Gefitinib is the well-tolerated first-line treatment of non-small cell lung cancer. As it needs analgesics during oncology treatment, particularly in the context of the coronavirus disease, where patients are more susceptible to contract high fever and sore throat.This has increased the likelihood of taking both gefitinib and antipyretic analgesic acetaminophen (APAP). Given that gefitinib and APAP overdose can predispose patients to liver injury or even acute liver failure, there is a risk of severe hepatotoxicity when these two drugs are used concomitantly. However, little is known regarding their safety at therapeutic doses. This study simulated the administration of gefitinib and APAP at clinically relevant doses in an animal model and confirmed that gefitinib in combination with APAP exhibited additional hepatotoxicity. We found that gefitinib plus APAP significantly exacerbated cell death, whereas each drug by itself had little or minor effect on hepatocyte survival. Mechanistically, combination of gefitinib and APAP induces hepatocyte death via the apoptotic pathway obviously. Reactive oxygen species (ROS) generation and DNA damage accumulation are involved in hepatocyte apoptosis. Gefitinib plus APAP also promotes the expression of Kelch-like ECH-associated protein 1 (Keap1) and downregulated the antioxidant factor, Nuclear factor erythroid 2-related factor 2 (Nrf2), by inhibiting p62 expression.Taken together, this study revealed the potential ROS-mediated apoptosis-dependent hepatotoxicity effect of the combination of gefitinib and APAP, in which the p62/Keap1/Nrf2 signaling pathway participates and plays an important regulatory role.

Objective Calculus Bovis(CB)is a kind of valuable traditional Chinese medicine,which has been used in clinic for a long time.It has been shown to have significant anti-stroke,anti-inflammatory and anti-tumor effects.But its mechanism for treating Prostate cancer(PCa)remains unclear.The purpose of this study was to explore the target and mechanism of its action in the treatment of prostate cancer throμgh network pharmacology and in vitro and in vivo experiments.Methods The effective compounds of Calculus Bovis were collected by TCM pharmacology database and analysis platform(TCMSP).Search for potential compound targets in TCMSP.Search the Drμgbank,GeneCards,OMIM,PharmGkb,and TTD databases for disease targets associated with prost cancer.Disease and compound targets were integrated in the STRING database to construct their interaction network(PPI)to reveal the key targets of compound treatment for prostate cancer.In order to elucidate the mechanism of Calculus Bovis in the treatment of prostate cancer,GO functional enrichment and KEGG pathway enrichment analysis were conducted using Cytoscape software.The mechanism of treating prostate cancer with Calculus Bovis was studied in vitro and in vivo.Results A total of 11 compounds with anti-prostate cancer activity were identified.Oleanolic acid,ursolic acid,ergosterol,deoxycorticosterone,methylcholine and cholverdin were potential effective components.A total of 367 targets of Calculus Bovis compounds and 2152 targets of prostate cancer were found.The core targets of Calculus Bovis in the treatment of prostate cancer included TP53,STAT3,AKT1,HSP90AA1,ESR1,SRC,JUN,RELA,CCND1,CDKN1A,EGFR,AR,etc.The biological functions of Calculus Bovis mainly involve oxidative stress response,response to steroid hormones,cell response to chemical stress,peptide-serine modification and phosphorylation,and protein serine/threonine kinase activity.Calculus Bovis treatment of prostate cancer mainly involves PI3K-AKT signaling pathway,TNF signaling pathway,MAPK signaling pathway,etc.In vitro and in vivo experiments showed that Calculus Bovis promoted apoptosis of PC3 cells of prostate cancer by inhibiting PI3K-AKT signaling pathway.Conclusion Calculus Bovis has a therapeutic effect on prostate cancer,and its function is related to inhibiting PI3K-AKT signaling pathway and promoting apoptosis of cancer cells.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is characterized by diffuse alveolar injury primarily caused by an excessive inflammatory response. Regrettably, the lack of effective pharmacotherapy currently available contributes to the high mortality rate in patients with this condition. Xuebijing (XBJ), a traditional Chinese medicine recognized for its potent anti-inflammatory properties, exhibits promise as a potential therapeutic agent for ALI/ARDS. This study aimed to explore the preventive effects of XBJ on ALI and its underlying mechanism. To this end, we established an LPS-induced ALI model and treated ALI mice with XBJ. Our results demonstrated that pre-treatment with XBJ significantly alleviated lung inflammation and increased the survival rate of ALI mice by 37.5%. Moreover, XBJ substantially suppressed the production of TNF-α, IL-6, and IL-1β in the lung tissue. Subsequently, we performed a network pharmacology analysis and identified identified 109 potential target genes of XBJ that were mainly involved in multiple signaling pathways related to programmed cell death and anti-inflammatory responses. Furthermore, we found that XBJ exerted its inhibitory effect on gasdermin-E-mediated pyroptosis of lung cells by suppressing TNF-α production. Therefore, this study not only establishes the preventive efficacy of XBJ in ALI but also reveals its role in protecting alveolar epithelial cells against gasdermin-E-mediated pyroptosis by reducing TNF-α release.
Animals ; Mice ; Alveolar Epithelial Cells ; Pyroptosis ; Gasdermins ; Lipopolysaccharides/adverse effects* ; Tumor Necrosis Factor-alpha ; Acute Lung Injury/drug therapy* ; Respiratory Distress Syndrome

OBJECTIVE: Identifying novel strategies to prevent particulate matter (PM)-induced lung injury is crucial for the reduction of the morbidity of chronic respiratory diseases. The combined intervention represented by herbal formulae for simultaneously targeting multiple pathological processes can provide a more beneficial effect than the single intervention. The aim of this paper is therefore to design a safe and effective medicinal and edible Chinese herbs (MECHs) formula against PM-induced lung injury. METHODS: PM-induced oxidative stress, inflammatory response and apoptosis A549 cell model were used to screen anti-oxidant, anti-inflammatory and anti-apoptotic MECHs, respectively. A network pharmacology method was utilized to rationally design a novel herbal formula. Ultra performance liquid chromatography-mass spectrometer was utilized to assess the quality control of MECHs formula. The excretion of magnetic iron oxide nanospheres of the MECHs formula was estimated in zebrafish. The MECH formula against PM-induced lung injury was investigated with mice experiments. RESULTS: Five selected herbs were rationally designed to form a new MECH formula, including Citri Exocarpium Rubrum (Juhong), Lablab Semen Album (Baibiandou), Atractylodis Macrocephalae Rhizoma (Baizhu), Mori Folium (Sangye) and Polygonati Odorati Rhizoma (Yuzhu). The formula effectively promoted the magnetic iron oxide nanospheres excretion in zebrafish. The mid/high dose formula significantly prevented PM-induced lung damage in mice by enhancing the activity of SOD and GSH-Px, reducing the MDA and ROS level and attenuating the upregulation of pro-inflammatory cytokine (IL-6, IL-8, IL-1β and TNF-α), down regulating the protein expression of NF-κB, STAT3 and Caspase-3. CONCLUSION Our findings suggest that the effective MECHs formula will become a novel strategy for preventing PM-induced lung injury and provide a paradigm for the development of functional foods using MECHs.

Objective To investigate the expression of miR-124 in glioblastoma (GBM) cell lines LN229 and LN229R,as well as the regulatory mechanism of miR-124 on radiosensitivity of LN229R cells.Methods miR-124 mimic (miR-124) and negative control (miR-NC),STAT3 overexpression plasmid (STAT3) and pcDNA3.1 vector (pcDNA) were transfected or co-transfected into radioresistant glioma cells LN229R.qRT-PCR was employed to analyze the expression of miR-124 in LN229 and LN229R cells.The survival rate and sensitivity-related parameters of LN229R cells at different doses were analyzed by cloning formation assay.Cell apoptosis of LN229R was evaluated by flow cytometry.Targeting gene of miR-124 was predicted using Targetscan software and verified by the double-luciferase reporter assay.Western blot assay was performed to detect STAT3 protein expression.Results The expression of miR-124 in LN229R cells (0.32 ± 0.03) was significantly lower than that in LN229 cells (1.02 ± 0.09) (t =12.780,P＜0.05).Transfection of miR-124 mimics promoted the expression of miR-124 in LN229R cells (4.02±0.39) compared with miR-NC group (0.95±0.06) (t=13.476,P＜0.05).After 8 Gy irradiation,the survival rate of LN229R cells transfected with miR-124 mimics (0.003 ± 0.000 4) was significantly lower than that in miR-NC group (0.033±0.005 0) (t=5.655,P＜0.05),and the apoptosis rate (22.34±2.42) ％ was significantly higher than that in miR-NC group (4.69 ± 0.51) ％ (t =12.361,P＜0.05).STAT3 was identified to be a target gene of miR-124.Exogenous restoration of STAT3 reversed the inhibitory effect of miR-124 on LN229R cell survival.Conclusion miR-124 increases the radiosensitivity of LN229R cells by targeting STAT3.

Objective To compare the effectiveness of stereotactic hematoma aspiration and conservative treatment for supratentorial hypertensive intracerebral hemorrhage (HICH) with hematoma volume 25-40 ml. Methods Patients with supratentorial HICH admitted to the Department of Neurosurgery, the Fifth Affiliated Hospital of Zhengzhou University from January 2014 to January 2017 were retrospectively enrolled. The incidence of rebleeding, good outcome (defined as the modified Rankin Scale score 0-2 at 3 months after onset) rate, and mortality were compared between the stereotactic hematoma aspiration group and the conservative treatment group. Results A total of 204 patients were enrolled. Their mean age was 61. 3 ±9. 2 years, 114 were males, and their median hematoma volume was 32 ml (interquartile range 25- 39 ml), median baseline Glasgow Coma Scale score was 11 (interquartile range 9-14), and there was no patient with brain herniation. One hundred and twenty patients (58. 8％) underwent stereotactic hematoma aspiration and 84 (41. 2％) received conservative treatment. Compared with the conservative treatment group, the incidence of rebleeding in the stereotactic hematoma aspiration group was significantly lower (2. 5％ vs. 22. 6％, χ2 =20. 788, P < 0. 001), and the rate of good outcome was significantly higher at 3 months after onset (85. 0％ vs. 70. 2％; χ2 = 8. 305, P = 0. 004 ), but there was no significant difference in mortality (5. 0％ vs. 11. 9％, χ2 =3. 259, P =0. 071). Multivariable logistic regression analysis showed that advanced age (odds ratio [OR] 1. 77, 95％ confidence interval [CI] 1. 25-2. 46; P = 0. 006), previous stroke history (OR 1. 36, 95％ CI 1. 12-1. 64; P =0. 032), and conservative treatment (OR 1. 42, 95％ CI 1. 25-1. 78; P = 0. 021) were the independent risk factors for poor outcomes. Conclusions Stereotactic hematoma aspiration can significantly reduce the incidences of rebleeding and risk of the poor outcome in the supratentorial HICH patients with hematoma volume 25-40 ml. Therefore, early active surgical treatment should be considered.

Objective:To study the formula of triptolide (TRI) self-microemulsifying drug delivery system (SMEDDS) and evaluate the pharmaceutical properties.Methods:The formula and preparation process of triptolide self-microemulsion were screened by the solubility test and pseudo-ternary phase diagram.With the average particle size and self-microemulsifying time as the indices,the further formula optimization of triptolide self-microemulsion was carried out.The pharmaceutical properties of triptolide self-microemulsion were evaluated.Results:The optimal formula of TRI SMEDDS was as follows:the amount of medium chain triglycerides (MCT) was 20%,that of polyoxyethylene castor oil (EL-35) was 40%,and that of polyethylene glycol 400 (PEG-400) was 40% in the oil phase.The average particle size was 43.48 nm,and the time of self-microemulsification was less than 30 s.Conclusion:The average particle size and the appearance of triptolide self-microemulsion are accordance with the requirements of pharmaceutics.Triptolide self-microemulsion has good sustained-release effect,which lays foundation for the further study on pharmacodynamics.

Objective To explore the down-regulation of advanced receptor for advanced glycation end products(RAGE)on expression of high mobility group protein B1(HMGB1)in glioma cells line and the volume change of transplanted tumor in nude mice. Methods HMGB1 expression in glioma LN229 cells line (divided into a control group and a study group) was observed by immunohistochemical assay and Western blot. The control group received normal saline,whereas the study group received RAGE receptor blocking agent FPS-ZM1. Expression of HMGB1 protein was detected by the same methods. The difference of the expression was examined by independent sample t test. 30 Nu/Nu nude mice were randomly divided into two groups;the above two kinds cell lines were injected into the same area of the left back of nude mice. Six weeks after injection ,the volume size was measured six times ,and the variance of repeated measurement data was used to analyze the difference of the volume change. Results HMGB1 protein was mainly expressed in the cytoplasm and nucleus. As compared with the control group,HMGB1 protein expression levels were decreased in the study group(P < 0.05),the growth rate of transplanted tumor in nude mice was significantly faster in the control group than in the study group ,the difference was statistically significant(P < 0.05). Conclusions The growth and invasion of HMGB1 protein may be involved in glioma by RAGE receptor. RAGE receptor blocker FPS-ZM1 can significantly reduce the expression of HMGB1 protein and inhibit the growth of transplanted tumor volume. It is expected to be used for the research on glioma cell apoptosis.

Objective: To establish a method for the determination of norcantharidin in norcantharidin in situ gel .Methods:An optimal HPLC method was set up and an Agilent ZORBAX SB-C18 column (150 mm ×4.6 mm, 5μm) was adopted.The mobile phase was acetonitrile-phosphate buffer solution(1∶9, adjusting pH to 3.1 with phosphorjc acid).The flow rate was 0.8 ml· min-1 and the column temperature was 25℃.The detection wavelength was set at 210 nm and the injection volume was 20μl.Results:Norcanthari-din had a good linear relationship within the range of 0.02-1.00 mg· ml-1 (r=0.999 9).The average recovery was 97.5%and RSD was 0.98%(n=9).Conclusion:The method is accurate, simple and reproducible, which can be used for the determination of nor-cantharidin in norcantharidin in situ gel .

Objective To investigate the feasibility, safety and effectiveness of stent-assisted coil embolization for the treatment of intracranial wide-necked aneurysms. Methods The clinical and imaging data of the patients with intracranial wide-necked aneurysm treated with stent-assisted coil embolization were analyzed retrospectively. Results A total of 200 patients with 205 aneurysms were enrolled. The mortality was 1. 5% and the disability rate was 1. 0% at discharge. One hundred seventy-seven patients were followed up for 16-51 months. The modified Rankin Scale scores: 0 in 174 cases, 2 in 2 cases, 4 in 1 case. Eleven patients (5. 5% ) had perioperative complications, including intraoperative bleeding in 3 cases, postoperative bleeding in 3 cases, postoperative cerebral infarction in 2 cases, coil protrusion in 2 cases, and postoperative epileptic seizure in 1 case. Univariate analysis showed that there were significant differences in the proportions of male patients (9. 1% vs. 5. 3% ; χ2 = 4. 42, P = 0. 026), hypertension (54. 5% vs. 23. 3% ; χ2 = 5. 42, P = 0. 03) and stent prior to coil implantation (54. 5% vs. 85. 1% ; χ2 = 3. 54, P =0. 021) between the complication group and the noncomplication group. Multivariate logistic regression analysis showed that the pre-stenting was an independent protective factor for surgery-related complications (odds ratio [OR] 0. 208, 95% confidence interval [CI] 0. 055-0. 791; P = 0. 021), and hypertension was an independent risk factor for surgery-related complications (OR 4. 380, 95% CI 1. 170-16. 399; P = 0. 028). The imaging follow-up of 167 aneurysms was obtained, including 26 recurrent aneurysms (15. 6% ). Univariate analysis showed that there was significant difference in the aneurysm site (anterior circulation aneurysms: 73. 1% vs. 89. 1% ; posterior circulation aneurysms: 26. 9% vs. 10. 6% ; χ2 = 5. 09, P = 0. 033) and size (giant aneurysms: 7. 7% vs. 0. 7% ; large artery aneurysm: 65. 4% vs. 29. 1% ; small aneurysms:26. 9% vs. 70. 2% ; χ2 = 20. 77, P < 0. 001) between the recurrence group and the nonrecurrence group. Multivariate logistic regression analysis showed that large aneurysms (OR 6. 057, 95% CI 2. 296-5. 983; P <0. 001), giant aneurysms (OR 25. 260, 95% CI 1. 903- 335. 267; P = 0. 014 ), and posterior circulation aneurysms ( OR 3. 184, 95% CI 1. 028- 9. 857; P = 0. 045 ) were the independent risk factors of postoperative recurrence. Conclusions Stent-assisted coil embolization is one of the effective methods for the treatment of complex wide-neck aneurysms. Hypertension and coils prior to stenting are the independent risk factors for perioperative complications, and larger aneurysm size and aneurysms in the posterior circulation are the independent risk factors for postoperative recurrence.