Safety of Phytoestrogenic Botanical Dietary Supplements: in vivo and in vitro Evaluation of Botanical-Drug Interactions

Popular botanical dietary supplements marketed for management of menopausal symptoms, including hops (Humulus lupulus L.), red clover (Trifolium pratense) and licorice (Glycyrrhiza uralensis), were evaluated for their potential to alter CYP-mediated drug metabolism clinically and pre-clinically. Both hops and red clover had been reported to inhibit certain cytochrome P450 (CYP) enzymes in vitro and to have long half-lives in vivo. Therefore, two Phase I clinical studies were conducted to test whether a hop dietary supplement or a red clover dietary supplement caused pharmacokinetic interactions with a probe substrate cocktail consisting of caffeine (probe for CYP1A2), tolbutamide (probe for CYP2C9), dextromethorphan (probe for CYP2D6) and alprazolam (probe for CYP3A4/5). In each clinical trial, the botanical dietary supplement was consumed twice daily for 2 weeks by 16 and 15 peri- and post-menopausal women, respectively. The pharmacokinetics of probe substrates were compared before and after supplementation. The serum levels of the probe substrates over time were measured using a sensitive, selective, robust, and fully validated UHPLC-MS/MS analytical method in the two clinical studies. In the hop-drug interaction study, the area under concentration-time curve (AUC) of alprazolam decreased 7.6% (p-value 0.047). In the red clover-drug interaction study, the peak serum concentrations of caffeine and alprazolam increased 13.9% and 24.5% (p-values of 0.0355 and 0.0121, respectively). However, neither the hop nor the red clover dietary supplement changed the AUC of any probe substrate enough to meet the FDA guidance of clinically relevant induction or inhibition with respect to CYP1A2, CYP2C9, CYP2D6, or CYP3A4/5. The post-intervention serum obtained from each clinical trial was analyzed to confirm compliance. The Phase II conjugated metabolites of the supplement constituents were detected using ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-Q-ToF MS). In the hop study, four monosulfates, six monoglucuronides, two sulfate-glucuronic acid diconjugates and two diglucuronides were found in participant serum. Among them, the four diconjugates were reported for the first time. In the red clover study, nine monosulfates, eight monoglucuronides and two sulfate-glucuronic acid diconjugates were detected. The inhibition of CYP enzymes by Glycyrrhiza uralensis was studied systematically in vitro using human liver microsomes and bioactivity-guided fractionation. A series of UHPLC-MS/MS based assays were conducted for screening the inhibitors, determining the IC50 values and studying the inhibitory mechanisms and kinetics. Two compounds, (R)-3’-(γ,γ-dimethylallyl)-kievitone (1) and licoisoflavone B (2) were identified and determined to be responsible for inhibition of human CYP enzymes by G. uralensis. The chemical structure of (R)-3’-(γ,γ-dimethylallyl)-kievitone is reported for the first time. Compounds 1 and 2 reversibly inhibited CYP2C8 with IC50 values of 9.2±1.2 and 7.4±1.1 µM, respectively, and CYP2C9 with IC50 6.3±0.8 and 4.9±0.4 µM, respectively. Both 1 and 2 inhibited human liver microsomal CYP2C8 and CYP2C9, and 1 inhibited recombinant CYP2C8 in a combination of competitive and mixed mechanisms. 1 and 2 were mixed type inhibitors of recombinant CYP2C9, whereas 2 inhibited recombinant CYP2C8 competitively. Finally, affinity constants Ki were determined. This comprehensive pre-clinical evaluation of CYP inhibition by G. uralensis suggests that G. uralensis is unlikely to cause clinically relevant CYP inhibitions because with normal dosage of G. uralensis, the in vivo concentrations of compounds 1 and 2 at CYP2C8 and CYP2C9 are expected to be much lower than their Ki values

Attributed Multi-order Graph Convolutional Network for Heterogeneous Graphs

Heterogeneous graph neural networks aim to discover discriminative node embeddings and relations from multi-relational networks.One challenge of heterogeneous graph learning is the design of learnable meta-paths, which significantly influences the quality of learned embeddings.Thus, in this paper, we propose an Attributed Multi-Order Graph Convolutional Network (AMOGCN), which automatically studies meta-paths containing multi-hop neighbors from an adaptive aggregation of multi-order adjacency matrices. The proposed model first builds different orders of adjacency matrices from manually designed node connections. After that, an intact multi-order adjacency matrix is attached from the automatic fusion of various orders of adjacency matrices. This process is supervised by the node semantic information, which is extracted from the node homophily evaluated by attributes. Eventually, we utilize a one-layer simplifying graph convolutional network with the learned multi-order adjacency matrix, which is equivalent to the cross-hop node information propagation with multi-layer graph neural networks. Substantial experiments reveal that AMOGCN gains superior semi-supervised classification performance compared with state-of-the-art competitors

A Robust Hybrid Approach Based on Estimation of Distribution Algorithm and Support Vector Machine for Hunting Candidate Disease Genes

Microarray data are high dimension with high noise ratio and relatively small sample size, which makes it a challenge to use microarray data to identify candidate disease genes. Here, we have presented a hybrid method that combines estimation of distribution algorithm with support vector machine for selection of key feature genes. We have benchmarked the method using the microarray data of both diffuse B cell lymphoma and colon cancer to demonstrate its performance for identifying key features from the profile data of high-dimension gene expression. The method was compared with a probabilistic model based on genetic algorithm and another hybrid method based on both genetics algorithm and support vector machine. The results showed that the proposed method provides new computational strategy for hunting candidate disease genes from the profile data of disease gene expression. The selected candidate disease genes may help to improve the diagnosis and treatment for diseases

Photo-functionalized TiO2 nanotubes decorated with multifunctional Ag nanoparticles for enhanced vascular biocompatibility

Titanium dioxide (TiO2) has a long history of application in blood contact materials, but it often suffers from insufficient anticoagulant properties. Recently, we have revealed the photocatalytic effect of TiO2 also induces anticoagulant properties. However, for long-term vascular implant devices such as vascular stents, besides anticoagulation, also anti-inflammatory, anti-hyperplastic properties, and the ability to support endothelial repair, are desired. To meet these requirements, here, we immobilized silver nanoparticles (AgNPs) on the surface of TiO2 nanotubes (TiO2-NTs) to obtain a composite material with enhanced photo-induced anticoagulant property and improvement of the other requested properties. The photo-functionalized TiO2-NTs showed protein-fouling resistance, causing the anticoagulant property and the ability to suppress cell adhesion. The immobilized AgNPs increased the photocatalytic activity of TiO2-NTs to enhances its photo-induced anticoagulant property. The AgNP density was optimized to endow the TiO2-NTs with anti-inflammatory property, a strong inhibitory effect on smooth muscle cells (SMCs), and low toxicity to endothelial cells (ECs). The in vivo test indicated that the photofunctionalized composite material achieved outstanding biocompatibility in vasculature via the synergy of photo-functionalized TiO2-NTs and the multifunctional AgNPs, and therefore has enormous potential in the field of cardiovascular implant devices. Our research could be a useful reference for further designing of multifunctional TiO2 materials with high vascular biocompatibility

CpSmt3, an ortholog of small ubiquitin-like modifier, is essential for growth, organelle function, virulence, and antiviral defense in Cryphonectria parasitica

IntroductionSUMOylation is an important post-translational modification that regulates the expression, localization, and activity of substrate proteins, thereby participating in various important cellular processes such as the cell cycle, cell metabolism, gene transcription, and antiviral activity. However, the function of SUMOylation in phytopathogenic fungi has not yet been adequately explored.MethodsA comprehensive analysis composed of proteomics, affinity pull-down, molecular and cellular approaches was performed to explore the roles of SUMOylation in Cryphonectria parasitica, the fungal pathogen responsible for chestnut blight.Results and discussionCpSmt3, the gene encoding the SUMO protein CpSmt3 in C. parasitica was identified and characterized. Deletion of the CpSmt3 gene resulted in defects in mycelial growth and hyphal morphology, suppression of sporulation, attenuation of virulence, weakening of stress tolerance, and elevated accumulation of hypovirus dsRNA. The ΔCpSmt3 deletion mutant exhibited an increase in mitochondrial ROS, swollen mitochondria, excess autophagy, and thickened cell walls. About 500 putative SUMO substrate proteins were identified by affinity pull-down, among which many were implicated in the cell cycle, ribosome, translation, and virulence. Proteomics and SUMO substrate analyses further revealed that deletion of CpSmt3 reduced the accumulation of CpRho1, an important protein that is involved in TOR signal transduction. Silencing of CpRho1 resulted in a phenotype similar to that of ΔCpSmt3, while overexpression of CpRho1 could partly rescue some of the prominent defects in ΔCpSmt3. Together, these findings demonstrate that SUMOylation by CpSmt3 is vitally important and provide new insights into the SUMOylation-related regulatory mechanisms in C. parasitica

Adenomatoid Tumor of the Adrenal Gland: Report of Two Cases and Review of the Literature

Adenomatoid tumor (AT) is an uncommon benign neoplasm of mesothelial origin, usually occurring in the female and male genital tracts. Extragenital localization such as the adrenal gland is extremely rare. Until now, only 39 cases of adrenal AT have been reported in the English literature. Here we report two novel cases of adrenal AT that occurred in male patients aged 30 and 31 years. The tumors were discovered incidentally by computed tomography (CT). Macroscopically, the tumors were unilateral and solid, and the greatest dimension of the tumors was 3.5 and 8.0 cm, respectively. Histologically, the tumors consisted of angiomatoid, cystic, and solid patterns and infiltrated the adrenal cortical or medullary tissue. The tumor cells had low nuclear/cytoplasmic ratio, with no pathological mitosis or nuclear pleomorphism. Thread-like bridging strands and signet-ring-like cells could be seen. Immunohistochemically, the tumor cells were positive for epithelial markers (AE1/AE3, CK7) and mesothelial markers (D2-40, calretinin, and WT-1). The Ki-67 index was approximately 1 and 2%, respectively. The differential diagnosis of adrenal AT includes a variety of benign and malignant tumors. The patients had neither local recurrence nor distant metastasis at 21 and 8 months after removal of the tumor. In the literature review, we comprehensively summarized the clinical, morphological, immunohistochemical, and prognostic features of adrenal AT. Adrenal ATs are morphologically and immunophenotypically identical to those that occur in the genital tracts. Combining the histology with immunohistochemical profiles is very supportive in reaching the diagnosis of this benign tumor, helping to avoid misdiagnosis and overtreatment

Deterministic processes dominate microbial assembly mechanisms in the gut microbiota of cold-water fish between summer and winter

Exploring the effects of seasonal variation on the gut microbiota of cold-water fish plays an important role in understanding the relationship between seasonal variation and cold-water fish. Gut samples of cold-water fish and environmental samples were collected during summer and winter from the lower reaches of the Yalong River. The results of the 16S rRNA sequencing showed that significant differences were identified in the composition and diversity of gut bacteria of cold-water fish. Co-occurrence network complexity of the gut bacteria of cold-water fish was higher in summer compared to winter (Sum: nodes: 256; edges: 20,450; Win: nodes: 580; edges: 16,725). Furthermore, from summer to winter, the contribution of sediment bacteria (Sum: 5.3%; Win: 23.7%) decreased in the gut bacteria of cold-water fish, while the contribution of water bacteria (Sum: 0%; Win: 27.7%) increased. The normalized stochastic ratio (NST) and infer community assembly mechanisms by phylogenetic bin-based null model analysis (iCAMP) showed that deterministic processes played a more important role than stochastic processes in the microbial assembly mechanism of gut bacteria of cold-water fish. From summer to winter, the contribution of deterministic processes to gut bacteria community assembly mechanisms decreased, while the contribution of stochastic processes increased. Overall, these results demonstrated that seasonal variation influenced the gut bacteria of cold-water fish and served as a potential reference for future research to understand the adaptation of fish to varying environments

Transforming medical equipment management in digital public health: a decision-making model for medical equipment replacement

IntroductionIn the rapidly evolving field of digital public health, effective management of medical equipment is critical to maintaining high standards of healthcare service levels and operational efficiency. However, current decisions to replace large medical equipment are often based on subjective judgments rather than objective analyses and lack a standardized approach. This study proposes a multi-criteria decision-making model that aims to simplify and enhance the medical equipment replacement process.MethodsThe researchers developed a multi-criteria decision-making model specifically for the replacement of medical equipment. The model establishes a system of indicators for prioritizing and evaluating the replacement of large medical equipment, utilizing game theory to assign appropriate weights, which uniquely combines the weights of the COWA and PCA method. In addition, which uses the GRA method in combination with the TOPSIS method for a more comprehensive decision-making model.ResultsThe study validates the model by using the MRI equipment of a tertiary hospital as an example. The results of the study show that the model is effective in prioritizing the most optimal updates to the equipment. Significantly, the model shown a higher level of differentiation compared to the GRA and TOPSIS methods alone.DiscussionThe present study shows that the multi-criteria decision-making model presented provides a powerful and accurate tool for optimizing decisions related to the replacement of large medical equipment. By solving the key challenges in this area as well as giving a solid basis for decision making, the model makes significant progress toward the field of management of medical equipment

RING finger 138 deregulation distorts NF-кB signaling and facilities colitis switch to aggressive malignancy

Prolonged activation of nuclear factor (NF)-кB signaling significantly contributes to the development of colorectal cancer (CRC). New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction. Here, we discovered the critical role of RING finger 138 (RNF138) in CRC tumorigenesis through regulating the NF-кB signaling, which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response. RNF138(−/−) mice were hyper-susceptible to the switch from colitis to aggressive malignancy, which coincided with sustained aberrant NF-кB signaling in the colonic cells. Furthermore, RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein (NIBP) to the cytoplasm, which requires the ubiquitin interaction motif (UIM) domain. More importantly, we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings, raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling. Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients, we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth. Overall, our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression, and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation

Helper T Cell (CD4(+)) Targeted Tacrolimus Delivery Mediates Precise Suppression of Allogeneic Humoral Immunity

Antibody-mediated rejection (ABMR) is a major cause of dysfunction and loss of transplanted kidney. The current treatments for ABMR involve nonspecific inhibition and clearance of T/B cells or plasma cells. However, the prognosis of patients following current treatment is poor. T follicular helper cells (Tfh) play an important role in allograft-specific antibodies secreting plasma cell (PC) development. Tfh cells are therefore considered to be important therapeutic targets for the treatment of antibody hypersecretion disorders, such as transplant rejection and autoimmune diseases. Tacrolimus (Tac), the primary immunosuppressant, prevents rejection by reducing T cell activation. However, its administration should be closely monitored to avoid serious side effects. In this study, we investigated whether Tac delivery to helper T (CD4(+)) cells using functionalized mesoporous nanoparticles can block Tfh cell differentiation after alloantigen exposure. Results showed that Tac delivery ameliorated humoral rejection injury in rodent kidney graft by suppressing Tfh cell development, PC, and donor-specific antibody (DSA) generation without causing severe side effects compared with delivery through the drug administration pathway. This study provides a promising therapeutic strategy for preventing humoral rejection in solid organ transplantation. The specific and controllable drug delivery avoids multiple disorder risks and side effects observed in currently used clinical approaches