Kaempferol inhibited invasion and metastasis of gastric cancer cells by targeting AKT/GSK3ß pathway based on network pharmacology and molecular docking.

This study aims to explore the mechanisms of the inhibitory effect of kaempferol on the invasion and metastasis of gastric cancer (GC) cells through network pharmacology prediction and experimental verification. It identifies core targets via PPI network analysis and finds that kaempferol binds to these targets well. In vitro experiments showed that kaempferol could inhibit the proliferation, colony formation, migration and invasion of GC cells. Western blotting indicated kaempferol may reduce AKT and GSK3ß phosphorylation, leading to lower expression of invasion-related genes SRC, MMP9, CXCR4, KDR, and MMP2. Overall, kaempferol may prevent migration and invasion of GC cells via the AKT/GSK3ß signaling pathway.

Altered gut microbiota and systemic immunity in Chinese patients with schizophrenia comorbid with metabolic syndrome.

BACKGROUND: Metabolic syndrome (MetS) is highly prevalent in individuals with schizophrenia (SZ), leading to negative consequences like premature mortality. Gut dysbiosis, which refers to an imbalance of the microbiota, and chronic inflammation are associated with both SZ and MetS. However, the relationship between gut dysbiosis, host immunological dysfunction, and SZ comorbid with MetS (SZ-MetS) remains unclear. This study aims to explore alterations in gut microbiota and their correlation with immune dysfunction in SZ-MetS, offering new insights into its pathogenesis. METHODS AND RESULTS: We enrolled 114 Chinese patients with SZ-MetS and 111 age-matched healthy controls from Zhejiang, China, to investigate fecal microbiota using Illumina MiSeq sequencing targeting 16 S rRNA gene V3-V4 hypervariable regions. Host immune responses were assessed using the Bio-Plex Pro Human Cytokine 27-Plex Assay to examine cytokine profiles. In SZ-MetS, we observed decreased bacterial α-diversity and significant differences in ß-diversity. LEfSe analysis identified enriched acetate-producing genera (Megamonas and Lactobacillus), and decreased butyrate-producing bacteria (Subdoligranulum, and Faecalibacterium) in SZ-MetS. These altered genera correlated with body mass index, the severity of symptoms (as measured by the Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms), and triglyceride levels. Altered bacterial metabolic pathways related to lipopolysaccharide biosynthesis, lipid metabolism, and various amino acid metabolism were also found. Additionally, SZ-MetS exhibited immunological dysfunction with increased pro-inflammatory cytokines, which correlated with the differential genera. CONCLUSION: These findings suggested that gut microbiota dysbiosis and immune dysfunction play a vital role in SZ-MetS development, highlighting potential therapeutic approaches targeting the gut microbiota. While these therapies show promise, further mechanistic studies are needed to fully understand their efficacy and safety before clinical implementation.

Efficacy and safety of HAIC combined with tyrosine kinase inhibitors versus HAIC monotherapy for advanced hepatocellular carcinoma: a multicenter propensity score matching analysis.

Purpose: This study aimed to assess the clinical efficacy and safety of the combined approach involving hepatic arterial infusion chemotherapy (HAIC) and tyrosine kinase inhibitors (TKIs) for the treatment of advanced hepatocellular carcinoma (HCC). Patients and methods: In this multicenter retrospective study conducted from January 2020 to December 2023, we reviewed advanced HCC patients who were treated either with HAIC alone or with a combination of HAIC and TKIs. To address initial disparities between the two groups, we employed propensity score matching (PSM). Tumor response evaluation was performed following RECIST 1.1 criteria. We compared survival outcomes, including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), between the two treatment groups. Safety assessments were conducted for all patients. Results: Following the eligibility review, 138 patients underwent combined treatment with HAIC and TKIs (HT group), while 198 patients received HAIC monotherapy (HA group) and met the inclusion criteria for enrollment in this study. After PSM, 107 patients were assigned to each group. The HT group exhibited a longer median OS (18.0 versus 8.8 months; hazard ratio [HR], 0.52, p < 0.001) compared to the HA group. Median PFS was also longer in the HT group, although without statistical significance (6.0 versus 4.7 months; HR, 0.85, p = 0.265). The HT group demonstrated a higher ORR (41.1% versus 25.2%; p = 0.020). No significant differences were observed between the two groups in the incidence of all adverse events (AEs) or grade 3/4 AEs (any grade: 81.2% for HT versus 78.8% for HA, p = 0.68; grade 3/4: 18.1% for HT versus 13.6% for HA, p = 0.29). Importantly, all AEs were manageable and acceptable. Notably, no grade 5 AEs occurred in either group. Conclusion: Combination therapy involving HAIC and TKIs effectively prolonged survival in advanced HCC patients. It represented a preferable alternative to HAIC monotherapy, with manageable safety.

Anti-inflammatory and DNA Repair Effects of Astragaloside IV on PC12 Cells Damaged by Lipopolysaccharide.

OBJECTIVE: This study aimed to establish a neural cell injury model in vitro by stimulating PC12 cells with lipopolysaccharide (LPS) and to examine the effects of astragaloside IV on key targets using high-throughput sequence technology and bioinformatics analyses. METHODS: PC12 cells in the logarithmic growth phase were treated with LPS at final concentrations of 0.25, 0.5, 0.75, 1, and 1.25 mg/mL for 24 h. Cell morphology was evaluated, and cell survival rates were calculated. A neurocyte inflammatory model was established with LPS treatment, which reached a 50% cell survival rate. PC12 cells were treated with 0.01, 0.1, 1, 10, or 100 µmol/L astragaloside IV for 24 h. The concentration of astragaloside IV that did not affect the cell survival rate was selected as the treatment group for subsequent experiments. NOS activity was detected by colorimetry; the expression levels of ERCC2, XRCC4, XRCC2, TNF-α, IL-1ß, TLR4, NOS and COX-2 mRNA and protein were detected by RT-qPCR and Western blotting. The differentially expressed genes (DEGs) between the groups were screened using a second-generation sequence (fold change>2, P<0.05) with the following KEGG enrichment analysis, RT-qPCR and Western blotting were used to detect the mRNA and protein expression of DEGs related to the IL-17 pathway in different groups of PC12 cells. RESULTS: The viability of PC12 cells was not altered by treatment with 0.01, 0.1, or 1 µmol/L astragaloside IV for 24 h (P>0.05). However, after treatment with 0.5, 0.75, 1, or 1.25 mg/mL LPS for 24 h, the viability steadily decreased (P<0.01). The mRNA and protein expression levels of ERCC2, XRCC4, XRCC2, TNF-α, IL-1ß, TLR4, NOS, and COX-2 were significantly increased after PC12 cells were treated with 1 mg/mL LPS for 24 h (P<0.01); however, these changes were reversed when PC12 cells were pretreated with 0.01, 0.1, or 1 µmol/L astragaloside IV in PC12 cells and then treated with 1 mg/mL LPS for 24 h (P<0.05). Second-generation sequencing revealed that 1026 genes were upregulated, while 1287 genes were downregulated. The DEGs were associated with autophagy, TNF-α, interleukin-17, MAPK, P53, Toll-like receptor, and NOD-like receptor signaling pathways. Furthermore, PC12 cells treated with a 1 mg/mL LPS for 24 h exhibited increased mRNA and protein expression of CCL2, CCL11, CCL7, MMP3, and MMP10, which are associated with the IL-17 pathway. RT-qPCR and Western blotting analyses confirmed that the DEGs listed above corresponded to the sequence assay results. CONCLUSION: LPS can damage PC12 cells and cause inflammatory reactions in nerve cells and DNA damage. astragaloside IV plays an anti-inflammatory and DNA damage protective role and inhibits the IL-17 signaling pathway to exert a neuroprotective effect in vitro.

FAM134B deletion exacerbates apoptosis and epithelial-to-mesenchymal transition in rat lungs exposed to hyperoxia.

Oxygen therapy is widely used in clinical practice; however, prolonged hyperoxia exposure may result in hyperoxic acute lung injury (HALI). In this study, we investigated the role of FAM134B in hyperoxia-induced apoptosis, cell proliferation, and epithelial-to-mesenchymal transition (EMT) using RLE-6TN cells and rat lungs. We also studied the effect of CeO2-NPs on RLE-6TN cells and lungs following hyperoxia exposure. FAM134B was inhibited in RLE-6TN cells and rat lungs following hyperoxia exposure. Overexpressing FAM134B promoted cell proliferation, and reduced EMT and apoptosis following hyperoxia exposure. FAM134B activation increased ER-phagy, decreased apoptosis, improved lung structure damage, and decreased collagen fiber deposition to limit lung injury. These effects could be reversed by PI3K/AKT pathway inhibitor LY294002. Additionally, CeO2-NPs protected RLE-6TN cells and lung damage following hyperoxia exposure by ameliorating impaired ER-phagy. Therefore, FAM134B restoration is a potential therapeutic target for the HALI. Moreover, CeO2-NPs can be used for the treatment of HALI.

Correlation analysis of 25(OH)D with cognitive function in epilepsy patients: A cross-sectional study.

OBJECTIVE: To analyze the correlation between the level of 25(OH)D in peripheral blood and cognitive function in patients with epilepsy, and to find the biomarkers of epilepsy complicated with cognitive dysfunction. METHODS: 68 patients with epilepsy and 30 healthy subjects were included in this study. The 25(OH)D level in peripheral blood of all subjects was detected and the score of the Montreal Cognitive Assessment Scale was performed. The patients with epilepsy were divided into a cognitively normal group (36 cases) and a cognitively impaired group (32 cases) according to the scale score. The inter-group scale score and 25(OH)D level were compared, and the correlation was analyzed. RESULTS: The levels of 25(OH)D and MOCA in epileptic group were significantly lower than those in healthy control group. The 25(OH)D and MOCA of the cognitively impaired group were significantly lower than those of the cognitively normal group. Logistic regression analysis indicated that serum 25(OH)D level was an independent risk factor for epilepsy combined with cognitive impairment (OR = 0.704, P = 0.014). The area under ROC curve of serum 25(OH)D for diagnosis of epilepsy combined with cognitive impairment was 0.924 (95 %CI 0.866,0.981), the critical value was 34.50 nmol/L, the sensitivity was 0.778, and the specificity was 0.906. CONCLUSION: Decreased levels of vitamin D are associated with cognitive impairment associated with epilepsy, and it may be a biomarker for early screening of cognitive impairment.

Genomic characterization revealing the high rate of tet(X4)-positive Escherichia coli in animals associated with successful genetic elements.

Introduction: The rapid spread of plasmid-mediated tet(X4) conferring high tigecycline resistance poses a significant threat to public health. Escherichia coli as the most common pathogen which carries tet(X4) has been widely disseminated in China. Thus, comprehensive investigations are required to understand the mechanism of transmission of tet(X4)-positive E. coli. Methods: In this study, a total of 775 nonduplicate samples were collected in Guangdong, China from 2019 to 2020. We screened for tet(X4)-positive E. coli by PCR amplification and species identification. Furthermore, we analyzed the phylogenetics and genetic context of tet(X4)-positive E. coli through whole-genome sequencing and long-reads sequencing. Results: Overall, 146 (18.84%) tet(X4)-positive E. coli were isolated, comprising 2 isolates from humans and 144 isolates from pigs. The majority of tet(X4)-positive E. coli exhibited resistance to multiple antibiotics but all of them were susceptible to amikacin and colistin. Phylogenetic analysis showed that ST877, ST871, and ST195 emerged as the predominant sequence types in tet(X4)-positive E. coli. Further analysis revealed various genetic environments associated with the horizontal transfer of tet(X4). Notably, a 100-kbp large fragment insertion was discovered downstream of tet(X4), containing a replicon and a 40-kbp gene cluster for the bacterial type IV secretion system. Discussion: The high colonization rate of tet(X4)-positive E. coli in animals suggests that colonization as a key factor in its dissemination to humans. Diverse genetic context may contribute to the transfer of tet(X4). Our findings underline the urgent need for controlling the spread of plasmid-mediated tigecycline resistance.

Phylogenomic data resolved the deep relationships of Gymnogynoideae (Selaginellaceae).

The unresolved phylogenetic framework within the Selaginellaceae subfamily Gymnogynoideae (ca. 130 species) has hindered our comprehension of the diversification and evolution of Selaginellaceae, one of the most important lineages in land plant evolution. Here, based on plastid and nuclear data extracted from genomic sequencing of more than 90% species of all genera except two in Gymnogynoideae, a phylogenomic study focusing on the contentious relationships among the genera in Gymnogynoideae was conducted. Our major results included the following: (1) Only single-copy region (named NR) and only one ribosomal operon was firstly found in Afroselaginella among vascular plants, the plastome structure of Gymnogynoideae is diverse among the six genera, and the direct repeats (DR) type is inferred as the ancestral state in the subfamily; (2) The first strong evidence was found to support Afroselaginella as a sister to Megaloselaginella. Alternative placements of Ericetorum and Gymnogynum were detected, and their relationships were investigated by analyzing the variation of phylogenetic signals; and (3) The most likely genus-level relationships in Gymnogynoideae might be: ((Bryodesma, Lepidoselaginella), (((Megaloselaginella, Afroselaginella), Ericetorum), Gymnogynum)), which was supported by maximum likelihood phylogeny based on plastid datasets, maximum likelihood, and Bayesian inference based on SCG dataset and concatenated nuclear and plastid datasets and the highest proportion of phylogenetic signals of plastid genes.

Adverse events profile associated with intermittent fasting in adults with overweight or obesity: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: There is little evidence to comprehensively summarize the adverse events (AEs) profile of intermittent fasting (IF) despite its widespread use in patients with overweight or obesity. METHODS: We searched the main electronic databases and registry websites to identify eligible randomized controlled trials (RCTs) comparing IF versus control groups. A direct meta-analysis using a fixed-effect model was conducted to pool the risk differences regarding common AEs and dropouts. Study quality was assessed by using the Jadad scale. Pre-specified subgroup and sensitivity analyses were conducted to explore potential heterogeneity. RESULTS: A total of 15 RCTs involving 1,365 adult individuals were included. Findings did not show a significant difference between IF and Control in risk rate of fatigue [0%, 95% confidence interval (CI), -1% to 2%; P = 0.61], headache [0%, 95%CI: -1% to 2%; P = 0.86] and dropout [1%, 95%CI: -2% to 4%; P = 0.51]. However, a numerically higher risk of dizziness was noted among the IF alone subgroup with non-early time restricted eating [3%, 95%CI: -0% to 6%; P = 0.08]. CONCLUSIONS: This meta-analysis suggested that IF was not associated with a greater risk of AEs in adult patients affected by overweight or obesity. Additional large-scale RCTs stratified by key confounders and designed to evaluate the long-term effects of various IF regimens are needed to ascertain these AEs profile.

A Pillararene-Based Cavitand: Synthesis and Solid-State Capsular Assemblies Induced by Linear Alkanes with Specific Lengths.

Herein, a novel pillararene-based cavitand with fixed planar chirality was synthesized by the SuFEx reaction. As demonstrated by single crystal X-ray analysis, host-guest capsules involving this cavitand and linear alkanes with specific lengths are observed in the solid state. The formation of each capsule is driven by hydrogen bonding interactions between a linear alkane molecule and two cavitand molecules, as well as noncovalent interactions between the two cavitand molecules in this capsule.

Pillar[5]arene-Based Ion-Pair Recognition for Encapsulation of a Stilbazolium-Type Dye with Enhanced Photophysical Properties and Nonlinear Optical Activity.

Constructing organic composite materials through molecular recognition has emerged as an important theme in materials science. Here we report an ion-pair recognition system involving the use of a propoxylated pillar[5]arene (PrP5) to modulate the solid-state photophysical properties of dye trans-4'-(dimethylamino)-N-methyl-4-stilbazolium hexafluorophosphate (DMASP). Single crystal X-ray diffraction analysis reveals that the dye guest DMASP is encapsulated by PrP5 to form a 2:1 host-guest complex 2PrP5⸧DMASP in the crystalline state. The macrocyclic skeleton of PrP5 imposes restrictions on the intramolecular motions of the dye guest, leading to a significant enhancement of its fluorescence emission. Additionally, within the 2PrP5⸧DMASP complex crystal structure, DMASP molecules are found to display two possible opposite orientations in the one-dimensional channels formed by PrP5 molecules. This arrangement is believed to alter the overall solid-state packing structure of DMASP, thereby activating its nonlinear optical activity. This work not only reports a novel ion-pair molecular recognition system based on pillararenes but also provides valuable insights into the modulation of the crystalline state photophysical properties of organic dyes via cocrystal engineering.

Construction of hydrocarbon belts based on macrocyclic arenes.

Hydrocarbon belts have garnered significant attention due to their intriguing structures, unique properties, and potential applications in supramolecular chemistry and materials science. However, their highly inherently strained structures pose challenges in their synthesis, and the resulting tedious synthesis strategies hinder their large-scale applications. Utilizing unstrained macrocyclic arenes as precursors presents an efficient strategy, allowing for a strain-induction step that mitigates the energy barrier associated with building strain in the formation of these belts. Accessible unstrained macrocyclic precursors play a pivotal role in enabling efficient and large-scale syntheses of highly strained belts, facilitating their broader practical applications. This review provides an overview of the recent advancements in the construction of hydrocarbon belts using accessible macrocyclic arenes as building blocks. The synthetic strategies for these partially and fully conjugated hydrocarbon belts are discussed, along with their unique properties. We hope that this review will inspire the development of novel nanocarbon molecules, opening pathways for emerging areas and applications.

Combined deep learning and radiomics in pretreatment radiation esophagitis prediction for patients with esophageal cancer underwent volumetric modulated arc therapy.

PURPOSE: To develop a combined radiomics and deep learning (DL) model in predicting radiation esophagitis (RE) of a grade ≥ 2 for patients with esophageal cancer (EC) underwent volumetric modulated arc therapy (VMAT) based on computed tomography (CT) and radiation dose (RD) distribution images. MATERIALS AND METHODS: A total of 273 EC patients underwent VMAT were retrospectively reviewed and enrolled from two centers and divided into training (n = 152), internal validation (n = 66), and external validation (n = 55) cohorts, respectively. Radiomic and dosiomic features along with DL features using convolutional neural networks were extracted and screened from CT and RD images to predict RE. The performance of these models was evaluated and compared using the area under curve (AUC) of the receiver operating characteristic curves (ROC). RESULTS: There were 5 and 10 radiomic and dosiomic features were screened, respectively. XGBoost achieved a best AUC of 0.703, 0.694 and 0.801, 0.729 with radiomic and dosiomic features in the internal and external validation cohorts, respectively. ResNet34 achieved a best prediction AUC of 0.642, 0.657 and 0.762, 0.737 for radiomics based DL model (DLR) and RD based DL model (DLD) in the internal and external validation cohorts, respectively. Combined model of DLD + Dosiomics + clinical factors achieved a best AUC of 0.913, 0.821 and 0.805 in the training, internal, and external validation cohorts, respectively. CONCLUSION: Although the dose was not responsible for the prediction accuracy, the combination of various feature extraction methods was a factor in improving the RE prediction accuracy. Combining DLD with dosiomic features was promising in the pretreatment prediction of RE for EC patients underwent VMAT.

Sophora flavescens-Astragalus mongholicus herb pair in the progression of hepatitis, cirrhosis, and hepatocellular carcinoma: a possible mechanisms and relevant therapeutic substances.

Background: Both Sophora flavescens (SF) and Astragalus mongholicus (AM) are known for their anti-inflammatory, antifibrotic, and anticancer activities. However, the efficacy, multi-target mechanisms, and therapeutic substances of SF-AM herb pair on the progression of hepatitis-cirrhosis-hepatocellular carcinoma hepatocellular carcinoma (HCC) remain unclear. Purpose: To investigate the efficacy, mechanisms, and potential therapeutic substances of SF-AM herb pair in the progression of hepatitis-cirrhosis-HCC. Methods: Firstly, diethylnitrosamine was used to establish the hepatitis-cirrhosis-HCC model. HE staining and non-targeted metabolomics were used to evaluate the efficacy of SF-AM herb pair. Subsequently, the absorbed components of SF-AM herb pair in the plasma of rats were determined through HPLC-Q-TOF-MS/MS analysis. Flow cytometry, Western blot, and qRT-PCR were then employed to assess CD4+ and CD8+ T lymphocytes, PI3K/Akt signaling pathway-related proteins, and their corresponding mRNAs. Simultaneously, the efficacy and mechanism of SF-AM herb pair on HCC were confirmed by in vitro experiments. Finally, Pearson correlation analysis was performed between pharmacodynamic indicators and in vivo components to identify the potential therapeutic substances of SF-AM herb pair. Results: SF-AM herb pair can alleviate the pathological damage and reverse metabolic abnormalities in hepatitis, cirrhosis, and HCC rats, particularly during the hepatitis and cirrhosis stages. Pharmacological researches have demonstrated that SF-AM herb pair can increase the proportion of CD8+ T lymphocytes, inhibit the expression of PI3K, Akt, p-Akt, NF-κB p65, NF-κB pp65, and Bcl-2, as well as increase the expression of IκBα, Bax, and cleaved caspase-3. These findings suggest that SF-AM herb pair has the ability to enhance immunity, anti-inflammation and promote apoptosis. Cell experiments have shown that SF-AM herb pair can inhibit the proliferation of HepG2 cell and regulate the PI3K/Akt signaling pathway. Moreover, 23 absorbed prototypical components and 53 metabolites of SF-AM herb pair were identified at different stages of HCC rats. Pearson correlation analysis revealed that matrine, cytisine, wogonoside, and isoastragaloside are potential therapeutic substances in SF-AM herb pair for the prevention and treatment of hepatitis, cirrhosis, and HCC. Conclusion: In summary, this study revealed the efficacy, mechanisms, and potential therapeutic substances of SF-AM herb pair in the hepatitis-cirrhosis-HCC axis and provided a reference for its clinical application.

Esketamine Combined with Dexmedetomidine to reduce Visceral Pain During elective Cesarean Section Under Combined Spinal-Epidural Anesthesia: A double-Blind Randomized Controlled Study.

Purpose: We aimed to evaluate the effect of intravenous esketamine combined with dexmedetomidine as supplemental analgesia in reducing intraoperative visceral pain during elective cesarean section under combined spinal-epidural anesthesia (CSEA). Patients and Methods: A total of 269 parturients scheduled for elective cesarean section under CSEA between May 2023 and August 2023 were assessed. The parturients were randomly allocated to receiving either intravenous infusion of 0.3-mg/kg esketamine combined with 0.5-µg/kg dexmedetomidine (group ED, n=76), 0.5-µg/kg dexmedetomidine (group D, n=76), or normal saline (group C, n=76) after umbilical cord clamping. The primary outcome was intraoperative visceral pain. Secondary outcomes included the visual analog scale (VAS) score for pain evaluation and other intraoperative complications. Results: The incidence of visceral pain was lower in group ED [9 (12.7%)] than in group D [32 (43.8%)] and group C [36 (48.6%), P <0.0001]. The VAS score was also lower in group ED when exploring abdominal cavity [0 (0), P <0.0001] and suturing the muscle layer [0 (0), P =0.036]. The mean arterial pressure was higher in group D [83 (9) mmHg] and group ED [81 (11) mmHg] than in group C [75 (10) mmHg, P <0.0001] after solution infusion. The heart rate after infusion of the solution was lower in group D [80 (12) bpm] than in group C [86 (14) bpm] and group ED [85 (12) bpm, P = 0.016]. The incidence of transient neurologic or mental symptoms was higher in group ED compared to group C and group D (76.1% vs 18.9% vs 23.3%, P<0.0001). Conclusion: During cesarean section, 0.3-mg/kg esketamine combined with 0.5-µg/kg dexmedetomidine can alleviate visceral traction pain and provide stable hemodynamics. Parturients receiving this regimen may experience transient neurologic or mental symptoms that can spontaneously resolve at the end of the surgery.

Some parturients endure experience indescribable pain and discomfort during fetal delivery. Esketamine combined with dexmedetomidine can alleviate this pain during cesarean section under combined spinal-epidural anesthesia. However, after intravenous injection of esketamine and dexmedetomidine, the parturients may experience nightmares, dizziness, hallucinations, and drowsiness, etc.

Determination of cotinine and 3-hydroxynicotinine in human serum by liquid chromatography-tandem mass spectrometry and its application.

In this study, we developed a method for determining cotinine and 3-hydroxycotinine in human serum and established a methodology for an in-depth study of tobacco exposure and health. After the proteins in the human serum samples were precipitated with acetonitrile, they were separated on a ZORBAX SB-Phenyl column with a mobile phase of methanol encompassing 0.3% formic acid-water encompassing 0.15% formic acid. The measurement was performed on an API5500 triple quadrupole mass spectrometer in the multiple reaction monitoring mode. Cotinine, 3-hydroxycotinine, and cotinine-d3 isotope internal standards were held for 2.56 minutes, 1.58 minutes, and 2.56 minutes, respectively. In serum, the linear range was 0.05 to 500 ng·mL-1 for cotinine and 0.50 to 1250 ng·mL-1 for 3-hydroxycotinine. The lower limit of quantification (LLOQ) was 0.05 ng·mL-1 and 0.5 ng·mL-1 for cotinine and 3-hydroxycotinine, respectively. The intra-day and inter-day relative standard deviations were <11%, and the relative errors were within ±â€…7%. Moreover, the mean extraction recoveries of cotinine and 3-hydroxycotinine were 98.54% and 100.24%, respectively. This method is suitable for the rapid determination of cotinine and 3-hydroxycotinine in human serum because of its rapidity, sensitivity, strong specificity, and high reproducibility. The detection of cotinine levels in human serum allows for the identification of the cutoff value, providing a basis for differentiation between smoking and nonsmoking populations.

Synthesis of C3'-Foused Aryl/Penta-1,4-Dien-3-One/Amine Hybrids as HSP90C-Terminal Inhibitors.

24 C3'-focused hybrids of aryl/penta-1,4-dien-3-one/amine (APDA) were designed and synthesized. Of these hybrids, 2 n demonstrated improved antiproliferative effects on HER2-positive breast cancer cells (SKBr3 and BT474) and triple-negative breast cancer (TNBC) cells (MDA-MB-231 and MDA-MB-468) with IC50 values ranging from 7.45 to 10.75 µM, but less toxicity to normal breast cells MCF-10A than the first generation of hybrid 1. Additionally, 2 n retained its ability to inhibit HSP90C-terminus, leading to the degradation of HSP90 client proteins HER2, EGFR, pAKT, AKT, and CDK4, without inducing a heat-shock response. Notably, 2 n also demonstrated improved thermostability compared to 1 and maintained in vitro metabolic stability in simulated intestinal fluid. These findings will provide a scientific basis for developing HSP90C-terminal inhibitors in the future.

Meliasanines A-L, tirucallane-type triterpenoids from Melia toosendan with anti-inflammatory properties via NF-κB signaling pathway.

Meliasanines A-L, twelve previously unreported tirucallane-type triterpenoids, together with fifteen known ones, have been isolated from the stem bark of Melia toosendan. Their structures and absolute configurations were determined based on HRESIMS, and NMR, combined with calculated ECD and single-crystal X-ray diffraction analyses. Subsequently, all compounds except 10 were evaluated for their inhibitory effect on the production of nitric oxide induced by lipopolysaccharide in RAW264.7 macrophage cells. The results indicated that seven compounds (1, 13, 14, 16, 20, 22, and 23) exhibited significant NO inhibitory effects, with IC50 values ranging from 1.35 to 5.93 µM, which were more effective than the positive control indomethacin (IC50 = 13.18 µM). Moreover, the corresponding results of Western blot analysis revealed that meliasanine A (1) can significantly suppress the protein expression of inducible nitric oxide synthase and cyclooxygenase 2 in a concentration-dependent manner. The mechanism study suggested that meliasanine A exerts an anti-inflammatory effect via the nuclear factor-κB signaling pathway by suppressing phosphorylation of P65 and IκBα.

Unraveling transcriptomic signatures and dysregulated pathways in systemic lupus erythematosus across disease states.

OBJECTIVES: This study aims to elucidate the transcriptomic signatures and dysregulated pathways in patients with Systemic Lupus Erythematosus (SLE), with a particular focus on those persisting during disease remission. METHODS: We conducted bulk RNA-sequencing of peripheral blood mononuclear cells (PBMCs) from a well-defined cohort comprising 26 remission patients meeting the Low Lupus Disease Activity State (LLDAS) criteria, 76 patients experiencing disease flares, and 15 healthy controls. To elucidate immune signature changes associated with varying disease states, we performed extensive analyses, including the identification of differentially expressed genes and pathways, as well as the construction of protein-protein interaction networks. RESULTS: Several transcriptomic features recovered during remission compared to the active disease state, including down-regulation of plasma and cell cycle signatures, as well as up-regulation of lymphocytes. However, specific innate immune response signatures, such as the interferon (IFN) signature, and gene modules involved in chromatin structure modification, persisted across different disease states. Drug repurposing analysis revealed certain drug classes that can target these persistent signatures, potentially preventing disease relapse. CONCLUSION: Our comprehensive transcriptomic study revealed gene expression signatures for SLE in both active and remission states. The discovery of gene expression modules persisting in the remission stage may shed light on the underlying mechanisms of vulnerability to relapse in these patients, providing valuable insights for their treatment.

Using an epidemiological model to explore the interplay between sharing and advertising in viral videos.

How to exploit social networks to make internet content spread rapidly and consistently is an interesting question in marketing management. Although epidemic models have been employed to comprehend the spread dynamics of internet content, such as viral videos, the effects of advertising and individual sharing on information dissemination are difficult to distinguish. This gap forbids us to evaluate the efficiency of marketing strategies. In this paper, we modify a classic mean-field SIR (susceptible-infected-recovered) model, incorporating the influences of sharing and advertising in viral videos. We mathematically analyze the global stability of the system and propose an agent-based modeling approach to evaluate the efficiency of sharing and advertising. We further provide a case study of music videos on YouTube to show the validity of our model.