Potential mechanisms underlying podophyllotoxin-induced cardiotoxicity in male rats: toxicological evidence chain (TEC) concept.

Introduction: Podophyllotoxin (PPT) is a high-content and high-activity compound extracted from the traditional Chinese medicinal plant Dysosma versipellis (DV) which exhibits various biological activities. However, its severe toxicity limits its use. In clinical settings, patients with DV poisoning often experience adverse reactions when taking large doses in a short period. The heart is an important toxic target organ, so it is necessary to conduct 24-h acute cardiac toxicity studies on PPT to understand its underlying toxicity mechanism. Methods: Based on the concept of the toxicological evidence chain (TEC), we utilized targeted metabolomic and transcriptomic analyses to reveal the mechanism of the acute cardiotoxicity of PPT. The manifestation of toxicity in Sprague-Dawley rats, including changes in weight and behavior, served as Injury Phenotype Evidence (IPE). To determine Adverse Outcomes Evidence (AOE), the hearts of the rats were evaluated through histopathological examination and by measuring myocardial enzyme and cardiac injury markers levels. Additionally, transcriptome analysis, metabolome analysis, myocardial enzymes, and cardiac injury markers were integrated to obtain Toxic Event Evidence (TEE) using correlation analysis. Results: The experiment showed significant epistaxis, hypokinesia, and hunched posture in PPT group rats within 24 h after exposure to 120 mg/kg PPT. It is found that PPT induced cardiac injury in rats within 24 h, as evidenced by increased serum myocardial enzyme levels, elevated concentrations of cardiac injury biomarkers, and altered cardiac cell morphology, all indicating some degree of cardiac toxicity. Transcriptome analysis revealed that primary altered metabolic pathway was arachidonic acid metabolism after PPT exposure. Cyp2e1, Aldob were positively correlated with differential metabolites, while DHA showed positive correlation with differential genes Fmo2 and Timd2, as well as with heart injury markers BNP and Mb. Conclusion: This study comprehensively evaluated cardiac toxicity of PPT and initially revealed the mechanism of PPT-induced acute cardiotoxicity, which involved oxidative stress, apoptosis, inflammatory response, and energy metabolism disorder.

Exploring the anxiolytic mechanism of Fructus gardeniae based on metabolomics, network pharmacology, and molecular docking.

OBJECTIVE: To explore the effect and anxiolytic mechanism of a natural remedy called Fructus gardeniae (FG). METHODS: The elevated-plus maze (EPM) test was used to confirm the anxiolytic effect of FG. The potential and anxiolytic components, targets, and route processes of FG were investigated using the network pharmacology method in conjunction with metabolomics and molecular docking technologies. RESULTS: FG could greatly enhance the proportion of time and times of opening arms, according to the EPM data. As to the metabolomics findings, a total of 61 distinct metabolites were found, mainly involved in glycine, serine, and threonine metabolism as well as alanine, aspartate, and glutamate metabolism. The primary active ingredients of FG, nicotiflorin, jasminodiol, and crocetin, demonstrated substantial binding affinities with monoamine oxidase A (MAOA), monoamine oxidase A (ACHE), malate dehydrogenase 2 (MDH2), glutamate decarboxylase 2 (GAD2), glutamate decarboxylase 1 (GAD1), and nitric oxide synthase (NOS1), according to the findings of network pharmacology and molecular docking. CONCLUSION: FG exerts an anxiolytic action via targeting MAOA, ACHE, MDH2, GAD2, GAD1, and NOS1, and regulating the metabolism of glycine, serine, and threonine as well as alanine, aspartic acid, and glutamic acid.

Antithrombotic pharmacodynamics and metabolomics study in raw and processed products of Whitmania pigra Whitman.

Objective: As a traditional Chinese medicine, leech has obvious pharmacological activities in anticoagulantion and antithrombosis. Whitmania pigra Whitman (WP) is the most commonly used leech in the Chinese market. It is often used in clinical applications after high-temperature processing by talcum powder to remove the fishy taste and facilitate crushing. The anticoagulant and thrombolytic active ingredients are protein and polypeptide, which may denaturate and lose activity after high-temperature processing. The rationality of its processing has been questioned in recent years. This study aims to investigate the effect of talcum powder scalding on the antithrombotic activity of WP in vivo and to discuss its pharmacodynamic mechanism in vivo. Methods: Raw and talcum-powdered processed WP were administered intragastrically for 14 days, and carrageenan was injected intraperitoneally to prepare a mouse model of tail vein thrombosis. The incidence rate of tail vein thrombosis and the thrombus area under pathological tissue sections were calculated to evaluate the antithrombotic effect between raw and processed WP. Non-targeted metabolomics was conducted using UPLC-Q-TOF/MS technology to analyze the changes of small molecule metabolites in the body after administration of WP. Results: After intragastric administration, both the raw product and the processed product of WP could inhibit the thrombosis induced by carrageenan, and the processed product had a more apparent antithrombotic effect than the raw product. The administration of WP could regulate the changes of some small molecular metabolites, such as amino acids, lipids, and steroids, in Sphingolipid metabolism and Glycerophospholipid metabolism. Conclusions: Based on the results of pharmacodynamics and metabolomics, processed WP will not reduce the antithrombotic activity of WP. This study provided a scientific basis for the rational use of leeches.

Structural characterization of chia seed polysaccharides and evaluation of its immunomodulatory and antioxidant activities.

This study aims to extract an active heteropolysaccharide Chia seed polysaccharide (CSP-A) and further purified by DEAE Sepharose Fast Flow and Sepharose CL-6B chromatographic column, characterize its structure, and evaluate its antioxidant and immunomodulatory activities. Structural analysis revealed that CSP-A was composed of d-mannose, d-glucuronic acid and d-xylose in a molar ratio of 1:3:4 with molecular weight of 1.688 × 105 Da, owning 4 sugar residues of ß-d-Manp-(1→, →4)-α-d-GlcpA-(1→, →2,4)-ß-d-Xylp-(1→, and â†’ 4)-ß-d-Manp-(1 â†’. Congo red assay and microscopic characteristics showed that CSP-A in its solution may possess a helical conformation. In vitro experiments showed that CSP-A had moderate DPPH· and OH· scavenging activities. CSP-A also enhanced the phagocytosis ability of RAW 264.7 cells and prompted the release of NO, TNF-α, IL-6 and IL-1ß from RAW 264.7 cells, which indicated CSP-A had immune regulation effect. This experiment provides scientific basis for further utilization and development of chia seeds, a kind of functional food.

Improving rib fracture detection accuracy and reading efficiency with deep learning-based detection software: a clinical evaluation.

OBJECTIVES: To investigate the impact of deep learning (DL) on radiologists' detection accuracy and reading efficiency of rib fractures on CT. METHODS: Blunt chest trauma patients (n = 198) undergoing thin-slice CT were enrolled. Images were read by two radiologists (R1, R2) in three sessions: S1, unassisted reading; S2, assisted by DL as the concurrent reader; S3, DL as the second reader. The fractures detected by the readers and total reading time were documented. The reference standard for rib fractures was established by an expert panel. The sensitivity and false-positives per scan were calculated and compared among S1, S2, and S3. RESULTS: The reference standard identified 865 fractures on 713 ribs (102 patients) The sensitivity of S1, S2, and S3 was 82.8, 88.9, and 88.7% for R1, and 83.9, 88.7, and 88.8% for R2, respectively. The sensitivity of S2 and S3 was significantly higher compared to S1 for both readers (all p < 0.05). The sensitivity between S2 and S3 did not differ significantly (both p > 0.9). The false-positive per scan had no difference between sessions for R1 (p = 0.24) but was lower for S2 and S3 than S1 for R2 (both p < 0.05). Reading time decreased by 36% (R1) and 34% (R2) in S2 compared to S1. CONCLUSIONS: Using DL as a concurrent reader can improve the detection accuracy and reading efficiency for rib fracture. ADVANCES IN KNOWLEDGE: DL can be integrated into the radiology workflow to improve the accuracy and reading efficiency of CT rib fracture detection.

Cervical Posterior Spinal Artery Syndrome Caused By Spontaneous Vertebral Artery Dissection: Two Case Reports and Literature Review.

Herein, we described 2 patients with posterior spinal artery syndrome (PSAS) caused by vertebral artery dissection. The patients complained of sudden neck pain or walking instability. Neurological examination revealed sensory loss, muscle weakness, and sensory ataxia. Angiography showed double lumen sign or intimal flap in the vertebral artery. T2-weighted imaging and diffusion-weighted imaging of MRI showed a hyperintense lesion in the dorsal side of the cervical spinal cord at different times after onset. Both patients had good outcome after antiplatelet therapy and physiotherapy. A review of previously reported PSAS cases was also conducted in order to improve the understanding and awareness of this rare myelopathy.