ObjectiveTo investigate the effects of Huanglian Jiedutang （HLJDT） on cognitive function in mice with ischemic stroke （IS） and to elucidate whether its neuroprotective effects are mediated by inhibition of the nuclear factor-κB （NF-κB） signaling pathway and subsequent suppression of NF-κB-regulated neuronal apoptosis. MethodsAn IS model was established using middle cerebral artery occlusion （MCAO）. Sixty C57BL/6J mice were randomly assigned to five groups （n =12 per group）， i.e.， sham operation， model， HLJDT low-dose （3.9 g·kg^-1·d^-1）， HLJDT high-dose （7.8 g·kg^-1·d^-1）， and Ginkgo biloba extract （GBE， 31.2 mg·kg^-1·d^-1）. Post-operatively， neurological deficit scores （Longa score）， cerebral infarct volume assessed by 2，3，5-triphenyltetrazolium chloride （TTC） staining， and brain water content were evaluated. Learning and memory were assessed using new object recognition （NOR） and fear conditioning （FC） tests. Hippocampal pathology was examined via hematoxylin and eosin （HE） staining. Immunofluorescence detected expression of glial fibrillary acidic protein （GFAP， astrocyte marker）， cellular oncogene Fos （c-Fos， neuronal activation marker）， and glutamate decarboxylase 65 （GAD65）. Western blot measured nuclear factor-κB inhibitor protein α （IκBα）， phosphorylated IκBα （p-IκBα）， NF-κB p65， phosphorylated NF-κB p65 （p-NF-κB p65）， ionic calcium binding adapter molecule 1 （Iba-1）， tumor necrosis factor （TNF）-α， interleukin （IL）-1β， and apoptosis-related proteins， such as cleaved cysteinyl aspartate-specific protease 3 （Caspase-3）， B-cell lymphoma 2 （Bcl-2）， and Bcl-2-associated X protein （Bax）. Real-time quantitative PCR （Real-time PCR） was used to assess mRNA levels of Iba-1， TNF-α， IL-1β， NF-κB p65， cleaved Caspase-3， Bax， and Bcl-2. ResultsCompared with the sham group， the model group exhibited significantly increased neurological deficit scores， brain water content， and cerebral infarct volume （P<0.01）. Hippocampal CA1 neurons were disorganized， showing nuclear pyknosis and karyolysis. NOR exploration time and FC freezing time were significantly reduced （P<0.01）. GFAP and c-Fos expression were increased， while GAD65 expression was decreased （P<0.01）. Cleaved Caspase-3 and Bax were upregulated， Bcl-2 was downregulated， and the Bax/Bcl-2 ratio was elevated （P<0.01）. Expression levels of p-IκBα， p-NF-κB p65， IL-1β， TNF-α， and Iba-1 were significantly increased （P<0.01）. Compared with the model group， HLJDT high-dose， low-dose， and GBE groups showed significant improvements in all parameters （P<0.01）. Among them， the HLJDT high-dose group showed the most pronounced neuronal structural recovery and superior performance in NOR and FC tests （P<0.01）. In this group， GFAP and c-Fos decreased， GAD65 increased （P<0.01）， apoptosis-related protein expression was reversed， and NF-κB signaling and related inflammatory factor expression were suppressed （P<0.01）. ConclusionHLJDT ameliorates cognitive dysfunction in mice after IS， potentially by inhibiting the NF-κB signaling pathway， thereby reducing neuroinflammation and hippocampal neuronal apoptosis.

Background In the context of climate change, the health burden associated with non-optimal temperature is becoming increasingly substantial. Emergency ambulance calls (EACs) are a sensitive indicator of acute health effects. However, most previous studies have relied on daily mean temperature (MT) or a single thermal stress indicator, and it remains unclear whether different temperature indicators yield materially different estimates of the health burden attributable to non-optimal temperature. Objective To compare multiple temperature indicators in evaluating the attributable burden of EACs associated with non-optimal temperature in Dezhou City, Shandong Province. Methods Daily EACs records and corresponding meteorological data in Dezhou from 2014 to 2023 were collected. A time-stratified case-crossover design with conditional logistic regression, combined with distributed lag non-linear models (DLNM), was employed to examine the exposure-response relationships and population attributable burden of EACs associated with the percentiles of daily MT and 12 commonly used thermal stress indicators. Results During the study period, a total of 952989 EACs were recorded in Dezhou. For all temperature indicators, the cumulative exposure-response curves showed a V-shaped pattern. Among the attributable fraction (AF) estimates, only those derived from the universal thermal climate index for outdoor shaded space (UTCI3) and wet-bulb temperature (WBT) were significantly lower than the estimates based on MT (P < 0.05); no statistically significant differences were observed for the other indicators. The AF based on MT was 5.24% (95%CI: 4.34%, 6.16%), and the attributable burden was mainly driven by cold temperatures (AF=3.57%, 95%CI: 2.65%, 4.48%). Spatially, high heat-attributable EACs rates per 1000 population were primarily concentrated in the central and southern Dezhou, whereas areas with high cold-attributable EACs rates were more dispersed. The overall spatial pattern of EACs attributable to non-optimum temperatures was more consistent with the distribution of cold-related risks. Subgroup analysis showed that, across susceptible population groups, the AF estimates derived from most thermal stress indicators did not differ significantly from those based on MT. Conclusion In Dezhou, most thermal stress indicators produce attributable burden estimates for EACs associated with non-optimal temperature that are similar to those based on daily MT, and cold temperatures contribute more to the overall attributable burden. The spatial distribution of EACs attributable to non-optimal temperature is dispersed, whereas heat-attributable hotspots are concentrated in central and southern Dezhou.

Acute lung injury （ALI） is a life-threatening condition characterized by uncontrolled pulmonary inflammatory responses， presenting high morbidity and mortality rates that pose serious threats to patient health. The pathogenesis of ALI involves complex interactions among pathological mechanisms including immune-inflammatory responses， disruption of the alveolar-capillary barrier， mesenchymal stem cell dysfunction， metabolic disorders， ferroptosis， and alterations in the gut microbiota. The dysregulation of programmed cell death （PCD） has increasingly emerged as a research focus. PCD represents a genetically regulated autonomous process of cell death， crucial for maintaining the internal stability of organisms. Recent studies indicate that multiple PCD modes， including apoptosis， pyroptosis， necroptosis， autophagy， and ferroptosis， participate in the development and progression of ALI by mediating pathological processes such as alveolar epithelial cell injury and vascular endothelial barrier disruption. Current therapeutic approaches for ALI encompass lung-protective ventilation， body fluid management， mesenchymal stem cell therapy， and pharmacological interventions. While these measures may alleviate clinical symptoms， they remain unable to reverse the pathological progression of lung injury. Traditional Chinese medicine （TCM） possesses the unique advantages of a holistic perspective and syndrome differentiation-based treatment， achieving breakthrough progress in targeted PCD intervention for ALI. It can mitigate pulmonary tissue injury by suppressing inflammatory responses， regulating immune function， and improving coagulation disorders， thereby delaying the onset and progression of ALI. This paper delves into the molecular mechanisms of PCD in ALI， systematically reviewing the effects of TCM extracts， active constituents （terpenoids， saponins， flavonoids， and phenols）， and compound formulas （e.g.， Qingjie Huagong prescription， Maxing Kugan Tang， and Yifei Jianpi prescription） in improving pulmonary epithelial cell function and mitigating lung injury by modulating PCD pathways. This review aims to provide theoretical underpinnings and novel directions for drug development in the clinical prevention and treatment of ALI.

Acute lung injury （ALI） is a life-threatening condition characterized by uncontrolled pulmonary inflammatory responses， presenting high morbidity and mortality rates that pose serious threats to patient health. The pathogenesis of ALI involves complex interactions among pathological mechanisms including immune-inflammatory responses， disruption of the alveolar-capillary barrier， mesenchymal stem cell dysfunction， metabolic disorders， ferroptosis， and alterations in the gut microbiota. The dysregulation of programmed cell death （PCD） has increasingly emerged as a research focus. PCD represents a genetically regulated autonomous process of cell death， crucial for maintaining the internal stability of organisms. Recent studies indicate that multiple PCD modes， including apoptosis， pyroptosis， necroptosis， autophagy， and ferroptosis， participate in the development and progression of ALI by mediating pathological processes such as alveolar epithelial cell injury and vascular endothelial barrier disruption. Current therapeutic approaches for ALI encompass lung-protective ventilation， body fluid management， mesenchymal stem cell therapy， and pharmacological interventions. While these measures may alleviate clinical symptoms， they remain unable to reverse the pathological progression of lung injury. Traditional Chinese medicine （TCM） possesses the unique advantages of a holistic perspective and syndrome differentiation-based treatment， achieving breakthrough progress in targeted PCD intervention for ALI. It can mitigate pulmonary tissue injury by suppressing inflammatory responses， regulating immune function， and improving coagulation disorders， thereby delaying the onset and progression of ALI. This paper delves into the molecular mechanisms of PCD in ALI， systematically reviewing the effects of TCM extracts， active constituents （terpenoids， saponins， flavonoids， and phenols）， and compound formulas （e.g.， Qingjie Huagong prescription， Maxing Kugan Tang， and Yifei Jianpi prescription） in improving pulmonary epithelial cell function and mitigating lung injury by modulating PCD pathways. This review aims to provide theoretical underpinnings and novel directions for drug development in the clinical prevention and treatment of ALI.

Objective This study aimed to develop an automated method for syndrome element differenti-ation in Traditional Chinese Medicine(TCM).Methods We first constructed and trained an Instruction-tuned Multi-Task TCM text embedding model(Instr-MT-TCM)using four distinct TCM task datasets,including domain knowledge,synonymous terminology,syndrome differentiation and treatment,and TCM case labels.Subsequently,five TCM diagnostics experts holding master's degrees or higher were organized to screen a real-world TCM case dataset and annotate symptoms and signs.The purpose was to evaluate the F1-score of the proposed method—the combination of Instr-MT-TCM and a Large Language Model(LLM)—by comparing its performance against the manual annotation result on the syndrome element differentiation task.Finally,to validate its feasibility in real-world clinical settings,the method was applied to 48 prostate cancer cases to calculate the syndrome element scores.Results The Instr-MT-TCM model showed rapid performance improvement in its early training phase,achieving a Recall@1(R@1)of 0.848.Experts curated a dataset of 1,793 real-world clinical cases,covering 34 common diseases and 66 syndrome patterns.In the syndrome element differentiation task,the collaborative framework of LLM and Instr-MT-TCM achieved a mean F1-score of 0.927,outperforming the 0.512 from manual annota-tion.The syndrome element analysis revealed that the predominant elements of disease nature were fire(heat)and yin deficiency,while the main elements of disease location were bladder and kidney.Conclusion This study proposes and validates a novel method for automated TCM syndrome element dif-ferentiation based on the synergy between LLM and our custom Instr-MT-TCM model.Achieving a high F1-score(0.927)on real-world data,the method demonstrates excellent accuracy and generalization ability.Its application in prostate cancer analysis highlights its significant clinical potential,offering effective technical support,and a new research direction for intelligent TCM syndrome element differentiation.

As the core technology of processing， the stir-frying method of traditional Chinese medicine（TCM） realizes the regulation of efficacy of medicinal substances through the coordination of fire gradient and excipients. This study aims to systematically analyze the influence of different stir-frying degrees（stir-frying until yellow， stir-frying to brown， stir-frying to charcoal） and excipient types（solid excipients such as rice， wheat bran， soil， liquid excipients such as rice wine， vinegar， honey） on the physicochemical properties， efficacy and toxicity of TCM， summarizing their common regulatory mechanisms and characteristics. Then， the three-dimensional regulatory common mechanisms and five-dimensional regulatory specificity mechanisms of different stir-frying processes were obtained. The three-dimensional regulatory common mechanisms are as follows：①Thermal effects break down inherent barriers of medicinal materials and improve the dissolution of components. ②Inducing Maillard reaction， carbonization and other reactions of medicinal materials to promote the transformation of components. ③Combining the catalytic and harmonizing effects of excipients to achieve targeted enrichment of efficacious substances and precise control of toxic components. The five-dimensional regulatory specificity mechanisms manifest as：①The efficacy gradient pattern where stir-frying until yellow strengthens the spleen， stir-frying to brown aids digestion， and stir-frying to charcoal stops bleeding. ②According to the polarity difference and intrinsic properties， the liquid excipients form a directional synergistic mechanism of wine processing enhances ascending nature， ginger processing to warm and disperse， salt processing directs effects to the kidneys， vinegar processing targets the liver， honey processing imparts sweetness and moderation. ③Through porous structure and interfacial properties， solid excipients give the synergistic effect of rice processing for diarrhea relief， bran processing for stomach tonification， soil processing for warming the middle warmer， and clam powder/talcum powder/sand processing for texture optimization. ④Thermal effects induce decomposition/oxidation/polymerization and other reactions to reshape the material basis， directing changes in the efficacy. ⑤The targeted distribution of efficacy is regulated by component enrichment and meridian-guiding effect， and the meridian tropism is changed. The system， driven by thermal effect， excipient synergy and physicochemical reconstruction， integrates five-dimensional regulation of fire， solvent， interface， composition and distribution. It systematically explains the inherent law of efficacy-substance-process of traditional stir-frying， and provides theoretical basis and practical guidance for standardizing TCM processing and enhancing the efficacy.

Traditional funding allocation methods often only consider working hours or income ratios,making it difficult to fully measure the quality and technical complexity of medical work.Therefore,it first analyzed the difficulties in managing the cost of personnel expenses in public hospitals.Then,the limitations of two traditional allocation methods,namely the labor based econometric allocation model and the profit oriented allocation model,were analyzed.Subsequently,a work achievement sharing method based on performance bonuses in one hospital with multiple districts was proposed,which comprehensively integrates multidimensional factors such as workload,technical difficulty,surgical category,and personnel titles.The results indicate that for the allocation of personnel and hospitalization expenses,the econometric allocation model has the highest allocation ratio,which is 54.35%,Next is the profit oriented allocation model,with an allocation ratio of 30.64%.The proposed performance-based bonus based work achievement sharing method has the lowest sharing ratio of 20.55%and better reflects the quality and labor value of doctors'work.The research aims to provide reference for optimizing the cost accounting system and improving operational efficiency of public hospitals.

Objective:To evaluate the effect of arctigenin (ARG) on cognitive dysfunction induced by sevoflurane anesthesia in aged rats and the role of autophagy-mediated pyroptosis.Methods:Fifty SPF male Sprague-Dawley rats, aged 18-20 months, weighing 550-600 g, were divided into 5 groups ( n=10 each) using a random number table method: control group (C group), sevoflurane anesthesia group (Sev group), sevoflurane anesthesia+ ARG group (Sev+ ARG group), sevoflurane anesthesia+ autophagy inducer rapamycin group (Sev+ RAPA group), and sevoflurane anesthesia+ ARG+ autophagy inhibitor 3-methyladenine (3-MA) group (Sev+ ARG+ 3-MA group). Except for group C, the rats in the other groups inhaled 6% sevoflurane for 3 h to establish the cognitive impairment model. At 30 min before anesthesia, ARG 20 mg/kg was intraperitoneally injected in Sev+ ARG group, rapamycin 7.5 mg/kg was intraperitoneally injected in Sev+ RAPA group, and ARG 20 mg/kg (dissolved in dimethyl sulfoxide) was intraperitoneally injected, followed by immediate intraperitoneal injection of 3-MA 1.5 mg/kg in Sev+ ARG+ 3-MA group. The equal volume of dimethyl sulfoxide was intraperitoneally injected in C group and Sev group. The Morris water maze test was conducted to assess the cognitive function at 48 h after the end of administration. After completion of the Morris water maze test, the hippocampal tissue was taken under deep anesthesia for observation of the pathological changes (after HE staining) which were scored and for determination of neuronal pyroptosis (after propidium iodide staining) and expression of neuronal autophagy-related proteins (microtubule-associated protein 1 light chain 3 [LC3], Beclin-1, p62), pyroptosis-related proteins (NOD-like receptor protein 3 [NLRP3], apoptosis-associated speck-like protein containing a CARD [ASC], pro-cysteine aspartate-specific protease 1 [pro-caspase-1], cleaved-caspase-1, gasdermin D [GSDMD], and N-terminal fragment of gasdermin D [GSDMD-N], interleukin-1β [IL-1β] and IL-18). Results:Compared with C group, the escape latency was significantly prolonged, the time of staying at the original platform quadrant was shortened, the number of crossing the original platform was reduced, the hippocampal injury score and neuronal pyroptosis rate were increased, LC3Ⅱ/LC3Ⅰ ratio was decreased, the expression of Beclin-1 was down-regulated, the expression of p62, NLRP3, ASC, IL-1β and IL-18 was up-regulated, and the cleaved-caspase-1/pro-caspase-1 ratio and GSDMD-N/GSDMD ratio were increased in Sev group ( P<0.05). Compared with Sev group, the escape latency was significantly shortened, the time of staying at the original platform quadrant was prolonged, the number of crossing the original platform was increased, the hippocampal injury score and neuronal pyroptosis rate were decreased, LC3Ⅱ/LC3Ⅰ ratio was increased, the expression of Beclin-1 was up-regulated, the expression of p62, NLRP3, ASC, IL-1β and IL-18 was down-regulated, and the cleaved-caspase-1/pro-caspase-1 ratio and GSDMD-N/GSDMD ratio were decreased in Sev+ ARG group and Sev+ RAPA group ( P<0.05). Compared with Sev+ ARG group, the escape latency was significantly prolonged, the time of staying at the original platform quadrant was shortened, the number of crossing the original platform was reduced, the hippocampal injury score and neuronal pyroptosis rate were increased, LC3Ⅱ/LC3Ⅰ ratio was decreased, the expression of Beclin-1 was down-regulated, the expression of p62, NLRP3, ASC, IL-1β and IL-18 was up-regulated, and the cleaved-caspase-1/pro-caspase-1 ratio and GSDMD-N/GSDMD ratio were increased in Sev+ ARG+ 3-MA group ( P<0.05). Conclusions:AGR can alleviate sevoflurane anesthesia-induced cognitive dysfunction in aged rats, and the mechanism is related to reduction of autophagy-mediated cell pyroptosis.

Therapeutic resistance in cancer is responsible for numerous cancer deaths in clinical practice. While target mutations are well recognized as the basis of genetic resistance to targeted therapy, nontarget mutation resistance (or nongenetic resistance) remains poorly characterized. Despite its complex and unintegrated mechanisms in the literature, nongenetic resistance is considered from our perspective to be a collective response of innate or acquired resistant subpopulations in heterogeneous tumors to therapy. These subpopulations, e.g., cancer stem-like cells, cancer cells with epithelial-to-mesenchymal transition, and drug-tolerant persisters, are protected by their resistance traits at cellular and molecular levels. This review summarizes recent advances in the research on resistant populations and their resistance traits. NOTCH signaling, as a central regulator of nongenetic resistance, is discussed with a special focus on its canonical maintenance of resistant cancer cells and noncanonical regulation of their resistance traits. This novel view of canonical and noncanonical NOTCH signaling pathways is translated into our proposal of reshaping therapeutic strategies targeting NOTCH signaling in resistant cancer cells. We hope that this review will lead researchers to study the canonical and noncanonical arms of NOTCH signaling as an integrated resistant mechanism, thus promoting the development of innovative therapeutic strategies.
Neoplasms/metabolism* ; Receptors, Notch/metabolism* ; Disease Resistance/physiology* ; Signal Transduction/physiology* ; Humans ; Drug Resistance, Neoplasm/physiology* ; Molecular Targeted Therapy/methods*

Chinese medicinal materials serve as the material foundation of traditional Chinese medicine （TCM） culture. The sustainable development of Chinese medicinal material resources is a focal point in the modernization of TCM. With the increasing scarcity of Chinese medicinal material resources， the expansion of new Chinese medicinal material resources has become a crucial means for the sustainable utilization of these resources. New Chinese medicinal material resources refer to natural resources that have been newly discovered or developed， possessing potential medicinal value or healthcare functions， which fall outside the traditional application scope of herbal medicines. These resources have not yet been widely recognized or applied within the framework of traditional TCM theory. They specifically include artificial substitutes for endangered medicinal materials， new medicinal parts of medicinal plants， medicinal materials with expanded clinical applications， and foreign medicinal resources. The rational compatability and formulation of new Chinese medicinal material resources are essential pathways for integrating them into the TCM system. Due to the weak foundational research on new Chinese medicinal material resources in China， the characteristics of these resources that align with the TCM theory are not yet fully understood， posing numerous constraints on formulating prescriptions based on the traditional compatibility principles of TCM. This paper integrates the traditional formulation theory of TCM with modern data integration methods， proposing four formulation models for new TCM resources： synergistic compatibility， substitutive compatibility， symptom-based compatibility， and efficacy semantic compatibility. These models provide new insights for the application of new Chinese medicinal material resources， not only facilitating their rational use in clinical practice but also offering theoretical support for the development and compatibility research of these resources.