ObjectiveTo investigate the mechanism of ferroptosis mediated by long-chain acyl-CoA synthetase 4 （ACSL4） signalling pathway in rats with coronary heart disease with blood stasis syndrome and the intervention effect of Xuefu Zhuyutang. MethodsSPF male SD rats were randomly divided into normal group， sham-operation group， model group， trimetazidine group （5.4 mg·kg^-1）， low-， medium-， and high-dose group （3.51， 7.02，14.04 g·kg^-1） of Xuefu Zhuyutang. The coronary artery left anterior descending ligation method was used to prepare a model of coronary heart disease with blood stasis syndrome， and continuous treatment for 7 d was conducted， while the sham-operation group was only threaded and not ligated. The general macroscopic symptoms of the rats were observed， and indicators such as electrocardiogram， echocardiography， and blood rheology were detected. The pathological morphology of myocardial tissue was observed by hematoxylin-eosin （HE） staining， and the changes in mitochondria in myocardial tissue were observed by transmission electron microscopy. The level of iron deposition in myocardial tissue was observed by Prussian blue staining. The levels of 12-hydroxyeicosatetraenoic acid （12-HETE） and 15-HETE were detected in serum by enzyme-linked immunosorbent assay. A biochemical colourimetric assay was used to detect the levels of Fe²⁺， lipid peroxidation （LPO）， glutathione （GSH）， and T-GSH/glutathione disulfide （GSSG） in myocardial tissue. DCFH-DA fluorescence quantitative assay was employed to detect the levels of reactive oxygen species （ROS）. Western blot and Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was adopted to detect the protein and mRNA expressions of glutathione peroxidase 4 （GPX4）， ferritin heavy chain 1 （FTH1）， ACSL4， and ly-sophosphatidylcholine acyltransferase3 （LPCAT3） in myocardial tissue. ResultsCompared with those in the normal group， the rats in the model group were poor in general macroscopic symptoms. The electrocardiogram showed widened QRS wave amplitude and increased voltage， bow-back elevation of the ST segments， elevated T waves， J-point elevation， and accelerated heart rate. Echocardiography showed a significant reduction in left ventricular ejection fraction （LVEF） and left ventricular fraction shortening （LVFS） （P<0.01）. Blood rheology showed that the viscosity of the whole blood （low， medium， and high rate of shear） was significantly increased （P<0.01）. HE staining showed an abnormal structure of myocardial tissue. There was a large area of myocardial necrosis and inflammatory cell infiltration and a large number of connective tissue between myocardial fibers. Transmission electron microscopy showed that the mitochondria were severely atrophy or swelling. The cristae were reduced or even broken， and the matrix was flocculent or even vacuolated. Prussian blue staining showed that there were a large number of iron-containing particles， and the iron deposition was obvious. The content of 12-HETE and 15-HETE in the serum was significantly increased （P<0.01）. The content of Fe²⁺， LPO， and ROS in myocardial tissue was significantly increased （P<0.01）. The content of GSH was significantly decreased （P<0.01）， and T-GSH/GSSG was decreased （P<0.01）. The protein and mRNA expressions of GPX4 and FTH1 in myocardial tissue were both significantly decreased （P<0.05， P<0.01）， while those of ACSL4 and LPCAT3 increased significantly （P<0.01）. Compared with the model group， the general macroscopic symptoms and electrocardiogram results of rats in low-， medium- and high-dose groups of Xuefu Zhuyutang were alleviated， and the differences in LVEF/LVFS ratios were all significantly increased （P<0.05， P<0.01）. The differences in whole-blood viscosity （low， medium， and high rate of shear） were all significantly decreased （P<0.01）. The results of HE staining and transmission electron microscopy showed that the morphology， structure， and mitochondria of cardiomyocytes were improved. The content of 12-HETE and 15-HETE in serum was reduced to different degrees in low-， medium-， and high-dose groups of Xuefu Zhuyutang （P<0.05， P<0.01）. The content of Fe²⁺， LPO， and ROS was significantly reduced in the medium- and high-dose groups of Xuefu Zhuyutang （P<0.05， P<0.01）， and the content of GSH and T-GSH/GSSG was significantly increased （P<0.05， P<0.01）. The protein and mRNA expressions of GPX4 and FTH1 were significantly increased to varying degrees in the medium- and high-dose groups of Xuefu Zhuyutang （P<0.05， P<0.01）， and ACSL4 and LPCAT3 were decreased to different degrees in the low-， medium-， and high-dose groups of Xuefu Zhuyutang （P<0.05， P<0.01）. ConclusionXuefu Zhuyutang can regulate iron metabolism and anti-lipid oxidation reaction to mediate ferroptosis through the ACSL4 signalling pathway， thus exerting a protective effect on rats with coronary heart disease with blood stasis syndrome.

OBJECTIVE To evaluate the influence of gene polymorphism on plasma minimum concentration （cmin） of voriconazole （VRZ） in patients with invasive fungal infection. METHODS The Cochrane Library， Embase， PubMed， Web of Science， China Biomedical Literature Database， CNKI， VIP and Wanfang Data were searched for literature on the correlation between gene polymorphisms and cmin of VRZ from inception to April 2024. After screening the literature， extracting data， and evaluating the quality of the literature， meta-analysis was performed using R 4.3.2 software. RESULTS A total of 21 studies with 2 454 patients were included. The results of meta-analysis showed that the VRZ cmin of CYP2C19 IM and PM types was significantly higher than EM type， and the VRZ cmin of IM type was significantly lower than PM type （P＜0.01）. The VRZ cmin of CYP2C9 rs1057910 AA type was significantly higher than AC/CC type， and that of CYP3A5 rs776746 CC type was significantly higher than TT type （P＜0.01）. The VRZ cmin of POR rs10954732 GG type was significantly higher than GA and AA types， and that of POR rs1057868 CT type was significantly lower than TT type （P＜0.01）. The VRZ cmin of ABCB1 rs1045642 CC type was significantly higher than TT type （P＜0.05）. The VRZ cmin of NR1I2 rs2472677 CT type was significantly higher than TT type， and rs7643645 AA type was significantly higher than AG type （P＜0.05）. The VRZ cmin of ABCC2 rs717620 CC type was significantly lower than CT type and TT type， and the CT type was significantly lower than TT type （P＜0.01）. CONCLUSIONS Mutant alleles in CYP2C19， CYP2C9 rs1057910， CYP3A5 rs776746， POR rs10954732， ABCB1 rs1045642 and NR1I2 rs7643645 can lead to a decrease in VRZ plasma concentration， and mutant allele in ABCC2 rs717620 can lead to an increase in VRZ plasma concentration.

OBJECTIVE To evaluate the influence of gene polymorphism on plasma minimum concentration （cmin） of voriconazole （VRZ） in patients with invasive fungal infection. METHODS The Cochrane Library， Embase， PubMed， Web of Science， China Biomedical Literature Database， CNKI， VIP and Wanfang Data were searched for literature on the correlation between gene polymorphisms and cmin of VRZ from inception to April 2024. After screening the literature， extracting data， and evaluating the quality of the literature， meta-analysis was performed using R 4.3.2 software. RESULTS A total of 21 studies with 2 454 patients were included. The results of meta-analysis showed that the VRZ cmin of CYP2C19 IM and PM types was significantly higher than EM type， and the VRZ cmin of IM type was significantly lower than PM type （P＜0.01）. The VRZ cmin of CYP2C9 rs1057910 AA type was significantly higher than AC/CC type， and that of CYP3A5 rs776746 CC type was significantly higher than TT type （P＜0.01）. The VRZ cmin of POR rs10954732 GG type was significantly higher than GA and AA types， and that of POR rs1057868 CT type was significantly lower than TT type （P＜0.01）. The VRZ cmin of ABCB1 rs1045642 CC type was significantly higher than TT type （P＜0.05）. The VRZ cmin of NR1I2 rs2472677 CT type was significantly higher than TT type， and rs7643645 AA type was significantly higher than AG type （P＜0.05）. The VRZ cmin of ABCC2 rs717620 CC type was significantly lower than CT type and TT type， and the CT type was significantly lower than TT type （P＜0.01）. CONCLUSIONS Mutant alleles in CYP2C19， CYP2C9 rs1057910， CYP3A5 rs776746， POR rs10954732， ABCB1 rs1045642 and NR1I2 rs7643645 can lead to a decrease in VRZ plasma concentration， and mutant allele in ABCC2 rs717620 can lead to an increase in VRZ plasma concentration.

ObjectiveTo clarify the protective effect of Danlou tablet， a representative traditional Chinese medicine of the stagnation of phlegm and blood stasis co-treatment method， on vascular endothelial function in patients with atherosclerosis （AS）. MethodsA randomized controlled trial was conducted. From September 2023 to November 2023， a total of 72 patients who were diagnosed at Guang'anmen Hospital， China Academy of Chinese Medical Sciences and met the inclusion and exclusion criteria for carotid atherosclerosis （CAS） combined with coronary atherosclerotic heart disease （CHD） and stable angina pectoris （SAP） were enrolled. The patients were randomly divided into a control group （receiving conventional Western medicine treatment） and an observation group （receiving Danlou tablet combined with conventional Western medicine treatment）， with 36 cases in each group. The intervention lasted for 12 weeks. The frequency of angina pectoris attacks was recorded to evaluate the clinical efficacy of Danlou tablet. Peripheral blood samples were collected from patients， and the expression levels of serum endothelial injury markers before and after treatment were detected by enzyme-linked immunosorbent assay （ELISA）. The nitrate reductase method was employed to evaluate the protective effect of Danlou tablet on vascular function. The expression levels of serum inflammatory factors and lipoproteins were determined by ELISA and an automatic biochemical analyzer （dynamic timed scatter turbidimetry and enzymatic method） to assess the anti-inflammatory and lipid-regulating effects of Danlou tablet. ResultsIn terms of angina pectoris attacks， compared with that in the control group， the frequency of attacks in the observation group was reduced （P<0.05）. In terms of endothelial injury markers， compared with the levels before treatment within the same group， the levels of endothelin-1 （ET-1）， intercellular adhesion molecule-1 （ICAM-1）， and vascular cell adhesion molecule-1 （VCAM-1） in the peripheral blood of the observation group were decreased （P<0.05）， while the levels of nitric oxide （NO） and vascular endothelial growth factor （VEGF） were increased （P<0.05）. Compared with the control group after treatment， the differences in ET-1， NO， ICAM-1， and VCAM-1 were significant （P<0.05）. In terms of serum inflammatory factors， after treatment， the interleukin-6 （IL-6） level in the observation group was decreased significantly （P<0.05）. Compared with the control group after treatment， the IL-6 level in the observation group was decreased significantly （P<0.01）. In terms of serum lipoproteins， after treatment， the level of low-density lipoprotein cholesterol （LDL-C） in the observation group was decreased （P<0.05）. After treatment， the level of high-density lipoprotein cholesterol （HDL-C） in the observation group was significantly higher than that in the control group （P<0.05）. In terms of safety evaluation， no serious adverse events occurred in either group during the intervention period. ConclusionDanlou tablet applied to patients with CAS combined with CHD can improve endothelial function， reduce inflammatory indicators， alleviate symptoms， improve the quality of life of patients， and demonstrate good safety.

ObjectiveTo clarify the protective effect of Danlou tablet， a representative traditional Chinese medicine of the stagnation of phlegm and blood stasis co-treatment method， on vascular endothelial function in patients with atherosclerosis （AS）. MethodsA randomized controlled trial was conducted. From September 2023 to November 2023， a total of 72 patients who were diagnosed at Guang'anmen Hospital， China Academy of Chinese Medical Sciences and met the inclusion and exclusion criteria for carotid atherosclerosis （CAS） combined with coronary atherosclerotic heart disease （CHD） and stable angina pectoris （SAP） were enrolled. The patients were randomly divided into a control group （receiving conventional Western medicine treatment） and an observation group （receiving Danlou tablet combined with conventional Western medicine treatment）， with 36 cases in each group. The intervention lasted for 12 weeks. The frequency of angina pectoris attacks was recorded to evaluate the clinical efficacy of Danlou tablet. Peripheral blood samples were collected from patients， and the expression levels of serum endothelial injury markers before and after treatment were detected by enzyme-linked immunosorbent assay （ELISA）. The nitrate reductase method was employed to evaluate the protective effect of Danlou tablet on vascular function. The expression levels of serum inflammatory factors and lipoproteins were determined by ELISA and an automatic biochemical analyzer （dynamic timed scatter turbidimetry and enzymatic method） to assess the anti-inflammatory and lipid-regulating effects of Danlou tablet. ResultsIn terms of angina pectoris attacks， compared with that in the control group， the frequency of attacks in the observation group was reduced （P<0.05）. In terms of endothelial injury markers， compared with the levels before treatment within the same group， the levels of endothelin-1 （ET-1）， intercellular adhesion molecule-1 （ICAM-1）， and vascular cell adhesion molecule-1 （VCAM-1） in the peripheral blood of the observation group were decreased （P<0.05）， while the levels of nitric oxide （NO） and vascular endothelial growth factor （VEGF） were increased （P<0.05）. Compared with the control group after treatment， the differences in ET-1， NO， ICAM-1， and VCAM-1 were significant （P<0.05）. In terms of serum inflammatory factors， after treatment， the interleukin-6 （IL-6） level in the observation group was decreased significantly （P<0.05）. Compared with the control group after treatment， the IL-6 level in the observation group was decreased significantly （P<0.01）. In terms of serum lipoproteins， after treatment， the level of low-density lipoprotein cholesterol （LDL-C） in the observation group was decreased （P<0.05）. After treatment， the level of high-density lipoprotein cholesterol （HDL-C） in the observation group was significantly higher than that in the control group （P<0.05）. In terms of safety evaluation， no serious adverse events occurred in either group during the intervention period. ConclusionDanlou tablet applied to patients with CAS combined with CHD can improve endothelial function， reduce inflammatory indicators， alleviate symptoms， improve the quality of life of patients， and demonstrate good safety.

Sennoside A (SA), a typical prodrug, exerts its laxative effect only after its transformation into rheinanthrone catalyzed by gut microbial hydrolases and reductases. Hydrolases have been identified, but reductases remain unknown. By linking a photoreactive group to the SA scaffold, we synthesized a photoaffinity probe to covalently label SA reductases and identified SA reductases using activity-based protein profiling (ABPP). From lysates of an active strain, Bifidobacterium pseudocatenulatum (B. pseudocatenulatum), 397 proteins were enriched and subsequently identified using mass spectrometry (MS). Among these proteins, chromate reductase/nicotinamide adenine dinucleotide (NADH) phosphate (NADPH)-dependent flavin mononucleotide (FMN) reductase/oxygen-insensitive NADPH nitroreductase (nfrA) was identified as a potent SA reductase through further bioinformatic analysis and The Universal Protein Resource (UniProt) database screening. We also determined that recombinant nfrA could reduce SA. Our study contributes to further illuminating mechanisms of SA transformation to rheinanthrone and simultaneously offers an effective method to identify gut bacterial reductases.

Gastric cancer (GC) is characterized by high morbidity and mortality rates. Chinese agarwood comprises the resin-containing wood of Aquilaria sinensis (Lour.) Gilg., traditionally utilized for treating asthma, cardiac ischemia, and tumors. However, comprehensive research regarding its anti-GC effects and underlying mechanisms remains limited. In this study, Chinese agarwood petroleum ether extract (CAPEE) demonstrated potent cytotoxicity against human GC cells, with half maximal inhibitory concentration (IC₅₀) values for AGS, HGC27, and MGC803 cells of 2.89, 2.46, and 2.37 μg·mL^-1, respectively, at 48 h. CAPEE significantly induced apoptosis in these GC cells, with B-cell lymphoma-2 (BCL-2) associated X protein (BAX)/BCL-2 antagonist killer 1 (BAK) likely mediating CAPEE-induced apoptosis. Furthermore, CAPEE induced G₀/G₁ phase cell cycle arrest in human GC cells via activation of the deoxyribonucleic acid (DNA) damage-p21-cyclin D1/cyclin-dependent kinase 4 (CDK4) signaling axis, and increased Fe²⁺, lipid peroxides and reactive oxygen species (ROS) levels, thereby inducing ferroptosis. Ribonucleic acid (RNA) sequencing, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting analyses revealed CAPEE-mediated upregulation of heme oxygenase-1 (HO-1) in human GC cells. RNA interference studies demonstrated that HO-1 knockdown reduced CAPEE sensitivity and inhibited CAPEE-induced ferroptosis in human GC cells. Additionally, CAPEE administration exhibited robust in vivo anti-GC activity without significant toxicity in nude mice while inhibiting tumor cell growth and promoting apoptosis in tumor tissues. These findings indicate that CAPEE suppresses human GC cell growth through upregulation of the DNA damage-p21-cyclin D1/CDK4 signaling axis and HO-1-mediated ferroptosis, suggesting its potential as a candidate drug for GC treatment.
Animals ; Humans ; Mice ; Antineoplastic Agents, Phytogenic ; Apoptosis/drug effects* ; Cell Line, Tumor ; Cyclin D1/genetics* ; Cyclin-Dependent Kinase 4/genetics* ; DNA Damage/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Ferroptosis/drug effects* ; G1 Phase Cell Cycle Checkpoints/drug effects* ; Heme Oxygenase-1/genetics* ; Mice, Inbred BALB C ; Mice, Nude ; Plant Extracts/pharmacology* ; Stomach Neoplasms/physiopathology* ; Thymelaeaceae/chemistry* ; Up-Regulation/drug effects*

Background::Hepatic ischemia-reperfusion injury (HIRI) remains a common complication during liver transplantation (LT) in patients. As a key downstream effector of the Hippo pathway, Yes-associated protein (YAP) has been reported to be involved in various physiological and pathological processes. However, it remains elusive whether and how YAP may control autophagy activation during ischemia-reperfusion.Methods::Human liver tissues from patients who had undergone LT were obtained to evaluate the correlation between YAP and autophagy activation. Both an in vitro hepatocyte cell line and in vivo liver-specific YAP knockdown mice were used to establish the hepatic ischemia-reperfusion models to determine the role of YAP in the activation of autophagy and the mechanism of regulation. Results::Autophagy was activated in the post-perfusion liver grafts during LT in patients, and the expression of YAP positively correlated with the autophagic level of hepatocytes. Liver-specific knockdown of YAP inhibited hepatocytes autophagy upon hypoxia-reoxygenation and HIRI ( P <0.05). YAP deficiency aggravated HIRI by promoting the apoptosis of hepatocytes both in the in vitro and in vivo models ( P <0.05). Attenuated HIRI by overexpression of YAP was diminished after the inhibition of autophagy with 3-methyladenine. In addition, inhibiting autophagy activation by YAP knockdown exacerbated mitochondrial damage through increasing reactive oxygen species ( P <0.05). Moreover, the regulation of autophagy by YAP during HIRI was mediated by AP1 (c-Jun) N-terminal kinase (JNK) signaling through binding to the transcriptional enhanced associate domain (TEAD). Conclusions::YAP protects against HIRI by inducing autophagy via JNK signaling that suppresses the apoptosis of hepatocytes. Targeting Hippo (YAP)-JNK-autophagy axis may provide a novel strategy for the prevention and treatment of HIRI.

Objective:To analyze the acupoint selection law in treating insomnia with warming-needle moxibustion using data mining technology.Methods:The clinical research literature on warming-needle moxibustion in treating insomnia was retrieved from the databases of CNKI, VIP, Wanfang Data, China Medical Journal Full-text Database, SinoMed, PubMed from the establishment of the databases to June 30, 2023. Acupuncture prescriptions were extracted and a database was established. Descriptive analysis was carried out on the intervention measures, the number of moxibustion numbers, the total effective rate, and the relevant information of acupoint selection. Clustering analysis and association rule analysis by using SPSS Statistics 26.0, SPSS Modeler 18.0 were performed on the high-frequency acupoints used in body acupuncture and warming acupuncture, respectively.Results:A total of 67 articles about warming-needle moxibustion for insomnia were included. The main intervention was single warming-needle moxibustion, followed by combined auricular acupuncture. Moxibustion with moxa sticks of 1 to 2 cm in length was often used. The total effective rate was mostly between 92% and 94%. A total of 85 prescriptions were obtained, involving 55 acupoints (569 times in frequency), among which Baihui (DU 20) (55 times), Shenmen (HT 7) (54 times) and Sanyinjiao (SP 6) (45 times) were widely used. The selected acupoints were mainly distributed on the head, face, back and waist, and the affiliated meridians were mainly bladder meridian, Governor Vessel and heart meridian. The specific acupoints were mainly crossing points, followed by back-shu acupoints. Clustering analysis of high-frequency acupoints obtained three effective groups, including "Xinshu (BL 15)- Pishu (BL 20) - Shenshu (BL 23) - Ganshu (BL 18)", etc. Baihui (DU 20) and Shenmen (HT 7) were the most relevant acupoint combinations. A total of 44 acupoints (frequency 272 times) were involved in the selection of warming acupuncture, among which Sanyinjiao (SP 6) (32 times), Xinshu (BL 15) (23 times) and Pishu (BL 20) (23 times) were more frequently used. Clustering analysis of high-frequency acupoints obtained three effective groups, including "Xinshu (BL 15)- Pishu (BL 20) - Shenshu (BL 23) - Ganshu (BL 18)", etc. Pishu (BL 20) and Xinshu (BL 15) were the most relevant acupoint combinations.Conclusions:Warming-needle moxibustion for the treatment of insomnia focuses on the application of acupoints on the bladder meridian on the back and waist, cooperates with the selection of acupoints on the head and face, and attaches importance to the application of intersection points in specific acupoints. The selection of acupoints by warming-needle moxibustion is mainly based on the back-shu acupoints of zang-fu organs, which plays the role of balancing yin and yang, regulating zang-fu organs, tonifying deficiency and tranquilizing mind to help sleep.

Objective:Patients with acute exacerbation of chronic obstructive pulmonary disease(AECOPD)combined with severe type Ⅱ respiratory failure have a high probability of ventilation failure using conventional non-invasive positive pressure ventilation(NPPV).This study aims to investigate the clinical efficacy of high intensity NPPV(HI-NPPV)for the treatment of AECOPD combined with severe type Ⅱ respiratory failure. Methods:The data of patients with AECOPD combined with severe type Ⅱ respiratory failure(blood gas analysis pH≤7.25)treated with NPPV in the Second Affiliated Hospital of Chongqing Medical University from July 2013 to July 2023 were collected to conduct a retrospective case-control study.The patients were divided into 2 groups according to the inspired positive airway pressure(IPAP)used during the NPPV treatment:a NPPV group(IPAP<20 cmH2O,1 cmH2O=0.098 kPa)and a HI-NPPV group(20 cmH2O≤IPAP<30 cmH2O).Ninety-nine and 95 patients were included in the NPPV group and the HI-NPPV group,respectively.A total of 86 pairs of data were matched using propensity score matching(PSM)for data matching.The primary outcome indexes(mortality and tracheal intubation rate)and secondary outcome indexes[blood gas analysis pH,arterial partial pressure of oxygen(PaO2)and arterial partial pressure of carbon dioxide(PaCO2),adverse reaction rate,and length of hospitalization]were compared between the 2 groups. Results:The tracheal intubation rates of the NPPV group and the HI-NPPV group were 6.98％and 1.16％,respectively,and the difference between the 2 groups was statistically significant(χ2=4.32,P<0.05);the mortality of the NPPV group and the HI-NPPV group was 23.26％and 9.30％,respectively,and the difference between the 2 groups was statistically significant(χ2=11.64,P<0.01).The PaO2 at 24 h and 48 h after treatment of the HI-NPPV group was higher than that of the NPPV group,and the PaCO2 of the HI-NPPV group was lower than that of the NPPV group,and the differences were statistically significant(all P<0.05).The differences of pH at 24 h and 48 h after treatment between the 2 groups were not statistically significant(both P>0.05).The differences between the 2 groups in adverse reaction rate and hospitalization length were not statistically significant(both P>0.05). Conclusion:HI-NPPV can reduce mortality and tracheal intubation rates by rapidly improving the ventilation of patients with AECOPD combined with severe type Ⅱ respiratory failure.This study provides a new idea for the treatment of patients with AECOPD combined with severe type Ⅱ respiratory failure.