolerance, and overall performance. The mechanisms underlying biostimulant action-such as enhancing antioxidant defenses, regulating hormonal pathways, and inducing metabolic adjustments-are reviewed. Furthermore, we incorporate the latest research findings, methodologies, and advancements in biostimulant applications for addressing abiotic stressors, including drought, salinity, high temperatures, and nutrient deficiencies. This review also highlights current challenges and future opportunities for optimizing biostimulant use in sustainable crop production. This revision aims to guide researchers and agronomists in applying biostimulants to improve crop resilience in the context of climate change.

PMID:39940896 | DOI:10.3390/ijms26031129

Int J Mol Sci. 2025 Jan 26;26(3):1080. doi: 10.3390/ijms26031080.

ABSTRACT

The use of plastics, valued for its affordability, durability, and convenience, has grown significantly with the advancement of industry. Paradoxically, these very properties of plastics have also led to significant environmental challenges. Plastics are highly resistant to decomposition, resulting in their accumulation on land, where they eventually enter aquatic environments, due to natural processes or human activities. Among these plastics, microplastics, which are tiny plastic particles, are particularly concerning when they enter aquatic ecosystems, including rivers and seas. Their small size makes them easily ingestible by aquatic organisms, either by mistake or through natural feeding behaviors, which poses serious risks. Moreover, microplastics readily adsorb other pollutants present in aquatic environments, creating pollutant complexes that can have a synergistic impact, magnifying their harmful effects compared to microplastics or pollutants acting alone. As a result, extensive research has focused on understanding the effects of microplastics on aquatic organisms. Numerous studies have demonstrated that aquatic organisms exposed to microplastics, either alone or in combination with other pollutants, exhibit abnormal hatching, development, and growth. Additionally, many genes, particularly those associated with the antioxidant system, display abnormal expression patterns in these conditions. In this review, we examine these impacts, by discussing specific studies that explore changes in phenotype and gene expression in aquatic organisms exposed to microplastics, both independently and in combination with adsorbed pollutants.

PMID:39940847 | DOI:10.3390/ijms26031080

Int J Mol Sci. 2025 Jan 26;26(3):1069. doi: 10.3390/ijms26031069.

ABSTRACT

The TEOSINTE-BRANCHED1/CYCLOIDEA/PROLIFERATING-CELL-FACTOR (TCP) gene family, a plant-specific transcription factor family, plays pivotal roles in various processes such as plant growth and development regulation, hormone crosstalk, and stress responses. However, a comprehensive genome-wide identification and characterization of the TCP gene family in peanut has yet to be fully elucidated. In this study, we conducted a genome-wide search and identified 51 TCP genes (designated as AhTCPs) in peanut, unevenly distributed across 17 chromosomes. These AhTCPs were phylogenetically classified into three subclasses: PCF, CIN, and CYC/TB1. Gene structure analysis of the AhTCPs revealed that most AhTCPs within the same subclade exhibited conserved motifs and domains, as well as similar gene structures. Cis-acting element analysis demonstrated that the AhTCP genes harbored numerous cis-acting elements associated with stress response, plant growth and development, plant hormone response, and light response. Intraspecific collinearity analysis unveiled significant collinear relationships among 32 pairs of these genes. Further collinear evolutionary analysis found that peanuts share 30 pairs, 24 pairs, 33 pairs, and 100 pairs of homologous genes with A. duranensis, A. ipaensis, Arabidopsis thaliana, and Glycine max, respectively. Moreover, we conducted a thorough analysis of the transcriptome expression profiles in peanuts across various tissues, under different hormone treatment conditions, in response to low- and high-calcium treatments, and under low-temperature and drought stress scenarios. The qRT-PCR results were in accordance with the transcriptome expression data. Collectively, these studies have established a solid theoretical foundation for further exploring the biological functions of the TCP gene family in peanuts, providing valuable insights into the regulatory mechanisms of plant growth, development, and stress responses.

PMID:39940846 | DOI:10.3390/ijms26031069

Int J Mol Sci. 2025 Jan 25;26(3):1016. doi: 10.3390/ijms26031016.

ABSTRACT

Colorectal cancer (CRC) and lung cancer (LC) are leading causes of cancer-related mortality, highlighting the need for minimally invasive diagnostic, prognostic, and predictive markers for these cancers. Proteins secreted by a tumor into the extracellular space directly, known as the tumor secretome, as well as proteins in the extra-cellular vesicles (EVs), represent an attractive source of biomarkers for CRC and LC. We performed proteomic analyses on secretome and EV samples from LC (A549, NCI-H23, NCI-H460) and CRC (Caco2, HCT116, HT-29) cell lines and targeted mass spectrometry on EVs from plasma samples of 20 patients with CRC and 19 healthy controls. A total of 782 proteins were identified across the CRC and LC secretome and EV samples. Of these, 22 and 44 protein markers were significantly elevated in the CRC and LC samples, respectively. Functional annotation revealed enrichment in proteins linked to metastasis and tumor progression for both cancer types. In EVs isolated from the plasma of patients with CRC, ITGB3, HSPA8, TUBA4A, and TLN1 were reduced, whereas FN1, SERPINA1, and CST3 were elevated, compared to healthy controls. These findings support the development of minimally invasive liquid biopsy methods for the detection, prognosis, and treatment monitoring of LC and CRC.

PMID:39940785 | DOI:10.3390/ijms26031016

Int J Mol Sci. 2025 Jan 24;26(3):979. doi: 10.3390/ijms26030979.

ABSTRACT

Parkinson's disease (PD) is a neurodegenerative disorder with a high variability of age at onset, disease severity, and progression. This suggests that other factors, including genetic, environmental, or biological factors, are at play in PD. The loss of PINK1 causes a recessive form of PD and is typically fully penetrant; however, it features a wide range in disease onset, further supporting the existence of protective factors, endogenous or exogenous, to play a role. The loss of Pink1 in Drosophila melanogaster results in locomotion deficits, also observed in PINK1-related PD in humans. In flies, Pink1 deficiency induces defects in the ability to fly; nonetheless, around ten percent of the mutant flies are still capable of flying, indicating that advantageous factors affecting penetrance also exist in flies. Here, we aimed to identify the mechanisms underlying this reduced penetrance in Pink1-deficient flies. We performed genetic screening in pink1-mutant flies to identify RNA expression alterations affecting the flying ability. The most important biological processes involved were transcriptional and translational activities, endoplasmic reticulum (ER) regulation, and flagellated movement and microtubule organization. We validated two ER-related proteins, zonda and windbeutel, to positively affect the flying ability of Pink1-deficient flies. Thus, our data suggest that these processes are involved in the reduced penetrance and that influencing them may be beneficial for Pink1 deficiency.

PMID:39940747 | DOI:10.3390/ijms26030979

Int J Mol Sci. 2025 Jan 21;26(3):872. doi: 10.3390/ijms26030872.

ABSTRACT

Amyotrophic lateral sclerosis (ALS) has an interactive, multifactorial etiology that makes treatment success elusive. This study evaluates how regulatory dynamics impact disease progression and treatment. Computational models of wild-type (WT) and transgenic SOD1-G93A mouse physiology dynamics were built using the first-principles-based first-order feedback framework of dynamic meta-analysis with parameter optimization. Two in silico models were developed: a WT mouse model to simulate normal homeostasis and a SOD1-G93A ALS model to simulate ALS pathology dynamics and their response to in silico treatments. The model simulates functional molecular mechanisms for apoptosis, metal chelation, energetics, excitotoxicity, inflammation, oxidative stress, and proteomics using curated data from published SOD1-G93A mouse experiments. Temporal disease progression measures (rotarod, grip strength, body weight) were used for validation. Results illustrate that untreated SOD1-G93A ALS dynamics cannot maintain homeostasis due to a mathematical oscillating instability as determined by eigenvalue analysis. The onset and magnitude of homeostatic instability corresponded to disease onset and progression. Oscillations were associated with high feedback gain due to hypervigilant regulation. Multiple combination treatments stabilized the SOD1-G93A ALS mouse dynamics to near-normal WT homeostasis. However, treatment timing and effect size were critical to stabilization corresponding to therapeutic success. The dynamics-based approach redefines therapeutic strategies by emphasizing the restoration of homeostasis through precisely timed and stabilizing combination therapies, presenting a promising framework for application to other multifactorial neurodegenerative diseases.

PMID:39940644 | DOI:10.3390/ijms26030872

Nutrients. 2025 Jan 30;17(3):518. doi: 10.3390/nu17030518.

ABSTRACT

Micronutrient deficiencies affect over three billion people globally; there is a particularly severe problem with iron and zinc nutrition in developing countries. While several strategies exist to combat these deficiencies, biofortification has emerged as a powerful and sustainable approach to enhance the nutritional value of staple crops. This review examines recent advances in crop biofortification and their potential to address global nutritional challenges. We present successful case studies including iron-enriched cassava, nutrient-enhanced tomatoes, and omega-3-fortified oilseed crops, demonstrating the diverse possibilities for improving nutritional outcomes. The integration of novel plant-based protein production techniques has further expanded opportunities for sustainable nutrition. However, significant challenges remain, including complex environmental interactions, regulatory considerations, and sociocultural barriers to adoption. Economic analyses suggest biofortification offers substantial return on investment, with every dollar invested generating up to seventeen dollars in benefits through reduced disease burden. As global food security challenges intensify due to climate change, biofortified crops represent a crucial tool for improving nutritional outcomes, particularly in low- and middle-income countries. We conclude by examining emerging opportunities and future directions in this rapidly evolving field.

PMID:39940376 | DOI:10.3390/nu17030518

Eur J Pharm Sci. 2025 Feb 10:107039. doi: 10.1016/j.ejps.2025.107039. Online ahead of print.

ABSTRACT

Adenosine, a pervasive signaling molecule mediated by its interaction with G-protein-coupled receptor subtypes, especially the A2A adenosine receptor (A2AAR), plays a crucial role in cancer treatment. Recently, A2AAR targeting adenosine analogs have been proposed as a potential therapeutic target for cancer treatment. However, the molecules targeting A2AAR and their mode of action in inhibiting glioblastoma cell progression remain unknown. We synthesized six adenosine derivatives substituted at the 9-, 2- and/or N6- and/or 8- positions, and their anti-proliferative efficacy against the GBM cell lines LN229 and SNB19 was assessed. Molecular dynamic simulation integrated with experimental analyses, including cell cycle arrest, apoptosis assay, ligand binding assay, absorption, distribution, metabolism, excretion and toxicity (ADMET) profiling, PAMPA assay, and 3D spheroid analysis, were performed to identify the interaction efficacy of the potential derivative with A2AAR and its ability to prevent GBM cell progression. The most potent A2AAR derivative (ANR), 4-(2-((6-Amino-9-ethyl-8-(furan-2-yl)-9H-purin-2-yl)amino)ethyl)phenol (ANR 672) inhibits 5'-N-Ethylcarboxamidoadenosine (NECA)-induced cAMP validating the antagonistic property with higher cytotoxicity effect against GBM cells. ANR 672 showed higher affinity toward A2AAR (Ki=1.02 ± 0.06 nM) and exhibited significant IC50 concentrations of ∼ 60-80 µM, than FDA approved drug istredefylline. The A2AAR-ANR 672 interaction profile showed well-defined hydrogen bonds and hydrophobic contacts, indicating a typical binding mechanism inside the receptor pocket and a higher degree of conformational flexibility than the A2AAR-Istradefylline complex. The antagonist effect of ANR 672 blocked the A2AAR signaling pathway, leading to necrosis-mediated cell death and cell cycle arrest at the S-phase in both the GBM cells. ANR 672 treated 3D tumour spheroids analysis with real-time spheroid volume and cell proliferation analysis revealed the potential ability of ANR 672 against GBM cell growth. Drug-likeness assessments also showed favorable pharmacokinetic profiles for ANR 672. Further validation of blood-brain barrier crossing potential revealed that ANR 672 possesses moderate permeability. Our findings shed light on how ANR 672 exerts its GBM-suppressive effect through the interaction of A2AAR. These preclinical results suggest that A2AAR blockade could be a unique strategy for treating GBM.

PMID:39938810 | DOI:10.1016/j.ejps.2025.107039

Nature. 2025 Feb 12. doi: 10.1038/s41586-024-08533-3. Online ahead of print.

ABSTRACT

Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function1,2. As a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma3, the most common embryonal brain tumour in children4. These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST5. However, their mechanism remains unresolved. Here we establish that KBTBD4 mutations promote CoREST degradation through engaging HDAC1/2 as the direct target of the mutant substrate receptor. Using deep mutational scanning, we chart the mutational landscape of the KBTBD4 cancer hotspot, revealing distinct preferences by which insertions and substitutions can promote gain-of-function and the critical residues involved in the hotspot interaction. Cryo-electron microscopy analysis of two distinct KBTBD4 cancer mutants bound to LSD1-HDAC1-CoREST reveals that a KBTBD4 homodimer asymmetrically engages HDAC1 with two KELCH-repeat β-propeller domains. The interface between HDAC1 and one of the KBTBD4 β-propellers is stabilized by the medulloblastoma mutations, which insert a bulky side chain into the HDAC1 active site pocket. Our structural and mutational analyses inform how this hotspot E3-neosubstrate interface can be chemically modulated. First, we unveil a converging shape-complementarity-based mechanism between gain-of-function E3 mutations and a molecular glue degrader, UM171. Second, we demonstrate that HDAC1/2 inhibitors can block the mutant KBTBD4-HDAC1 interface and proliferation of KBTBD4-mutant medulloblastoma cells. Altogether, our work reveals the structural and mechanistic basis of cancer mutation-driven neomorphic protein-protein interactions.

PMID:39939763 | DOI:10.1038/s41586-024-08533-3