Banxia Xiexin decoction promotes gastric lymphatic pumping by regulating lymphatic smooth muscle cell contraction and energy metabolism in a stress-induced gastric ulceration rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine (TCM) formula Banxia Xiexin decoction (BXD) has definite therapeutic effect in treating stress-induced gastric ulceration (SIGU) and many other gastrointestinal diseases, but its effect on gastric lymphatic pumping (GLP) remains unclear. AIM OF THE STUDY: Elucidating the role of GLP in SIGU and BXD treatment, and exploring the molecular mechanisms of GLP regulation. MATERIALS AND METHODS: In vivo GLP imaging were performed on SIGU rat model, and the lymphatic dynamic parameters were evaluated. Gastric antrum tissues and serum were collected for macroscopic, histopathological and ulcerative parameters analysis. Gastric lymphatic vessel (GLV) tissues were collected for RNA-Seq assays. Differentially expressed genes (DEGs) were screened from RNA-Seq result and submitted for transcriptomic analysis. Key DEGs and their derivative proteins were measured by qRT-PCR and WB. RESULTS: GLP was significantly suppressed in SIGU rats. BXD could recover GLP, ameliorate stomach lymphostasis, and alleviate the ulcerative damage. Transcriptome analysis of GLV showed the top up-DEGs were concentrated in smooth muscle contraction signaling pathway, while the top the down-DEGs were concentrated in energy metabolism pathways especially fatty acid degradation pathway, which indicated BXD can promote lymphatic smooth muscle contraction, regulate energy metabolism, and reduce fatty acid degradation. The most possible target of these mechanisms was the lymphatic smooth muscle cells (LSMCs) which drove the GLP. This speculation was further validated by the qRT-PCR and WB assessments for the level of key genes and proteins. CONCLUSIONS: By activating the smooth muscle contraction signaling pathway, restoring energy supply, modulating energy metabolism program and reducing fatty acid degradation, BXD effectively recovered GLP, mitigated the accumulation of inflammatory cytokines and metabolic wastes in the stomach, which importantly contributes to its efficacy in treating SIGU.

Sulforaphane-Enriched Extracts from Broccoli Exhibit Antimicrobial Activity against Plant Pathogens, Promising a Natural Antimicrobial Agent for Crop Protection.

Sulforaphane (SFN) is one of the hydrolysates of glucosinolates (GSLs), primarily derived from Brassica vegetables like broccoli. In clinical therapy, SFN has been proven to display antimicrobial, anticancer, antioxidant, and anti-inflammatory properties. However, the antimicrobial effects and mechanism of SFN against plant pathogens need to be further elucidated, which limits its application in agriculture. In this study, the genetic factors involved in SFN biosynthesis in 33 B. oleracea varieties were explored. The finding showed that besides the genetic background of different B. oleracea varieties, myrosinase and ESP genes play important roles in affecting SFN content. Subsequently, the molecular identification cards of these 33 B. oleracea varieties were constructed to rapidly assess their SFN biosynthetic ability. Furthermore, an optimized protocol for SFN extraction using low-cost broccoli curds was established, yielding SFN-enriched extracts (SFN-ee) containing up to 628.44 µg/g DW of SFN. The antimicrobial activity assay confirmed that SFN-ee obtained here remarkably inhibit the proliferation of nine tested microorganisms including four plant pathogens by destroying their membrane integrity. Additionally, the data demonstrated that exogenous application of SFN-ee could also induce ROS accumulation in broccoli leaves. These results indicated that SFN-ee should play a dual role in defense against plant pathogens by directly killing pathogenic cells and activating the ROS signaling pathway. These findings provide new evidence for the antimicrobial effect and mechanism of SFN against plant pathogens, and suggest that SFN-ee can be used as a natural plant antimicrobial agent for crop protection and food preservation.

Integrating metabolomics and network pharmacology to assess the effects of Mahuang Xixin Fuzi decoction on migraine rats induced by nitroglycerin.

OBJECTIVES: This study was designed to investigate the pharmacological activity and therapeutic mechanism of Mahuang Xixin Fuzi decoction (MXFD) on migraine. METHODS: Migraine model rats induced by nitroglycerin were established, and then orally administered with MXFD for 7 days. Blood and urine samples were collected to identify differential metabolites with metabolomics. To integrate the findings from network pharmacology and metabolomics analysis, the metabolites and targets related to MXFD therapy for migraine were filtered. KEY FINDINGS: MXFD was found to alleviate the symptoms of migraines in rats. After treatment with MXFD, nine metabolites were found to be regulated and returned to normal levels. MXFD acted directly on nine key targets including MAOB, MAOA, ADRB1, ADRB2, ADRB3, ADORA2A, ADORA2B, DRD5, and HTR4 and regulated two out of nine metabolites, namely deoxycholic acid and 5-methoxyindoleacetate. CONCLUSIONS: The study found that MXFD can alleviate migraines through multitarget and multicomponent interaction networks.

Association between lactic acidosis and multiple organ dysfunction syndrome after cardiopulmonary bypass.

Background: The relationship between hyperlactatemia and prognosis after cardiopulmonary bypass (CPB) is controversial, and some studies ignore the presence of lactic acidosis in patients with severe hyperlactacemia. This study explored the association between lactic acidosis (LA) and the occurrence of multiple organ dysfunction syndrome (MODS) after cardiopulmonary bypass. Methods: This study was a post hoc analysis of patients who underwent cardiac surgery between February 2017 and August 2018 and participated in a prospective study at Taizhou Hospital. The data were collected at: ICU admission (H0), and 4, 8, 12, 24, and 48 h after admission. Blood lactate levels gradually increased after CPB, peaking at H8 and then gradually decreasing. The patients were grouped as LA, hyperlactatemia (HL), and normal control (NC) based on blood test results 8 h after ICU admission. Basic preoperative, perioperative, and postoperative conditions were compared between the three groups, as well as postoperative perfusion and oxygen metabolism indexes. Results: There were 22 (19%), 73 (64%), and 19 (17%) patients in the LA, HL, and NC groups, respectively. APACHE II (24h) and SOFA (24h) scores were the highest in the LA group (P < 0.05). ICU stay duration was the longest for the LA group (48.5 (42.5, 50) h), compared with the HL (27 (22, 48) h) and NC (27 (25, 46) h) groups (P = 0.012). The LA group had the highest incidence of MODS (36%), compared with the HL (14%) and NC (5%) groups (P = 0.015). In the LA group, the oxygen extraction ratio (O2ER) was lower (21.5 (17.05, 32.8)%) than in the HL (31.3 (24.8, 37.6)%) and the NC group (31.3 (29.0, 35.4) %) (P = 0.018). In the univariable analyses, patient age (OR = 1.054, 95% CI [1.003-1.109], P = 0.038), the LA group (vs. the NC group, (OR = 10.286, 95% CI [1.148-92.185], P = 0.037), and ΔPCO2 at H8 (OR = 1.197, 95% CI [1.022-1.401], P = 0.025) were risk factor of MODS after CPB. Conclusions: We speculated that there was correlation between lactic acidosis and MODS after CPB. In addition, LA should be monitored intensively after CPB.

Integrated transcriptome and DNA methylome analysis reveal the biological base of increased resistance to gray leaf spot and growth inhibition in interspecific grafted tomato scions.

BACKGROUND: Grafting is widely used as an important agronomic approach to deal with environmental stresses. However, the molecular mechanism of grafted tomato scions in response to biotic stress and growth regulation has yet to be fully understood. RESULTS: This study investigated the resistance and growth performance of tomato scions grafted onto various rootstocks. A scion from a gray leaf spot-susceptible tomato cultivar was grafted onto tomato, eggplant, and pepper rootstocks, creating three grafting combinations: one self-grafting of tomato/tomato (TT), and two interspecific graftings, namely tomato/eggplant (TE) and tomato/pepper (TP). The study utilized transcriptome and DNA methylome analyses to explore the regulatory mechanisms behind the resistance and growth traits in the interspecific graftings. Results indicated that interspecific grafting significantly enhanced resistance to gray leaf spot and improved fruit quality, though fruit yield was decreased compared to self-grafting. Transcriptome analysis demonstrated that, compared to self-grafting, interspecific graftings triggered stronger wounding response and endogenous immune pathways, while restricting genes related to cell cycle pathways, especially in the TP grafting. Methylome data revealed that the TP grafting had more hypermethylated regions at CHG (H = A, C, or T) and CHH sites than the TT grafting. Furthermore, the TP grafting exhibited increased methylation levels in cell cycle related genes, such as DNA primase and ligase, while several genes related to defense kinases showed decreased methylation levels. Notably, several kinase transcripts were also confirmed among the rootstock-specific mobile transcripts. CONCLUSIONS: The study concludes that interspecific grafting alters gene methylation patterns, thereby activating defense responses and inhibiting the cell cycle in tomato scions. This mechanism is crucial in enhancing resistance to gray leaf spot and reducing growth in grafted tomato scions. These findings offer new insights into the genetic and epigenetic contributions to agronomic trait improvements through interspecific grafting.

Screening and verification of hemostatic effective components group of Panax Notoginseng based on spectrum-effect relationships.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax Notoginseng (PN) can disperse blood stasis, hemostasis, and detumescence analgesic, which can be used for hemoptysis, hematemesis and another traumatic bleeding, and it is known as "A miracle hemostatic medicine". Studies show that the chemical composition of PN is relatively comprehensive, however, its hemostatic active ingredients have not been fully clarified. AIM OF STUDY: This study aimed to clarify the hemostatic effective components group (HECG) of PN, provide a foundation for the assessment of PN's quality and its comprehensive development, and for further studies on the pharmacodynamic material basis of other Traditional Chinese Medicines (TCMs). MATERIALS AND METHODS: UPLC-MS was used to establish the fingerprint and identify the common peaks in 44 batches of PN extracts (PNE). In addition, the plasma recalcification time and in vitro coagulation time were measured. For spectrum-effect analysis, bivariate correlation analysis (BCA) and partial least squares regression analysis (PLSR) were used to screen the hemostasis candidate active monomers of PN. The monomers were prepared by combining several preparative chromatography techniques. The efficacy was verified by plasma recalcification time, in vitro coagulation time, and a rat model of gastric hemorrhage. RESULTS: A total of 30 common peaks and hemostatic efficacy indexes of 44 batches of PNE were obtained. A total of 18 components were positively correlated with the comprehensive coagulation index by two statistical methods. Six and eleven monomers were obtained respectively by chromatographic preparation and procurement, and one monomer was eliminated due to preparation difficulty and other reasons. Seven active monomers with direct hemostatic effect and one active monomer with synergistic hemostatic effect were screened through plasma recalcification time, and their combinations were used as candidate HECG for hemostatic effect verification. The results of in vitro experiments showed that plasma recalcification time and in vitro coagulation time were significantly reduced (P < 0.05) in the HECG group, compared to the PNE group. The results of in vivo experiment also indicated that the hemostatic effect of HECG was comparable to that of PNE and PN powder. CONCLUSION: The composition and efficacy of the HECG of PN were screened and verified using the spectral correlation method and in vivo and in vitro efficacy verification; the HECG included Dencichine, Ginsenoside Rg1, Ginsenoside Rd, Ginsenoside Rh1, Ginsenoside F1, Notoginsenoside R1, Notoginsenoside Ft1 and Notoginsenoside Fe. These results laid a foundation for the quality evaluation of PN and provided a reference for the basic research of pharmacodynamic material basis of other TCMs.

Investigating material basis and molecular mechanism of Qing Cuo formula in the treatment of acne based on animal experiments, UPLC-LTQ-Orbitrap-MS and network pharmacology.

CONTEXT: Qing Cuo Formula (QCF) is a traditional Chinese medicine for treating acne, but its active compounds and molecular mechanisms are unclear. OBJECTIVE: To investigate the material basis and molecular mechanism of QCF. MATERIALS AND METHODS: In vivo experiments were conducted on 60 male golden hamsters with damp-heat acne, with a blank group, a spironolactone group and 3 QCF administration groups (given high, medium and low doses) over a 30-day period. Serum androgen and inflammatory cytokine levels were tested by ELISA. In vitro, chemical compositions of QCF were investigated by UPLC-LTQ-Orbitrap-MS. Network pharmacology approaches were used to analyse the protein-protein interaction (PPI) network and QCF active compounds-intersection targets-acne network. GO enrichment and KEGG pathway analysis was conducted subsequently. RESULTS: Low-dose QCF group (11.4 g/kg/day) showed significantly reduced levels of serum T (4.94 ± 0.36; 5.51 ± 0.36 ng/mL), DHT (6.67 ± 0.61; 8.09 ± 0.59 nmol/L), E2 (209.01 ± 20.92; 237.08 ± 13.94 pg/mL), IL-1α (36.84 ± 3.23; 44.07 ± 4.00 pg/mL) and FFA (128.32 ± 10.94; 148.00 ± 12.12 µmol/L) compared to the blank group (p < 0.05). In vitro experiments identified 75 compounds in QCF decoction, with 27 active compounds absorbed in serum. Network pharmacology identified 6 active components connecting 17 targets. GO enrichment and KEGG pathway analysis indicated that QCF's anti-acne targets mainly regulate extracellular matrix function, inflammatory processes, immune response and endocrine function. CONCLUSIONS: This study provides evidence of the molecular mechanism and material basis of QCF in treating androgen-related damp-heat acne, paving the way for further research on its potential in treating other conditions related to damp-heat constitution.

Changes to PUFA-PPAR pathway during mesaconitine induced myocardial coagulative necrosis.

Coagulation necrosis is characterized by the denaturation of structural proteins and lysosomal enzymes; its occurrence in myocardium can lead to heart failure. Current studies on myocardial injury primarily focus on inflammation, hypertrophy, and hemorrhage, while those on myocardial coagulation necrosis are still limited. Mesaconitine (MA), a C19 diester diterpenoid alkaloid derived from Aconitum carmichaelii Debx, has strong cardiotoxicity. During this study, the myocardial cells of SD rats showed significant coagulative necrosis after 6 days of oral administration of MA at a dose of 1.2 mg/kg/day. Investigations of its biological mechanism showed abnormal levels of polyunsaturated fatty acids (PUFAs) and Peroxisome proliferator activated receptors Alpha (PPARα) pathway related protein. Moreover, MA affected the PPARα signaling pathway through interactions with proteins such as POR, TFAM and GPD1, indirectly indicating that these above proteins are important targets for blocking myocardial coagulative necrosis. This study thus discusses the effects of the use of cardiotoxic compound, MA, to initiate myocardial coagulative necrosis and its associated toxic mechanisms.

Scutellarin Alleviates Ischemic Brain Injury in the Acute Phase by Affecting the Activity of Neurotransmitters in Neurons.

Cerebral ischemic stroke is a common neuron loss disease that is caused by the interruption of the blood supply to the brain. In order to enhance the CIS outcome, both identifying the treatment target of ischemic brain damage in the acute phase and developing effective therapies are urgently needed. Scutellarin had been found to be beneficial to ischemic injuries and has been shown to have potent effects in clinical application on both stroke and myocardial infarction. However, whether scutellarin improves ischemic brain damage in the acute phase remains unknown. In this study, the protective effects of scutellarin on ischemic brain damage in the acute phase (within 12 h) were illustrated. In middle cerebral artery occlusion and reperfusion (MCAO/R) modeling rats, the Z-Longa score was significantly down-regulated by 25% and 23.1%, and the brain infarct size was reduced by 26.95 ± 0.03% and 25.63 ± 0.02% when responding to high-dose and low-dose scutellarin treatments, respectively. H&E and TUNEL staining results indicated that the neuron loss of the ischemic region was improved under scutellarin treatment. In order to investigate the mechanism of scutellarin's effects on ischemic brain damage in the acute phase, changes in proteins and metabolites were analyzed. The suppression of scutellarin on the glutamate-inducing excitatory amino acid toxicity was strongly indicated in the study of both proteomics and metabolomics. A molecular docking experiment presented strong interactions between scutellarin and glutamate receptors, which score much higher than those of memantine. Further, by performing a parallel reaction monitoring-mass spectrometry (PRM-MS) study on both the cortex and hippocampus tissue of the ischemic region, we screened the scutellarin-regulating molecules that are involved in both the release and transportation of neurotransmitters. It was found that the aberrant levels of glutamate receptors, including EAAT2, GRIN1, GRIN2B, and GRM1, as well as of other glutamatergic pathway-involving proteins, including CAMKK2, PSD95, and nNOS, were significantly regulated in the ischemic cortex. In the hippocampus, EAAT2, GRIN1, nNOS, and CAM were significantly regulated. Taken together, scutellarin exerts potent effects on ischemic brain damage in the acute phase by regulating the activity of neurotransmitters and reducing the toxicity of excitatory amino acids in in neurons.

[Rapid identification of components in Wuzhuyu Decoction using UHPLC Q-Exactive Orbitrap MS~n and molecular network technology].

Wuzhuyu Decoction, the classical formula recorded in the Treatise on Febrile Diseases(Shang Han Lun), has been included in the Catalogue of Ancient Classic Prescriptions(the First Batch). Consisting of Euodiae Fructus, Ginseng Radix et Rhizoma, Zingiberis Rhizoma Recens, and Jujubae Fructus, it is effective in warming the middle, tonifying deficiency, dispelling cold, and descending adverse Qi, and is widely applied clinically with remarkable efficacies. For a classical formula, the chemical composition is the material basis and an important premise for quantity value transfer. This study aimed to establish a rapid identification method of chemical components in Wuzhuyu Decoction by high-resolution mass spectrometry(HR-MS) and molecular network. AQUITY UPLC BEH C_(18) column(2.1 mm×100 mm, 1.7 µm) was used for sample separation, and acetonitrile-0.1% formic acid in water was used as mobile phases for gradient elution. Q-Exactive Orbitrap MS data were collected in positive and negative ion modes, and GNPS molecular network was plotted according to the similarity of MS/MS fragmentation modes. Cytoscape 3.6.1 was used to screen molecular clusters with similar structures. Finally, the chemical components of Wuzhuyu Decoction were rapidly identified according to the controls, as well as the information of retention time, accurate relative molecular weight of HR-MS, and MS/MS multistage fragments. A total of 105 chemical components were identified in Wuzhuyu Decoction. This study can provide data for the follow-up quality control, standard substance research, and pharmacodynamic material research on Wuzhuyu Decoction, as well as references for the rapid qualitative analysis of the chemical components of Chinese medicine.

[Identification of chemical constituents in Simiao Yong'an Decoction based on UPLC-LTQ-Orbitrap-MS].

This study aims to identify the chemical constituents of Simiao Yong'an Decoction based on ultra-performance liquid chromatography coupled with linear quadrupole ion trap-orbitrap mass spectrometry(UPLC-LTQ-Orbitrap-MS). The elution was performed through a UPLC BEH C_(18) column(2.1 mm × 100 mm, 1.7 µm) with the mobile phase of water(containing 0.1% formic acid)-acetonitrile at a flow rate of 0.4 mL·min~(-1). LTQ-Orbitrap-MS with heat electrospray ion(HESI) source was employed to collect MS fragment information in the negative ion mode. A total of 72 compounds were identified based on reference substance comparison, fragmentation rules, accurate molecular weight, related reports and databases(MassBank and HMDB), including 30 iridoid glycosides, 9 organic acids, 15 flavonoids, 10 phenylpropanoids, 7 triterpenoids, and 1 saccharide. The method established in this study is comprehensive, rapid, and accurate, which can help summarize the fragmentation rules of constituents and provide reference for revealing the active constituents and pharmacodynamic mechanism of Simiao Yong'an Decoction.

The crosstalk signals of Sodium Tanshinone â ¡A Sulfonate in rats with cerebral ischemic stroke: Insights from proteomics.

BACKGROUND: Stroke could cause long-term disability, even mortality around the world. Recently, Sodium tanshinone IIA sulfonate (STS), identified from Salvia miltiorrhiza Bunge and was found to have unique efficiency in clinical practice as a potential therapeutic agent for ischemic cerebral infarction. However, systematic investigation about the biological mechanism is still lacking. Herein, we utilized high-throughput proteomics approach to identify the underlying targets for the treatment of STS in stroke. METHODS: We investigated the effect of STS on stroke outcomes on rat model of the Middle Cerebral Artery Occlusion and Reperfusion (MCAO/R), assessing by Z-Longa score, infarct volume and HE staining. Pharmacoproteomic profiling of ischemic penumbra in cortical (IPC) was performed using DIA-based label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique. Bioinformatics analysis was processed for further investigation. The expression of core proteins was semi-quantified by DIA, and the major protein correlating with stroke was examined using parallel reaction monitoring (PRM). RESULTS: Rats in the MCAO/R group showed neurological function deterioration, which was improved by STS. There were 423 differentially expressed proteins (DEPs) in IPC being detected and quantified in both the sham group and the MCAO/R group. Meanwhile, 285 proteins were significantly changed in the STS treated group, compared to the MCAO/R model. Protein-protein interaction (PPI) network, pathway and biological function enrichment were processed for the DEPs across each two groups, the results of which were integrated for analysis. Alb, mTOR, Dync1h1, Stxbp1, Cltc, and Sptan1 were contained as the core proteins. Altered molecules were discovered to be enriched in 18 signal pathways such as phosphatidylinositol signaling system, PI3K/AKT signal pathway and HIF-1 signal pathway. The results also showed the correlation with sleep disturbances and depression post-stroke. CONCLUSIONS: We concluded that STS could prevent penumbra from progressively ongoing damage and improve neurological deficits in MCAO/R model rats. The intersected pathways and protein networks predicted by proteomics might provide much more detailed information for the therapeutic mechanisms of STS in the treatment of CIS.

A single-arm, multicenter, phase II clinical study of tislelizumab plus albumin-bound paclitaxel/cisplatin as neoadjuvant therapy for borderline resectable esophageal squamous cell carcinoma.

Background: Esophageal cancer responds poorly to conventional radiotherapy, chemotherapy, and/or surgery. Immunotherapy works by boosting the body's immune system, and preoperative immunotherapy combined with chemotherapy may increase the survival rate of patients with esophageal cancer. Here we further explore immunotherapy's role in treating borderline resectable (BR) esophageal squamous cell carcinoma (ESCC) by combining immunotherapy with chemotherapy. Methods: In this multicenter, randomized controlled study of preoperative immunotherapy plus chemotherapy for BR ESCC, immunotherapy plus chemotherapy [i.e., tislelizumab plus albumin-bound paclitaxel (ABP)/cisplatin] will be given according to the inclusion and exclusion criteria. Patients are to be observed and recorded for various indicators, the follow-up visits are standardized, and a database is to be established for the statistical analysis, with an attempt to clarify the value of preoperative immunotherapy plus chemotherapy in improving the survival of patients with BR ESCC. The primary endpoints are disease-free survival (DFS), major pathologic response (MPR), and pathologic complete response (pCR). The secondary endpoints include the objective response rate (ORR) and overall survival (OS) in subjects with PD-L1 expression levels of <1%, ≥1%, ≥20%, and ≥50%. Discussion: The role of preoperative concurrent immunotherapy plus chemotherapy in improving the survival rates of patients with BR ESCC will be explored in this study. Given that the 5-year survival rate of BR ESCC is 10%, we hope that a reasonable immunotherapy plus chemotherapy regimen with higher efficacy and lower toxicity will further increase the pCR. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2100051514.

Silencing of A-kinase anchor protein 4 inhibits the metastasis and growth of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the most malignant tumors. The treatment of advanced NSCLC can be challenging due to drug resistance. The discovery of novel cancer-testis antigens to develop new strategies for advanced metastatic NSCLC is required. AKAP4 is an oncogene discovered in some malignant tumors, and its molecular function of AKAP4 in NSCLC is unknown. This study aimed to explore the potential function of AKAP4 in the development and progression of NSCLC. AKAP-4 was found to be significantly upregulated in both clinical NSCLC tissues and NSCLC cell lines. Cell viability and migration were suppressed, apoptosis was induced, and tube formation was inhibited by the knockdown of AKAP-4, accompanied by the downregulation of VEGF, N-cadherin, EphA2, and MMP-2, and upregulation of c-AMP, PKA, and E-cadherin. In vivo xenograft experiments revealed that tumor growth was inhibited by the knockdown of AKAP4, accompanied by the activation of c-AMP/PKA signaling and inhibition of epithelial-mesenchymal transition progression. Our results show that AKAP4 might be an important target for treating NSCLC because of its function in promoting the migration and proliferation of NSCLC cells.

(Neo)adjuvant Chemoradiotherapy is Beneficial to the Long-term Survival of Locally Advanced Esophageal Squamous Cell Carcinoma: A Network Meta-analysis.

PURPOSE: To determine the most effective and safest treatment mode for locally advanced resectable esophageal squamous cell carcinoma through a network meta-analysis. METHOD: A Bayesian model was used for a network meta-analysis comparing the efficacy and safety of surgery alone, neoadjuvant therapy, and adjuvant therapy. RESULTS: Thirty clinical studies, including thirty-one articles, 4866 patients, were analyzed. Overall survival rate: Adjuvant chemoradiotherapy and neoadjuvant chemoradiotherapy were significantly advantageous over surgery alone [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.57-0.93; HR 0.75, 95%CI 0.65-0.86]. There was no statistically significant difference between adjuvant chemoradiotherapy and neoadjuvant chemoradiotherapy [HR 0.97, 95%CI 0.75-1.28]. Disease-free survival rate: Compared with surgery alone, neoadjuvant chemoradiotherapy had significant benefits [HR 0.65, 95%CI 0.53-0.78]; adjuvant chemoradiotherapy had similar, but not significant benefits [HR 0.7, 0.95%CI 0.45-1.06]. The difference between neoadjuvant chemoradiotherapy and adjuvant chemoradiotherapy was also not statistically significant [HR 0.94, 0.95%CI 0.61-1.43]. Surgery after neoadjuvant chemoradiotherapy: The R0 resection rate was significantly improved [relative risk (RR) 0.25, 95%CI 0.07-0.86], but the overall postoperative morbidity rate and 30-day postoperative mortality rate tended to increase [RR 1.27, 95%CI 0.8-2.01; RR 1.59, 95%CI 0.7-3.22]. Neither neoadjuvant chemotherapy nor neoadjuvant radiotherapy significantly altered the surgical safety or R0 resection rate. CONCLUSION: Both neoadjuvant chemoradiotherapy and adjuvant chemoradiotherapy appear to be the best supplements to surgery for locally advanced resectable esophageal squamous cell carcinoma.

ΔPCO2 and ΔPCO2/C(a-cv)O2 Are Not Predictive of Organ Dysfunction After Cardiopulmonary Bypass.

Background: Cardiac surgery is associated with a substantial risk of major adverse events. Although carbon dioxide (CO2)-derived variables such as venous-to-arterial CO2 difference (ΔPCO2), and PCO2 gap to arterial-venous O2 content difference ratio (ΔPCO2/C(a-cv)O2) have been successfully used to predict the prognosis of non-cardiac surgery, their prognostic value after cardiopulmonary bypass (CPB) remains controversial. This hospital-based study explored the relationship between ΔPCO2, ΔPCO2/C(a-cv)O2 and organ dysfunction after CPB. Methods: We prospectively enrolled 114 intensive care unit patients after elective cardiac surgery with CPB. Patients were divided into the organ dysfunction group (OI) and non-organ dysfunction group (n-OI) depending on whether organ dysfunction occurred or not at 48 h after CPB. ΔPCO2 was defined as the difference between central venous and arterial CO2 partial pressure. Results: The OI group has 37 (32.5%) patients, 27 of which (23.7%) had one organ dysfunction and 10 (8.8%) had two or more organ dysfunctions. No statistical significance was found (P = 0.84) for ΔPCO2 in the n-OI group at intensive care unit (ICU) admission (9.0, 7.0-11.0 mmHg), and at 4 (9.0, 7.0-11.0 mmHg), 8 (9.0, 7.0-11.0 mmHg), and 12 h post admission (9.0, 7.0-11.0 mmHg). In the OI group, ΔPCO2 also showed the same trend [ICU admission (9.0, 8.0-12.8 mmHg) and 4 (10.0, 7.0-11.0 mmHg), 8 (10.0, 8.5-12.5 mmHg), and 12 h post admission (9.0, 7.3-11.0 mmHg), P = 0.37]. No statistical difference was found for ΔPCO2/C(a-cv)O2 in the n-OI group (P = 0.46) and OI group (P = 0.39). No difference was detected in ΔPCO2, ΔPCO2/C(a-cv)O2 between groups during the first 12 h after admission (P > 0.05). Subgroup analysis of the patients with two or more failing organs compared to the n-OI group showed that the predictive performance of lactate and Base excess (BE) improved, but not of ΔPCO2 and ΔPCO2/C(a-cv)O2. Regression analysis showed that the BE at 8 h after admission (odds ratio = 1.37, 95%CI: 1.08-1.74, P = 0.009) was a risk factor for organ dysfunction 48 h after CBP. Conclusion : ΔPCO2 and ΔPCO2/C(a-cv)O2 cannot be used as reliable indicators to predict the occurrence of organ dysfunction at 48 h after CBP due to the pathophysiological process that occurs after CBP.

Five Constituents Contributed to the Psoraleae Fructus-Induced Hepatotoxicity via Mitochondrial Dysfunction and Apoptosis.

Backgrounds: Psoraleae Fructus (PF)-induced hepatotoxicity has been reported in clinical and animal experiments. However, the hepatotoxic constituents and mechanisms underlying PF-induced toxicity have remained unclear. Therefore, this study explored the potentially toxic PF components and revealed their relative mechanisms. Methods: The hepatotoxicity of PF water (PFW) and ethanol (PFE) extracts was compared using Kunming mice. The different compositions between PFW and PFE, which were considered toxic compositions, were identified using the UHPLC-Q-Exactive MS method. Then, L02 and HepG2 cell lines were used to evaluate the toxicity of these compositions. Cell viability and apoptosis were determined through the Cell Counting Kit-8 (CCK-8) assay and flow cytometry, respectively. An automatic biochemical analyzer detected the aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). Lastly, we used high-content screening (HCS) to determine the levels of reactive oxygen species (ROS), lipid, and mitochondrial membrane potential (MMP). Results: The ethanol extraction process aggravated the hepatotoxicity of PF, causing more severe injuries. The content of psoralen, isopsoralen, bavachin, psoralidin, bavachinin, neobavaisoflavone, and bakuchiol was higher in the PFE than PFW. Bavachin, psoralidin, bavachinin, neobavaisoflavone, and bakuchiol induced cell apoptosis and the AST, ALT, and ALP leakages. Furthermore, these five constituents increased intracellular lipid accumulation and ROS levels but decreased the MMP level. Conclusion: The ethanol extraction process could induce severe PF hepatotoxicity. Bavachin, psoralidin, bavachinin, neobavaisoflavone, and bakuchiol are the main hepatotoxic ingredients. This mechanism could be associated with oxidative stress and mitochondrial damage-mediated apoptosis. Taken together, this study provides a basis for the clinical application of PF that formulates and improves its herbal standards.

Pathological complete response after neoadjuvant treatment determines survival in esophageal squamous cell carcinoma patients (NEOCRTEC5010).

BACKGROUND: Few studies have exclusively investigated the value of pathological complete response (pCR), in esophageal squamous cell carcinoma (ESCC) patients, although it is a clinically significant parameter to evaluate the impact of neoadjuvant chemoradiotherapy (nCRT) on treatment outcome after surgery. The aim of our study was to explore the relationship between pCR after nCRT and survival among patients with local ESCC. METHODS: All patients receiving nCRT followed by surgery in NEOCRTEC5010-trial (NCT01216527) were included. Non-pCR patients were classified into three subgroups: ypTanyN0M0, ypT0NanyM0 and ypTanyNanyM0. The Kaplan-Meier method with log-rank test was employed to evaluate disease-free survival (DFS) and overall survival (OS). Multivariate regression analysis was performed using a Cox proportional hazards model to identify clinicopathological parameters associated with pCR. RESULTS: Among the 185 patients included, 80 (43.2%) achieved pCR after nCRT. The mean survival time of the pCR group was significantly longer than that of the non-pCR group (92.6 vs. 69.2 months; HR, 2.70; 95% CI: 1.48-4.92; P=0.001). The 5-year OS and DFS of the pCR group were 79.3% and 77% respectively, compared to 54.8% and 51.2%, respectively, in the non-pCR group. The results showed that the OS and DFS of the ypTanyN0M0 group were better than those of the ypT0NanyM0 group and the ypTanyNanyM0 group. We also found that the number of dissected lymph nodes and pCR were independent risk factors for DFS and OS rates. CONCLUSIONS: pCR after nCRT is an important prognostic indicator of OS and DFS in patients with ESCC. In addition, lymph-node status could represent an important parameter in the prognostic evaluation of esophageal cancer patients.

Vegetarian diet duration's influence on women's gut environment.

BACKGROUND: Nutrient composition of vegetarian diets is greatly different from that of omnivore diets, which may fundamentally influence the gut microbiota and fecal metabolites. The interactions between diet pattern and gut environment need further illustration. This study aims to compare the difference in the gut microbiota and fecal metabolites between vegetarian and omnivore female adults and explore associations between dietary choices/duration and gut environment changes. METHODS: In this study, investigations on the fecal metabolome together with the gut microbiome were performed to describe potential interactions with quantitative functional annotation. In order to eliminate the differences brought by factors of gender and living environment, 80 female adults aged 20 to 48 were recruited in the universities in Beijing, China. Quantitative Insights Into Microbial Ecology (QIIME) analysis and Ingenuity Pathway Analysis (IPA) were applied to screen differential data between groups from gut microbiota and fecal metabolites. Furthermore, weighted gene correlation network analysis (WGCNA) was employed as the bioinformatics analysis tool for describing the correlations between gut microbiota and fecal metabolites. Moreover, participants were further subdivided by the vegetarian diet duration for analysis. RESULTS: GPCR-mediated integration of enteroendocrine signaling was predicted to be one of the regulatory mechanisms of the vegetarian diet. Intriguingly, changes in the gut environment which occurred along with the vegetarian diet showed attenuated trend as the duration increased. A similar trend of returning to "baseline" after a 10-year vegetarian diet was detected in both gut microbiota and fecal metabolome. CONCLUSIONS: The vegetarian diet is beneficial more than harmful to women. Gut microbiota play roles in the ability of the human body to adapt to external changes.