The theory of "fire and primordial qi incompatibility" was proposed by LI Gao in Clarifying Doubts about Damage from Internal and External Causes, which has important guiding significance for explaining the pathogenesis, prognosis and treatment of immune-related adverse events (irAEs). "Fire" refers to yin fire, a type of deficient fire transformed from the deficiency of the spleen and stomach, reflecting the pathological state of coexisting deficiency and heat patterns in patients with tumor after immune checkpoint inhibitor (ICI) therapy. "Primordial qi" is the most fundamental essence of human life activities and serves as the source of all bodily qi. Based on the theory of "fire and primordial qi incompatibility" and Western medicine research, we found that excessive use of ICIs can damage the spleen and stomach, leading to excessive yin fire. When yin fire becomes excessive, it consumes and injures the primordial qi; when the primordial qi is depleted, it leads to more excessive yin fire and further deficiency of the spleen and stomach, forming a syndrome in which deficiency and excess coexist. Starting from the theory of "fire and primordial qi incompatibility, "combined with our team′s clinical practice and modern pharmacological research, this study explores the application characteristics of sweet-natured herbs for irAEs during ICIs therapy and interval periods, and summarizes the treatment principles, aiming to provide new perspectives and approaches for the prevention and treatment of tumor-related irAEs with traditional Chinese medicine.

Deactivation of the mitochondrial pyruvate dehydrogenase complex (PDC) is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis. Studies examining PDC activity regulation have mainly focused on the phosphorylation of pyruvate dehydrogenase (E1), leaving other post-translational modifications largely unexplored. Here, we demonstrate that the acetylation of Lys 488 of pyruvate dehydrogenase complex component X (PDHX) commonly occurs in hepatocellular carcinoma, disrupting PDC assembly and contributing to lactate-driven epigenetic control of gene expression. PDHX, an E3-binding protein in the PDC, is acetylated by the p300 at Lys 488, impeding the interaction between PDHX and dihydrolipoyl transacetylase (E2), thereby disrupting PDC assembly to inhibit its activation. PDC disruption results in the conversion of most glucose to lactate, contributing to the aerobic glycolysis and H3K56 lactylation-mediated gene expression, facilitating tumor progression. These findings highlight a previously unrecognized role of PDHX acetylation in regulating PDC assembly and activity, linking PDHX Lys 488 acetylation and histone lactylation during hepatocellular carcinoma progression and providing a potential biomarker and therapeutic target for further development.
Humans ; Acetylation ; Carcinoma, Hepatocellular/genetics* ; Liver Neoplasms/genetics* ; Pyruvate Dehydrogenase Complex/genetics* ; Gene Expression Regulation, Neoplastic ; Animals ; Mice ; Cell Line, Tumor ; Protein Processing, Post-Translational ; Histones/metabolism* ; Disease Progression

This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both Na_V1.7, Na_V1.8, and Na_V1.9 and K_V7 channels, a crucial regulator in controlling NP symptoms. The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP. Through an experimental design involving both in vitro and in vivo methods, E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury (CCI) mouse model. The results demonstrated that E0199 significantly inhibited Na_V1.7, Na_V1.8, and Na_V1.9 channels with a particularly low half maximal inhibitory concentration (IC₅₀) for Na_V1.9 by promoting sodium channel inactivation, and also effectively increased K_V7.2/7.3, K_V7.2, and K_V7.5 channels, excluding K_V7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses, indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically. The safety of E0199 was supported by neurobehavioral evaluations. Conclusively, E0199 represents a ground-breaking approach in NP treatment, showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.

ChuanWu (CW), the dried mother root of Aconitum carmichaelii Debx., is a well-known traditional Chinese medicine (TCM) recognized for its potent efficacy but inherent toxicity, primarily due to its alkaloid content. Traditional and modern detoxification methods for CW include proper processing, rational compatibility, and specialized decoction techniques, among which honey-boiled CW is particularly distinctive. However, research on the detoxification mechanism of honey-boiled CW remains limited. This study investigated this mechanism by analyzing alkaloid transformation and supramolecular aggregation. Honey-boiled and water-boiled CW preparations were compared. Ultra-high-performance liquid chromatography-tandem mass spectrometry was used to analyze CW alkaloids, specifically diester alkaloids (DDAs), monoester alkaloids (MDAs), and non-esterified diterpenoid alkaloids (NDAs). Transmission electron microscopy was employed to observe and identify supramolecular aggregates in the honey-boiled CW decoction. In vivo absorption of water-boiled, honey-boiled, and NADES-boiled CW was compared. Median lethal dose (LD₅₀) tests assessed toxicity, including hepatotoxicity and nephrotoxicity. In vitro experiments evaluated the safety, anti-inflammatory, and analgesic effects of CW-medicated serum on RAW264.7 cells, with in vivo validation in mice. Results showed that honey promoted the conversion of highly toxic DDAs to less toxic MDAs and prevented MDAs from hydrolyzing into NDAs. Honey-boiled CW formed approximately 250 nm supramolecular aggregates that encapsulated MDAs, inhibiting their conversion to NDAs. These encapsulated MDAs acted as a stable delivery system with higher bioavailability than free benzoylmesaconine. Subsequent mouse experiments confirmed that honey-boiled CW significantly increased the LD₅₀ of CW while reducing hepatotoxicity and nephrotoxicity. Additionally, honey-boiled CW significantly improved cell safety and enhanced anti-inflammatory and analgesic effects. Our findings reveal that honey-boiled CW exhibits a potent detoxification mechanism by influencing alkaloid transformation and facilitating the formation of supramolecular aggregates. This study lays the groundwork for developing detoxification or synergistic strategies within honey-boiled TCM.

Puerarin is a monomeric isoflavone compound derived from Puerariae Lobatae Radix. It exhibits poor solubility in both water and lipids, resulting in suboptimal oral absorption and low bioavailability. There is therefore an urgent need to develop new methods of applying puerarin to enhance its solubility and bioavailability. Studies have revealed that puerarin possesses distinctive physical and chemical properties, including the ability to self-assemble into supramolecular hydrogels in response to temperature changes. In this review, the research progress of puerarin as a hydrogel system containing loaded drugs, as well as a hydrogel system composed of hydrogel matrix in the field of tissue regeneration was summarized. This is intended to provide a reference for the rational and efficient use of drugs and lay the groundwork for the development and preparation of new drug carrier platforms.

This research study focuses on addressing the limitations of current neuropathic pain(NP)treatments by developing a novel dual-target modulator,E0199,targeting both Nav1.7,Nay1.8,and Nay1.9 and Kv7 channels,a crucial regulator in controlling NP symptoms.The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP.Through an experimental design involving both in vitro and in vivo methods,E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury(CCI)mouse model.The results demonstrated that E0199 significantly inhibited Nav1.7,Nav1.8,and Nav1.9 channels with a particularly low half maximal inhibitory concentration(ICs0)for Nay1.9 by promoting sodium channel inactivation,and also effectively increased Kv7.2/73,Kv7.2,and Kv7.5 channels,excluding Kv7.1 by promoting potassium channel acti-vation.This dual action significantly reduced the excitability of dorsal root ganglion neurons and alle-viated pain hypersensitivity in mice at low doses,indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically.The safety of E0199 was supported by neurobehavioral evaluations.Conclusively,E0199 represents a ground-breaking approach in NP treatment,showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe thera-peutic option for NP.This study introduces a promising direction for the future development of NP therapeutics.

Objective This study aimed to evaluate the measurement attributes of the QLU-C10D scale in breast cancer pa-tients,and provide the evidence for the application of the tool in the measurement of health effectiveness of breast cancer patients.Methods Since July 2022,the data of breast cancer patients in Harbin Medical University Cancer Hospital and the First Affiliated Hospital of Harbin Medical University were collected,and the utility values for the QLU-C10D and EQ-5D-5L were calculated based on the Chinese utility scoring system.The validity of the first collected sample data was evaluated by convergent validity and known-group validity,The data were collected again three months after treatment to evaluate the responsiveness of QLU-C10D in breast canc-er patients.Results In terms of convergent validity,the theoretical correlation dimension between the QLU-C10D and EQ-5D-5L scale was higher than that of irrelevant dimensions.Among them,the correlation between pain in QLU-C10D scale and pain in EQ-5D-5L scale was the highest(r=0.546),while the correlation between insomnia in QLU-C10D scale and self-care in EQ-5D-5L scale was the lowest(r=0.219).In terms of known-group validity,the QLU-C10D scale had a relative efficiency(RE)greater than 1 in all groups(education level,residential address,frequency of physical examinations,economic pressures,and ECOG score).In terms of responsiveness,the QLU-C10D scale could effectively reflect the changes in health status of breast cancer patients after treatment,especially in the dimensions of role function(ES=0.415,SRM=0.645)and bowel problems(ES=0.433,SRM=0.708).Conclusion The QLU-C10D scale has good convergent validity,known-group validity and good responsiveness.It is a disease-specific health utility measurement tool that can be used for health utility measurement of breast cancer patients and health technology evaluation re-search.

Objective:To analyze the guiding value of index of consciousness 1(IoC1) and index of consciousness 2(IoC2) in anesthesia management of laparoscopic surgery.Methods:A total of 100 elderly patients undergoing laparoscopic surgery under general anesthesia in the Beijing Coal Group General Hospital from June 2022 to October 2023 were prospectively selected as research objects, and they were divided into the observation group and the control group according to random number table method, with 50 cases in each group. The observation group used IoC1 and IoC2 to monitor and guide anesthesia management, while the control group used bispectral index (BIS) to monitor the depth of anesthesia, and combined with the experience of anesthesiologists to guide anesthesia management. The changes of vital signs of patients in the two groups were compared after calm entry (T 0), induction of anesthesia (T 1), implantation of laryngeal mask 1 min (T 2), carbon dioxide (CO 2) pneumoperitoneum 1 min (T 3), and removal of laryngeal mask 1 min (T 4). The time of resuscitation extubation, dosage of anesthetic drugs, dosage of vasoactive drugs, IoC1, IoC2 and BIS were compared between the two groups. Results:The pneumoperitoneum time and incidence of circulatory instability between the two groups had no statistical differences ( P>0.05). The time of resuscitation and extubation in the observation group was shorter than that in the control group : (8.16 ± 6.08) min vs. (13.10 ± 7.09) min, the dosage of propofol and remifentanil were lower than those in the control group : (382.10 ± 201.90) mg vs. (465.48 ± 213.51) mg, (0.81 ± 0.62) mg vs. (1.17 ± 0.55) mg, there were statistical differences ( P<0.05). The amount of ephedrine and atropine between the two groups had no statistical differences ( P>0.05). The dosage of norepinephrine in the observation group was lower than that in the control group: (106.42 ± 46.12) μg vs. (147.04 ± 51.38) μg, there was statistical difference ( P<0.05). The heart rate, mean arterial pressure (MAP) and IoC1/BIS between the two groups had no statistical differences ( P>0.05). The IoC2 values of T 0, T 1, T 2, T 3 and T 4 in the observation group were 97.46 ± 2.46, 45.28 ± 5.08, 48.64 ± 4.51, 50.44 ± 4.21 and 96.08 ± 2.69, respectively. The IoC2 value of T 3 was higher than that of T 1 and T 2 in the observation group, there were statistical differences ( P<0.05). Conclusions:The application of IoC1 and IoC2 to monitor and guide the anesthesia management of laparoscopic patients under general anesthesia makes the application of anesthetic drugs more quantitative and precise, the perioperative vital signs more stable, and the recovery time faster.

Objective:It aims to systematically evaluate the current status of knowledge,attitude,and practice(KAP)regarding universal commercial medical insurance among residents of the sample province from the demand-side perspective.Methods:Utilizing a quota sampling method,face-to-face surveys were conducted via the Questionnaire Star platform to collect demographic characteristics and KAP data of the participants.Comparisons of differences among different groups were made using t-tests,analysis of variance,and chi-square tests.Furthermore,multiple linear regression and structural equation modeling were utilized to analyze the influencing factors of KAP,as well as the pathways among these three factors.Results:Out of the 415 valid questionnaires collected,there were notable differences in KAP among respondents with diverse demographic backgrounds.Regression analysis revealed that education level,frequency of health check-ups,and engagement in other commercial health insurances significantly influenced knowledge;education level,involvement in other commercial health insurances,and self-assessed health status were pivotal in shaping attitudes;whereas age,education level,frequency of health check-ups,and participation in other commercial health insurances were critical in affecting practice.The path analysis results indicate that knowledge of universal commercial medical insurance has a significant direct association with attitude(β=0.379,P＜0.001)and practice(β=0.323,P＜0.001).It also influences practice through attitude as a mediator(β=0.016,P＜0.001),but the direct effect of attitude on practice is not significant(β=0.04,P=0.403).Conclusion:While residents in the sample province exhibit a positive attitude towards universal commercial medical insurance,there is a need to enhance their level of knowledge and engagement in practice.It is recommended to strengthen targeted educational and promotional measures to promote the healthy and sustainable development of universal insurance.

AIM:To explore the mechanism of BLJZF in the treatment of abnormal lipid metabo-lism based on network pharmacology,molecular docking andin vivo animal experiments.METHODS:TCMSP database,Swiss Target Prediction database,STITCH database and literature search were used to collect and query the chemical composition infor-mation of BLJZF and the corresponding target of drug chemical composition.Disease targets of lipid abnormalities were collected through GeneCards and OMIM databases.Metascape database was used to analyze the gene ontology function and the Kyoto Encyclopedia gene and genome pathway en-richment of common intersection targets.Cyto-scape software was used to construct the correla-tion network diagram of components and targets,so as to select major components and targets for molecular docking study.The hyperlipidemia model was induced by high fat diet,and the control group,model group,positive group and BLJZF group were set up.The serum lipid index contents of triglyceride(TG),total cholesterol(TC),low lipo-protein cholesterol(LDL-C)and high lipoprotein cholesterol(HDL-C)were detected after continuous administration for 4 weeks.The contents of oxida-tive stress index were detected:alanine amino-transferase(ALT)and aspartate aminotransferase(AST).The contents of superoxide dismutase(SOD)and malondialdehyde(MDA)were detected by ELI-SA.Hematoxylin-eosin(HE)staining was used to de-tect the pathological changes of liver tissue.RE-SULTS:A total of 25 components and 315 corre-sponding targets of BLJZF were obtained,1729 tar-gets of lipid abnormalities and 116 common tar-gets of BLJZF,among which the core targets were AKT1,TNF,IL1β,CASP3,etc.GO and KEGG enrich-ment analysis suggested that BLJZF may play a role through the lipid and atherosclerotic pathway,PI3K-Akt,AGE-RAGE in diabetic complications and other signaling pathways.Molecular docking showed that most of the core targets had high binding activity with the active ingredients.Animal experiments showed that compared with model group,TC,TG,LDL-C,ALT,AST and MDA in BLJZF group were sig-nificantly decreased,HDL-C and SOD were signifi-cantly increased,and the degree of liver fat defor-mation was reduced.CONCLUSION:BLJZF has a therapeutic effect on lipid abnormalities.It can treat lipid metabolism abnormalities through multi-component,multi-target and multi-pathway,and provide reference for subsequent drug research on BLJZF.