Background: High-mobility group box protein 1 (HMGB1) is a chromatin-binding protein involved in arthritis, ischemia, sepsis, atherosclerosis, neurodegenerative disorders, meningitis, and cancer. HMGB1 exhibits dual roles in cancer, acting as either a tumor suppressor or oncoprotein depending on context. Objective: This research aimed to elucidate HMGB1’s functional significance in cutaneous squamous cell carcinoma (cSCC). Methods: We overexpressed HMGB1 in cSCC cell lines using recombinant adenovirus and examined its effects on cell proliferation, colony formation, and cell migration. Results: Immunohistochemical analysis revealed elevated HMGB1 expression levels in cSCC tissue relative to normal epidermis. To assess the influence of HMGB1, we employed recombinant adenoviruses expressing HMGB1 to transduce SCC cell lines (SCC12 and SCC13). Enhanced HMGB1 expression significantly promoted cellular proliferation and colony formation capacity.Notably, HMGB1 overexpression elevated the levels of proliferation regulators, including P63, SOX2, CDK4 and CDK6. Furthermore, HMGB1 overexpression substantially enhanced tumor invasiveness, accompanied by upregulation of epithelial-mesenchymal transition (EMT) biomarkers. Mechanistically, overexpression of HMGB1 enhanced transforming growth factor-β signaling by increasing phosphorylation of SMAD2/3, the key mediators of EMT. Conclusion These data imply that HMGB1 acts as a tumor-promoting factor in cSCC.

OBJECTIVE To formulate the Hazardous Drug List in China， and provide a scientific basis for standardizing the management of hazardous drugs， preventing and controlling occupational exposure risks in medical institutions at all levels in China. METHODS Under the joint organization of the Intravenous Medication Admixture Management Professional Committee of the Chinese Pharmaceutical Association and the National Medical Quality Control Center for Pharmaceutical Management， based on literature research and international hazardous drug lists and their development procedures， the scope of hazardous drug selection， selection principles， and evidence confirmation criteria were determined through expert panel seminars and expert questionnaire survey method （Delphi method）. Chemical drugs， biological agents， and Chinese patent medicines marketed in China that met the selecti on principles were screened to form the Chinese Expert Consensus on the Hazardous Drug List . RESULTS Five principles for selecting hazardous drugs were established （including protective labeling in package inserts， carcinogenicity， reproductive toxicity， genotoxicity， and organ toxicity at low doses）， along with the corresponding evidence confirmation criteria. The Hazardous Drug List containing 210 drugs was formulated， covering anti-tumor drugs， endocrine system drugs， nervous system drugs， immunomodulators， anti-infective drugs， cardiovascular system drugs， hematological system drugs， urinary system drugs， obstetrics and gynecology drugs， dermatological drugs and other categories. Compared with international hazardous drug lists， 25 newly included hazardous drugs were added， including 15 anti-tumor drugs， 6 Chinese patent medicines and 4 biological agents. In addition， 88 Chinese patent medicines that may have potential occupational exposure risks are listed in the appendix for reference by medical institutions in management. CONCLUSIONS The development of this consensus closely aligns with the actual clinical drug use in China， with a scientific and rigorous methodology， and can serve as a reference for medical institutions at all levels to standardize the management of hazardous drugs and prevent and control occupational exposure risks.

In recent years, remarkable advances have been made in lung transplantation regarding donor evaluation, perioperative support, and immune regulation, laying a foundation for improving the long-term survival of recipients. The rational application of extended criteria donor lungs and the popularization of ex vivo lung perfusion technology have enhanced the utilization efficiency and safety of marginal donor lungs. Refined assessment of risk factors such as donors’ smoking history and infectious status has reduced the incidence of primary graft dysfunction and postoperative infection. In terms of recipient management, individualized assessment systems have been gradually optimized. The standardized application of intraoperative extracorporeal membrane oxygenation and the development of minimally invasive surgical techniques have effectively alleviated perioperative injuries. The optimization of postoperative immunosuppressive regimens and advances in rejection monitoring technologies have further improved the long-term survival of grafts. Nevertheless, chronic graft dysfunction and recurrent or refractory infections remain the major bottlenecks restricting long-term prognosis. Future research should focus on expanding donor sources, improving the repair quality of marginal donor lungs, promoting precise immunosuppression and anti-infection strategies, and comprehensively enhancing the long-term survival rate and quality of life of lung transplant recipients.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and abnormal accumulation of α‑synuclein. Its pathogenesis involves multiple interconnected processes, including oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, neuroinflammation, and impaired protein homeostasis. Extracellular signal-regulated kinase 1/2 (ERK1/2), a major component of the mitogen-activated protein kinase signaling network, plays an important role in neuronal survival, synaptic plasticity, stress responses, and cell death. However, accumulating evidence indicates that ERK signaling in PD is not unidirectional, as both insufficient activity and sustained overactivation have been associated with neuronal dysfunction and disease progression. In this review, we systematically summarize the evidence for the pathological and protective roles of ERK signaling in PD. Insufficient ERK activity may impair neurotrophic support, synaptic plasticity, mitochondrial homeostasis, and neuronal adaptation to stress, thereby increasing the vulnerability of dopaminergic neurons. In contrast, persistent and excessive ERK activation may promote neuroinflammation, oxidative stress, mitochondrial dysfunction, apoptosis, autophagy-lysosomal impairment, and abnormal α-synuclein accumulation. Conversely, moderate and transient ERK activation induced by neurotrophic factors, bioactive compounds, or exercise may enhance neuronal survival, antioxidant defense, synaptic plasticity, and functional recovery. These apparently contradictory findings suggest that ERK activation itself cannot be simply classified as either neuroprotective or neurotoxic. Based on the available evidence, we propose the concept of an “ERK activity window” to explain the context-dependent effects of ERK signaling in PD. This hypothesis suggests that ERK activity needs to remain within an appropriate dynamic range to maintain neuronal homeostasis and adaptive responses. ERK activity below this range may weaken neurotrophic support and stress resistance, whereas prolonged and high-intensity activation may exceed the adaptive capacity of neurons and glial cells, thereby promoting inflammatory and degenerative processes. Importantly, this functional window should not be regarded as a fixed threshold. Its biological effects are likely determined by the intensity and duration of activation, cell type, subcellular localization, upstream stimuli, interaction with other signaling pathways, and disease stage. This framework may therefore help reconcile the apparently inconsistent findings among different PD models and experimental conditions. From a therapeutic perspective, these findings indicate that ERK should not necessarily be considered a target for simple activation or inhibition. Instead, restoring ERK signaling toward an appropriate functional state may represent a more rational strategy. Exercise is of particular interest because it can simultaneously influence neurotrophic signaling, oxidative stress, inflammation, synaptic plasticity, and ERK activity, potentially promoting adaptive remodeling of ERK signaling according to pathological conditions. Nevertheless, current evidence is predominantly derived from cellular and animal studies, and the dynamic, cell-specific, and spatial characteristics of ERK signaling remain insufficiently defined. Blood-brain barrier penetration, long-term safety, preservation of physiological ERK functions, and the lack of reliable biomarkers for monitoring brain ERK activity also limit clinical translation. Importantly, the “ERK activity window” remains a theoretical framework, and direct clinical evidence that ERK modulation can alter the progression of human PD is currently lacking. Future studies should therefore integrate longitudinal analysis, cell-specific and spatial approaches, and clinical biomarker validation to determine whether precise regulation of ERK signaling can provide a viable strategy for disease-modifying intervention in PD.

ObjectiveTo explore the mechanism by which aerobic exercise improves hippocampal neuroinflammation and learning and memory ability in brain-aged mice via interferon regulatory factor 7 (IRF7). MethodsA total of 60 male specific pathogen-free (SPF) C57BL/6J mice were enrolled in the experiment, including 30 young mice (2 months old) and 30 naturally aging mice (12 months old). Young mice and old mice were respectively randomly assigned to four groups: young control group (group C, n=15), young exercise group (group CE, n=15), and aging control group (group A, n=15), aging exercise group (group AE, n=15). Mice in the exercise groups received an 8-week continuous treadmill aerobic exercise intervention, while control mice were kept under routine feeding without exercise intervention. After the intervention, Barnes maze and Y-maze behavioral tests were performed to comprehensively assess the learning and memory abilities of each group of mice. Transmission electron microscopy was used to observe the ultrastructural morphological changes of hippocampal synapses. Western blot assay was utilized to detect the protein expression and phosphorylation levels of Janus kinase 1 (JAK1), signal transducer and activator of transcription 1 (STAT1), as well as the expression of postsynaptic density protein 95 (PSD95). Immunofluorescence staining was applied to quantify the fluorescence intensity of ionized calcium-binding adapter molecule 1 (IBA1) in hippocampal tissues. The expression levels of inflammatory cytokines including interferon-α (IFN-α), interferon-β (IFN-β), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured by enzyme-linked immunosorbent assay (ELISA). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the mRNA expression level of IRF7, and DNA methylation assay was further conducted to analyze the methylation level of the IRF7 gene in mouse hippocampus. ResultsAt the molecular level, compared with group C, the protein expression levels of JAK1, STAT1, p‑JAK1, and p‑STAT1 in group A were significantly increased (P<0.05), whereas PSD95 expression was decreased (P<0.05). ELISA assays showed that the levels of IFN‑α, IFN‑β, TNF‑α, and IL‑1β were significantly elevated in group A (P<0.001). RT‑PCR analysis revealed that, compared with group C, the mRNA expression of IRF7 in group A was markedly upregulated (P<0.000 1), while the CpG methylation rate of the IRF7 promoter was significantly reduced (P<0.05). In contrast, all the above parameters in the AE group showed improvements relative to those in group A. Immunofluorescence staining indicated positive IBA1 expression in the brain tissues of group A mice. Exercise intervention reversed these abnormal changes. ConclusionIn aged mice, aerobic exercise induces hypermethylation of the IRF7 promoter region, suppresses IRF7 expression and activation of the downstream IFN‑I/JAK1/STAT1 signaling pathway, accompanied by alleviated neuroinflammation, improved learning and memory, and ameliorated brain aging-related phenotypes.

Aim To explore the relevant mechanisms of isoliquiritigenin(ISL)in inhibiting the proliferation and migration of vascular smooth muscle cells(VSMCs)by regulating the GRB2/ERK signaling pathway.Methods Human primary vascular smooth muscle cells(hVSMCs)were cultured,and stimulated with different concentrations of ISL and fixed concen-trations of growth factors PDGF-BB and EGF,respec-tively.Subsequently,the effect of overexpressing GRB2 on the efficacy of ISL was observed.CCK-8 assay was used to detect cell proliferation;BrdU assay was used to detect DNA synthesis;Western blot was used to de-tect the expression levels of OPN,ICAM-1,VCAM-1,GRB2,ERK1/2,and p-ERK1/2;wound healing assay was used to detect cell migration;transwell assay was used to detect cell invasion.Results Compared with the blank control group and the ISL 20 mg·L-1 group,the PDGF-BB group and the EGF group showed increased cell viability and DNA synthesis,decreased cell migration distance,and increased number of inva-sive cells.Additionally,the expression levels of GRB2 and p-ERK1/2 increased.Compared with the PDGF-BB 40 μg·L-1group or the EGF 10 mg·L-1 group,the ISL drug intervention group showed decreased cell viability and DNA synthesis,increased migration dis-tance of cells,decreased number of invasive cells,and decreased expression levels of GRB2 and p-ERK1/2.Compared with the ISL 20 mg·L-1+PDGF-BB and ISL 20 mg·L-1+EGF groups,the groups with ISL+PDGF-BB+pcDNA-GRB2 group and ISL+EGF+pcDNA-GRB2 group showed increased expression lev-els of GRB2,p-ERK1/2,OPN,ICAM-1,and VCAM-1,increased cell viability and DNA synthesis,decreased migration distance,and increased number of invasive cells.Compared with the ISL+PDGF-BB+pcDNA-GRB2 group and the ISL+EGF+pcDNA-GRB2 group,the pcDNA-GRB2+PDGF-BB group or the pcDNA-GRB2+EGF group showed increased expres-sion levels of GRB2,p-ERK1/2,OPN,ICAM-1,and VCAM-1,increased cell viability and DNA synthesis,decreased migration distance,and increased number of invasive cells.Conclusions Isoliquiritigenin inhibits the proliferation and migration of vascular smooth mus-cle cells by regulating the GRB2/ERK signaling path-way.

Objective To investigate the correlation between enlarged perivascular spaces(EPVS)in different regions and glymphatic system(GS)function with cognitive function in patients with recent subcortical small infarction(RSSI).Methods A retrospective study was conducted by consecutively enrolling patients with RSSI who were hospitalized in the Department of Neurology at the Third Affiliated Hospital of Nanjing Medical University(Changzhou Second People's Hospital)from December 2023 to December 2024.Baseline and clinical data were collected,including age,sex,body mass index(BMI),history of smoking and alcohol consumption,hypertension,diabetes mellitus,atrial fibrillation,coronary heart disease,and laboratory indicators(including homocysteine,total cholesterol,triglycerides,low-density lipoprotein cholesterol,high-density lipoprotein cholesterol,glycated hemoglobin,uric acid,and creatinine).Cognitive function was assessed within 7 d of onset using the mini-mental state examination(MMSE)and Montreal cognitive assessment(MoCA)scale,which covers seven cognitive domains:visuospatial and executive functioning,naming,attention,language,abstraction,memory,and orientation.All patients underwent brain MRI within 3 d of admission,including diffusion tensor imaging(DTI)sequences.The DTI along the perivascular space(DTI-ALPS)post-processing tool was used to calculate the DTI-ALPS index on both sides,and the mean value was taken as an indicator to evaluate overall GS function.The volumes of EPVS in the basal ganglia(BG)and centrum semiovale(CSO)were measured.EPVS severity was visually rated based on Potter's method(on a scale range from 0 to 4)and categorized into a none-to-mild(grades 0-1)and a moderate-to-severe(grades 2-4)group.Patients were further classified by region into a BG-EPVS and a CSO-EPVS subgroups under each severity group.(1)Univariate analyses were performed to compare baseline characteristics,DTI-ALPS index,and cognitive assessment scores between groups.Variables with P＜0.05 in univariate analyses were tested for multicollinearity using variance inflation factor.Variables without multicollinearity were included in multivariate Logistic regression to identify independent factors associated with BG-EPVS.To assess the robustness of the predictive value of the DTI-ALPS index,outlier diagnostics and exclusion were performed,followed by re-estimation of the Logistic regression model.Spearman's correlation analysis was used to examine the associations of BG-EPVS volume with the DTI-ALPS index,MMSE scale score,MoCA scale score,and each cognitive domain score.Mediation analysis was conducted to evaluate whether the DTI-ALPS index mediated the relationship between BG-EPVS volume and MoCA scale score.Results A total of 65 RSSI patients were included in the study,comprising 34 males and 3 1 females,aged 37 to 78 years,with a mean age of(53±15)years.Among them,30 patients were classified into the none-to-mild EPVS group and 35 into the moderate-to-severe EPVS group.For regional classification,34 were in the none-to-mild BG-EPVS group and 31 in the moderate-to-severe BG-EPVS group;36 were in the none-to-mild CSO-EPVS group and 29 in the moderate-to-severe CSO-EPVS group.(1)Univariate analysis showed,in both overall EPVS and BG-EPVS subgroup,the none-to-mild groups had lower age,lower proportions of male and hypertensive patients,and higher DTI-ALPS indices,MMSE scale scores,and MoCA scale scores than the moderate-to-severe groups(all P＜0.05).No significant differences were found in other baseline or clinical characteristics(all P＞0.05).In the CSO-EPVS subgroup,age was the only variable differed significantly between the none-to-mild group(significantly younger)and the moderate-to-severe group(P＜0.05),no other variables showed significant differences between the groups(all P＞0.05).(2)No multicollinearity was found among age,sex,hypertension,and the DTI-ALPS index through the multicollinearity analysis.Multivariate Logistic regression identified older age(OR,4.410,95％CI 1.211-16.025,P=0.024),male(OR,1.076,95％CI 1.001-1.156,P=0.048),and hypertension(OR,6.287,95％CI 1.635-24.167,P=0.007)as independent risk factors for moderate-to-severe BG-EPVS in RSSI patients,while a higher DTI-ALPS index was an independent protective factor(OR,0.002,95％CI 0.000-0.904,P=0.046).To assess the robustness of this model,six outlier cases were identified and excluded.After reanalysis,the negative association between the DTI-ALPS index and BG-EPVS risk remained significant(OR,0.050,95％CI 0.003-0.974,P=0.048).(3)Spearman correlation analysis revealed that the BG-EPVS volume in RSSI patients was negatively correlated with the DTI-ALPS index(rs=-0.842,P=0.007),MMSE scale score(rs=-0.491,P=0.033),MoCA scale score(rs=-0.563,P=0.018),and visuospatial/executive function score(rs=-0.596,P=0.001).No significant correlations were found between BG-EPVS volume and other cognitive domains,including naming,attention,language,abstraction,memory,and orientation(all P＞0.05).(4)Mediation analysis showed that the total effect size of BG-EPVS volume on MoCA scale score was-0.673,with a direct effect size of-0.537(account for 79.79％of the total effect size)and an indirect effect size via the DTI-ALPS index of-0.136(account for 20.21％).Conclusions In RSSI patients,age,sex,hypertension,and the DTI-ALPS index were identified as independent factors associated with the severity of BG-EPVS.BG-EPVS volume was negatively correlated with the DTI-ALPS index and cognitive function scores in RSSI patients.Moreover,the DTI-ALPS index mediated the relationship between BG-EPVS volume and cognitive function in RSSI patients.

BACKGROUND:Radiotherapy for head and neck tumors can easily cause xerostomia,seriously affecting the quality of life of patients.In recent years,engineered stem cells and their paracrine factors have shown therapeutic potential in the repair of salivary gland injury.However,there is currently no experimental study on the application of amniotic mesenchymal stem cell-derived exosome in radiation-induced salivary gland injury.OBJECTIVE:To preliminarily explore the repair effect of exosome derived from human amniotic mesenchymal stem cells on radiation-induced submandibular gland injury.METHODS:H uman amniotic mesenchymal stem cell exosomes were extracted and identified by ultrafiltration and ultracentrifugation.SD rats were randomly divided into a control group,a radiation injury group,and a radiation injury+exosome group.An in vitro model of radiation-induced submandibular gland injury was constructed using the submandibular gland tissue of SD rats irradiated with 18 Gy of radiation.One day after radiation modeling,exosome derived from human amniotic mesenchymal stem cells was injected into the submandibular gland in situ.Samples are taken at 1,3,7,and 14 days to detect the resting salivary flow rate.The structure of the submandibular gland tissue was observed by hematoxylin-eosin staining.The expression of glycogen particles in the submandibular gland tissue was observed by Periodic Acid-Schiff staining.Fibrosis in the submandibular gland tissue was observed by Masson staining.The secretion of salivary amylase was detected by enzyme-linked immunosorbent assay.The expression of aquaporin and tight junction proteins in submandibular gland tissue was observed by immunofluorescence staining.Real-time fluorescence quantitative PCR was used to detect the relative expression levels of aquaporins and salivary amylase mRNA in submandibular gland tissue.TUNEL assay was used to detect the apoptosis rate of submandibular gland tissues in each group.RESULTS AND CONCLUSION:After radiomodeling,compared with the radiation injury group,(1)hematoxylin-eosin staining observed that the submandibular gland tissue structure in the radiation injury+exosome group was restored,the nucleoli increased,the number of acinus increased,and the acinar atrophy improved.(2)Glycogen staining observed that the number and density of positive zymogen granules in the acinar cytoplasm of the radiation injury+exosome group gradually increased.(3)Masson staining results observed that the number and density of positive collagen fibers in the interstitium and around the ducts in the radiation injury+exosome group gradually decreased,the degree of fibrosis decreased,and the collagen deposition decreased.(4)The salivary flow rate in the radiation injury+exosome group increased(P＜0.05).The fluorescence intensity of aquaporin-5 was enhanced(P＜0.05)and the gene expression was significantly enhanced(P＜0.01).The fluorescence distribution of tight junction protein 4 was weakened and the fluorescence intensity decreased(P＜0.05,P＜0.01).The content of salivary amylase increased(P＜0.05)and gene expression were significantly increased(P＜0.01).The number of positive apoptotic cells decreased(P＜0.05,P＜0.01).It is indicated that local injection of exosome derived from human amniotic mesenchymal stem cells could improve the pathological morphology of submandibular gland tissue,promote saliva flow rate and amylase expression,and may play a functional repair role in radioactive submandibular gland injury by inhibiting acinar apoptosis.

OBJECTIVE: This study investigated the antidepression mechanisms of Xiaoyaosan (XYS), a classic Chinese prescription, from the perspective of energy metabolism in the brain and intestinal tissues. METHODS: Chronic unpredictable mild stress model-a classic depression rat model-was established. Effects of XYS on behaviors and gastrointestinal motility of depressed rats were investigated. Effects of XYS on energetic charge (EC), adenosine triphosphate-related enzymes, and key enzymes of energy metabolism in both hippocampus and jejunum tissues of depressed rats were investigated using high-performance liquid chromatography, biochemical analysis, and real-time quantitative polymerase chain reaction, respectively. Spearman correlation analysis was conducted to construct a correlation network of "behavior-brain energy metabolism-intestinal energy metabolism" of depression. RESULTS: XYS significantly reduced the abnormal behaviors that observed in depressed rats and increased the EC and the activity of Na⁺-K⁺-adenosine triphosphatase (ATPase) and Ca²⁺-Mg²⁺-ATPase in hippocampus and jejunum tissues of depressed rats. XYS restored the key energetic pathways that had been interrupted by depression, including glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. Furthermore, XYS exhibited antidepressive effects in terms of regulating energy metabolism in tissues of both brain and intestine. CONCLUSION XYS significantly corrected the disturbances in EC and energy metabolism-related enzymes of both brain and intestinal tissues, alleviating both core and concomitant symptoms of depression. The current findings underscore the role of energy metabolism in the antidepressive activity of XYS, providing a fresh perspective on depression, and novel research strategies for revealing the mechanism of actions of traditional Chinese medicines on multi-site and multi-symptom diseases. Please cite this article as: Xiao MT, Wang SY, Wu XL, Zhao ZY, Wang HM, Liu HM, Qin XM, Liu XJ. Antidepressant mechanism of Xiaoyaosan: A perspective from energy metabolism of the brain and intestine. J Integr Med. 2025; 23(6):706-720.
Animals ; Energy Metabolism/drug effects* ; Antidepressive Agents/therapeutic use* ; Drugs, Chinese Herbal/therapeutic use* ; Brain/drug effects* ; Male ; Depression/metabolism* ; Rats ; Rats, Sprague-Dawley ; Intestines/drug effects* ; Hippocampus/drug effects*