Time-varying formation tracking for multi-agent systems with maneuvering leader under DDoS attacks and actuator faults.

Time-varying formation tracking problems for multi-agent systems (MASs) under distributed Denial-of-Service (DDoS) attacks and actuator faults are studied. To deal with the hybrid threats at the cyber and physical layers, an estimator-based fault-tolerant hierarchical control scheme is introduced, which is applicable to channel-wise asynchronous communication. Sufficient conditions for formation tracking of maneuvering leader with ultimately bounded error are obtained, and the particular case of periodic communication and attacks with constrained duration and frequency is further analyzed. Comparative physical simulations based on ROS and Gazebo are first conducted to show the resilience of our scheme against the threats. Finally, an experimental platform containing DJI Tello quadrotors and a self-developed ground control station is built, based on which practical experiments with four quadrotors are carried out to evaluate the effectiveness and engineering practicability of the proposed control framework.

Epiberberine induced p53/p21-dependent G2/M cell cycle arrest and cell apoptosis in gastric cancer cells by activating γ-aminobutyric acid receptor- ß3.

BACKGROUND AND PURPOSE: Epiberberine (EPI) is one of the most important bioalkaloid found in the rhizome of Coptis chinensis, which has been observed to exhibit pharmaceutical effects against gastric cancer (GC). Nevertheless, the potential mechanism of EPI against GC cells still remains unclear. This study aimed to identify the core receptor on GC cells through which EPI inhibited the growth of GC cells and to explore the underlying inhibitory mechanisms. METHODS: To identify hub receptor targets that respond to EPI treatment, RNA sequencing (RNA-Seq) data from a tumor-bearing mouse model were analyzed using bioinformatics method and molecular docking. The binding interaction between EPI and GABRB3 was validated through western blotting based-cellular thermal shift assay (WB-CETSA). To further verify the binding region between EPI and GABRB3 through circular dichroism (CD) chromatography, fragments of the extracellular and transmembrane domains of the GABRB3 protein were expressed and purified in vitro. Stable cell lines with the overexpression or knockdown of GABRB3 were established using the recombinant lentivirus system. MTT ((3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide)) assay, colony formation assay, invasion and migration experiments, and flow cytometry were conducted to validate the inhibitory effect of EPI on the GC cells via GABRB3. Additionally, western blotting was utilized to explore the potential inhibitory mechanisms. RESULTS: Through the combination of multiple bioinformatics methods and molecular docking, we found that the γ-aminobutyric acid type A receptor subunit -ß3 (GABRB3) might be the critical receptor target in response to EPI treatment. The results of WB-CETSA analysis indicated that EPI significantly promoted the thermostability of the GABRB3 protein. Importantly, EPI could directly bind to GABRB3 and alter the secondary structure of GABRB3 fragments similar to the natural agonist, γ-aminobutyric acid (GABA). The EPI-induced suppression of the malignant phenotype of GC cells was dependent on the presence of GABRB3. GABRB3 expression was positively correlated with TP53 in patients with GC. The binding of EPI to GABRB3 stimulated p53 accumulation in GC cells. This activated the p21/CDK1/cyclinB1 pathway, resulting in G2/M cell cycle arrest, and induced the Bcl-2/BAX/Caspase axis-dependent cell apoptosis. CONCLUSION: This study revealed the target receptor for EPI in GC cells and provided new insights into its anticancer mechanisms.

Integrating transcriptomics and network pharmacology to reveal the mechanisms of total Rhizoma Coptidis alkaloids against nonalcoholic steatohepatitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Non-alcoholic steatohepatitis (NASH) has emerged as a major cause of cirrhosis and hepatocellular carcinoma, posing a significant threat to public health. Rhizoma Coptidis, a traditional Chinese medicinal herb has been shown to have significant curative effects on liver diseases. Total Rhizoma Coptidis Alkaloids (TRCA) is a primarily alkaloid mixture extracted from Rhizoma Coptidis, and its constituents are widely accepted to have hepatoprotective effects. AIM OF THE STUDY: This work aimed to investigate the efficacy and potential mechanisms of TRCA in ameliorating NASH through both in vitro experiments and in vivo mouse models. MATERIALS AND METHODS: The study employed a mice model induced by a high-fat diet (HFD) to evaluate the effectiveness and pharmacological mechanisms of TRCA in alleviating NASH. Transcriptomic sequencing and network pharmacology were used to explore the possible targets and mechanisms of TRCA to ameliorate NASH. Further validation was performed in free fatty acid (FFA)-induced human hepatocytes (LO2) and human hepatocellular carcinoma cells (HepG2). RESULTS: TRCA effectively ameliorated the main features of NASH such as lipid accumulation, hepatitis and hepatic fibrosis in the liver tissue of mice induced by HFD, as well as improved glucose tolerance and insulin resistance in mice. Combined with transcriptomic and network pharmacological analyses, 68 core targets associated with the improvement of NASH by TRCA were obtained. According to the KEGG results, the core targets were significantly enriched in the PI3K-AKT signaling pathway whereas TRCA ameliorated the aberrant down-regulation of the PI3K-AKT signaling pathway induced by HFD. Furthermore, the five highest-ranked genes were obtained by PPI network analysis. Moreover, our findings suggest that TRCA may impede the progression of HFD-induced NASH by regulating the expression of PPARG, MMP9, ALB, CCL2, and EGFR. CONCLUSIONS: TRCA can ameliorate HFD-induced liver injury by modulating aberrant downregulation of the PI3K-AKT signaling pathway. Key proteins such as PPARG, MMP9, ALB, CCL2, and EGFR may be critical targets for TRCA to ameliorate NASH. This finding supports using Rhizoma Coptidis, a well-known herbal medicine, as a potential therapeutic agent for NASH.

8-octyl berberine combats Staphylococcus aureus by preventing peptidoglycan synthesis.

Staphylococcus aureus is an important pathogenic bacterium responsible for various organ infections. The serious side effects and the development of antibiotic resistance have rendered the antibiotic therapy against S. aureus increasingly challenging, emphasizing the pressing need for the exploration of novel therapeutic agents. Our research has uncovered the promising antimicrobial properties of 8-octyl berberine (OBBR), a novel compound derived from berberine (BBR), against S. aureus. OBBR exhibited a minimum inhibitory concentration (MIC) of 1.0 µg/mL, which closely approximated that of levofloxacin. Intriguingly, a multipassage resistance assay demonstrated that the MIC of OBBR against S. aureus remained relatively stable, while levofloxacin exhibited a 4-fold increase over 20 days, suggesting that OBBR was less prone to inducing resistance. Mechanistically, our investigation, employing Zeta potential measurements, flow cytometry, scanning electron microscopy, and transmission electron microscopy, unveiled that OBBR induced morphological alterations in the bacteria. Furthermore, it disrupted the bacterial cell wall and membrane by altering membrane potential and compromising membrane integrity. These actions culminated in bacterial disintegration and apoptosis. Transcriptomic analysis shed light on significant downregulation of gene ontology terms, predominantly associated with membranes. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis implicated OBBR in disturbing peptidoglycan biosynthesis, with the membrane protein MraY emerging as a potential target for OBBR's action against S. aureus. Notably, experiments involving the overexpression of MraY confirmed OBBR's inhibitory effect on peptidoglycan synthesis. Furthermore, molecular docking and cellular thermal shift assay revealed OBBR's direct interaction with MraY, potentially leading to the inhibition of the enzymatic activity of MraY and, consequently, impeding peptidoglycan synthesis. In summary, OBBR, by targeting MraY and inhibiting peptidoglycan synthesis, emerges as a promising alternative antibiotic against S. aureus, offering potential advantages in terms of limited drug resistance development.

Berberine promotes IGF2BP3 ubiquitination by TRIM21 to induce G1/S phase arrest in colorectal cancer cells.

The increasing incidence of colorectal cancer (CRC) has become a major global public health burden. The natural drug Berberine (BBR) has shown potential in preventing CRC, and IGF2 mRNA binding protein 3 (IGF2BP3) may be a target of BBR. This study aims to investigate the mechanisms of BBR acting on IGF2BP3 to improve CRC. The results showed that IGF2BP3 played an important role in the development of CRC. BBR down-regulated IGF2BP3 expression and inhibited CRC growth in mice. Cell thermodynamic stability analysis (CETSA) and drug affinity responsive target stability (DARTS) analysis showed BBR may bind to IGF2BP3. BBR may induce structural changes in IGF2BP3 and decrease its protein stability in cytoplasm. The results from Co-Immunoprecipitation (Co-IP) suggested that BBR promoted the ubiquitination of IGF2BP3 by tripartite motif-containing protein 21 (TRIM21). Through RNA binding protein Immunoprecipitation (RIP) assay, it was found BBR inhibited the stabilization of CDK4/CCND1 mRNA by IGF2BP3 and promoted G1/S phase arrest in CRC cells. Overexpression of IGF2BP3 in vitro and in vivo attenuated the inhibition of CRC growth by BBR. This work demonstrated the potential of BBR targeting to IGF2BP3 in improving CRC and provided a new strategy for clinical treatment on CRC as well as novel anticancer drug design based on IGF2BP3 and TRIM21.

Epiberberine regulates lipid synthesis through SHP (NR0B2) to improve non-alcoholic steatohepatitis.

Epiberberine (EPI), extracted from Rhizome Coptidis, has been shown to attenuate hyperlipidemia in vivo. Herein we have studied the mechanism by which EPI is active against non-alcoholic steatohepatitis (NASH) using, mice fed on a methionine- and choline-deficient (MCD) diet and HepG2 cells exposed to free fatty acids (FFA). We show that small heterodimer partner (SHP) protein is key in the regulation of lipid synthesis. In HepG2 cells and in the livers of MCD-fed mice, EPI elevated SHP levels, and this was accompanied by a reduction in sterol regulatory element-binding protein-1c (SREBP-1c) and FASN. Therefore, EPI reduced triglyceride (TG) accumulation in steatotic hepatocytes, even in HepG2 cells treated with siRNA-SHP, and also improved microbiota. Thus, EPI suppresses hepatic TG synthesis and ameliorates liver steatosis by upregulating SHP and inhibiting the SREBP1/FASN pathway, and improves gut microbiome.

Prenatal diagnosis identifies compound heterozygous variants in RYR1 that causes ultrasound abnormalities in a fetus.

OBJECTIVE: We presented a non-consanguineous healthy Chinese couple with five pregnancies, three early miscarriages, the fetus II-2 and II-5 with similar abnormal phenotypes of fetal hydrops, scoliosis, fetal akinesia and polyhydramnios. This study aimed to uncover the molecular etiology of this family with a history of multiple adverse pregnancies. MATERIALS AND METHODS: DNA extracted from the fifth fetal umbilical cord and parents' peripheral blood were subjected to SNP-array and whole exome sequencing. The result was verified by Sanger sequencing. Functional characterization of the c.2682G > C (p.Ile860_Pro894del) variant was completed by minigene splicing assay. RESULTS: Trio whole-exome sequencing has identified compound heterozygous variants in RYR1 (c.2682G > C; p.Ile860_Pro894del and c.12572G > A; p.Arg4191His) in fetus II-5. The variant c.2682G > C (p.Ile860_Pro894del) comes from the father and the c.12572G > A (p.Arg4191His) comes from the mother. The c.2682G > C (p.Ile860_Pro894del) affects the splice site resulting in exon 21 skipping, therefore is classified as likely pathogenic. The c.12572G > A (p.Arg4191His) locates in the C-terminal hot spots region of the RYR1, classified as of uncertain significance. CONCLUSIONS: We report the first prenatal case of RYR1-related disorders in Chinese population, expanding the variant spectrum of RYR1 in fetuses.

Differences between primary peritoneal serous carcinoma and advanced serous ovarian carcinoma: a study based on the SEER database.

OBJECTIVE: This study aimed to compare clinical features and overall survival (OS) between patients with primary peritoneal serous carcinoma (PPSC) and those with advanced serous ovarian carcinoma (ASOC) and to identify prognostic factors. METHODS: Patients diagnosed with PPSC and ASOC from 2010 to 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were enrolled. Pearson's chi-square test was used to compare clinical features. The primary endpoint was OS. The Kaplan-Meier method and log-rank test were used to perform the survival analysis. Propensity score matching was also conducted. Univariate, multivariate and subgroup analyses were performed using the Cox proportional hazards model. RESULTS: A total of 708 PPSC patients and 7610 ASOC patients were enrolled. The clinical features of PPSC patients were noticeably different from those of ASOC patients. The survival analysis showed that PPSC patients had poorer outcomes than ASOC patients. Even after the clinical features were balanced, PPSC patients still had poorer survival. Univariate and multivariate analyses indicated that older age, higher tumor grade and advanced American Joint Committee on Cancer stage were adverse prognostic factors in both groups, while surgery and chemotherapy were protective factors. A subgroup analysis demonstrated that most factors favored ASOC patients. The total distant metastasis rates of PPSC and ASOC were similar. Liver or lung metastasis was common, but bone and brain metastases were rare. A higher proportion of liver metastasis was observed in the ASOC group. CONCLUSION: The clinical features and survival outcomes between PPSC patients and ASOC patients are clearly different, and PPSC is more aggressive than ASOC.

[Preparative isolation and purification of scopoletin from Lycium barbarum L. by high-speed countercurrent chromatography].

An effective and rapid method for the separation of scopoletin from Lycium barbarum L. by high-speed counter-current chromatography (HSCCC) was established. The ethyl alcohol extract of the Lycium barbarum L. was initially separated using D-101 macroporous resins and further purified by HSCCC. The thin layer chromatography coupling with fluorometric spectrophotometry (TLC-F) method was used to determine the partitioning coefficient of scopoletin in different solvent systems. The results showed the solvent system of chloroformmethanol-water (10:7:3, v/v/v) was the best one for the HSCCC separation. A total of 10.2 mg of scopoletin with high purity (98. 3%, analyzed by high performance liquid chromatography (HPLC)) was obtained in one step by the following separation procedures: the upper phase as the stationary phase, the lower phase as the mobile phase, with a flow rate of 1.5 mL/min, with the apparatus rotated at 850 r/min, and detected at 365 nm. The structure of the obtained compound was identified by 'H-nuclear magnetic resonance and 13C-nuclear magnetic resonance. The sample could be injected into HSCCC twice successively and the whole separation was achieved with satisfactory peak resolution. These results suggested that the TLC-F method is useful in measuring the partitioning coefficients of the target compound in HSCCC solvent systems and HSCCC is a fast and convenient method for the separation of scopoletin.

Separation of two constituents from purple sweet potato by combination of silica gel column and high-speed counter-current chromatography.

It is known that the choice of solvent system for high speed counter-current chromatography separation is of utmost importance. In this study, a simple and rapid thin layer chromatograph coupling with fluorometric (TLC-F) method has been used to determine the partition coefficient of target compounds in HSCCC solvent system. Two components, 6,7-dimethoxycoumarin and 5-hydroxymethyl-2-furfural were successfully separated from purple sweet potato extracts by successive sample injection for the first time, using n-hexane-ethyl acetate-methanol-water (1:2:1:1, v/v/v/v) as the solvent system. Additionally, statistical analysis showed that there was no significant difference in partition coefficient obtained by the TLC-F method and by HPLC, which demonstrated the usefulness of TLC-F method.