Anti-Biofilm Activity of Assamsaponin A, Theasaponin E1, and Theasaponin E2 against Candida albicans.

Biofilm formation plays a crucial role in the pathogenesis of Candida albicans and is significantly associated with resistance to antifungal agents. Tea seed saponins, a class of non-ionic triterpenes, have been proven to have fungicidal effects on planktonic C. albicans. However, their anti-biofilm activity and mechanism of action against C. albicans remain unclear. In this study, the effects of three Camellia sinensis seed saponin monomers, namely, theasaponin E1 (TE1), theasaponin E2 (TE2), and assamsaponin A (ASA), on the metabolism, biofilm development, and expression of the virulence genes of C. albicans were evaluated. The results of the XTT reduction assay and crystal violet (CV) staining assay demonstrated that tea seed saponin monomers concentration-dependently suppressed the adhesion and biofilm formation of C. albicans and were able to eradicate mature biofilms. The compounds were in the following order in terms of their inhibitory effects: ASA > TE1 > TE2. The mechanisms were associated with reductions in multiple crucial virulence factors, including cell surface hydrophobicity (CSH), adhesion ability, hyphal morphology conversion, and phospholipase activity. It was further demonstrated through qRT-PCR analysis that the anti-biofilm activity of ASA and TE1 against C. albicans was attributed to the inhibition of RAS1 activation, which consequently suppressed the cAMP-PKA and MAPK signaling pathways. Conversely, TE2 appeared to regulate the morphological turnover and hyphal growth of C. albicans via a pathway that was independent of RAS1. These findings suggest that tea seed saponin monomers are promising innovative agents against C. albicans.

Biogenic Selenium Nanoparticles Synthesized by L. brevis 23017 Enhance Aluminum Adjuvanticity and Make Up for its Disadvantage in Mice.

The most popular vaccine adjuvants are aluminum ones, which have significantly reduced the incidence and mortality of many diseases. However, aluminum-adjuvanted vaccines are constrained by their limited capacity to elicit cellular and mucosal immune responses, thus constraining their broader utilization. Biogenic selenium nanoparticles are a low-cost, environmentally friendly, low-toxicity, and highly bioactive form of selenium supplementation. Here, we purified selenium nanoparticles synthesized by Levilactobacillus brevis 23017 (L-SeNP) and characterized them using Fourier-transform infrared spectroscopy, energy-dispersive X-ray spectroscopy, scanning electron microscopy, and transmission electron microscopy. The results indicate that the L-SeNP has a particle size ranging from 30 to 200 nm and is coated with proteins and polysaccharides. Subsequently, we assessed the immune-enhancing properties of L-SeNP in combination with an adjuvant-inactivated Clostridium perfringens type A vaccine using a mouse model. The findings demonstrate that L-SeNP can elevate the IgG and SIgA titers in immunized mice and modulate the Th1/Th2 immune response, thereby enhancing the protective effect of aluminum-adjuvanted vaccines. Furthermore, we observed that L-SeNP increases selenoprotein expression and regulates oxidative stress in immunized mice, which may be how L-SeNP regulates immunity. In conclusion, L-SeNP has the potential to augment the immune response of aluminum adjuvant vaccines and compensate for their limitations in eliciting Th1 and mucosal immune responses.

Network pharmacology prediction and molecular docking analysis reveal the mechanism of modified Bushen Yiqi formulas on chronic obstructive pulmonary disease.

BACKGROUND: The present study aimed to explore the mechanism of the modified Bushen Yiqi formula (MBYF) in the treatment of chronic obstructive pulmonary disease (COPD) based on network pharmacology and molecular docking. METHODS: First, the active ingredients and corresponding targets in MBYF were mined through the Traditional Chinese Medicine Systems Pharmacology database. Subsequently, Online Mendelian Inheritance in Man, DrugBank, and GeneCard were used to screen COPD-related targets. Cytoscape was used to construct a network of candidate components of MBYF in COPD treatment. The overlapping targets of COPD and MBYF were used to treat COPD, and then CytoHubba and CytoNAC plug-ins in Cytoscape were used for topology analysis to build the core network. In addition, core targets were used for Gene Ontology analysis and enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes. Finally, AutoDock Vina software was used to conduct a molecular docking study on the core active ingredients and core targets to verify the above network pharmacological analysis. RESULTS: Seventy-nine active components of MBYF were screened and 261 corresponding targets were found. At the same time, 1307 related targets corresponding to COPD were screened and 111 overlapping targets were matched. By bioinformatics analysis, 10 core targets were identified, and subsequently, enrichment analysis revealed 385 BP, two CC, eight MF and 78 related signaling pathways. The binding of the core active components in MBYF to the core target was further verified by molecular docking, and all showed good binding. CONCLUSIONS: The active components of MBYF, such as quercetin, kaempferol, luteolin, and baicalein, may be the material basis for the treatment of chronic obstructive pulmonary disease. They affect the expression of inflammatory cells and inflammatory factors, protein phosphorylation, and smooth muscle hyperplasia through tumor necrosis factor, interleukin-17, mitogen-activated protein kinase, nuclear factor-kappa B and other signaling pathways.

Formation and isomerization of (Z)-methyl epijasmonate, the key contributor of the orchid-like aroma, during tea processing.

The elegant orchid-like fragrance of tea has always been tea processors and consumers' top priority. Controlling the production process is very important for tea aroma formation. This study aims to investigate the synthesis of (Z)-methyl epijasmonate (epi-MeJA), a key contributor to orchid-like aroma properties in tea, during tea processing. The changes in content of epi-MeJA were analysed during the processing of two tea varieties (Anxi Tieguanyin and Taiping Houkui) with typical orchid-like fragrance. It was found to be mainly synthesized and accumulated during tea processing, as fresh tea leaves contained little or even no epi-MeJA. Its content was positively correlated with the processing time in the enzyme active stages (before fixation). During the fixation stages, isomerization occurred due to high temperatures, with a degree of epimerization to the much less odor active isomer (Z)-methyl jasmonate. Isomerization could also occurred during the drying process, which is dominated by the drying temperature.

Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.

Nonalcoholic fatty liver disease (NAFLD) is usually characterized with disrupted bile acid (BA) homeostasis. However, the exact role of certain BA in NAFLD is poorly understood. Here we show levels of serum hyodeoxycholic acid (HDCA) decrease in both NAFLD patients and mice, as well as in liver and intestinal contents of NAFLD mice compared to their healthy counterparts. Serum HDCA is also inversely correlated with NAFLD severity. Dietary HDCA supplementation ameliorates diet-induced NAFLD in male wild type mice by activating fatty acid oxidation in hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent way because the anti-NAFLD effect of HDCA is abolished in hepatocyte-specific Pparα knockout mice. Mechanistically, HDCA facilitates nuclear localization of PPARα by directly interacting with RAN protein. This interaction disrupts the formation of RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer. Our results demonstrate the therapeutic potential of HDCA for NAFLD and provide new insights of BAs on regulating fatty acid metabolism.

Berberine ameliorates iron levels and ferroptosis in the brain of 3 × Tg-AD mice.

BACKGROUND: Berberine (BBR) is a natural alkaloid extracted from the herb Coptis chinensis. This compound has the ability to penetrate the blood-brain barrier (BBB) and exhibit neuroprotective value in the treatment of Alzheimer's disease (AD). AD is a neurodegenerative disease characterized by ß-amyloid (Aß) deposition, hyperphosphorylated tau and other characters. Iron accumulation and ferroptosis were also detected in AD brain, which can result in neuronal damage. However, it is still unclear whether BBR can suppress ferroptosis in AD and alleviate its underlying pathology. PURPOSE: This study investigated whether BBR may affect ferroptosis and related signaling pathways in triple transgenic AD (3 × Tg-AD) mice. METHODS: Four-month-old 3 × Tg-AD mice received oral administration of BBR at a dose of 50 mg/kg for 7.5 months. Cognitive function and anxiety levels in mice were assessed using the morris water maze test, open field test, and novel object recognition test. Western blot, immunohistochemistry, and ICP-MS were employed to assess the pathology of AD, brain iron metabolism, and ferroptosis signaling pathways. Transmission electron microscopy was used to detect mitochondrial changes. The synergistic effects of BBR combined with Nrf2 were investigated using molecular docking programs and surface plasmon resonance technology. Co-inmunoprecipitation assay was used to examine the effect of BBR on the binding ability of Nrf2 and Keap1. RESULTS: The results indicated that chronic treatment of BBR mitigated cognitive disorders in 3 × Tg-AD model mice. Reductions in Aß plaque, hyperphosphorylated tau protein, neuronal loss, and ferroptosis in the brains of 3 × Tg-AD mice suggested that BBR could alleviate brain injury. In addition, BBR treatment attenuated ferroptosis, as evidenced by decreased levels of iron, MDA, and ROS, while enhancing SOD, GSH, GPX4, and SLC7A11. Consistent with the in vivo assay, BBR inhibited RSL3-induced ferroptosis in N2a-sw cells. BBR increased the expression levels of GPX4, FPN1 and SLC7A11 by regulating Nrf2 transcription levels, thereby inhibiting ferroptosis. Molecular docking programs and surface plasmon resonance technology demonstrated the direct combination of BBR with Nrf2. Co-inmunoprecipitation analysis showed that BBR inhibited the interaction between Keap1 and Nrf2. CONCLUSION: For the first time, these results showed that BBR could inhibit iron levels and ferroptosis in the brains of 3 × Tg-AD model mice and partially protect against RSL3-induced ferroptosis via the activation of Nrf2 signaling.

Ccrl2-centred immune-related lncRNA-mRNA co-expression network revealed the local skin immune activation mechanism of moxibustion on adjuvant arthritis mice.

BACKGROUND: Moxibustion is an important external therapy of traditional medicine that operates on some acupoints on the skin and is usually used for immune-related diseases. However, whether the immune function of the skin, especially the immune-related lncRNAs, contributes to the mechanism of moxibustion remains unclear. METHODS: Adjuvant arthritis (AA) was induced by injection of Complete Freund's adjuvant (CFA) into the right hind paw of mice. Moxibustion was administered on the Zusanli (ST36) acupoint for 3 weeks. The alteration of foot volume and cytokine concentration in serum was used to evaluate the anti-inflammation effect of moxibustion. CD83 expression in the local skin of ST36 was measured by immunofluorescence staining. Transcriptome RNA sequencing (RNA-seq) and lncRNA-mRNA network analysis were performed to construct a moxibustion-induced Immune-related lncRNA-mRNA co-expression network. qRT-PCR was used to validate the RNA-seq data. RESULTS: Moxibustion at ST36 relieved the foot swelling, decreased the TNF-α and IL-1ß concentrations in serum, and obviously increased the CD83 expression at the local skin of ST36. A total of 548 differentially expressed lncRNAs and 520 linked mRNAs were screened out. The significantly and predominately enriched Go term was inflammatory and immune response, and the main pathways related to inflammatory and immune responses include Toll-like receptor, cytokine-cytokine receptor, and MAPK signaling. The immune-related lncRNA-mRNA co-expression network showed 88 lncRNAs and 36 mRNAs, and Ccrl2 is the central hub of this network. CONCLUSION: Local immune activation is significantly triggered by moxibustion in ST36 of AA mice. The Ccrl2-centered immune-related lncRNA-mRNA co-expression network would be a promising target for decoding the mechanism of moxibustion for immune-related diseases.

Metabolite analysis and sensory evaluation reveal the effect of roasting on the characteristic flavor of large-leaf yellow tea.

Roasting is essential for processing large-leaf yellow tea (LYT). However, the effect of the roasting on the metabolic and sensory profiles of LYT remains unknown. Herein, the metabolomics and sensory quality of LYT at five roasting degrees were evaluated by liquid/gas chromatography mass spectrometry and quantitative descriptive analysis. A higher degree of roasting resulted in a significantly stronger crispy rice, fried rice, and smoky-burnt aroma (p < 0.05), which is closely associated with heterocyclic compound accumulation (concentrations: 6.47 ± 0.27 - 1065.00 ± 5.58 µg/g). Amino acids, catechins, flavonoid glycosides and N-ethyl-2-pyrrolidone-substituted flavan-3-ol varied with roasting degree. The enhancement of crispy-rice and burnt flavor coupled with the reduction of bitterness and astringency. Correlations analysis revealed the essential compounds responsible for roasting degree, including 2,3-diethyl-5-methylpyrazine, hexanal, isoleucine, N-ethyl-2-pyrrolidone-substituted flavan-3-ol (EPSF), and others. These findings provide a theoretical basis for improving the specific flavors of LYT.

A NETWORK PHARMACOLOGY-BASED TREATMENT ANALYSIS OF LUTEOLIN FOR REGULATING PYROPTOSIS IN ACUTE LUNG INJURY.

ABSTRACT: Background: Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome, are complicated pulmonary inflammatory conditions for which standard therapeutics are still not well established. Although increasing research has indicated the anti-inflammatory, anticancer, and antioxidant effects of luteolin, especially in lung diseases, the molecular mechanisms underlying luteolin treatment remain largely unclear. Methods: The potential targets of luteolin in ALI were explored using a network pharmacology-based strategy and further validated in a clinical database. The relevant targets of luteolin and ALI were first obtained, and the key target genes were analyzed using a protein-protein interaction network, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. The targets of luteolin and ALI were then combined to ascertain the relevant pyroptosis targets, followed by Gene Ontology analysis of core genes and molecular docking of key active compounds to the antipyroptosis targets of luteolin in resolving ALI. The expression of the obtained genes was verified using the Gene Expression Omnibus database. In vivo and in vitro experiments were performed to explore the potential therapeutic effects and mechanisms of action of luteolin against ALI. Results: Fifty key genes and 109 luteolin pathways for ALI treatment were identified through network pharmacology. Key target genes of luteolin for treating ALI via pyroptosis were identified. The most significant target genes of luteolin in ALI resolution included AKT1, NOS2, and CTSG. Compared with controls, patients with ALI had lower AKT1 expression and higher CTSG expression. Luteolin simply reduced systemic inflammation and lung tissue damage in septic mice. Furthermore, we blocked AKT1 expression and found luteolin reduced the degree of lung injury and affected NOS2 levels. Conclusions: As demonstrated by a network pharmacology approach, luteolin may exert an antipyroptosis effect on ALI via AKT1, NOS2, and CTSG.

Pinocembrin alleviates pyroptosis and apoptosis through ROS elimination in random skin flaps via activation of SIRT3.

Random skin flap grafting is the most common skin grafting technique in reconstructive surgery. Despite progress in techniques, the incidence of distal flap necrosis still exceeds 3%, which limits its use in clinical practice. Current methods for treating distal flap necrosis are still lacking. Pinocembrin (Pino) can inhibit reactive oxygen species (ROS) and cell death in a variety of diseases, such as cardiovascular diseases, but the role of Pino in random flaps has not been explored. Therefore, we explore how Pino can enhance flap survival and its specific upstream mechanisms via macroscopic examination, Doppler, immunohistochemistry, and western blot. The results suggested that Pino can enhance the viability of random flaps by inhibiting ROS, pyroptosis and apoptosis. The above effects were reversed by co-administration of Pino with adeno-associated virus-silencing information regulator 2 homolog 3 (SIRT3) shRNA, proving the beneficial effect of Pino on the flaps relied on SIRT3. In addition, we also found that Pino up-regulates SIRT3 expression by activating the AMP-activated protein kinase (AMPK) pathway. This study proved that Pino can improve random flap viability by eliminating ROS, and ROS-induced cell death through the activation of SIRT3, which are triggered by the AMPK/PGC-1α signaling pathway.

Emulsifying properties, in vitro digestive characteristics, and ß-carotene bioaccessibility of mandarin peel pectin emulsions prepared with different carrier oil phases.

Mandarin peel pectin (MPP) emulsions were prepared with different oil phase loadings with or without ß-carotene, and their emulsifying characteristics, digestive properties and ß-carotene bioaccessibility were investigated. Results revealed that all MPP emulsions exhibited good loading efficiency for ß-carotene, while their apparent viscosity and interfacial pressure (π) of MPP emulsions increased significantly after the addition of ß-carotene. Emulsification of MPP emulsions as well as digestibility were significantly dependent on the kind of oil. MPP emulsions prepared with long-chain triglycerides (LCT) oil (soybean, corn, and olive oil) exhibited higher volume average particle size (D4,3), apparent viscosity, π values, and bioaccessibility of carotene compared to those prepared with medium-chain oils (MCT). MPP emulsions with LCT rich in monosaturated fatty acids (olive oil) had the highest ß-carotene encapsulation efficiency, bioaccessibility, etc. than from other oils. This study provides a theoretical basis for the efficient encapsulation and high bioaccessibility of carotenoids with pectin emulsions.

The Emotion Regulation Mechanism in Neurotic Individuals: The Potential Role of Mindfulness and Cognitive Bias.

Neuroticism is a personality trait that impacts daily life and raises the risk of mental problems and physical illnesses. To understand the emotion regulation mechanism of neurotic individuals, we developed two complementary studies to examine the effects of mindfulness and negative cognitive bias. In Study 1, four scales (EPQ-RSC, FFMQ, CERQ, NCPBQ) were used for assessment. Correlation analysis and structural comparison showed that: (1) the level of neuroticism was positively correlated with negative emotion regulation; (2) negative cognitive bias mediated the relationship between neuroticism and emotion regulation; (3) mindfulness and negative cognitive bias mediated the relationship in a chain. Study 1 showed that cognitive bias may play a key role in the emotion regulation mechanism. Study 2 further explored the cognitive bias of neurotic individuals using three behavioral experiments. A mixed-design ANOVA indicated that individuals with high neuroticism levels exhibited negative attention, memory, and interpretation biases. Our findings extend previous research on emotion regulation problems of neurotic individuals and broaden the field to personality-based emotion disorders. In particular, a theoretical rationale is provided for the application of cognitive behavioral therapy, such as mindfulness-based cognitive therapy (MBCT), to the emotion regulation of neurotic individuals.

Effect of combined aging treatment on biochar adsorption and speciation distribution for Cd(II).

As a passivation material for heavy metals in-situ remediation, biochar (BC) has often been expected to maintain long-term adsorption performance for target pollutants. There is still lack of consensus about the impact of aging processes on biochar properties, particularly with respect to its long-term sorption performance. In this study, the changes to immobilization mechanisms as well as the speciation distribution of Cd(II) triggered by combined aging simulation (dry-wet, freeze-thaw cycle and oxidation treatment) on BC prepared under three levels of pyrolysis temperatures (300, 500 and 700 °C) were investigated. The results showed significant inhibition of aging on adsorption performance with the adsorptive capacity of BC300, BC500 and BC700 for Cd(II) decreased by 31.12 %, 50.63 % and 14.94 %, respectively. However, sequential extraction results indicated little influence of the aging process on the relative fractionation of Cd(II) speciation. The distribution of readily bioavailable, potentially bioavailable and non-bioavailable fractions of Cd(II) on BC showed only minimal changes post-aging. Overall, there was less Cd(II) sorption following aging, but the fractional availability (in relative terms) remained the same. Compared with 300 and 700 °C, the biochar prepared under 500 °C accounted the highest fraction of non-bioavailable Cd(II) (67.23 % of BC500, 59.17 % of Aged-500), and thus showed most promising for Cd(II) immobilization. This study has important practical significance for the long-term application of biochar in real environment.

Associations of Multiple Serum Trace Elements with Abnormal Sleep Duration Patterns in Hospitalized Patient with Cirrhosis.

The associations of circulating trace elements with sleep health have attracted increasing attention given their potential link. However, there is scant data on the relationship between serum trace elements and abnormal sleep duration patterns in cirrhosis. We aimed to investigate these associations with the purpose of identifying modifiable risk factors. The blood samples were collected from inpatients with cirrhosis, and serum levels of several trace elements were assessed by inductively coupled plasma mass spectrometry. Self-reported sleep duration was categorized to short- (< 7 h/night), optimal (7-8 h/night), and long-sleep duration (> 8 h/night). The dose-response trends and associations of trace elements levels with sleep duration were determined by restricted cubic splines (RCS) and logistic regression, respectively. Cirrhotic patients with optimal sleep duration experienced the highest levels of serum Zinc (Zn) and the lowest values of copper to zinc ratio (CZr). RCS model corroborated non-linear associations of serum Zn and CZr against sleep duration. Multiple regression analysis showed that both CZr (short vs optimal sleep duration: OR 4.785, P < 0.001; long vs optimal sleep duration: OR 4.150, P = 0.019) and serum Zn levels (short vs optimal sleep duration: OR 0.985, P = 0.040; long vs optimal sleep duration: OR 0.956, P = 0.008) serve as independent risk factors for sleep duration abnormalities. In conclusion, our findings unraveled a close relationship of serum Zn and CZr with sleep duration in cirrhosis. Further trace element-based therapy such as Zn supplementation may be novel approach to reverse this sleep problem.

Identification of the Mechanism of Matrine Combined with Glycyrrhizin for Hepatocellular Carcinoma Treatment through Network Pharmacology and Bioinformatics Analysis.

Matrine and glycyrrhizin are representative active ingredients of traditional Chinese medicine (TCM) used in clinical practice. Studies have demonstrated that matrine has antitumor pharmacological effects and that glycyrrhizin protects liver function. However, the potential bioactive compounds and mechanisms remain unknown, as well as whether they have synergistic effects in killing cancer cells and protecting liver cells. To investigate the synergistic effects and mechanism of matrine combined with glycyrrhizin in hepatocellular carcinoma (HCC) treatment, we used both network pharmacology and bioinformatics analyses. First, the chemical gene interaction information of matrine and glycyrrhizin was obtained from the PubChem database. The pathogenic genes of HCC were accessed from five public databases. The RNA sequencing data and clinical information of HCC patients were downloaded from The Cancer Genome Atlas (TCGA). Next, the overlapping genes among the potential targets of matrine and glycyrrhizin and HCC-related targets were determined using bioinformatics analysis. We constructed the drug-target interaction network. Prognosis-associated genes were acquired through the univariate Cox regression model and Lasso-Cox regression model. The results were verified by the International Cancer Genome Consortium (ICGC) database. Finally, we predicted the immune function of the samples. The drug-target interaction network consisted of 10 matrine and glycyrrhizin targets. We selected a Lasso-Cox regression model consisting of 3 differentially expressed genes (DEGs) to predict the efficacy of the combination in HCC. Subsequently, we successfully predicted the overall survival of HCC patients using the constructed prognostic model and investigated the correlation of the immune response. Matrine and glycyrrhizin have synergistic effects on HCC. The model we obtained consisted of three drug-target genes by Lasso-Cox regression analysis. The model independently predicted the combined effect of matrine and glycyrrhizin in HCC treatment and OS, which will be helpful for guiding clinical treatment. The prognostic model was correlated with the immune cells and immune checkpoints of patients, which had an adjuvant effect on HCC immunotherapy. Matrine and glycyrrhizin can have therapeutic effects on HCC by promoting the production or enhancing the core gene activity in the drug network and improving the immune system function of patients.

Establishment and Validation of a Tumor Microenvironment Prognostic Model for Predicting Bladder Cancer Survival Status Based on Integrated Bioinformatics Analyses.

This study was designed to analyze the characteristics of bladder cancer-related genes and establish a prognostic model of bladder cancer. The model passed an independent external validation set test. Differentially expressed genes (DEGs) related to bladder cancer were obtained from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and Genotype-Tissue Expression (GTEx) databases. WGCNA was used to fit the GSE188715, TCGA, and GTEx RNA-Seq data. Fusing the module genes with the high significance in tumor development extracted from WGCNA and DEGs screened from multiple databases. 709 common prognostic-related genes were obtained. The 709 genes were enriched in the Gene Ontology database. Univariate Cox and LASSO regression analyses were used to screen out 21 prognostic-related genes and further multivariate Cox regression established a bladder cancer prognostic model consisting of 8 genes. After the eight-gene prognostic model was established, the Human Protein Atlas (HPA) database, GEPIA 2, and quantitative real-time PCR (qRT-PCR) verified the differential expression of these genes. Gene Set Enrichment Analysis and immune infiltration analysis found biologically enrichment pathways and cellular immune infiltration related to this bladder cancer prognostic model. Then, we selected bladder cancer patients in the TCGA database to evaluate the predictive ability of the model on the training set and validation set. The overall survival status of the two TCGA patient groups in the training and the test sets was obtained by Kaplan-Meier survival analysis. Three-year survival rates in the training and test sets were 37.163% and 25.009% for the low-risk groups and 70.000% and 62.235% for the high-risk groups, respectively. Receiver operating characteristic curve (ROC) analysis showed that the areas under the curve (AUCs) for the training and test sets were above 0.7. In an external independent validation database GSE13507, Kaplan-Meier survival analysis showed that the three-year survival rates of the high-risk and the low-risk groups in this database were 56.719% and 76.734%, respectively. The AUCs of the ROC drawn in the external validation set were both above 0.65. Here, we constructed a prognostic model of bladder cancer based on data from the GEO, TCGA, and GTEx databases. This model has potential prognostic and clinical auxiliary diagnostic value.

Assembly of Celastrol to Zeolitic Imidazolate Framework-8 by Coordination as a Novel Drug Delivery Strategy for Cancer Therapy.

Celastrol (Cel), a compound derived from traditional Chinese medicine Tripterygium wilfordii Hook. F, has attracted considerable attention as an anticancer drug. However, its clinical application is limited due to its low bioavailability and potential toxicity. With the advancement of nanoscale metal organic frameworks (MOF), the nano-delivery of drugs can effectively improve those disadvantages. Nevertheless, hydrophobic drugs apparently cannot be encapsulated by the hydrophilic channels of MOF-based drug delivery systems. To address these issues, a new assembly strategy for hydrophobic Cel was developed by coordinating the deprotonated Cel to zeolitic imidazolate framework-8 (ZIF-8) with the assistance of triethylamine (Cel-ZIF-8). This strategy greatly elevates the assembly efficiency of Cel from less than 1% to ca. 80%. The resulted Cel-ZIF-8 remains stable in the physiological condition while dissociating and releasing Cel after a 45-minute incubation in an acidic tumor microenvironment (pH 5.5). Furthermore, Cel-ZIF-8 is proved to be easily taken up by cancer cells and exhibits a better therapeutic effect on tumor cells than free Cel. Overall, the Cel-ZIF-8 provides a novel assembly strategy for hydrophobic drugs, and the findings are envisaged to facilitate the application of Cel in cancer therapies.

Collagenase-I decorated co-delivery micelles potentiate extracellular matrix degradation and hepatic stellate cell targeting for liver fibrosis therapy.

Liver fibrosis is a pathological process of multiple chronic liver diseases progressing to cirrhosis for which there are currently no effective treatment options. During fibrosis progression, the overproduction of extracellular matrix (ECM) collagen secreted by hepatic stellate cells (HSCs) greatly impedes drug delivery and reduces drug therapeutic effects. In this study, a glycyrrhetinic acid (GA)-conjugated prodrug micellar system with collagenase I (COL) decoration (COL-HA-GA, abbreviated as CHG) was designed to codelivery sorafenib (Sora/CHG, abbreviated as S/CHG) for potentiating ECM degradation and HSCs targeting on liver fibrosis therapy. In ECM barrier models established in vitro or in vivo, CHG micelles efficiently degraded pericellular collagen and demonstrated enormous ECM penetration abilities as well as superior HSCs internalization. Moreover, CHG micelles exhibited more Sora & GA accumulations and activated HSCs targeting efficiencies in the fibrotic livers than those in the normal livers. More importantly, S/CHG micelles were more effective in anti-liver fibrosis by lowering the collagen content, inhibiting the HSCs activation, as well as down-regulating the fibrosis-related factors, leading to reverse the fibrotic liver to normal liver through the multi-mechanisms including angiogenesis reduction, liver fibrosis microenvironment regulation, and epithelial-mesenchymal transition inhibition. In conclusion, the developed COL decorated nano-codelivery system with fibrotic ECM collagen degradation and activated HSCs targeting dual-functions exhibited great potential for liver fibrosis therapy. STATEMENT OF SIGNIFICANCE: A glycyrrhetinic acid (GA)-conjugated prodrug with collagenase I (COL) decoration (CHG) was designed for codelivery with sorafenib (S/CHG), potentiating extracellular matrix (ECM) degradation-penetration and hepatic stellate cells (HSCs) targeting on liver fibrosis therapy. In ECM barrier models, CHG micelles efficiently degraded pericellular collagen and demonstrated ECM penetration abilities, as well as displayed superior HSCs internalization. Moreover, S/CHG micelles were more effective in anti-liver fibrosis by lowering the collagen content, inhibiting the HSCs activation, as well as down-regulating cytokines, reversing the fibrotic liver to normal through various mechanisms. In conclusion, the developed fibrotic ECM degradation and HSCs targeting dual-functional nano-codelivery system provided a prospective potentiality in liver fibrosis therapy.

Protective effect of quercetin on kidney diseases: From chemistry to herbal medicines.

Kidney injuries may trigger renal fibrosis and lead to chronic kidney disease (CKD), but effective therapeutic strategies are still limited. Quercetin is a natural flavonoid widely distributed in herbal medicines. A large number of studies have demonstrated that quercetin may protect kidneys by alleviating renal toxicity, apoptosis, fibrosis and inflammation in a variety of kidney diseases. Therefore, quercetin could be one of the promising drugs in the treatment of renal disorders. In the present study, we review the latest progress and highlight the beneficial role of quercetin in kidney diseases and its underlying mechanisms. The pharmacokinetics and bioavailability of quercetin and its proportion in herbal medicine will also be discussed.