Frontiers in Pharmacology最新文献

Background: Although population pharmacokinetic models are the standard approach for identifying inter-individual variability and optimizing infliximab concentration, their development and validation are complex and time-consuming. Therefore, this study aimed to develop and evaluate machine learning (ML) models to predict infliximab and anti-drug antibody (ADA) concentrations in patients with inflammatory bowel disease (IBD) receiving maintenance infliximab therapy.

Methods: A total of 1,806 infliximab and ADA concentration measurements were prospectively collected from 149 IBD patients. Recurrent neural networks (RNN)-based models, including long short-term memory (LSTM) and gated recurrent unit (GRU) architectures, as well as regression-based models such as Elastic Net, Support Vector Regression, Random Forest (RF), and extreme gradient boosting (XGBoost), were developed. Recursive multi-step prediction was applied to evaluate short-term forecasting performance.

Results: RF outperformed in predicting infliximab concentrations, and XGBoost yielded the best performance in predicting ADA levels (2-fold accuracy, 86.67% and 96.67%, respectively). The infliximab prediction model maintained acceptable accuracy up to two recursive predictions steps but exhibited a notable performance decline at the third step. In contrast, the ADA model showed robust performance across all three recursive steps, maintaining 2-fold accuracy exceeding 96%.

Conclusion: ML models were developed to predict infliximab and ADA concentrations, with RF and XGBoost showing the best performance for infliximab and ADA prediction, respectively. The ADA model demonstrated stable multi-step forecasting capability. These models may support individualized dosing strategies and reduce the need for frequent therapeutic drug monitoring in clinical practice.

KRAS^G12D is a predominant mutation in pancreatic and colorectal cancers whose targeting has remained a therapeutic challenge. In this study, we introduced LPM5140276 as a potent KRAS^G12D inhibitor that forms a salt bridge with the Asp12 residue; furthermore, we evaluated its antitumor efficacy, action mechanism, and synergy with the SHP2 inhibitor RMC4550. LPM5140276 was observed to bind to GDP-loaded KRAS^G12D with high affinity, exhibiting a dissociation constant (K_D) of 3.1 × 10^-3 nM and an IC₅₀ of 0.5 nM, which was superior to its binding to GTP-loaded KRAS^G12D. In KRAS^G12D-mutant cells, LPM5140276 significantly inhibited cell viability by suppressing ERK and AKT phosphorylation to induce G₀/G₁ cell-cycle arrest and promote apoptosis, which contributed to its antitumor effect in vivo. However, rebound phosphorylation of ERK/AKT and increased SHP2 phosphorylation following the treatment suggested the emergence of bypass resistance. Notably, the combination of LPM5140276 and RMC4550 synergistically suppressed ERK and SHP2 phosphorylation, enhanced G₀/G₁ arrest and apoptosis, and improved the antitumor efficacy. Thus, LPM5140276 is a promising KRAS^G12D inhibitor, whose combination with SHP2 inhibition represents a viable strategy for overcoming resistance.

Background: Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children and is characterized by rapid progression and, in some cases, a high risk of relapse. Targeted therapies have revolutionized treatment with greater specificity, reduced systemic toxicity and a better prognosis.

Objective: This review provides a comprehensive analysis of current targeted therapies for pediatric B-cell ALL, focusing on their mechanisms of action, efficacy, safety profiles, advantages, and remaining challenges.

Methods: A systematic review of clinical trials published over the past 15 years was conducted. The analyzed therapies include monoclonal antibodies, antibody‒drug conjugates, tyrosine kinase inhibitors, proteasome inhibitors, and chimeric antigen-receptor T-cell (CAR-T cell) immunotherapy.

Results: Targeted therapies improved progression-free survival and overall response rates, particularly in patients with relapsed/refractory ALL. CD19-directed CAR-T-cell therapy and bispecific antibodies (e.g., blinatumomab) have demonstrated high remission rates in early-phase clinical trials. Additionally, BCR-ABL1-positive ALL patients show benefit from tyrosine kinase inhibitors when combined with chemotherapy.

Conclusion: Targeted therapies represent a paradigm shift in ALL treatments, enabling more personalized and effective strategies. Their integration into standard protocols, especially for high-risk and relapsed patients, is crucial to enhancing long-term outcomes.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251110522, identifier CRD420251110522.

Background/objective: This study evaluated the antidiabetic and antihypercholesterolemic potential of the botanical metabolite troxerutin (TRX) and compared it with that of metformin in high-fat diet-fed streptozotocin-induced diabetic male Wistar rats.

Methods: The rats (n = 48) were divided into six groups. Diabetes was induced in the treatment groups, and different doses of troxerutin (TRX)-25 mg/kg/day (TRX25-D), 50 mg/kg/day (TRX50-D), and 75 mg/kg/day (TRX75-D)-or the standard drug (10 mg/kg/day; MET10-D) were administered for a period of 7 weeks, compared to the negative (non-diabetic control, NDC) and positive (diabetic control, DC) control groups. At the end of the trial period, serum was collected to determine the lipid profile (high-density lipoprotein, low-density lipoprotein, and very-low-density lipoprotein (VLDL)) and the concentrations of hepatic (aspartate aminotransferase and alanine aminotransferase), renal (urea and creatinine), and oxidative stress (catalase and malondialdehyde) markers. Adipose tissue, skeletal muscle, and liver tissue samples were collected to determine mRNA expression, of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] and genes involved in lipid metabolism [peroxisome proliferator-activated receptor α (PPARα), peroxisome proliferator-activated receptor γ (PPARγ), fatty acid synthase (FAS), and sterol regulatory element-binding protein-1c (SREBP-1c)].

Results: The results showed a significant decrease (p < 0.05) in total cholesterol (TC), triglycerides (TGs), VLDL, and LDL levels, along with hepatic, renal, and stress markers, in the rats treated with a higher concentration of troxerutin (TRX75-D) compared to diabetic control rats. Moreover, troxerutin significantly (p < 0.05) upregulated the expression of PPARα and PPARγ, while the expression of FAS, SREBP-1c, TNF-α, and IL-6 genes were significantly (p < 0.05) downregulated simultaneously in the adipose tissue, skeletal muscles, and liver in a dose-dependent manner, compared to diabetic ct control rats.

Conclusion: Troxerutin has considerable antidiabetic and antihypercholesterolemic potential and thus could be safely used as an alternative therapeutic compound to the standard antidiabetic drug metformin.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by repetitive behaviors and a lack of social communication. The role of probiotics, phytochemicals and their combination phytochemicals as treatment options for ASD is still under study.

Objective: This study aimed to evaluate the associated molecular pathways and explore the impact of Lactobacillus rhamnosus (L. rhamnosus), thymol (Thy) and their combination on propionic acid (PA)-induced ASD rats.

Methods: Fifty 3-week-old male albino rat pups were randomly distributed into five groups. The groups included a control group, a PA-induced ASD group, in which PA (250 mg/kg, p.o.) was administered for 3 days, and three other groups that received PA (250 mg/kg, p.o.) for 3 days along with either L. rhamnosus (1 × 10^6 CFU/day, p.o), Thy (30 mg/kg/day, p.o), or both. Brain tissues were collected for biochemical, histological, and immunohistochemical studies following behavioral evaluations.

Results: Compared with the group administered only PA, treatment with L. rhamnosus, Thy and their combination significantly improved the neurobehavioral deficits in the autistic group. Improvements were observed in tests assessing memory consolidation, learning capacity, attention, spatial memory, locomotor activity, and contextual information processing. In addition to histopathological improvements, L. rhamnosus, Thy and their combination demonstrated notable ameliorative effects on PA-induced abnormalities in brain neurotransmitters, oxidative stress, inflammation, apoptosis, and endoplasmic reticulum (ER) stress and autophagy biomarkers. Furthermore, treatment with L. rhamnosus, Thy and their combination improved abnormalities in the tested biomarkers and modulated associated pathways, including significant upregulation of BDNF, TrkB, CREB, Nrf2, and HO-1 content and downregulation of TLR4/NF-κB-mediated neuroinflammation, leading to substantial improvements in ASD symptoms.

Conclusion: Our results suggest that L. rhamnosus, Thy and their combination have promising therapeutic potentials in alleviating biochemical and behavioral deficits in PA-induced autism. These effects may be mediated by halting apoptosis, inflammation, and endoplasmic reticulum stress, inducing autophagy, and improving different biomarkers and modulation pathways, such as Wnt3/β-catenin/GSK3β, pI3K/p-Akt/mTOR, and BDNF/p-TrkB/CREB.

In traditional Chinese medicine theory, Scutellaria baicalensis Georgi [Lamiaceae; Scutellariae radix] (SR) is bitter and cold in nature. It enters the lung, gallbladder, spleen, large intestine, and small intestine meridians. It clears heat and dries dampness, purges fire and detoxifies, stops bleeding, and stabilizes pregnancy. It excels at clearing lung fire and upper-body heat. Flavonoids, the primary active compound of SR, undergo metabolism in vivo through Phase I and Phase II reactions as well as intestinal flora-mediated processes. Modern pharmacological research indicates that flavonoid compounds exhibit diverse biological activities in immune modulation, antiviral, anti-inflammatory, antibacterial, and antitumor effects. In recent years, novel formulations such as nanomedicines and liposomes have garnered increasing attention to enhance their stability and bioavailability. This review systematically summarizes the research progress on flavonoid compounds in SR, comprehensively elaborating on their phytochemistry, extraction methods, separation and purification techniques, in vivo metabolism, immunological and pharmacological effects, toxicity, and novel dosage forms. It provides theoretical foundations and practical references for the further research, development, and rational application of these compounds.

Background: Sepsis is a life-threatening condition caused by a dysregulated host response to infection, characterized by biphasic immune dysregulation and high mortality rates. Artesunate (AS), a semisynthetic artemisinin derivative, has demonstrated broad pharmacological properties, yet its overall efficacy and mechanisms in sepsis remain systematically unassessed at the preclinical level.

Objectives: In this study, we aimed to conduct the first systematic review and meta-analysis to evaluate the therapeutic efficacy and underlying mechanisms of AS in animal models of sepsis.

Methods: We systematically searched five electronic databases up to 3 September 2025, for controlled in vivo studies analyzing the effects of AS in septic animals. The study quality was assessed using the SYRCLE risk-of-bias tool, and evidence certainty was rated via the GRADE approach. Statistical analyses, including meta-analysis, publication bias, and sensitivity analyses, were performed using RevMan 5.4 and Stata 17.0.

Results: Fifteen studies involving mice and rats were included. Meta-analysis indicated that AS was associated with improved survival (10 studies, OR: 6.87, 95% CI: 3.81-12.41, p < 0.00001), reduced bacterial load, and promotion of body weight recovery. Organ protection was evidenced by attenuated lung injury (reduced histological scores, MPO activity, and wet-to-dry ratio) and improved liver function (decreased AST and ALT levels). Analysis of cytokine data from different time-points suggested a potential phase-dependent immunomodulatory effect: AS suppressed pro-inflammatory cytokines (TNF-α and IL-6) during the hyperinflammatory phase while restoring immune competence in the immunosuppressive phase, accompanied by elevated IL-1β. Furthermore, AS reduced apoptosis (decreased TUNEL-positive cells) and enhanced pro-survival signaling (increased p-mTOR/mTOR ratio); however, its effect on caspase-3 was not significant. Sensitivity analyses supported the robustness of the primary findings, and no significant publication bias was detected within the limits of the available studies.

Conclusion: AS is associated with survival benefits and multi-organ protection in septic animal models through multimodal mechanisms, potential phase-aware immunomodulation, antiapoptotic effects, and enhanced bacterial clearance. Despite methodological heterogeneity across studies, these preclinical findings support further investigation of AS as a potential therapeutic candidate for sepsis treatment.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251146068.

Background: Fibrotic interstitial lung diseases (ILDs) are characterized by different degrees of inflammation and fibrosis of the lung parenchyma that are associated with progressive loss of breath, high morbidity and mortality. Current therapeutic options are limited, so there remains a significant need for effective and well-tolerated treatments. GTX-11 is an orally available small molecule in development for the treatment of fibrotic diseases. In this study, we aimed to assess the therapeutic potential of GTX-11 in different preclinical models of lung fibrotic disease.

Methods: We assessed the activity of GTX-11 and its active metabolite, GTX-11m, in the bleomycin-induced pulmonary fibrosis model and in vitro in primary fibroblast cell cultures, including human normal lung fibroblasts (hNLFs) and ILD patient-derived fibroblasts.

Results: In the murine model, GTX-11 treatment improved animal survival and significantly reduced lung fibrosis as measured by Ashcroft score and collagen deposition. GTX-11 also reduced the inflammatory cell count in bronchoalveolar lavage fluid and pro-inflammatory factors in lung tissue. Additionally, GTX-11 significantly improved lung vascular dysfunction and reduced pulmonary vascular remodeling. The preclinical anti-fibrotic effects of GTX-11 were comparable to, or in some cases exceeded, those of currently approved anti-fibrotic drugs used in clinical practice. In vitro, GTX-11m demonstrated anti-fibrotic and anti-inflammatory activity in hNLFs and ILD patient-derived fibroblasts. GTX-11m inhibited TGFβ-induced expression of key fibrotic markers and reduced fibroblast-to-myofibroblast transition and inflammatory cytokine production. The effects were consistent across the different tested ILD cultures and resulted from the prevention of SMAD2 and SMAD3 activation by TGFβ. The GTX-11m anti-fibrotic and anti-inflammatory effects were comparable or better than nintedanib.

Conclusion: Altogether, our studies reveal that GTX-11 is an effective antifibrotic both in vivo and in vitro, suggesting that GTX-11 has potential as a therapeutic option for fibrotic ILDs.

[This retracts the article DOI: 10.3389/fphar.2020.572616.].

Introduction: Wuji Wan (WJW) is a classical Chinese formula traditionally prescribed for diarrhea/dysentery and abdominal pain. In ulcerative colitis (UC), inflammatory diarrhea reflects not only mucosal inflammation but also inflammation-linked disruption of epithelial electrolyte and water handling, highlighting membrane transport as a mechanistic bridge between symptom burden and immune activation. However, it remains unclear whether WJW confers therapeutic benefit in UC and whether any benefit is accompanied by coordinated regulation of membrane-transport-linked pathways. This study therefore asked whether WJW shows therapeutic effects in a UC model and whether these effects are accompanied by changes in epithelial Na⁺/Cl^- transport and water-channel programs and by modulation of the T-cell-linked potassium channel Kv1.3.

Methods: We investigated this question in a mouse model of DSS-induced colitis (3% dextran sulfate sodium). Our assessment included disease activity index (DAI) scores, histopathological analysis, ELISA, Western blotting, untargeted metabolomics, and whole-cell patch-clamp electrophysiology.

Results: WJW significantly ameliorated DSS-induced colitis, as reflected by improved colonic pathology and partial normalization of DSS-associated serum metabolic perturbations. Untargeted metabolomics highlighted transport-related pathways. WJW increased/normalized the expression of key epithelial transport proteins involved in Na⁺/Cl^- absorption and water handling, including sodium/hydrogen exchanger 3 (NHE3), epithelial sodium channel (ENaC), downregulated in adenoma (DRA), aquaporin-3 (AQP3), and aquaporin-8 (AQP8). In parallel, WJW reduced IL-6, IL-17A, and IFN-γ and dampened ERK/NF-κB pathway activation. WJW also reduced colonic Kv1.3 protein expression, and WJW-containing plasma directly inhibited Kv1.3 currents in Jurkat T cells.

Conclusion: WJW ameliorated DSS-induced colitis and was accompanied by coordinated modulation of epithelial and immune membrane-transport-linked readouts.