Unraveling the mechanism of ethyl acetate extract from Prismatomeris connata Y. Z. Ruan root in treating pulmonary fibrosis: insights from bioinformatics, network pharmacology, and experimental validation.

Introduction: Pulmonary fibrosis is a terminal lung disease characterized by fibroblast proliferation, extracellular matrix accumulation, inflammatory damage, and tissue structure destruction. The pathogenesis of this disease, particularly idiopathic pulmonary fibrosis (IPF), remains unknown. Macrophages play major roles in organ fibrosis diseases, including pulmonary fibrosis. The phenotype and polarization of macrophages are closely associated with pulmonary fibrosis. A new direction in research on anti-pulmonary fibrosis is focused on developing drugs that maintain the stability of the pulmonary microenvironment. Methods: We obtained gene sequencing data and clinical information for patients with IPF from the GEO datasets GSE110147, GSE15197, GSE24988, GSE31934, GSE32537, GSE35145, GSE53845, GSE49072, GSE70864, and GSE90010. We performed GO, KEGG enrichment analysis and GSEA analysis, and conducted weighted gene co-expression network analysis. In addition, we performed proteomic analysis of mouse lung tissue. To verify the results of bioinformatics analysis and proteomic analysis, mice were induced by intratracheal instillation of bleomycin (BLM), and gavaged for 14 days after modeling. Respiratory function of mice in different groups was measured. Lung tissues were retained for histopathological examination, Western Blot and real-time quantitative PCR, etc. In addition, lipopolysaccharide, interferon-γ and interleukin-4 were used to induce RAW264.7 cells for 12h in vitro to establish macrophage inflammation and polarization model. At the same time, HG2 intervention was given. The phenotype transformation and cytokine secretion of macrophages were investigated by Western Blot, RT-qPCR and flow cytometry, etc. Results: Through bioinformatics analysis and experiments involving bleomycin-induced pulmonary fibrosis in mice, we confirmed the importance of macrophage polarization in IPF. The analysis revealed that macrophage polarization in IPF involves a change in the phenotypic spectrum. Furthermore, experiments demonstrated high expression of M2-type macrophage-associated biomarkers and inducible nitric oxide synthase, thus indicating an imbalance in M1/M2 polarization of pulmonary macrophages in mice with pulmonary fibrosis. Discussion: Our investigation revealed that the ethyl acetate extract (HG2) obtained from the roots of Prismatomeris connata Y. Z. Ruan exhibits therapeutic efficacy against bleomycin-induced pulmonary fibrosis. HG2 modulates macrophage polarization, alterations in the TGF-ß/Smad pathway, and downstream protein expression in the context of pulmonary fibrosis. On the basis of our findings, we believe that HG2 has potential as a novel traditional Chinese medicine component for treating pulmonary fibrosis.

Honokiol Microemulsion Causes Stage-Dependent Toxicity Via Dual Roles in Oxidation-Reduction and Apoptosis through FoxO Signaling Pathway.

Honokiol, the main bioactive extract of Magnolia officinalis, exhibits extensive therapeutic actions. Its treatment for advanced non-small cell lung cancer is undergoing clinical trials in China. However, the published safety evaluation studies have focused on extract mixtures of Magnolia officinalis in which the honokiol content was well below the reported clinical dose of the honokiol monomer. Therefore, safety assessment of the honokiol monomer is urgently needed. Our previous studies have already demonstrated that a high dose of the honokiol microemulsion (0.6 µg/mL) induces developmental toxicity in rats and zebrafish by inducing oxidative stress. By exploring the relationship between time and toxicity, we found that developmental toxic responses were stage-dependent. They mainly occurred within the first 24 h post fertilization (hpf) especially the first 12 hpf. In zebrafish, low doses of honokiol microemulsion (0.15, 0.21 µg/mL) significantly decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increased the mRNA expression of bcl-2. In contrast, high dose (0.6 µg/mL) increased the levels of ROS and MDA, decreased activities and mRNA expression of superoxide dismutase (SOD) and catalase (CAT), and increased mRNA expression of bax, c-jnk, p53 and bim. By acridine orange staining, we found that a high dose of honokiol microemulsion induced apoptosis mainly in zebrafish brain. In rat pheochromocytoma cells (PC12 cells), low doses of the honokiol microemulsion (1, 5, 10 µM) exerted a protective effect against H2O2-induced oxidative damage while high doses (≥20 µM) induced oxidative stress, which further confirms the dual effects of honokiol microemulsion on nerve cells. These dual roles of the honokiol microemulsion in oxidation-reduction reactions and apoptosis may be regulated by the forkhead box class O (FoxO) signaling pathway. Due to the potential of developmental toxicity, we recommend that the administration of high dose honokiol microemulsion in pregnant women should be considered with caution.

Integrated spatially resolved metabolomics and network toxicology to investigate the hepatotoxicity mechanisms of component D of Polygonum multiflorum Thunb.

ETHNOPHARMACOLOGICAL RELEVANCE: The liver toxicity of Reynoutria multiflora (Thunb.) Moldenke. (Polygonaceae) (Polygonum multiflorum Thunb, PM) has always attracted much attention, but the related toxicity materials and mechanisms have not been elucidated due to multi-component and multi-target characteristics. In previous hepatotoxicity screening, different components of PM were first evaluated and the hepatotoxicity of component D [95% ethanol (EtOH) elution] in a 70% EtOH extract of PM (PM-D) showed the highest hepatotoxicity. Furthermore, the main components of PM-D were identified and their hepatotoxicity was evaluated based on a zebrafish embryo model. However, the hepatotoxicity mechanism of PM-D is unknown. AIM OF THE STUDY: This work is to explore the hepatotoxicity mechanisms of PM-D by integrating network toxicology and spatially resolved metabolomics strategy. MATERIALS AND METHODS: A hepatotoxicity interaction network of PM-D was constructed based on toxicity target prediction for eight key toxic ingredients and a hepatotoxicity target collection. Then the key signaling pathways were enriched, and molecular docking verification was implemented to evaluate the ability of toxic ingredients to bind to the core targets. The pathological changes of liver tissues and serum biochemical assays of mice were used to evaluate the liver injury effect of mice with oral administration of PM-D. Furthermore, spatially resolved metabolomics was used to visualize significant differences in metabolic profiles in mice after drug administration, to screen hepatotoxicity-related biomarkers and analyze metabolic pathways. RESULTS: The contents of four key toxic compounds in PM-D were detected. Network toxicology identified 30 potential targets of liver toxicity of PM-D. GO and KEGG enrichment analyses indicated that the hepatotoxicity of PM-D involved multiple biological activities, including cellular response to endogenous stimulus, organonitrogen compound metabolic process, regulation of the apoptotic process, regulation of kinase, regulation of reactive oxygen species metabolic process and signaling pathways including PI3K-Akt, AMPK, MAPK, mTOR, Ras and HIF-1. The molecular docking confirmed the high binding activity of 8 key toxic ingredients with 10 core targets, including mTOR, PIK3CA, AKT1, and EGFR. The high distribution of metabolites of PM-D in the liver of administrated mice was recognized by mass spectrometry imaging. Spatially resolved metabolomics results revealed significant changes in metabolic profiles after PM-D administration, and metabolites such as taurine, taurocholic acid, adenosine, and acyl-carnitines were associated with PM-D-induced liver injury. Enrichment analyses of metabolic pathways revealed tht linolenic acid and linoleic acid metabolism, carnitine synthesis, oxidation of branched-chain fatty acids, and six other metabolic pathways were significantly changed. Comprehensive analysis revealed that the hepatotoxicity caused by PM-D was closely related to cholestasis, mitochondrial damage, oxidative stress and energy metabolism, and lipid metabolism disorders. CONCLUSIONS: In this study, the hepatotoxicity mechanisms of PM-D were comprehensively identified through an integrated spatially resolved metabolomics and network toxicology strategy, providing a theoretical foundation for the toxicity mechanisms of PM and its safe clinical application.

Relationship of superior mesenteric artery thrombus density with transmural intestinal necrosis on multidetector computed tomography in acute mesenteric ischemia.

BACKGROUND: Acute arterial occlusive mesenteric ischemia with transmural intestinal necrosis (TIN) is a fatal disease, which is difficult to diagnose on multidetector computed tomography (MDCT). The aim of the present study was to determine the relationship of superior mesenteric artery (SMA) thrombus density with TIN on MDCT in patients with acute mesenteric ischemia (AMI) due to SMA thromboembolism. METHODS: In this retrospective study, 33 patients who underwent abdominal MDCT and angiography for AMI due to SMA thromboembolism were divided into two groups: the AMI with TIN group and the AMI without TIN group. We analyzed the relationships of clinical characteristics, qualitative MDCT signs, and SMA thrombus density with TIN. The SMA thrombus density was measured on non-contrast MDCT. Univariate and multivariate analyses were performed to determine the risk factors for predicting TIN. The diagnostic performances of risk factors were evaluated by receiver-operating characteristic (ROC) curve analysis. RESULTS: Of the patients with AMI enrolled in this study, 33.3% (11/33) were diagnosed with TIN. Peritonitis (P=0.042), bowel wall thinning (P=0.033), and pneumatosis/portomesenteric gas (P=0.010) were significantly associated with TIN. AMI patients with TIN exhibited a higher SMA thrombus density than AMI patients without TIN [41.2±6.1 vs. 34.2±3.0 Hounsfield unit (HU), P=0.003]. Multivariate analysis showed that SMA thrombus density was an independent predictor of TIN [P=0.044, hazard ratio (HR): 1.82, 95% confidence interval (CI): 1.02-3.25]. For diagnosing AMI with TIN, the area under the ROC curve (AUC) of SMA thrombus density (0.83) was larger than those of peritonitis (0.68), bowel wall thinning (0.66), and pneumatosis/portomesenteric gas (0.71). CONCLUSIONS: In patients with AMI, erythrocyte-rich thrombus blocking the SMA trunk which has a higher density on MDCT is prone to the occurrence of TIN compared with erythrocyte-scarce thrombus with a lower density. SMA thrombus density could be an independent risk factor for TIN in patients with AMI due to SMA thromboembolism.

Prediction of bowel obstruction caused by obturator hernia using risk factor categories on clinical characteristics and multidetector computed tomographic findings.

PURPOSE: To detect risk factors on clinical characteristics and multidetector computed tomographic (MDCT) findings for predicting bowel obstruction in patients with obturator hernia. METHODS: We retrospectively reviewed 47 patients who had an obturator hernia diagnosed by MDCT and/or surgery. The patients were divided into obstruction and non-obstruction group based on the presence or absence of bowel obstruction on MDCT images. Uni- and multivariate analyses were performed to identify risk factors for predicting bowel obstruction. RESULTS: There were 26 patients (55.32%) in the obstruction group and 21 patients (44.68%) in the non-obstruction group. Patients in the obstruction group were older (P = 0.002) and had more women (P = 0.033) and lower body mass index (BMI) (P = 0.0001) than patients in the non-obstruction group. The non-obstruction group suffered fewer bowel obstruction symptoms (P = 0.0001), Howship-Romberg (HR) sign (P = 0.012), deaths (P = 0.008) and major postoperative complications (P = 0.047). The hernia sac in the obstruction group had greater mean major diameter (P = 0.0001) and volume (P = 0.001) than those in the non-obstruction group. Multivariate analysis showed that age [odds ratio (OR) 1.18, 95% confidence interval (CI) 1.00-1.39, P = 0.046] and major diameter of hernia sac (OR 68.17, 95% CI 4.52-1027.70, P = 0.002) were independent risk factors associated with bowel obstruction in patients with obturator hernia. CONCLUSIONS: Patient's age and major diameter of hernia sac are independent risk factors resulting in bowel obstruction in patients with obturator hernia. Obturator hernia repair before bowel obstruction development may result in better outcomes and fewer postoperative complications.

Risk factors of geriatrics index of comorbidity and MDCT findings for predicting mortality in patients with acute mesenteric ischemia due to superior mesenteric artery thromboembolism.

OBJECTIVES: To identify risk factors of geriatrics index of comorbidity (GIC) and multidetector CT (MDCT) findings for predicting mortality in patients with acute mesenteric ischemia (AMI) due to superior mesenteric artery (SMA) thromboembolism. METHODS: 33 patients with AMI due to SMA thromboembolism underwent abdominal MDCT and angiography. Patients' comorbidities and MDCT findings of ischemic bowel/mesenteric injuries, regions of SMA involved by thromboembolism, and degrees of SMA stenosis were retrospectively reviewed. The comorbidities were classified into 1-4 levels according to GIC. The association of MDCT signs and GIC classification with mortality were analyzed. Diagnostic performances of risk factors associated with mortality were evaluated by receiver operating characteristic (ROC) curve analyses. RESULTS: Eighteen patients (54.5%) died during hospitalization or follow-up, including one patient with class 1, two patients with class 2, eight patients with class 3, and seven patients with class 4 according to GIC. Three risk factors significantly associated with mortality were identified, including pneumatosis and/or portomesenteric venous gas (PPMVG) (p = 0.017), four regions of SMA involved by thromboembolism (region I + II + III + IV) (p = 0.036), and class 3 + 4 of comorbidities (p = 0.001). The sensitivity and specificity of PPMVG, region I + II + III + IV, class 3 + 4 of comorbidities, and the three risk factors combined for diagnosing mortality were 33.3 and 100%, 27.8 and 100%, 83.3 and 73.3%, and 88.9 and 73.3%, respectively. The areas under the ROC curve (AUC) of the three risk factors combined (0.88) and class 3 + 4 of comorbidities (0.78) were larger than that of PPMVG (0.67) and region I + II + III + IV (0.64). The mortality rate rose from 15.4% in patients without risk factor to 66.7%, 100%, and 100% in patients with one, two, and three factors, respectively. CONCLUSION: Three risk factors for mortality were identified in patients with AMI due to SMA thromboembolism, including PPMVG and four regions of SMA involved by thromboembolism on MDCT images, and class 3 + 4 of comorbidities. Close monitoring of these risk factors could possibly lower the mortality. ADVANCES IN KNOWLEDGE: Risk factors based on GIC and MDCT findings may be used to predict mortality in patients with AMI. Close monitoring of these risk factors could possibly lower the mortality.

Celiomesenteric trunk: New classification based on multidetector computed tomography angiographic findings and probable embryological mechanisms.

BACKGROUND: In previous studies, celiomesenteric trunk (CMT) was narrowly defined as a hepato-gastro-spleno-mesenteric (HGSM) trunk, but other possible types were ignored. With the widespread use of multidetector computed tomography (MDCT) angiography, it is easy to collect a large sampling of data on arterial anatomy of the abdomen in daily radiological practice. A new classification system for CMT may be created based on its MDCT angiographic findings and variation patterns. AIM: To identify the spectrum and prevalence of CMT according to a new classification based on MDCT angiographic findings, and discuss the probable embryological mechanisms to explain the CMT variants. METHODS: A retrospective study was carried out on 5580 abdominal MDCT angiography images. CMT was defined as a single common trunk arising from the aorta and its branches including the superior mesenteric artery and at least two major branches of the celiac trunk. Various types of CMT were investigated. RESULTS: Of the 5580 patients, 171 (3.06%) were identified as having CMT. According to the new definitions and classification, the CMT variants included five types: I, II, III, IV and V, which were found in 96 (56.14%), 57 (33.33%), 4 (2.34%), 3 (1.75%) and 8 (4.68%) patients, respectively. The CMT variants also were classified as long type (106 patients, 61.99%) and short type (65 patients, 38.01%) based on the length of single common trunk. Further CMT classification was based on the origin of the left gastric artery: Type a (92 patients, 53.80%), type b (57 patients, 33.33%), type c (11 patients, 6.43%) and type d (8 patients, 4.68%). CONCLUSION: We systematically classified CMT variants according to our new classification system based on MDCT angiographic findings. Dislocation interruption, incomplete interruption and persistence of the longitudinal anastomosis could all be embryological mechanisms of various types of CMT variants.

Optimized protocol of multiple post-processing techniques improves diagnostic accuracy of multidetector computed tomography in assessment of small bowel obstruction compared with conventional axial and coronal reformations.

BACKGROUND: Axial and coronal reformations have been a widely used image post-processing protocol for the ordinary multidetector computed tomography (MDCT) examination of patients with small bowel obstruction (SBO) or other abdominal diseases. The diagnostic accuracy of MDCT for assessing SBO is expected to be further improved through the use of multiple post-processing techniques. AIM: To systemically evaluate the diagnostic accuracy and efficiency of an optimized protocol using multiple post-processing techniques for MDCT assessment of SBO and secondary bowel ischemia. METHODS: This retrospective cross-sectional study included 106 patients with clinically suspected SBO. Two readers applied three protocols to image post-processing and interpretation of patients' MDCT volume data. We compared the three protocols based on time spent, number of images, diagnostic self-confidence, agreement, detection rate, and accuracy of detection of SBO and secondary bowel ischemia. RESULTS: Protocol 2 resulted in more time spent and number of images than protocols 1 and 3 (P < 0.01), but the results of the two readers using the same protocol were not different (P > 0.05). Using protocol 3, both readers added multiple post-processing techniques at frequencies of 29.2% and 34.9%, respectively, for obstruction cause, and 32.1% and 30.2%, respectively, for secondary bowel ischemia. Protocols 2 and 3 had higher total detection rates of obstruction cause and secondary bowel ischemia than protocol 1 (P < 0.01), but no difference was detected between protocols 2 and 3 (P > 0.05). The accuracy, sensitivity, specificity, positive predictive value and negative predictive value of protocols 2 and 3 were superior to those of protocol 1 for evaluating obstruction cause and secondary bowel ischemia. CONCLUSION: Our optimized protocol of multiple post-processing techniques can both guarantee efficiency and improve diagnostic accuracy of MDCT for assessing SBO and secondary bowel ischemia.

Prediction of Small Bowel Obstruction Caused by Bezoars Using Risk Factor Categories on Multidetector Computed Tomographic Findings.

Objectives. The aim of this study was to detect factors associated with small bowel obstruction (SBO) caused by bezoars on multidetector computed tomographic findings. Methods. We retrospectively reviewed 61 patients who had bezoars in the small bowels on MDCT. The patients were divided into SBO patients group and non-SBO patients group. The mean values of the diameter, volume, and CT attenuation as well as location and characteristics of the bezoars were compared between the two groups. Multivariate analysis was performed to determine factors associated with SBO. Results. There were 32 patients (52.5%) in the SBO group and 29 patients (47.5%) in the non-SBO group. The bezoars in the SBO group had greater values of each mean diameter and mean volume than those in the non-SBO group (3.2 ± 0.5 cm versus 1.6 ± 0.7 cm, P < 0.0001, 14.9 ± 6.4 cm(3) versus 2.5 ± 2.7 cm(3), P < 0.0001, resp.) and had a lower CT attenuation than the non-SBO group (55.5 ± 23.4 versus 173.0 ± 68.0, P < 0.0001). The SBO group had higher prevalence of phytobezoar appearance (75.0% versus 10.3%, P < 0.0001). Major diameters of bezoar and phytobezoar were significant independent risk factors associated with SBO (odds ratio = 36.09, 8.26, resp., and P = 0.0004, 0.044, resp.). Conclusions. Major diameter of bezoar or phytobezoar is a potential risk factor associated with SBO.

A New Approach Using Manganese-Enhanced MRI to Diagnose Acute Mesenteric Ischemia in a Rabbit Model: Initial Experience.

PURPOSE: Manganese-enhanced MRI (MEMRI) has been applied to a wide range of biological and disease research. The purpose of the study was to use MEMRI to diagnose the acute mesenteric ischemia (AMI). METHODS: The institutional experimental animal ethics committee approved this study. To optimize the dose of Mn(2+) infusion, a dose-dependent curve was obtained using Mn(2+)-enhanced T 1 map MRI by an intravenous infusion 2.5-20 nmol/g body weight (BW) of 50 nmol/L MnCl2. The eighteen animals were divided into control, sham-operated, and AMI groups. AMI models were performed by ligating the superior mesenteric artery (SMA). T 1 values were measured on T 1 maps in regions of the small intestinal wall and relaxation rate (ΔR 1) was calculated. RESULTS: A nonlinear relationship between infused MnCl2 solution dose and increase in small intestinal wall ΔR 1 was observed. Control animal exhibited significant Mn(2+) clearance over time at the dose of 15 nmol/g BW. In the AMI model, ΔR 1 values (0.95 ± 0.13) in the small intestinal wall were significantly lower than in control group (2.05 ± 0.19) after Mn(2+) infusion (P < 0.01). CONCLUSION: The data suggest that MEMRI shows potential as a diagnostic technique that is directly sensitive to the poor or absent perfusion in AMI.

Mixed Supra- and Intracardiac Totally Anomalous Pulmonary Venous Connection in an Adult Female: Pre- and Postoperative Evaluation with Emphasis on MDCT Angiographic Advantages.

All cases with total anomalous pulmonary venous connection (TAPVC) were reported in neonates and children in the previous literature. This report describes the only case in which a mixed supra- and intracardiac TAPVC was discovered in a 25-year-old adult female and multidetector-row computed tomography (MDCT) angiography was used in its pre- and postoperative evaluation. Multidetector-row computed tomography angiography is superior to echocardiography in showing the draining sites and courses of the anomalous connected pulmonary veins, as well as postoperative evaluation in a patient with mixed TAPVC. It indicates that MDCT angiography may be a more suitable diagnostic modality for use in the pre- and postoperative evaluation of the mixed TAPVC.