Prognostic value of the systemic immuno-inflammatory index in critically ill patients with vertebral fractures.

Inflammation plays a critical role in vertebral fractures. However, there is a lack of sufficient evidence regarding the prognostic significance of the systemic immuno-inflammatory index (SII), a novel marker of systemic inflammation, in patients with vertebral fractures. In this study, we aimed to assess the predictive value of SII in critically ill patients with vertebral fractures. The data were from the Medical Information Mart for Intensive Care III (MIMIC-III) version 1.4 and Wenzhou Hospital of Traditional Chinese Medicine. The cutoff values for SII were determined using the receiver operating characteristic curve, and the subjects were grouped accordingly. The clinical outcome measured was mortality within 30 days, 90 days, or 1 year. The following formula was used to calculate the SII: SII = (platelet count) × (neutrophil count)/ (lymphocyte count). Cox proportional-hazard models were employed to assess the relationship between SII and survival. Additionally, propensity score matching analysis and COX models were utilized to examine the association between SII and survival outcomes. The Pearson correlation test confirmed the correlation between SII and vertebral T-values measured by bone mineral density and pain indicator. A total of 354 patients were finally included from MIMIC-III in the univariate analysis, for the 30-day mortality, SII ≥ 3164 group, the hazard ratio (HR) (95% confidence interval) was 1.71 (1.01, 2.94). After adjusting for age, gender, race, anion gap, creatinine, systolic blood pressure (SBP), DBP MBP, SOFA, acute physiologic score III, chronic kidney disease, and SAPS II, SII ≥ 3164 was found to be an independent significant risk factor for death in patients (HR = 1.85, 95% CI: 1.06-3.24, P = .0315). A similar trend was observed for 90-day mortality and 1-year mortality. Propensity scores matching analysis further confirmed the association of SII and the prognosis of patients. Our validation results were consistent with it. Besides, the Pearson correlation test confirmed a significant correlation between SII and vertebral T-values measured by bone mineral density and pain indicator. The study findings revealed that SII is an independent predictor of mortality in patients with vertebral fractures. This indicates that SII can serve as a reliable and easily accessible prognostic indicator for newly diagnosed critically ill patients with vertebral fractures.

Qingda granule alleviates cerebral ischemia/reperfusion injury by inhibiting TLR4/NF-κB/NLRP3 signaling in microglia.

ETHNOPHARMACOLOGICAL RELEVANCE: Qingda granule (QDG) is effective for treating hypertension and neuronal damage after cerebral ischemia/reperfusion. However, the anti-neuroinflammatory effect of QDG on injury due to cerebral ischemia/reperfusion is unclear. AIM OF THE STUDY: The objective was to evaluate the effectiveness and action of QDG in treating neuroinflammation resulting from cerebral ischemia/reperfusion-induced injury. MATERIALS AND METHODS: Network pharmacology was used to predict targets and pathways of QDG. An in vivo rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) as well as an in vitro model of LPS-stimulated BV-2 cells were established. Magnetic resonance imaging (MRI) was used to quantify the area of cerebral infarction, with morphological changes in the brain being assessed by histology. Immunohistochemistry (IHC) was used to assess levels of the microglial marker IBA-1 in brain tissue. Bioplex analysis was used to measure TNF-α, IL-1ß, IL-6, and MCP-1 in sera and in BV-2 cell culture supernatants. Simultaneously, mRNA levels of these factors were examined using RT-qPCR analysis. Proteins of the TLR4/NF-κB/NLRP3 axis were examined using IHC in vivo and Western blot in vitro, respectively. While NF-κB translocation was assessed using immunofluorescence. RESULTS: The core targets of QDG included TNF, NF-κB1, MAPK1, MAPK3, JUN, and TLR4. QDG suppressed inflammation via modulation of TLR4/NF-κB signaling. In addition, our in vivo experiments using MCAO/R rats demonstrated the therapeutic effect of QDG in reducing brain tissue infarction, improving neurological function, and ameliorating cerebral histopathological damage. Furthermore, QDG reduced the levels of TNF-α, IL-1ß, IL-6, and MCP-1 in both sera from MCAO/R rats and supernatants from LPS-induced BV-2 cells, along with a reduction in the expression of the microglia biomarker IBA-1, as well as that of TLR4, MyD88, p-IKK, p-IκBα, p-P65, and NLRP3 in MCAO/R rats. In LPS-treated BV-2 cells, QDG downregulated the expression of proinflammatory factors and TLR4/NF-κB/NLRP3 signaling-related proteins. Additionally, QDG reduced translocation of NF-κB to the nucleus in both brains of MCAO/R rats and LPS-induced BV-2 cells. Moreover, the combined treatment of the TLR4 inhibitor TAK242 and QDG significantly reduced the levels of p-P65, NLRP3, and IL-6. CONCLUSIONS: QDG significantly suppressed neuroinflammation by inhibiting the TLR4/NF-κB/NLRP3 axis in microglia. This suggests potential for QDG in treating ischemia stroke.

Liensinine improves AngII-induced vascular remodeling via MAPK/TGF-ß1/Smad2/3 signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Liensinine(Lien, C37H42N2O6) is an alkaloid compound from plumula nelumbinis that demonstrates an antihypertensive effect. The protective effects of Lien on target organs during hypertension are still unclear. AIM OF THE STUDY: This study aimed to understand the mechanism of Lien during the treatment of hypertension, with emphasis on vascular protection. MATERIALS AND METHODS: Lien was extracted and isolated from plumula nelumbinis for further study. In vivo model of Ang II-induced hypertension, non-invasive sphygmomanometer was used to detect the blood pressure in and out of the context of Lien intervention. Ultrasound was used to detect the abdominal aorta pulse wave and media thickness of hypertensive mice, and RNA sequencing was used to detect the differential genes and pathways of blood vessels. The intersection of Lien and MAPK protein molecules was detected by molecular interconnecting technique. The pathological conditions of abdominal aorta vessels of mice were observed by HE staining. The expression of PCNA, α-SMA, Collagen Type Ⅰ and Collagen Type Ⅲ proteins were detected by IHC. The collagen expression in the abdominal aorta was detected by Sirius red staining. The MAPK/TGF-ß1/Smad2/3 signaling and the protein expression of PCNA and α-SMA was detected by Western blot. In vitro, MAPK/TGF-ß1/Smad2/3 signaling and the protein expression of PCNA and α-SMA were detected by Western blot, and the expression of α-SMA was detected by immunofluorescence; ELISA was used to detect the effect of ERK/MAPK inhibitor PD98059 on Ang Ⅱ-induced TGF-ß1secrete; and the detection TGF-ß1and α-SMA protein expression by Western blot; Western blot was used to detect the effect of ERK/MAPK stimulant12-O-tetradecanoyl phorbol-13-acetate (TPA) on the protein expression of TGF-ß1 and α-SMA. RESULTS: Lien displayed an antihypertensive effect on Ang Ⅱ-induced hypertension, reducing the pulse wave conduction velocity of the abdominal aorta and the thickness of the abdominal aorta vessel wall, ultimately improving the pathological state of blood vessels. RNA sequencing further indicated that the differential pathways expressed in the abdominal aorta of hypertensive mice were enriched in proliferation-related markers compared with the Control group. The profile of differentially expressed pathways was ultimately reversed by Lien. Particularly, MAPK protein demonstrated good binding with the Lien molecule. In vivo, Lien inhibited Ang Ⅱ-induced abdominal aorta wall thickening, reduced collagen deposition in the ventral aortic vessel, and prevented the occurrence of vascular remodeling by inhibiting MAPK/TGF-ß1/Smad2/3 signaling activation. In addition, Lien inhibited the activation of Ang II-induced MAPK and TGF-ß1/Smad2/3 signaling, attenuating the expression of PCNA and inhibiting the reduction of α-SMA, collectively playing a role in the inhibition of Ang Ⅱ-induced hypertensive vascular remodeling. PD98059 alone could inhibit Ang Ⅱ-induced elevation of TGF-ß1 and the decrease of α-SMA expression. Further, PD98059 combined with Lien had no discrepancy with the inhibitors alone. Simultaneously TPA alone could significantly increase the expression of TGF-ß1 and decrease the expression of α-SMA. Further, Lien could inhibit the effect of TPA. CONCLUSION: This study helped clarify the protective mechanism of Lien during hypertension, elucidating its role as an inhibitor of vascular remodeling and providing an experimental basis for the research and development of novel antihypertensive therapies.

Research on Anti-inflammatory Targets and Mechanisms of alkaloids in Picrasma quassioides Benn Through Network Pharmacology

Abstract This study aimed to investigate the molecular mechanism of Picrasma quassioides Benn against inflammation by means of network pharmacology. The paper will provide a reference for multi-target and multi-channel treatment of inflammation with traditional Chinese medicine. Through screening and analysis, 11 active ingredients and 109 anti-inflammation prediction targets were obtained and constructed a compound-target network. The targets such as VEGFA, TLR4 and STAT3 may play a crucial role. Network enrichment analysis showed that the 109 potential targets constitute a number of pathways or inflammatory reactions closely related to inflammation, including NF-κB signaling pathway and MAPK signaling pathway. The docking results indicated that the binding energy of Picrasidine Y and the inflammatory factors VEGFA is the highest. This study predicted the role of multiple active compounds in the alkaloids of Picrasma in the inflammatory response, and provided a theoretical basis for the anti-inflammatory mechanism of Picrasma

Anti-inflammatory effects of three withanolides isolated from Physalis angulata L. in LPS-activated RAW 264.7 cells through blocking NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Physalis angulata L. is commonly used in many countries as popular medicine for the treatment of a variety of diseases such as malaria, hepatitis, dermatitis and rheumatism. But the anti-inflammatory active constituents of this medicinal plant and their molecular mechanism are still not elucidated clearly. AIM OF THE STUDY: The aim of the study is to isolate and identify a series of compounds from the ethanolic extract of Physalis angulata L., and to investigate the anti-inflammatory activities in vitro and the molecular mechanism of physagulin A, physagulin C, and physagulin H. MATERIALS AND METHODS: In order to further understand the anti-inflammatory mechanism of the three compounds, their potential anti-inflammatory activities were investigated in vitro in LPS-activated RAW 264.7 macrophage cells by Griess assay, ELISA, Western blot and immunofluorescence methods in the present study. RESULTS: Physagulin A, physagulin C, and physagulin H could not only inhibit the release of NO, PGE2, IL-6 and TNF-α, but also could down-regulate the expression of iNOS and COX-2 proteins. Furthermore, physagulin A, physagulin C, and physagulin H could remarkably block the degradation of IκB-α and the nuclear translocation of NF-κB/p65 in LPS-activated RAW 264.7 cells. However, none of them could inhibit the phosphorylation of MAPKs family proteins ERK, JNK and p38. Thus, the anti-inflammatory actions of physagulin A, physagulin C, and physagulin H were mainly due to the significant inhibition of NF-κB signaling pathway rather than MAPKs signaling pathway. CONCLUSIONS: All the results clearly showed that physagulin A, physagulin C, and physagulin H demonstrated potent anti-inflammatory activity and can be used as novel NF-κB inhibitors. They are potential to be developed as an alternative or complementary agents for inflammatory diseases.

Effects of zein stabilized clove essential oil Pickering emulsion on the structure and properties of chitosan-based edible films.

Clove essential oil (CLO) Pickering emulsions were prepared with zein colloid particles as stabilizer, and the effects of CLO Pickering emulsion incorporation on the structure, mechanical, barrier and antimicrobial properties of chitosan-based edible films were explored. CLO Pickering emulsions with 3% w/v zein and 50% v/v CLO had smaller particle size and more even distribution. Incorporation of CLO Pickering emulsion in the films decreased the water vapor permeability and tensile strength, but the elongation at break firstly increased then decreased with the maximum value of 19.2% when the content of emulsion was 0.4%. Scanning electron microscopy revealed the formation of microstructure-sized holes in the films by the addition of CLO Pickering emulsion. The emulsified oil droplets were uniformly distributed, due to the good compatibility between oil phase and chitosan matrix. The antimicrobial properties of the films were strengthened by CLO Pickering emulsion incorporation and mainly depended on its concentration.

Hypoglycemic Effect of the Degraded Polysaccharides from the Wood Ear Medicinal Mushroom Auricularia auricula-judae (Agaricomycetes).

Auricularia auricula-judae is an important culinary-medicinal mushroom. The A. auricula-judae polysaccharides (AAPs) were prepared from A. auricula-judae in the early stage through alkali extraction and deproteination with the Sevag method, and optimal acid hydrolysis conditions were established by Box-Behnken to prepare the degraded polysaccharides (AAPs-F) from AAPs. In this study, a nonenzymatic glycosylation reaction system was used for the evaluation of the inhibitory effects on the formation of advanced glycation end products (AGEs). In addition, high glucose resistance was assessed by glucose consumption of HepG2 cells and the lifespan of Caenorhabditis elegans under high sugar stress. It was found that both 0.5 mg·mL-1 AAPs and 0.2 mg·mL-1 AAPs-F could significantly inhibit AGE formation in short- and long-term glycosylation (P < .05) in a dose-dependent manner, determined by ultraviolet and fluorospectrophotometry. It indicated activity against AGE formation for different concentrations of AAPs and AAPs-F. AAPs-F at 0.5 mg·mL-1 significantly enhanced the glucose absorption of HepG2 cells by 24.4% (P < .05) in a dose-dependent manner at 24 h, and markedly extended the lifespan of C. elegans by 32.9% (P < 0.05) under high sugar stress conditions. This study demonstrated that the derived hydrolysates produced by the hydrolysis of acid had a prominent effect on the inhibition of AGE formation and relieved the stress state caused by high sugar levels.

Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth.

The importance of BET protein BRD4 in gene transcription is well recognized through the study of chemical modulation of its characteristic tandem bromodomain (BrD) binding to lysine-acetylated histones and transcription factors. However, while monovalent inhibition of BRD4 by BET BrD inhibitors such as JQ1 blocks growth of hematopoietic cancers, it is much less effective generally in solid tumors. Here, we report a thienodiazepine-based bivalent BrD inhibitor, MS645, that affords spatially constrained tandem BrD inhibition and consequently sustained repression of BRD4 transcriptional activity in blocking proliferation of solid-tumor cells including a panel of triple-negative breast cancer (TNBC) cells. MS645 blocks BRD4 binding to transcription enhancer/mediator proteins MED1 and YY1 with potency superior to monovalent BET inhibitors, resulting in down-regulation of proinflammatory cytokines and genes for cell-cycle control and DNA damage repair that are largely unaffected by monovalent BrD inhibition. Our study suggests a therapeutic strategy to maximally control BRD4 activity for rapid growth of solid-tumor TNBC cells.