A real-world study and network pharmacology analysis of EGFR-TKIs combined with ZLJT to delay drug resistance in advanced lung adenocarcinoma.

OBJECTIVE: This study aimed to explore the efficacy and safety of combining epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) with ZiLongJin Tablet (ZLJT) in delaying acquired resistance in advanced EGFR-mutant lung adenocarcinoma (LUAD) patients. Furthermore, we employed network pharmacology and molecular docking techniques to investigate the underlying mechanisms. METHODS: A retrospective comparative study was conducted on stage IIIc/IV LUAD patients treated with EGFR-TKIs alone or in combination with ZLJT at the Second Affiliated Hospital of the Air Force Medical University between January 1, 2017, and May 1, 2023. The study evaluated the onset of TKI resistance, adverse reaction rates, safety indicators (such as aspartate aminotransferase, alanine aminotransferase, and creatinine), and inflammatory markers (neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio) to investigate the impact of EGFR-TKI combined with ZLJT on acquired resistance and prognostic indicators. Additionally, we utilized the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine, PubChem, UniProt, and Swiss Target Prediction databases to identify the active ingredients and targets of ZLJT. We obtained differentially expressed genes related to EGFR-TKI sensitivity and resistance from the Gene Expression Omnibus database using the GSE34228 dataset, which included sensitive (n = 26) and resistant (n = 26) PC9 cell lines. The "limma" package in R software was employed to detect DEGs. Based on this, we constructed a protein‒protein interaction network, performed gene ontology and KEGG enrichment analyses, and conducted pathway network analysis to elucidate the correlation between the active ingredients in ZLJT and signaling pathways. Finally, molecular docking was performed using AutoDockVina, PYMOL 2.2.0, and Discovery Studio Client v19.1.0 software to simulate spatial and energy matching during the recognition process between predicted targets and their corresponding compounds. RESULTS: (1) A total of 89 patients were included, with 40 patients in the EGFR-TKI combined with ZLJT group (combination group) and 49 patients in the EGFR-TKI alone group (monotherapy group). The baseline characteristics of the two groups were comparable. There was a significant difference in the onset of resistance between the combination group and the monotherapy group (P < 0.01). Compared to the monotherapy group, the combination group showed a prolongation of 3.27 months in delayed acquired resistance. There was also a statistically significant difference in the onset of resistance to first-generation TKIs between the two groups (P < 0.05). (2) In terms of safety analysis, the incidence of adverse reactions related to EGFR-TKIs was 12.5% in the combination group and 14.3% in the monotherapy group, but this difference was not statistically significant (P > 0.05). There were no statistically significant differences in serum AST, ALT, CREA, TBIL, ALB and BUN levels between the two groups after medication (P > 0.05). (3) Regarding inflammatory markers, there were no statistically significant differences in the changes in neutrophil-to-lymphocyte Ratio(NLR) and Platelet-to-lymphocyte Ratio(PLR) values before and after treatment between the two groups (P > 0.05). (4) Network pharmacology analysis identified 112 active ingredients and 290 target genes for ZLJT. From the GEO database, 2035 differentially expressed genes related to resistant LUAD were selected, and 39 target genes were obtained by taking the intersection. A "ZLJT-compound-target-disease" network was successfully constructed using Cytoscape 3.7.0. GO enrichment analysis revealed that ZLJT mainly affected biological processes such as adenylate cyclase-modulating G protein-coupled receptor. In terms of cellular components, ZLJT was associated with the cell projection membrane. The molecular function primarily focused on protein heterodimerization activity. KEGG enrichment analysis indicated that ZLJT exerted its antitumor and anti-drug resistance effects through pathways such as the PI3K-Akt pathway. Molecular docking showed that luteolin had good binding activity with FOS (-9.8 kJ/mol), as did tanshinone IIA with FOS (-9.8 kJ/mol) and quercetin with FOS (-8.7 kJ/mol). CONCLUSION: ZLJT has potential antitumor progression effects. For patients with EGFR gene-mutated non-small cell LUAD, combining ZLJT with EGFR-TKI treatment can delay the occurrence of acquired resistance. The underlying mechanisms may involve altering signal transduction pathways, blocking the tumor cell cycle, inhibiting tumor activity, enhancing cellular vitality, and improving the bioavailability of combination therapy. The combination of EGFR-TKI and ZLJT represents an effective approach for the treatment of tumors using both Chinese and Western medicine.

Correlation between lactate dehydrogenase and QTc interval prolongation in maintenance hemodialysis patients: a cross-sectional study.

BACKGROUND: Corrected QT (QTc) interval prolongation is one of the common causes of sudden cardiac death in patients with maintenance hemodialysis (MHD) patients. However, there are few studies on QTc prolongation in MHD patients. The concentration of lactate dehydrogenase (LDH) in hemodialysis population increased, and LDH was associated with the mortality of MHD patients. This study aimed to investigate the relationship between QTc interval prolongation and LDH in MHD patients. METHODS: This is a cross-sectional observational study. Patients who underwent MHD for more than 3 months in the Second Affiliated Hospital of Nantong University from November 2012 to November 2019 with complete data were selected as the research subjects. The patients were divided into the normal QTc interval group and the QTc interval prolongation group. The general data of patients and clinical laboratory indicators were collected retrospectively from the electronic medical record system. Pearson correlation analysis and binary logistic regression were used to analyze the correlation between LDH and QTc interval prolongation; the cut-off value of LDH predicting QTc interval prolongation was calculated by receiver operating characteristic (ROC) curve. RESULTS: The LDH level in the prolonged QTc interval group was significantly higher than that in the normal group (301.96±110.91 vs. 215.39±67.65, t=-8.03, P<0.001). QTc interval and LDH (r=0.386) were positively correlated. Binary logistic regression analysis showed that LDH, serum potassium <4 mmol/L, serum phosphorus, and left ventricular end-diastolic diameter (LVDd) were independent related factors for QTc interval prolongation. The ROC curve results showed that LDH =220 U/L was the best cutoff point for predicting QTc interval prolongation in MHD patients, with a sensitivity of 81.45% and a specificity of 59.35%. Binary logistic regression analysis showed that the LDH >220 U/L group was 6.34 times more likely to have QTc interval prolongation than the LDH ≤220 U/L group (OR 6.34, 95% CI: 3.47-11.58, P<0.001). CONCLUSIONS: LDH in MHD patients is closely related to QTc interval prolongation. Serum LDH, ionic calcium, serum phosphorus and potassium may predict QTc interval prolongation. Monitoring related indicators can remind clinicians to intervene as soon as possible to reduce the potential risk of arrhythmia and sudden cardiac death (SCD).

Effect of Pien Tze Huang against EV71 / 中国中药杂志

This study aims to investigate the inhibitory effect of Pien Tze Huang(PZH) on enterovirus 71(EV71). To be speci-fic, chemiluminescence method was adopted to evaluate the toxicity of PZH to African green monkey kidney(Vero) cells and human rhabdomyosarcoma(RD) cells, and cytopathic effect(CPE) method to assess the inhibition on EV71-GFP reporter virus and EV71 C4 wild-type virus. The results showed that PZH had low cytotoxicity to Vero cells and RD cells, with the half-maximal cytotoxic concentration(CC_(50)) of about 0.691 3-0.879 2 mg·mL~(-1) for the two. In addition, PZH can effectively inhibit the replication of EV71 within the non-cytotoxic concentration range, and dose-dependently alleviate the cytopathic changes caused by virus infection, with the half-maximal effective concentration(EC_(50)) of 0.009 2-0.106 3 mg·mL~(-1). On the basis of the above results, the green fluorescent protein(GFP), indirect immunofluorescence assay(IFA), and median tissue culture infective dose(TCID_(50)) were employed to assess and verify the anti-EV71-GFP and anti-EV71 C4 activity of PZH. The results demonstrated that PZH can dose-dependently lower the expression of GFP by EV71-GFP and structural protein VP-1 by EV71 C4 and decrease the production of progeny infectious viruses. The EC_(50) of PZH for EV71-GFP and EV71 C4 was about 0.006 0-0.006 2 mg·mL~(-1) and 0.006 6-0.025 6 mg·mL~(-1), respectively. This study suggested that PZH may exert antiviral activity by acting on EV71 and interfering with the expression of VP-1. At the moment, there is still a lack of specific anti-EV71 drugs. This study proposed a new idea for the symptomatic treatment of EV71 infections such as hand-foot-mouth disease and verified an effective drug for the treatment of EV71 infections.

Analysis of Molecular Mechanism of Erxian Decoction in Treating Osteoporosis Based on Formula Optimization Model.

Osteoporosis (OP) is a highly prevalent orthopedic condition in postmenopausal women and the elderly. Currently, OP treatments mainly include bisphosphonates, receptor activator of nuclear factor kappa-B ligand (RANKL) antibody therapy, selective estrogen receptor modulators, teriparatide (PTH1-34), and menopausal hormone therapy. However, increasing evidence has indicated these treatments may exert serious side effects. In recent years, Traditional Chinese Medicine (TCM) has become popular for treating orthopedic disorders. Erxian Decoction (EXD) is widely used for the clinical treatment of OP, but its underlying molecular mechanisms are unclear thanks to its multiple components and multiple target features. In this research, we designed a network pharmacology method, which used a novel node importance calculation model to identify critical response networks (CRNs) and effective proteins. Based on these proteins, a target coverage contribution (TCC) model was designed to infer a core active component group (CACG). This approach decoded the mechanisms underpinning EXD's role in OP therapy. Our data indicated that the drug response network mediated by the CACG effectively retained information of the component-target (C-T) network of pathogenic genes. Functional pathway enrichment analysis showed that EXD exerted therapeutic effects toward OP by targeting PI3K-Akt signaling (hsa04151), calcium signaling (hsa04020), apoptosis (hsa04210), estrogen signaling (hsa04915), and osteoclast differentiation (hsa04380) via JNK, AKT, and ERK. Our method furnishes a feasible methodological strategy for formula optimization and mechanism analysis and also supplies a reference scheme for the secondary development of the TCM formula.

Changes in the nutritional status of nine vitamins in patients with esophageal cancer during chemotherapy.

BACKGROUND: Many studies have investigated the relationships between vitamins and esophageal cancer (EC). Most of these studies focused on the roles of vitamins in the prevention and treatment of EC, and few studies have examined the changes in vitamin nutritional status and their influencing factors before and after chemotherapy for EC. Chemotherapy may have a considerable effect on EC patients' vitamin levels and hematological indicators. AIM: To research the nutritional status of multiple vitamins in EC patients during chemotherapy and to assess its clinical significance. METHODS: EC patients admitted to our center from July 2017 to September 2020 were enrolled in this study. Serum concentrations of nine vitamins (A, D, E, B9, B12, B1, C, B2 and B6), hemoglobin, total protein, albumin, blood calcium, blood phosphorus concentrations and body mass index (BMI) were measured in all EC patients. The changes in nine vitamins, hematological indicators and BMI were compared before and after two cycles of chemotherapy. The possible influential factors were analyzed. RESULTS: In total, 203 EC patients receiving chemotherapy were enrolled in this study. Varying degrees of vitamin A, D, C and B2 deficiency and weight loss were found in these patients, and the proportions of vitamin B2 and vitamin C deficiencies increased significantly after chemotherapy (both P < 0.05). Serum concentrations of vitamins A, C, B2 and B6 and BMI before and after chemotherapy were statistically significant (all P < 0.05). Multivariate analysis showed that vitamin A levels significantly differed between male and female EC patients, whereas vitamin D concentration significantly differed in EC patients in different stages (all P < 0.05). Correlations were observed between the changes in serum concentrations of vitamin A and C before and after two cycles chemotherapy and the change in BMI (P < 0.05). Hemoglobin, total protein, serum albumin and blood calcium concentrations significantly decreased in EC patients after chemotherapy (all P < 0.05), while the blood phosphorus level significantly increased after chemotherapy (P < 0.05). Using the difference in vitamin concentrations as the independent variables and the difference in BMI as the dependent variable, logistic regression analysis revealed statistically significant differences for vitamin A, vitamin D and vitamin C (F = 5.082, P = 0.002). CONCLUSION: Vitamin A, D, C and B2 were mainly deficient in patients with EC during chemotherapy. Multivitamin supplementation may help to improve the nutritional status, chemotherapy tolerance and efficacy.

[Research on application of fluorescence spectrum imaging method in Banlangen granule quality evaluation].

The curative effect of Banlangen granule is directly affected by its quality, so it is very important to choose a kind of effective method for testing it. The chemical treatment is needed as a pre-treatment for the quality testing by using common method at present, which will change or destroy the sample. For dealing with this problem, in the present paper, a fluorescence spectrum imaging experimental system based on LCTF (liquid crystal tunable filter) is set up to detect the characteristics fluorescence spectrum of Banlangen granules. The characteristic fluorescence spectrum curve of Banlangen standard material provided by Chinese Food Drugs Examination Research Institute is used as a reference substance for a comparison with other Banlangen granules. By normalizing the corresponding characteristic fluorescence spectrum of Banlangen granules of different raw materials, different manufacturers and different batches, the relationship between the characteristic fluorescence spectrum curve and the quality of Banlangen granule is discussed by using the method of comparative and cluster analysis. The experimental results show that the qualities of Banlangen granules are quite different from different manufacturers, which are basically reflected by the change in the intensity of fluorescence and peak position. All of these indicate that fluorescence spectrum imaging technology is a simple, rapid and nondestructive detection method for the quality control of Banlangen granule.

[Study of cortex phellodendri chinensis decoction experiment based on the spectral imaging technology].

The purpose of decoction traditional Chinese medicine is to make full exhalation of medicinal materials active ingredients, thus it has the maximum effect of traditional Chinese medicine to treat disease. In order to detect the dissolution change of medicinal materials active ingredients in decoction process, this paper applys spectral imaging technology, with Chinese traditional medicine cortex phellodendri as an example, discussing its fluorescence intensity at different time in decoction process. And the analysis results reflect edgewise the dissolution rule of cortex phellodendri active ingredients.

Terminal nickel(ii) amide, alkoxide, and thiolate complexes containing amido diphosphine ligands of the type [N(o-C6H4PR2)2]- (R = Ph, (i)Pr, Cy).

A series of nickel(ii) complexes of the type [R-PNP]Ni(ER') ([R-PNP](-) = [N(o-C(6)H(4)PR(2))(2)](-); R = Ph, (i)Pr, Cy; E = NH, O, S; R' = Ph, (t)Bu) featuring unsupported, covalently bound pi-donor ligands have been prepared and characterized. The metathetical reactions of [R-PNP]NiCl (R = Ph, (i)Pr, Cy) with LiNHPh, NaOPh, or NaSPh, respectively, produced the corresponding anilide [R-PNP]Ni(NHPh), phenolate [R-PNP]Ni(OPh), and thiophenolate [R-PNP]Ni(SPh) derivatives. Treatment of [Ph-PNP]NiCl with either LiNH(t)Bu or NaO(t)Bu generated tert-butyl amide [Ph-PNP]Ni(NH(t)Bu) and tert-butoxide [Ph-PNP]Ni(O(t)Bu), respectively. In contrast, attempts to prepare analogous tert-butyl amide and tert-butoxide complexes of [(i)Pr-PNP](-) or [Cy-PNP](-) were not successful. Protonolysis studies of these nickel(ii)-heteroatom complexes revealed the basic reactivity of these pi-donor ligands. The basicity follows the order NH(t)Bu > O(t)Bu > NHPh > OPh > SPh. In addition to solution NMR spectroscopic data for all new compounds, X-ray structures of [(i)Pr-PNP]Ni(NHPh) and [(i)Pr-PNP]Ni(OPh) are presented.