Alpinia oxyphylla Miq. (i.e., A. oxyphylla), a traditional Chinese medicine, can exert neuroprotective effects in ameliorating mild cognitive impairment and improving the pathological hallmarks of Alzheimer’s disease (AD). Here, 50 active compounds and 164 putative targets were collected and identified with 251 clinically tested AD-associated target proteins using network pharmacology approaches. Based on the Gene Ontology/Kyoto Encyclopedia of Genes and Genomes pathway enrichments, the compound-target-pathway-disease/protein–protein interaction network constructions, and the network topological analysis, we concluded that A. oxyphylla may have neuroprotective effects by regulating neurotransmitter function, as well as brain plasticity in neuronal networks. Moreover, closely-related AD proteins, including the amyloid-beta precursor protein, the estrogen receptor 1, acetylcholinesterase, and nitric oxide synthase 2, were selected as the bottleneck nodes of network for further verification by molecular docking. Our analytical results demonstrated that terpene, as the main compound of A. oxyphylla extract, exerts neuroprotective effects, providing new insights into the development of a natural therapy for the prevention and treatment of AD.

Alzheimer’s disease (AD) is a brain disease with a peculiarity of multiformity and an insidious onset. Multiple-target drugs, especially Chinese traditional medicine, have achieved a measure of success in AD treatment. Evodia rutaecarpa (Juss.) Benth. (Wuzhuyu, WZY, i.e., E. rutaecarpa), a traditional Chinese herb, has been identified as an effective drug to cure migraines. To our surprise, our in silico study showed that rather than migraines, Alzheimer’s disease was the primary disease to which the E. rutaecarpa active compounds were targeted. Correspondingly, a behavioral experiment showed that E. rutaecarpa extract could improve impairments in learning and memory in AD model mice. However, the mechanism underlying the way that E. rutaecarpa compounds target AD is still not clear. For this purpose, we employed methods of pharmacology networking and molecular docking to explore this mechanism. We found that E. rutaecarpa showed significant AD-targeting characteristics, and alkaloids of E. rutaecarpa played the main role in binding to the key nodes of AD. Our research detected that E. rutaecarpa affects the pathologic development of AD through the serotonergic synapse signaling pathway (SLC6A4), hormones (PTGS2, ESR1, AR), anti-neuroinflammation (SRC, TNF, NOS3), transcription regulation (NR3C1), and molecular chaperones (HSP90AA1), especially in the key nodes of PTGS2, AR, SLCA64, and SRC. Graveoline, 5-methoxy-N, N-dimethyltryptamine, dehydroevodiamine, and goshuyuamide II in E. rutaecarpa show stronger binding affinities to these key proteins than currently known preclinical and clinical drugs, showing a great potential to be developed as lead molecules for treating AD.

Tissue plasminogen activator (tPA) remains the only drug approved for acute ischemic stroke (AIS). However, its clinical application is limited by a narrow therapeutic window, hemorrhagic transformation (HT), and neurotoxicity. Recently, considerable progress has been made in exploring the protective mechanisms of Chinese herbal medicines (CHMs) against AIS, and several of these agents have been reported to improve the therapeutic efficacy of tPA. This review explores the underlying mechanisms of adverse effects induced by tPA and summarizes the CHMs that have been demonstrated to mitigate these outcomes, with the aim of providing insights for the development of additional CHMs as adjuvants to tPA. In accordance with the PRISMA guidelines, a comprehensive literature search was conducted across 6 scientific databases (PubMed, CNKI, Wanfang, CQVIP, Embase, and Cochrane Library) to identify studies published between January 2000 and November 2025, focusing on tPA thrombolysis, combined tPA and CHMs, and the application of CHMs in ischemic stroke. Preclinical studies have identified 17 types of CHMs that alleviate the adverse effects of tPA-mediated thrombolysis by inhibiting inflammation, oxidative stress, matrix metalloproteinase (MMP) activation, blood-brain barrier (BBB) injury, or cell death. Among these, 13 types of CHMs exert a protective effect on the BBB. Furthermore, 21 types of CHMs have shown clinical efficacy in improving outcomes of tPA treatment. Notably, Danhong injection (DHI), Butylphthalide, Ginkgo Biloba extract and Shuxuening injection exhibit substantial potential for clinical application. Specifically, DHI has demonstrated consistent benefits in both preclinical and clinical settings, whereas Butylphthalide, Ginkgo Biloba extract and Shuxuening injection have demonstrated clinical efficacy across multiple independent trials. However, similar to other CHMs, these agents remain limited by insufficient investigation of their underlying mechanisms of action. CHMs hold considerable potential as ancillary treatments for tPA, due to their unique advantage of multiple therapeutic effects. Future research should prioritize clinical validation to facilitate the integration of CHMs into modern therapeutic regimens as adjuvants to tPA.

Environmental contaminants are increasingly recognized as key risk factors for chronic diseases, including neurodegenerative disorders. Tris(2-butoxyethyl) phosphate (TBOEP) is a representative organophosphate ester that is widely detected in environmental matrices and human tissues, yet whether chronic exposure to environmentally relevant concentrations of TBOEP drives progressive neurodegenerative pathology remains unclear. Here, using Caenorhabditis elegans as a model organism, we performed a 20-day, time-resolved life-cycle exposure to environmentally relevant concentrations of TBOEP (50-5000 ng/L) to systematically assess chronic neurotoxicity. TBOEP exposure induced progressive, age-dependent neurodegenerative phenotypes. Early effects were characterized by selective impairment of locomotor performance starting at 50 ng/L, followed by broader systemic toxicity, including growth retardation, feeding deficits, and accelerated aging. Consistent with a Parkinson's disease-like trajectory, hallmark pathological features progressively worsened with exposure duration, including dopamine-dependent functional impairment, while α-synuclein aggregation and dopaminergic neuronal impairment were mainly observed at concentrations ≥ 500 ng/L. Mechanistically, time-resolved transcriptomics identified the lysosomal pathway as a central target of TBOEP. Functional assays further confirmed that TBOEP significantly impaired lysosomal acidification. Pharmacological validation with the lysosomal chaperone ambroxol showed that improving lysosomal function mitigated TBOEP-induced neurotoxicity, supporting lysosomal dysfunction as a primary contributor to the observed pathology. Collectively, our findings identify TBOEP as a potential environmental risk factor for neurodegeneration, providing important insights that could inform further studies assessing the environmental health risks of organophosphate esters.