Application of angiogenesis-related genes associated with immune infiltration in the molecular typing and diagnosis of acute myocardial infarction.

BACKGROUND: Angiogenesis has been discovered to be a critical factor in developing tumors and ischemic diseases. However, the role of angiogenesis-related genes (ARGs) in acute myocardial infarction (AMI) remains unclear. METHODS: The GSE66360 dataset was used as the training cohort, and the GSE48060 dataset was used as the external validation cohort. The random forest (RF) algorithm was used to identify the signature genes. Consensus clustering analysis was used to identify robust molecular clusters associated with angiogenesis. The ssGSEA was used to analyze the correlation between ARGs and immune cell infiltration. In addition, we constructed miRNA-gene, transcription factor network, and targeted drug network of signature genes. RT-qPCR was used to verify the expression levels of signature genes. RESULTS: Seven signature ARGs were identified based on the RF algorithm. Receiver operating characteristic curves confirmed the classification accuracy of the risk predictive model based on signature ARGs (area under the curve [AUC] = 0.9596 in the training cohort and AUC = 0.7773 in the external validation cohort). Subsequently, the ARG clusters were identified by consensus clustering. Cluster B had a more generalized high expression of ARGs and was significantly associated with immune infiltration. The miRNA and transcription factor network provided new ideas for finding potential upstream targets and biomarkers. Finally, the results of RT-qPCR were consistent with the bioinformatics analysis, further validating our results. CONCLUSIONS: Angiogenesis is closely related to AMI, and characterizing the angiogenic features of patients with AMI can help to risk-stratify patients and provide personalized treatment.

Survival outcome and predictors of WHO grade 2 and 3 insular gliomas: A classification based on the tumor spread.

OBJECTIVE: The study aimed to identify if clinical features and survival outcomes of insular glioma patients are associated with our classification based on the tumor spread. METHODS: Our study included 283 consecutive patients diagnosed with histological grade 2 and 3 insular gliomas. A new classification was proposed, and tumors restricted to the paralimbic system were defined as type 1. When tumors invaded the limbic system (referred to as the hippocampus and its surrounding structures in this study) simultaneously, they were defined as type 2. Tumors with additional internal capsule involvement were defined as type 3. RESULTS: Tumors defined as type 3 had a higher age at diagnosis (p = 0.002) and a higher preoperative volume (p < 0.001). Furthermore, type 3 was more likely to be diagnosed as IDH wild type (p < 0.001), with a higher rate of Ki-67 index (p = 0.015) and a lower rate of gross total resection (p < 0.001). Type 1 had a slower tumor growth rate than type 2 (mean 3.3%/month vs. 19.8%/month; p < 0.001). Multivariate Cox regression analysis revealed the extent of resection (HR 0.259, p = 0.004), IDH status (HR 3.694, p = 0.012), and tumor spread type (HR = 1.874, p = 0.012) as independent predictors of overall survival (OS). Tumor grade (HR 2.609, p = 0.008), the extent of resection (HR 0.488, p = 0.038), IDH status (HR 2.225, p = 0.025), and tumor spread type (HR 1.531, p = 0.038) were significant in predicting progression-free survival (PFS). CONCLUSION: The current study proposes a classification of the insular glioma according to the tumor spread. It indicates that the tumors defined as type 1 have a relatively better nature and biological characteristics, and those defined as type 3 can be more aggressive and refractory. Besides its predictive value for prognosis, the classification has potential value in formulating surgical strategies for patients with insular gliomas.

Epilepsy alters brain networks in patients with insular glioma.

AIMS: We intend to elucidate the alterations of cerebral networks in patients with insular glioma-related epilepsy (GRE) based on resting-state functional magnetic resonance images. METHODS: We collected 62 insular glioma patients, who were subsequently categorized into glioma-related epilepsy (GRE) and glioma with no epilepsy (GnE) groups, and recruited 16 healthy individuals matched to the patient's age and gender to form the healthy control (HC) group. Graph theoretical analysis was applied to reveal differences in sensorimotor, default mode, visual, and executive networks among different subgroups. RESULTS: No significant alterations in functional connectivity were found in either hemisphere insular glioma. Using graph theoretical analysis, differences were found in visual, sensorimotor, and default mode networks (p < 0.05). When the glioma located in the left hemisphere, the degree centrality was reduced in the GE group compared to the GnE group. When the glioma located in the right insula, the degree centrality, nodal efficiency, nodal local efficiency, and nodal clustering coefficient of the GE group were lower than those of the GnE group. CONCLUSION: The impact of insular glioma itself and GRE on the brain network is widespread. The networks altered by insular GRE differ depending on the hemisphere location. GRE reduces the nodal properties of brain networks than that in insular glioma.

New natural protein tyrosine phosphatase 1B inhibitors from Gynostemma pentaphyllum.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease mainly caused by insulin resistance, which can lead to a series of complications such as cardiovascular disease, retinopathy, and its typical clinical symptom is hyperglycaemia. Glucosidase inhibitors, including Acarbose, Miglitol, are commonly used in the clinical treatment of hypoglycaemia. In addition, Protein tyrosine phosphatase 1B (PTP1B) is also an important promising target for the treatment of T2DM. Gynostemma pentaphyllum is a well-known oriental traditional medicinal herbal plant, and has many beneficial effects on glucose and lipid metabolism. In the present study, three new and nine known dammarane triterpenoids isolated from G. pentaphyllum, and their structures were elucidated by spectroscopic methods including HR-ESI-MS,1H and 13C NMR and X-ray crystallography. All these compounds were evaluated for inhibitory activity against α-glucosidase, α-amylase and PTP1B. The results suggested that compounds 7∼10 were potential antidiabetic agents with significantly inhibition activity against PTP1B in a dose-dependent manner.

Uptake, subcellular distribution, and fate of tetracycline in two wetland plants supplemented with microbial agents: Effect and mechanism.

The use of wetland plants in the context of phytoremediation is effective in the removal of antibiotics from contaminated water. However, the effectiveness and efficiency of many of these plants in the removal of antibiotics remain undetermined. In this study, the effectiveness of two plants-Phragmites australis and Iris pseudacorus-in the removal of tetracycline (TC) in hydroponic systems was investigated. The uptake of TC at the roots of I. pseudacorus and P. australis occurred at concentrations of 588.78 and 106.70 µg/g, respectively, after 7-day exposure. The higher uptake of TC in the root of I. pseudacorus may be attributed to its higher secretion of root exudates, which facilitate conditions conducive to the reproduction of microorganisms. These rhizosphere-linked microorganisms then drove the TC uptake, which was higher than that in the roots of P. australis. By elucidating the mechanisms underlying these uptake-linked outcomes, we found that the uptake of TC for both plants was significantly suppressed by metabolic and aquaporin inhibition, suggesting uptake and transport of TC were active (energy-dependent) and passive (aquaporin-dominated) processes, respectively. The subcellular distribution patterns of I. pseudacorus and P. australis in the roots were different, as expressed by differences in organelles, cell wall concentration levels, and transport-related dynamics. Additionally, the microbe-driven enhancement of the remediation capacities of the plants was studied comprehensively via a combined microbial-phytoremediation hydroponic system. We confirmed that the microbial agents increased the secretion of root exudates, promoting the variation of TC chemical speciation and thus enhancing the active transport of TC. These results contribute toward the improved application of wetland plants in the context of antibiotic phytoremediation.

Chemical characterization and comparative analysis of different parts of Cocculus orbiculatus through UHPLC-Q-TOF-MS.

Cocculus orbiculatus (L.) DC. (C. orbiculatus) is a medicinal herb valued for its dried roots with anti-inflammatory, analgesic, diuretic, and other therapeutic properties. Despite its traditional applications, chemical investigations into C. orbiculatus remain limited, focusing predominantly on alkaloids and flavonoids. Furthermore, the therapeutic use of C. orbiculatus predominantly focuses on the roots, leaving the stems, a significant portion of the plant, underutilized. This study employed ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) with in-house and online databases for comprehensive identification of components in various plant parts. Subsequently, untargeted metabolomics was employed to analyze differences in components across different harvest periods and plant sections of C. orbiculatus, aiming to screen for distinct components in different parts of the plant. Finally, metabolomic analysis of the roots and stems, which contribute significantly to the plant's weight, was conducted using chemometrics, including principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), orthogonal partial least squares discriminant analysis (OPLS-DA), and heatmaps. A total of 113 components, including alkaloids, flavonoids, and organic acids, were annotated across the root, stem, leaf, flower, and fruit, along with numerous previously unreported compounds. Metabolomic analyses revealed substantial differences in components between the root and stem compared to the leaf, flower, and fruit during the same harvest period. PLS-DA and OPLS-DA annotated 10 differentiating components (VIP > 1.5, P < 0.05, FC > 2 or FC < 0.67), with 5 unique to the root and stem, exhibiting lower mass spectrometric responses. This study provided the first characterization of 113 chemical constituents in different parts of C. orbiculatus, laying the groundwork for pharmacological research and advocating for the enhanced utilization of its stem.

Robotic versus laparoscopic distal gastrectomy for resectable gastric cancer: a randomized phase 2 trial.

Robotic surgery may be an alternative to laparoscopic surgery for gastric cancer (GC). However, randomized controlled trials (RCTs) reporting the differences in survival between these two approaches are currently lacking. From September 2017 to January 2020, 300 patients with cT1-4a and N0/+ were enrolled and randomized to either the robotic (RDG) or laparoscopic distal gastrectomy (LDG) group (NCT03313700). The primary endpoint was 3-year disease-free survival (DFS); secondary endpoints reported here are the 3-year overall survival (OS) and recurrence patterns. The remaining secondary outcomes include intraoperative outcomes, postoperative recovery, quality of lymphadenectomy, and cost differences, which have previously been reported. There were 283 patients in the modified intention-to-treat analysis (RDG group: n = 141; LDG group: n = 142). The trial has met pre-specified endpoints. The 3-year DFS rates were 85.8% and 73.2% in the RDG and LDG groups, respectively (p = 0.011). Multivariable Cox regression model including age, tumor size, sex, ECOG PS, lymphovascular invasion, histology, pT stage, and pN stage showed that RDG was associated with better 3-year DFS (HR: 0.541; 95% CI: 0.314-0.932). The RDG also improved the 3-year cumulative recurrence rate (RDG vs. LDG: 12.1% vs. 21.1%; HR: 0.546, 95% CI: 0.302-0.990). Compared to LDG, RDG demonstrated non-inferiority in 3-year DFS rate.

Enlightenment of robotic gastrectomy from 527 patients with gastric cancer in the minimally invasive era: 5 years of optimizing surgical performance in a high-volume center - a retrospective cohort study.

BACKGROUND: Learning curves have been used in the field of RG. However, it should be noted that the previous study did not comprehensively investigate all changes related to the learning curve.This study aims to establish a learning curve for radical robotic gastrectomy (RG) and evaluate its effect on the short-term outcomes of patients with gastric cancer. METHODS: The clinicopathological data of 527 patients who underwent RG between August 2016 and June 2021 were retrospectively analyzed. Learning curves related to the operation time and postoperative hospital stay were determined separately using cumulative sum (CUSUM) analysis. Then, the impact of the learning curve on surgical efficacy was analyzed. RESULTS: Combining the CUSUM curve break points and technical optimization time points, the entire cohort was divided into three phases (patients 1-100, 101-250, and 251-527). The postoperative complication rate and postoperative recovery time tended to decrease significantly with phase advancement (P<0.05). More extraperigastric examined lymph nodes (LN) were retrieved in phase III than in phase I (I vs. III, 15.12±6.90 vs. 17.40±7.05, P=0.005). The rate of LN noncompliance decreased with phase advancement. Textbook outcome (TO) analysis showed that the learning phase was an independent factor in TO attainment (P<0.05). CONCLUSION: With learning phase advancement, the short-term outcomes were significantly improved. It is possible that our optimization of surgical procedures could have contributed to this improvement. The findings of this study facilitate the safe dissemination of RG in the minimally invasive era.

Barley Protein LFBEP-C1 from Lactiplantibacillus plantarum dy-1 Fermented Barley Extracts by Inhibiting Lipid Accumulation in a Caenorhabditis elegans Model.

Objective: This study aimed to investigate the lipid-lowering activity of LFBEP-C1 in high glucose-fed Caenorhabditis elegans (C. elegans). Methods: In this study, the fermented barley protein LFBEP-C1 was prepared and tested for its potential anti-obesity effects on C. elegans. The worms were fed Escherichia coli OP50 ( E. coli OP50), glucose, and different concentrations of LFBEP-C1. Body size, lifespan, movement, triglyceride content, and gene expression were analyzed. The results were analyzed using ANOVA and Tukey's multiple comparison test. Results: Compared with the model group, the head-swing frequency of C. elegans in the group of LFBEP-C1 at 20 µg/mL increased by 33.88%, and the body-bending frequency increased by 27.09%. This indicated that LFBEP-C1 improved the locomotive ability of C. elegans. The average lifespan of C. elegans reached 13.55 days, and the body length and width of the C. elegans decreased after LFBEP-C1 intake. Additionally, LFBEP-C1 reduced the content of lipid accumulation and triglyceride levels. The expression levels of sbp-1, daf-2, and mdt-15 significantly decreased, while those of daf-16, tph-1, mod-1, and ser-4 significantly increased after LFBEP-C1 intake. Changes in these genes explain the signaling pathways that regulate lipid metabolism. Conclusion: LFBEP-C1 significantly reduced lipid deposition in C. elegans fed a high-glucose diet and alleviated the adverse effects of a high-glucose diet on the development, lifespan, and exercise behavior of C. elegans. In addition, LFBEP-C1 regulated lipid metabolism mainly by mediating the expression of genes in the sterol regulatory element-binding protein, insulin, and 5-hydroxytryptamine signaling pathways.

Impact of chemotherapy delay on long-term prognosis of laparoscopic radical surgery for locally advanced gastric cancer: a pooled analysis of four randomized controlled trials.

BACKGROUND: Adjuvant chemotherapy following curative surgery for locally advanced gastric cancer (AGC) significantly improves long-term patient prognosis. However, delayed chemotherapy (DC), in which patients are unable to receive timely treatment, is a common phenomenon in clinical practice for various reasons. This study aimed to investigate the impact of DC on the prognosis of patients with stage II-III locally AGC and explore the associated risk factors. METHODS: Data from four prospective studies were included in the pooled analysis. The planned chemotherapy (PC) group was defined as the time interval between surgery and the first chemotherapy ≤ 49 d, while the DC group was defined as the time interval between surgery and chemotherapy > 49 d. The prognosis, recurrence, and risk factors were compared, and a nomogram for predicting DC was established. RESULTS: In total, 596 patients were included, of whom 531 (89.1%) had PC and 65 (10.9%) had DC. Survival analysis revealed that the 5-year overall survival (OS) and disease-free survival (DFS) were significantly lower in the DC group than those in the PC group (log-rank P < 0.001). Cox univariable and multivariable analyses showed that DC was an independent risk factor for OS and DFS in stage II-III patients (P < 0.05). Based on the significant factors for DC, a prediction model was established that had a good fit, high accuracy (AUC = 0.780), and clinical applicability in both the training and validation sets. CONCLUSION: Delayed chemotherapy after gastrectomy is associated with poor long-term prognosis in patients with locally advanced stage II-III GC disease. But standardized, full-cycle adjuvant chemotherapy after surgery may play a remedial role, and can to a certain extent compensate the poor effects caused by delayed chemotherapy.

Laparoscopic Spleen-Preserving Hilar Lymphadenectomy for Advanced Proximal Gastric Cancer Without Greater Curvature Invasion: Five-Year Outcomes From the Fuges-02 Randomized Clinical Trial.

Importance: Splenic hilar lymphadenectomy has been recommended for locally advanced proximal gastric cancer (APGC) involving the greater curvature. However, it is unclear whether laparoscopic spleen-preserving splenic hilar lymphadenectomy (LSPSHL) is associated with a long-term survival benefit for APGC without greater curvature invasion. Objective: To present the 5-year follow-up data from a randomized clinical trial that compared laparoscopic total gastrectomy (D2 group) with D2 plus LSPSHL (D2 + No. 10 group) among patients with resectable APGC. Design, Setting, and Participants: This is a post hoc secondary analysis of a randomized clinical trial that enrolled 536 patients with potentially resectable APGC (cT2-4a, N0 or N+, and M0) without greater curvature invasion from January 5, 2015, to October 10, 2018. All patients were tracked for at least 5 years. The final follow-up was on October 30, 2023. Interventions: Patients were randomly assigned in a 1:1 ratio to the D2 + No. 10 or D2 groups. Main Outcomes and Measures: The 5-year disease-free survival (DFS) and overall survival (OS) rates were measured. Recurrence patterns and causes of death were compared. Results: A total of 526 patients (392 men [74.5%]; mean [SD] age, 60.6 [9.6] years) were included in the modified intent-to-treat analysis, with 263 patients in each group. The 5-year DFS rate was 63.9% (95% CI, 58.1%-69.7%) for the D2 + No. 10 group and 55.1% (95% CI, 49.1%-61.1%) for the D2 group (log-rank P = .04). A statistically significant difference was observed in the 5-year OS between the D2 + No. 10 group and the D2 group (66.2% [95% CI, 60.4%-71.9%] vs 57.4% [95% CI, 51.4%-63.4%]; log-rank P = .03). The No. 10 lymph node exhibited a therapeutic value index (TVI) of 6.5, surpassing that of Nos. 8a (TVI, 3.0), 11 (TVI, 5.8), and 12a (TVI, 0.8). A total of 86 patients in the D2 + No. 10 group (cumulative incidence, 32.7%) and 111 patients in the D2 group (cumulative incidence, 42.2%) experienced recurrence (hazard ratio, 0.72; 95% CI, 0.54-0.95; P = .02). The multivariable competing risk regression model demonstrated that D2 + No. 10 remained an independent protective factor for a lower 5-year cumulative recurrence rate after surgery (hazard ratio, 0.75; 95% CI, 0.56-1.00; P = .05). There was a significant difference in the 5-year cumulative recurrence rate at the No. 10 lymph node area between the 2 groups (D2 + No. 10 group vs D2 group: 0% vs 2.3% [n = 6]; P = .01). Conclusions: This post hoc secondary analysis of a randomized clinical trial found that laparoscopic total gastrectomy with LSPSHL can improve the prognosis and reduce recurrence for APGC without greater curvature invasion. Future multicenter studies are warranted to validate these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT02333721.

Comprehensive multi-omics analysis of pyroptosis for optimizing neoadjuvant immunotherapy in patients with gastric cancer.

Background: Pyroptosis plays a crucial role in immune responses. However, the effects of pyroptosis on tumor microenvironment remodeling and immunotherapy in gastric cancer (GC) remain unclear. Patients and Methods: Large-sample GEO data (GSE15459, GSE54129, and GSE62254) were used to explore the immunoregulatory roles of pyroptosis. TCGA cohort was used to elucidate multiple molecular events associated with pyroptosis, and a pyroptosis risk score (PRS) was constructed. The prognostic performance of the PRS was validated using postoperative GC samples from three public databases (n=925) and four independent Chinese medical cohorts (n=978). Single-cell sequencing and multiplex immunofluorescence were used to elucidate the immune cell infiltration landscape associated with PRS. Patients with GC who received neoadjuvant immunotherapy (n=48) and those with GC who received neoadjuvant chemotherapy (n=49) were enrolled to explore the value of PRS in neoadjuvant immunotherapy. Results: GC pyroptosis participates in immune activation in the tumor microenvironment and plays a powerful role in immune regulation. PRS, composed of four pyroptosis-related differentially expressed genes (BATF2, PTPRJ, RGS1, and VCAN), is a reliable and independent biomarker for GC. PRSlow is associated with an activated pyroptosis pathway and greater infiltration of anti-tumor immune cells, including more effector and CD4+ T cells, and with the polarization of tumor-associated macrophages in the tumor center. Importantly, PRSlow marks the effectiveness of neoadjuvant immunotherapy and enables screening of GC patients with combined positive score ≥1 who benefit from neoadjuvant immunotherapy. Conclusion: Our study demonstrated that pyroptosis activates immune processes in the tumor microenvironment. A low PRS correlates with enhanced infiltration of anti-tumor immune cells at the tumor site, increased pyroptotic activity, and improved patient outcomes. The constructed PRS can be used as an effective quantitative tool for pyroptosis analysis to guide more effective immunotherapeutic strategies for patients with GC.

Advancements and challenges in pharmacokinetic and pharmacodynamic research on the traditional Chinese medicine saponins: a comprehensive review.

Recent research on traditional Chinese medicine (TCM) saponin pharmacokinetics has revealed transformative breakthroughs and challenges. The multicomponent nature of TCM makes it difficult to select representative indicators for pharmacokinetic studies. The clinical application of saponins is limited by their low bioavailability and short half-life, resulting in fluctuating plasma concentrations. Future directions should focus on novel saponin compounds utilizing colon-specific delivery and osmotic pump systems to enhance oral bioavailability. Optimizing drug combinations, such as ginsenosides with aspirin, shows therapeutic potential. Rigorous clinical validation is essential for practical applications. This review emphasizes a transformative era in saponin research, highlighting the need for clinical validation. TCM saponin pharmacokinetics, guided by traditional principles, are in development, utilizing multidisciplinary approaches for a comprehensive understanding. This research provides a theoretical basis for new clinical drugs and supports rational clinical medication.

Effects of tumor marker regression load score on long-term prognosis of gastric cancer patients undergoing radical surgery after neoadjuvant chemotherapy.

BACKGROUND: The effects of the dynamics of serum tumor markers (CA72-4, CEA, CA19-9, CA125 and AFP) before and after neoadjuvant chemotherapy (NACT) on the prognosis of gastric cancer(GC) patients remain unclear. METHODS: The training set contained 334 GC patients from Fujian Medical University Union Hospital (FJMUUH) and 113 GC patients in Qinghai University Affiliated Hospital (QhUAH) were used as an external validation set. Tumor marker regression load (ΔTMRL) indicator, including ΔCA72-4, ΔCEA, ΔCA19-9, ΔCA125, and ΔAFP, is defined as [(postNACT marker- preNACT marker)/preNACT marker]. Tumor marker regression load score (TMRLS) consists of ΔCA72-4, ΔCEA and ΔCA125. The predictive performance of the nomogram-TMRLS was evaluated using the area under the receiver operating characteristic(ROC) curve(AUC), decision curve analysis(DCA), and C-index. RESULTS: Patients from FJMUUH were divided into two groups, TMRLS-low and TMRLS-high, determined by R package maxstat. Survival analysis revealed a higher 3-year overall survival(OS) in the TMRLS-low than in the TMRLS-high group. The TMRLS-high group who received postoperative adjuvant chemotherapy(AC) showed a significantly higher 3-year OS rate than those who did not. Multivariate COX regression analysis indicated that TMRLS was an independent prognostic factor for OS. A nomogram for predicting OS based on TMRLS showed a significantly higher C-index and AUC than the ypTNM stage. The above results were also found in the QhUAH external validation cohort. CONCLUSION: TMRLS is a novel independent prognostic factor for GC who underwent NACT and a radical gastrectomy. Furthermore, the TMRLS-high group, who received postoperative AC, may achieve better survival outcomes. Notably, the predictive performance of the nomogram-TMRLS significantly outperformed that of the ypTNM stage.

Pyroptosis inhibitors MCC950 and VX-765 mitigate myocardial injury by alleviating oxidative stress, inflammation, and apoptosis in acute myocardial hypoxia.

Acute myocardial infarction (AMI) is a prevalent cardiovascular disease with high morbidity and mortality rates worldwide. Pyroptosis is an inflammatory form of programmed cell death that has been linked to various pathological conditions. However, its exact contribution to the onset and progression of heart injury in AMI has not yet fully elucidated. Herein, we established mouse AMI model by ligating the left anterior descending artery and performed transcriptome analysis during the early phase of AMI. Mouse HL-1 and human AC-16 cardiomyocytes were subjected to hypoxia to simulate ischemic injury in vitro. Our results revealed a significant activation of the inflammatory response at 3 h post-ligation, as confirmed by RNA sequencing. We identified the occurrence of NLRP3 inflammasome-mediated pyroptosis in the cardiac tissues of human cases with AMI, as well as in mouse models of AMI and hypoxia-induced cardiomyocytes, using immunohistochemistry staining and Western blotting assays. Concurrently, pharmacological inhibition of NLRP3 inflammasome-mediated pyroptosis with MCC950 and VX-765 effectively decreased hypoxia-induced cardiomyocytes injury, while mitigating myocardial oxidative stress, apoptosis and inflammation caused by hypoxia. Moreover, the circulating levels of gasdermin D (GSDMD), the pyroptosis executor, were remarkably elevated in the plasma of mice with early AMI and in the supernatant of hypoxia-exposed cardiomyocytes in a time-dependent manner using ELISA and Western blotting. Furthermore, the change in circulating GSDMD positively correlated with Creatine Kinase-MB (CK-MB) in the plasma of early-stage AMI mouse. In summary, these findings indicated a critical role for NLRP3 inflammasome-mediated pyroptosis in the progression of AMI, the administration of MCC950 and VX-765 may be attractive candidate therapeutic approaches for cardiac injury caused by acute hypoxia or even AMI. Additionally, the circulating GSDMD exhibits potential as a newly diagnostic biomarker for AMI.

USP22 as a key regulator of glycolysis pathway in osteosarcoma: insights from bioinformatics and experimental approaches.

Background: Osteosarcoma is the most common primary malignant bone tumor, but its pathogenesis remains unclear. Ubiquitin-specific processing peptidase 22 (USP22) is reported to be highly expressed and associated with tumor malignancy and prognosis in cancers. However, the role and mechanism of USP22 in osteosarcoma is not fully understood. This study aims to investigate the function and potential mechanism of USP22 in osteosarcoma using bioinformatics analysis combined with experimental validation. Methods: We first integrated transcriptomic datasets and clinical information of osteosarcoma from GEO and TCGA databases to assess the expression and prognostic value of USP22 in osteosarcoma. Then, differential expression analysis and weighted gene co-expression network analysis (WGCNA) were conducted to identify USP22-related co-expressed genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the biological functions and signaling pathways of USP22 co-expressed genes. To validate the accuracy of bioinformatics analyses, we downregulated USP22 expression in osteosarcoma cell line Sao-2 using siRNA and assessed its effect on cell proliferation, migration, invasion, apoptosis, and regulation of key signaling pathways. Results: We found that USP22 was highly expressed in osteosarcoma tissues and correlated with poor prognosis in osteosarcoma patients. USP22 also showed potential as a diagnostic marker for osteosarcoma. In addition, 344 USP22-related co-expressed genes were identified, mainly involved in signaling pathways such as glycolysis, oxidative phosphorylation, spliceosome, thermogenesis, and cell cycle. The in vitro experiments confirmed the accuracy and reliability of bioinformatics analyses. We found that downregulation of USP22 could inhibit Sao-2 cell proliferation, migration, invasion, and induce apoptosis. Furthermore, downregulation of USP22 significantly reduced aerobic glycolysis levels in Sao-2 cells and inhibited the expression of key enzymes and transporters in aerobic glycolysis pathways such as HK2, PKM2, and GLUT1. Conclusions: USP22 plays a critical role in the occurrence, development, and prognosis of osteosarcoma. USP22 could influence Sao-2 cell proliferation, apoptosis, migration, and invasion by regulating the glycolysis pathway, thereby promoting osteosarcoma progression. Therefore, USP22 may be a potential therapeutic target for the treatment of osteosarcoma.

The safety and efficacy of neoadjuvant immunochemotherapy following laparoscopic gastrectomy for gastric cancer: a multicenter Real-world clinical study.

BACKGROUND: The safety and efficacy of neoadjuvant immunochemotherapy (nICT) for locally advanced gastric cancer (LAGC) remain controversial. METHODS: Patients with LAGC who received either nICT or neoadjuvant chemotherapy (nCT) at 3 tertiary referral teaching hospitals in China between January 2016 and October 2022 were analysed. After propensity-score matching (PSM), comparing the radiological response, pathological response rate, perioperative outcomes, and early recurrence between the two groups. RESULTS: After PSM, 585 patients were included, with 195 and 390 patients comprising the nICT and nCT groups, respectively. The nICT group exhibited a higher objective response rate (79.5% versus [vs.] 59.0%; P<0.001), pathological complete response rate (14.36% vs. 6.41%; P=0.002) and major pathological response rate (39.49% vs. 26.15%; P=0.001) compared with the nCT group. The incidence of surgical complications (17.44% vs. 16.15%, P=0.694) and proportion of perioperative textbook outcomes (80.0% vs. 81.0%; P=0.767) were similar in both groups. The nICT group had a significantly lower proportion of early recurrence than the nCT group (29.7% vs. 40.8%; P=0.047). Furthermore, the multivariable logistic analysis revealed that immunotherapy was an independent protective factor against early recurrence (odds ratio 0.62 [95% CI 0.41-0.92]; P=0.018). No significant difference was found in neoadjuvant therapy drug toxicity between the two groups (51.79% vs. 45.38%; P=0.143). CONCLUSIONS: Compared with nCT, nICT is safe and effective, which significantly enhanced objective and pathological response rates, and reduced the risk for early recurrence among patients with LAGC. TRIAL REGISTRATION: Clinical Trials.gov.

[Effects of Controlled-release Blended Fertilizer on Crop Yield and Greenhouse Gas Emissions in Wheat-maize Rotation System].

The increasing use of nitrogen fertilizers exerts extreme pressure on the environment (e.g., greenhouse gas emissions, GHGs) for winter wheat-summer maize rotation systems in the North China Plain. The application of controlled-release fertilizers is considered as an effective measure to improve crop yield and nitrogen fertilizer utilization efficiency. To explore the impact of one-time fertilization of controlled-release blended fertilizer on crop yield and GHGs of a wheat-maize rotation system, field experiments were carried out in Dezhou Modern Agricultural Science and Technology Park from 2020 to 2022. Five treatments were established for both winter wheat and summer maize, including no nitrogen control (CK), farmers' conventional nitrogen application (FFP), optimized nitrogen application (OPT), CRU1 (the blending ratio of coated urea and traditional urea on winter wheat and summer maize was 5:5 and 3:7, respectively), and CRU2 (the blending ratio of coated urea and traditional urea on winter wheat and summer maize was 7:3 and 5:5, respectively). The differences in yield, nitrogen fertilizer utilization efficiency, fertilization economic benefits, and GHGs among different treatments were compared and analyzed. The results showed that nitrogen application significantly increased the single season and annual crop yields of the wheat-maize rotation system (P < 0.05). Compared with those of FFP, the CRU1 and CRU2 treatments increased the yields of summer maize by 0.4% to 5.6%, winter wheat by -5.4% to 4.1%, and annual yields by -1.1% to 3.9% (P > 0.05). N recovery efficiency (NRE), N agronomic efficiency (NAE), and N partial factor productivity (NPFP) were increased by -8.6%-43.4%, 2.05-6.24 kg·kg-1, and 4.24-10.13 kg·kg-1, respectively. Annual net income increased by 0.2% to 6.3%. Nitrogen application significantly increased the annual emissions of soil N2O and CO2 in the rotation system (P < 0.05) but had no effect on the annual emissions of CH4 (except for in the FFP treatment in the first year). The annual total N2O emissions under the CRU1 and CRU2 treatments were significantly reduced by 23.4% to 30.2% compared to those under the FFP treatment (P < 0.05). Additionally, nitrogen application significantly increased the annual global warming potential (GWP) of the rotation system (P < 0.05), but the intensity of greenhouse gas emissions was reduced due to the increase in crop yields. Compared with that under FFP, the annual GWP under the CRU1 and CRU2 treatments decreased by 9.6% to 11.5% (P < 0.05), and the annual GHGs decreased by 11.2% to 13.8% (P > 0.05). In summary, the one-time application of controlled-release blended fertilizer had a positive role in improving crop yield and economic benefits, reducing nitrogen fertilizer input and labor costs, and GHGs, which is an effective nitrogen fertilizer management measure to promote cleaner production of food crops in the North China Plain.

ACSL4 accelerates osteosarcoma progression via modulating TGF-ß/Smad2 signaling pathway.

Osteosarcoma (OS) is a malignant bone sarcoma arising from mesenchymal stem cells. The biological role of Acyl-CoA synthetase long-chain family member 4 (ACSL4), recently identified as an oncogene in numerous tumor types, remains largely unclear in OS. In this study, we investigated the expression of ACSL4 in OS tissues using immunohistochemistry staining (IHC) staining of a human tissue microarray and in OS cells by qPCR assay. Our findings revealed a significant up-regulation of ACSL4 in both OS tissues and cells. To further understand its biological effects, we conducted a series of loss-of-function experiments using ACSL4-depleted MNNG/HOS and U-2OS cell lines, focusing on OS cell proliferation, migration, and apoptosis in vitro. Our results demonstrated that ACSL4 knockdown remarkably suppressed OS cell proliferation, arrested cells in the G2 phase, induced cell apoptosis, and inhibited cell migration. Additionally, a subcutaneous xenograft mice model was established to validate the in vivo impact of ACSL4, revealing ACSL4 silencing impaired tumor growth in the OS xenograft mice. Additionally, we discovered that ACSL4 could regulate the phosphorylation level of Smad2 through cooperative interactions, and treatment with a TGF-ß inhibitor weakened the promoting effects of ACSL4 overexpression. In short, ACSL4 regulated OS progression by modulating TGF-ß/Smad2 signaling pathway. These findings underscore ACSL4 as a promising therapeutic target for OS patients and contribute novel insights into the pathogenesis of OS.

Anti-inflammatory and protective effects of Pimpinella candolleana on ulcerative colitis in rats: a comprehensive study of quality, chemical composition, and molecular mechanisms.

Introduction: P. candolleana Wight et Arn. Is a traditional Chinese herbal medicine used by the Gelao nationality in southwest China, has been historically applied to treat various gastrointestinal disorders. Despite its traditional usage, scientific evidence elucidating its efficacy and mechanisms in treating ulcerative colitis (UC) remains sparse. This study aimed to determine the quality and chemical composition of Pimpinella candolleana and to identify its potential therapeutic targets and mechanisms in acetic acid-induced ulcerative colitis (UC) rats through integrated approaches. Methods: Morphological and microscopic characteristics, thin layer chromatography (TLC) identification, and quantitative analysis of P. candolleana were performed. UPLC-Q-TOF-MS, network pharmacology, and molecular docking were used to identify its chemical composition and predict its related targets in UC. Furthermore, a rat model was established to evaluate the therapeutic effect and potential mechanism of P. candolleana on UC. Results: Microscopic identification revealed irregular and radial arrangement of the xylem in P. candolleana, with a light green cross-section and large medullary cells. UPLC-Q-TOF-MS analysis detected and analyzed 570 metabolites, including flavonoids, coumarins, and terpenoids. Network pharmacology identified 12 effective components and 176 target genes, with 96 common targets for P. candolleana-UC, including quercetin, luteolin, and nobiletin as key anti-inflammatory components. GO and KEGG revealed the potential involvement of their targets in RELA, JUN, TNF, IKBKB, PTGS2, and CHUK, with action pathways such as PI3K-Akt, TNF, IL-17, and apoptosis. Molecular docking demonstrated strong affinity and binding between these key components (quercetin, luteolin, and nobiletin) and the key targets of the pathway, including JUN and TNF. Treatment with P. candolleana improved body weight loss, the disease activity index, and colonic histological damage in UC rats. Pimpinella candolleana also modulated the levels of IL-2 and IL-6 in UC rats, reduced the expression of pro-inflammatory cytokines such as IL-6, MAPK8, TNF-α, CHUK, and IKBKB mRNA, and decreased the expression of TNF, IKBKB, JUN, and CHUK proteins in the colon of UC rats, thereby reducing inflammation and alleviating UC symptoms. Conclusion: P. candolleana exerts its protective effect on UC by reducing the expression of proinflammatory cytokines and inhibiting inflammation, providing scientific evidence for its traditional use in treating gastrointestinal diseases. This study highlights the potential of P. candolleana as a natural therapeutic agent for UC and contributes to the development of novel medicines for UC treatment.