Female reproductive health depends on precisely coordinated metabolic, hormonal, immune, and epigenetic networks. Lactylation is a lactate-derived lysine post-translational modification that provides a direct mechanism by which glycolytic metabolism influences chromatin activity and protein function. Lactylation exerts diverse biological effects across multiple systems, including the cardiovascular, musculoskeletal, nervous, and urinary systems. Although individual studies have indicated that lactylation participates in key reproductive processes and contributes to various female reproductive disorders, the mechanisms connecting lactylation with female reproductive health and disease have not been systematically reviewed. Thus, we provide an integrated overview of lactylation-associated cellular mechanisms and the research progress in female reproductive health and disease. This review examines the molecular mechanisms of lactylation and its interactions with other post-translational modifications. We further summarize the physiological and pathological functions of lactylation in the female reproductive system, with particular emphasis on its context-dependent and double-edged role. We also outline emerging therapeutic strategies targeting lactate production, transport, lactylation enzymes, specific lactylation sites, together with clinical trials, while emphasizing key challenges associated with tissue specificity, reproductive safety, and precise modulation. This review highlights lactylation as a metabolic-epigenetic regulator and a potential therapeutic target for precision management of female reproductive diseases.
Detection and discrimination of chemosensory stimuli (usually known as odorants) by the olfactory system exert a crucial role in animal survival. Olfactory receptors (ORs) are a large family of G protein-coupled receptors (GPCRs) mainly expressed by the main olfactory neuroepithelium (OE) at the nasal level and can sense different odorants affecting the electric activity of olfactory sensory neurons (OSNs) eventually generating the sense of smell. Recent evidence suggests that the olfactory mucosa, namely, the OE plus the olfactory mucus, plays a critical role as an immune barrier. Healthy olfactory pathways need intact function and anatomy within the nose itself, the OE, the olfactory bulb, and the central brain structures in charge of olfactory processing. Olfactory loss influences nutrition, safety, and social relationships, and subjects with olfactory impairment have been revealed to be at greater risk for overall mortality. Of note, ORs are not only expressed within the OE but an ecnomotopic expression has also been identified, serving different physiological functions, such as glucose and lipid metabolism and wound healing. It should be noted that ligands of ecnomotopic ORs may originate from naturally occurring or synthetic odor compounds present in the foods and/or food additives, as well as from endogenous compounds produced by host and/or microbiome cells. This review summarizes the anatomy, physiology, and immunology of the human olfactory system. Then, it delves into the ecnomotopic OR expression and signaling pathways. Finally, it reports recent data highlighting how the OR expression can be modulated offering guidance and future directions for clinical translatability.
Efficient drug discovery is essential to mitigate the high attrition rates and capital-intensive nature of traditional pharmaceutical research. Deep learning (DL) has catalyzed a paradigm shift, offering unprecedented computational capabilities to accelerate this process. This review systematically summarizes advancements in DL methodologies for drug discovery. First, the critical data foundations, Molecular Representation Learning, and core architectures underpinning artificial intelligence (AI)-driven therapeutics are elucidated, with a particular emphasis on the evolution of generative AI frameworks (such as Variational Autoencoders (VAEs), Generative Adversarial Networks (GANs), and diffusion models) for chemical space exploration. Subsequently, diverse DL applications across the discovery pipeline are investigated, encompassing target identification, virtual screening, de novo molecular design, retrosynthetic analysis, absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling, and drug repurposing. Furthermore, persistent challenges, particularly data scarcity, model opacity, experimental validation bottlenecks, and escalating computational resource requirements, are critically evaluated. To bridge the gap between in silico predictions, chemical synthesis, and biological reality, emerging solutions such as federated learning, causality-aware Explainable AI (XAI), closed-loop autonomous laboratories, and efficiency-oriented algorithmic strategies are explored. Ultimately, this article provides strategic insights into leveraging DL, underscoring its transformative potential in driving next-generation medicinal and therapeutic innovation.
Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous breast cancer subtype with early recurrence and limited therapeutic targets. The evidence reviewed here spans several non-equivalent intervention classes: licensed or commercial multi-component Chinese medicine products, standardized trial formulations, experimental botanical mixtures, and isolated constituents, fractions, or derivatives. We use the umbrella term Chinese medicine-based interventions (CMBIs) only for evidence mapping and do not assume pharmacological, manufacturing, or regulatory equivalence among these classes. Evidence was appraised on two independent dimensions: relevance to TNBC and study design/methodological robustness. TNBC-specific clinical evidence is limited to a small number of randomized and observational studies with dissimilar endpoints; a 2022 meta-analysis reported favorable pooled estimates but also substantial methodological weaknesses and intervention heterogeneity. Preclinical findings suggest pathway-associated effects involving apoptosis, ferroptosis, immune regulation, epithelial-mesenchymal transition, metabolism, and chemotherapy response. Ferroptosis evidence is currently limited to preclinical Shuganning injection studies showing iron-dependent lipid peroxidation and ferrostatin-1-sensitive cell death, without clinical validation in TNBC. Overall, CMBIs should be regarded as investigational adjunctive approaches rather than established TNBC-specific therapies. Priorities include product-level chemical characterization, clinically relevant exposure assessment, model-diverse causal validation, multicenter trials, and preparation-specific safety and interaction monitoring.
Abnormal scarring, such as hypertrophic and keloid scars, are a result of pathological skin wound healing, and can reduce quality of life through psychological factors, persistent pain, and reduced mobility. Under physiological conditions, wounds proceed sequentially through the hemostatic, inflammatory, proliferative, and remodeling phases of healing. However, dysregulated wound healing can overstimulate fibrotic activity, resulting in the development of hypertrophic or keloid scars. These scars present a significant clinical challenge, as hypertrophic scars develop in more than 70% of burn survivors with a 40%–94% incidence rate following surgery. While hypertrophic and keloid scars are a common health concern, treatment options are limited due to the complex nature of pathological scar development. Furthermore, the development of new therapeutics is complicated by limitations in research models mimicking scars in vitro and in vivo. We present a review of the available therapeutic strategies and clinical data addressing fibrotic scars, in vitro and in vivo models, and methods used to study scars. We then summarize recent clinical trial data addressing hypertrophic scars. Lastly, we discuss the translatability of hypertrophic scar research to other pathological scars, such as mechanically weak scars and scars from spinal cord injury-induced pressure wounds that increase the risk of wound recurrence after healing in certain types of wounds. Findings identify several early inflammatory signaling targets to investigate for the improvement of hypertrophic scarring.
Migraine is a prevalent, complex, and disabling neurological disorder. Available treatments consist of repurposed drugs, with medication switching and treatment failure a common occurrence. Pathophysiological models have shifted from migraine being a primarily vascular disorder to a complex network disease encompassing cortical, hypothalamic, thalamic, brainstem, trigeminovascular, and meningeal structures. These areas are interconnected by cascades of multiple signalling transmitters and hormones. This review explores how these molecules may offer novel pharmacological targets for efficacious treatments tailored to the pathophysiology of migraine. Calcitonin gene-related peptide (CGRP) directed therapies include antagonists (“gepants”) and monoclonal antibodies. Both drug classes have shown promising effects in managing pain in acute migraine attacks and in prophylactically reducing headache frequency, even within treatment-resistant migraine populations. Animal studies have shown drugs targeting pituitary adenylate cyclase-activating polypeptide (PACAP) signalling to reduce meningeal vasodilation and chronic allodynia. PACAP ligand-directed monoclonal antibodies offer therapeutic promise in patients with treatment-resistant migraine; however, this evidence base is limited and requires further research. Amylin may offer a novel therapeutic target for migraine; however, currently no such therapies have been developed. Neurokinin receptor antagonists have so far shown little promise in clinical trials, further challenging the role of substance p and neurogenic inflammation in migraine pathophysiology. Building upon the success of triptan therapy, novel serotonergic medications such as 5-HT1F agonists (‘ditans’) have shown positive benefit in clinical studies as an alternative treatment to triptans. Additional emerging molecular targets include Kir6.1/SUR2B KATP and Kv7 potassium channels, together with GluK1 and mGluR5 glutamate receptors. In contrast, despite a strong mechanistic rationale, therapeutic strategies targeting orexinergic pathways, nitric oxide synthase, and phosphodiesterase/cyclic nucleotide signalling have yet to demonstrate clinical efficacy in migraine. Overall, CGRP, PACAP, and serotonergic signalling offer the greatest promise as emerging pharmacological targets for migraine therapy. Most other emerging pathways remain in early, preclinical stages, with further research needed to bridge the gap between pathophysiological plausibility and robust clinical translation.
IntroductionChemotherapy-induced cognitive impairment, commonly referred to as “chemobrain”, represents a frequent and distressing complication of cancer therapy. Doxorubicin (DOX), a widely used chemotherapeutic agent, contributes to these deficits partly through mechanisms involving oxidative stress, inflammatory cascades, and disruption of glutamate homeostasis, but unfortunately, the precise role of altered glutamate transport and neurotrophic signaling remains poorly addressed. Lurasidone (LURA), an atypical antipsychotic, exhibits potent 5-HT7 receptor antagonism and pro-cognitive properties, making it a strong candidate to counteract these deficits. However, its potential to rescue glutamate homeostasis and neuroplasticity pathways in chemobrain has not been explored. This study investigated whether LURA could counteract DOX-induced chemobrain by restoring CREB/BDNF/Glt-1 signaling and re-establishing glutamate homeostasis in the hippocampus and prefrontal cortex.MethodsForty-eight male Wistar rats were assigned to control, LURA, DOX, or DOX/LURA groups. Behavioral performance was assessed using the open field, novel object recognition, and Morris water maze tests. Hippocampal and prefrontal tissues were evaluated for protein expression of the CREB/BDNF/Glt-1 pathway, glutamate and GABA levels, oxidative stress indices, and histopathological and immunohistochemical markers of neurodegeneration, apoptosis, and astrocytic activation.ResultsDOX administration resulted in pronounced cognitive decline, oxidative stress, neuroinflammation, neuronal loss, and substantial downregulation of CREB/BDNF/Glt-1 signaling, accompanied by elevated glutamate and reduced GABA levels. LURA co-treatment markedly improved behavioral outcomes, reinstated CREB/BDNF/Glt-1 expression, ameliorated glutamate/GABA balance, and reduced neurodegeneration, caspase-3 activation, and astrocytic reactivity.DiscussionThis study provides the first evidence that lurasidone mitigates doxorubicin-induced chemobrain. This neuroprotective effect is associated with the restoration of glutamate homeostasis and the upregulation of hippocampal and prefrontal CREB/BDNF/Glt-1 signaling, highlighting lurasidone as a promising therapeutic option for chemotherapy-induced cognitive impairment.
BackgroundBee venom (Apis mellifera) is a complex biological secretion rich in peptides, enzymes, and bioactive molecules with recognized pharmacological potential. Environmental conditions may influence venom composition; however, geographic variation in the bee venom proteome remains insufficiently characterized, particularly in South American Mediterranean ecosystems, including central Chile.MethodsVenom from multiple A. mellifera colonies within each sampling area of the Valparaíso Region, Chile, was pooled to generate one composite sample per geographic zone: Sea Level, Inland Valley, and Andean Foothill. Two analytical aliquots from each pooled sample were independently processed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Protein identification and label-free quantification were performed using MaxLFQ and iBAQ, and differential abundance was assessed using DEqMS.ResultsOverall, 679 proteins were identified. Principal component analysis and hierarchical clustering showed reproducible grouping of analytical duplicates by geographic origin, indicating distinct proteomic profiles among zones. Differential abundance analysis identified proteins with significant abundance changes between regions, particularly between Sea Level and Inland Valley. Classical venom components, including melittin and phospholipase A2, predominated across samples, whereas proteins associated with stress response, redox regulation, metabolism, and secretion showed geographic variation.ConclusionBee venom from geographically distinct areas of central Chile exhibited exploratory proteomic differences, primarily in protein abundance patterns. Although the absence of independent biological replicates limits population-level inference, these patterns suggest environmentally associated proteomic plasticity potentially relevant to biological activity and pharmacological standardization. Further studies incorporating biological replication, targeted validation, and functional assays are required to confirm these findings.
BackgroundFinerenone and steroidal mineralocorticoid receptor antagonists (sMRAs) reduce proteinuria in chronic kidney disease (CKD), but direct comparative data from routine clinical practice remain limited. The objective of this study was to compare the effectiveness, hemodynamic effects, kidney function trajectory, and safety of finerenone versus sMRAs in patients with proteinuric CKD in routine clinical practice.MethodsThis retrospective single-center cohort study included adults receiving finerenone or an sMRA between January 2021 and May 2025. Longitudinal analyses included 174 patients with at least one post-baseline assessment (finerenone, n = 96; sMRA, n = 78). Changes in proteinuria, estimated glomerular filtration rate (eGFR), blood pressure, potassium, and glycated hemoglobin were assessed using mixed-effects models. A 1:1 propensity score-matched sensitivity analysis was performed.ResultsBoth treatments were associated with significant proteinuria reductions at 12 months, with percentage changes of −45.63% (95% confidence interval [CI], −59.42 to −27.15) with finerenone and −44.44% (95% CI, −60.08 to −22.66) with sMRAs, without a significant between-group difference (p = 0.927). Proteinuria reduction was already significant at 1 month with sMRAs, whereas it became significant from month 6 with finerenone. Both groups showed an early eGFR decline. At month 12, the decline remained significant in the sMRA group (−4.66 mL/min/1.73 m2; 95% CI, −7.35 to −1.97) but not in the finerenone group; however, no significant between-group difference in eGFR trajectory was observed. sMRAs produced a greater reduction in systolic blood pressure at 12 months than finerenone, with a between-group difference of 7.24 mmHg (95% CI, 2.25–17.66). Serum potassium increased in both groups without a significant between-group difference. Treatment discontinuation was less frequent with finerenone than with sMRAs (13.8% vs. 28.7%; p = 0.021). Findings for proteinuria and eGFR were consistent in the matched sensitivity analysis.ConclusionIn this real-world cohort, finerenone and sMRAs showed comparable antiproteinuric effectiveness. sMRAs were associated with a more pronounced blood pressure reduction, whereas finerenone showed more favorable renal profile, with lower treatment discontinuation and side effects.
IntroductionIntravenous (IV) proton pump inhibitors (PPIs) are commonly used in hospitalized patients, although a substantial proportion of this use may be inappropriate, particularly when enteral therapy is feasible. Restriction policies may help optimize prescribing and reduce unnecessary drug costs. This study evaluated the impact of an IV PPI restriction policy on prescribing patterns and estimated direct drug cost at a regional secondary care hospital in Saudi Arabia.MethodsThis retrospective before-and-after study was conducted from April 2023 to April 2024. The pre-restriction period was April to September 2023, and the post-restriction period was November 2023 to April 2024; October 2023 was excluded as the implementation washout month. Monthly hospital pharmacy records were used to collect IV and oral PPI prescriptions and recorded units, and prescribing and cost outcomes were normalized per 100 inpatient admissions. Clinical outcomes were not assessed. Pre- and post-restriction monthly values were compared using the Mann–Whitney U test.ResultsAfter policy implementation, mean monthly IV PPI prescriptions per 100 inpatient admissions decreased from 92.1 to 37.8, a 59.0% reduction (p = 0.0131), whereas oral PPI prescriptions increased from 15.5 to 41.6 per 100 inpatient admissions, a 169.2% increase (p = 0.0202). Total PPI prescriptions decreased from 107.6 to 79.3 per 100 inpatient admissions, a 26.2% reduction (p = 0.0082). The proportion of IV PPI prescriptions declined from 85.6% to 45.0% (p = 0.0152). Mean estimated total PPI drug cost per 100 inpatient admissions decreased from 3,534.6 to 1,642.9 SAR, a 53.5% reduction (p = 0.0131).ConclusionImplementation of an IV PPI restriction policy was associated with lower IV PPI prescribing, increased oral PPI use, and lower estimated direct drug cost. Clinical safety and efficacy were not evaluated and require further investigation.
ETN101 is a new therapeutic candidate with anti-hepatocellular carcinoma activity. In the present study, three complementary liquid chromatography–tandem mass spectrometry (LC–MS/MS) methods using protein precipitation and matrix-matched calibration were developed for quantifying ETN101 and its metabolites M1 and M2 in rat plasma, tissue homogenates, urine, and feces. The methods were validated with reference to U.S. Food and Drug Administration (FDA) and International Council for Harmonisation (ICH) M10 guidance. A simultaneous assay was used for plasma, urine, and feces, and two LC–MS/MS systems were used for tissue homogenates. Calibration ranges in plasma were 2–2,000 ng/mL for ETN101 and 0.2–2,000 ng/mL for M1 and M2. The corresponding ranges were 50–5,000 and 5–500 ng/mL in tissue homogenates and 20–2,000 and 2–2,000 ng/mL in urine and feces. Across the evaluated matrices, intra- and inter-day accuracy was 87.4%–115.7%, precision was ≤15.0%, and extraction recovery was 56.8%–104.8%. Absolute matrix effects varied among matrices but were reproducible across six individual lots (coefficient of variation ≤15%), and stability met the prespecified criteria. The methods were applied to absorption, distribution, metabolism, and excretion (ADME) studies in rats. After once-daily oral administration at 20 mg/kg for 5 days, ETN101 was slowly absorbed, and M1 and M2 were present in plasma and declined in parallel with the parent drug. No statistically significant fasted–fed differences in 0–24 h systemic exposure were detected on Day 1 or Day 5, and systemic exposure to M2 exceeded that to M1. ETN101 and M2 were quantifiable in all examined tissues (liver, lung, kidney, brain, heart, spleen, testis, thyroid, stomach, small intestine, large intestine, fat, and muscle), whereas M1 was frequently below the limit of quantification in the brain and fat. The highest ETN101 tissue-to-plasma concentration ratios (Kp) occurred in the lung and kidney. After intravenous administration at 10 mg/kg, urinary recovery of each analyte was ≤0.03%, and fecal recoveries of ETN101, M1, and M2 were 0.25%, 0.76%, and 2.21%, respectively, giving a low combined recovery (approximately 3.3% of the administered dose). These methods can be selected according to the study purpose and are applicable to further preclinical pharmacokinetic and ADME studies of ETN101.
ObjectiveTo evaluate the temporal association between voriconazole and hypomagnesemia in pediatric patients with hematologic diseases using prescription sequence symmetry analysis (PSSA) and to assess the utility of hospital information system (HIS)-based active drug safety surveillance.MethodsInpatient data were extracted from the Children’s Hospital of Chongqing Medical University from November 2013 to December 2024. The first year served as a data integrity verification window and the subsequent approximately 10-year period as the formal analysis phase. Patients with hematologic diseases were identified using ICD-10 codes C81–C96, D45–D47, and D60–D61. Each patient contributed the first voriconazole prescription and first hypomagnesemia event (Mg2+ < 0.6 mmol/L). The primary analysis used a 365-day washout period, 90-day exposure window, and 7-day blackout period. Adjusted sequence ratios (aSRs) with 95% confidence intervals (CIs) were estimated, with 10 parameter sensitivity analyses, monitoring-intensity correction, four control analyses, and stratified analyses by concomitant medications.ResultsAmong 536 eligible patients, 364 (67.9%) had serum magnesium measurements. The post-exposure sequence comprised 58 patients and the reverse sequence eight patients, yielding an aSR of 5.76 (95% CI: 2.75–12.06). Median time to hypomagnesemia after voriconazole initiation was 28 days (IQR: 20–43), and 32/58 events (55.2%) occurred within 30 days. Exploratory dose-response analysis showed no association between weight-based voriconazole dose and hypomagnesemia occurrence (P = 0.437). All parameter sensitivity analyses produced aSRs >3.9; after correction for monitoring intensity, the aSR was 3.33 (95% CI: 1.59–6.98); in a sensitivity grid, the association remained statistically significant for monitoring-intensity ratios up to 2.75. All four control analyses agreed with their prespecified expectations. Associations remained significant in the PPI and aminoglycoside strata, whereas the loop-diuretic non-user stratum showed the same direction but was not statistically significant.ConclusionVoriconazole initiation was temporally associated with subsequent hypomagnesemia in pediatric patients with hematologic diseases. PSSA may complement spontaneous reporting systems for detecting laboratory-defined safety signals. Weekly serum magnesium monitoring should be considered during the first 30 days of voriconazole therapy. These findings support a temporal association but do not establish causality.
A 74-year-old male patient with renal cell carcinoma developed disease progression in the left adrenal gland and lungs 12.8 years after surgery. He presented with symptoms of cholecystitis 4 weeks after starting pazopanib and 8 weeks after starting axitinib. The symptoms were relieved after treatment with drug discontinuation, anti-infective therapy and symptomatic supportive care. The Naranjo Adverse Drug Reaction Probability Scale scores showed 4 points for pazopanib and 6 points for axitinib, indicaing a probable association of the event with the above two drugs. Meanwhile, a literature review was conducted by retrieving studies on tyrosine kinase inhibitor-induced cholecystitis from the PubMed database from 2005 to 2025, followed by systematic collation and summary. The study suggests that anti-angiogenic tyrosine kinase inhibitors may induce rare episodes of cholecystitis in specific patient populations. Clinicians should maintain adequate vigilance, conduct close clinical monitoring, and adjust therapeutic regimens in a timely manner to ensure patient safety and optimize prognosis.
MethodsThree transcriptomic cohorts, GSE30528, GSE96804, and GSE104948, comprising 62 DKD and 59 control samples, were integrated for differential expression and weighted gene co-expression network analyses. Candidate genes were prioritized using disease databases, protein–protein interaction analysis, 113 machine-learning algorithm combinations, and SHAP analysis. Model performance was evaluated in GSE30529 and GSE99339. The prioritized genes were then subjected to reverse network pharmacology, followed by FN1 validation in GSE47184 and surface plasmon resonance (SPR). An independently generated mouse single-cell RNA-sequencing dataset comprising 36,819 cells from three DKD and three control mice was subsequently used to localize Fn1 expression. Finally, db/db mouse experiments and an Fn1-overexpression rescue experiment in high-glucose-treated mesangial cells were performed.ResultsWe identified 441 differentially expressed genes, including 197 upregulated and 244 downregulated genes. Intersection analysis yielded 94 candidate genes. The blue WGCNA module contained 1,346 genes and was positively correlated with DKD (r = 0.59, P = 1 × 10–12). The glmBoost model achieved the highest mean area under the receiver operating characteristic curve (0.938), and SHAP analysis prioritized FN1, COL1A2, VCAN, FBN1, and COL4A1. Reverse network pharmacology mapped baicalein only to FN1. GSE47184 independently confirmed the direction of FN1 upregulation in DKD. SPR detected a concentration-dependent interaction between baicalein and immobilized recombinant human FN1, with an apparent KD of 8.04 × 10–5 M. Single-cell analysis localized Fn1 expression to mesangial cells, and subsequent mouse-level pseudobulk analysis showed increased mesangial Fn1 expression in DKD mice. Baicalein reduced serum creatinine and blood urea nitrogen levels, ameliorated renal histopathological injury, and decreased fibronectin and other fibrosis-associated molecules in db/db mice. In mesangial cells, Fn1 overexpression aggravated the high-glucose-induced profibrotic molecular phenotype and partially attenuated the inhibitory effects of baicalein on ECM-associated molecular changes.ConclusionBaicalein attenuated renal injury and ECM remodeling in experimental DKD. FN1 was functionally involved in the profibrotic phenotype and the cellular response to baicalein.
BackgroundAntibody–drug conjugates (ADCs) are increasingly used across breast cancer subtypes, but their postmarketing safety-reporting patterns differ across agents and are difficult to interpret across spontaneous-reporting and clinical settings. We integrated breast-cancer-restricted FDA Adverse Event Reporting System (FAERS) analyses, temporal machine-learning prioritization, and an independent institutional cohort to characterize drug-specific safety patterns across complementary evidence layers.MethodsFAERS quarterly files from 2013Q1 through 2025Q4 were deduplicated and analyzed at the report level. The primary dataset comprised 13,529 breast-cancer primary-suspect reports involving trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), or sacituzumab govitecan; 20,526 all-indication reports were retained for supportive sensitivity analysis. Analyses included clinically reviewed preferred-term disproportionality, 11 prespecified adverse events of special interest (AESIs), intraclass adjusted reporting odds, reported time to onset, and temporally validated exploratory machine-learning models for report-level AESI prioritization. An independent retrospective cohort of 105 patients was analyzed descriptively for clinical contextualization.ResultsThe primary dataset included 3,962 T-DM1, 6,452 T-DXd, and 3,115 sacituzumab govitecan reports. Compared with T-DM1, T-DXd showed higher adjusted reporting odds for interstitial lung disease (ILD)/pneumonitis (adjusted reporting odds ratio [aROR], 3.23; 95% CI, 2.55–4.09) and gastrointestinal toxicity (aROR, 2.45; 95% CI, 2.07–2.90), whereas sacituzumab govitecan showed higher reporting odds for hematologic (aROR, 1.95; 95% CI, 1.67–2.28) and gastrointestinal toxicity (aROR, 2.91; 95% CI, 2.44–3.46). T-DM1 showed higher hepatobiliary reporting odds than both comparators. Temporal-validation AUROC values ranged from 0.593 to 0.772. In the institutional cohort, hepatobiliary toxicity was most frequent with T-DM1 (32.3%), ILD/pneumonitis with T-DXd (12.0%), and hematologic toxicity with sacituzumab govitecan (66.7%).ConclusionThe three ADCs showed distinct breast-cancer FAERS safety-reporting patterns. Machine learning provided exploratory report-level prioritization, while institutional observations provided clinical context. These findings support pharmacovigilance signal prioritization but should not be interpreted as incidence, comparative clinical risk, causal effects, or patient-level toxicity prediction.
Excipients make up the majority of most medicines by mass, yet they are still called “inactive,” still largely qualified against a 2005 guidance, and still assessed product by product with animal studies that answer the wrong questions. The past decade has dismantled the “inactive” assumption: polyethylene glycol and polysorbate anaphylaxis, benzyl alcohol gasping syndrome, propylene glycol acidosis, benzalkonium bronchospasm, and the recurrent diethylene glycol mass poisonings of children all show that excipient risk is real, but that it is contextual rather than intrinsic. I argue that this contextual character makes excipients an almost ideal proving ground for New Approach Methodologies (NAMs). Excipient hazard depends on route, dose, duration, formulation, impurities, and patient population—exactly the variables that exposure science, computational toxicology, and human in vitro systems handle well and that whole-animal testing handles poorly. I propose replacing the test-list mentality with a context-of-use excipient safety passport, sketch where NAMs already carry decisions and where they only inform them and offer a phased implementation agenda. The goal is to convert excipient safety from a static checklist into a human-relevant, exposure-led, mechanistic discipline.
IntroductionInfantile hemangiomas (IH) are the most common childhood vascular tumors, potentially complicated by ulceration and permanent functional or aesthetic sequelae. Current treatments include corticosteroids, β-blockers, and lasers, among others, existing evidence relies predominantly on direct pairwise comparisons. Consequently, the relative benefits and risks across these modalities remain inadequately defined. We conducted a systematic review and network meta-analysis (NMA) evaluating pharmacologic, laser, and combination therapies for IH to establish treatment hierarchies and inform clinical practice and future guidelines.MethodsFollowing a PROSPERO-registered protocol (CRD420261388356), we searched PubMed, Embase, the Cochrane Library, and Web of Science from inception to 1 March 2026, for randomized controlled trials comparing various interventions for IH. The primary endpoint was excellent response rate. Secondary outcomes included other response rates, VAS/HAS changes, healing time, treatment emergent adverse events, and recurrence. After independent risk-of-bias assessment (RoB2) and data extraction, we performed a random-effects NMA. Treatments were ranked using SUCRA probabilities, and evidence certainty was appraised via GRADE and CINeMA.ResultsThe synthesis comprised 25 trials (2044 patients) evaluating 16 distinct interventions. Risk of bias was low in six trials, raised “some concerns” in 14, and high in 5. Overall, the evidence body was of moderate certainty. Regarding the primary endpoint, intralesional bleomycin combined with oral propranolol yielded significantly higher excellent response rates than oral propranolol alone (RR = 1.55, 95% CI 1.28–1.89; high certainty). Topical timolol with intralesional lauromacrogol (RR = 7.98, 95% CI 1.52–41.79) and oral propranolol with corticosteroids (RR = 2.00, 95% CI 1.03–3.88) showed higher excellent response rates, supported by moderate-certainty evidence. No statistically significant differences in adverse-event incidence were detected across evaluated regimens, but the safety data were limited. Oral atenolol was associated with numerically lower recurrence rates compared to oral propranolol, but the difference did not reach statistical significance (RR = 0.64, 95% CI 0.32–1.28; moderate certainty).DiscussionOral propranolol remains the standard of care for IH. However, our analysis shows that some combination regimens showed favorable efficacy for excellent clinical response. Still, sparse comparative data and low-certainty evidence currently obscure the optimal combination strategy. Defining precise risk-benefit profiles requires rigorous head-to-head trials utilizing uniform outcome measures.Systematic Review Registerationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420261388356; Identifier: CRD420261388356.
Background and purposeAtrial fibrillation (AF) is the most prevalent clinical arrhythmia, yet current antiarrhythmic pharmacotherapies have limited efficacy and pose risks of off-target ventricular block. LY294002 was reported to inhibit the ultrarapid delayed-rectifier potassium current (IKur) carried by Kv1.5 channels, a promising atrium-selective therapeutic target for AF. To determine whether LY294002 exhibits functional selectivity for IKur, this study comprehensively examined its inhibitory effects on major counter-target cardiac ion currents.MethodsThe cDNAs encoding the principal pore-forming subunits of major cardiac channels—mediating IKr(Kv11.1), IKs(Kv7.1), IK1(Kir2.1), Ito(Kv4.3), INa(Nav1.5), and ICa-L(Cav1.2)—were heterologously expressed in Chinese hamster ovary cells. The inhibitory effects of LY294002 on these channels were assessed using the whole-cell patch-clamp technique. Furthermore, molecular docking analysis was conducted to characterize the structural interactions and binding configurations of LY294002 with Kv1.5.ResultsLY294002 inhibited all investigated currents in a concentration-dependent manner, albeit with markedly varying potencies. Based on Hill equation fits, the half-maximal inhibitory concentration (IC50) values for LY294002 on IKs, IKr, Ito, IK1, INa, and ICa-L were 21.5, 26.3, 55.9, 81.5, 131.6, and 46.5 μM, respectively. Notably, the lowest off-target IC50 (IKs) was approximately 2.7-fold higher than the previously reported IC50 for IKur (7.9 μM). Molecular docking analysis revealed that LY294002 bound within the internal cavity of Kv1.5, with predicted binding affinity of −8.3 kcalImol−1.ConclusionThe inhibitory potency of LY294002 against IKur is substantially higher than its potency against other major cardiac currents, demonstrating its potential to act as a selective IKur blocker. Structurally, this preferential inhibition is likely mediated by the compound’s favorable occupancy of key gating or pore regions unique to the Kv1.5 channel conformation.
BackgroundPrimary membranous nephropathy (PMN) and minimal change disease (MCD) are common causes of nephrotic syndrome in adults and represent the two diseases in which anti-CD20 monoclonal antibodies are most widely used. Previous studies have demonstrated that the clinical efficacy of rituximab (RTX) is influenced by the baseline level of proteinuria. Obinutuzumab is a novel anti-CD20 monoclonal antibody with superior efficacy and safety to RTX. However, whether its therapeutic efficacy in PMN and MCD is similarly influenced by baseline proteinuria remains unclear.MethodsWe recruited 40 patients with PMN and 42 patients with MCD confirmed by renal biopsy. All patients received obinutuzumab. All patients with PMN were divided into two groups based on baseline proteinuria: ≤8 g/d group and >8 g/d group. MCD patients were divided into two groups: the GC + obinutuzumab group and the Obinutuzumab group. Compared the clinical outcomes and side-effects of patients in different groups after a 12-month follow-up.ResultsAmong patients with PMN and MCD, no statistically significant differences were observed between the two groups in complete remission (CR) rates, partial remission (PR) rates, or composite remission rates at the first, third, sixth, ninth, and 12th months. Kaplan-Meier analysis showed that there is no significant difference in cumulative CR rates and composite remission rates between two groups in patients with PMN and patients with MCD. At the end of follow-up, all patients exhibited a significant reduction in proteinuria, an increase in serum albumin, and no deterioration in kidney function. Furthermore, the safety profile of obinutuzumab was favorable in this study.ConclusionOur findings suggest that the efficacy of obinutuzumab in PMN and MCD is not affected by the baseline level of proteinuria. Besides, obinutuzumab monotherapy has shown satisfactory therapeutic effects in both PMN and MCD.
Liver cancer is one of the most common and highly lethal malignancies worldwide, and current therapeutic strategies remain limited, posing significant clinical challenges. Thermal processing of natural products is not only used for the extraction of active constituents, but may also induce structural reconstruction and bioactivity transformation of endogenous components. Recent studies have demonstrated that certain natural products can generate carbon dots (CDs) with specific biological activities under high-temperature conditions, suggesting that these nanoparticles may serve as novel active components formed during thermal processing. Phellinus igniarius, a traditional medicinal fungus, possesses anti-inflammatory and immunomodulatory activities. However, the formation of carbon dots during its thermal processing and their biological functions have not been systematically investigated. In this study, Phellinus igniarius-derived carbon dots (PI-CDs) were synthesized using a hydrothermal method, and their antitumor activities and underlying mechanisms were systematically evaluated both in vitro and in vivo. The results showed that PI-CDs exhibited uniform nanoscale morphology with good dispersibility. In vitro experiments demonstrated that PI-CDs significantly inhibited the viability, migration, and invasion of liver cancer cells in a concentration-dependent manner. Transcriptomic analysis revealed significant enrichment of MAPK signaling and apoptosis-related pathways, which was further supported by increased phosphorylation of p38 and JNK. Mechanistically, PI-CDs induced intracellular reactive oxygen species (ROS) accumulation, promoted mitochondrial membrane depolarization, and triggered apoptotic cell death. Furthermore, PI-CDs effectively suppressed tumor growth in vivo xenograft model without obvious systemic toxicity. Collectively, these findings suggest that PI-CDs exert antitumor effects through oxidative stress-associated MAPK signaling and mitochondria-dependent apoptosis. This study demonstrates that carbon dots generated from the medicinal fungus Phellinus igniarius possess significant anti-liver cancer activity and reveals a ROS/MAPK-associated mechanism underlying their biological effects. More importantly, our findings highlight thermal processing as a promising strategy for transforming traditional medicinal resources into functional nanomaterials with intrinsic therapeutic potential, thereby providing a new perspective for the development of natural product-derived nanomedicines for cancer treatment.
