Plant seeds accumulate triacylglycerol (TAG) as a major storage reserve that supports post-germination growth and seedling establishment. Vegetable oils are also essential for human nutrition and provide renewable feedstocks for industrial and biotechnological applications. In 1998, Focks and Benning published a landmark study in Plant Physiology describing the Arabidopsis WRINKLED1 mutants (wri1), which display a distinctive wrinkled seed phenotype and a dramatic reduction in seed oil accumulation. The conceptual importance of this discovery was not simply the identification of a low-oil mutant, but the demonstration that seed oil accumulation depends on developmental control of carbon flux from carbohydrates into fatty acid precursors. Cloning of the Arabidopsis WRI1 (AtWRI1) gene in 2004 transformed this physiological phenotype into a molecular framework by identifying WRI1 as a member of the APETALA2 (AP2) family of transcription factors that activates late glycolytic and fatty acid biosynthetic genes. Subsequent work uncovered the AW-box cis-element, upstream seed-maturation regulators, WRI1-interacting partners, post-transcriptional and post-translational modification mechanisms controlling WRI1 stability and activity, and the structural basis of WRI1-DNA recognition. These discoveries established WRI1 as a central regulatory node linking seed development, carbohydrate metabolism, and seed oil accumulation. More recent studies have broadened WRI1 biology beyond canonical seed oil biosynthesis to include non-seed oil-storing tissues, hormone and nutrient-associated processes, environmental responses, and structure-guided crop engineering. Here, we revisit the original Plant Physiology classic and trace how one mutant phenotype reshaped modern understanding of plant carbon partitioning, transcriptional regulation, and metabolic engineering.
The pharmaceutical industry's shift toward new drug modalities, including therapeutic peptides, modified oligonucleotides, and antibody-drug conjugates, has exposed fundamental gaps in cheminformatics infrastructure. Unlike small molecules, which benefit from mature representation standards and reliable data exchange, new modalities lack robust and interoperable systems capable of capturing their structural and chemical complexity. Drawing on our experience at AstraZeneca, we examine these challenges across peptides, oligonucleotides, and ADCs, focusing on the limitations of current approaches, particularly HELM. We show that these limitations arise from both technical constraints, as new modalities exceed the scope of purely atomistic or sequence-based representations, and organizational gaps, including unresolved standardization and governance. We argue that local solutions exacerbate fragmentation, and that vendor- and community-driven standards, open implementations, and stronger governance are required to enable standardized and interoperable chemical information systems for next-generation therapeutics.
The disparity between the complex structures of synthesized materials and their simplified computational models leads to deviations between theoretically calculated and experimental performance. To narrow this gap, we introduce the statistical descriptor φ, which is defined as the proportion of high-activity configurations in a given element combination. By considering the activity distribution of multiple structures rather than relying on a single model structure, φ can more accurately quantify macroscopic catalytic activity. Using the Seq-Equiformer model, a graph neural network we developed by augmenting EquiformerV2 with LSTM to capture dynamic structural changes during oxygen evolution reaction, we predict overpotentials for 250 million structures of 3d transition metal doped CoOOH. Based on these predictions, the value of φ for each element combination is calculated, and six optimal dopant combinations with the highest φ values are determined. For the leading MnFeNiCu combination, Bayesian optimization-driven AI experiments further optimize the elemental ratios. After only 40 experimental iterations, exploring 0.44% of the search space, the catalyst Mn0.07Fe0.09Ni0.14Cu0.01Co0.69OOH is identified, delivering an overpotential of 246.5 mV at 100 mA cm-2 and retaining 98.5% activity over 1000 h at 1 A cm-2. In validation, the statistical descriptor achieves 80% accuracy in identifying the top catalysts, a 30% improvement over single-structure screening, which evaluates the element combination based on the best configuration. The integration of statistical modeling, machine learning, and autonomous experimentation offers a powerful strategy to accelerate catalyst discovery and enhance prediction accuracy.
To describe the data analytic strategy used to develop new quality-of-life measures for the Limb Injury Measurement Battery for Quality of Life (LIMB-QOL). Several item pools were created and administered to a large sample of individuals with a history of major extremity injury or limb loss (n = 603). Item analyses adhered to modern psychometric standards (e.g., PROMIS®, COSMIN) and aimed to create several item response theory-based (IRT) item banks based on the graded response model. Items were removed iteratively based on pre-defined criteria and IRT model assumptions were met for the final item pools (monotonicity, unidimensionality, local item independence); differential item functioning, test-retest reliability, and convergent validity were then evaluated. Computer adaptive test and short-form versions of final item banks were created and examined using data simulation. Item analyses led to the development of 8 new item banks and two fixed-length scales. These 10 new LIMB-QOL measures demonstrated initial evidence of reliability (α range = 0.94-0.98, test-retest ICC range: 0.68-0.91) and convergent validity for use in individuals with a history of major extremity injury or limb loss, and abbreviated formats of the full item banks exhibited comparable performance. The new LIMB-QOL measures demonstrated strong psychometric properties and can be used to collect patient-reported assessments of quality of life following major extremity injury and limb loss. The analytic strategy described herein exemplifies how the PROMIS methodology can be utilized to design IRT-based patient-reported outcome measures to fill measurement gaps for specific clinical populations.
Tumor-agnostic therapies focus on shared molecular biomarkers independent of tissue of origin, allowing a single drug to target a common biomarker across different tumor types. Such targets with regulatory drug approvals include NTRK fusion, RET fusion, BRAF V600E mutation, FGFR1 rearrangement, HER2 overexpression, microsatellite instability or mismatch repair deficiency (MSI-H/dMMR), and high tumor mutational burden (TMB-H). Novel strategies against molecular alterations such as NRG1 fusion, ALK fusion, MTAP loss, KRAS G12C, TP53 Y220C and homologous repair deficiency (HRD) have also emerged. While the list of potential tumor-agnostic biomarkers continues to expand, contemporary efforts are still predominantly focused on solid cancers over hematological malignancies, including lymphoma, representing a peculiar and perhaps unwarranted strategic gap. In this review, we thus provide a narrative overview of currently approved tumor-agnostic therapies and highlight emerging biomarkers, addressing the need to focus on their potential application beyond solid tumors.
Pharmacokinetics is fundamental to drug discovery, therapeutic optimization, and patient safety. Despite its importance, students consistently demonstrate limited mastery of pharmacokinetic core concepts. Studies reveal that students have persistent misconceptions of pharmacokinetic core concepts, difficulty applying mathematical principles, and challenges in transferring theoretical knowledge to medical and biomedical practices. Contributing factors include mathematical skill deficits upon entering university programs, fragmented curricular integration, and limited opportunities for active application of knowledge. These gaps raise concerns about the preparedness of graduates entering health professions and drug design/discovery fields, where pharmacokinetic competence directly impacts the fundamentals of drug discovery, therapeutic optimization, and patient safety. In addition to student challenges with learning pharmacokinetics, this commentary highlights innovative teaching strategies for educators to support student comprehension and application of pharmacokinetic core concepts. Approaches such as team-based learning, case-based exercises, simulations, games, and prerequisite review tutorials have shown promise in strengthening conceptual understanding and bridging theory with practice. These strategies have largely been studied in isolated contexts, underscoring the need for broader evaluations examining how course design, delivery methods, and teaching strategies shape student learning of pharmacokinetic core concepts. Future research could explore pharmacology educator and student perspectives on pharmacokinetics to develop an international framework for pharmacokinetics education. Such a framework would ensure progressive reinforcement of core concepts, integration across curricula, and alignment of teaching practices with real-world application, ultimately preparing students for diverse careers where pharmacokinetics proficiency is essential.
After the first definition of the term "Holobiont" by Margulis in the introduction of symbiosis as "Association throughout a significant portion of the life history" in 1991 [1], the understanding of holobiont has become an important goal in modern biology today [2]. Recent advances in microbial collection, genome/metagenome/transcriptome sequencings, and bioassays for host-microbes interactions push us towards a fuller understanding of holobiont in various aspects of life on Earth. Historically, holobiont and related hologenome concepts have been tested and expanded through research on marine organisms such as coral, fish, sea cucumber, sponge, and squid. In particular, the sea cucumber Apostichopus japonicus is a physiologically and ecologically unique marine invertebrate in which the holobiont can be studied with its significant capability of organ regeneration, presence of microbes in coelomic fluid, their mysterious nutrition connected to slow growth, and improvements in seed production for the bio-conservation of endangered and essential fisheries resources. The animals are also important in evolutionary terms on a branch of the Deuterostomia clade sharing ancestry with humans, so we can also compare to and learn from knowledge on the human-microbes interactions. In this review, recent progress in the sea cucumber A. japonicus holobiont studies, and the discovery of probiotics candidates among its pioneer microbiomes are described. By understanding this recent progress, we expect to stimulate new and further perspectives on basic biology, bio-conservation, and sustainable aquaculture of sea cucumber.
Chyawanprash is an ancient Ayurvedic superfood described for its antioxidant, anti-ageing and immunity-boosting properties. Prolonged exposure to environmental stressors such as extreme heat, air pollution and toxins could lead to several diseases by triggering oxidative stress and inflammation. These stress response pathways, conserved in humans and C. elegans, play crucial roles in the progression of neurological and metabolic diseases. Present study examines the role of the ancient Ayurvedic superfood, Patanjali Special Chyawanprash (PSCP), on heat stress-induced behavioural and molecular damages, using C. elegans as the model organism. Phytochemical analysis of PSCP by high-performance liquid chromatography (HPLC) revealed the presence of several antioxidant and anti-inflammatory phytometabolites like gallic acid, corilagin, chebulagic acid, 5-HMF, cinnamic acid, eugenol, and ellagic acid. PSCP supplementation in C. elegans prevented the production of Advanced Glycation End products (AGEs) and heat stress-induced alterations in locomotory and feeding behaviours. Nuclear Localization of DAF-16, expression of SOD-3::GFP and MYO-3::GFP, along with sarcomeric F-actin arrangement in heat-stressed C. elegans, was analyzed using fluorescence microscopy. PSCP supplementation along with the food to the heat-stressed C. elegans resulted in ~2-fold increase in mitochondrial membrane potential and in MYO-3::GFP expression. Additionally, PSCP exhibited a strong antioxidant profile in heat-stressed worms, indicated by normalized ROS, GSH levels and SOD-3 activity. mRNA levels of thermo-tolerance genes like hsf-1 and heat-shock proteins: hsp-70, hsp-16.2 and hsp-12.6 in heat-stressed C. elegans were normalized by PSCP treatment. PSCP also promoted longevity and prevented heat stress-induced lifespan reduction in C. elegans. Overall, these findings indicate that Patanjali Special Chyawanprash (PSCP) could serve as an important food supplement for enhancing stress resistance in organisms including humans, potentially benefiting longevity and reducing disease susceptibility.
The Dame Barbara Windsor Dementia Goals Programme was launched by the UK Government to accelerate the development and delivery of new treatments for dementia. We present the recommendations from the Scientific Advisory Board, to enable timely access to therapies for the wider population, reducing health system burden while improving patient outcomes. The recommendations focus on three areas: (i) establishing a new dynamic national patient registry for clinical trial recruitment; (ii) the use of biomarkers to improve early and accurate diagnosis; and (iii) a framework for end-to-end implementation across the landscape of healthcare, research and regulators. A Brain Aging Registry for Biomarkers, Access to trials, Research and Adoption would support recruitment, monitoring, and personalized care. Embedding digital and biomarker innovations into routine care would improve personalized and equitable dementia services, with earlier diagnosis and more effective prevention. Robust patient and public involvement is required, to ensure transparency, trustworthiness, and meaningful participation.
Colorectal cancer (CRC) is one of the most common malignancies worldwide and remains a major clinical challenge, underscoring the urgent need for novel therapeutic targets and treatment strategies. Ferroptosis, a form of cell death triggered by iron-dependent lipid peroxidation, is emerging as a promising new anti-cancer therapeutic strategy. This study aims to identify a key target regulating the ferroptosis process in CRC, screen for small molecule modulators against this target, and elucidate their potential anti-tumor mechanisms. We developed a Drug Discovery Strategy for Targeted Ferroptosis Therapy Based on Bioinformatics-Machine Learning Integration for the Treatment of CRC (DDTF-BMLI-CRC), aiming to identify key ferroptosis regulators. The functional role of this factor in CRC and ferroptosis was validated through knockdown and overexpression techniques, establishing it as a potential therapeutic target. Subsequently, candidate compounds were screened from natural product and FDA databases using a dual-scoring model combining machine learning and deep learning. The direct binding of candidate compounds to target proteins was validated through molecular docking, molecular dynamics simulations, DARTS, CETSA, and SPR techniques. Finally, a series of in vitro and in vivo experiments were conducted to systematically evaluate their anti-tumor effects and potential mechanisms. PANX2 was identified as a key ferroptosis-suppressing gene in CRC. We discovered the natural small molecule dihydroberberine (dhBBR) to be a potent and direct inhibitor of the PANX2 protein. In vitro, dhBBR significantly inhibited the proliferation, migration, and invasion of CRC cells while inducing ferroptosis. In vivo, dhBBR effectively suppressed xenograft tumor growth. Mechanistic studies revealed that dhBBR-induced ferroptotic stress activates autophagy, which in turn promotes GPX4 degradation, thereby amplifying the ferroptotic effect and establishing a ferroptosis-autophagy positive feedback loop. Crucially, PANX2 knockdown largely abolished the additional anti-tumor effect of dhBBR, and dhBBR did not further suppress tumor growth beyond PANX2 knockdown alone. This study demonstrates that PANX2 knockdown suppresses CRC progression by inducing ferroptosis. Furthermore, we identified dhBBR for the first time as a PANX2-targeting small-molecule inhibitor. Our research reveals a novel therapeutic strategy targeting the PANX2-mediated ferroptosis-autophagy axis and provides a highly promising candidate compound for the treatment of CRC.
Medicinal plants remain a vital source of new therapeutic agents, yet many species remain underexplored. Echinops niveus Wall. ex Royle, a member of the Asteraceae family, has not been comprehensively evaluated for multifunctional bioactivity. This study aimed to assess the phytochemical composition, antioxidant, antimicrobial, anti-leishmanial, and cytotoxic properties of E. niveus extracts.The aerial parts of E. niveus were extracted with six different solvents: aqueous, methanolic, ethanolic, chloroform, ethyl acetate and n-hexane. They were characterized by phytochemical profiling and FT-IR spectroscopy. The antioxidant activity was measured by DPPH free radical scavenging and reducing power assays. Antimicrobial activity was assessed against Gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus), Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae) and some fungal strains. The anti-leishmanial activity was assessed by the MTT assay and the cytotoxic activity was explored in the brine shrimp lethality assay and prostate cancer cell lines (PC3). The n-hexane extract showed the strongest DPPH scavenging activity (IC₅₀ = 104.76 ± 1.2 µg/mL). The chloroform extract demonstrated the highest reducing power (73.14 ± 1.47 mg AAE/g) and total antioxidant capacity (63.49 ± 1.46 mg AAE/g). The aqueous extract exhibited the best antibacterial potential against tested strains. Anti-leishmanial activity exceeded 50% inhibition for all extracts, with the aqueous extract showing 64% inhibition. The n-hexane extract was most cytotoxic against brine shrimp (LD₅₀ = 56.15 µg/mL) and PC3 cells.Echinops niveus possesses significant multifunctional pharmacological potential, supporting further investigation into its bioactive compounds and mechanisms as a candidate for drug discovery.
Bullfrog (Lithobates catesbeianus) muscle protein remains an underexplored source of bioactive peptides. This study applied an integrated in silico-in vitro-in vivo workflow to identify tyrosinase (TYR)-inhibitory peptides from bullfrog muscle protein hydrolysates. Among five proteases evaluated, acid protease hydrolysis for 3 h produced the highest TYR-inhibitory activity. Following ultrafiltration and Sephadex G-15 gel filtration, the most active fraction (<1 kDa) was analyzed by LC-MS/MS, yielding 71 candidate peptide sequences. The dipeptide FW and tripeptide LAW were prioritized through PeptideRanker scoring, safety prediction, and molecular docking against mushroom TYR (PDB ID: 2Y9X), with predicted docking scores of -8.0 and - 7.9 kcal/mol, respectively. Synthetic FW and LAW exhibited concentration-dependent TYR inhibition, with IC₅₀ values of 0.21 mg/mL (approximately 0.60 mM) and 0.14 mg/mL (approximately 0.36 mM), respectively. Kinetic analysis indicated competitive inhibition by FW and non-competitive inhibition by LAW, while molecular docking suggested distinct interaction patterns broadly consistent with these kinetic profiles. Following simulated gastrointestinal digestion, the corresponding post-digestion samples retained approximately 90% of their initial inhibitory activity, although LAW showed chromatographic evidence of partial degradation or transformation. In zebrafish larvae, neither peptide significantly affected survival or caused apparent developmental abnormalities at 0.0125-0.05 mg/mL, and FW and LAW reduced whole-body melanin content by 30% and 27%, respectively, at 0.05 mg/mL. These findings identify bullfrog muscle protein as a potential source of TYR-inhibitory peptides and support further investigation of FW and LAW for anti-melanogenic applications.
E3112 is a recombinant human hepatocyte growth factor (HGF) intended for the treatment of acute liver failure. As the presence of anti-drug antibody (ADA) against E3112 could pose a significant risk in clinical settings if it cross-reacts with the body's natural HGF, we have developed assays for E3112 and its ADA in human serum. Assays of E3112 and its ADA developed by ligand binding assays were validated in accordance with bioanalytical guidelines and applied to clinical pharmacokinetic (PK) and immunogenicity assessments. These assays demonstrated the ability to detect E3112 at a concentration as low as 0.156 ng/mL, whereas the sensitivity of ADA was determined to be 42.3 ng/mL. The validation studies, incorporating quality control for the PK assay and positive control of ADA, substantiated the reproducibility of the assays. The ADA and PK assays were applied to the real sample assays supporting a clinical trial of E3112. Following the intravenous administration of E3112, serum E3112 levels declined with a half-life of 19.3 h. No ADA was detected in predose or postdose samples. These findings collectively indicate that E3112 exhibited a favorable PK profile with minimal immunogenicity within the clinical context. E3112 is a new protein-based medicine being developed to treat acute liver injury. To understand how this drug works in the body, it is important to measure both the drug levels in the blood and whether the body produces anti-drug antibodies (ADA), which may affect its safety or efficacy. In this study, we developed simple and reliable assays to measure E3112 and its ADA in human serum. These methods were fully validated according to regulatory guidelines and were successfully used in a clinical study to evaluate how E3112 behaves in the body (pharmacokinetics) and whether it triggers immune responses (immunogenicity).Using these methods, we showed that E3112 can be accurately measured in human serum, and no ADA was detected after administration in the clinical study. These results suggest that E3112 has a favorable pharmacokinetic profile and a low risk of immune reactions in humans. Overall, this study provides practical tools and important information that help clinicians and researchers better understand how E3112 behaves in the body.
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Organoid-AI platforms are becoming decision systems in drug discovery, not just combined tools. They shape compound prioritisation, toxicity assessment, and programme progression. Yet governance often validates the biological model and the computational model separately, even when the evidential claim depends on their interaction. But separate validation can create false assurance: donor imbalance, batch effects, and culture drift can become algorithmic shortcuts, while confident model outputs can obscure weak biological transportability. This Feature proposes proportionate, platform-level governance built around a single context of use, linked provenance, transportability testing, and predefined fallback rules, scaled to decision stakes. The aim is not to slow adoption, but to make these platforms credible enough to act as preclinical gatekeepers.
The phage display technology allows to select peptides, exposed on the surface of bacteriophage virions, which can specifically bind to virtually any materials, including proteins, lipids, carbohydrates, and other organic macromolecules, as well as metals or metal oxides. In this chapter, we describe and discuss procedures for effective selection of peptides characterized with affinity to metallic or metal oxide nanoparticles. The use of a peptide library displayed on virions of the M13 bacteriophage, the most commonly used phage display system, is presented. Specific notes indicate what are crucial steps in the procedure, what should be avoided and why, and what should be done if common problems appear. The scheme of the biopanning process, the crucial step in selecting specific peptides, which bind to nanoparticles composed of metals or metal oxides, is presented and discussed.
Modulation of splicing is an established therapeutic strategy with clinical applications and potential to target specific exons to influence gene expression. Small-molecule splicing modifiers such as Risdiplam and Branaplam induce inclusion of exons typically skipped due to weak 5' splice sites. Risdiplam preferentially induces exons with an N-3G-2A-1 sequence at the 3' exon end, whereas Branaplam favors A-3G-2A-1-ending exons. However, determinants of specificity remain unclear, as many motif-matching exons are not induced. Here, we investigate the molecular basis of splicing-modulator specificity. Using biochemical assays, transcriptome analyses, and genetic perturbations, we identify sequence-dependent features that determine exon responsiveness to splicing-modulator induction. We further demonstrate that specificity can be reprogrammed through manipulation of U1 snRNA. These findings refine the determinants of splicing-modulator target space and may support identification of additional target exons and compounds.
mRNA display is a powerful in vitro selection technique that enables the discovery of peptide and protein ligands from libraries exceeding 10 trillion unique sequences. The technique allows for exquisite control over binding stringency and specificity, and it is highly amenable to high-throughput ligand profiling and integration with machine learning approaches. Here, we describe general methods for performing mRNA display selections.
Precise quantification of the causative agent of syphilis, Treponema pallidum (T. pallidum) is critical for advancing research in pathogenesis, treatment response, and vaccine development. However, current methods have certain limitations. Dark-field microscopy (DFM) suffers from low sensitivity, poor reproducibility, and strong operator dependence, while quantitative PCR (qPCR) offers high precision but is time-consuming, technically demanding, and reliant on high-quality, consistent commercial reagents. This methodological bottleneck highlights the urgent need for a technique that integrates the speed and simplicity of direct detection with the precision, objectivity, and throughput of an automated assay. Herein, to bridge this gap, we propose a strategy for rapid, high-throughput quantification of T. pallidum using a novel, fluorescence-based flow cytometric assay implemented on an automated urine analyzer (the Sysmex UF-5000 analyzer). The assay demonstrated a limit of detection of 7.02 × 10³T. pallidum/mL and excellent precision (all coefficients of variation < 20%). It showed strong quantitative agreement with qPCR across a wide dynamic range (4.98 × 103-2.10 × 107T. pallidum/mL), with an excellent correlation (r = 0.9967), without significant proportional or constant bias (Passing-Bablok slope = 1.003). Bland-Altman analysis confirmed a close agreement (mean difference: -1.14 × 105T.pallidum/mL). In contrast, DFM exhibited substantially higher variability (CVs 15.19-83.52%) and failed to detect low-concentration samples. Operationally, the flow cytometric assay provides results within 30 s per sample at a low consumable cost (approximately $0.35 per test), outperforming DFM in objectivity and throughput and qPCR in both speed and cost-effectiveness. In summary, this novel flow cytometric assay effectively overcomes the historical challenges associated with T.pallidum quantification. This automated, precise, and rapid assay integrates the simplicity of direct detection with the accuracy of molecular quantification, offering a standardized and practical tool to enhance research in syphilis microbiology, pharmacology, and immunology, paving the way for more reproducible and translatable scientific discoveries.
Identifying differentially expressed miRNAs in plasma-derived exosomes associated with type 2 diabetes mellitus (T2DM) complicated by atherosclerosis (AS) and elucidating their roles in high-glucose/high-lipid-induced vascular endothelial dysfunction. Plasma-derived exosomal miRNAs were isolated from people with T2DM complicated by AS and healthy controls. Followed by miRNA sequencing to characterize differential expression profiles between groups. GO and KEGG pathway enrichment analyses were performed on differentially expressed miRNAs. Human umbilical vein endothelial cells (HUVECs) were exposed to combined hyperglycemia and hyperlipidemia to establish an in vitro model of diabetic endothelial injury. HUVECs were subsequently transfected with miR-887-5p mimics, inhibitors or negative controls, and assessed for proliferation, migration, apoptosis, oxidative stress, and nitric oxide (NO) content. Sequencing revealed globally reduced plasma exosomal miRNA expression in people with T2DM and AS relative to healthy controls, with 21 upregulated and 23 downregulated miRNAs identified. Among these, hsa-miR-887-5p exhibited the greatest fold change of all detected miRNAs, while hsa-miR-96-5p and hsa-miR-183-5p (upregulated) and hsa-miR-410-3p (downregulated) harbored the most target genes implicated in diabetic atherosclerosis. Functionally, miR-887-5p enhanced HUVEC proliferation and migration under high-glucose/high-lipid conditions, elevated superoxide dismutase (SOD) activity, reduced lactate dehydrogenase (LDH) and malondialdehyde (MDA) levels, suppressed intracellular iNOS/NO and attenuated apoptosis. Plasma exosomal miRNA expression is broadly reduced in people with T2DM complicated by AS. hsa-miR-887-5p, hsa-miR-96-5p, hsa-miR-183-5p, and hsa-miR-410-3p may emerge as candidates with diagnostic and therapeutic relevance in this context. Specifically, miR-887-5p mitigates high-glucose/high-lipid-induced vascular endothelial injury, warranting further investigation as a therapeutic target.