搜索结果：Pharmacology & therapeutics

Metabolic diseases such as type 2 diabetes and obesity represent a rapidly escalating global health burden, yet current therapeutic strategies largely target isolated symptoms or single molecular pathways. To this end, we developed an integrated computational pipeline leveraging knowledge graph, pathway analysis and network pharmacology to elucidate the multi-target mechanisms of Ayurvedic Single Herbal Drugs (SHDs). SHDs associated with diabetes and obesity were curated from the Ayurvedic Pharmacopoeia of India, followed by phytochemical identification using IMPPAT database, yielding a shortlist of 11 SHDs and their 188 phytochemicals after drug-likeness and bioavailability filtering. Subsequently, molecular targets of the phytochemicals in SHDs, disease-associated genes and therapeutic targets of FDA-approved drugs, were curated via integration of data from several databases. Pathway enrichment analysis revealed significant functional overlap between SHD-associated and disease-associated pathways. All curated data were embedded into a Neo4j-based knowledge graph, enabling SHD-disease intersection analysis that prioritized key disease-relevant targets, including PTPN1, GLP1R, and

The morphological form of a word can often give cues to its meaning, but purely relying on these mappings can lead to overgeneralization in high-stakes domains. In the medical domain, for instance, LLMs can confidently reason about fictitious drugs from their affixes alone (e.g., wugcillin) and generate plausible-looking clinical content. We present a behavioral and mechanistic study of LLM "affix heuristics" in pharmacology. Using fictitious drug names built from real affixes, we show that affix signals alone elicit class-level pharmacological responses. We introduce a framework for identifying whether a model's drug semantics are driven mainly by the affix, the stem, or the drug name as a whole. Applied across 653 drugs, our framework reveals that models often induce drug meaning primarily through affix cues, yet rarely explicitly indicate this reliance, and sometimes incorrectly conflate properties among affix-sharing drugs. Activation patching across models further localizes this behavior to early-mid layers. These findings show that morphological shortcuts pose a subtle but measurable risk to safety.

Chronic superficial gastritis (CSG) severely affects quality of life and can progress to worse gastric pathologies. Traditional Chinese Medicine (TCM) effectively treats CSG, as exemplified by Jinhong Tablets (JHT) with known anti-inflammatory properties, though their mechanism remains unclear. This study integrated network pharmacology, untargeted metabolomics, and gut microbiota analyses to investigate how JHT alleviates CSG. A rat CSG model was established and evaluated via H&E staining. We identified JHT's target profiles and constructed a multi-layer biomolecular network. Differential metabolites in plasma were determined by untargeted metabolomics, and gut microbiota diversity/composition in fecal and cecal samples was assessed via 16S rRNA sequencing. JHT markedly reduced gastric inflammation. Network pharmacology highlighted metabolic pathways, particularly lipid and nitric oxide metabolism, as essential to JHT's therapeutic effect. Metabolomics identified key differential metabolites including betaine (enhancing gut microbiota), phospholipids, and citrulline (indicating severity of CSG). Pathway enrichment supported the gut microbiota's involvement. Further microbiota

The contributions of model complexity, data volume, and feature modalities to knowledge graph-based drug repurposing remain poorly quantified under rigorous temporal validation. We constructed a pharmacology knowledge graph from ChEMBL 36 comprising 5,348 entities including 3,127 drugs, 1,156 proteins, and 1,065 indications. A strict temporal split was enforced with training data up to 2022 and testing data from 2023 to 2025, together with biologically verified hard negatives mined from failed assays and clinical trials. We benchmarked five knowledge graph embedding models and a standard graph neural network with 3.44 million parameters that incorporates drug chemical structure using a graph attention encoder and ESM-2 protein embeddings. Scaling experiments ranging from 0.78 to 9.75 million parameters and from 25 to 100 percent of the data, together with feature ablation studies, were used to isolate the contributions of model capacity, graph density, and node feature modalities. Removing the graph attention based drug structure encoder and retaining only topological embeddings combined with ESM-2 protein features improved drug protein PR-AUC from 0.5631 to 0.5785 while reducing V

Quantitative Systems Pharmacology (QSP) modeling is essential for drug development but it requires significant time investment that limits the throughput of domain experts. We present \textbf{GRASP} -- a multi-agent, graph-reasoning framework with a human-in-the-loop conversational interface -- that encodes QSP models as typed biological knowledge graphs and compiles them to executable MATLAB/SimBiology code while preserving units, mass balance, and physiological constraints. A two-phase workflow -- \textsc{Understanding} (graph reconstruction of legacy code) and \textsc{Action} (constraint-checked, language-driven modification) -- is orchestrated by a state machine with iterative validation. GRASP performs breadth-first parameter-alignment around new entities to surface dependent quantities and propose biologically plausible defaults, and it runs automatic execution/diagnostics until convergence. In head-to-head evaluations using LLM-as-judge, GRASP outperforms SME-guided CoT and ToT baselines across biological plausibility, mathematical correctness, structural fidelity, and code quality (\(\approx\)9--10/10 vs.\ 5--7/10). BFS alignment achieves F1 = 0.95 for dependency discovery,

Background: Radiation-induced leukopenia caused by low-dose exposure is frequently associated with Traditional Chinese Medicine (TCM) syndromes like "blood deficiency" and "fatigue syndrome". Ci Bai Capsule (CB) has been reported to enhance white blood cell levels; however, its mechanisms and bioactive compounds remain unclear.Aim: This study aimed to identify the bioactive compounds group of CB and elucidate its potential mechanisms in radiation-induced leukopenia.Methods: Syndrome-related data were gathered from SYMMAP and CTD database. CB's target profile is predicted by DrugCIPHER. Network pharmacology approaches were employed to identify active compounds and related pathways. Experimental validation was conducted through flow cytometry and RNA-sequencing in both ex vivo and in vivo models.Results: A total of 22 pathways related to cellular processes, immune responses, and signal transduction were identified. Five key bioactive compounds (kaempferol-3-glucorhamnoside, syringin, schisandrin, 3-hydroxytyrosol 3-O-glucoside and salidroside) were found to significantly modulate syndrome-related pathways. Optimal dosing of this compound combination enhanced leukocyte counts and sple

Objective: To investigate the mechanism by which quercetin inhibits triple-negative breast cancer (TNBC) through regulating T-cell-related targets, providing a novel strategy for TNBC immunotherapy.Methods: Single-cell RNA sequencing (GSE161529 dataset) and network pharmacology were integrated. PCA and UMAP clustering identified T-cell subsets and differentially expressed genes in TNBC microenvironment. TNBC-related targets were screened via CTD and OMIM databases, with functional pathways analyzed by GO/KEGG enrichment. Molecular docking and PPI networks validated interactions between quercetin and core targets.Results: Quercetin intersected with 79 TNBC targets, including AKT1, EGFR, and MMP9, enriched in EGFR inhibitor resistance and endocrine resistance pathways. Molecular docking revealed the highest affinity between quercetin and GSK3B (-13.2 kJ/mol). AKT1 and MMP9 expression correlated with patient survival.Conclusion: Quercetin may reverse TNBC immunosuppression by multi-target modulation of T-cell function, but clinical application requires solutions for its low bioavailability, such as delivery systems or combination therapies.

Physics-Informed Kolmogorov-Arnold Networks (PIKANs) are gaining attention as an effective counterpart to the original multilayer perceptron-based Physics-Informed Neural Networks (PINNs). Both representation models can address inverse problems and facilitate gray-box system identification. However, a comprehensive understanding of their performance in terms of accuracy and speed remains underexplored. In particular, we introduce a modified PIKAN architecture, tanh-cPIKAN, which is based on Chebyshev polynomials for parametrization of the univariate functions with an extra nonlinearity for enhanced performance. We then present a systematic investigation of how choices of the optimizer, representation, and training configuration influence the performance of PINNs and PIKANs in the context of systems pharmacology modeling. We benchmark a wide range of first-order, second-order, and hybrid optimizers, including various learning rate schedulers. We use the new Optax library to identify the most effective combinations for learning gray-boxes under ill-posed, non-unique, and data-sparse conditions. We examine the influence of model architecture (MLP vs. KAN), numerical precision (single

Non-small cell lung cancer (NSCLC) is often intrinsically resistant to several first- and second-line therapeutics and can rapidly acquire further resistance after a patient begins receiving treatment. Treatment outcomes are therefore significantly impacted by the optimization of therapeutic scheduling. Previous preclinical research has suggested scheduling bevacizumab in sequence with combination antiproliferatives could significantly improve clinical outcomes. Mathematical modeling is a well-suited tool for investigating this proposed scheduling modification. To address this critical need, individual patient tumor data from 11 clinical trials in NSCLC has been collated and used to develop a semi-mechanistic model of NSCLC growth and response to the various therapeutics represented in those trials. Precise estimates of clinical parameters fundamental to cancer modeling have been produced - such as the rate of acquired resistance to various pharmaceuticals, the relationship between drug concentration and cancer cell death, as well as the fine temporal dynamics of vascular remodeling in response to bevacizumab. In a reserved portion of the dataset, this model was used to predict the

Therapeutic development is a costly and high-risk endeavor that is often plagued by high failure rates. To address this, we introduce TxGemma, a suite of efficient, generalist large language models (LLMs) capable of therapeutic property prediction as well as interactive reasoning and explainability. Unlike task-specific models, TxGemma synthesizes information from diverse sources, enabling broad application across the therapeutic development pipeline. The suite includes 2B, 9B, and 27B parameter models, fine-tuned from Gemma-2 on a comprehensive dataset of small molecules, proteins, nucleic acids, diseases, and cell lines. Across 66 therapeutic development tasks, TxGemma achieved superior or comparable performance to the state-of-the-art generalist model on 64 (superior on 45), and against state-of-the-art specialist models on 50 (superior on 26). Fine-tuning TxGemma models on therapeutic downstream tasks, such as clinical trial adverse event prediction, requires less training data than fine-tuning base LLMs, making TxGemma suitable for data-limited applications. Beyond these predictive capabilities, TxGemma features conversational models that bridge the gap between general LLMs an

First-line antiproliferatives for non-small cell lung cancer (NSCLC) have a relatively high failure rate due to high intrinsic resistance rates and acquired resistance rates to therapy. 57% patients are diagnosed in late-stage disease due to the tendency of early-stage NSCLC to be asymptomatic. For patients first diagnosed with metastatic disease the 5-year survival rate is approximately 5%. To help accelerate the development of novel therapeutics and computer-based tools for optimizing individual therapy, we have collated data from 11 different clinical trials in NSCLC and developed a semi-mechanistic, clinical model of NSCLC growth and pharmacodynamics relative to the various therapeutics represented in the study. In this study, we have produced extremely precise estimates of clinical parameters fundamental to cancer modeling such as the rate of acquired resistance to various pharmaceuticals, the relationship between drug concentration and rate of cancer cell death, as well as the fine temporal dynamics of anti-VEGF therapy. In the simulation sets documented in this study, we have used the model to make meaningful descriptions of efficacy gain in making bevacizumab-antiproliferat

A fundamental mistake in receptor theory has led to an enduring misunderstanding of how to estimate the affinity and efficacy of an agonist. These properties are inextricably linked and cannot be easily separated in any case where the binding of a ligand induces a conformation change in its receptor. Consequently, binding curves and concentration-response relationships for receptor agonists have no straightforward interpretation. This problem, the affinity-efficacy problem, remains overlooked and misunderstood despite it being recognised in 1987. To avoid the further propagation of this misunderstanding, we propose that the affinity-efficacy problem should be included in the core curricula for pharmacology undergraduates proposed by the British Pharmacological Society and IUPHAR.

Developing therapeutics is a lengthy and expensive process that requires the satisfaction of many different criteria, and AI models capable of expediting the process would be invaluable. However, the majority of current AI approaches address only a narrowly defined set of tasks, often circumscribed within a particular domain. To bridge this gap, we introduce Tx-LLM, a generalist large language model (LLM) fine-tuned from PaLM-2 which encodes knowledge about diverse therapeutic modalities. Tx-LLM is trained using a collection of 709 datasets that target 66 tasks spanning various stages of the drug discovery pipeline. Using a single set of weights, Tx-LLM simultaneously processes a wide variety of chemical or biological entities(small molecules, proteins, nucleic acids, cell lines, diseases) interleaved with free-text, allowing it to predict a broad range of associated properties, achieving competitive with state-of-the-art (SOTA) performance on 43 out of 66 tasks and exceeding SOTA on 22. Among these, Tx-LLM is particularly powerful and exceeds best-in-class performance on average for tasks combining molecular SMILES representations with text such as cell line names or disease names

Background: Allium vegetables (garlic and onion) are one of the flavorings in people's daily diets. Observational studies suggest that intake of allium vegetables may be correlated with a lower incidence of digestive system cancers. However, the existence of a causal relationship is still controversial due to confounding factors and reverse causation. Therefore, we explored the causal relationship between intake of allium vegetables and digestive system cancers using Mendelian randomization approach. Methods: First, we performed Mendelian randomization analyses using inverse variance weighting (IVW), weighted median, and MR-Egger approaches, and demonstrated the reliability of the results in the sensitivity step. Second, Multivariable Mendelian randomization was applied to adjust for smoking and alcohol consumption. Third, we explored the molecular mechanisms behind the positive results through network pharmacology and molecular docking methods. Results: The study suggests that increased intake of garlic reduced gastric cancer risk. However, onion intake was not statistically associated with digestive system cancer. Conclusion: Garlic may have a protective effect against gastric ca

Large language models (LLMs) have shown strong empirical performance across pharmacology and drug discovery tasks, yet the internal mechanisms by which they encode pharmacological knowledge remain poorly understood. In this work, we investigate how drug-group semantics are represented and retrieved within Llama-based biomedical language models using causal and probing-based interpretability methods. We apply activation patching to localize where drug-group information is stored across model layers and token positions, and complement this analysis with linear probes trained on token-level and sum-pooled activations. Our results demonstrate that early layers play a key role in encoding drug-group knowledge, with the strongest causal effects arising from intermediate tokens within the drug-group span rather than the final drug-group token. Linear probing further reveals that pharmacological semantics are distributed across tokens and are already present in the embedding space, with token-level probes performing near chance while sum-pooled representations achieve maximal accuracy. Together, these findings suggest that drug-group semantics in LLMs are not localized to single tokens but

Digit therapeutics are novel software devices that clinicians may utilize in delivering quality mental health care and ensuring positive outcomes. However, uptake of digital therapeutics and clinically tested software-based programs remains low. This article presents possible reasons for attrition and low engagement in clinical studies investigating digital therapeutics, analyses of studies in which engagement was high, and design constructs that may encourage user engagement. The aim is to shed light on the importance of real-world attrition data of digital therapeutics, and important characteristics of medical devices that have positively influenced user engagement. The findings presented in this article will be useful to relevant stakeholders and medical device experts tasked with addressing the gap between software medical design and user engagement present in digital therapeutic clinical trials.

Objective: The study explored therapeutic targets and mechanisms of Gegen Qinlian Decoction for Helicobacter pylori infection and related gastric cancer using network pharmacology, molecular docking, and Mendelian randomization. Methods: Medicinal components of Gegen Qinlian Decoction were extracted from TCMSP and HERB databases. Disease treatment targets were sourced from DisGeNET and PubChem. Interaction networks were constructed via the STRING database and visualized using Cytoscape 3.9.1. Enrichment analysis of intersected targets was performed using DAVID and Metascapes. Molecular docking employed Autodock Tools 1.5.6 and PyMOL 2.5.2. Mendelian randomization was based on the ukb-b-531 sample from UK Biobank. Results: 146 active components and 248 targets from Gegen Qinlian Decoction were identified. 66 targets overlapped with Helicobacter pylori infection genes. Molecular docking highlighted interactions between primary drug components like quercetin, wogonin, kaempferol, and target genes PTGS1, PTGS2, MAPK14. Mendelian randomization pinpointed genes like IGF2, PIK3CG, GJA1, and PLAU associated with Helicobacter pylori infection. Conclusion: Gegen Qinlian Decoction's active co

Many multi-genic systemic diseases such as neurological disorders, inflammatory diseases, and the majority of cancers do not have effective treatments yet. Reinforcement learning powered systems pharmacology is a potentially effective approach to design personalized therapies for untreatable complex diseases. In this survey, state-of-the-art reinforcement learning methods and their latest applications to drug design are reviewed. The challenges on harnessing reinforcement learning for systems pharmacology and personalized medicine are discussed. Potential solutions to overcome the challenges are proposed. In spite of successful application of advanced reinforcement learning techniques to target-based drug discovery, new reinforcement learning strategies are needed to address systems pharmacology-oriented personalized de novo drug design.

In recent years, there has been tremendous progress in the development of quantum computing hardware, algorithms and services leading to the expectation that in the near future quantum computers will be capable of performing simulations for natural science applications, operations research, and machine learning at scales mostly inaccessible to classical computers. Whereas the impact of quantum computing has already started to be recognized in fields such as cryptanalysis, natural science simulations, and optimization among others, very little is known about the full potential of quantum computing simulations and machine learning in the realm of healthcare and life science (HCLS). Herein, we discuss the transformational changes we expect from the use of quantum computation for HCLS research, more specifically in the field of cell-centric therapeutics. Moreover, we identify and elaborate open problems in cell engineering, tissue modeling, perturbation modeling, and bio-topology while discussing candidate quantum algorithms for research on these topics and their potential advantages over classical computational approaches.