[Mechanism of Ganke Granules intervening acute lung injury based on network pharmacology and experimental verification].

This study aims to explore the potential mechanism of action in the intervention of acute lung injury(ALI) based on the blood entry components of Ganke Granules in rats and in conjunction with network pharmacology, molecular docking, and animal experimental validation. The blood entry components of Ganke Granules in rats were imported into the SwissTargetPrediction platform to predict drug targets, and ALI-related targets were collected from the disease database. Intersections were taken, and protein-protein interaction(PPI) networks were constructed to screen the core targets, followed by Gene Ontology(GO) functional and Kyoto encyclopedia of genes and gnomes(KEGG) pathway enrichment analyses. A "blood entry components-target-pathway-disease" network was constructed, and the core components for disease intervention based on their topological parameters were screened. Molecular docking was used to predict the binding ability of the core components to key targets. The key targets of Ganke Granules in the intervention of ALI were verified by the lipopolysaccharide(LPS)-induced ALI mouse model. Through PPI topological parameter analysis, the top six key targets of STAT3, SRC, HSP90AA1, MAPK3, HRAS, and MAPK1 related to ALI were obtained. GO functional analysis showed that it was mainly related to ERK1 and ERK2 cascade, inflammatory response, and response to LPS. KEGG analysis showed that the main enrichment pathways were MAPK, neutrophil extracellular trap(NET) formation, and so on. Six core components(schizantherin B, schisandrin, besigomsin, harpagoside, isotectorigenin, and trachelanthamine) were filtered out by the "blood entry components-target-pathway-disease" network based on the analysis of topological parameters. Molecular docking results showed that the six core components and Tectoridin with the highest content in the granules had a high affinity with the key targets of MAPK3, SRC, MAPK1, and STAT3. In vivo experiment results showed that compared with the model group, Ganke Granules could effectively alleviate LPS-induced histopathological injury in the lungs of mice and reduce the percentage of inflammatory infiltration. The total protein content, nitric oxide(NO) level, myeloperoxidase(MPO) content, tumor necrosis factor-α(TNF-α), gamma interferon(IFN-γ), interleukin-1ß(IL-1ß), interleukin-6(IL-6), vascular endothelial growth factor(VEGF), and chemokine(C-X-C motif) ligand 1(CXCL1) chemokines in bronchoalveolar lavage fluid(BALF) were decreased, and the expression levels of lymphocyte antigen 6G(Ly6G), citrullinated histones 3(Cit-H3), and phosphorylated proteins SRC, ERK1/2, and STAT3 in lung tissue were significantly down-regulated. In conclusion, Ganke Granules could effectively inhibit the inflammatory response of ALI induced by LPS, protect lung tissue, regulate the release of inflammatory factors, and inhibit neutrophil infiltration and NET formation, and the mechanism of action may be related to inhibiting the activation of SRC/ERK1/2/STAT3 signaling pathway.

Potential mechanisms of formononetin against inflammation and oxidative stress: a review.

Formononetin (FMNT) is a secondary metabolite of flavonoids abundant in legumes and graminaceous plants such as Astragalus mongholicus Bunge [Fabaceae; Astragali radix] and Avena sativa L. [Poaceae]. Astragalus is traditionally used in Asia countries such as China, Korea and Mongolia to treat inflammatory diseases, immune disorders and cancers. In recent years, inflammation and oxidative stress have been found to be associated with many diseases. A large number of pharmacological studies have shown that FMNT, an important bioactive metabolite of Astragalus, has a profoundly anti-inflammatory and antioxidant potential. This review focuses on providing comprehensive and up-to-date findings on the efficacy of the molecular targets and mechanisms involve of FMNT and its derivatives against inflammation and oxidative stress in both in vitro and in vivo. Relevant literature on FMNT against inflammation and oxidative stress between 2013 and 2023 were analyzed. FMNT has antioxidant and anti-inflammatory potential and shows mild or no toxicity in various diseases. Moreover, in the medical field, FMNT has shown potential in the prevention and treatment of cancers, neurological diseases, fibrotic diseases, allergic diseases, metabolic diseases, cardiovascular diseases, gastrointestinal diseases and autoimmune diseases. Thus, it is expected to be utilized in more products in the medical, food and cosmetic industries in the future.

Vacuum-Assisted vs Conventional Minimally Invasive Percutaneous Nephrolithotomy for the Treatment of Two-to-Four-Centimeter Stones: A Multicenter Prospective and Randomized Trial.

Introduction: Percutaneous nephrolithotomy (PCNL) is the recommended treatment for 2-4-cm renal stones. Minimally invasive PCNL (MPCNL) with ≤22F sheath was frequently used instead of standard PCNL. MPCNL uses pressurized irrigation to flush out stone fragments through a conventional nephrostomy sheath (cNS), which may result in higher intrarenal pressure (IRP) and longer operating time. The novel vacuum-assisted nephrostomy sheath (vaNS) was developed to mitigate higher IRP and to facilitate stone removal. It might improve the performance of MPCNL. This prospective and randomized trial compares these two sheaths. Materials and Methods: In total, 120 patients with 2-4-cm renal stones were accrued in six tertiary medical centers with equal numbers in 2021. In total, 120 patients underwent mPCNL, 60 using 18F cNS and 60 using 18F vaNS, in a prospective and randomized assignment. The primary outcome measurement is decrease in IRP. The secondary outcome is efficacy in stone retrieval. Results: The IRP was lower with vaNS than with cNS: mean IRP during lithotripsy was 12.0 ± 2.7 mm Hg with vaNS vs 20.4 ± 6.0 mm Hg with cNS, p = 0.000. IRP duration ≥30 mm Hg was shorter with vaNS than with cNS (6.7 ± 7.4 seconds vs 113.4 ± 222.7 seconds, p = 0.001). vaNS has shorter stone removal time (26.9 ± 14.3 minutes vs 35.7 ± 11.8 minutes, p = 0.000). Stone extraction rate was higher (166.4 ± 88.1 mm3/min vs 90.4 ± 31.7 mm3/min, p = 0.000). Stone grasper usage was less (1.4 ± 2.6 vs 11.9 ± 9.7, p = 0.000). vaNS maintained the safety profile. Blood loss, creatinine changes, perioperative complications, and hospital stays were the same in both groups, all p > 0.05. Conclusion: MPCNL for stones 2-4 cm using vaNS has shorter stone removal time, higher stone extraction rate, and less use of stone extractor. vaNS is superior to cNS at reducing IRP and is associated with improved stone free rates at 3 days but not at 30 days postoperatively. The trial was registered with Chinese Clinical Trial Registry (ClinicalTrials.gov, NCT ChiCTR2000039681).

[Research progress in treatment of Sjögren's syndrome by traditional Chinese medicine].

Sj9gren's syndrome(SS) is an autoimmune disease with glandular dysfunction caused by the massive infiltration of the exocrine glands by lymphocytes. The pathogenesis of this disease is related to the chronic inflammatory response of the exocrine glands due to excessive activation of B cells and T cells. In addition to dry mouth and eyes, SS can also cause damage to other organs and systems in the human body, seriously affecting the quality of life of patients. Traditional Chinese medicine(TCM) has definite clinical efficacy in the treatment of SS as it can alleviate symptoms and regulate immune disorders without causing adverse reactions, demonstrating high safety. This paper reviews the current status of preclinical and clinical trials about the TCM treatment of SS in the past decade. TCM mainly mitigates SS symptoms such as dry mouth, dry eyes, dry skin, and joint pain and improves the prognosis and quality of life of patients by regulating the abnormally activated B cells and T cells, inhibiting the autoimmune response, restoring the balance between pro-inflammatory and anti-inflammatory cytokines, and reducing the pathological damage caused by immune complexes to exocrine glands and joints in SS patients.

Jing-Fang n-butanol extract and its isolated JFNE-C inhibit ferroptosis and inflammation in LPS induced RAW264.7 macrophages via STAT3/p53/SLC7A11 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine has accumulated valuable experience in the treatment of inflammatory diseases caused by Ferroptosis. Jing Jie and Fang Feng are two warm acrid exterior-resolving medicinal herbs that play an important role in the prevention and treatment of inflammatory diseases. The pairing of the two forms a drug pair (Jing-Fang) that shows significant advantages in fighting oxidative stress and inflammation. Whereas, the underlying mechanism needs to be further improved. AIM OF THE STUDY: In this study, the anti-inflammatory effect of Jing-Fang n-butanol extract (JFNE) and its isolate C (JFNE-C) on LPS-induced RAW264.7 cells and the regulation effect on ferroptosis were investigated, and also the mechanism of STAT3/p53/SLC7A11 signal pathway-related to ferroptosis. MATERIALS AND METHODS: Jing-Fang n-butanol extract (JFNE) and its active isolate (JFNE-C) were extracted and isolated. LPS-induced inflammation model in RAW264.7 cells was established to assess the anti-inflammatory effect and ferroptosis mechanism of JFNE and JFNE-C. The levels of interleukin 6 (IL-6), interleukin 1ß (IL-1ß) and tumor necrosis factor α (TNF-α) were measured. The activity levels of antioxidant substances such as glutathione (GSH), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were measured. Flow cytometry, immunofluorescence and transmission electron microscopy were used to assess ROS level, ferrous iron content and mitochondrial morphological changes. Through administration of Ferrostatin-1 (Fer-1), an ferroptosis inhibitor, to verify the role of JFNE and JFNE-C in regulating ferroptosis in resistance to the inflammatory response. Western blotting was used to determine whether the JFNE and JFNE-C exerted effectiveness by modulating the STAT3/p53/SLC7A11 signaling pathway. In addition, the important role of STAT3/p53/SLC7A11 signaling pathway in drug regulation of ferroptosis and inflammatory response was further validated by administration of S3I-201 (STAT3 inhibitor). Finally, high performance liquid chromatography-mass spectrometry (HPLC-MS) was used to determine the major active components of JFNE and JFNE-C. RESULTS: The results showed that treated with JFNE-C significantly reduced the contents of interleukin 6 (IL-6), interleukin 1ß (IL-1ß) and tumor necrosis factor α (TNF-α) in the supernatant of LPS-induced RAW264.7 cells. The pretreatment with JFNE and JFNE-C significantly decreased intracellular oxidative stress levels, including reductions of ROS and MDA levels, and increases of GSH-Px, SOD and GSH levels. In addition, JFNE and JFNE-C obviously reduced intracellular ferrous iron level, and JFNE-C was effective in alleviating mitochondrial damage which includes mitochondrial shrinkage, increase of mitochondrial membrane density and reduction and absence of cristae. Further results indicated that JFNE-C showed a reduction of p53 and p-p53 protein levels in LPS-induced RAW264.7 cells, while significantly increasing the protein expression levels of STAT3, p-STAT3, SLC7A11 and GPX4. Besides, JFNE-C contains key active substances such as 5-O-Methylvisammioside, Hesperidin and Luteolin. Remarkably, this is different from JFNE, which is rich in nutrients such as sucrose, choline and various amino acids. CONCLUSION: These results suggest that JFNE and JFNE-C may exert anti-inflammatory effect through activating the STAT3/p53/SLC7A11 signaling pathway to inhibit ferroptosis.

DRRNets: Dynamic Recurrent Routing via Low-Rank Regularization in Recurrent Neural Networks.

Recurrent neural networks (RNNs) continue to show outstanding performance in sequence learning tasks such as language modeling, but it remains difficult to train RNNs for long sequences. The main challenges lie in the complex dependencies, gradient vanishing or exploding, and low resource requirement in model deployment. In order to address these challenges, we propose dynamic recurrent routing neural networks (DRRNets), which can: 1) shorten the recurrent lengths by allocating recurrent routes dynamically for different dependencies and 2) reduce the number of parameters significantly by imposing low-rank constraints on the fully connected layers. A novel optimization algorithm via low-rank constraint and sparsity projection is developed to train the network. We verify the effectiveness of the proposed method by comparing it with multiple competitive approaches in several popular sequential learning tasks, such as language modeling and speaker recognition. The results in terms of different criteria demonstrate the superiority of our proposed method.

Four collateral circulation pathways were observed after common carotid artery occlusion.

BACKGROUND: Common carotid artery (CCA) occlusion (CCAO) is a rare condition. Owing to collateral circulation, ipsilateral internal carotid artery (ICA) and external carotid artery (ECA) are often patent. METHODS: This study included 16 patients with unilateral CCAO and patent ipsilateral ICA and ECA. The pathways which supplied ICA were investigated by digital subtraction angiography (DSA), transcranial Doppler (TCD), magnetic resonance angiography (MRA) and computed tomography angiography (CTA). RESULTS: In all 16 patients, TCD found antegrade blood flow in ipsilateral ICA, which was supplied by retrograde blood flow in ipsilateral ECA through carotid bifurcation. We call this phenomenon "ICA steal". DSA and CTA discovered four pathways of ICA steal, including 1) ipsilateral vertebral artery - occipital artery - ECA - ICA, 2) ipsilateral thyrocervical trunk or costocervical trunk - ascending cervical artery or deep cervical artery - occipital artery - ECA - ICA, 3) contralateral ECA - contralateral superior thyroid artery - ipsilateral superior thyroid artery - ipsilateral ECA - ICA, and 4) ipsilateral thyrocervical trunk - inferior thyroid artery - superior thyroid artery - ECA - ICA. CONCLUSIONS: ICA is possible to be patent and supplied by several collateral circulation pathways after CCAO.

Neovascularization in the carotid atherosclerotic plaque is not associated with inflammatory cell aggregation.

BACKGROUND: Monocytes and macrophages in atherosclerotic plaque lead to plaque instability. The aim of the study was to determine if plaque neovascularization led to inflammation. METHODS: Patients were consecutively enrolled if their carotid intimal media thickness was > 2 mm, as revealed by duplex ultrasound. The patients then underwent dynamic contrast enhanced magnetic resonance imaging (DCE MRI) and fluorine-18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography combined with computed tomography (PET CT). A target to background ratio (TBR) of ≥ 1.25 or < 1.25 served as the cutoff point for the presence and absence of inflammation, respectively. RESULTS: Twenty-six patients underwent bilateral carotid DCE MRI and 24 patients also underwent PET CT. One hundred and fifty-five plaques were evaluated by both DCE MRI and PET CT. There was no significant difference in plaque morphology between the TBR ≥ 1.25 (n = 61) and TBR < 1.25 (n = 94) groups. No significant differences were found in plasma volume and transfer constant between the TBR ≥ 1.25 and TBR < 1.25 groups. CONCLUSION: Our study did not find a significant correlation between plaque neovascularization and the aggregation of inflammatory cells.

[Evaluation of carotid artery plaque stability with ¹8F-FDG PET/CT and contrast-enhanced ultrasonography].

OBJECTIVE: To assess the value of contrast-enhanced ultrasonography (CEUS) and fluorodeoxyglucose positron emission tomography-computed tomography (¹8F-FDG PET/CT) in evaluating the stability of carotid atherosclerosis. METHODS: Seventeen patients with 21 carotid artery plaques received examinations with CEUS. According to the nature of the plaques, the patients were divided into soft and mixed plaque group and hard and calcified plaque group. The maximal enhancement intensity of the plaques (I(MAX)) and maximal plaque density (D(MAX)) were measured to quantify the neovasculature. The patients also underwent concurrent ¹8F-FDG PET/CT, and ¹8F-FDG uptake was quantified by the mean standard uptake values (SUV(mean)), an index reflecting the inflammatory activity in the plaque. The findings in CEUS and PET/CT were comparatively analyzed for these cases. RESULTS: The D(MAX) of the plaque in soft and mixed plaque group was significantly greater than that in hard and calcified plaque group (4.26±3.65 vs 1.41±1.47, P<0.05); the I(MAX) was also greater in the former group, but this difference was not statistically significant (26.83±19.61 vs 24.73±29.85, P=0.869). The soft and mixed plaques tended to have higher SUVmean than the hard and calcified plaques (1.70±0.45 vs 1.47±0.12, P=0.099). The values of I(MAX) and D(MAX) were not found to correlate to SUV(mean) in these patients. CONCLUSION: CEUS can sensitively show the status of neovascularization within the carotid atherosclerosis plaques, and PET/CT reflects the inflammatory activity in the plaques. The combination of these two imaging modalities allows the evaluation of plaque stability in terms of neoangiogenesis and inflammatory activity.