Mechanosensation by endothelial PIEZO1 is required for leukocyte diapedesis.

The extravasation of leukocytes is a critical step during inflammation that requires the localized opening of the endothelial barrier. This process is initiated by the close interaction of leukocytes with various adhesion molecules such as ICAM-1 on the surface of endothelial cells. Here we reveal that mechanical forces generated by leukocyte-induced clustering of ICAM-1 synergize with fluid shear stress exerted by the flowing blood to increase endothelial plasma membrane tension and to activate the mechanosensitive cation channel PIEZO1. This leads to increases in [Ca2+]i and activation of downstream signaling events including phosphorylation of tyrosine kinases sarcoma (SRC) and protein tyrosine kinase 2 (PYK2), as well as of myosin light chain, resulting in opening of the endothelial barrier. Mice with endothelium-specific Piezo1 deficiency show decreased leukocyte extravasation in different inflammation models. Thus, leukocytes and the hemodynamic microenvironment synergize to mechanically activate endothelial PIEZO1 and subsequent downstream signaling to initiate leukocyte diapedesis.

Tenascin-X Mediates Flow-Induced Suppression of EndMT and Atherosclerosis.

BACKGROUND: Endothelial-to-mesenchymal transition (EndMT) has been identified as a critical driver of vascular inflammation and atherosclerosis, and TGF-ß (transforming growth factor ß) is a key mediator of EndMT. Both EndMT and atherosclerosis are promoted by disturbed flow, whereas unidirectional laminar flow limits EndMT and is atheroprotective. How EndMT and endothelial TGF-ß signaling are regulated by different flow patterns is, however, still poorly understood. METHODS: Flow chamber experiments in vitro and endothelium-specific knockout mice were used to study the role of tenascin-X in the regulation of EndMT and atherosclerosis as well as the underlying mechanisms. RESULTS: In human endothelial cells as well as in human and mouse aortae, unidirectional laminar flow but not disturbed flow strongly increased endothelial expression of the extracellular matrix protein TN-X (tenascin-X) in a KLF4 (Krüppel-like factor 4) dependent manner. Mice with endothelium-specific loss of TN-X (EC-Tnxb-KO) showed increased endothelial TGF-ß signaling as well as increased endothelial expression of EndMT and inflammatory marker genes. When EC-Tnxb-KO mice were subjected to partial carotid artery ligation, we observed increased vascular remodeling. EC-Tnxb-KO mice crossed to low-density lipoprotein receptor-deficient mice showed advanced atherosclerotic lesions after being fed a high-fat diet. Treatment of EC-Tnxb-KO mice with an anti-TGF-beta antibody or additional endothelial loss of TGF-beta receptors 1 and 2 normalized endothelial TGF-beta signaling and prevented EndMT. In in vitro studies, we found that TN-X through its fibrinogen-like domain directly interacts with TGF-ß and thereby interferes with its binding to the TGF-ß receptor. CONCLUSIONS: In summary, we show that TN-X is a central mediator of flow-induced inhibition of EndMT, endothelial inflammation and atherogenesis, which functions by binding to and by blocking the activity of TGF-ß. Our data identify a novel mechanism of flow-dependent regulation of vascular TGF-ß, which holds promise for generating new strategies to prevent vascular inflammation and atherosclerosis.

Periodontitis and risk of mortality in patients with chronic kidney disease: A systematic review with meta-analysis.

Studies examining the link between periodontitis and survival outcomes have yielded conflicting results in patients with chronic kidney disease (CKD). This systematic review with meta-analysis aims to assess the association between periodontitis and cardiovascular or all-cause mortality in CKD patients. A thorough search was conducted on the PubMed, Web of Science, and Embase databases for studies investigating the association between periodontitis and survival outcomes in CKD patients. Two authors independently scanned the titles or abstracts and then identified the eligible full-text article based on the PECOS criteria: Participants (CKD patients), Exposure (periodontitis), Comparison (mild/no periodontitis), Outcomes (cardiovascular or all-cause mortality), and Study design (retrospective or prospective cohort). Six cohort studies, including 7731 patients, were identified. The included studies had low-to-moderate risk of bias. The mean/median follow-up duration ranged from 18.1 months to 8.67 years. The all-cause mortality rate was 44.8% for patients with periodontitis and 28.0% for controls. Meta-analysis showed that periodontitis, defined through clinical attachment loss (CAL), was significantly associated with an increased risk of all-cause (adjusted hazard ratio [HR] 1.24; 95% confidence intervals [CI] 0.89-1.72; I2 = 80.9%) and cardiovascular mortality (HR 1.57; 95% CI 1.08-2.27; I2 = 34.0%). Additionally, a significant association between periodontitis and the risk of cardiovascular or all-cause mortality was observed in studies with a predominance of females, follow-up duration ≥5 years, all stages of CKD, and low risk of bias subgroups. Periodontitis is significantly associated with an increased risk of all-cause and cardiovascular mortality in CKD patients within low risk of bias subgroup or based on defining periodontitis through CAL. Registration number: PROSPERO CRD42018512391.

Preparation of Alcohol Dehydrogenase-Zinc Phosphate Hybrid Nanoflowers through Biomimetic Mineralization and Its Application in the Inhibitor Screening.

A biomimetic mineralization method was used in the facile and rapid preparation of nanoflowers for immobilizing alcohol dehydrogenase (ADH). The method mainly uses ADH as an organic component and zinc phosphate as an inorganic component to prepare flower-like ADH/Zn3(PO4)2 organic-inorganic hybrid nanoflowers (HNFs) with the high specific surface area through a self-assembly process. The synthesis conditions of the ADH HNFs were optimized and its morphology was characterized. Under the optimum enzymatic reaction conditions, the Michaelis-Menten constant (Km) of ADH HNFs (ß-NAD+ as substrate) was measured to be 3.54 mM, and the half-maximal inhibitory concentration (IC50) of the positive control ranitidine (0.2-0.8 mM) was determined to be 0.49 mM. Subsequently, the inhibitory activity of natural medicine Penthorum chinense Pursh and nine small-molecule compounds on ADH was evaluated using ADH HNFs. The inhibition percentage of the aqueous extract of P. chinense is 57.9%. The vanillic acid, protocatechuic acid, gallic acid, and naringenin have obvious inhibitory effects on ADH, and their percentages of inhibition are 55.1%, 68.3%, 61.9%, and 75.5%, respectively. Moreover, molecular docking analysis was applied to explore the binding modes and sites of the four most active small-molecule compounds to ADH. The results of this study can broaden the application of immobilized enzymes through biomimetic mineralization, and provide a reference for the discovery of ADH inhibitors from natural products.

Dietary Bile Acid Supplementation Could Regulate the Glucose, Lipid Metabolism, and Microbiota of Common Carp (Cyprinus carpio L.) Fed with a High-Lipid Diet.

This study sought to examine the role of bile acids in the regulation of glucose and lipid metabolism, intestinal flora, and growth in high-fat diet-fed common carp (Cyprinus carpio L.). Fish (6.34 ± 0.07 g) were fed for 56 days with three different diets, the control diet (CO, 5.4% lipid), high-fat diet (HF, 11% lipid), and high-fat diet with 60 mg/kg bile acids (BAs, 11% lipid). The results showed that high-fat diets resulted in poor growth performance and increased triglyceride (TG) in serum and the liver. The addition of bile acids significantly alleviated the adverse effects of a high-fat diet. The mRNA expression results indicated that bile acids may improve lipid metabolism through the enhancement of the peroxisome proliferator-activated receptor (PPARa). The expression of gluconeogenesis-related phosphoenolpyruvate carboxykinase (PEPCK) mRNA was inhibited, while fibroblast growth factor 19 (FGF19) was significantly higher. Bile acids reshaped the intestinal microflora community, with the level of Bacteroidetes increasing. The correlation analysis indicated that Patescibacteria, Dependentiae, Myxococcota, and Planctomycetota in the gut are associated with genes involved in glucose and lipid metabolism. These results indicated that bile acids could ameliorate the negative effects of high-fat diets on common carp.

BMP9 and BMP10 Act Directly on Vascular Smooth Muscle Cells for Generation and Maintenance of the Contractile State.

BACKGROUND: Vascular smooth muscle cells (VSMCs) show a remarkable phenotypic plasticity, allowing acquisition of contractile or synthetic states, but critical information is missing about the physiologic signals, promoting formation, and maintenance of contractile VSMCs in vivo. BMP9 and BMP10 (bone morphogenetic protein) are known to regulate endothelial quiescence after secretion from the liver and right atrium, whereas a direct role in the regulation of VSMCs was not investigated. We studied the role of BMP9 and BMP10 for controlling formation of contractile VSMCs. METHODS: We generated several cell type-specific loss- and gain-of-function transgenic mouse models to investigate the physiologic role of BMP9, BMP10, ALK1 (activin receptor-like kinase 1), and SMAD7 in vivo. Morphometric assessments, expression analysis, blood pressure measurements, and single molecule fluorescence in situ hybridization were performed together with analysis of isolated pulmonary VSMCs to unravel phenotypic and transcriptomic changes in response to absence or presence of BMP9 and BMP10. RESULTS: Concomitant genetic inactivation of Bmp9 in the germ line and Bmp10 in the right atrium led to dramatic changes in vascular tone and diminution of the VSMC layer with attenuated contractility and decreased systemic as well as right ventricular systolic pressure. On the contrary, overexpression of Bmp10 in endothelial cells of adult mice dramatically enhanced formation of contractile VSMCs and increased systemic blood pressure as well as right ventricular systolic pressure. Likewise, BMP9/10 treatment induced an ALK1-dependent phenotypic switch from synthetic to contractile in pulmonary VSMCs. Smooth muscle cell-specific overexpression of Smad7 completely suppressed differentiation and proliferation of VSMCs and reiterated defects observed in adult Bmp9/10 double mutants. Deletion of Alk1 in VSMCs recapitulated the Bmp9/10 phenotype in pulmonary but not in aortic and coronary arteries. Bulk expression analysis and single molecule RNA-fluorescence in situ hybridization uncovered vessel bed-specific, heterogeneous expression of BMP type 1 receptors, explaining phenotypic differences in different Alk1 mutant vessel beds. CONCLUSIONS: Our study demonstrates that BMP9 and BMP10 act directly on VSMCs for induction and maintenance of their contractile state. The effects of BMP9/10 in VSMCs are mediated by different combinations of BMP type 1 receptors in a vessel bed-specific manner, offering new opportunities to manipulate blood pressure in the pulmonary circulation.

GDF11 knockdown downregulates SMURF1 to inhibit breast cancer progression by activation of p53 and inactivation of ERα signaling.

Breast cancer (BC) is a prevalent neoplasm that occurs in women all over the world. Growth and differentiation factor 11 (GDF11) plays an essential role in cancer progression. This study focused on investigating the biological role and underlying mechanisms of GDF11 in BC. We detected the expression of GDF11 in 27 patients with BC and BC cell lines. Kaplan-Meier plotter was employed to analyze the relationship between GDF11 expression and overall survival (OS) of BC patients. The proliferative, migratory, invasive, and apoptotic abilities of T47D cells were examined. Correlation analysis of GDF11 with Smad ubiquitination regulatory factor 1 (SMURF1) was conducted. The association between GDF11 and the p53 pathway was analyzed by western blot and PFT-α (a p53 inhibitor)-mediated rescue assays. A brief analysis of the role of estrogen receptor alpha (ERα) signaling in BC progression was performed. The results showed that GDF11 was increased in BC tissues and cell lines, and the high expression of GDF11 was associated with the poor OS of BC patients. GDF11 knockdown inhibited the proliferation, migration, and invasion of T47D cells, but promoted cell apoptosis. Meanwhile, the GDF11 knockdown reduced the SMURF1 expression and invoked the p53 pathway activation. SMURF1 overexpression and PFT-α partially blocked the effects of GDF11 knockdown. In addition, GDF11 knockdown and SMURF1 silencing inhibited the activation of the ERα signaling pathway. In summary, GDF11 was involved in the progression of BC by regulating SMURF1-mediated p53 and ERα pathways, opening up a new way for BC treatment.

Role of herbal medicine for prevention and treatment of migraine.

Migraine is a disabling neurovascular disease with unilateral or bilateral pulsatile headache, which intensively affects human health and quality of life due to high morbidity worldwide. Migraine is commonly accompanied by abnormal pain sensitization, neuroinflammatory response, and vasomotor dysfunction. Owing to the management dilemmas of migraine, there is an urgent need to develop effective and low-cost therapies. In recent years, herbal medicines as a promising strategy with analgesic activity and minor side effect, have been proposed for the prevention and treatment of migraine. Considering the lack of a review integrating experimental studies regarding the herbal treatment of migraine, this review systematically summarizes the important potential applications of herbal medicines in ameliorating migraine via multiple therapeutic targets and pathways, as well as provides a reference for further development of novel antimigraine drugs.

Notoginsenoside R1 ameliorates mitochondrial dysfunction to circumvent neuronal energy failure in acute phase of focal cerebral ischemia.

Due to sudden loss of cerebral blood circulation, acute ischemic stroke (IS) causes neuronal energy attenuation or even exhaustion by mitochondrial dysfunction resulting in aggravation of neurological injury. In this study, we investigated if Notoginsenoside R1 ameliorated cerebral energy metabolism by limiting neuronal mitochondrial dysfunction in acute IS. Male Sprague-Dawley rats (260-280 g) were selected and performed by permanent middle cerebral artery occlusion model. In vitro, the oxygen glucose deprivation (OGD) model of Neuro2a (N2a) cells was established. We found Notoginsenoside R1 treatment reduced rats' cerebral infarct volume and neurological deficits, with increased Adenosine triphosphate (ATP) level together with upregulated expression of glucose transporter 1/3, monocarboxylate transporter 1 and citrate synthase in brain peri-ischemic tissue. In vitro, OGD-induced N2a cell death was inhibited, cell mitochondrial morphology was improved. Mitochondrial amount, mitochondrial membrane potential, and mitochondrial DNA copy number were increased by Notoginsenoside R1 administration. Furthermore, mitochondrial energy metabolism-related mRNA array found Atp12a and Atp6v1g3 gene expression were upregulated more than twofold, which were also verified in rat ischemic tissue by quantitative polymerase chain reaction (qPCR) assay. Therefore, Notoginsenoside R1 administration increases cerebral glucose and lactate transportation and ATP levels, ameliorates neuronal mitochondrial function after IS. Notoginsenoside R1 may be a novel protective agent for neuronal mitochondria poststroke.

Glycyrrhizic Acid and Its Derivatives: Promising Candidates for the Management of Type 2 Diabetes Mellitus and Its Complications.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, which is characterized by hyperglycemia, chronic insulin resistance, progressive decline in ß-cell function, and defect in insulin secretion. It has become one of the leading causes of death worldwide. At present, there is no cure for T2DM, but it can be treated, and blood glucose levels can be controlled. It has been reported that diabetic patients may suffer from the adverse effects of conventional medicine. Therefore, alternative therapy, such as traditional Chinese medicine (TCM), can be used to manage and treat diabetes. In this review, glycyrrhizic acid (GL) and its derivatives are suggested to be promising candidates for the treatment of T2DM and its complications. It is the principal bioactive constituent in licorice, one type of TCM. This review comprehensively summarized the therapeutic effects and related mechanisms of GL and its derivatives in managing blood glucose levels and treating T2DM and its complications. In addition, it also discusses existing clinical trials and highlights the research gap in clinical research. In summary, this review can provide a further understanding of GL and its derivatives in T2DM as well as its complications and recent progress in the development of potential drugs targeting T2DM.

Neuroendocrine-Immune Regulatory Network of Eucommia ulmoides Oliver.

Eucommia ulmoides Oliver (E. ulmoides) is a popular medicinal herb and health supplement in China, Japan, and Korea, and has a variety of pharmaceutical properties. The neuroendocrine-immune (NEI) network is crucial in maintaining homeostasis and physical or psychological functions at a holistic level, consistent with the regulatory theory of natural medicine. This review aims to systematically summarize the chemical compositions, biological roles, and pharmacological properties of E. ulmoides to build a bridge between it and NEI-associated diseases and to provide a perspective for the development of its new clinical applications. After a review of the literature, we found that E. ulmoides has effects on NEI-related diseases including cancer, neurodegenerative disease, hyperlipidemia, osteoporosis, insomnia, hypertension, diabetes mellitus, and obesity. However, clinical studies on E. ulmoides were scarce. In addition, E. ulmoides derivatives are diverse in China, and they are mainly used to enhance immunity, improve hepatic damage, strengthen bones, and lower blood pressure. Through network pharmacological analysis, we uncovered the possibility that E. ulmoides is involved in functional interactions with cancer development, insulin resistance, NAFLD, and various inflammatory pathways associated with NEI diseases. Overall, this review suggests that E. ulmoides has a wide range of applications for NEI-related diseases and provides a direction for its future research and development.

Characterization of Roasting Time on Sensory Quality, Color, Taste, and Nonvolatile Compounds of Yuan An Yellow Tea.

Roasting is crucial for producing Yuan An yellow tea (YAYT) as it substantially affects sensory quality. However, the effect of roasting time on YAYT flavor quality is not clear. To investigate the effect of roasting time on the sensory qualities, chemical components, odor profiles, and metabolic profile of YAYTs produced with 13 min roasting, 16 min roasting, 19 min roasting, 22 min roasting, and 25 min roasting were determined. The YAYTs roasted for 22 min got higher sensory scores and better chemical qualities, such as the content of gallocatechin (GC), gallocatechin gallate (GCG), free amino acids, solutable sugar, meanwhile the lightness decreased, the hue of tea brew color (b) increased, which meant the tea brew got darker and yellower. YAYTs roasted for 22 min also increased the contents of key odorants, such as benzaldehyde, nonanal, ß-cyclocitral, linalool, nerol, α-cedrol, ß-ionone, limonene, 2-methylfuran, indole, and longiborneol. Moreover, non-targeted metabolomics identified up to 14 differentially expressed metabolites through pair-wise comparisons, such as flavonoids, phenolic acids, sucrose, and critical metabolites, which were the main components corresponding to YAYT roasted for 22 min. In summary, the current results provide scientific guidance for the production of high quality YAYT.

Regulation of the NLRP3 inflammasome with natural products against chemical-induced liver injury.

The past decades have witnessed significant progress in understanding the process of sterile inflammation, which is dependent on a cytosolic complex termed the nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome. Activation of NLRP3 inflammasome requires two steps, including the activation of Toll-like receptor (TLR) by its ligands, resulting in transcriptional procytokine and inflammasome component activation, and the assembly and activation of NLRP3 inflammasome triggered by various danger signals, leading to caspase-1 activation, which could subsequently cleave procytokines into their active forms. Metabolic disorders, ischemia and reperfusion, viral infection and chemical insults are common pathogenic factors of liver-related diseases that usually cause tissue damage and cell death, providing numerous danger signals for the activation of NLRP3 inflammasome. Currently, natural products have attracted much attention as potential agents for the prevention and treatment of liver diseases due to their multitargets and nontoxic natures. A great number of natural products have been shown to exhibit beneficial effects on liver injury induced by various chemicals through regulating NLRP3 inflammasome pathways. In this review, the roles of the NLRP3 inflammasome in chemical-induced liver injury (CILI) and natural products that exhibit beneficial effects in CILI through the regulation of inflammasomes were systematically summarized.

Dietary bile acid supplementation reveals beneficial effects on intestinal healthy status of tongue sole (Cynoglossus semiliaevis).

The aim of this study was to investigate the effects of dietary bile acids (BAs) on intestinal healthy status of tongue sole in terms of immunity, antioxidant status, digestive ability, mucosal barrier-related genes expression and microbiota. Three experimental diets were prepared with BA levels at 0 mg/kg (CT), 300 mg/kg (BA1) and 900 mg/kg (BA2) in a commercial basal diet. Each diet was fed to three replicates with 120 fish (10.87 ± 0.32 g) in each tank. After an 8-week feeding trial, growth parameters were significantly enhanced in both BAs supplementary groups (P < 0.05), and compared with CT group, survival rate in BA2 group was significantly improved (P < 0.05). Intestinal lysozyme activity and contents of immunoglobulin M and complement 3 were significantly increased in both BAs supplementary groups (P < 0.05), suggesting an enhancement effect on the non-specific immune response. BAs inclusion also significantly improved intestinal antioxidant capabilities by increasing antioxidase activities and decreasing malondialdehyde levels. In addition, compared with CT group, intestinal digestive ability was substantially enhanced as indicated by the significantly increased lipase activity in BA2 group (P < 0.05) and significantly increased amylase activity in BA1 and BA2 groups (P < 0.05). Coincidentally, BAs inclusion significantly upregulated the relative expression of intestinal mucosal barrier-related genes (P < 0.05). Further, dietary BAs distinctly remodeled intestinal microbiota by decreased the abundance of some potential pathogenic bacteria. In conclusion, dietary BAs supplementation is an effective way to improve the intestinal healthy status of tongue sole.

The hemolymph melanization response is related to defence against the AcMNPV infection in Bombyx mori.

Melanization is mediated by the prophenoloxidase (proPO) activation cascade and plays an important role in the arthropods immune system. Previously, we found that the hemolymph of the p50 strain does not perform melanization after infection with Autographa californica multiple nucleopolyhedrovirus (AcMNPV). However, this mechanism is still unclear. In this study, the underlying mechanism of the inhibition of hemolymph melanization was investigated by analysing the AcMNPV-susceptible or -resistant silkworm strains after inoculation with AcMNPV. The results showed that the level of hemolymph melanization was higher in resistant strain C108 than in susceptible strain p50 at the late stage (72 to 120 h postinoculation). The PO activity decreased significantly at the late stage of infection (72 to 120 hpi), and the expression of BmPPO1 and BmPPO2 was downregulated in p50. However, the PO activity increased in the resistant strain C108, while the expression level of BmPPO1 and BmPPO2 displayed no significant changes. The expression of the BmPPAE gene was upregulated in two strains during viral infection. In addition, the hemolymph melanization can weaken the viral activity in vitro. Our results suggested that the silkworm hemolymph melanization response is related to defence against the AcMNPV infection.

Metabolomics Provides A Novel Interpretation of the Changes in Main Compounds during Black Tea Processing through Different Drying Methods.

This study aimed to compare the effect of hot roller (HR) drying and hot air (HA) drying on the sensory evaluation, chemical quality, antioxidant activity, and metabolic profile of Yihong Congou black tea processed from E'cha NO1. The Yihong Congou black tea dried with HA obtained higher sensory scores and better chemical qualities such as the hue of tea brew color (a and b), content of theaflavins, thearubigins, water extract, free amino acids, tea polyphenol, and the ratio of polyphenol to amino acids as well as higher antioxidant capacities compared to that dried with HR. The HA drying tea increased the contents of volatile compounds that had positive correlation with sweet and flowery flavor, while the HR drying tea increased the contents of volatile compounds related to fruity flavor. Moreover, non-targeted metabolomics data indicated that the levels of most free amino acids significantly increased, while the levels of most soluble sugars reduced in the HA drying method compared to the HR drying method. The metabolic analysis was also consistent with the above results and revealed that D-ribose and gallic acid were the main characteristic metabolites of HA drying. Our results could provide a technical reference and theoretical guide to processing a high quality of Yihong Congou black tea.

A prognostic nomogram for the cancer-specific survival of patients with upper-tract urothelial carcinoma based on the Surveillance, Epidemiology, and End Results Database.

BACKGROUND: The aim of this study was to establish a comprehensive nomogram for the cancer-specific survival (CSS) of patients with upper-tract urothelial carcinoma (UTUC) and compare it with the traditional American Joint Committee on Cancer (AJCC) staging system in order to determine its reliability. METHODS: This study analyzed 9505 patients with UTUC in the Surveillance, Epidemiology, and End Results (SEER) database. R software was used to randomly divided the patients in a 7-to-3 ratio to form a training cohort (n = 6653) and a validation cohort (n = 2852). Multivariable Cox regression was used to identify predictive variables. The new survival model was compared with the AJCC prognosis model using the concordance index (C-index), the area under the time-dependent receiver operating characteristics curve (AUC), the net reclassification improvement (NRI), the integrated discrimination improvement (IDI), calibration plotting, and decision-curve analysis (DCA). RESULTS: We have established a nomogram for determining the 3-, 5-, and 8-year CSS probabilities of UTUC patients. The nomogram indicates that the AJCC stage has the greatest influence on CSS in UTUC, followed by the age at diagnosis, surgery status, tumor size, radiotherapy status, histological grade, marital status, chemotherapy status, race, and finally sex. The C-index was higher for the nomogram than the AJCC staging system in both the training cohort (0.785 versus 0.747) and the validation cohort (0.779 versus 0.739). Calibration plotting demonstrated that the model has good calibration ability. The AUC, NRI, IDI, and DCA of the nomogram showed that it performs better than the AJCC staging system alone. CONCLUSIONS: This study is the first to establish a comprehensive UTUC nomogram based on the SEER database and evaluate it using a series of indicators. Our novel nomogram can help clinical staff to predict the 3-, 5-, and 8-year CSS probabilities of UTUC patients more accurately than using the AJCC staging system.

Bilirubin Nanomedicines for the Treatment of Reactive Oxygen Species (ROS)-Mediated Diseases.

Reactive oxygen species (ROS) are chemically reactive species that are produced in cellular aerobic metabolism. They mainly include superoxide anion, hydrogen peroxide, hydroxyl radicals, singlet oxygen, ozone, and nitric oxide and are implicated in many physiological and pathological processes. Bilirubin, a cardinal pigment in the bile, has been increasingly investigated to treat cancer, diabetes, ischemia-reperfusion injury, asthma, and inflammatory bowel diseases (IBD). Indeed, bilirubin has been shown to eliminate ROS production, so it is now considered as a promising therapeutic agent for ROS-mediated diseases and can be used for the development of antioxidative nanomedicines. This review summarizes the current knowledge of the physiological mechanisms of ROS production and its role in pathological changes and focuses on discussing the antioxidative effects of bilirubin and its application in the experimental studies of nanomedicines. Previous studies have shown that bilirubin was mainly used as a responsive molecule in the microenvironment of ROS overproduction in neoplastic tissues for the development of anticancer nanodrugs; however, it could also exert powerful ROS scavenging activity in chronic inflammation and ischemia-reperfusion injury. Therefore, bilirubin, as an inartificial ROS scavenger, is expected to be used for the development of nanomedicines against more diseases due to the universality of ROS involvement in human pathological conditions.

An integrated microbiome and metabolomic analysis identifies immunoenhancing features of Ganoderma lucidum spores oil in mice.

Ganoderma lucidum (Leyss. ex Fr.) Karst. is a valuable dietary supplement used worldwide for promoting health as well as a medicinal fungus for handling fatigue, immunological disorders, and cancer. Previous studies have revealed the immunoenhancing effect of G. lucidum and the polysaccharide extract, with potential involvement of gut microbiome. The oil of G. lucidum spores (GLSO)is one of the well-known G. lucidum-related products. However, there is little evidence supporting the immune promotion activity and the underlying mechanisms. The present study aims to investigate the immunoenhancing effect of GLSO in mice. GLSO enhanced macrophage phagocytosis and NK cell cytotoxicity of mice. Further microbiome and metabolomics studies showed that GLSO induced structural rearrangement of gut microbiota, mediating alterations in a wide range of metabolites. By clustering, multivariate and correlation analysis, the immunoenhancing effect of GLSO was found to be highly correlated with elevated abundance of several bacterial genera (Lactobacillus, Turicibacter and Romboutsia) and species (Lactobacillus_intestinalis and Lactobacillus_reuteri), and decreased level of Staphylococcus and Helicobacter, which resulted in the regulation of a range of key metabolites such as dopamine, prolyl-glutamine, pentahomomethionine, leucyl-glutamine, l-threonine, stearoylcarnitine, dolichyl ß-d-glucosyl phosphate, etc. These results provide new insights into the understanding of the modulatory effect of GLSO on immune system.

Establishment and Validation of a Nomogram for Tonsil Squamous Cell Carcinoma: A Retrospective Study Based on the SEER Database.

This study aimed to establish and validate a comprehensive nomogram for predicting the cause-specific survival (CSS) probability in tonsillar squamous cell carcinoma (TSCC). We screened and extracted data from the SEER (Surveillance, Epidemiology, and End Results) database for the period 2004 to 2016. We randomly divided the 7243 identified patients into a training cohort (70%) for constructing the model and a validation cohort (30%) for evaluating the model using R software. Multivariate Cox stepwise regression was used to select predictive variables. The concordance index (C-index), the area under the time-dependent receiver operating characteristics curve (AUC), the net reclassification improvement (NRI), the integrated discrimination improvement (IDI), calibration plotting, and decision-curve analysis (DCA) were used to evaluate the model. The multivariate Cox stepwise regression analysis successfully established a nomogram for the 1-, 3-, and 5-year CSS probabilities for TSCC patients. The C-index, AUC, NRI, and IDI were all showed that the model has good discrimination. The calibration plots were very close to the standard lines, indicating that the model has a good degree of calibration, and the DCA curve further illustrated that the model has good clinical validity. We have established the first nomogram for predicting the 1-, 3-, and 5-year CSS probabilities for TSCC based on a large retrospective sample. Our rigorous validation and evaluation indicated that the model can provide useful guidance to clinical workers making clinical decisions about individual patients.