Elucidation of the Anti-Lung Cancer Mechanism of Xiao'ai Jiedu Prescription Based on Network Pharmacology and Molecular Docking.

Objective: Network pharmacology is an emerging discipline that applies computational methods to understand drug actions and interactions with multiple molecular targets. Xiao'ai Jiedu is a valued traditional Chinese medicine preparation for which the mechanism of action is not yet established. This study aims to explore the mechanism of Xiao'ai Jiedu in treating lung cancer through network pharmacology. Methods: First, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) data platform was used to analyze the target treatment results of different medicinal materials in Mr. Zhou's cancer prescriptions. Then, functional enrichment analysis was performed to conduct a secondary analysis of the dissemination of cancer biological and pharmacological information in the human body. The Cancer Genome Atlas (TCGA) was used to obtain several cancer-aggressive target groups, and their transcription RNA was extracted for collection. The CIBERSORT evaluation method was used to conduct a Spearman correlation analysis on the data processing results. Then the matching degree between the experimental cells and the principle of drug treatment was analyzed to improve the statistical analysis. Results: Pharmacology research results showed that the network can accurately eliminate cancer detoxification targeted target correlation set, and through the data interpretation found that four different gene transcription have significant influence on lung cancer. The findings also confirmed that the degree of immune cell infiltration has a key role in lung cancer The study summarizes the active ingredients and their targets and mechanisms of action of the elimination of Xiao'ai Jiedu formula for the treatment of lung cancer. Conclusion: Network pharmacology can carry on the processing of the data, find the key to conform to the goal of research data, and the corresponding results are obtained, and the development of network pharmacology is not limited to, the study of lung cancer.

Low energy consumption pathway to improve sulfamethoxazole degradation by carbon fiber@Fe3O4-CuO: Electrocatalysis activity, mechanism and toxicity.

Catalysts play a pivotal role in advanced oxidation processes for the remediation of organic wastewater. In this study, a 3D carbon fiber@Fe3O4-CuO catalyst was fabricated, and its efficacy for persulfate activation to remove sulfamethoxazole (SMX) was investigated at extremely low current density. The results of characterization revealed that the catalyst was uniformly distributed on the carbon fiber, and the loaded catalyst was Fe3O4-CuO nanoparticles with a diameter range of 20-50 nm. The SMX removal rate was significantly enhanced at extremely low current density by the metallic oxide catalyst loaded on carbon fiber. Approximately 90 % of SMX was degraded within 90 min when the electric current density was set at 0.1 mA cm-2. This modification process not only improved the persulfate activation efficiency but also enhanced the generation of hydrogen peroxide. Both radical and non-radical pathways were involved in the degradation of SMX. The degradation pathway mainly included hydroxylation, carboxylation, aniline cleavage, and desulfonation reactions. The quantitative structure-activity relationship model indicated that the potential risk of intermediate products to fish, daphnia, and green algae significantly decreased during the electrocatalytic oxidation process. This study provides a novel strategy for persulfate activation, which can significantly enhance the degradation efficiency, toxicity abatement, and energy usage effectiveness of electrocatalytic technology.

The long noncoding RNA HNF1A-AS1 with dual functions in the regulation of cytochrome P450 3A4.

Cytochrome P450 3A4 (CYP3A4) is the most important and abundant drug-metabolizing enzyme in the human liver. Inter-individual differences in the expression and activity of CYP3A4 affect clinical and precision medicine. Increasing evidence indicates that long noncoding RNAs (lncRNAs) play crucial roles in the regulation of CYP3A4 expression. Here, we showed that lncRNA hepatocyte nuclear factor 1 alpha-antisense 1 (HNF1A-AS1) exerted dual functions in regulating CYP3A4 expression in Huh7 and HepG2 cells. Mechanistically, HNF1A-AS1 served as an RNA scaffold to interact with both protein arginine methyltransferase 1 and pregnane X receptor (PXR), thereby facilitating their protein interactions and resulting in the transactivation of PXR and transcriptional alteration of CYP3A4 via histone modifications. Furthermore, HNF1A-AS1 bound to the HNF1A protein, a liver-specific transcription factor, thereby blocking its interaction with the E3 ubiquitin ligase tripartite motif containing 25, ultimately preventing HNF1A ubiquitination and protein degradation, further regulating the expression of CYP3A4. In summary, these results reveal the novel functions of HNF1A-AS1 as the transcriptional and post-translational regulator of CYP3A4; thus, HNF1A-AS1 may serve as a new indicator for establishing or predicting individual differences in CYP3A4 expression.

Purine Metabolic Pathway Alterations and Serum Urate Changes after Oral Inosine Loading in Male Chinese Volunteers.

BACKGROUND: Oral inosine loading is a new method to evaluate the effects of purine on urate metabolism. However, individuals respond differently to acute purine intake, and the effects on the metabolism of other purines remain to be explored. METHODS: 35 male participants are recruited. Participants received 500 mg of inosine orally after an overnight fast, and blood and urine samples are collected before and at various time points over 180 min after inosine administration. RESULTS: The serum urate concentration is significantly different between the hyperuricemia (n = 14) and non-hyperuricemia (n = 16) groups before inosine intake, but there is no in urate change after inosine intake. When grouped according to the baseline estimated glomerular filtration rate (eGFR), the increase in urate level in the high-eGFR group is significantly higher than that in the low-eGFR group (p  =  0.047). The high-eGFR group showed higher levels of serum xanthine and xanthine oxidase (XOD), the key enzyme in urate synthesis, after inosine loading (p < 0.01). CONCLUSIONS: The increase in urate level is positively related to eGFR after oral acute inosine administration, which may have been due to a higher level of XOD.

Pathogenicity of duck circovirus 1 in experimentally infected specific pathogen-free ducks.

Ducks infected with duck circovirus (DuCV) show symptoms such as feather loss, growth retardation and low body weight in the flock. The virus induces immunosuppression and increases the prevalence of infection with other pathogens. However, most studies on duck circovirus were focused on coinfection, and fewer studies had been conducted on the pathogenicity of duck circovirus alone. The aim of the present study was to investigate the pathogenesis of DuCV-1 in experimentally infected specific pathogen-free ducks. In this study, we sequenced the whole genome of a strain of duck circovirus and identified the virus genotype as DuCV-1b. This strain of duck circovirus was named SDLH(OR567883). Animal pathogenicity experiments were then conducted, wherein specific pathogen-free ducks were infected by mucosal injection and abdominal injection. Infected ducks were sampled for 4 consecutive weeks after infection and showed symptoms of dwarfism. We further examined the replication of DuCV-1 in the ducks. The highest virus titers in the 2 infection groups were found in the liver and spleen, with different results for the different routes of infection. Pathological sections of duck organs were made and it was found that organs such as the liver and spleen were damaged by DuCV-1. In conclusion, our experimental results indicate that DuCV-1 can infect ducks individually and cause widespread organ damage in infected ducks.

Tailoring the Activity of Electrocatalytic Methanol Oxidation on Cobalt Hydroxide by the Incorporation of Catalytically Inactive Zinc Ions.

Catalytically inactive Zn2+ is incorporated into cobalt hydroxide to synthesize hierarchical ZnCo-layered double hydroxide nanosheet networks supported on carbon fiber (ZnCo-LDH/CF). The incorporation of Zn2+ is revealed to endow ZnCo-LDH/CF with significantly superior performance in the aspects of the activity and selectivity for methanol electrooxidation to formic acid and the boosting effect for cathodic hydrogen production compared with the counterpart without Zn2+. Density functional theory (DFT) calculation reveals that the incorporation of nonactive Zn2+ can increase the density of states near the Fermi level of LDH (i.e., elevate electrical conductivity to form favorable charge transportation during electrocatalysis) and promote the adsorption and subsequent cleavage of methanol, thus leading to the enhanced methanol electrooxidation performance.

High-Glucose-Induced Injury to Proximal Tubules of the Renal System Is Alleviated by Netrin-1 Suppression of Akt/mTOR.

The kidneys have a high level of Netrin-1 expression, which protects against some acute and chronic kidney disorders. However, it is yet unknown how Netrin-1 affects renal proximal tubule cells in diabetic nephropathy (DN) under pathological circumstances. Research has shown that autophagy protects the kidneys in animal models of renal disease. In this study, we looked at the probable autophagy regulation mechanism of Netrin-1 and its function in the pathogenesis of DN. We proved that in HK-2 cell, high blood sugar levels caused Netrin-1 to be downregulated, which then triggered the Akt/mTOR signaling pathway and enhanced cell death and actin cytoskeleton disruption. By adding Netrin-1 or an autophagy activator in vitro, these pathogenic alterations were reverted. Our results indicate that Netrin-1 stimulates autophagy by blocking the Akt/mTOR signaling pathway, which underlies high-glucose-induced malfunction of the renal proximal tubules. After HK-2 cells were incubated with Netrin-1 recombination protein and rapamycin under HG conditions for 24 h, the apoptosis was significantly reduced, as shown by the higher levels of Bcl-2, as well as lower levels of Bax and cleaved caspase-3 (P = 0.012, Cohen's d = 0.489, Glass's delta = 0.23, Hedges' g = 0.641). This study reveals that targeting Netrin-1-related signaling has therapeutic potential for DN and advances our knowledge of the processes operating in renal proximal tubules in DN.

Azadirachtin Inhibits Nuclear Receptor HR3 in the Prothoracic Gland to Block Larval Ecdysis in the Fall Armyworm, Spodoptera frugiperda.

Azadirachtin has been used to control agricultural pests for a long time; however, the molecular mechanism of azadirachtin on lepidopterans is still not clear. In this study, the fourth instar larvae of fall armyworm were fed with azadirachtin, and then the ecdysis was blocked in the fourth instar larval stage (L4). The prothoracic glands (PGs) of the treated larvae were dissected for RNA sequencing to determine the effect of azadirachtin on ecdysis inhibition. Interestingly, one of the PG-enriched genes, the nuclear hormone receptor 3 (HR3), was decreased after azadirachtin treatment, which plays a critical role in the 20-hydroxyecdysone action during ecdysis. To deepen the understanding of azadirachtin on ecdysis, the HR3 was knocked out by using the CRISPR/Cas9 system, while the HR3 mutants displayed embryonic lethal phenotype; thus, the stage-specific function of HR3 during larval molting was not enabled to unfold. Hence, the siRNA was injected into the 24 h L4 larvae to knock down HR3. After 96 h, the injected larvae were blocked in the old cuticle during ecdysis which is consistent with the azadirachtin-treated larvae. Taken together, we envisioned that the inhibition of ecdysis in the fall armyworm after the azadirachtin treatment is due to an interference with the expression of HR3 in PG, resulting in larval mortality. The results in this study specified the understanding of azadirachtin on insect ecdysis and the function of HR3 in lepidopteran in vivo.

Plant immunity suppression by an exo-ß-1,3-glucanase and an elongation factor 1α of the rice blast fungus.

Fungal cell walls undergo continual remodeling that generates ß-1,3-glucan fragments as products of endo-glycosyl hydrolases (GHs), which can be recognized as pathogen-associated molecular patterns (PAMPs) and trigger plant immune responses. How fungal pathogens suppress those responses is often poorly understood. Here, we study mechanisms underlying the suppression of ß-1,3-glucan-triggered plant immunity by the blast fungus Magnaporthe oryzae. We show that an exo-ß-1,3-glucanase of the GH17 family, named Ebg1, is important for fungal cell wall integrity and virulence of M. oryzae. Ebg1 can hydrolyze ß-1,3-glucan and laminarin into glucose, thus suppressing ß-1,3-glucan-triggered plant immunity. However, in addition, Ebg1 seems to act as a PAMP, independent of its hydrolase activity. This Ebg1-induced immunity appears to be dampened by the secretion of an elongation factor 1 alpha protein (EF1α), which interacts and co-localizes with Ebg1 in the apoplast. Future work is needed to understand the mechanisms behind Ebg1-induced immunity and its suppression by EF1α.

The diapause-like colorectal cancer cells induced by SMC4 attenuation are characterized by low proliferation and chemotherapy insensitivity.

In response to adverse environmental conditions, embryonic development may reversibly cease, a process termed diapause. Recent reports connect this phenomenon with the non-genetic responses of tumors to chemotherapy, but the mechanisms involved are poorly understood. Here, we establish a multifarious role for SMC4 in the switching of colorectal cancer cells to a diapause-like state. SMC4 attenuation promotes the expression of three investment phase glycolysis enzymes increasing lactate production while also suppressing PGAM1. Resultant high lactate levels increase ABC transporter expression via histone lactylation, rendering tumor cells insensitive to chemotherapy. SMC4 acts as co-activator of PGAM1 transcription, and the coordinate loss of SMC4 and PGAM1 affects F-actin assembly, inducing cytokinesis failure and polyploidy, thereby inhibiting cell proliferation. These insights into the mechanisms underlying non-genetic chemotherapy resistance may have significant implications for the field, advancing our understanding of aerobic glycolysis functions in tumor and potentially informing future therapeutic strategies.

Electrochemical detection of glycoproteins using boronic acid-modified metal-organic frameworks as dual-functional signal reporters.

The sensitive analysis of glycoproteins is of great importance for early diagnosis and prognosis of diseases. In this work, a sandwich-type electrochemical aptasensor was developed for the detection of glycoproteins using 4-formylphenylboric acid (FPBA)-modified Cu-based metal-organic frameworks (FPBA-Cu-MOFs) as dual-functional signal probes. The target captured by the aptamer-modified electrode allowed the attachment of FPBA-Cu-MOFs based on the interaction between boronic acid and glycan on glycoproteins. Large numbers of Cu2+ ions in FPBA-Cu-MOFs produced an amplified signal for the direct voltammetric detection of glycoproteins. The electrochemical aptasensor showed a detection limit as low as 6.5 pg mL-1 for prostate specific antigen detection. The method obviates the use of antibody and enzymes for molecular recognition and signal output. The dual-functional MOFs can be extended to the design of other biosensors for the determination of diol-containing biomolecules in clinical diagnosis.

Hepatic vessel segmentation based on 3D swin-transformer with inductive biased multi-head self-attention.

PURPOSE: Segmentation of liver vessels from CT images is indispensable prior to surgical planning and aroused a broad range of interest in the medical image analysis community. Due to the complex structure and low-contrast background, automatic liver vessel segmentation remains particularly challenging. Most of the related researches adopt FCN, U-net, and V-net variants as a backbone. However, these methods mainly focus on capturing multi-scale local features which may produce misclassified voxels due to the convolutional operator's limited locality reception field. METHODS: We propose a robust end-to-end vessel segmentation network called Inductive BIased Multi-Head Attention Vessel Net(IBIMHAV-Net) by expanding swin transformer to 3D and employing an effective combination of convolution and self-attention. In practice, we introduce voxel-wise embedding rather than patch-wise embedding to locate precise liver vessel voxels and adopt multi-scale convolutional operators to gain local spatial information. On the other hand, we propose the inductive biased multi-head self-attention which learns inductively biased relative positional embedding from initialized absolute position embedding. Based on this, we can gain more reliable queries and key matrices. RESULTS: We conducted experiments on the 3DIRCADb dataset. The average dice and sensitivity of the four tested cases were 74.8[Formula: see text] and 77.5[Formula: see text], which exceed the results of existing deep learning methods and improved graph cuts method. The Branches Detected(BD)/Tree-length Detected(TD) indexes also proved the global/local feature capture ability better than other methods. CONCLUSION: The proposed model IBIMHAV-Net provides an automatic, accurate 3D liver vessel segmentation with an interleaved architecture that better utilizes both global and local spatial features in CT volumes. It can be further extended for other clinical data.

NIPSNAP1 directs dual mechanisms to restrain senescence in cancer cells.

BACKGROUND: Although the executive pathways of senescence are known, the underlying control mechanisms are diverse and not fully understood, particularly how cancer cells avoid triggering senescence despite experiencing exacerbated stress conditions within the tumor microenvironment. METHODS: Mass spectrometry (MS)-based proteomic screening was used to identify differentially regulated genes in serum-starved hepatocellular carcinoma cells and RNAi employed to determine knockdown phenotypes of prioritized genes. Thereafter, gene function was investigated using cell proliferation assays (colony-formation, CCK-8, Edu incorporation and cell cycle) together with cellular senescence assays (SA-ß-gal, SAHF and SASP). Gene overexpression and knockdown techniques were applied to examine mRNA and protein regulation in combination with luciferase reporter and proteasome degradation assays, respectively. Flow cytometry was applied to detect changes in cellular reactive oxygen species (ROS) and in vivo gene function examined using a xenograft model. RESULTS: Among the genes induced by serum deprivation, NIPSNAP1 was selected for investigation. Subsequent experiments revealed that NIPSNAP1 promotes cancer cell proliferation and inhibits P27-dependent induction of senescence via dual mechanisms. Firstly, NIPSNAP1 maintains the levels of c-Myc by sequestering the E3 ubiquitin ligase FBXL14 to prevent the proteasome-mediated turnover of c-Myc. Intriguingly, NIPSNAP1 levels are restrained by transcriptional repression mediated by c-Myc-Miz1, with repression lifted in response to serum withdrawal, thus identifying feedback regulation between NIPSNAP1 and c-Myc. Secondly, NIPSNAP1 was shown to modulate ROS levels by promoting interactions between the deacetylase SIRT3 and superoxide dismutase 2 (SOD2). Consequent activation of SOD2 serves to maintain cellular ROS levels below the critical levels required to induce cell cycle arrest and senescence. Importantly, the actions of NIPSNAP1 in promoting cancer cell proliferation and preventing senescence were recapitulated in vivo using xenograft models. CONCLUSIONS: Together, these findings reveal NIPSNAP1 as an important mediator of c-Myc function and a negative regulator of cellular senescence. These findings also provide a theoretical basis for cancer therapy where targeting NIPSNAP1 invokes cellular senescence.

Sestrin2-mediated disassembly of stress granules dampens aerobic glycolysis to overcome glucose starvation.

Sestrins are a small gene family of pleiotropic factors whose actions promote cell adaptation to a range of stress conditions. In this report we disclose the selective role of Sestrin2 (SESN2) in dampening aerobic glycolysis to adapt to limiting glucose conditions. Removal of glucose from hepatocellular carcinoma (HCC) cells inhibits glycolysis associated with the downregulation of the rate-limiting glycolytic enzyme hexokinase 2 (HK2). Moreover, the accompanying upregulation of SESN2 through an NRF2/ATF4-dependent mechanism plays a direct role in HK2 regulation by destabilizing HK2 mRNA. We show SESN2 competes with insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) for binding with the 3'-UTR region of HK2 mRNA. Interactions between IGF2BP3 and HK2 mRNA result in their coalescence into stress granules via liquid-liquid phase separation (LLPS), a process which serves to stabilize HK2 mRNA. Conversely, the enhanced expression and cytoplasmic localization of SESN2 under glucose deprivation conditions favors the downregulation of HK2 levels via decreases in the half-life of HK2 mRNA. The resulting dampening of glucose uptake and glycolytic flux inhibits cell proliferation and protect cells from glucose starvation-induced apoptotic cell death. Collectively, our findings reveal an intrinsic survival mechanism allowing cancer cells to overcome chronic glucose shortages, also providing new mechanistic insights into SESN2 as an RNA-binding protein with a role in reprogramming of cancer cell metabolism.

Recent Developments in Direct C-H Functionalization of Quinoxalin-2(1H)-Ones via Multi-Component Tandem Reactions.

The direct C-H multifunctionalization of quinoxalin-2(1H)-ones via multicomponent reactions has attracted considerable interest due to their diverse biological activities and chemical profile. This review will focus on recent achievements. It mainly covers reaction methods for the simultaneous introduction of C-C bonds and C-RF/C/O/N/Cl/S/D bonds into quinoxalin-2(1H)-ones and their reaction mechanisms. Meanwhile, future developments of multi-component reactions of quinoxalin-2(1H)-ones are envisaged, such as the simultaneous construction of C-C and C-B/SI/P/F/I/SE bonds through multi-component reactions; the construction of fused ring and macrocyclic compounds; asymmetric synthesis; green chemistry; bionic structures and other fields. The aim is to enrich the methods for the reaction of quinoxalin-2(1H)-ones at the C3 position, which have rich applications in materials chemistry and pharmaceutical pharmacology.

Uric acid is independently associated with interleukin-1ß levels in tear fluid of hyperuricemia and gout patients.

OBJECTIVES: To explore pro-inflammatory cytokines status in the tear fluid of patients with hyperuricemia and gout and its association with uric acid level. METHODS: A total of 58 control subjects, 58 hyperuricemia patients including 40 asymptomatic hyperuricemia and 18 gout participants were recruited in this study. For tear analysis, each patient's tears were collected using capillary action microcaps after stimulation. Tear uric acid levels were measured using chemiluminescence. Tear and serum interleukin-1beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) levels were measured using enzyme-linked immunosorbent assay. The correlation of serum and tear uric acid levels with IL-1ß and TNF-α were determined. RESULTS: Tear uric acid levels were significantly higher in hyperuricemia group (98.2 ± 51.5 vs. 42.7 ± 24.0 µmol/L, p < .001) than in controls group. IL-1ß concentrations were significantly higher in hyperuricemia eyes compared to control eyes (210.2 ± 113.9 vs. 142.6 ± 29.8 pg/mL, p < .001). Multiple linear regression analysis showed that tear uric acid levels were independently positively associated with tear IL-1ß concentrations (B = 0.192, p < .001). However, no significant correlations were found between serum or tear uric acid and TNF-α level. Moreover, there were no statistically differences of tear IL-1ß and TNF-α levels between the asymptomatic hyperuricemia and gout groups. CONCLUSIONS: Tear uric acid levels were higher in patients with hyperuricemia and gout than in controls. There was a significant positive correlation between tear uric acid value and tear IL-1ß level, implying an interaction between hyperuricemia and ocular inflammation responses.

Collecting, transporting and sorting micro-particles via the optical slings generated by a liquid crystal q(φ)-plate.

We disclose a transporting/collecting optical sling generated by a liquid crystal geometric phase optical element with spatial variant topological charge, which shows the intriguing repelling/indrawing effect on the micro-particle along the spiral orbit. Two proof-of-concept prototypes, i.e., an optical conveyor and a particle collector, are demonstrated. Based on the distinct dynamic characteristics of the micro-particles in different sizes, we conceptually propose a design for particle sorting. Thus, our proposed method to generate a spiral optical sling with spatial variant orbital angular momentum for on-demand collecting, transporting and sorting micro-particles is substantiated, which can find extensive applications in bio-medicine, micro-biology, etc.

Integration of artificial intelligence performance prediction and learning analytics to improve student learning in online engineering course.

As a cutting-edge field of artificial intelligence in education (AIEd) that depends on advanced computing technologies, AI performance prediction model is widely used to identify at-risk students that tend to fail, establish student-centered learning pathways, and optimize instructional design and development. A majority of the existing AI prediction models focus on the development and optimization of the accuracy of AI algorithms rather than applying AI models to provide student with in-time and continuous feedback and improve the students' learning quality. To fill this gap, this research integrated an AI performance prediction model with learning analytics approaches with a goal to improve student learning effects in a collaborative learning context. Quasi-experimental research was conducted in an online engineering course to examine the differences of students' collaborative learning effect with and without the support of the integrated approach. Results showed that the integrated approach increased student engagement, improved collaborative learning performances, and strengthen student satisfactions about learning. This research made contributions to proposing an integrated approach of AI models and learning analytics (LA) feedback and providing paradigmatic implications for future development of AI-driven learning analytics.

Glycolytic Pfkp acts as a Lin41 protein kinase to promote endodermal differentiation of embryonic stem cells.

Unveiling the principles governing embryonic stem cell (ESC) differentiation into specific lineages is critical for understanding embryonic development and for stem cell applications in regenerative medicine. Here, we establish an intersection between LIF-Stat3 signaling that is essential for maintaining murine (m) ESCs pluripotency, and the glycolytic enzyme, the platelet isoform of phosphofructokinase (Pfkp). In the pluripotent state, Stat3 transcriptionally suppresses Pfkp in mESCs while manipulating the cells to lift this repression results in differentiation towards the ectodermal lineage. Pfkp exhibits substrate specificity changes to act as a protein kinase, catalyzing serine phosphorylation of the developmental regulator Lin41. Such phosphorylation stabilizes Lin41 by impeding its autoubiquitination and proteasomal degradation, permitting Lin41-mediated binding and destabilization of mRNAs encoding ectodermal specification markers to favor the expression of endodermal specification genes. This provides new insights into the wiring of pluripotency-differentiation circuitry where Pfkp plays a role in germ layer specification during mESC differentiation.