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 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.

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*

ObjectiveThe antitumor activity of sesquiterpenoid M36 isolated from Myrrha against human hepatoma HepG2 cells was investigated in this study. MethodHepG2 cells were treated with M36 at different concentrations （0， 2， 4， 6， 8， 10 μmol·L^-1）. Firstly， the effects of M36 on the proliferation of human hepatoma HepG2 cells were detected by methyl thiazolyl tetrazolium （MTT）， colony formation assay， and EdU proliferation assay. Hoechst staining， flow cytometry analysis， and Western blot were used to explore the effect of M36 on the apoptosis of human hepatoma HepG2 cells. Acridine orange staining and western blotting were used to examine the effect of M36 on autophagy in HepG2 cells. Finally， Western blot was used to detect protein expression of cancer-related signaling pathways. ResultCompared with the blank group， M36 treatment significantly inhibited the proliferation of human hepatoma HepG2 cells （P<0.01）， and the half inhibitory concentration （IC₅₀） value of M36 for 48 h was 5.03 μmol·L^-1， in a dose- and time-dependent manner. M36 was also able to induce apoptosis and autophagy in human hepatoma HepG2 cells. After treatment with 8 μmol·L^-1 M36 for 48 hours， the apoptosis rate of HepG2 cells was （42.03±9.65）% （P<0.01）. Compared with the blank group， HepG2 cells treated with 4 and 8 μmol·L^-1 M36 for 48 h had a significant increase in cleaved poly ADP-ribose polymerase （cleaved-PARP） protein levels （P<0.01）. Acridine orange staining showed that autophagy was significantly activated in HepG2 cells treated with 4 and 8 μmol·L^-1 M36 for 48 h compared with the blank group （P<0.01）， which was further verified by the up-regulation of microtubule-associated protein 1 light chain 3 Ⅱ （LC3 Ⅱ）. Western blot results showed that compared with the blank group， the levels of phosphorylated extracellular regulated protein kinase （p-ERK）， phosphorylated p38 mitogen-activated protein kinase （p-p38 MAPK）， phosphorylated c-Jun N-terminal kinase （p-JNK）， and its downstream nuclear transcription factors c-Jun and p-c-Jun protein were significantly increased in M36 group （P<0.05， P<0.01）. The mechanism may be related to the up-regulation of MAPK signaling pathway. ConclusionThe sesquiterpenoid M36 isolated from Myrrha inhibits the proliferation of human hepatoma HepG2 cells and promotes apoptosis and autophagy， which may be related to the activation of the MAPK signaling pathway.

In recent years, the number of lung surgeries has increased year by year, and the number of patients with postoperative cough has also increased gradually. Chronic cough after lung surgery seriously affects patients' quality of life and surgical outcome, and has become one of the clinical problems that clinicians need to solve. However, there is currently no guideline or consensus for the treatment of chronic cough after lung surgery in China, and there is no standardized treatment method. Therefore, we searched databases such as PubMed, Web of Science, CNKI, and Wanfang databases ect. from 2000 to 2023 to collected relevant literatures and research data, and produced the first expert consensus on chronic cough after lung surgery in China by Delphi method. We gave 11 recommendations from five perspectives including timing of chronic cough treatment, risk factors (surgical method, lymph node dissection method, anesthesia method), prevention methods (preoperative, intraoperative, postoperative), and treatment methods (etiological treatment, cough suppressive drug treatment, traditional Chinese medicine treatment, and postoperative physical therapy). We hope that this consensus can improve the standardization and effectiveness of chronic cough treatment after lung surgery, provide reference for clinical doctors, and ultimately improve the quality of life of patients with chronic cough after lung surgery.

Cold and heat belong to the eight-principal syndrome differentiation of traditional Chinese medicine， which can reflect the rise and fall of Yin and Yang in the body and the Yin and Yang nature of the disease. At present， traditional Chinese medicine has an inconsistent understanding of cold and heat in acute coronary syndrome. The emphasis on pathogenic factors of cold and heat is biased， and the elements of cold and heat syndrome are not fully reflected in the scale. Therefore， the literature has been reviewed from the perspectives of etiology， pathogenesis， symptom elements， and test signs with drugs. From the perspective of etiology， both cold evil and heat evil can increase the risk of acute coronary syndrome. It was previously believed that acute coronary syndrome occurs frequently in cold climates such as winter and spring. Based on this understanding， hot weather can also induce acute coronary syndrome， and different temperatures have different effects on patients of different ages and with different underlying diseases. In addition， artificial pathogenic factors such as excessive consumption of cold food and refrigeration air conditioners were added. From the perspective of pathogenesis， on the basis of the traditional ''asthenia in origin and asthenia in superficiality'' and ''phlegm stagnation''， it is found that Yin-cold and fire-heat can both cause paralysis of the heart chakra and pain induced by the blockage. The pathogenesis of acute coronary syndrome characterized by heat stagnation and coldness featuring heartburn should be distinguished from gastroesophageal reflux disease. Moreover， the pathogenesis of Yin cold coagulation and pulse stagnation and wind obstruction are different. The acute coronary syndrome is in line with the wind characteristics of frequent changes and can be treated with wind medicine. From the perspective of syndrome elements， the syndrome elements such as cold condensation， heat accumulation， and toxicity are analyzed， and the use of basic syndrome elements and their combination forms facilitates clinical and scientific research. In addition， according to the test sign with the drug， it can be seen that the attributes of cold and heat of traditional Chinese medicine prescriptions for acute coronary syndrome can be explained according to the temperature-sensitive transient receptor potential （TRP） ion channel， thus proving the pathogenesis of cold and heat of acute coronary syndrome.