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Background: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, and its dysregulation is implicated in HF pathophysiology. Traditional Chinese Medicine (TCM) has been investigated in HF management, but a systematic synthesis of preclinical evidence on TCM-mediated AMPK modulation is lacking. Methods: PubMed and Web of Science were searched from January 2020 to December 2025 using a comprehensive strategy combining terms for AMPK, HF, and TCM. Studies were included if they were original research investigating TCM-derived compounds or formulas in HF models and reporting AMPK modulation. Study quality and evidence levels were assessed using predefined criteria. The review was conducted in accordance with PRISMA 2020 guidelines. Results: Of 243 records identified, 56 studies met the inclusion criteria (7 from database search and 49 from manual screening). Direct evidence for AMPK-dependent cardioprotection was limited. Cinnamaldehyde and paeoniflorin showed the most rigorous validation with confirmed target engagement and loss-of-function rescue. Berberine, crocin, ginsenoside Rb1, and honokiol demonstrated pathway-specific effects validated by pharmacological or genetic approaches. Most complex herbal formulas provided correlative evidence only, with Fuyu Decoction being a notable exception where AMPK agonist EX229 confirmed pathway involvement. Conclusions: Current evidence for TCM-mediated AMPK modulation in HF remains predominantly preliminary and correlative. Future research should prioritize causality validation using genetic models and human-relevant systems.

Background: Ischemic stroke (IS) is a significant cause of global mortality and disability. Yiqi Huoxue Jieyu granules (YHJGs) show therapeutic potential for IS, but their mechanisms remain unclear. This study investigated YHJGs’ effects through network pharmacology, molecular docking, and experimental validation. Methods: Active YHJG components and IS targets were identified from TCMSP, GeneCards, and DisGeNET databases. Network analysis and molecular docking (AutoDock Vina) were performed. In vivo studies used 72 male Sprague-Dawley rats (MCAO model) divided into sham, model, nimodipine (10.8 mg/kg), and three YHJG dose groups (0.72, 1.44, 2.88 g/kg). Assessments included neurological scores, TTC staining, histopathology, and molecular analyses (qPCR/Western blot). Results: Network analysis identified 256 shared targets between YHJG and IS, with PI3K-AKT and MAPK as key pathways. Molecular docking showed strong binding between YHJG compounds (e.g., quercetin) and core targets (AKT1, ERK1/2). YHJG treatment significantly improved neurological function (p < 0.01), reduced infarct volume (p < 0.01), and attenuated neuronal damage. The expression of IL-1β, TNF-α, IL-6, AKT1, and pERK1/2/ERK1/2 significantly increased in the MCAO group (p < 0.01), while YHJG treatment significantly reduced their expression (p < 0.01). PPAR-γ expression significantly increased in the YHJG-H group (p < 0.01). Conclusions: The expression of IL-1β, TNF-α, IL-6, AKT1, and pERK1/2/ERK1/2 significantly increased in the MCAO group, while YHJG treatment significantly reduced their expression. PPAR-γ expression significantly increased in the YHJG-H group. YHJGs could treat IS through diverse ingredients, targets, and pathways by inhibiting inflammatory indices and AKT1 expression, and reducing ERK1/2 phosphorylation.

Chronic inflammation linked to atherosclerosis is closely related to a trained immunoregulatory network. Traditional studies primarily focus on the pro-inflammatory memory of monocytes, they frequently neglect important aspects such as the cell’s plasticity, interactions between different organs, and the dynamic regulation of the metabolism-vascular axis. This review presents four novel frameworks, including the trained immunity plasticity spectrum model. It demonstrates how monocytes maintain a dynamic balance between pro-inflammatory, tolerogenic, and anti-inflammatory phenotypes, regulated by mTOR/AMPK signaling and competitive histone modifications. The trained immunity–metabolism–vascular axis shows that metabolic disorders can change the way immune memory is formed. They achieve this by modifying the vascular microenvironment through epigenetic changes, exosomes, and products of mitochondrial stress. The cross-organ trained immunity framework reveals how remote epigenetic communication between the bone marrow, gut, and liver influences the development of monocytes. Finally, dynamic immune reprogramming integrates CRISPR-based epigenetic editing, metabolism-focused interventions, and AI-driven multi-omics predictions. This approach signifies a major transition from simply alleviating symptoms to accurately reshaping immune memory. This review reinterprets the immunometabolic mechanisms of atherosclerosis. It also lays the foundation for personalized therapies enhanced by AI and explores new interdisciplinary research avenues.

Helper T cells 17 (Th17) and their effector cytokine, interleukin-17A (IL-17A), play a dual role in immune homeostasis. On one hand, they are essential in defense against extracellular pathogens, such as bacteria and fungi, by inducing chemokine production and recruiting neutrophils. On the other hand, their dysregulated activity is strongly linked to autoimmune and inflammatory disorders, including multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and others. This article reviews the molecular mechanisms regulating Th17 differentiation and function, emphasizing the role of transcription factors like RORγt and RORα, as well as the influence of cytokines such as IL-6, IL-23, and TGF-β. Additionally, it explores the imbalance between pro-inflammatory Th17 cells and regulatory T cells (Tregs), a critical axis in the pathogenesis of autoimmune and neuroinflammatory diseases. In the context of neurological disorders, Th17 cells can infiltrate the central nervous system (CNS), where they contribute to neuroinflammation by activating microglia and astrocytes, exacerbating damage in conditions such as multiple sclerosis, traumatic brain injury, and neurodegenerative diseases. Emerging therapies, including anti-IL-17 monoclonal antibodies and natural modulators, are discussed as potential strategies to restore the Th17/Treg balance without compromising protective immunity. Finally, the need for further research is highlighted to elucidate the specific mechanisms of Th17 infiltration into the CNS, their interaction with the gut microbiota, and the development of personalized therapies. The integration of immunological, metabolic, and environmental approaches offers promising perspectives for the treatment of Th17/IL-17-mediated diseases.

Many traditional Chinese medicines, including Danhong injection (DHI), can be used to treat cerebral ischemia-reperfusion injury and have neuroprotective effects on the brain; however, few studies have explored the mechanism by which this effect is generated. In this study, we investigated the neuroprotective effect of DHI against cerebral ischemia-reperfusion injury mediated via the PI3K-Akt signaling pathway. After establishing the model of middle cerebral artery occlusion (MCAO), 60 male Sprague-Dawley rats were allocated to six groups as follows: sham, MCAO, DHI (MCAO + DHI), LY294002 (MCAO + LY294002 [PI3K-Akt pathway specific inhibitor]), DHI + LY294002 (MCAO + DHI + LY294002), and NMDP + LY294002 (MCAO + NMDP [nimodipine] + LY294002). Hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining were used to evaluate the pathological changes of brain tissue and the degree of neuronal apoptosis. Real-time quantitative polymerase chain reaction (qRT-PCR), western blot analysis and enzyme-linked immunosorbent assays were used to measure the expression of Bad, Bax, Bcl-2, Bim, P53, MDM2, Akt, PI3K, p-Akt, p-PI3K, and Cyt-C. Compared with the MCAO group, brain tissue cell apoptosis was significantly reduced in the DHI group, and the brain function score was significantly improved. In addition, the expression of pro-apoptotic factors (Bad, Bax, and Bim) was significantly downregulated in the DHI group, while expression of the anti-apoptotic factor Bcl-2 was significantly upregulated, and expression of the apoptotic gene p53 was also significantly attenuated. Moreover, this neuroprotective effect was attenuated by the PI3K-Akt signaling pathway inhibitor (LY294002). Thus, our results confirmed the neuroprotective effects of DHI in rats with ischemia-reperfusion injury and indicate that these effects on the brain are partly generated by activation of the PI3K-Akt signaling pathway.

Traumatic brain injury (TBI) leads to structural damage in the brain, and is one of the major causes of disability and death in the world. Herein, we developed a composite injectable hydrogel (HA/Gel) composed of hyaluronic acid (HA) and gelatin (Gel), loaded with vascular endothelial growth factor (VEGF) and salvianolic acid B (SAB) for treatment of TBI. The HA/Gel hydrogels were formed by the coupling of phenol-rich tyramine-modified HA (HA-TA) and tyramine-modified Gel (Gel-TA) catalyzed by horseradish peroxidase (HRP) in the presence of hydrogen peroxide (H2O2). SEM results showed that HA/Gel hydrogel had a porous structure. Rheological test results showed that the hydrogel possessed appropriate rheological properties, and UV spectrophotometry results showed that the hydrogel exhibited excellent SAB release performance. The results of LIVE/DEAD staining, CCK-8 and Phalloidin/DAPI fluorescence staining showed that the HA/Gel hydrogel possessed good cell biocompatibility. Moreover, the hydrogels loaded with SAB and VEGF (HA/Gel/SAB/VEGF) could effectively promote the proliferation of bone marrow mesenchymal stem cells (BMSCs). In addition, the results of H&E staining, CD31 and α-SMA immunofluorescence staining showed that the HA/Gel/SAB/VEGF hydrogel possessed good in vivo biocompatibility and pro-angiogenic ability. Furthermore, immunohistochemical results showed that the injection of HA/Gel/SAB/VEGF hydrogel to the injury site could effectively reduce the volume of defective tissues in traumatic brain injured mice. Our results suggest that the injection of HA/Gel hydrogel loaded with SAB and VEGF might provide a new approach for therapeutic brain tissue repair after traumatic brain injury.

Ischemic stroke is a worldwide complex brain disease that results in numerous disabilities and deaths. It leads to the deprivation of oxygen and glucose, which causes energy failure and neuronal death. The activation of astrocytes contributes to neuronal damage or repair after brain ischemia/reperfusion, although astrocytes get little attention as potential drug targets. This study investigated the protective effects of Astragaloside IV (AS-IV) on oxygen glucose deprivation/reoxygenation (OGD/R)-induced damage in rat primary cultured astrocytes and the underlying molecular mechanism. The results showed that compared with the control group, astrocytes under OGD/R exposure significantly decreased cell viability and increased the number of apoptotic cells, whereas AS-IV evidently protected the astrocytes against OGD/R-induced cell damage. In addition, low and medium concentrations of AS-IV can promote the increase of intracellular superoxide dismutase (SOD) level, as well as restored the morphological changes caused by OGD/R exposure. Supplementation with AS-IV after OGD/R exposure promoted the expression of oxidation and apoptosis indexes and further study demonstrated that AS-IV inhibited CXCR4 receptor and downregulated the activation of p-JNK/JNK pathway, which suppressed the expression of Bax/Bcl-2, and finally uprising Nrf2/Keap1 signaling. In conclusion, these findings revealed that AS-IV protected against OGD/R-induced astrocytes through inhibiting oxidative stress and apoptotic pathways.

Background/Objective: Myocardial fibrosis (MF) is a prevalent pathological endpoint in various heart diseases, characterized by extracellular matrix (ECM) dysregulation and oxidative stress. Hyperoside (Hyp) plays a role in regulating cardiac oxidative stress and fibrosis. This study aimed to elucidate whether Hyp regulates isoproterenol (ISO)-induced MF in mice by modulating the GATA4/HIF-1α signaling pathway and reducing oxidative stress. Methods: The binding affinity of Hyp to GATA4 and HIF-1α was assessed through molecular docking and dynamics simulation. The MF model of mice was established by subcutaneous injection of ISO. Cardiac function was measured by echocardiography. Myocardial injury and collagen deposition were examined using H&E and Sirius red staining. Levels of fibrosis markers, oxidative stress indicators, and GATA4/HIF-1α pathway indicators in serum and heart tissue were quantified by ELISA, Western blot, RT-qPCR and flow cytometry. The distribution of myocardial marker proteins was visualized by immunofluorescence and immunohistochemistry. Results: Molecular docking revealed high binding affinity of Hyp to GATA4 and HIF-1α (binding energies < −5.0 kcal·mol−1), and dynamics simulation showed that the complex’s structure remained stable over 100 nanoseconds (RMSD < 0.1 nm). High-dose Hyp (36 mg/kg) significantly improved cardiac function, myocardial injury, collagen deposition, and inflammatory infiltration in MF mice. Molecularly, Hyp effectively reduces oxidative stress and fibrosis through upregulating GATA4 and downregulating HIF-1α. Conclusions: Hyp suppresses oxidative stress by activating the GATA4/HIF-1α pathway, presenting a promising therapeutic target for the treatment of MF.

Guanxin Jieyu Granules, a novel traditional Chinese medicine (TCM) in development, targets stable angina pectoris with accompanying anxiety. To improve stability, its volatile oil components—including borneol—are stabilized via β-cyclodextrin inclusion. In compliance with ICH Q14 guidelines, a gas chromatography (GC) analytical method was developed, incorporating knowledge management, risk management, experimental design, and results analysis, as well as performance evaluation of the analytical method. Accelerated Destructive Degradation Tests (ADDTs) using this method revealed a dramatic stability enhancement from β-cyclodextrin encapsulation. At 25 °C over 730 days, the inclusion complex showed only a 1.10% probability of failure (defined as ≥ 5% content loss), compared to 88.50% for the physical mixture. These results underscore the critical role of cyclodextrin inclusion in preserving volatile TCM constituents.

Objective: The objective is to investigate and optimize the β-cyclodextrin inclusion process for volatile oils in Ligusticum Chuanxiong–Vinegar cyperus rotundus based on Quality by Design (QbD) principles. Methods: First, ligustilide and α-cyperone were selected as inclusion process indicator components using high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS). Single-factor experiments were conducted to preselect the inclusion speed based on ligustilide and α-cyperone content as evaluation criteria. Subsequently, using the inclusion rates of ligustilide and α-cyperone as evaluation criteria, a factorial design was employed to investigate the inclusion temperature, inclusion time, and the volume ratio of β-cyclodextrin solution to essential oil, thereby optimizing the inclusion process parameters. Finally, the inclusion process parameters were validated, and the inclusion rates were determined. The obtained inclusion complexes were characterized by microscopic analysis, Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction analysis (XRD), and differential scanning calorimetry (DSC). Furthermore, phase dissolution studies and molecular docking were employed for confirmation. Results: The optimal process parameters were determined as follows: encapsulation speed of 300 rpm, β-cyclodextrin solution excess of 6, encapsulation time of 2.5~3 h, and encapsulation temperature of 30~35 °C. The encapsulation rates for ligustilide and α-cyperone in the resulting inclusion complex were 63.15~64.74% and 71.33~76.89%, respectively. Structural characterization confirmed the formation of the inclusion complex. Conclusions: This inclusion process is reliable and provides a reference for preparing β-cyclodextrin inclusion complexes of volatile oils in formulations containing the Chuanxiong–Vinegar cyperus rotundus drug pair.