This study aimed to investigate the mechanism of liquiritin (LQ) in the improvement of ventricular remodeling (VR) after acute myocardial infarction (AMI). Molecular docking was used to predict the binding affinity of liquiritin to thioredoxin-interacting protein (TXNIP). After 2 weeks of modeling, the rats were randomly divided into a model group, a low-dose liquiritin group (20 mg/kg LQ), and a high-dose liquiritin group (40 mg/kg LQ). Liquiritin was administered by gavage once a day, and the sham group and model group were given the same volume of 0.5% sodium carboxymethylcellulose (CMC-Na), with intervention of 4 consecutive weeks. Echocardiography was employed to detect the cardiac function, HE staining was used to observe cardiological changes, ELISA was used to detect the activity of serum creatine kinase-MB (CK-MB) activity, and the colorimetric method was adopted to detect serum malondialdehyde (MDA), total superoxide dismutase (T-SOD) and catalase (CAT) activities. RT-qPCR was used to detect the gene expressions of TXNIP, thioredoxin (TRX) and NACHT, LRR, and PYD domains-containing protein 3(NLRP3). Western blot was used to detect the protein expressions of TXNIP, TRX and NLRP3 in rat myocardial tissue. Molecular docking results showed that liquiritin had a good binding affinity to TNXIP target. After 20 and 40 mg/kg liquiritin intervention, the levels of ejection fraction (EF) and fractional shortening (FS) were significantly increased (P<0.01), and the levels of LVIDs, LVIDd, LVESV, and LVEDV were decreased (P<0.01). The myocardial structure was significantly improved, the cell arrangement tended to be regular, and the area of inflammatory cell infiltration and necrosis was reduced. Liquiritin significantly reduced the level of CK-MB (P<0.01), decreased the activity of MDA, and increased the activities of CAT and T-SOD (P<0.01). Liquiritin effectively inhibited the overexpression of TXNIP and NLRP3 genes and proteins, and enhanced the expression of TRX genes and proteins in the myocardial tissues of AMI rats. In conclusion, liquiritin has a regulatory effect on the TXNIP/TRX signaling pathway, inhibits the activation of the NLRP3 inflammasome, and thus improves ventricular remodeling after acute myocardial infarction.

Cardiotoxicity induced by antineoplastic agents is an important factor affecting the prognosis of cancer patients. This article systematically summarizes the clinical manifestations of cardiotoxicity caused by chemotherapeutic drugs, molecular targeted cancer therapies, and immunotherapeutic drugs, and identifies the core injury mechanisms, including cardiomyocyte apoptosis, oxidative stress, and mitochondrial dysfunction. In Traditional Chinese Medicine (TCM) theory, anticancer drug-induced cardiotoxicity falls under the category of “heat toxins” characterized by dual deficiency of qi and blood, upward flaming of heart heat, stagnation of the heart vessels, and meridian obstruction induced by phlegm-dampness. Therefore, by reviewing the preventive and therapeutic effects and the underlying mechanisms of tonic medicines, interior heat-clearing medicines, blood-circulating and stasis-resolving medicines, phlegm-transforming, cough-suppressing and panting-relieving medicines, and interior-warming medicines, this paper concludes that TCM prevention and treatment of this condition adheres to the formulation principle of “reinforcing healthy qi, removing toxins, and resolving blood stasis”. Its mechanisms of action—including antioxidation effects, regulation of autophagic balance, antagonism of inflammatory responses, and improvement of microcirculation—are highly consistent with modern medical treatment strategies (e.g., dexrazoxane for inhibiting iron-dependent oxidative stress, statins for anti-inflammatory effects). This study provides theoretical support and practical guidance for the collaborative and precise prevention and treatment of anticancer drug-induced cardiotoxicity through the integration of traditional Chinese and Western medicine.

Background/Aims: Lenvatinib resistance remains a critical barrier in advanced hepatocellular carcinoma (HCC) therapy. However, the underlying mechanisms and strategies for reversing resistance remain incompletely understood. Methods: Integrated transcriptomics of lenvatinib-resistant patient tumors and an acquired-resistance murine model identified a novel macrophage subpopulation. Functional validation employed CRISPR-SAM screening, conditioned medium (CM) assays, subcutaneous/orthotopic xenografts, patient-derived organoids (PDOs), and patient-derived xenografts (PDXs). Mechanistic studies included ChIP-qPCR, co-immunoprecipitation, and pharmacologic targeting. Clinical relevance was assessed in a retrospective cohort. Results: Resistant HCC exhibited significant enrichment of a COLEC12high TAM subset , which correlated with poor survival and treatment response. These TAMs secreted neuregulin-1 (NRG1) , activating HER2/HER3-AKT signaling in tumor cells to drive cancer stemness and lenvatinib resistance. Mechanistically, in TAMs COLEC12 sequestered STAT1 in the cytoplasm, preventing its phosphorylation, and thereby derepressing STAT3-mediated NRG1 transcription. Depletion of NRG1 reversed the stemness phenotypes and resensitized tumors to lenvatinib both in vitro and in vivo. Clinically, high NRG1 expression predicted an inferior lenvatinib response and shorter survival. Crucially, the bispecific anti-HER2/HER3 antibody zenocutuzumab restored lenvatinib efficacy in PDOs, PDXs, and murine models. Conclusions Our work establishes the COLEC12high TAM/NRG1 axis as a master regulator of therapeutic resistance and identifies NRG1 as a predictive biomarker, providing a clinically actionable strategy to overcome lenvatinib resistance in HCC.

To analyze the clinical and genetic features of oculopharyngodistal myopathy (OPDM) patients and compare the phenotypic differences among various causative genes.

ObjectiveThis study employs a special conformational engineering (CE) technology to construct an α-chymotrypsin-like active center, which includes a catalytic triad, an oxyanion hole, and a substrate-binding site, on silver nanoparticles (AgNPs), thereby creating an AgNP-based artificial hydrolase with high catalytic activity. This study provides a new approach for the design of highly efficient artificial enzymes and enzyme-mimicking. MethodsAgNPs were chosen as the scaffold to build the an α-chymotrypsin-like active center. A special CE procedure enables the designed peptide, Triad5, to adopt an α‑helical conformation on AgNPs, with the key catalytic residues located on one side of the α-helix forming a catalytic active center with a catalytic triad, an oxyanion hole, and a substrate-binding site. The CE procedure consists of three steps, including conformation induction via trifluoroethanol (TFE), conformation stabilization on AgNPs via Ag-S bonds, and TFE removal via lyophilization. Circular dichroism (CD) spectra were used to confirm the formation and stabilization of the α-helix conformation. Mutations of the key residues combined with stopped-flow kinetic experiments were used to demonstrate the indispensability of each key residue and the synergistic effects among the catalytic triad, the oxyanion hole, and the substrate-binding site. ResultsCD spectra show that the designed Triad5 alone is in random coil conformation; when conjugated on AgNPs, Triad5 still remains largely unstructured; but after the CE treatment, Triad5 adopts a typical α-helical conformation on AgNPs as designed, thus produces an AgNP-based artificial hydrolase, Silverzyme. Silverzyme exhibits extremely high hydrolytic activity towards p-nitrophenyl acetate (p-NPA), with an extremely high catalytic turnover number per active site of 3.5 s^-1, which is even higher than that of α-chymotrypsin. As a comparison, the AgNP-Triad5 conjugate without CE treatment shows much lower catalytic activity than Silverzyme, highlighting the important role of the right conformation of the active center for the catalytic activity and the power of the CE treatment. When the key residues of the catalytic triad of Silverzyme were mutated to alanine, the overall catalytic efficiency of this mutant dropped by about 2 orders of magnitude, unambiguously demonstrating the key role of the designed catalytic triad. Similarly, when the residues for the oxyanion hole were deleted, the mutant with the intact catalytic triad also showed significantly decreased catalytic activity, highlighting the indispensable role of the oxyanion hole for the catalytic activity. Unexpectedly, when both the catalytic triad and the oxyanion hole were kept intact, a slight change of the binding site also resulted in significantly decreased catalytic activity, indicating that the designed binding site is at the right position to align the substrate in the right orientation in the active center for catalytic hydrolysis. These results confirm the synergy among the catalytic triad, the oxyanion hole, and the substrate-binding site, indicating successful mimicking of the active center of α-chymotrypsin. Moreover, Silverzyme shows better thermal stability than α-chymotrypsin, and can even hydrolyze the tough non-activated ester diethyl phthalate, a priority pollutant by the United States Environmental Protection Agency (USEPA). ConclusionThis study successfully mimicked the complex catalytic active center of α-chymotrypsin using a conformational engineering strategy, and produced a highly active artificial hydrolase with a well-defined structure and catalytic mechanism. The findings highlight the significant potential of conformational engineering.

ObjectiveThe present study aimed to investigate alterations in white matter microstructure and spontaneous neural activity in male college smokers, and to further explore their associations with nicotine dependence. Given that adolescence and early adulthood represent critical periods for brain maturation, particularly for white matter development, understanding the neural correlates of smoking behavior during this stage is of substantial importance for both neuroscience and public health. MethodsA total of 115 male undergraduate students were initially recruited for this study. After quality control and exclusion procedures, 52 male college smokers and 42 demographically matched healthy non-smokers were included in the final analysis. All participants underwent multimodal magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI) and resting-state functional MRI (rs-fMRI). White matter fiber tracts were reconstructed using the automated fiber quantification (AFQ) method, which enables precise identification and quantification of major fiber bundles. Eighteen major white matter tracts were segmented for each participant. Along the core trajectory of each tract, 100 equidistant nodes were sampled. Fractional anisotropy (FA) was calculated at each node to assess white matter microstructural integrity, while amplitude of low-frequency fluctuation (ALFF) was computed to evaluate spontaneous neural activity within white matter tracts. Between-group differences in FA and ALFF were assessed using two-sample t-tests, with appropriate corrections applied for multiple comparisons. Furthermore, Pearson correlation analyses were conducted to examine the relationships between imaging-derived metrics (FA and ALFF values in regions showing significant group differences) and nicotine dependence severity, as measured by the Fagerström test for nicotine dependence (FTND). ResultsCompared with healthy non-smokers, male college smokers exhibited significantly increased FA values in several white matter tracts, including the left thalamic radiation, right corticospinal tract, forceps major of the corpus callosum, left uncinate fasciculus, and right arcuate fasciculus. These findings suggest altered microstructural organization or increased directional coherence within these pathways. In addition, smokers demonstrated significantly elevated ALFF values in the forceps major, right uncinate fasciculus, and left arcuate fasciculus, indicating enhanced spontaneous neural activity in these white matter regions. Correlation analyses revealed that FA values in the left thalamic radiation and right corticospinal tract were negatively correlated with FTND scores, suggesting that higher levels of nicotine dependence were associated with reduced microstructural integrity or altered fiber organization in these regions. In contrast, ALFF values in the forceps major and right uncinate fasciculus were positively correlated with FTND scores, indicating that greater nicotine dependence was associated with increased spontaneous neural activity in specific white matter pathways. ConclusionThe present study provides evidence that male college smokers exhibit distinct alterations in both white matter microstructure and functional activity. These abnormalities are not uniformly distributed but rather localized to specific fiber tracts implicated in sensorimotor processing, interhemispheric communication, and higher-order cognitive and emotional regulation. Importantly, the observed associations between imaging metrics and nicotine dependence severity suggest that these structural and functional alterations may reflect neurobiological mechanisms underlying addiction. The combination of AFQ-based tract profiling and multimodal MRI offers a sensitive approach for detecting subtle changes along white matter pathways, highlighting its potential utility in identifying neuroimaging biomarkers of nicotine dependence. Overall, these findings indicate that smoking during early adulthood may disrupt ongoing white matter maturation, potentially leading to long-term consequences for brain function. This study provides novel insights into the neural basis of nicotine dependence and underscores the importance of early intervention and prevention strategies targeting young smokers.

ObjectiveTo clarify whether METTL14 mediates the core role of acupuncture at Neiguan (PC6) in promoting myelination and improving behavior in young autistic rats through gene intervention technology. MethodsThe ASD model was established by intraperitoneal injection of valproic acid (VPA) in pregnant rats. Male offspring were intracerebroventricularly injected with adenovirus-packaged METTL14 shRNA (sh-METTL14) or its control (sh-NC) on postnatal day 1, with a model group set as well. Subsequently, the juvenile rats were divided into model group, acupuncture group, acupuncture+sh-NC group, and acupuncture+sh-METTL14 group. The acupuncture group received acupuncture at Neiguan (PC6) from postnatal day 7, once daily for 21 consecutive days. Neurobehavioral changes were evaluated by behavioral tests; METTL14 knockdown efficiency and the expression of METTL14, METTL3, and PTEN were detected by quantitative real-time PCR (qRT-PCR) and Western blot (WB); PTEN m⁶A levels were measured by RNA immunoprecipitation-qPCR (RIP-qPCR); myelin ultrastructure, expression of myelin basic protein (MBP) and neurofascin 155 (NF155), and dendritic spine density were observed using transmission electron microscopy (TEM), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, qRT-PCR, and primary neuron culture. ResultsBehaviorally, knockdown of METTL14 significantly counteracted the beneficial effects of acupuncture in improving self-grooming, open field exploration, three-chamber social interaction, and Morris water maze learning and memory (P<0.05, P<0.01). Compared with the acupuncture+sh-NC group, the acupuncture+sh-METTL14 group showed significantly decreased mRNA and protein expression of hippocampal METTL14 (P<0.01), and the upregulating effects of acupuncture on METTL3 and PTEN expression were reversed (P<0.01). Meanwhile, knockdown of METTL14 significantly inhibited the acupuncture-induced increase in PTEN m⁶A levels (P<0.01). Morphologically, knockdown of METTL14 attenuated the improvement of myelin structure by acupuncture, reversed the downregulation of MBP and upregulation of NF155 induced by acupuncture, and blocked the increase in dendritic spine density (P<0.05, P<0.01). ConclusionMETTL14 is a key molecule mediating the therapeutic effect of acupuncture at Neiguan. Acupuncture at Neiguan upregulates METTL14, thereby enhancing m⁶A methylation modification of PTEN mRNA to stabilize its expression, ultimately promoting myelin development and improving behavioral symptoms in ASD juvenile rats. This preliminarily reveals the modern biological connotation of “opening Xuanfu and dredging myelin”.

ObjectiveTo explore the possible mechanism of Jianpi Huazhuo Tiaozhi Granule （健脾化浊调脂颗粒， JHTG） in treating atherosclerosis （AS） based on the regulation of perivascular adipose tissue （PVAT） browning via the phosphoinositide 3-kinase/protein kinase B （PI3K/AKT） signaling pathway. MethodsFifteen SPF male C57BL/6J mice served as control group， while 76 ApoE^-/- mice were first fed a high-fat diet for 16 weeks to establish AS model. After successful modeling， they were randomly divided into model group （n=16）， as well as the browning group， the low-， medium- and high-dose JHTG group， with 15 mice in each group. The browning group was intraperitoneally injected with β3-adrenergic receptor agonist CL 316243 at 1 mg/（kg·d） once daily. The low-， medium- and high-dose JHTG groups were treated with 4.3 g/（kg·d）， 8.6 g/（kg·d）， and 17.2 g/（kg·d） of JHTG by gavage， respectively， while the control group and the model group were given normal saline at 10 ml/（kg·d） by intragastric administration， once daily. All groups received continuous intervention for 4 weeks. The aorta was collected to assess the plaque ratio by gross oil red O staining. HE staining was used to measure the plaque area in cross-sections. Masson staining was employed to detect the proportion of collagen fibers in plaque. Transmission electron microscopy was used to observe the quantity and morphological changes of mitochondria and lipid droplets in adipocytes. The levels of serum triglycerides （TG）， total cholesterol （TC）， high-density lipoprotein cholesterol （HDL-C）， and low-density lipoprotein cholesterol （LDL-C） were detected， as well as tumor necrosis factor α （TNF-α） and interleukin 6 （IL-6） levels in the PVAT and aorta. The protein levels of adiponectin and leptin in PVAT， and protein expression levels of phosphoinositide 3-kinase （PI3K）， phosphorylated phosphoinositide 3-kinase （p-PI3K）， protein kinase B （AKT）， phosphorylated protein kinase B （p-AKT）， uncoupling protein 1 （UCP1）， peroxisome proliferator-activated receptor γ coactivator 1α （PGC-1α）， and PR domain containing 16 （PRDM16） were measured. The mRNA expression levels of UCP1， PGC-1α and PRDM16 in PVAT were detected. ResultsCompared to the control group， the model group showed increased serum TG， TC， and LDL-C levels and decreased HDL-C level， elevated TNF-α and IL-6 levels in PVAT and aorta， decreased average fluorescence intensity of adiponectin， increased average fluorescence intensity of leptin， reduced p-PI3K/PI3K and p-AKT/AKT values as well as protein levels and mRNA expression levels of UCP1， PGC-1α and PRDM16 （P＜0.01）. The pathological results showed that no significant plaque formation was observed in the aortas of mice in the control group. In the model group， multiple plaques were observed in the aortas， with large numbers of foam cells， cholesterol crystals， and inflammatory cell aggregation in the plaques. Compared to the model group， the browning group and the high-dose JHTG group significantly improved the above indicators and aortic pathological changes （P＜0.05 or P＜0.01）. Three JHTG groups showed a dose-dependent effect in reducing LDL-C level and plaque ratio by gross oil red O staining， elevating the average fluorescence intensity of adiponectin， the p-AKT/AKT value， the protein level of PGC-1α， and the mRNA expression levels of UCP1 and PRDM16 （P＜0.05）. The high-dose JHTG group and the browning group showed similar efficacy in improving the pathology of the aorta. ConclusionJHTG may promote PVAT browning in AS model mice through the PI3K/AKT pathway， improve the endocrine function of PVAT， inhibit aortic inflammation， and thereby ameliorate the formation of AS plaques.

Neurodegenerative diseases such as Alzheimer's disease （AD）， Parkinson's disease （PD）， and Huntington's disease （HD） are increasingly becoming major challenges to global public health. The pathogenesis of these diseases is highly complex， with oxidative damage and ferroptosis emerging as potential core factors. Oxidative damage primarily results from the accumulation of reactive oxygen species （ROS） within cells， a process that impairs cellular function and viability. Ferroptosis， an iron-dependent form of programmed cell death， plays a crucial role in neuronal injury and apoptosis. Multiple studies indicate a significant interaction between oxidative damage and ferroptosis. This interplay not only accelerates the progression of neurodegenerative diseases but also offers new directions for potential therapeutic targets. This review systematically analyzes the mechanisms of oxidative damage and ferroptosis in various neurodegenerative diseases， evaluates current research frontiers， and explores feasible therapeutic strategies， aiming to provide new insights and perspectives for in-depth research in this field.

ObjectiveTo investigate the therapeutic efficacy of Qizhi Tongluo granules on proteinuria in membranous nephropathy （MN） and its potential protective effects and underlying mechanism against endoplasmic reticulum stress. MethodsAfter 70 Sprague-Dawley （SD） rats were adaptively fed for one week， the MN rat model was established by injecting cationic bovine serum albumin （C-BSA） into the tail vein. Rats were divided into the normal group， model group， low-dose Qizhi Tongluo granules group （2.43 g·kg^-1）， medium-dose group （4.86 g·kg^-1）， high-dose group （9.72 g·kg^-1）， and benazepril group （0.01 g·kg^-1）， with 10 rats in each group. Treatment was administered for four weeks. The 24-hour urinary total protein （UTP） content， as well as the levels of reactive oxygen species （ROS）， malondialdehyde （MDA）， and glutathione peroxidase （GPX） in renal tissues， were measured. Renal pathological changes were assessed using immunoglobulin G （IgG） staining， periodic acid-silver methenamine （PASM） staining， and transmission electron microscopy （TEM）. The localization and expression levels of glucose-regulated protein 78 （GRP78）， phosphorylated inositol-requiring enzyme 1α （p-IRE1α）， phosphorylated protein kinase R-like endoplasmic reticulum kinase （p-PERK）， activating transcription factor 4 （ATF4）， nuclear factor erythroid 2-related factor 2 （Nrf2）， and 2'-5' oligoadenylate synthetase-like protein 1 （OASL1） in rat kidneys were detected by immunohistochemistry （IHC）. The mRNA and protein expression levels of Nrf2， thioredoxin 1 （Trx1）， thioredoxin-interacting protein （TXNIP）， and OASL1 in rat kidneys were measured using real-time quantitative polymerase chain reaction （Real-time PCR） and Western blot analysis. ResultsCompared with the normal group， UTP levels were significantly increased in the model rats （P<0.05）， with obvious renal pathological damage. GPX content levels were significantly decreased in renal tissue （P<0.05）， while ROS and MDA content levels were significantly increased （P<0.05）. The expression of GRP78， p-IRE1α， p-PERK， and ATF4 proteins was significantly increased in the kidneys （P<0.05）， while the mRNA and protein expression levels of Trx1 and Nrf2 were significantly decreased （P<0.05）. The mRNA and protein expression levels of TXNIP and OASL1 were significantly increased （P<0.05）. Compared with the model group， the UTP levels of rats in the Qizhi Tongluo granules groups and the benazepril group decreased to varying degrees （P<0.05）， and renal pathological damage was significantly alleviated. The GPX content in renal tissue was significantly increased （P<0.05）， while the ROS and MDA levels were significantly decreased （P<0.05）. The expression of GRP78， p-IRE1α， p-PERK， and ATF4 proteins in the kidney was significantly decreased （P<0.05）. The mRNA and protein expression levels of Trx1 and Nrf2 were significantly increased （P<0.05）， while the mRNA and protein expression levels of TXNIP and OASL1 were significantly decreased （P<0.05）. ConclusionQizhi Tongluo granules alleviates proteinuria in MN rats by modulating the Nrf2/OASL1 signaling pathway in renal tissues to reduce endoplasmic reticulum stress， which represents its underlying mechanism.